E. Albert Reece

Shoulder dystocia is not an uncommon obstetric complication, occurring in as many as 2 per 100 vaginal births. This obstetric emergency is associated with a number of adverse perinatal outcomes for both the mother and infant, the most serious of which remains neonatal brachial plexus injury. In a minority of cases in which there is prolonged impaction of the shoulders, birth asphyxia also may occur.

Obstetricians and other birth attendants must be fully prepared to effectively manage shoulder dystocia when it occurs. They also should understand the existing controversies regarding prevention and the pathogenesis of injuries associated with shoulder dystocia.

Shoulder dystocia generally is not a predictable event, which makes prevention extremely difficult. Because of the limited accuracy of ultrasound for estimating fetal size, the risk of shoulder dystocia and resulting injury must be fairly significant before prophylactic cesarean is considered as a preventive measure. There are, however, certain high-risk scenarios that call for consideration of prophylactic cesarean delivery.

Prevention

For the past several decades, clinical research has focused on whether shoulder dystocia can be predicted and/or prevented. Overall, most analyses have shown us that shoulder dystocia can be only minimally predicted, at best, and that prevention of this complication as well as associated injury is far from a simple undertaking.

The leading risk factor for shoulder dystocia is excessive birth weight, yet not all cases of shoulder dystocia involve infants who weigh more than 4,500 g, or even more than 4,000 g. In fact, most shoulder dystocia cases actually occur when birth weights are less than 4,000 g – especially in nondiabetic pregnancies. (In diabetic pregnancies, most shoulder dystocias and brachial plexus injuries do occur in infants with birth weights greater than 4,000 g.)

The possibility that birth weight estimates may help us to predict and/or prevent shoulder dystocia also is hindered by the fact that it remains difficult to identify large babies prior to delivery. Clinical estimation of size and the use of ultrasound are the two most commonly employed techniques for estimating birth size, but both have limited accuracy and may either underestimate or overestimate fetal size. Most large babies, moreover, can successfully undergo vaginal birth without the complication of shoulder dystocia, let alone brachial plexus injury.

All told, these realities limit our ability to use estimated birth weight in selecting those pregnancies that might benefit from prophylactic cesarean delivery.

To consider prophylactic cesarean delivery, the level of risk for shoulder dystocia and resultant injury must be fairly significant. The following are two clinical scenarios in which the risk of complications reaches a level at which the option of prophylactic cesarean section (including informed consent) should be discussed with the mother:

▸ A pregnancy complicated by diabetes in which the estimated fetal weight is greater than or equal to 4,500 g. Some experts have suggested that this threshold should, in fact, be lower in diabetic pregnancies. However, utilization of a lower threshold (such as 4,000 g or 4,250 g) must come with the recognition that it will spur the use of more cesarean deliveries to prevent injury.

▸ A patient with a history of shoulder dystocia birth, particularly when the fetus is believed to be of similar or greater weight than the previously affected fetus.

Determining the recurrence risk of shoulder dystocia has proved difficult because, in most clinical series, a large proportion of women with a history of the complication will undergo scheduled cesarean delivery in their subsequent pregnancies. This bias toward operative delivery may lead to an underestimation of the true recurrence risk. Regardless of this potential estimation bias, unless the estimated fetal weight in the woman's current pregnancy is significantly less than that of the prior pregnancy, we should counsel women with prior shoulder dystocia and offer them prophylactic cesarean delivery.

With respect to the predictive value of labor abnormalities, studies have yielded mixed results. The bottom line is that labor abnormalities are not particularly useful in predicting shoulder dystocia – except for cases of a prolonged second stage of labor when there is suspicion of a large infant. This combination of factors should alert the physician to the potential for shoulder dystocia. Operative vaginal delivery should generally be avoided in this scenario, because delivery above an outlet station may further increase the risk of shoulder dystocia and resultant injury.

Management, Medicolegal Issues

As with any delivery, the goal of management should always be to deliver the infant as safely as possible, minimizing the risk of traumatic injury and birth asphyxia. In most cases of shoulder dystocia, the shoulders remain in an anterior-posterior position and fail to rotate. This creates the potential for brachial plexus injury as the nerves of the brachial plexus are stretched with the descent of the fetal head.

There is little objective study of the maneuvers employed for shoulder dystocia and their effectiveness in preventing neonatal injury, let alone prospective studies comparing the effectiveness of one maneuver vs. another. The choice of maneuvers thus remains provider specific. The maneuvers that are most commonly employed for shoulder dystocia, however, are utilized in order to disimpact the anterior shoulder from behind the symphysis pubis by effecting its rotation.

It is important to appreciate that the McRoberts maneuver, with or without suprapubic pressure, may be successful in only approximately 50% of shoulder dystocia cases.

Unfortunately, many young obstetricians have had limited exposure to shoulder dystocia and may have employed only this maneuver, and not others, in their clinical training. At some point, they will likely encounter a shoulder dystocia case that does not respond to the McRoberts and/or suprapubic pressure maneuvers. It is critical to be competent in performing a full repertoire of potentially effective maneuvers.

There is increasing evidence that obstetricians should have a low threshold for utilizing delivery of the posterior shoulder in the management of shoulder dystocia.

In one recently published, multicenter review of shoulder dystocia maneuvers, for instance, investigators identified women who had incurred a shoulder dystocia during delivery and compared cases involving neonatal injury with injury-free cases. Delivery of the posterior shoulder was associated with the highest rate of successful delivery, when compared with other maneuvers, and with similar rates of neonatal injury (Obstet. Gynecol. 2011;117:1272-8).

The value of posterior arm release lies in its ability to reduce the anterior-posterior diameter of the fetus more significantly than any other maneuver. It has been associated with a marked decrease in anterior nerve stretch and the force required to effect delivery (Obstet. Gynecol. 2003;101:1068-72; Am. J. Obstet. Gynecol. 2010;203:339.e1-5).

In many litigated cases involving shoulder dystocia and brachial plexus injury, it is asserted that unnecessary excess traction must have been employed for a permanent injury to have occurred. Such assertions imply that the obstetrician can perfectly gauge the amount of traction or force necessary to deliver the infant and yet avoid injury in the setting of shoulder dystocia, which is not the case.

Increasing evidence suggests that many cases of brachial plexus injury accompanying shoulder dystocia are multifactorial in origin, and are not simply a result of operator-induced traction and stretching of the nerves. Obstetricians are continually instructed early on in their careers that excess traction should be avoided, as should any fundal pressure that might further disimpact the shoulders.

I simply recommend abandoning any traction efforts once shoulder dystocia is clearly recognized. When the complication occurs, a team consisting of additional nursing personnel, anesthesia, and the most experienced obstetrician available should be immediately summoned, and expulsive efforts on behalf of the mother should be curtailed while maneuvers are being undertaken to disimpact the shoulders.

If two obstetricians are present, it often is helpful for the stronger of the two to deliver appropriate suprapubic pressure from above. The goal is to move the shoulders to an oblique position by exerting pressure from the back of the fetus. This maneuver cannot really be done effectively by a single operator or from below as has been depicted in some textbooks. Again, if this fails to work, a low threshold should exist for attempting a posterior arm release.

Maintaining accurate documentation in the medical record of all events preceding and surrounding the shoulder dystocia is important. This includes but is not limited to the following:

▸ Consideration of significant risk factors for macrosomia, including diabetic pregnancy management and results of gestational diabetes screening tests.

▸ Estimation of fetal size, either clinically or by ultrasound. Most experts believe that diabetic mothers should undergo ultrasound at term to assess fetal size.

▸ Description of instrumental delivery, including indication and station at application and duration of use.

▸ A detailed step-by-step description of the maneuvers used to disimpact the shoulders. The anterior shoulder should be identified as part of the documentation.

Training and Simulation

During the past few years, simulation and drills and other enhanced teaching methods have become an increasingly common part of the curriculum for training residents and nursing personnel in the management of shoulder dystocia. Because the complication occurs relatively infrequently but can have devastating consequences when it does, shoulder dystocia is one of only several obstetric emergencies to be targeted in efforts to improve patient safety.

As with the few other obstetric events that receive such attention, data on the impact of enhanced training on perinatal outcomes remain limited. There clearly is evidence that simulation and drills improve team performance, and it has been hoped that improved team performance will ultimately translate to better outcomes. At present, two studies have indicated that the incidence of brachial plexus injury may decline with the implementation of targeted training for maternity staff.

One of these studies retrospectively compared the management and neonatal outcomes of almost 20,000 births that were complicated by shoulder dystocia in the years before and after the introduction of shoulder dystocia training for all maternity staff in a hospital in the United Kingdom (Obstet. Gynecol. 2008;112:14-20). The rate of brachial plexus injury at birth was significantly reduced, from 7.4% to 2.3%, as was the rate of neonatal injury more broadly (from 9.3% to 2.3%).

In the other study – also a retrospective assessment – the rate of obstetric brachial plexus injury in cases of shoulder dystocia fell from 30% before a training protocol was implemented for maternity staff at Jamaica Hospital in New York, to 11% afterward (Am. J. Obstet. Gynecol. 2011;204:322.e1-6).

A recently published study from Ireland, however, failed to reveal any difference in the frequency of brachial plexus injury after the introduction of specific staff training in managing shoulder dystocia. In this single-hospital study, investigators assessed outcomes associated with more than 77,000 deliveries that occurred during two 5-year time periods, before and after training was instituted. The incidence of brachial plexus injury remained unchanged from 1.5 per 1,000 in 1994-1998 to 1.7 per 1,000 in 2004-2008 (Am. J. Obstet. Gynecol. 2011;204:324.e1-6).

Although the results of this latter study are disappointing, I believe they are unlikely to limit the enthusiasm for the simulation training and shoulder dystocia drills that have become fairly routine in many large maternity hospitals in the United States.

Regardless of the limited outcomes data we have available thus far, experience with simulation training has taught us that in order to retain necessary skills, repetitive participation in simulation training appears to be required. The relatively infrequent nature of severe shoulder dystocia cases makes the simulation model for learning very attractive.

The doctor inserts a hand (left), then he/she sweeps the arm across the baby's chest and over the mother's perineum.

Source Images: ©Elsevier, From Obstetrics: Normal and Problem Pregnancies, 5th Edition

Shoulder Dystocia

obnews@elsevier.com

Routine vaginal deliveries can sometimes quickly become not-so-routine deliveries. When an otherwise normal labor process – and sometimes even a near-delivery – ends with a delayed or obstructed delivery of the fetal shoulder, the obstetrician and his or her team are challenged – physically and emotionally.

This complication is a nightmare for the family as well as the obstetrician who struggles to complete the process. What actually may be a matter of seconds or a minute can feel like an eternity.

We now know that diabetes and obesity are conditions that are increasing at a rapid pace in our society. With the rise in these two conditions (known collectively as diabesity), we can anticipate a rise in fetal macrosomia.

On the other hand, we know that not every macrosomic infant results in obstructed labor or shoulder dystocia. In addition, we currently do not have a very good biometric methodology by which we can precisely estimate fetal weight, or even the pelvic size. Thus, it is difficult to come to an objective conclusion regarding the probability of obstructed labor.

These are the variables that, together, create such a vexing and sometimes underappreciated conundrum.

To attempt to anticipate and to manage the problem, obstetrical specialists must rely on less-than-satisfactory biomedical parameters, historical experience, and their best judgment about medical condition.

Despite such imprecision and the lack of certainty we have for addressing the problem, there is some guidance that can be helpful in predicting the level of risk of shoulder dystocia, and in managing the complication should it occur. It is in this light that we have invited Dr. Mark B. Landon, a maternal-fetal medicine specialist, to discuss the problem of shoulder dystocia. Dr. Landon is the Richard L. Meiling Professor and chairman of the department of ob.gyn. at the Ohio State University, Columbus.

As Dr. Landon discusses, it is almost impossible to be absolutely perfect in preventing and managing shoulder dystocia. We can, however, improve our understanding of which scenarios call for the consideration of prophylactic cesarean section, and of how we can deliver affected infants as safely as possible. As Dr. Landon duly notes, it is critical for the obstetrician to be able to perform a repertoire of potentially effective maneuvers to manage shoulder dystocia.

Shoulder dystocia is not an uncommon obstetric complication, occurring in as many as 2 per 100 vaginal births. This obstetric emergency is associated with a number of adverse perinatal outcomes for both the mother and infant, the most serious of which remains neonatal brachial plexus injury. In a minority of cases in which there is prolonged impaction of the shoulders, birth asphyxia also may occur.

Obstetricians and other birth attendants must be fully prepared to effectively manage shoulder dystocia when it occurs. They also should understand the existing controversies regarding prevention and the pathogenesis of injuries associated with shoulder dystocia.

Shoulder dystocia generally is not a predictable event, which makes prevention extremely difficult. Because of the limited accuracy of ultrasound for estimating fetal size, the risk of shoulder dystocia and resulting injury must be fairly significant before prophylactic cesarean is considered as a preventive measure. There are, however, certain high-risk scenarios that call for consideration of prophylactic cesarean delivery.

Prevention

For the past several decades, clinical research has focused on whether shoulder dystocia can be predicted and/or prevented. Overall, most analyses have shown us that shoulder dystocia can be only minimally predicted, at best, and that prevention of this complication as well as associated injury is far from a simple undertaking.

The leading risk factor for shoulder dystocia is excessive birth weight, yet not all cases of shoulder dystocia involve infants who weigh more than 4,500 g, or even more than 4,000 g. In fact, most shoulder dystocia cases actually occur when birth weights are less than 4,000 g – especially in nondiabetic pregnancies. (In diabetic pregnancies, most shoulder dystocias and brachial plexus injuries do occur in infants with birth weights greater than 4,000 g.)

The possibility that birth weight estimates may help us to predict and/or prevent shoulder dystocia also is hindered by the fact that it remains difficult to identify large babies prior to delivery. Clinical estimation of size and the use of ultrasound are the two most commonly employed techniques for estimating birth size, but both have limited accuracy and may either underestimate or overestimate fetal size. Most large babies, moreover, can successfully undergo vaginal birth without the complication of shoulder dystocia, let alone brachial plexus injury.

All told, these realities limit our ability to use estimated birth weight in selecting those pregnancies that might benefit from prophylactic cesarean delivery.

To consider prophylactic cesarean delivery, the level of risk for shoulder dystocia and resultant injury must be fairly significant. The following are two clinical scenarios in which the risk of complications reaches a level at which the option of prophylactic cesarean section (including informed consent) should be discussed with the mother:

▸ A pregnancy complicated by diabetes in which the estimated fetal weight is greater than or equal to 4,500 g. Some experts have suggested that this threshold should, in fact, be lower in diabetic pregnancies. However, utilization of a lower threshold (such as 4,000 g or 4,250 g) must come with the recognition that it will spur the use of more cesarean deliveries to prevent injury.

▸ A patient with a history of shoulder dystocia birth, particularly when the fetus is believed to be of similar or greater weight than the previously affected fetus.

Determining the recurrence risk of shoulder dystocia has proved difficult because, in most clinical series, a large proportion of women with a history of the complication will undergo scheduled cesarean delivery in their subsequent pregnancies. This bias toward operative delivery may lead to an underestimation of the true recurrence risk. Regardless of this potential estimation bias, unless the estimated fetal weight in the woman's current pregnancy is significantly less than that of the prior pregnancy, we should counsel women with prior shoulder dystocia and offer them prophylactic cesarean delivery.

With respect to the predictive value of labor abnormalities, studies have yielded mixed results. The bottom line is that labor abnormalities are not particularly useful in predicting shoulder dystocia – except for cases of a prolonged second stage of labor when there is suspicion of a large infant. This combination of factors should alert the physician to the potential for shoulder dystocia. Operative vaginal delivery should generally be avoided in this scenario, because delivery above an outlet station may further increase the risk of shoulder dystocia and resultant injury.

Management, Medicolegal Issues

As with any delivery, the goal of management should always be to deliver the infant as safely as possible, minimizing the risk of traumatic injury and birth asphyxia. In most cases of shoulder dystocia, the shoulders remain in an anterior-posterior position and fail to rotate. This creates the potential for brachial plexus injury as the nerves of the brachial plexus are stretched with the descent of the fetal head.

There is little objective study of the maneuvers employed for shoulder dystocia and their effectiveness in preventing neonatal injury, let alone prospective studies comparing the effectiveness of one maneuver vs. another. The choice of maneuvers thus remains provider specific. The maneuvers that are most commonly employed for shoulder dystocia, however, are utilized in order to disimpact the anterior shoulder from behind the symphysis pubis by effecting its rotation.

It is important to appreciate that the McRoberts maneuver, with or without suprapubic pressure, may be successful in only approximately 50% of shoulder dystocia cases.

Unfortunately, many young obstetricians have had limited exposure to shoulder dystocia and may have employed only this maneuver, and not others, in their clinical training. At some point, they will likely encounter a shoulder dystocia case that does not respond to the McRoberts and/or suprapubic pressure maneuvers. It is critical to be competent in performing a full repertoire of potentially effective maneuvers.

There is increasing evidence that obstetricians should have a low threshold for utilizing delivery of the posterior shoulder in the management of shoulder dystocia.

In one recently published, multicenter review of shoulder dystocia maneuvers, for instance, investigators identified women who had incurred a shoulder dystocia during delivery and compared cases involving neonatal injury with injury-free cases. Delivery of the posterior shoulder was associated with the highest rate of successful delivery, when compared with other maneuvers, and with similar rates of neonatal injury (Obstet. Gynecol. 2011;117:1272-8).

The value of posterior arm release lies in its ability to reduce the anterior-posterior diameter of the fetus more significantly than any other maneuver. It has been associated with a marked decrease in anterior nerve stretch and the force required to effect delivery (Obstet. Gynecol. 2003;101:1068-72; Am. J. Obstet. Gynecol. 2010;203:339.e1-5).

In many litigated cases involving shoulder dystocia and brachial plexus injury, it is asserted that unnecessary excess traction must have been employed for a permanent injury to have occurred. Such assertions imply that the obstetrician can perfectly gauge the amount of traction or force necessary to deliver the infant and yet avoid injury in the setting of shoulder dystocia, which is not the case.

Increasing evidence suggests that many cases of brachial plexus injury accompanying shoulder dystocia are multifactorial in origin, and are not simply a result of operator-induced traction and stretching of the nerves. Obstetricians are continually instructed early on in their careers that excess traction should be avoided, as should any fundal pressure that might further disimpact the shoulders.

I simply recommend abandoning any traction efforts once shoulder dystocia is clearly recognized. When the complication occurs, a team consisting of additional nursing personnel, anesthesia, and the most experienced obstetrician available should be immediately summoned, and expulsive efforts on behalf of the mother should be curtailed while maneuvers are being undertaken to disimpact the shoulders.

If two obstetricians are present, it often is helpful for the stronger of the two to deliver appropriate suprapubic pressure from above. The goal is to move the shoulders to an oblique position by exerting pressure from the back of the fetus. This maneuver cannot really be done effectively by a single operator or from below as has been depicted in some textbooks. Again, if this fails to work, a low threshold should exist for attempting a posterior arm release.

Maintaining accurate documentation in the medical record of all events preceding and surrounding the shoulder dystocia is important. This includes but is not limited to the following:

▸ Consideration of significant risk factors for macrosomia, including diabetic pregnancy management and results of gestational diabetes screening tests.

▸ Estimation of fetal size, either clinically or by ultrasound. Most experts believe that diabetic mothers should undergo ultrasound at term to assess fetal size.

▸ Description of instrumental delivery, including indication and station at application and duration of use.

▸ A detailed step-by-step description of the maneuvers used to disimpact the shoulders. The anterior shoulder should be identified as part of the documentation.

Training and Simulation

During the past few years, simulation and drills and other enhanced teaching methods have become an increasingly common part of the curriculum for training residents and nursing personnel in the management of shoulder dystocia. Because the complication occurs relatively infrequently but can have devastating consequences when it does, shoulder dystocia is one of only several obstetric emergencies to be targeted in efforts to improve patient safety.

As with the few other obstetric events that receive such attention, data on the impact of enhanced training on perinatal outcomes remain limited. There clearly is evidence that simulation and drills improve team performance, and it has been hoped that improved team performance will ultimately translate to better outcomes. At present, two studies have indicated that the incidence of brachial plexus injury may decline with the implementation of targeted training for maternity staff.

One of these studies retrospectively compared the management and neonatal outcomes of almost 20,000 births that were complicated by shoulder dystocia in the years before and after the introduction of shoulder dystocia training for all maternity staff in a hospital in the United Kingdom (Obstet. Gynecol. 2008;112:14-20). The rate of brachial plexus injury at birth was significantly reduced, from 7.4% to 2.3%, as was the rate of neonatal injury more broadly (from 9.3% to 2.3%).

In the other study – also a retrospective assessment – the rate of obstetric brachial plexus injury in cases of shoulder dystocia fell from 30% before a training protocol was implemented for maternity staff at Jamaica Hospital in New York, to 11% afterward (Am. J. Obstet. Gynecol. 2011;204:322.e1-6).

A recently published study from Ireland, however, failed to reveal any difference in the frequency of brachial plexus injury after the introduction of specific staff training in managing shoulder dystocia. In this single-hospital study, investigators assessed outcomes associated with more than 77,000 deliveries that occurred during two 5-year time periods, before and after training was instituted. The incidence of brachial plexus injury remained unchanged from 1.5 per 1,000 in 1994-1998 to 1.7 per 1,000 in 2004-2008 (Am. J. Obstet. Gynecol. 2011;204:324.e1-6).

Although the results of this latter study are disappointing, I believe they are unlikely to limit the enthusiasm for the simulation training and shoulder dystocia drills that have become fairly routine in many large maternity hospitals in the United States.

Regardless of the limited outcomes data we have available thus far, experience with simulation training has taught us that in order to retain necessary skills, repetitive participation in simulation training appears to be required. The relatively infrequent nature of severe shoulder dystocia cases makes the simulation model for learning very attractive.

The doctor inserts a hand (left), then he/she sweeps the arm across the baby's chest and over the mother's perineum.

Source Images: ©Elsevier, From Obstetrics: Normal and Problem Pregnancies, 5th Edition

Shoulder Dystocia

obnews@elsevier.com

Routine vaginal deliveries can sometimes quickly become not-so-routine deliveries. When an otherwise normal labor process – and sometimes even a near-delivery – ends with a delayed or obstructed delivery of the fetal shoulder, the obstetrician and his or her team are challenged – physically and emotionally.

This complication is a nightmare for the family as well as the obstetrician who struggles to complete the process. What actually may be a matter of seconds or a minute can feel like an eternity.

We now know that diabetes and obesity are conditions that are increasing at a rapid pace in our society. With the rise in these two conditions (known collectively as diabesity), we can anticipate a rise in fetal macrosomia.

On the other hand, we know that not every macrosomic infant results in obstructed labor or shoulder dystocia. In addition, we currently do not have a very good biometric methodology by which we can precisely estimate fetal weight, or even the pelvic size. Thus, it is difficult to come to an objective conclusion regarding the probability of obstructed labor.

These are the variables that, together, create such a vexing and sometimes underappreciated conundrum.

To attempt to anticipate and to manage the problem, obstetrical specialists must rely on less-than-satisfactory biomedical parameters, historical experience, and their best judgment about medical condition.

Despite such imprecision and the lack of certainty we have for addressing the problem, there is some guidance that can be helpful in predicting the level of risk of shoulder dystocia, and in managing the complication should it occur. It is in this light that we have invited Dr. Mark B. Landon, a maternal-fetal medicine specialist, to discuss the problem of shoulder dystocia. Dr. Landon is the Richard L. Meiling Professor and chairman of the department of ob.gyn. at the Ohio State University, Columbus.

As Dr. Landon discusses, it is almost impossible to be absolutely perfect in preventing and managing shoulder dystocia. We can, however, improve our understanding of which scenarios call for the consideration of prophylactic cesarean section, and of how we can deliver affected infants as safely as possible. As Dr. Landon duly notes, it is critical for the obstetrician to be able to perform a repertoire of potentially effective maneuvers to manage shoulder dystocia.

Shoulder dystocia is not an uncommon obstetric complication, occurring in as many as 2 per 100 vaginal births. This obstetric emergency is associated with a number of adverse perinatal outcomes for both the mother and infant, the most serious of which remains neonatal brachial plexus injury. In a minority of cases in which there is prolonged impaction of the shoulders, birth asphyxia also may occur.

Obstetricians and other birth attendants must be fully prepared to effectively manage shoulder dystocia when it occurs. They also should understand the existing controversies regarding prevention and the pathogenesis of injuries associated with shoulder dystocia.

Shoulder dystocia generally is not a predictable event, which makes prevention extremely difficult. Because of the limited accuracy of ultrasound for estimating fetal size, the risk of shoulder dystocia and resulting injury must be fairly significant before prophylactic cesarean is considered as a preventive measure. There are, however, certain high-risk scenarios that call for consideration of prophylactic cesarean delivery.

Prevention

For the past several decades, clinical research has focused on whether shoulder dystocia can be predicted and/or prevented. Overall, most analyses have shown us that shoulder dystocia can be only minimally predicted, at best, and that prevention of this complication as well as associated injury is far from a simple undertaking.

The leading risk factor for shoulder dystocia is excessive birth weight, yet not all cases of shoulder dystocia involve infants who weigh more than 4,500 g, or even more than 4,000 g. In fact, most shoulder dystocia cases actually occur when birth weights are less than 4,000 g – especially in nondiabetic pregnancies. (In diabetic pregnancies, most shoulder dystocias and brachial plexus injuries do occur in infants with birth weights greater than 4,000 g.)

The possibility that birth weight estimates may help us to predict and/or prevent shoulder dystocia also is hindered by the fact that it remains difficult to identify large babies prior to delivery. Clinical estimation of size and the use of ultrasound are the two most commonly employed techniques for estimating birth size, but both have limited accuracy and may either underestimate or overestimate fetal size. Most large babies, moreover, can successfully undergo vaginal birth without the complication of shoulder dystocia, let alone brachial plexus injury.

All told, these realities limit our ability to use estimated birth weight in selecting those pregnancies that might benefit from prophylactic cesarean delivery.

To consider prophylactic cesarean delivery, the level of risk for shoulder dystocia and resultant injury must be fairly significant. The following are two clinical scenarios in which the risk of complications reaches a level at which the option of prophylactic cesarean section (including informed consent) should be discussed with the mother:

▸ A pregnancy complicated by diabetes in which the estimated fetal weight is greater than or equal to 4,500 g. Some experts have suggested that this threshold should, in fact, be lower in diabetic pregnancies. However, utilization of a lower threshold (such as 4,000 g or 4,250 g) must come with the recognition that it will spur the use of more cesarean deliveries to prevent injury.

▸ A patient with a history of shoulder dystocia birth, particularly when the fetus is believed to be of similar or greater weight than the previously affected fetus.

Determining the recurrence risk of shoulder dystocia has proved difficult because, in most clinical series, a large proportion of women with a history of the complication will undergo scheduled cesarean delivery in their subsequent pregnancies. This bias toward operative delivery may lead to an underestimation of the true recurrence risk. Regardless of this potential estimation bias, unless the estimated fetal weight in the woman's current pregnancy is significantly less than that of the prior pregnancy, we should counsel women with prior shoulder dystocia and offer them prophylactic cesarean delivery.

With respect to the predictive value of labor abnormalities, studies have yielded mixed results. The bottom line is that labor abnormalities are not particularly useful in predicting shoulder dystocia – except for cases of a prolonged second stage of labor when there is suspicion of a large infant. This combination of factors should alert the physician to the potential for shoulder dystocia. Operative vaginal delivery should generally be avoided in this scenario, because delivery above an outlet station may further increase the risk of shoulder dystocia and resultant injury.

Management, Medicolegal Issues

As with any delivery, the goal of management should always be to deliver the infant as safely as possible, minimizing the risk of traumatic injury and birth asphyxia. In most cases of shoulder dystocia, the shoulders remain in an anterior-posterior position and fail to rotate. This creates the potential for brachial plexus injury as the nerves of the brachial plexus are stretched with the descent of the fetal head.

There is little objective study of the maneuvers employed for shoulder dystocia and their effectiveness in preventing neonatal injury, let alone prospective studies comparing the effectiveness of one maneuver vs. another. The choice of maneuvers thus remains provider specific. The maneuvers that are most commonly employed for shoulder dystocia, however, are utilized in order to disimpact the anterior shoulder from behind the symphysis pubis by effecting its rotation.

It is important to appreciate that the McRoberts maneuver, with or without suprapubic pressure, may be successful in only approximately 50% of shoulder dystocia cases.

Unfortunately, many young obstetricians have had limited exposure to shoulder dystocia and may have employed only this maneuver, and not others, in their clinical training. At some point, they will likely encounter a shoulder dystocia case that does not respond to the McRoberts and/or suprapubic pressure maneuvers. It is critical to be competent in performing a full repertoire of potentially effective maneuvers.

There is increasing evidence that obstetricians should have a low threshold for utilizing delivery of the posterior shoulder in the management of shoulder dystocia.

In one recently published, multicenter review of shoulder dystocia maneuvers, for instance, investigators identified women who had incurred a shoulder dystocia during delivery and compared cases involving neonatal injury with injury-free cases. Delivery of the posterior shoulder was associated with the highest rate of successful delivery, when compared with other maneuvers, and with similar rates of neonatal injury (Obstet. Gynecol. 2011;117:1272-8).

The value of posterior arm release lies in its ability to reduce the anterior-posterior diameter of the fetus more significantly than any other maneuver. It has been associated with a marked decrease in anterior nerve stretch and the force required to effect delivery (Obstet. Gynecol. 2003;101:1068-72; Am. J. Obstet. Gynecol. 2010;203:339.e1-5).

In many litigated cases involving shoulder dystocia and brachial plexus injury, it is asserted that unnecessary excess traction must have been employed for a permanent injury to have occurred. Such assertions imply that the obstetrician can perfectly gauge the amount of traction or force necessary to deliver the infant and yet avoid injury in the setting of shoulder dystocia, which is not the case.

Increasing evidence suggests that many cases of brachial plexus injury accompanying shoulder dystocia are multifactorial in origin, and are not simply a result of operator-induced traction and stretching of the nerves. Obstetricians are continually instructed early on in their careers that excess traction should be avoided, as should any fundal pressure that might further disimpact the shoulders.

I simply recommend abandoning any traction efforts once shoulder dystocia is clearly recognized. When the complication occurs, a team consisting of additional nursing personnel, anesthesia, and the most experienced obstetrician available should be immediately summoned, and expulsive efforts on behalf of the mother should be curtailed while maneuvers are being undertaken to disimpact the shoulders.

If two obstetricians are present, it often is helpful for the stronger of the two to deliver appropriate suprapubic pressure from above. The goal is to move the shoulders to an oblique position by exerting pressure from the back of the fetus. This maneuver cannot really be done effectively by a single operator or from below as has been depicted in some textbooks. Again, if this fails to work, a low threshold should exist for attempting a posterior arm release.

Maintaining accurate documentation in the medical record of all events preceding and surrounding the shoulder dystocia is important. This includes but is not limited to the following:

▸ Consideration of significant risk factors for macrosomia, including diabetic pregnancy management and results of gestational diabetes screening tests.

▸ Estimation of fetal size, either clinically or by ultrasound. Most experts believe that diabetic mothers should undergo ultrasound at term to assess fetal size.

▸ Description of instrumental delivery, including indication and station at application and duration of use.

▸ A detailed step-by-step description of the maneuvers used to disimpact the shoulders. The anterior shoulder should be identified as part of the documentation.

Training and Simulation

During the past few years, simulation and drills and other enhanced teaching methods have become an increasingly common part of the curriculum for training residents and nursing personnel in the management of shoulder dystocia. Because the complication occurs relatively infrequently but can have devastating consequences when it does, shoulder dystocia is one of only several obstetric emergencies to be targeted in efforts to improve patient safety.

As with the few other obstetric events that receive such attention, data on the impact of enhanced training on perinatal outcomes remain limited. There clearly is evidence that simulation and drills improve team performance, and it has been hoped that improved team performance will ultimately translate to better outcomes. At present, two studies have indicated that the incidence of brachial plexus injury may decline with the implementation of targeted training for maternity staff.

One of these studies retrospectively compared the management and neonatal outcomes of almost 20,000 births that were complicated by shoulder dystocia in the years before and after the introduction of shoulder dystocia training for all maternity staff in a hospital in the United Kingdom (Obstet. Gynecol. 2008;112:14-20). The rate of brachial plexus injury at birth was significantly reduced, from 7.4% to 2.3%, as was the rate of neonatal injury more broadly (from 9.3% to 2.3%).

In the other study – also a retrospective assessment – the rate of obstetric brachial plexus injury in cases of shoulder dystocia fell from 30% before a training protocol was implemented for maternity staff at Jamaica Hospital in New York, to 11% afterward (Am. J. Obstet. Gynecol. 2011;204:322.e1-6).

A recently published study from Ireland, however, failed to reveal any difference in the frequency of brachial plexus injury after the introduction of specific staff training in managing shoulder dystocia. In this single-hospital study, investigators assessed outcomes associated with more than 77,000 deliveries that occurred during two 5-year time periods, before and after training was instituted. The incidence of brachial plexus injury remained unchanged from 1.5 per 1,000 in 1994-1998 to 1.7 per 1,000 in 2004-2008 (Am. J. Obstet. Gynecol. 2011;204:324.e1-6).

Although the results of this latter study are disappointing, I believe they are unlikely to limit the enthusiasm for the simulation training and shoulder dystocia drills that have become fairly routine in many large maternity hospitals in the United States.

Regardless of the limited outcomes data we have available thus far, experience with simulation training has taught us that in order to retain necessary skills, repetitive participation in simulation training appears to be required. The relatively infrequent nature of severe shoulder dystocia cases makes the simulation model for learning very attractive.

The doctor inserts a hand (left), then he/she sweeps the arm across the baby's chest and over the mother's perineum.

Source Images: ©Elsevier, From Obstetrics: Normal and Problem Pregnancies, 5th Edition

Shoulder Dystocia

obnews@elsevier.com

Routine vaginal deliveries can sometimes quickly become not-so-routine deliveries. When an otherwise normal labor process – and sometimes even a near-delivery – ends with a delayed or obstructed delivery of the fetal shoulder, the obstetrician and his or her team are challenged – physically and emotionally.

This complication is a nightmare for the family as well as the obstetrician who struggles to complete the process. What actually may be a matter of seconds or a minute can feel like an eternity.

We now know that diabetes and obesity are conditions that are increasing at a rapid pace in our society. With the rise in these two conditions (known collectively as diabesity), we can anticipate a rise in fetal macrosomia.

On the other hand, we know that not every macrosomic infant results in obstructed labor or shoulder dystocia. In addition, we currently do not have a very good biometric methodology by which we can precisely estimate fetal weight, or even the pelvic size. Thus, it is difficult to come to an objective conclusion regarding the probability of obstructed labor.

These are the variables that, together, create such a vexing and sometimes underappreciated conundrum.

To attempt to anticipate and to manage the problem, obstetrical specialists must rely on less-than-satisfactory biomedical parameters, historical experience, and their best judgment about medical condition.

Despite such imprecision and the lack of certainty we have for addressing the problem, there is some guidance that can be helpful in predicting the level of risk of shoulder dystocia, and in managing the complication should it occur. It is in this light that we have invited Dr. Mark B. Landon, a maternal-fetal medicine specialist, to discuss the problem of shoulder dystocia. Dr. Landon is the Richard L. Meiling Professor and chairman of the department of ob.gyn. at the Ohio State University, Columbus.

As Dr. Landon discusses, it is almost impossible to be absolutely perfect in preventing and managing shoulder dystocia. We can, however, improve our understanding of which scenarios call for the consideration of prophylactic cesarean section, and of how we can deliver affected infants as safely as possible. As Dr. Landon duly notes, it is critical for the obstetrician to be able to perform a repertoire of potentially effective maneuvers to manage shoulder dystocia.

We now know that gestational diabetes mellitus is a serious condition that, if not properly diagnosed and managed, can have cyclic, intergenerational consequences. Newborns exposed to maternal hyperglycemia during pregnancy have a high risk of being born overweight and of eventually becoming obese children and adults. These newborns also are at a high risk of developing diabetes themselves later in life.

The prevalence of gestational diabetes mellitus (GDM) is increasing in every ethnic group. In the Kaiser Permanente system in Colorado, a state which has traditionally had the lowest obesity rate of any state in the United States, the prevalence of GDM doubled from 1994 to 2002, with significant increases in all racial/ethnic groups (Diabetes Care 2005;28:579-84). Such increases in GDM prevalence are happening worldwide – one part of a worldwide epidemic of obesity and diabetes that is overtaking our youth.

We've learned that GDM is one sign post on the way to the development of overt type 2 diabetes. Indeed, a majority of women with GDM will acquire diabetes within 5 years.

In the last decade or so, our clinical research focus has centered on the in utero risks to the fetus. In a striking study of the potential impact of intrauterine hyperglycemia exposure on later development, Dr. D. Dabelea and coinvestigators compared siblings in the Pima Indian population who were born before and after their mothers were diagnosed with diabetes. The children who were born after their mothers had developed diabetes had almost double the rate of obesity as adolescents than their siblings who were born before their mother's diagnosis of diabetes. Even though these siblings ate the same diet and came from the same gene pools (with the same fathers), they experienced dramatically different health outcomes in adolescence as a result of the differing intrauterine environments (Diabetes 2000;49:2208-11).

This and other studies have given us a body of supplementary science showing that exposure to high blood glucose in utero causes accumulation of fat in the fetus. Even though that baby fat might be lost in early childhood, prenatal exposure nevertheless genetically programs the fetus for a higher risk of developing fatness as an adult.

As I detailed in the last Master Class in obstetrics (see Ob.Gyn News, July 2011, pp. 24–25), we now also have evidence from two randomized controlled trials that interventions to control blood glucose are effective in reducing rates of newborn obesity and therefore should improve adolescent and adult health downstream.

The two randomized trials – the Australian Carbohydrate Intolerance Study in Pregnant Women (N. Engl. J. Med. 2005;352:2477-86) and a study published several years later by Dr. Mark B. Landon and his colleagues (N. Engl. J. Med. 2009; 361:1339-48) – demonstrated the positive impact of treating even mild forms of GDM, with the largest effects being on reducing newborn obesity. Although the offspring of mothers who were treated and not treated in those studies have not yet been followed into adulthood, it seems fair to expect that the children of mothers who were treated for GDM will have significantly better health profiles downstream.

Treating GDM, and learning how to maximize glucose control, has thus moved to center stage in obstetric practice.

Trials of Dietary Change

In Dr. Landon's landmark study, more than 90% of the women randomized to the treatment group (versus usual prenatal care) needed only dietary counseling and education about blood glucose control for effective treatment of abnormal blood glucose levels. Surprisingly, fewer than 10% needed insulin as well.

That we can manage many of our patients with diet alone is welcome good news. To be successful with this approach, however, we must be vigilant in monitoring the effectiveness of dietary counseling and identifying early on those patients for whom dietary treatment is not enough.

We also must be more vigilant in detecting GDM, because the maximal time of fetal fat accretion is at about 32-34 weeks' gestation. GDM is typically diagnosed at about 28 weeks' gestation, and patients usually are not engaged in a regime of blood sugar testing and dietary change until about 30-31 weeks. If we wait until 34-35 weeks' gestation to change course with treatment – adding insulin or oral hypoglycemic agents – significant body fat accumulation by the fetus already will have occurred.

Screening for GDM even earlier than currently recommended, at 26 weeks' gestation if possible, and providing dietary counseling as early as possible are worthwhile goals. Our advice is that patients be moved on to a medication regimen if more than one-third of their blood glucose measurements are still abnormal after 2 weeks of dietary change. A more stringent standard may be more prudent, but for now we believe there is enough evidence to warrant this modest change in practice, and we find that it is a rule that most patients can understand.

We also must caution that the effectiveness of dietary change may be significantly less in many populations than it was in Dr. Landon's study because his study focused on a subset of women who had only mild glucose intolerance. In our patient population, for example, we can achieve good glucose control with diet alone in about 60%-70% of cases.

The Science on Glyburide

Pharmacologic therapy for patients in whom dietary measures fail is no longer limited to insulin. Insulin is certainly still an option as a first-line therapy, and is necessary as an adjunct therapy in patients who are not achieving glucose targets with another agent. It has proven efficacy and well-studied pharmacokinetics. It does not cross the placenta, and research has shown that it may be beneficial by “resting” pancreatic islet cells.

Insulin is not an optimal therapy for GDM for several reasons, however. Many patients find it cumbersome to use, and most offices are not equipped for, or used to, teaching women how to give themselves the insulin injections. Insulin itself is also unfamiliar to many patients and can even be scary; some of the families we care for see insulin as a stigma, believing that a person who takes insulin has diabetes while a person who takes a pill does not truly have the condition.

In our practice, we have found that women who take oral hypoglycemics are more likely to have better glycemic control, probably because their drug compliance is better. With insulin, our patients tend to be suboptimally compliant.

Glyburide, one of the oral anti-hyperglycemic drugs that we have been able to transfer from use in the nonpregnant diabetic population to use during pregnancy, has been well used and studied by this point in time.

When Dr. Oded Langer and his colleagues led the first and only randomized trial comparing glyburide and insulin more than a decade ago, women with GDM were rarely treated with a sulfonylurea drug largely because of reports of prolonged severe hypoglycemia in neonates born to mothers who were receiving the drug at the time of delivery. There were also questions about whether glyburide, a second-generation sulfonylurea, could effectively control postprandial peaks in blood glucose while avoiding periods of hypoglycemia in the mother.

In the nonpregnant population, glyburide has been used for decades as a twice-daily oral medication. After months of use, patients develop active metabolites that prolong the drug's half-life and enable it to last for 12 hours, at least.

Glyburide use in pregnancy is a slightly different story, however. Patients take the medication for a relatively short time and consequently may not build up the active metabolites that nonpregnant patients acquire. The metabolic changes in pregnancy also make women vulnerable to hypoglycemia at certain times of the day, typically in the late morning, the late afternoon, and between 3 a.m. and 4 a.m.

Dr. Langer's trial, which randomized 404 women with GDM to receive glyburide or insulin, demonstrated similar outcomes in the insulin and glyburide groups. There were no differences in mean birth weight, the percentage of large for gestational age newborns, macrosomia, fetal anomalies, or newborn hypoglycemia. The rate of maternal hypoglycemia, however, was much higher in the insulin-treated group; 20% of the women receiving insulin experienced symptomatic hypoglycemia, compared with only 2% of the women taking glyburide.

In short, glyburide was just as effective as insulin in achieving desired levels of glycemic control (a fasting blood glucose less than 90 mg/dL and 2-hour postprandial glucose of 120 mg/dL) and controlling fetal obesity, while being significantly less likely to cause hypoglycemia in the mothers. (N. Engl. J. Med. 2000;343:1134-8).

Glyburide dosing in Dr. Langer's trial was increased weekly, as needed, to a maximum of 20 mg per day; women took the drug twice a day. Insulin was administered per a standard intensified schedule of regular NPH (intermediate-acting, lasting 6-12 hours) and regular TID (lasting 2-4 hours).

Despite the impressive findings from the trial, some have contended that the results of one randomized trial are insufficient for adopting glyburide as a first-line therapy. However, numerous retrospective or case-controlled studies also have since shown glyburide to be a clinically effective alternative to insulin therapy, with no adverse neonatal or fetal effects. These studies have shown, moreover, that it can be easier to avoid hypoglycemia and achieve optimal glycemic control with glyburide than with insulin.

One of the best large retrospective studies looked at 584 women at Kaiser Permanente Northern California and found that glyburide was at least as effective as insulin in achieving glycemic control and resulted in similar birth weights in women with GDM who had failed diet therapy alone (Am. J. Obstet. Gynecol. 2005;193:118-24).

Several recent reviews of glyburide studies, such as one that looked at nine glyburide studies covering 745 patients taking glyburide and 645 patients taking insulin, also have been published (Ann. Pharmacother. 2008;42:483-90). In 2007, moreover, the 5th International Workshop-Conference on GDM concluded that glyburide is a legitimate alternative to insulin for GDM (Diabetes Care 2007; 30:S251-60).hWe also now know that unlike other, first-generation sulfonylureas that tend to cross the placenta freely, glyburide is 99.8% protein-bound and thus crosses the placenta only minimally.

Theoretically, there is one potential problem with glyburide. Because the drug acts by stimulating maternal pancreatic insulin production, it could potentially promote “pancreatic burnout,” thus shortening the time to development of overt diabetes in women whose pancreas is struggling to begin with. Women who are obese and have significant insulin resistance at the start of their pregnancies thus might be susceptible to pancreatic burnout. Although this potential effect has not been demonstrated in any trials, it must be kept in mind.

It would be informative to conduct long-term follow-up studies that track the children of mothers who used glyburide during their pregnancies, but at this point it is unclear if such studies will be designed and carried out. The likelihood of additional randomized trials being conducted is practically nil, given the extent to which women already are choosing the oral hypoglycemics over insulin.

Glyburide in Practice

As clinicians, we must appreciate that the pharmacodynamics of glyburide are quite different in pregnant women, with important dosing implications for our patients. Indeed, for pregnant women, glyburide is not the 12-hour medication that it is in nonpregnant women.

During pregnancy, glyburide action peaks about 2.5 hours after it's taken, and the increased renal clearance and metabolism of pregnancy (in addition to the short duration of therapy in this patient population) leave the drug with a “useful” life of only about 6-8 hours.

Because blood glucose peaks 60-90 minutes after a meal, we instruct our patients to take a glyburide dose a full hour before a planned meal. Otherwise, postprandial glucose peaks will not be controlled. Usually, a dose taken an hour before breakfast will help control postprandial peaks after breakfast and lunch but will not last for dinner. Another dose 1 hour before an evening meal can be given.

To effectively control fasting blood glucose, we instruct patients to take a glyburide dose between 10 p.m. and midnight so that the drug will still be active in the early morning when it is needed. If the dose is taken too early at night – at 8-9 p.m., for instance – it will peak between 10 p.m. and midnight, and will not be working at 6 a.m.

As it is with insulin, careful glucose monitoring is critical for determining optimal administration of glyburide and for balancing glyburide action with meals and snacks. Individual glycemic profiles should be analyzed each week, with the goal of keeping fasting blood glucose below 90 mg/dL, and postprandial levels below 130 mg/dL, while preventing maternal hypoglycemia.

Attention must be paid not only to times of consistent elevation in blood glucose levels, but also to the potential for dosage overlap – for instance, a prelunch dosage administered to correct consistently high postprandial glucose levels after the mid-day meal could lead to low blood glucose levels at about 4-5 p.m. as its action overlaps with the end duration of a morning dose. Patients should always be prepared for vulnerable times and have a glucose tablet, juice box, or food with them to correct any periods of hypoglycemia.

Insulin should be added if more than 30% of blood glucose readings are above target with administration of 15-20 mg/day of glyburide.

Metformin as an Option

As ob.gyns, our experience with metformin, the other oral anti-hyperglycemic agent now available for treating GDM, came originally from its use as an infertility treatment in women with polycystic ovary syndrome (PCOS).

Metformin is frequently prescribed for women with PCOS to improve ovulation. These women have significant insulin resistance and are at high risk for developing GDM during their pregnancies. The main concern in this population, however, has been infertility, and studies have shown that metformin induces ovulation in women with PCOS.

Although metformin crosses the placenta, numerous studies have shown no increase in birth anomalies in women who conceive while taking the agent.

A study published a decade ago in women who chose whether or not to continue metformin treatment throughout their pregnancies showed that of those who discontinued metformin, 31% developed GDM, compared with only 3% of those who continued their metformin treatment (Fertil. Steril. 2002;77:520-5). These results helped fuel the idea that the agent may be a logical treatment for women with GDM.

Metformin also has a theoretical advantage over glyburide since its mechanism of action gets directly to the root of the problem of GDM. Metformin is an insulin sensitizer, and the root cause of GDM is resistance to insulin, or insulin insensitivity, at the tissue level.

In a study by Dr. J.A. Rowan published in 2008 that randomized more than 700 patients to either insulin or metformin, there were no appreciable differences in neonatal and maternal outcomes – from birth weight and neonatal morbidity to maternal hypoglycemia and glycemic control (N. Engl J. Med. 2008;358:2003-15). However, whereas 4% of the glyburide group in Dr. Langer's trial had to eventually add insulin (and up to 10%-20% in other studies), 47% of the patients taking metformin in this trial had to add insulin to maintain glycemic control.

Indeed, the downside to metformin, this and other studies have shown, is a high so-called failure rate – the need for supplementary insulin, which in this case typically occurs later in the pregnancy – of between 30% and 50%. On the other hand, patients generally will be more satisfied starting treatment with metformin than insulin. In weighing glyburide and metformin, patients should be counseled about their chances of needing insulin later in the pregnancy: about 10% with glyburide and closer to 50% with metformin.

In terms of glycemic control and other outcomes, several smaller, recent studies comparing the two agents have shown no statistical difference between them. Interestingly, most studies have shown less maternal weight gain in patients taking metformin than glyburide – about 6 pounds – but the significance of this difference is unclear since the babies' birth weights were not appreciably different.

Source Elsevier Global Medical News

GDM and the Developing Fetus

obnews@elsevier.com

A growing body of research has convincingly demonstrated that even periods of mild hyperglycemia during pregnancy can have long-term adverse consequences on the developing fetus. Therefore, there is a growing sentiment in the ob.gyn. and diabetes communities for an aggressive approach to the detection, treatment, and monitoring of the most frequent causes of hyperglycemic events during pregnancy. Significant controversies remain on how best to implement this approach.

In the area of gestational diabetes mellitus (GDM) treatment, multiple controversies exist regarding whether to manage GDM very aggressively (i.e., with insulin as the first line of therapy) or with less aggressive approaches first, followed by insulin as a last resort. The former approach, while likely to be effective in controlling hyperglycemia, is viewed by many physicians – and their patients – as not acceptable given that GDM is a relatively mild form of diabetes and most cases will resolve spontaneously after pregnancy.

In this month's Master Class, Dr. Thomas R. Moore, professor and chairman of the department of reproductive medicine at the University of California, San Diego, returns to provide us with a superbly written essay on the state of the evidence in managing GDM. Dr. Moore's Master Class briefly discusses the growing prevalence of GDM in the United States and worldwide, as well as the scientific evidence linking intrauterine hyperglycemia with adverse pregnancy outcomes. He then provides a detailed analysis of the best available science on trials of dietary approaches to GDM as well as trials on oral antihyperglycemic drugs and how they compare with one another and with insulin.

Dr. Moore also demonstrates how this knowledge is being applied to his own patients as well as how they've been able to adapt, accept, and comply with this relatively new approach to managing GDM. Once again, we are honored that Dr. Moore has agreed serve as the Master Class guest professor, providing important insights into how GDM might be managed optimally.

Key Points

▸ Prenatal exposure to hyperglycemia programs the fetus for a higher risk of being born overweight, of becoming obese in adolescence or adulthood, and of developing diabetes later in life. Two randomized trials have demonstrated the positive impact of treating even mild forms of GDM.

▸ Many patients can be managed with diet alone, but the effectiveness of dietary treatment must be carefully monitored, with insulin or oral antihyperglycemic agents added early – before significant body fat is accumulated by the fetus.

▸ Glyburide is just as effective as insulin in achieving optimal glycemic control and is significantly less likely to cause hypoglycemia in mothers, with no adverse neonatal or fetal effects, numerous studies have shown. Glyburide is not a 12-hour medication in pregnant women as it is in nonpregnant women, however. Ob.gyns must appreciate the dosing implications of the agent's different pharmacodynamics in pregnancy.

▸ Metformin also has equivalent efficacy to insulin, and several small recent studies have shown no significant difference with glyburide. Metformin has a theoretical advantage over glyburide in that it's an insulin sensitizer, but the downside is a higher chance of needing supplementary insulin later in pregnancy. Patients can be counseled accordingly.

We now know that gestational diabetes mellitus is a serious condition that, if not properly diagnosed and managed, can have cyclic, intergenerational consequences. Newborns exposed to maternal hyperglycemia during pregnancy have a high risk of being born overweight and of eventually becoming obese children and adults. These newborns also are at a high risk of developing diabetes themselves later in life.

The prevalence of gestational diabetes mellitus (GDM) is increasing in every ethnic group. In the Kaiser Permanente system in Colorado, a state which has traditionally had the lowest obesity rate of any state in the United States, the prevalence of GDM doubled from 1994 to 2002, with significant increases in all racial/ethnic groups (Diabetes Care 2005;28:579-84). Such increases in GDM prevalence are happening worldwide – one part of a worldwide epidemic of obesity and diabetes that is overtaking our youth.

We've learned that GDM is one sign post on the way to the development of overt type 2 diabetes. Indeed, a majority of women with GDM will acquire diabetes within 5 years.

In the last decade or so, our clinical research focus has centered on the in utero risks to the fetus. In a striking study of the potential impact of intrauterine hyperglycemia exposure on later development, Dr. D. Dabelea and coinvestigators compared siblings in the Pima Indian population who were born before and after their mothers were diagnosed with diabetes. The children who were born after their mothers had developed diabetes had almost double the rate of obesity as adolescents than their siblings who were born before their mother's diagnosis of diabetes. Even though these siblings ate the same diet and came from the same gene pools (with the same fathers), they experienced dramatically different health outcomes in adolescence as a result of the differing intrauterine environments (Diabetes 2000;49:2208-11).

This and other studies have given us a body of supplementary science showing that exposure to high blood glucose in utero causes accumulation of fat in the fetus. Even though that baby fat might be lost in early childhood, prenatal exposure nevertheless genetically programs the fetus for a higher risk of developing fatness as an adult.

As I detailed in the last Master Class in obstetrics (see Ob.Gyn News, July 2011, pp. 24–25), we now also have evidence from two randomized controlled trials that interventions to control blood glucose are effective in reducing rates of newborn obesity and therefore should improve adolescent and adult health downstream.

The two randomized trials – the Australian Carbohydrate Intolerance Study in Pregnant Women (N. Engl. J. Med. 2005;352:2477-86) and a study published several years later by Dr. Mark B. Landon and his colleagues (N. Engl. J. Med. 2009; 361:1339-48) – demonstrated the positive impact of treating even mild forms of GDM, with the largest effects being on reducing newborn obesity. Although the offspring of mothers who were treated and not treated in those studies have not yet been followed into adulthood, it seems fair to expect that the children of mothers who were treated for GDM will have significantly better health profiles downstream.

Treating GDM, and learning how to maximize glucose control, has thus moved to center stage in obstetric practice.

Trials of Dietary Change

In Dr. Landon's landmark study, more than 90% of the women randomized to the treatment group (versus usual prenatal care) needed only dietary counseling and education about blood glucose control for effective treatment of abnormal blood glucose levels. Surprisingly, fewer than 10% needed insulin as well.

That we can manage many of our patients with diet alone is welcome good news. To be successful with this approach, however, we must be vigilant in monitoring the effectiveness of dietary counseling and identifying early on those patients for whom dietary treatment is not enough.

We also must be more vigilant in detecting GDM, because the maximal time of fetal fat accretion is at about 32-34 weeks' gestation. GDM is typically diagnosed at about 28 weeks' gestation, and patients usually are not engaged in a regime of blood sugar testing and dietary change until about 30-31 weeks. If we wait until 34-35 weeks' gestation to change course with treatment – adding insulin or oral hypoglycemic agents – significant body fat accumulation by the fetus already will have occurred.

Screening for GDM even earlier than currently recommended, at 26 weeks' gestation if possible, and providing dietary counseling as early as possible are worthwhile goals. Our advice is that patients be moved on to a medication regimen if more than one-third of their blood glucose measurements are still abnormal after 2 weeks of dietary change. A more stringent standard may be more prudent, but for now we believe there is enough evidence to warrant this modest change in practice, and we find that it is a rule that most patients can understand.

We also must caution that the effectiveness of dietary change may be significantly less in many populations than it was in Dr. Landon's study because his study focused on a subset of women who had only mild glucose intolerance. In our patient population, for example, we can achieve good glucose control with diet alone in about 60%-70% of cases.

The Science on Glyburide

Pharmacologic therapy for patients in whom dietary measures fail is no longer limited to insulin. Insulin is certainly still an option as a first-line therapy, and is necessary as an adjunct therapy in patients who are not achieving glucose targets with another agent. It has proven efficacy and well-studied pharmacokinetics. It does not cross the placenta, and research has shown that it may be beneficial by “resting” pancreatic islet cells.

Insulin is not an optimal therapy for GDM for several reasons, however. Many patients find it cumbersome to use, and most offices are not equipped for, or used to, teaching women how to give themselves the insulin injections. Insulin itself is also unfamiliar to many patients and can even be scary; some of the families we care for see insulin as a stigma, believing that a person who takes insulin has diabetes while a person who takes a pill does not truly have the condition.

In our practice, we have found that women who take oral hypoglycemics are more likely to have better glycemic control, probably because their drug compliance is better. With insulin, our patients tend to be suboptimally compliant.

Glyburide, one of the oral anti-hyperglycemic drugs that we have been able to transfer from use in the nonpregnant diabetic population to use during pregnancy, has been well used and studied by this point in time.

When Dr. Oded Langer and his colleagues led the first and only randomized trial comparing glyburide and insulin more than a decade ago, women with GDM were rarely treated with a sulfonylurea drug largely because of reports of prolonged severe hypoglycemia in neonates born to mothers who were receiving the drug at the time of delivery. There were also questions about whether glyburide, a second-generation sulfonylurea, could effectively control postprandial peaks in blood glucose while avoiding periods of hypoglycemia in the mother.

In the nonpregnant population, glyburide has been used for decades as a twice-daily oral medication. After months of use, patients develop active metabolites that prolong the drug's half-life and enable it to last for 12 hours, at least.

Glyburide use in pregnancy is a slightly different story, however. Patients take the medication for a relatively short time and consequently may not build up the active metabolites that nonpregnant patients acquire. The metabolic changes in pregnancy also make women vulnerable to hypoglycemia at certain times of the day, typically in the late morning, the late afternoon, and between 3 a.m. and 4 a.m.

Dr. Langer's trial, which randomized 404 women with GDM to receive glyburide or insulin, demonstrated similar outcomes in the insulin and glyburide groups. There were no differences in mean birth weight, the percentage of large for gestational age newborns, macrosomia, fetal anomalies, or newborn hypoglycemia. The rate of maternal hypoglycemia, however, was much higher in the insulin-treated group; 20% of the women receiving insulin experienced symptomatic hypoglycemia, compared with only 2% of the women taking glyburide.

In short, glyburide was just as effective as insulin in achieving desired levels of glycemic control (a fasting blood glucose less than 90 mg/dL and 2-hour postprandial glucose of 120 mg/dL) and controlling fetal obesity, while being significantly less likely to cause hypoglycemia in the mothers. (N. Engl. J. Med. 2000;343:1134-8).

Glyburide dosing in Dr. Langer's trial was increased weekly, as needed, to a maximum of 20 mg per day; women took the drug twice a day. Insulin was administered per a standard intensified schedule of regular NPH (intermediate-acting, lasting 6-12 hours) and regular TID (lasting 2-4 hours).

Despite the impressive findings from the trial, some have contended that the results of one randomized trial are insufficient for adopting glyburide as a first-line therapy. However, numerous retrospective or case-controlled studies also have since shown glyburide to be a clinically effective alternative to insulin therapy, with no adverse neonatal or fetal effects. These studies have shown, moreover, that it can be easier to avoid hypoglycemia and achieve optimal glycemic control with glyburide than with insulin.

One of the best large retrospective studies looked at 584 women at Kaiser Permanente Northern California and found that glyburide was at least as effective as insulin in achieving glycemic control and resulted in similar birth weights in women with GDM who had failed diet therapy alone (Am. J. Obstet. Gynecol. 2005;193:118-24).

Several recent reviews of glyburide studies, such as one that looked at nine glyburide studies covering 745 patients taking glyburide and 645 patients taking insulin, also have been published (Ann. Pharmacother. 2008;42:483-90). In 2007, moreover, the 5th International Workshop-Conference on GDM concluded that glyburide is a legitimate alternative to insulin for GDM (Diabetes Care 2007; 30:S251-60).hWe also now know that unlike other, first-generation sulfonylureas that tend to cross the placenta freely, glyburide is 99.8% protein-bound and thus crosses the placenta only minimally.

Theoretically, there is one potential problem with glyburide. Because the drug acts by stimulating maternal pancreatic insulin production, it could potentially promote “pancreatic burnout,” thus shortening the time to development of overt diabetes in women whose pancreas is struggling to begin with. Women who are obese and have significant insulin resistance at the start of their pregnancies thus might be susceptible to pancreatic burnout. Although this potential effect has not been demonstrated in any trials, it must be kept in mind.

It would be informative to conduct long-term follow-up studies that track the children of mothers who used glyburide during their pregnancies, but at this point it is unclear if such studies will be designed and carried out. The likelihood of additional randomized trials being conducted is practically nil, given the extent to which women already are choosing the oral hypoglycemics over insulin.

Glyburide in Practice

As clinicians, we must appreciate that the pharmacodynamics of glyburide are quite different in pregnant women, with important dosing implications for our patients. Indeed, for pregnant women, glyburide is not the 12-hour medication that it is in nonpregnant women.

During pregnancy, glyburide action peaks about 2.5 hours after it's taken, and the increased renal clearance and metabolism of pregnancy (in addition to the short duration of therapy in this patient population) leave the drug with a “useful” life of only about 6-8 hours.

Because blood glucose peaks 60-90 minutes after a meal, we instruct our patients to take a glyburide dose a full hour before a planned meal. Otherwise, postprandial glucose peaks will not be controlled. Usually, a dose taken an hour before breakfast will help control postprandial peaks after breakfast and lunch but will not last for dinner. Another dose 1 hour before an evening meal can be given.

To effectively control fasting blood glucose, we instruct patients to take a glyburide dose between 10 p.m. and midnight so that the drug will still be active in the early morning when it is needed. If the dose is taken too early at night – at 8-9 p.m., for instance – it will peak between 10 p.m. and midnight, and will not be working at 6 a.m.

As it is with insulin, careful glucose monitoring is critical for determining optimal administration of glyburide and for balancing glyburide action with meals and snacks. Individual glycemic profiles should be analyzed each week, with the goal of keeping fasting blood glucose below 90 mg/dL, and postprandial levels below 130 mg/dL, while preventing maternal hypoglycemia.

Attention must be paid not only to times of consistent elevation in blood glucose levels, but also to the potential for dosage overlap – for instance, a prelunch dosage administered to correct consistently high postprandial glucose levels after the mid-day meal could lead to low blood glucose levels at about 4-5 p.m. as its action overlaps with the end duration of a morning dose. Patients should always be prepared for vulnerable times and have a glucose tablet, juice box, or food with them to correct any periods of hypoglycemia.

Insulin should be added if more than 30% of blood glucose readings are above target with administration of 15-20 mg/day of glyburide.

Metformin as an Option

As ob.gyns, our experience with metformin, the other oral anti-hyperglycemic agent now available for treating GDM, came originally from its use as an infertility treatment in women with polycystic ovary syndrome (PCOS).

Metformin is frequently prescribed for women with PCOS to improve ovulation. These women have significant insulin resistance and are at high risk for developing GDM during their pregnancies. The main concern in this population, however, has been infertility, and studies have shown that metformin induces ovulation in women with PCOS.

Although metformin crosses the placenta, numerous studies have shown no increase in birth anomalies in women who conceive while taking the agent.

A study published a decade ago in women who chose whether or not to continue metformin treatment throughout their pregnancies showed that of those who discontinued metformin, 31% developed GDM, compared with only 3% of those who continued their metformin treatment (Fertil. Steril. 2002;77:520-5). These results helped fuel the idea that the agent may be a logical treatment for women with GDM.

Metformin also has a theoretical advantage over glyburide since its mechanism of action gets directly to the root of the problem of GDM. Metformin is an insulin sensitizer, and the root cause of GDM is resistance to insulin, or insulin insensitivity, at the tissue level.

In a study by Dr. J.A. Rowan published in 2008 that randomized more than 700 patients to either insulin or metformin, there were no appreciable differences in neonatal and maternal outcomes – from birth weight and neonatal morbidity to maternal hypoglycemia and glycemic control (N. Engl J. Med. 2008;358:2003-15). However, whereas 4% of the glyburide group in Dr. Langer's trial had to eventually add insulin (and up to 10%-20% in other studies), 47% of the patients taking metformin in this trial had to add insulin to maintain glycemic control.

Indeed, the downside to metformin, this and other studies have shown, is a high so-called failure rate – the need for supplementary insulin, which in this case typically occurs later in the pregnancy – of between 30% and 50%. On the other hand, patients generally will be more satisfied starting treatment with metformin than insulin. In weighing glyburide and metformin, patients should be counseled about their chances of needing insulin later in the pregnancy: about 10% with glyburide and closer to 50% with metformin.

In terms of glycemic control and other outcomes, several smaller, recent studies comparing the two agents have shown no statistical difference between them. Interestingly, most studies have shown less maternal weight gain in patients taking metformin than glyburide – about 6 pounds – but the significance of this difference is unclear since the babies' birth weights were not appreciably different.

Source Elsevier Global Medical News

GDM and the Developing Fetus

obnews@elsevier.com

A growing body of research has convincingly demonstrated that even periods of mild hyperglycemia during pregnancy can have long-term adverse consequences on the developing fetus. Therefore, there is a growing sentiment in the ob.gyn. and diabetes communities for an aggressive approach to the detection, treatment, and monitoring of the most frequent causes of hyperglycemic events during pregnancy. Significant controversies remain on how best to implement this approach.

In the area of gestational diabetes mellitus (GDM) treatment, multiple controversies exist regarding whether to manage GDM very aggressively (i.e., with insulin as the first line of therapy) or with less aggressive approaches first, followed by insulin as a last resort. The former approach, while likely to be effective in controlling hyperglycemia, is viewed by many physicians – and their patients – as not acceptable given that GDM is a relatively mild form of diabetes and most cases will resolve spontaneously after pregnancy.

In this month's Master Class, Dr. Thomas R. Moore, professor and chairman of the department of reproductive medicine at the University of California, San Diego, returns to provide us with a superbly written essay on the state of the evidence in managing GDM. Dr. Moore's Master Class briefly discusses the growing prevalence of GDM in the United States and worldwide, as well as the scientific evidence linking intrauterine hyperglycemia with adverse pregnancy outcomes. He then provides a detailed analysis of the best available science on trials of dietary approaches to GDM as well as trials on oral antihyperglycemic drugs and how they compare with one another and with insulin.

Dr. Moore also demonstrates how this knowledge is being applied to his own patients as well as how they've been able to adapt, accept, and comply with this relatively new approach to managing GDM. Once again, we are honored that Dr. Moore has agreed serve as the Master Class guest professor, providing important insights into how GDM might be managed optimally.

Key Points

▸ Prenatal exposure to hyperglycemia programs the fetus for a higher risk of being born overweight, of becoming obese in adolescence or adulthood, and of developing diabetes later in life. Two randomized trials have demonstrated the positive impact of treating even mild forms of GDM.

▸ Many patients can be managed with diet alone, but the effectiveness of dietary treatment must be carefully monitored, with insulin or oral antihyperglycemic agents added early – before significant body fat is accumulated by the fetus.

▸ Glyburide is just as effective as insulin in achieving optimal glycemic control and is significantly less likely to cause hypoglycemia in mothers, with no adverse neonatal or fetal effects, numerous studies have shown. Glyburide is not a 12-hour medication in pregnant women as it is in nonpregnant women, however. Ob.gyns must appreciate the dosing implications of the agent's different pharmacodynamics in pregnancy.

▸ Metformin also has equivalent efficacy to insulin, and several small recent studies have shown no significant difference with glyburide. Metformin has a theoretical advantage over glyburide in that it's an insulin sensitizer, but the downside is a higher chance of needing supplementary insulin later in pregnancy. Patients can be counseled accordingly.

We now know that gestational diabetes mellitus is a serious condition that, if not properly diagnosed and managed, can have cyclic, intergenerational consequences. Newborns exposed to maternal hyperglycemia during pregnancy have a high risk of being born overweight and of eventually becoming obese children and adults. These newborns also are at a high risk of developing diabetes themselves later in life.

The prevalence of gestational diabetes mellitus (GDM) is increasing in every ethnic group. In the Kaiser Permanente system in Colorado, a state which has traditionally had the lowest obesity rate of any state in the United States, the prevalence of GDM doubled from 1994 to 2002, with significant increases in all racial/ethnic groups (Diabetes Care 2005;28:579-84). Such increases in GDM prevalence are happening worldwide – one part of a worldwide epidemic of obesity and diabetes that is overtaking our youth.

We've learned that GDM is one sign post on the way to the development of overt type 2 diabetes. Indeed, a majority of women with GDM will acquire diabetes within 5 years.

In the last decade or so, our clinical research focus has centered on the in utero risks to the fetus. In a striking study of the potential impact of intrauterine hyperglycemia exposure on later development, Dr. D. Dabelea and coinvestigators compared siblings in the Pima Indian population who were born before and after their mothers were diagnosed with diabetes. The children who were born after their mothers had developed diabetes had almost double the rate of obesity as adolescents than their siblings who were born before their mother's diagnosis of diabetes. Even though these siblings ate the same diet and came from the same gene pools (with the same fathers), they experienced dramatically different health outcomes in adolescence as a result of the differing intrauterine environments (Diabetes 2000;49:2208-11).

This and other studies have given us a body of supplementary science showing that exposure to high blood glucose in utero causes accumulation of fat in the fetus. Even though that baby fat might be lost in early childhood, prenatal exposure nevertheless genetically programs the fetus for a higher risk of developing fatness as an adult.

As I detailed in the last Master Class in obstetrics (see Ob.Gyn News, July 2011, pp. 24–25), we now also have evidence from two randomized controlled trials that interventions to control blood glucose are effective in reducing rates of newborn obesity and therefore should improve adolescent and adult health downstream.

The two randomized trials – the Australian Carbohydrate Intolerance Study in Pregnant Women (N. Engl. J. Med. 2005;352:2477-86) and a study published several years later by Dr. Mark B. Landon and his colleagues (N. Engl. J. Med. 2009; 361:1339-48) – demonstrated the positive impact of treating even mild forms of GDM, with the largest effects being on reducing newborn obesity. Although the offspring of mothers who were treated and not treated in those studies have not yet been followed into adulthood, it seems fair to expect that the children of mothers who were treated for GDM will have significantly better health profiles downstream.

Treating GDM, and learning how to maximize glucose control, has thus moved to center stage in obstetric practice.

Trials of Dietary Change

In Dr. Landon's landmark study, more than 90% of the women randomized to the treatment group (versus usual prenatal care) needed only dietary counseling and education about blood glucose control for effective treatment of abnormal blood glucose levels. Surprisingly, fewer than 10% needed insulin as well.

That we can manage many of our patients with diet alone is welcome good news. To be successful with this approach, however, we must be vigilant in monitoring the effectiveness of dietary counseling and identifying early on those patients for whom dietary treatment is not enough.

We also must be more vigilant in detecting GDM, because the maximal time of fetal fat accretion is at about 32-34 weeks' gestation. GDM is typically diagnosed at about 28 weeks' gestation, and patients usually are not engaged in a regime of blood sugar testing and dietary change until about 30-31 weeks. If we wait until 34-35 weeks' gestation to change course with treatment – adding insulin or oral hypoglycemic agents – significant body fat accumulation by the fetus already will have occurred.

Screening for GDM even earlier than currently recommended, at 26 weeks' gestation if possible, and providing dietary counseling as early as possible are worthwhile goals. Our advice is that patients be moved on to a medication regimen if more than one-third of their blood glucose measurements are still abnormal after 2 weeks of dietary change. A more stringent standard may be more prudent, but for now we believe there is enough evidence to warrant this modest change in practice, and we find that it is a rule that most patients can understand.

We also must caution that the effectiveness of dietary change may be significantly less in many populations than it was in Dr. Landon's study because his study focused on a subset of women who had only mild glucose intolerance. In our patient population, for example, we can achieve good glucose control with diet alone in about 60%-70% of cases.

The Science on Glyburide

Pharmacologic therapy for patients in whom dietary measures fail is no longer limited to insulin. Insulin is certainly still an option as a first-line therapy, and is necessary as an adjunct therapy in patients who are not achieving glucose targets with another agent. It has proven efficacy and well-studied pharmacokinetics. It does not cross the placenta, and research has shown that it may be beneficial by “resting” pancreatic islet cells.

Insulin is not an optimal therapy for GDM for several reasons, however. Many patients find it cumbersome to use, and most offices are not equipped for, or used to, teaching women how to give themselves the insulin injections. Insulin itself is also unfamiliar to many patients and can even be scary; some of the families we care for see insulin as a stigma, believing that a person who takes insulin has diabetes while a person who takes a pill does not truly have the condition.

In our practice, we have found that women who take oral hypoglycemics are more likely to have better glycemic control, probably because their drug compliance is better. With insulin, our patients tend to be suboptimally compliant.

Glyburide, one of the oral anti-hyperglycemic drugs that we have been able to transfer from use in the nonpregnant diabetic population to use during pregnancy, has been well used and studied by this point in time.

When Dr. Oded Langer and his colleagues led the first and only randomized trial comparing glyburide and insulin more than a decade ago, women with GDM were rarely treated with a sulfonylurea drug largely because of reports of prolonged severe hypoglycemia in neonates born to mothers who were receiving the drug at the time of delivery. There were also questions about whether glyburide, a second-generation sulfonylurea, could effectively control postprandial peaks in blood glucose while avoiding periods of hypoglycemia in the mother.

In the nonpregnant population, glyburide has been used for decades as a twice-daily oral medication. After months of use, patients develop active metabolites that prolong the drug's half-life and enable it to last for 12 hours, at least.

Glyburide use in pregnancy is a slightly different story, however. Patients take the medication for a relatively short time and consequently may not build up the active metabolites that nonpregnant patients acquire. The metabolic changes in pregnancy also make women vulnerable to hypoglycemia at certain times of the day, typically in the late morning, the late afternoon, and between 3 a.m. and 4 a.m.

Dr. Langer's trial, which randomized 404 women with GDM to receive glyburide or insulin, demonstrated similar outcomes in the insulin and glyburide groups. There were no differences in mean birth weight, the percentage of large for gestational age newborns, macrosomia, fetal anomalies, or newborn hypoglycemia. The rate of maternal hypoglycemia, however, was much higher in the insulin-treated group; 20% of the women receiving insulin experienced symptomatic hypoglycemia, compared with only 2% of the women taking glyburide.

In short, glyburide was just as effective as insulin in achieving desired levels of glycemic control (a fasting blood glucose less than 90 mg/dL and 2-hour postprandial glucose of 120 mg/dL) and controlling fetal obesity, while being significantly less likely to cause hypoglycemia in the mothers. (N. Engl. J. Med. 2000;343:1134-8).

Glyburide dosing in Dr. Langer's trial was increased weekly, as needed, to a maximum of 20 mg per day; women took the drug twice a day. Insulin was administered per a standard intensified schedule of regular NPH (intermediate-acting, lasting 6-12 hours) and regular TID (lasting 2-4 hours).

Despite the impressive findings from the trial, some have contended that the results of one randomized trial are insufficient for adopting glyburide as a first-line therapy. However, numerous retrospective or case-controlled studies also have since shown glyburide to be a clinically effective alternative to insulin therapy, with no adverse neonatal or fetal effects. These studies have shown, moreover, that it can be easier to avoid hypoglycemia and achieve optimal glycemic control with glyburide than with insulin.

One of the best large retrospective studies looked at 584 women at Kaiser Permanente Northern California and found that glyburide was at least as effective as insulin in achieving glycemic control and resulted in similar birth weights in women with GDM who had failed diet therapy alone (Am. J. Obstet. Gynecol. 2005;193:118-24).

Several recent reviews of glyburide studies, such as one that looked at nine glyburide studies covering 745 patients taking glyburide and 645 patients taking insulin, also have been published (Ann. Pharmacother. 2008;42:483-90). In 2007, moreover, the 5th International Workshop-Conference on GDM concluded that glyburide is a legitimate alternative to insulin for GDM (Diabetes Care 2007; 30:S251-60).hWe also now know that unlike other, first-generation sulfonylureas that tend to cross the placenta freely, glyburide is 99.8% protein-bound and thus crosses the placenta only minimally.

Theoretically, there is one potential problem with glyburide. Because the drug acts by stimulating maternal pancreatic insulin production, it could potentially promote “pancreatic burnout,” thus shortening the time to development of overt diabetes in women whose pancreas is struggling to begin with. Women who are obese and have significant insulin resistance at the start of their pregnancies thus might be susceptible to pancreatic burnout. Although this potential effect has not been demonstrated in any trials, it must be kept in mind.

It would be informative to conduct long-term follow-up studies that track the children of mothers who used glyburide during their pregnancies, but at this point it is unclear if such studies will be designed and carried out. The likelihood of additional randomized trials being conducted is practically nil, given the extent to which women already are choosing the oral hypoglycemics over insulin.

Glyburide in Practice

As clinicians, we must appreciate that the pharmacodynamics of glyburide are quite different in pregnant women, with important dosing implications for our patients. Indeed, for pregnant women, glyburide is not the 12-hour medication that it is in nonpregnant women.

During pregnancy, glyburide action peaks about 2.5 hours after it's taken, and the increased renal clearance and metabolism of pregnancy (in addition to the short duration of therapy in this patient population) leave the drug with a “useful” life of only about 6-8 hours.

Because blood glucose peaks 60-90 minutes after a meal, we instruct our patients to take a glyburide dose a full hour before a planned meal. Otherwise, postprandial glucose peaks will not be controlled. Usually, a dose taken an hour before breakfast will help control postprandial peaks after breakfast and lunch but will not last for dinner. Another dose 1 hour before an evening meal can be given.

To effectively control fasting blood glucose, we instruct patients to take a glyburide dose between 10 p.m. and midnight so that the drug will still be active in the early morning when it is needed. If the dose is taken too early at night – at 8-9 p.m., for instance – it will peak between 10 p.m. and midnight, and will not be working at 6 a.m.

As it is with insulin, careful glucose monitoring is critical for determining optimal administration of glyburide and for balancing glyburide action with meals and snacks. Individual glycemic profiles should be analyzed each week, with the goal of keeping fasting blood glucose below 90 mg/dL, and postprandial levels below 130 mg/dL, while preventing maternal hypoglycemia.

Attention must be paid not only to times of consistent elevation in blood glucose levels, but also to the potential for dosage overlap – for instance, a prelunch dosage administered to correct consistently high postprandial glucose levels after the mid-day meal could lead to low blood glucose levels at about 4-5 p.m. as its action overlaps with the end duration of a morning dose. Patients should always be prepared for vulnerable times and have a glucose tablet, juice box, or food with them to correct any periods of hypoglycemia.

Insulin should be added if more than 30% of blood glucose readings are above target with administration of 15-20 mg/day of glyburide.

Metformin as an Option

As ob.gyns, our experience with metformin, the other oral anti-hyperglycemic agent now available for treating GDM, came originally from its use as an infertility treatment in women with polycystic ovary syndrome (PCOS).

Metformin is frequently prescribed for women with PCOS to improve ovulation. These women have significant insulin resistance and are at high risk for developing GDM during their pregnancies. The main concern in this population, however, has been infertility, and studies have shown that metformin induces ovulation in women with PCOS.

Although metformin crosses the placenta, numerous studies have shown no increase in birth anomalies in women who conceive while taking the agent.

A study published a decade ago in women who chose whether or not to continue metformin treatment throughout their pregnancies showed that of those who discontinued metformin, 31% developed GDM, compared with only 3% of those who continued their metformin treatment (Fertil. Steril. 2002;77:520-5). These results helped fuel the idea that the agent may be a logical treatment for women with GDM.

Metformin also has a theoretical advantage over glyburide since its mechanism of action gets directly to the root of the problem of GDM. Metformin is an insulin sensitizer, and the root cause of GDM is resistance to insulin, or insulin insensitivity, at the tissue level.

In a study by Dr. J.A. Rowan published in 2008 that randomized more than 700 patients to either insulin or metformin, there were no appreciable differences in neonatal and maternal outcomes – from birth weight and neonatal morbidity to maternal hypoglycemia and glycemic control (N. Engl J. Med. 2008;358:2003-15). However, whereas 4% of the glyburide group in Dr. Langer's trial had to eventually add insulin (and up to 10%-20% in other studies), 47% of the patients taking metformin in this trial had to add insulin to maintain glycemic control.

Indeed, the downside to metformin, this and other studies have shown, is a high so-called failure rate – the need for supplementary insulin, which in this case typically occurs later in the pregnancy – of between 30% and 50%. On the other hand, patients generally will be more satisfied starting treatment with metformin than insulin. In weighing glyburide and metformin, patients should be counseled about their chances of needing insulin later in the pregnancy: about 10% with glyburide and closer to 50% with metformin.

In terms of glycemic control and other outcomes, several smaller, recent studies comparing the two agents have shown no statistical difference between them. Interestingly, most studies have shown less maternal weight gain in patients taking metformin than glyburide – about 6 pounds – but the significance of this difference is unclear since the babies' birth weights were not appreciably different.

Source Elsevier Global Medical News

GDM and the Developing Fetus

obnews@elsevier.com

A growing body of research has convincingly demonstrated that even periods of mild hyperglycemia during pregnancy can have long-term adverse consequences on the developing fetus. Therefore, there is a growing sentiment in the ob.gyn. and diabetes communities for an aggressive approach to the detection, treatment, and monitoring of the most frequent causes of hyperglycemic events during pregnancy. Significant controversies remain on how best to implement this approach.

In the area of gestational diabetes mellitus (GDM) treatment, multiple controversies exist regarding whether to manage GDM very aggressively (i.e., with insulin as the first line of therapy) or with less aggressive approaches first, followed by insulin as a last resort. The former approach, while likely to be effective in controlling hyperglycemia, is viewed by many physicians – and their patients – as not acceptable given that GDM is a relatively mild form of diabetes and most cases will resolve spontaneously after pregnancy.

In this month's Master Class, Dr. Thomas R. Moore, professor and chairman of the department of reproductive medicine at the University of California, San Diego, returns to provide us with a superbly written essay on the state of the evidence in managing GDM. Dr. Moore's Master Class briefly discusses the growing prevalence of GDM in the United States and worldwide, as well as the scientific evidence linking intrauterine hyperglycemia with adverse pregnancy outcomes. He then provides a detailed analysis of the best available science on trials of dietary approaches to GDM as well as trials on oral antihyperglycemic drugs and how they compare with one another and with insulin.

Dr. Moore also demonstrates how this knowledge is being applied to his own patients as well as how they've been able to adapt, accept, and comply with this relatively new approach to managing GDM. Once again, we are honored that Dr. Moore has agreed serve as the Master Class guest professor, providing important insights into how GDM might be managed optimally.

Key Points

▸ Prenatal exposure to hyperglycemia programs the fetus for a higher risk of being born overweight, of becoming obese in adolescence or adulthood, and of developing diabetes later in life. Two randomized trials have demonstrated the positive impact of treating even mild forms of GDM.

▸ Many patients can be managed with diet alone, but the effectiveness of dietary treatment must be carefully monitored, with insulin or oral antihyperglycemic agents added early – before significant body fat is accumulated by the fetus.

▸ Glyburide is just as effective as insulin in achieving optimal glycemic control and is significantly less likely to cause hypoglycemia in mothers, with no adverse neonatal or fetal effects, numerous studies have shown. Glyburide is not a 12-hour medication in pregnant women as it is in nonpregnant women, however. Ob.gyns must appreciate the dosing implications of the agent's different pharmacodynamics in pregnancy.

▸ Metformin also has equivalent efficacy to insulin, and several small recent studies have shown no significant difference with glyburide. Metformin has a theoretical advantage over glyburide in that it's an insulin sensitizer, but the downside is a higher chance of needing supplementary insulin later in pregnancy. Patients can be counseled accordingly.

The tide has turned in our understanding of both the effects of maternal hyperglycemia and the effectiveness of current treatment approaches. Consequently, we are facing an impending sea change in the way in which gestational diabetes is diagnosed and managed.

Recent research has detailed the risks posed to a fetus exposed to hyperglycemia during pregnancy – even at levels that in the past have been considered mild and, thus, largely inconsequential. We also now have evidence that we can offer therapies for gestational diabetes mellitus (GDM) with confidence that we can use them to change the outcome for the fetus, the newborn, the child, and possibly the adult.

This impending change comes after decades of diagnosing gestational diabetes based largely on relatively arbitrary thresholds. Dr. John B. O'sullivan and statistician Claire Mahan developed the diagnostic criteria more than 40 years ago based on certain statistical phenomena associated with the development of adult-onset diabetes after pregnancy. Before then, during the 1940s, 1950s, and 1960s, 1%-2% of all pregnant women were diagnosed with GDM.

In recent years, many of us have had the experience as clinicians of delivering larger, more obese babies whose mothers had been found to have “normal” blood glucose levels. Many of us also have delivered babies with significant adiposity, sometimes perilously low blood glucose, shoulder dystocia, nerve injuries, and other complications that typically occur as a consequence of fetal overgrowth.

We often attribute these complications to a diagnostic method we have known for some time wasn't perfect, but until recently, we did not have the clinical research findings to guide us in our efforts to fine-tune the diagnosis of GDM and turn the tide.

Insights on Fetal Risk

The landmark Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study, led by Dr. Boyd E. Metzger, was an attempt to clarify what level of maternal glucose intolerance is associated with an excess risk of an adverse pregnancy outcome.

The HAPO study, which involved 15 centers in nine countries, examined the outcomes of more than 25,000 pregnancies. In designing the HAPO study, Dr. Metzger and his colleagues did something that had never formally been done before: They administered a 75-g oral glucose tolerance test (OGTT) to the mothers between 24 and 32 weeks' gestation (as close to 28 weeks as possible), and defined GDM as an abnormal 2-hour 75-g OGTT result. They then followed the births of women identified as having GDM, and compared them with the births of mothers who did not have gestational diabetes as defined by traditional measures.

Outside the United States, the 75-g, one-step OGTT has been the standard for GDM diagnosis for some time. In the United States, many of us still use an awkward two-step system in which women initially are given a 50-g oral challenge. Only if they register an excessive value on the 50-g challenge do they come back for a definitive 3-hour, 100-g OGTT.

Quite a few outcomes were measured in the HAPO study, but the major outcomes were birth weight greater than the 90th percentile, the level of cord-blood serum-C-peptide (an index of fetal beta-cell function and fetal hyperinsulinemia) above the 90th percentile, and percent body fat greater than the 90th percentile.

The glucose results of the majority of women remained blinded (data were not blinded if the 2-hour plasma glucose level was greater than 200 mg/dL, or diagnostic of diabetes, or if the fasting plasma glucose level exceeded 105 mg/dL or the random plasma glucose level was 160 mg/dL). After birth and the assessment of fetal outcomes, these outcomes were arrayed against earlier results of the mothers' 2-hour 75-g glucose challenge tests and the fasting blood glucose levels, both of which were measured at the same time during pregnancy. (Fasting plasma glucose levels varied from as little as 75 mg/dL all the way up to the predefined threshold of 100 mg/dL.)

Considering percent of body fat greater than the 90th percentile, one would expect no more than 10% of babies without diagnosed GDM in the mothers to have hyperinsulinemia and large amounts of body fat.

Dr. Metzger found otherwise: 17% of babies whose mothers had a fasting blood glucose of 90 mg/dL, for instance – a level most clinicians have viewed as normal – had large levels of body fat, and many of these babies also had hyperinsulinemia. Overall, there was no “golden” level of maternal glucose that predicted a fat baby. However, neonatal adiposity increased progressively as fasting blood glucose levels rose above 80 mg/dL.

In the case of 1-hour 75-g OGTT results, fatness increased progressively at levels greater than 105 mg/dL, and with 2-hour results, fatness rose progressively at levels over 90 mg/dL (Diabetes 2009;58:453–9).

Such continuous linear relationships between maternal glucose and adverse fetal outcomes were seen studywide for birth weight and other outcomes (N. Engl. J. Med. 2008;358:1991–2002).

Among the most striking findings was that a significant number of fat babies were born to women whose blood glucose levels were considered “normal.”

The question at this point became, What should we do about it? Should we allow these obese babies to be born without any intervention, or can we treat them before birth?

Insights on Treatment

Many experts have been doubtful that treatment of mothers with GDM would be effective in altering newborn outcomes. However, the Australian Carbohydrate Intolerance Study in Pregnant Women, published in 2005, concluded that early treatment of GDM reduces serious perinatal morbidity and may improve health-related quality of life. In this study, women with GDM were randomized to receive dietary advice, blood glucose monitoring, and insulin therapy as needed (the treatment group), or routine care (N. Engl. J. Med. 2005;352:2477–86).

In another randomized study published several years later, Dr. Mark B. Landon and his colleagues finally convinced many experts of the value of aggressive screening and early intervention for GDM. Dr. Landon focused on a subset of women who had an abnormal result on a 3-hour 100-g OGTT but a fasting glucose level below 95 mg/L. These women thus had only mild glucose intolerance. (An abnormal result was defined as two or three timed glucose measurements that exceeded certain thresholds: 1-hour, 180 mg/dL; 2-hour, 155 mg/dL; and 3-hour, 140 mg/dL.)

In 14 centers across the United States, 958 patients were randomized to receive treatment of their diabetes or nothing but usual prenatal care. Treatment included formal nutritional counseling and diet therapy, along with insulin if needed. The majority of the women (93%) needed only dietary counseling and education about blood glucose control, while the other 7% needed insulin as well.

Women receiving dietary counseling checked their blood glucose levels before they got up in the morning, and 2 hours after each major meal. In essence, they planned and adjusted their diet based on their blood glucose readings.

What did we learn from this trial? We learned that the incidence of large-for-gestational-age births (greater than the 90th percentile) was cut in half from approximately 14% in the untreated group to 7% in the treated group. There also was a 10%-14% reduction in fat mass in the babies born to the women who received treatment, as well as significant reductions in mean birth weight and birth weight greater than 4,000 g. Most importantly, treatment also reduced the number of injuries that occurred during birth, while the number of small-for-gestational-age infants did not increase (N. Engl. J. Med. 2009;361:1339–48).

With these two randomized studies demonstrating significantly reduced risks with early GDM treatment, the question shifted from the broader issue of whether it is worthwhile to treat women with GDM to the more specific question of who needs treatment the most.

A New Approach

Today, in most demographic and ethnic groups in the United States, the incidence of gestational diabetes is between 4% and 12%, with a national incidence of about 8%. These are the patients we are already treating.

The HAPO trial, however, has shown us that there are a significant number of babies whose mothers have mild hyperglycemia and who are not being treated for this condition. These babies have neonatal adiposity and subsequently are being injured during the birth process.

In addition, we now have multiple epidemiologic studies demonstrating that adiposity at birth markedly increases – by as much as 30%–40% – the risk of being fat as a child and as an adolescent. Studies also have shown that the risk of developing childhood and adolescent type 2 diabetes proportionately increases with increasing neonatal adiposity.

Thus, the goal is no longer just to prevent neonatal adiposity so that babies will not be injured during birth; it now includes helping mothers control their glucose profiles so that their babies will have better health during their childhood and adult years.

However, the answer to the current, pressing question of whether we should offer treatment to women who are not now defined as having gestational diabetes is not yet clearly answered.

In 2008, after the initial release of HAPO study findings, a group called the International Association of Diabetes and Pregnancy Study Groups (IADPSG) was created to discuss the definition of gestational diabetes in light of the new HAPO findings and other research demonstrating improved outcomes with treatment.

In 2010, the consensus group released revised recommendations for glucose tolerance testing, suggesting that everyone convert to the 2-hour 75-g OGTT and that we lower the cutoff points used for diagnosis to protect as many babies as possible from becoming obese.

The group deliberated how much risk to address, or cover, with new cut points. Is a 150% increase in risk, for example, too much? Or a doubling of newborn fatness? In looking at a possible lifetime of obesity, type 2 diabetes, and heart disease, how much testing and treatment is just right? In the end, the group chose cutoff points for the fasting, 1-hour, and 2-hour plasma glucose measurements that conveyed an odds ratio for adverse outcomes of at least 1.75.

This means that a fasting plasma glucose of 92 mg/dL or more almost doubles the adverse fetal outcome risk; so does a 1-hour value after the 75-g OGTT of at least 180 mg/dL, and a 2-hour value of at least 153 mg/dL. If any one of these values is elevated, according to the IADPSG, a fetus is at risk and the mother should be treated for hyperglycemia (Diabetes Care 2010;33:676–82).

The Near Future

With the new criteria proposed by the IADPSG, the number of women who will be defined as having GDM using the 75-g OGTT will double to approximately 16%, compared with about 8% today. This doubling of incidence obviously will require additional resources and intervention.

The question now is, Are we going to adopt these new criteria? The practice approach for GDM in the United States normally follows guidelines for diabetes put forth by the American Diabetes Association and/or guidelines for pregnancy developed by the American College of Obstetricians and Gynecologists. Although the ADA has revised its recommendations for diagnosis of GDM to embrace the criteria of IADPSG, neither body has issued a directive or a formal set of guidelines for clinicians.

The National Institute of Child Health and Human Development is planning a workshop on GDM for next year, and it is quite possible that the proceedings from this NICHD workshop will inform future statements or guidelines from these organizations. In all likelihood, new screening criteria will be widely adopted within several years.

In the meantime, providers must decide what to do. There is nothing wrong with continuing two-stage testing. However, those who do should realistically consider its disadvantages: For one, this process identifies only 80%–90% of the women who actually have abnormal glucose levels, so many at-risk newborns will be missed even though their mothers were tested.

Secondly, the timing of the two-step process is problematic. Most women are given lab orders for the OGTT at about 28 weeks' gestation. By 29 or 30 weeks, they'll have results. If abnormal, the office staff must call and tell the patient to schedule the second OGTT test. Our own studies have shown that each step takes about 7–12 days to complete. In our system, it can then take up to 10 days for a woman diagnosed with GDM to receive care. She will be instructed in glucose monitoring and her care team will check with her every week.

In the end, it may be 6–8 weeks after initial testing before the woman's glucose intolerance is effectively addressed. The maximal time of fetal fat accretion is at about 34 weeks. If we do not have a diagnosis made and treatment plan underway by 32 weeks, we will have significantly decreased our chance of preventing obesity in her newborn.

Aggressive efforts to get screening done at about 26 weeks would be worthwhile, especially if you are working within a system that can accommodate a greater number of women with identified glucose intolerance. To ensure the outcomes that we're seeking, we must ensure that our patients receive adequate dietary and other interventions.

There also are questions about whether the identification of more women at risk of an adverse pregnancy outcome could itself create risk, particularly since it is well documented that women with GDM are more likely to be delivered earlier or through cesarean section, regardless of the level of achieved glucose control. (In the Landon study, interestingly, the rate of cesarean delivery was reduced in the intervention group.)

On the other hand, wider identification offers such hope for reducing fetal adiposity, and its many adverse consequences, that it should be immediately considered.

'Old' (Current) vs. 'New' (Upcoming)

Two-Step Approach to GDM Dx:

▸ Initial screening with a 50-g glucose challenge test at 24–28 weeks' gestation in women at greater than low risk of GDM. Women at very high risk should be screened as soon as possible after confirmation of pregnancy.

▸ Diagnostic 100-g oral glucose tolerance test (on separate day, after overnight fast) in women who meet or exceed chosen threshold on 50-g screening (140 mg/dL or more, or 130 mg/dL or more for higher sensitivity).

▸ GDM diagnosis made if at least two of these plasma glucose values are met or exceeded after the 100-g OGTT: fasting, 95 mg/dL; 1 hour, 180 mg/dL; 2 hour, 155 mg/dL; 3 hour, 140 mg/dL (if a 3-hour test is done).

One-Step Approach to GDM Dx:

▸ Screening of all women at 24–28 weeks' gestation not known to have type 2 diabetes with 75-g oral glucose tolerance test (after overnight fast).

▸ GDM diagnosis made if any one of these fasting plasma glucose values are met or exceeded: fasting, 92 mg/dL; 1 hour, 180 mg/dL; 2 hour, 153 mg/dL.

Sources: American Diabetes Association's Standards of Medical Care in Diabetes 2010 (Diabetes Care 2010;33:S11–61); American College of Obstetricians and Gynecologists Practice Bulletin, September 2001; ADA's Standards of Medical Care in Diabetes 2011 (Diabetes Care 2011;34:S11–61).

The Consequences of GDM

obnews@elsevier.com

The thresholds for deciding when to begin treating hyperglycemia were established almost 50 years ago at a time when we had significantly less knowledge about the risk factors for and consequences of hyperglycemia in pregnancy. Because of this lack of understanding about the causes and consequences of hyperglycemia and our sometimes rigid adherence to these cutoffs, many women were not treated who should have been.

There is a growing recognition in the research and clinical communities that gestational diabetes mellitus (GDM) is a much more serious condition than had been previously believed even a decade ago. We now know that GDM, if not properly diagnosed and managed, can have intergenerational consequences in terms of propagating risks for obesity, diabetes, heart disease, and other disorders. Furthermore, there is a new and growing realization that even mild hyperglycemia significantly below what has traditionally been defined as diabetes can have significant adverse consequences for both mother and infant.

Perhaps the most significant complication of maternal hyperglycemia faced by ob.gyns. is the growing number of large-for-gestational-age (LGA) infants being born. For obvious reasons, LGA infants are more difficult to deliver and significantly more prone to experiencing shoulder dystocia and other injuries during normal or cesarean delivery, and cesarean delivery has its own set of complications for both baby and mother.

The large, multicenter Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study recently documented that by managing hyperglycemia – even among women who previously had not been considered to have any glucose control problems – the incidence of LGA-related problems and other adverse birth outcomes could be significantly reduced.

To discuss in detail the findings of the HAPO study and its potential clinical implications, we have invited Dr. Thomas R. Moore, professor and chairman of the department of reproductive medicine at the University of California, San Diego, to write this Master Class.

Dr. Moore's essay discusses both the unique design and findings of the HAPO study, and also explores the quandary faced by members of the International Association of Diabetes and Pregnancy Study Groups (IADPSG) in their attempts to translate HAPO's findings into clinically useful recommendations and guidelines.

In a sign of how complex and time consuming it can be to translate clinical research findings into clinical practice, the recommendations of the IADPSG are now being debated among research and medical societies, with some suggesting that the thresholds introduced by the HAPO study and advanced by the IADPSG are not significantly different from the current levels.

We greatly appreciate Dr. Moore's insights into these complicated but exciting developments. His Master Class installment will help all of us to better understand this complex issue so that we can potentially play a role in speeding up the process of changing the way we manage GDM.

The tide has turned in our understanding of both the effects of maternal hyperglycemia and the effectiveness of current treatment approaches. Consequently, we are facing an impending sea change in the way in which gestational diabetes is diagnosed and managed.

Recent research has detailed the risks posed to a fetus exposed to hyperglycemia during pregnancy – even at levels that in the past have been considered mild and, thus, largely inconsequential. We also now have evidence that we can offer therapies for gestational diabetes mellitus (GDM) with confidence that we can use them to change the outcome for the fetus, the newborn, the child, and possibly the adult.

This impending change comes after decades of diagnosing gestational diabetes based largely on relatively arbitrary thresholds. Dr. John B. O'sullivan and statistician Claire Mahan developed the diagnostic criteria more than 40 years ago based on certain statistical phenomena associated with the development of adult-onset diabetes after pregnancy. Before then, during the 1940s, 1950s, and 1960s, 1%-2% of all pregnant women were diagnosed with GDM.

In recent years, many of us have had the experience as clinicians of delivering larger, more obese babies whose mothers had been found to have “normal” blood glucose levels. Many of us also have delivered babies with significant adiposity, sometimes perilously low blood glucose, shoulder dystocia, nerve injuries, and other complications that typically occur as a consequence of fetal overgrowth.

We often attribute these complications to a diagnostic method we have known for some time wasn't perfect, but until recently, we did not have the clinical research findings to guide us in our efforts to fine-tune the diagnosis of GDM and turn the tide.

Insights on Fetal Risk

The landmark Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study, led by Dr. Boyd E. Metzger, was an attempt to clarify what level of maternal glucose intolerance is associated with an excess risk of an adverse pregnancy outcome.

The HAPO study, which involved 15 centers in nine countries, examined the outcomes of more than 25,000 pregnancies. In designing the HAPO study, Dr. Metzger and his colleagues did something that had never formally been done before: They administered a 75-g oral glucose tolerance test (OGTT) to the mothers between 24 and 32 weeks' gestation (as close to 28 weeks as possible), and defined GDM as an abnormal 2-hour 75-g OGTT result. They then followed the births of women identified as having GDM, and compared them with the births of mothers who did not have gestational diabetes as defined by traditional measures.

Outside the United States, the 75-g, one-step OGTT has been the standard for GDM diagnosis for some time. In the United States, many of us still use an awkward two-step system in which women initially are given a 50-g oral challenge. Only if they register an excessive value on the 50-g challenge do they come back for a definitive 3-hour, 100-g OGTT.

Quite a few outcomes were measured in the HAPO study, but the major outcomes were birth weight greater than the 90th percentile, the level of cord-blood serum-C-peptide (an index of fetal beta-cell function and fetal hyperinsulinemia) above the 90th percentile, and percent body fat greater than the 90th percentile.

The glucose results of the majority of women remained blinded (data were not blinded if the 2-hour plasma glucose level was greater than 200 mg/dL, or diagnostic of diabetes, or if the fasting plasma glucose level exceeded 105 mg/dL or the random plasma glucose level was 160 mg/dL). After birth and the assessment of fetal outcomes, these outcomes were arrayed against earlier results of the mothers' 2-hour 75-g glucose challenge tests and the fasting blood glucose levels, both of which were measured at the same time during pregnancy. (Fasting plasma glucose levels varied from as little as 75 mg/dL all the way up to the predefined threshold of 100 mg/dL.)

Considering percent of body fat greater than the 90th percentile, one would expect no more than 10% of babies without diagnosed GDM in the mothers to have hyperinsulinemia and large amounts of body fat.

Dr. Metzger found otherwise: 17% of babies whose mothers had a fasting blood glucose of 90 mg/dL, for instance – a level most clinicians have viewed as normal – had large levels of body fat, and many of these babies also had hyperinsulinemia. Overall, there was no “golden” level of maternal glucose that predicted a fat baby. However, neonatal adiposity increased progressively as fasting blood glucose levels rose above 80 mg/dL.

In the case of 1-hour 75-g OGTT results, fatness increased progressively at levels greater than 105 mg/dL, and with 2-hour results, fatness rose progressively at levels over 90 mg/dL (Diabetes 2009;58:453–9).

Such continuous linear relationships between maternal glucose and adverse fetal outcomes were seen studywide for birth weight and other outcomes (N. Engl. J. Med. 2008;358:1991–2002).

Among the most striking findings was that a significant number of fat babies were born to women whose blood glucose levels were considered “normal.”

The question at this point became, What should we do about it? Should we allow these obese babies to be born without any intervention, or can we treat them before birth?

Insights on Treatment

Many experts have been doubtful that treatment of mothers with GDM would be effective in altering newborn outcomes. However, the Australian Carbohydrate Intolerance Study in Pregnant Women, published in 2005, concluded that early treatment of GDM reduces serious perinatal morbidity and may improve health-related quality of life. In this study, women with GDM were randomized to receive dietary advice, blood glucose monitoring, and insulin therapy as needed (the treatment group), or routine care (N. Engl. J. Med. 2005;352:2477–86).

In another randomized study published several years later, Dr. Mark B. Landon and his colleagues finally convinced many experts of the value of aggressive screening and early intervention for GDM. Dr. Landon focused on a subset of women who had an abnormal result on a 3-hour 100-g OGTT but a fasting glucose level below 95 mg/L. These women thus had only mild glucose intolerance. (An abnormal result was defined as two or three timed glucose measurements that exceeded certain thresholds: 1-hour, 180 mg/dL; 2-hour, 155 mg/dL; and 3-hour, 140 mg/dL.)

In 14 centers across the United States, 958 patients were randomized to receive treatment of their diabetes or nothing but usual prenatal care. Treatment included formal nutritional counseling and diet therapy, along with insulin if needed. The majority of the women (93%) needed only dietary counseling and education about blood glucose control, while the other 7% needed insulin as well.

Women receiving dietary counseling checked their blood glucose levels before they got up in the morning, and 2 hours after each major meal. In essence, they planned and adjusted their diet based on their blood glucose readings.

What did we learn from this trial? We learned that the incidence of large-for-gestational-age births (greater than the 90th percentile) was cut in half from approximately 14% in the untreated group to 7% in the treated group. There also was a 10%-14% reduction in fat mass in the babies born to the women who received treatment, as well as significant reductions in mean birth weight and birth weight greater than 4,000 g. Most importantly, treatment also reduced the number of injuries that occurred during birth, while the number of small-for-gestational-age infants did not increase (N. Engl. J. Med. 2009;361:1339–48).

With these two randomized studies demonstrating significantly reduced risks with early GDM treatment, the question shifted from the broader issue of whether it is worthwhile to treat women with GDM to the more specific question of who needs treatment the most.

A New Approach

Today, in most demographic and ethnic groups in the United States, the incidence of gestational diabetes is between 4% and 12%, with a national incidence of about 8%. These are the patients we are already treating.

The HAPO trial, however, has shown us that there are a significant number of babies whose mothers have mild hyperglycemia and who are not being treated for this condition. These babies have neonatal adiposity and subsequently are being injured during the birth process.

In addition, we now have multiple epidemiologic studies demonstrating that adiposity at birth markedly increases – by as much as 30%–40% – the risk of being fat as a child and as an adolescent. Studies also have shown that the risk of developing childhood and adolescent type 2 diabetes proportionately increases with increasing neonatal adiposity.

Thus, the goal is no longer just to prevent neonatal adiposity so that babies will not be injured during birth; it now includes helping mothers control their glucose profiles so that their babies will have better health during their childhood and adult years.

However, the answer to the current, pressing question of whether we should offer treatment to women who are not now defined as having gestational diabetes is not yet clearly answered.

In 2008, after the initial release of HAPO study findings, a group called the International Association of Diabetes and Pregnancy Study Groups (IADPSG) was created to discuss the definition of gestational diabetes in light of the new HAPO findings and other research demonstrating improved outcomes with treatment.

In 2010, the consensus group released revised recommendations for glucose tolerance testing, suggesting that everyone convert to the 2-hour 75-g OGTT and that we lower the cutoff points used for diagnosis to protect as many babies as possible from becoming obese.

The group deliberated how much risk to address, or cover, with new cut points. Is a 150% increase in risk, for example, too much? Or a doubling of newborn fatness? In looking at a possible lifetime of obesity, type 2 diabetes, and heart disease, how much testing and treatment is just right? In the end, the group chose cutoff points for the fasting, 1-hour, and 2-hour plasma glucose measurements that conveyed an odds ratio for adverse outcomes of at least 1.75.

This means that a fasting plasma glucose of 92 mg/dL or more almost doubles the adverse fetal outcome risk; so does a 1-hour value after the 75-g OGTT of at least 180 mg/dL, and a 2-hour value of at least 153 mg/dL. If any one of these values is elevated, according to the IADPSG, a fetus is at risk and the mother should be treated for hyperglycemia (Diabetes Care 2010;33:676–82).

The Near Future

With the new criteria proposed by the IADPSG, the number of women who will be defined as having GDM using the 75-g OGTT will double to approximately 16%, compared with about 8% today. This doubling of incidence obviously will require additional resources and intervention.

The question now is, Are we going to adopt these new criteria? The practice approach for GDM in the United States normally follows guidelines for diabetes put forth by the American Diabetes Association and/or guidelines for pregnancy developed by the American College of Obstetricians and Gynecologists. Although the ADA has revised its recommendations for diagnosis of GDM to embrace the criteria of IADPSG, neither body has issued a directive or a formal set of guidelines for clinicians.

The National Institute of Child Health and Human Development is planning a workshop on GDM for next year, and it is quite possible that the proceedings from this NICHD workshop will inform future statements or guidelines from these organizations. In all likelihood, new screening criteria will be widely adopted within several years.

In the meantime, providers must decide what to do. There is nothing wrong with continuing two-stage testing. However, those who do should realistically consider its disadvantages: For one, this process identifies only 80%–90% of the women who actually have abnormal glucose levels, so many at-risk newborns will be missed even though their mothers were tested.

Secondly, the timing of the two-step process is problematic. Most women are given lab orders for the OGTT at about 28 weeks' gestation. By 29 or 30 weeks, they'll have results. If abnormal, the office staff must call and tell the patient to schedule the second OGTT test. Our own studies have shown that each step takes about 7–12 days to complete. In our system, it can then take up to 10 days for a woman diagnosed with GDM to receive care. She will be instructed in glucose monitoring and her care team will check with her every week.

In the end, it may be 6–8 weeks after initial testing before the woman's glucose intolerance is effectively addressed. The maximal time of fetal fat accretion is at about 34 weeks. If we do not have a diagnosis made and treatment plan underway by 32 weeks, we will have significantly decreased our chance of preventing obesity in her newborn.

Aggressive efforts to get screening done at about 26 weeks would be worthwhile, especially if you are working within a system that can accommodate a greater number of women with identified glucose intolerance. To ensure the outcomes that we're seeking, we must ensure that our patients receive adequate dietary and other interventions.

There also are questions about whether the identification of more women at risk of an adverse pregnancy outcome could itself create risk, particularly since it is well documented that women with GDM are more likely to be delivered earlier or through cesarean section, regardless of the level of achieved glucose control. (In the Landon study, interestingly, the rate of cesarean delivery was reduced in the intervention group.)

On the other hand, wider identification offers such hope for reducing fetal adiposity, and its many adverse consequences, that it should be immediately considered.

'Old' (Current) vs. 'New' (Upcoming)

Two-Step Approach to GDM Dx:

▸ Initial screening with a 50-g glucose challenge test at 24–28 weeks' gestation in women at greater than low risk of GDM. Women at very high risk should be screened as soon as possible after confirmation of pregnancy.

▸ Diagnostic 100-g oral glucose tolerance test (on separate day, after overnight fast) in women who meet or exceed chosen threshold on 50-g screening (140 mg/dL or more, or 130 mg/dL or more for higher sensitivity).

▸ GDM diagnosis made if at least two of these plasma glucose values are met or exceeded after the 100-g OGTT: fasting, 95 mg/dL; 1 hour, 180 mg/dL; 2 hour, 155 mg/dL; 3 hour, 140 mg/dL (if a 3-hour test is done).

One-Step Approach to GDM Dx:

▸ Screening of all women at 24–28 weeks' gestation not known to have type 2 diabetes with 75-g oral glucose tolerance test (after overnight fast).

▸ GDM diagnosis made if any one of these fasting plasma glucose values are met or exceeded: fasting, 92 mg/dL; 1 hour, 180 mg/dL; 2 hour, 153 mg/dL.

Sources: American Diabetes Association's Standards of Medical Care in Diabetes 2010 (Diabetes Care 2010;33:S11–61); American College of Obstetricians and Gynecologists Practice Bulletin, September 2001; ADA's Standards of Medical Care in Diabetes 2011 (Diabetes Care 2011;34:S11–61).

The Consequences of GDM

obnews@elsevier.com

The thresholds for deciding when to begin treating hyperglycemia were established almost 50 years ago at a time when we had significantly less knowledge about the risk factors for and consequences of hyperglycemia in pregnancy. Because of this lack of understanding about the causes and consequences of hyperglycemia and our sometimes rigid adherence to these cutoffs, many women were not treated who should have been.

There is a growing recognition in the research and clinical communities that gestational diabetes mellitus (GDM) is a much more serious condition than had been previously believed even a decade ago. We now know that GDM, if not properly diagnosed and managed, can have intergenerational consequences in terms of propagating risks for obesity, diabetes, heart disease, and other disorders. Furthermore, there is a new and growing realization that even mild hyperglycemia significantly below what has traditionally been defined as diabetes can have significant adverse consequences for both mother and infant.

Perhaps the most significant complication of maternal hyperglycemia faced by ob.gyns. is the growing number of large-for-gestational-age (LGA) infants being born. For obvious reasons, LGA infants are more difficult to deliver and significantly more prone to experiencing shoulder dystocia and other injuries during normal or cesarean delivery, and cesarean delivery has its own set of complications for both baby and mother.

The large, multicenter Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study recently documented that by managing hyperglycemia – even among women who previously had not been considered to have any glucose control problems – the incidence of LGA-related problems and other adverse birth outcomes could be significantly reduced.

To discuss in detail the findings of the HAPO study and its potential clinical implications, we have invited Dr. Thomas R. Moore, professor and chairman of the department of reproductive medicine at the University of California, San Diego, to write this Master Class.

Dr. Moore's essay discusses both the unique design and findings of the HAPO study, and also explores the quandary faced by members of the International Association of Diabetes and Pregnancy Study Groups (IADPSG) in their attempts to translate HAPO's findings into clinically useful recommendations and guidelines.

In a sign of how complex and time consuming it can be to translate clinical research findings into clinical practice, the recommendations of the IADPSG are now being debated among research and medical societies, with some suggesting that the thresholds introduced by the HAPO study and advanced by the IADPSG are not significantly different from the current levels.

We greatly appreciate Dr. Moore's insights into these complicated but exciting developments. His Master Class installment will help all of us to better understand this complex issue so that we can potentially play a role in speeding up the process of changing the way we manage GDM.

The tide has turned in our understanding of both the effects of maternal hyperglycemia and the effectiveness of current treatment approaches. Consequently, we are facing an impending sea change in the way in which gestational diabetes is diagnosed and managed.

Recent research has detailed the risks posed to a fetus exposed to hyperglycemia during pregnancy – even at levels that in the past have been considered mild and, thus, largely inconsequential. We also now have evidence that we can offer therapies for gestational diabetes mellitus (GDM) with confidence that we can use them to change the outcome for the fetus, the newborn, the child, and possibly the adult.

This impending change comes after decades of diagnosing gestational diabetes based largely on relatively arbitrary thresholds. Dr. John B. O'sullivan and statistician Claire Mahan developed the diagnostic criteria more than 40 years ago based on certain statistical phenomena associated with the development of adult-onset diabetes after pregnancy. Before then, during the 1940s, 1950s, and 1960s, 1%-2% of all pregnant women were diagnosed with GDM.

In recent years, many of us have had the experience as clinicians of delivering larger, more obese babies whose mothers had been found to have “normal” blood glucose levels. Many of us also have delivered babies with significant adiposity, sometimes perilously low blood glucose, shoulder dystocia, nerve injuries, and other complications that typically occur as a consequence of fetal overgrowth.

We often attribute these complications to a diagnostic method we have known for some time wasn't perfect, but until recently, we did not have the clinical research findings to guide us in our efforts to fine-tune the diagnosis of GDM and turn the tide.

Insights on Fetal Risk

The landmark Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study, led by Dr. Boyd E. Metzger, was an attempt to clarify what level of maternal glucose intolerance is associated with an excess risk of an adverse pregnancy outcome.

The HAPO study, which involved 15 centers in nine countries, examined the outcomes of more than 25,000 pregnancies. In designing the HAPO study, Dr. Metzger and his colleagues did something that had never formally been done before: They administered a 75-g oral glucose tolerance test (OGTT) to the mothers between 24 and 32 weeks' gestation (as close to 28 weeks as possible), and defined GDM as an abnormal 2-hour 75-g OGTT result. They then followed the births of women identified as having GDM, and compared them with the births of mothers who did not have gestational diabetes as defined by traditional measures.

Outside the United States, the 75-g, one-step OGTT has been the standard for GDM diagnosis for some time. In the United States, many of us still use an awkward two-step system in which women initially are given a 50-g oral challenge. Only if they register an excessive value on the 50-g challenge do they come back for a definitive 3-hour, 100-g OGTT.

Quite a few outcomes were measured in the HAPO study, but the major outcomes were birth weight greater than the 90th percentile, the level of cord-blood serum-C-peptide (an index of fetal beta-cell function and fetal hyperinsulinemia) above the 90th percentile, and percent body fat greater than the 90th percentile.

The glucose results of the majority of women remained blinded (data were not blinded if the 2-hour plasma glucose level was greater than 200 mg/dL, or diagnostic of diabetes, or if the fasting plasma glucose level exceeded 105 mg/dL or the random plasma glucose level was 160 mg/dL). After birth and the assessment of fetal outcomes, these outcomes were arrayed against earlier results of the mothers' 2-hour 75-g glucose challenge tests and the fasting blood glucose levels, both of which were measured at the same time during pregnancy. (Fasting plasma glucose levels varied from as little as 75 mg/dL all the way up to the predefined threshold of 100 mg/dL.)

Considering percent of body fat greater than the 90th percentile, one would expect no more than 10% of babies without diagnosed GDM in the mothers to have hyperinsulinemia and large amounts of body fat.

Dr. Metzger found otherwise: 17% of babies whose mothers had a fasting blood glucose of 90 mg/dL, for instance – a level most clinicians have viewed as normal – had large levels of body fat, and many of these babies also had hyperinsulinemia. Overall, there was no “golden” level of maternal glucose that predicted a fat baby. However, neonatal adiposity increased progressively as fasting blood glucose levels rose above 80 mg/dL.

In the case of 1-hour 75-g OGTT results, fatness increased progressively at levels greater than 105 mg/dL, and with 2-hour results, fatness rose progressively at levels over 90 mg/dL (Diabetes 2009;58:453–9).

Such continuous linear relationships between maternal glucose and adverse fetal outcomes were seen studywide for birth weight and other outcomes (N. Engl. J. Med. 2008;358:1991–2002).

Among the most striking findings was that a significant number of fat babies were born to women whose blood glucose levels were considered “normal.”

The question at this point became, What should we do about it? Should we allow these obese babies to be born without any intervention, or can we treat them before birth?

Insights on Treatment

Many experts have been doubtful that treatment of mothers with GDM would be effective in altering newborn outcomes. However, the Australian Carbohydrate Intolerance Study in Pregnant Women, published in 2005, concluded that early treatment of GDM reduces serious perinatal morbidity and may improve health-related quality of life. In this study, women with GDM were randomized to receive dietary advice, blood glucose monitoring, and insulin therapy as needed (the treatment group), or routine care (N. Engl. J. Med. 2005;352:2477–86).

In another randomized study published several years later, Dr. Mark B. Landon and his colleagues finally convinced many experts of the value of aggressive screening and early intervention for GDM. Dr. Landon focused on a subset of women who had an abnormal result on a 3-hour 100-g OGTT but a fasting glucose level below 95 mg/L. These women thus had only mild glucose intolerance. (An abnormal result was defined as two or three timed glucose measurements that exceeded certain thresholds: 1-hour, 180 mg/dL; 2-hour, 155 mg/dL; and 3-hour, 140 mg/dL.)

In 14 centers across the United States, 958 patients were randomized to receive treatment of their diabetes or nothing but usual prenatal care. Treatment included formal nutritional counseling and diet therapy, along with insulin if needed. The majority of the women (93%) needed only dietary counseling and education about blood glucose control, while the other 7% needed insulin as well.

Women receiving dietary counseling checked their blood glucose levels before they got up in the morning, and 2 hours after each major meal. In essence, they planned and adjusted their diet based on their blood glucose readings.

What did we learn from this trial? We learned that the incidence of large-for-gestational-age births (greater than the 90th percentile) was cut in half from approximately 14% in the untreated group to 7% in the treated group. There also was a 10%-14% reduction in fat mass in the babies born to the women who received treatment, as well as significant reductions in mean birth weight and birth weight greater than 4,000 g. Most importantly, treatment also reduced the number of injuries that occurred during birth, while the number of small-for-gestational-age infants did not increase (N. Engl. J. Med. 2009;361:1339–48).

With these two randomized studies demonstrating significantly reduced risks with early GDM treatment, the question shifted from the broader issue of whether it is worthwhile to treat women with GDM to the more specific question of who needs treatment the most.

A New Approach

Today, in most demographic and ethnic groups in the United States, the incidence of gestational diabetes is between 4% and 12%, with a national incidence of about 8%. These are the patients we are already treating.

The HAPO trial, however, has shown us that there are a significant number of babies whose mothers have mild hyperglycemia and who are not being treated for this condition. These babies have neonatal adiposity and subsequently are being injured during the birth process.

In addition, we now have multiple epidemiologic studies demonstrating that adiposity at birth markedly increases – by as much as 30%–40% – the risk of being fat as a child and as an adolescent. Studies also have shown that the risk of developing childhood and adolescent type 2 diabetes proportionately increases with increasing neonatal adiposity.

Thus, the goal is no longer just to prevent neonatal adiposity so that babies will not be injured during birth; it now includes helping mothers control their glucose profiles so that their babies will have better health during their childhood and adult years.

However, the answer to the current, pressing question of whether we should offer treatment to women who are not now defined as having gestational diabetes is not yet clearly answered.

In 2008, after the initial release of HAPO study findings, a group called the International Association of Diabetes and Pregnancy Study Groups (IADPSG) was created to discuss the definition of gestational diabetes in light of the new HAPO findings and other research demonstrating improved outcomes with treatment.

In 2010, the consensus group released revised recommendations for glucose tolerance testing, suggesting that everyone convert to the 2-hour 75-g OGTT and that we lower the cutoff points used for diagnosis to protect as many babies as possible from becoming obese.

The group deliberated how much risk to address, or cover, with new cut points. Is a 150% increase in risk, for example, too much? Or a doubling of newborn fatness? In looking at a possible lifetime of obesity, type 2 diabetes, and heart disease, how much testing and treatment is just right? In the end, the group chose cutoff points for the fasting, 1-hour, and 2-hour plasma glucose measurements that conveyed an odds ratio for adverse outcomes of at least 1.75.

This means that a fasting plasma glucose of 92 mg/dL or more almost doubles the adverse fetal outcome risk; so does a 1-hour value after the 75-g OGTT of at least 180 mg/dL, and a 2-hour value of at least 153 mg/dL. If any one of these values is elevated, according to the IADPSG, a fetus is at risk and the mother should be treated for hyperglycemia (Diabetes Care 2010;33:676–82).

The Near Future

With the new criteria proposed by the IADPSG, the number of women who will be defined as having GDM using the 75-g OGTT will double to approximately 16%, compared with about 8% today. This doubling of incidence obviously will require additional resources and intervention.

The question now is, Are we going to adopt these new criteria? The practice approach for GDM in the United States normally follows guidelines for diabetes put forth by the American Diabetes Association and/or guidelines for pregnancy developed by the American College of Obstetricians and Gynecologists. Although the ADA has revised its recommendations for diagnosis of GDM to embrace the criteria of IADPSG, neither body has issued a directive or a formal set of guidelines for clinicians.

The National Institute of Child Health and Human Development is planning a workshop on GDM for next year, and it is quite possible that the proceedings from this NICHD workshop will inform future statements or guidelines from these organizations. In all likelihood, new screening criteria will be widely adopted within several years.

In the meantime, providers must decide what to do. There is nothing wrong with continuing two-stage testing. However, those who do should realistically consider its disadvantages: For one, this process identifies only 80%–90% of the women who actually have abnormal glucose levels, so many at-risk newborns will be missed even though their mothers were tested.

Secondly, the timing of the two-step process is problematic. Most women are given lab orders for the OGTT at about 28 weeks' gestation. By 29 or 30 weeks, they'll have results. If abnormal, the office staff must call and tell the patient to schedule the second OGTT test. Our own studies have shown that each step takes about 7–12 days to complete. In our system, it can then take up to 10 days for a woman diagnosed with GDM to receive care. She will be instructed in glucose monitoring and her care team will check with her every week.

In the end, it may be 6–8 weeks after initial testing before the woman's glucose intolerance is effectively addressed. The maximal time of fetal fat accretion is at about 34 weeks. If we do not have a diagnosis made and treatment plan underway by 32 weeks, we will have significantly decreased our chance of preventing obesity in her newborn.

Aggressive efforts to get screening done at about 26 weeks would be worthwhile, especially if you are working within a system that can accommodate a greater number of women with identified glucose intolerance. To ensure the outcomes that we're seeking, we must ensure that our patients receive adequate dietary and other interventions.

There also are questions about whether the identification of more women at risk of an adverse pregnancy outcome could itself create risk, particularly since it is well documented that women with GDM are more likely to be delivered earlier or through cesarean section, regardless of the level of achieved glucose control. (In the Landon study, interestingly, the rate of cesarean delivery was reduced in the intervention group.)

On the other hand, wider identification offers such hope for reducing fetal adiposity, and its many adverse consequences, that it should be immediately considered.

'Old' (Current) vs. 'New' (Upcoming)

Two-Step Approach to GDM Dx:

▸ Initial screening with a 50-g glucose challenge test at 24–28 weeks' gestation in women at greater than low risk of GDM. Women at very high risk should be screened as soon as possible after confirmation of pregnancy.

▸ Diagnostic 100-g oral glucose tolerance test (on separate day, after overnight fast) in women who meet or exceed chosen threshold on 50-g screening (140 mg/dL or more, or 130 mg/dL or more for higher sensitivity).

▸ GDM diagnosis made if at least two of these plasma glucose values are met or exceeded after the 100-g OGTT: fasting, 95 mg/dL; 1 hour, 180 mg/dL; 2 hour, 155 mg/dL; 3 hour, 140 mg/dL (if a 3-hour test is done).

One-Step Approach to GDM Dx:

▸ Screening of all women at 24–28 weeks' gestation not known to have type 2 diabetes with 75-g oral glucose tolerance test (after overnight fast).

▸ GDM diagnosis made if any one of these fasting plasma glucose values are met or exceeded: fasting, 92 mg/dL; 1 hour, 180 mg/dL; 2 hour, 153 mg/dL.

Sources: American Diabetes Association's Standards of Medical Care in Diabetes 2010 (Diabetes Care 2010;33:S11–61); American College of Obstetricians and Gynecologists Practice Bulletin, September 2001; ADA's Standards of Medical Care in Diabetes 2011 (Diabetes Care 2011;34:S11–61).

The Consequences of GDM

obnews@elsevier.com

The thresholds for deciding when to begin treating hyperglycemia were established almost 50 years ago at a time when we had significantly less knowledge about the risk factors for and consequences of hyperglycemia in pregnancy. Because of this lack of understanding about the causes and consequences of hyperglycemia and our sometimes rigid adherence to these cutoffs, many women were not treated who should have been.

There is a growing recognition in the research and clinical communities that gestational diabetes mellitus (GDM) is a much more serious condition than had been previously believed even a decade ago. We now know that GDM, if not properly diagnosed and managed, can have intergenerational consequences in terms of propagating risks for obesity, diabetes, heart disease, and other disorders. Furthermore, there is a new and growing realization that even mild hyperglycemia significantly below what has traditionally been defined as diabetes can have significant adverse consequences for both mother and infant.

Perhaps the most significant complication of maternal hyperglycemia faced by ob.gyns. is the growing number of large-for-gestational-age (LGA) infants being born. For obvious reasons, LGA infants are more difficult to deliver and significantly more prone to experiencing shoulder dystocia and other injuries during normal or cesarean delivery, and cesarean delivery has its own set of complications for both baby and mother.

The large, multicenter Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study recently documented that by managing hyperglycemia – even among women who previously had not been considered to have any glucose control problems – the incidence of LGA-related problems and other adverse birth outcomes could be significantly reduced.

To discuss in detail the findings of the HAPO study and its potential clinical implications, we have invited Dr. Thomas R. Moore, professor and chairman of the department of reproductive medicine at the University of California, San Diego, to write this Master Class.

Dr. Moore's essay discusses both the unique design and findings of the HAPO study, and also explores the quandary faced by members of the International Association of Diabetes and Pregnancy Study Groups (IADPSG) in their attempts to translate HAPO's findings into clinically useful recommendations and guidelines.

In a sign of how complex and time consuming it can be to translate clinical research findings into clinical practice, the recommendations of the IADPSG are now being debated among research and medical societies, with some suggesting that the thresholds introduced by the HAPO study and advanced by the IADPSG are not significantly different from the current levels.

We greatly appreciate Dr. Moore's insights into these complicated but exciting developments. His Master Class installment will help all of us to better understand this complex issue so that we can potentially play a role in speeding up the process of changing the way we manage GDM.

The decades-long shift in our approach to prenatal screening which brought us from a point that maternal age was the main criterion for assessing risk of chromosomal abnormalities to a more precise first-trimester screening approach – one that combines biochemistry and imaging – is continuing to evolve.

Indeed, researchers are honing in on a “platform” of first-trimester assessments that can screen for an even wider array of risks and pregnancy complications than previously envisioned – an array that extends far beyond chromosomal abnormalities. Much of this first-trimester screening platform is currently being applied and is poised to become a new standard of care.

The continued evolution of first-trimester screening is critical, as a massive amount of time and resources is spent trying to identify problem pregnancies. Many of these resources still are used inefficiently because detection is incomplete or too late to make a difference. With an expanded and precise first-trimester platform for assessment, we can offer women and their physicians significantly more information early on. This will enable us to channel our resources to improve decision -making, direct management, and enhance pregnancy outcome.

Early Screening's Development

Prenatal screening used to be all about maternal age. Our early methods were based on the fact that risk increases with age, and then on the idea that particular age cut-offs may signify varying levels of risk.

However, advances in ultrasound, and the identification of four pregnancy-related maternal blood analytes, provided us new and exciting insights on fetal status. These chemicals became part of a second-trimester screening process focused largely on trisomy 21. Although we still used age as a factor to assess risk, we learned that the cut-offs we had identified earlier were arbitrary and that risk could now be individualized.

As research continued, it became apparent that versions of the biochemical tests used in second-trimester screening could be done in the first trimester – even by 12–14 weeks of gestation – and could be used to assess the risks not only of Down syndrome, but of other chromosomal abnormalities and some physical abnormalities. These biochemical tests (free beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A) were combined with first-trimester ultrasound measurements of nuchal translucency into a screening algorithm that took hold more than 5 years ago and has steadily gained acceptance.

Since then, a number of parameters have been added to first-trimester screening to make the prediction of normality, or abnormality, even more precise. Assessment of the nasal bone, of the frontonasal facial angle, and of various structures inside the brain have become part of an anatomic review, for instance, that help us better define which babies we should be most concerned about.

Additionally, Doppler assessment of blood flow measurement – specifically of tricuspid regurgitation and of flow through the ductus venosus, a small fetal blood vessel that leads to the heart – can provide valuable information about fetal cardiac status and can easily be done in the context of the first-trimester ultrasound evaluation. Abnormal first-trimester Doppler findings also appear to predict Down syndrome and other adverse outcomes independently of a normal nuchal translucency measurement.

Combined with additional, early biochemical tests on maternal serum, these imaging advances (for fetal anatomic reviews and blood flow measurements) have led to an improved detection rate as high as 90% for trisomy 21 and other chromosomal abnormalities. More importantly, this detection rate is achieved without invasive testing, enabling us to reserve invasive procedures such as chorionic villus sampling (CVS) or amniocentesis for women with higher identified risks.

A New Cardiac Focus

The nuchal translucency test, which measures levels of fluid in a small area in the back of the fetal neck, has been available in the United States for approximately 15 years. With time, we have come to appreciate that a number of problems, in addition to Down syndrome, are associated with increases in nuchal translucency. We also better understand that abnormal nuchal translucency measurements are not always indicative of a problem, and that when there is a problem, the issue is not always chromosomal in nature.

The quest to detect other kinds of problems (mainly structural abnormalities, and congenital heart defects, in particular) as early as we can detect chromosomal problems has taken on added urgency in recent years.

Indeed, significant improvements in the overall computing capability of modern ultrasound equipment, in three-dimensional color ultrasonography, and in ultrasound image resolution – as well as specific new technologic developments such as tomographic imaging and spatiotemporal image correlation – have opened the door to first-trimester cardiac screening.

In the majority of patients, up to 12 parameters of fetal cardiac structure can be visualized. Each of the three segments of the exam takes only a few seconds to perform, so the actual collection of information is rapid. The technologic advances have also made the acquisition of images easier and less operator dependent. Moreover, the analysis is then performed offline, so the mother can go home afterward. Offline analysis of images also means that the ultrasound scan itself can be performed by trained sonographers at a distance from a cardiac center, with the information transmitted to the center for expert analysis.

It wasn't long ago that second-trimester fetal echocardiography was the gold standard for any prenatal evaluation of fetal cardiac structure and function. Now, with an early and integrated screening approach that utilizes first-trimester fetal cardiac examination, we can in fact diagnose many of the most severe heart defects as early as 12 weeks of gestation. At this stage, the fetal heart is as small as the tip of the little finger.

This component of first-trimester screening is just now coming to the forefront. Its availability can benefit populations at high risk of cardiac anomalies (such as women who have long-standing diabetes). It may be especially beneficial to those who were in poor glycemic control at the beginning of their pregnancy. It appears, though, that the exam can be meaningfully applied in low-risk populations as well. Research is underway to determine the best approaches to counseling and to determine which patients should have subsequent invasive testing.

Other New Frontiers

Another area of interest is the potential ability to predict which women will develop preeclampsia later in pregnancy based on how the fetus and placenta are faring at approximately 12 weeks' gestation.

Doppler investigations have shown us that placental abnormalities are difficult to distinguish from normal placental development early in pregnancy. In the first trimester, therefore, Doppler alone is a fair mechanism for knowing whether placental development is deficient enough to put the mother at high risk for developing preeclampsia or isolated hypertension.

However, when Doppler is combined with measurement of a family of maternal serum analytes – some of them inflammatory substances and some of them chemicals that regulate the formation of blood vessels – it can be employed to predict who will develop early hypertensive complications. And when other factors such as maternal weight and blood pressure at the time of first-trimester assessment are added to the equation, the accuracy of our predictions increases further.

We are proceeding in this area with a bit of caution, as we cannot yet predict the onset of preeclampsia later on in pregnancy. The predictive value of the first-trimester assessment for hypertensive problems that occur closer to term is not very good, so patients with normal early assessments still need careful prenatal care.

Still, in many ways we can tackle the most severe problems through early detection. There is some evidence that the administration of low-dose aspirin can reduce the incidence of hypertension and preeclampsia, as well as complications with the baby's growth, in women with detected placental abnormalities. This means that not only are we able to define and identify those women at highest risk, but we also have the ability to potentially modify the course of placental development and perhaps even eliminate hypertensive complications.

Current research is aimed at defining who will best benefit from this approach, because while low-dose aspirin appears in some research to work when started early in high-risk women, benefits have not been duplicated in other studies.

More broadly, first-trimester assessment of maternal characteristics (such as weight), serum analytes, and ultrasound features set the stage for ongoing maternal evaluation of characteristics such as weight gain during pregnancy to predict her risk of developing preeclampsia, diabetes, and other serious problems, including neonatal concerns requiring specialized newborn care.

The Big Picture

As first-trimester screening evolves with technologic developments to become more comprehensive and precise, one of its ever-important components involves the art of history taking, physician-patient dialogue, and the incorporation of low-tech risk assessments for coping with and possibly preventing preterm labor and delivery.

Measuring the cervix at this very early stage is not a good predictor of its ability to contain the pregnancy for the rest of the gestation or even until a reasonably mature gestation is reached. In the first trimester, the cervix generally is not under enough pressure from the weight of the pregnancy to disclose whether it is a strong or weak cervix or whether it has the potential to shorten in an extreme way or not. This is different from measuring the cervix later in pregnancy when the shortening process has already started, and when intervention is based on proven results.

The first trimester is an excellent time, however, to have the mother recount her history. It is also a good time to make decisions about the use of progesterone, which in weekly injections has been shown to reduce the incidence of preterm delivery, and to institute a serial monitoring program so that any changes may be detected before the patient presents with rapidly advancing preterm labor – i.e., before a clinical emergency.

Such dialogue and interaction emphasizes to me the importance of a team approach to first-trimester screening that involves the ob.gyn. physicians, well-trained sonographers, well-trained perinatal nurses, and perinatologists who specialize in high-risk maternal and fetal complications.

Prenatal screening is no longer an in-and-out assessment of two or three measures. That began to change more than 5 years ago with adoption of the first-trimester screening approach combining biochemistry and imaging. It continues to evolve as prenatal screening provides an even more thorough and comprehensive view of fetal, placental, and maternal function that allows us to thoroughly map out the care of our patients. For women who have normal pregnancies, this is incredibly reassuring. And for those with any kind of outlying results or overt complications, it provides a starting point for making the best of even the most challenging pregnancies.

At left, the narrow nuchal translucency and brightly echogenic nasal bone at 12 weeks' gestation reduce the likelihood of aneuploidy. At right, the fetus has a NT over 4 mm and nonvisualizing nasal bone. CVS on the second fetus revealed Down syndrome.

Source Images courtesy Dr. Christopher R. Harman

In another pair of fetuses appearing at 12 weeks' gestation for nucal translucency screening, tricuspid valve Doppler shows normal flow on the left. The fetus on the right has a large downward jet of tricuspid regurgitation, suggesting possible abnormalities; pulmonary stenosis was later diagnosed.

Source Images courtesy Dr. Christopher R. Harman

3-D blocks analyzed by tomographic section in a systematic approach yield a complete catalogue of anatomic cardiac landmarks in over 80% of fetuses at 12 weeks.

Complete endocardial cushion defect was diagnosed at 12 weeks. First trimester echocardiography was triggered by abnormal ductus venosus alone during routine screening.

Source Elsevier Global Medical News

The Evolution of Prenatal Assessment

obnews@elsevier.com

It is astonishing how much obstetrics and maternal-fetal medicine have grown. There was a time not too long ago when obstetric care was primarily delivered to the mother, with the fetus being a hopeful beneficiary. We could listen to the fetal heart rate using the fetoscope, but access to the fetus for its early developmental analysis was otherwise off-limits; its growth and development were assumed as part of maternal-focused obstetric care.

The introduction of electronic fetal monitoring gave us the opportunity to see a recording of the fetal heart rate pattern – its rhythm, and its quality – and we used that as an indirect measure of fetal well-being. Subsequently, ultrasound became available, and we could then evaluate the anatomy of the fetus – though usually in the latter part of pregnancy – and appreciate the morphology and overall growth performance.

It was not until relatively recently that the focus of prenatal assessment has shifted to the first trimester. In large measure, this change has been consumer driven. Families have become very interested in the development of their unborn children, and that interest increasingly has centered on obtaining more information earlier on. Such demand has pushed physician scientists working in the field to adapt their technologies to the first trimester. Recent research has, in large measure, advanced in response to parental interests.

Fetal diagnosis in the first trimester was thus born of this great desire and has evolved to the point where, as stated in this month's Master Class, it is becoming the standard of care. The field of first-trimester fetal diagnosis now consists of a series of biochemical and biophysical assessments that can truly evaluate fetal well-being at the current time and can contribute to the prediction of later development and later fetal well-being, or more importantly, the loss of fetal well-being.

It is in light of this burgeoning field of first-trimester evaluation that we decided to develop a Master Class to review this new state of the art. I have invited Dr. Christopher R. Harman, an international expert in the field of ultrasound and Doppler technology, to serve as this month's guest professor.

Dr. Harman is professor and interim chair of the department of obstetrics, gynecology, and reproductive sciences at the University of Maryland, Baltimore, as well as director of the school's maternal-fetal medicine division. He will explain how research is honing in on a first-trimester platform of assessments that holds even more potential for predicting risks and complications than we realized with the first-trimester screening algorithm that took hold more than 5 years ago.

The decades-long shift in our approach to prenatal screening which brought us from a point that maternal age was the main criterion for assessing risk of chromosomal abnormalities to a more precise first-trimester screening approach – one that combines biochemistry and imaging – is continuing to evolve.

Indeed, researchers are honing in on a “platform” of first-trimester assessments that can screen for an even wider array of risks and pregnancy complications than previously envisioned – an array that extends far beyond chromosomal abnormalities. Much of this first-trimester screening platform is currently being applied and is poised to become a new standard of care.

The continued evolution of first-trimester screening is critical, as a massive amount of time and resources is spent trying to identify problem pregnancies. Many of these resources still are used inefficiently because detection is incomplete or too late to make a difference. With an expanded and precise first-trimester platform for assessment, we can offer women and their physicians significantly more information early on. This will enable us to channel our resources to improve decision -making, direct management, and enhance pregnancy outcome.

Early Screening's Development

Prenatal screening used to be all about maternal age. Our early methods were based on the fact that risk increases with age, and then on the idea that particular age cut-offs may signify varying levels of risk.

However, advances in ultrasound, and the identification of four pregnancy-related maternal blood analytes, provided us new and exciting insights on fetal status. These chemicals became part of a second-trimester screening process focused largely on trisomy 21. Although we still used age as a factor to assess risk, we learned that the cut-offs we had identified earlier were arbitrary and that risk could now be individualized.

As research continued, it became apparent that versions of the biochemical tests used in second-trimester screening could be done in the first trimester – even by 12–14 weeks of gestation – and could be used to assess the risks not only of Down syndrome, but of other chromosomal abnormalities and some physical abnormalities. These biochemical tests (free beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A) were combined with first-trimester ultrasound measurements of nuchal translucency into a screening algorithm that took hold more than 5 years ago and has steadily gained acceptance.

Since then, a number of parameters have been added to first-trimester screening to make the prediction of normality, or abnormality, even more precise. Assessment of the nasal bone, of the frontonasal facial angle, and of various structures inside the brain have become part of an anatomic review, for instance, that help us better define which babies we should be most concerned about.

Additionally, Doppler assessment of blood flow measurement – specifically of tricuspid regurgitation and of flow through the ductus venosus, a small fetal blood vessel that leads to the heart – can provide valuable information about fetal cardiac status and can easily be done in the context of the first-trimester ultrasound evaluation. Abnormal first-trimester Doppler findings also appear to predict Down syndrome and other adverse outcomes independently of a normal nuchal translucency measurement.

Combined with additional, early biochemical tests on maternal serum, these imaging advances (for fetal anatomic reviews and blood flow measurements) have led to an improved detection rate as high as 90% for trisomy 21 and other chromosomal abnormalities. More importantly, this detection rate is achieved without invasive testing, enabling us to reserve invasive procedures such as chorionic villus sampling (CVS) or amniocentesis for women with higher identified risks.

A New Cardiac Focus

The nuchal translucency test, which measures levels of fluid in a small area in the back of the fetal neck, has been available in the United States for approximately 15 years. With time, we have come to appreciate that a number of problems, in addition to Down syndrome, are associated with increases in nuchal translucency. We also better understand that abnormal nuchal translucency measurements are not always indicative of a problem, and that when there is a problem, the issue is not always chromosomal in nature.

The quest to detect other kinds of problems (mainly structural abnormalities, and congenital heart defects, in particular) as early as we can detect chromosomal problems has taken on added urgency in recent years.

Indeed, significant improvements in the overall computing capability of modern ultrasound equipment, in three-dimensional color ultrasonography, and in ultrasound image resolution – as well as specific new technologic developments such as tomographic imaging and spatiotemporal image correlation – have opened the door to first-trimester cardiac screening.

In the majority of patients, up to 12 parameters of fetal cardiac structure can be visualized. Each of the three segments of the exam takes only a few seconds to perform, so the actual collection of information is rapid. The technologic advances have also made the acquisition of images easier and less operator dependent. Moreover, the analysis is then performed offline, so the mother can go home afterward. Offline analysis of images also means that the ultrasound scan itself can be performed by trained sonographers at a distance from a cardiac center, with the information transmitted to the center for expert analysis.

It wasn't long ago that second-trimester fetal echocardiography was the gold standard for any prenatal evaluation of fetal cardiac structure and function. Now, with an early and integrated screening approach that utilizes first-trimester fetal cardiac examination, we can in fact diagnose many of the most severe heart defects as early as 12 weeks of gestation. At this stage, the fetal heart is as small as the tip of the little finger.

This component of first-trimester screening is just now coming to the forefront. Its availability can benefit populations at high risk of cardiac anomalies (such as women who have long-standing diabetes). It may be especially beneficial to those who were in poor glycemic control at the beginning of their pregnancy. It appears, though, that the exam can be meaningfully applied in low-risk populations as well. Research is underway to determine the best approaches to counseling and to determine which patients should have subsequent invasive testing.

Other New Frontiers

Another area of interest is the potential ability to predict which women will develop preeclampsia later in pregnancy based on how the fetus and placenta are faring at approximately 12 weeks' gestation.

Doppler investigations have shown us that placental abnormalities are difficult to distinguish from normal placental development early in pregnancy. In the first trimester, therefore, Doppler alone is a fair mechanism for knowing whether placental development is deficient enough to put the mother at high risk for developing preeclampsia or isolated hypertension.

However, when Doppler is combined with measurement of a family of maternal serum analytes – some of them inflammatory substances and some of them chemicals that regulate the formation of blood vessels – it can be employed to predict who will develop early hypertensive complications. And when other factors such as maternal weight and blood pressure at the time of first-trimester assessment are added to the equation, the accuracy of our predictions increases further.

We are proceeding in this area with a bit of caution, as we cannot yet predict the onset of preeclampsia later on in pregnancy. The predictive value of the first-trimester assessment for hypertensive problems that occur closer to term is not very good, so patients with normal early assessments still need careful prenatal care.

Still, in many ways we can tackle the most severe problems through early detection. There is some evidence that the administration of low-dose aspirin can reduce the incidence of hypertension and preeclampsia, as well as complications with the baby's growth, in women with detected placental abnormalities. This means that not only are we able to define and identify those women at highest risk, but we also have the ability to potentially modify the course of placental development and perhaps even eliminate hypertensive complications.

Current research is aimed at defining who will best benefit from this approach, because while low-dose aspirin appears in some research to work when started early in high-risk women, benefits have not been duplicated in other studies.

More broadly, first-trimester assessment of maternal characteristics (such as weight), serum analytes, and ultrasound features set the stage for ongoing maternal evaluation of characteristics such as weight gain during pregnancy to predict her risk of developing preeclampsia, diabetes, and other serious problems, including neonatal concerns requiring specialized newborn care.

The Big Picture

As first-trimester screening evolves with technologic developments to become more comprehensive and precise, one of its ever-important components involves the art of history taking, physician-patient dialogue, and the incorporation of low-tech risk assessments for coping with and possibly preventing preterm labor and delivery.

Measuring the cervix at this very early stage is not a good predictor of its ability to contain the pregnancy for the rest of the gestation or even until a reasonably mature gestation is reached. In the first trimester, the cervix generally is not under enough pressure from the weight of the pregnancy to disclose whether it is a strong or weak cervix or whether it has the potential to shorten in an extreme way or not. This is different from measuring the cervix later in pregnancy when the shortening process has already started, and when intervention is based on proven results.

The first trimester is an excellent time, however, to have the mother recount her history. It is also a good time to make decisions about the use of progesterone, which in weekly injections has been shown to reduce the incidence of preterm delivery, and to institute a serial monitoring program so that any changes may be detected before the patient presents with rapidly advancing preterm labor – i.e., before a clinical emergency.

Such dialogue and interaction emphasizes to me the importance of a team approach to first-trimester screening that involves the ob.gyn. physicians, well-trained sonographers, well-trained perinatal nurses, and perinatologists who specialize in high-risk maternal and fetal complications.

Prenatal screening is no longer an in-and-out assessment of two or three measures. That began to change more than 5 years ago with adoption of the first-trimester screening approach combining biochemistry and imaging. It continues to evolve as prenatal screening provides an even more thorough and comprehensive view of fetal, placental, and maternal function that allows us to thoroughly map out the care of our patients. For women who have normal pregnancies, this is incredibly reassuring. And for those with any kind of outlying results or overt complications, it provides a starting point for making the best of even the most challenging pregnancies.

At left, the narrow nuchal translucency and brightly echogenic nasal bone at 12 weeks' gestation reduce the likelihood of aneuploidy. At right, the fetus has a NT over 4 mm and nonvisualizing nasal bone. CVS on the second fetus revealed Down syndrome.

Source Images courtesy Dr. Christopher R. Harman

In another pair of fetuses appearing at 12 weeks' gestation for nucal translucency screening, tricuspid valve Doppler shows normal flow on the left. The fetus on the right has a large downward jet of tricuspid regurgitation, suggesting possible abnormalities; pulmonary stenosis was later diagnosed.

Source Images courtesy Dr. Christopher R. Harman

3-D blocks analyzed by tomographic section in a systematic approach yield a complete catalogue of anatomic cardiac landmarks in over 80% of fetuses at 12 weeks.

Complete endocardial cushion defect was diagnosed at 12 weeks. First trimester echocardiography was triggered by abnormal ductus venosus alone during routine screening.

Source Elsevier Global Medical News

The Evolution of Prenatal Assessment

obnews@elsevier.com

It is astonishing how much obstetrics and maternal-fetal medicine have grown. There was a time not too long ago when obstetric care was primarily delivered to the mother, with the fetus being a hopeful beneficiary. We could listen to the fetal heart rate using the fetoscope, but access to the fetus for its early developmental analysis was otherwise off-limits; its growth and development were assumed as part of maternal-focused obstetric care.

The introduction of electronic fetal monitoring gave us the opportunity to see a recording of the fetal heart rate pattern – its rhythm, and its quality – and we used that as an indirect measure of fetal well-being. Subsequently, ultrasound became available, and we could then evaluate the anatomy of the fetus – though usually in the latter part of pregnancy – and appreciate the morphology and overall growth performance.

It was not until relatively recently that the focus of prenatal assessment has shifted to the first trimester. In large measure, this change has been consumer driven. Families have become very interested in the development of their unborn children, and that interest increasingly has centered on obtaining more information earlier on. Such demand has pushed physician scientists working in the field to adapt their technologies to the first trimester. Recent research has, in large measure, advanced in response to parental interests.

Fetal diagnosis in the first trimester was thus born of this great desire and has evolved to the point where, as stated in this month's Master Class, it is becoming the standard of care. The field of first-trimester fetal diagnosis now consists of a series of biochemical and biophysical assessments that can truly evaluate fetal well-being at the current time and can contribute to the prediction of later development and later fetal well-being, or more importantly, the loss of fetal well-being.

It is in light of this burgeoning field of first-trimester evaluation that we decided to develop a Master Class to review this new state of the art. I have invited Dr. Christopher R. Harman, an international expert in the field of ultrasound and Doppler technology, to serve as this month's guest professor.

Dr. Harman is professor and interim chair of the department of obstetrics, gynecology, and reproductive sciences at the University of Maryland, Baltimore, as well as director of the school's maternal-fetal medicine division. He will explain how research is honing in on a first-trimester platform of assessments that holds even more potential for predicting risks and complications than we realized with the first-trimester screening algorithm that took hold more than 5 years ago.

The decades-long shift in our approach to prenatal screening which brought us from a point that maternal age was the main criterion for assessing risk of chromosomal abnormalities to a more precise first-trimester screening approach – one that combines biochemistry and imaging – is continuing to evolve.

Indeed, researchers are honing in on a “platform” of first-trimester assessments that can screen for an even wider array of risks and pregnancy complications than previously envisioned – an array that extends far beyond chromosomal abnormalities. Much of this first-trimester screening platform is currently being applied and is poised to become a new standard of care.

The continued evolution of first-trimester screening is critical, as a massive amount of time and resources is spent trying to identify problem pregnancies. Many of these resources still are used inefficiently because detection is incomplete or too late to make a difference. With an expanded and precise first-trimester platform for assessment, we can offer women and their physicians significantly more information early on. This will enable us to channel our resources to improve decision -making, direct management, and enhance pregnancy outcome.

Early Screening's Development

Prenatal screening used to be all about maternal age. Our early methods were based on the fact that risk increases with age, and then on the idea that particular age cut-offs may signify varying levels of risk.

However, advances in ultrasound, and the identification of four pregnancy-related maternal blood analytes, provided us new and exciting insights on fetal status. These chemicals became part of a second-trimester screening process focused largely on trisomy 21. Although we still used age as a factor to assess risk, we learned that the cut-offs we had identified earlier were arbitrary and that risk could now be individualized.

As research continued, it became apparent that versions of the biochemical tests used in second-trimester screening could be done in the first trimester – even by 12–14 weeks of gestation – and could be used to assess the risks not only of Down syndrome, but of other chromosomal abnormalities and some physical abnormalities. These biochemical tests (free beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A) were combined with first-trimester ultrasound measurements of nuchal translucency into a screening algorithm that took hold more than 5 years ago and has steadily gained acceptance.

Since then, a number of parameters have been added to first-trimester screening to make the prediction of normality, or abnormality, even more precise. Assessment of the nasal bone, of the frontonasal facial angle, and of various structures inside the brain have become part of an anatomic review, for instance, that help us better define which babies we should be most concerned about.

Additionally, Doppler assessment of blood flow measurement – specifically of tricuspid regurgitation and of flow through the ductus venosus, a small fetal blood vessel that leads to the heart – can provide valuable information about fetal cardiac status and can easily be done in the context of the first-trimester ultrasound evaluation. Abnormal first-trimester Doppler findings also appear to predict Down syndrome and other adverse outcomes independently of a normal nuchal translucency measurement.

Combined with additional, early biochemical tests on maternal serum, these imaging advances (for fetal anatomic reviews and blood flow measurements) have led to an improved detection rate as high as 90% for trisomy 21 and other chromosomal abnormalities. More importantly, this detection rate is achieved without invasive testing, enabling us to reserve invasive procedures such as chorionic villus sampling (CVS) or amniocentesis for women with higher identified risks.

A New Cardiac Focus

The nuchal translucency test, which measures levels of fluid in a small area in the back of the fetal neck, has been available in the United States for approximately 15 years. With time, we have come to appreciate that a number of problems, in addition to Down syndrome, are associated with increases in nuchal translucency. We also better understand that abnormal nuchal translucency measurements are not always indicative of a problem, and that when there is a problem, the issue is not always chromosomal in nature.

The quest to detect other kinds of problems (mainly structural abnormalities, and congenital heart defects, in particular) as early as we can detect chromosomal problems has taken on added urgency in recent years.

Indeed, significant improvements in the overall computing capability of modern ultrasound equipment, in three-dimensional color ultrasonography, and in ultrasound image resolution – as well as specific new technologic developments such as tomographic imaging and spatiotemporal image correlation – have opened the door to first-trimester cardiac screening.

In the majority of patients, up to 12 parameters of fetal cardiac structure can be visualized. Each of the three segments of the exam takes only a few seconds to perform, so the actual collection of information is rapid. The technologic advances have also made the acquisition of images easier and less operator dependent. Moreover, the analysis is then performed offline, so the mother can go home afterward. Offline analysis of images also means that the ultrasound scan itself can be performed by trained sonographers at a distance from a cardiac center, with the information transmitted to the center for expert analysis.

It wasn't long ago that second-trimester fetal echocardiography was the gold standard for any prenatal evaluation of fetal cardiac structure and function. Now, with an early and integrated screening approach that utilizes first-trimester fetal cardiac examination, we can in fact diagnose many of the most severe heart defects as early as 12 weeks of gestation. At this stage, the fetal heart is as small as the tip of the little finger.

This component of first-trimester screening is just now coming to the forefront. Its availability can benefit populations at high risk of cardiac anomalies (such as women who have long-standing diabetes). It may be especially beneficial to those who were in poor glycemic control at the beginning of their pregnancy. It appears, though, that the exam can be meaningfully applied in low-risk populations as well. Research is underway to determine the best approaches to counseling and to determine which patients should have subsequent invasive testing.

Other New Frontiers

Another area of interest is the potential ability to predict which women will develop preeclampsia later in pregnancy based on how the fetus and placenta are faring at approximately 12 weeks' gestation.

Doppler investigations have shown us that placental abnormalities are difficult to distinguish from normal placental development early in pregnancy. In the first trimester, therefore, Doppler alone is a fair mechanism for knowing whether placental development is deficient enough to put the mother at high risk for developing preeclampsia or isolated hypertension.

However, when Doppler is combined with measurement of a family of maternal serum analytes – some of them inflammatory substances and some of them chemicals that regulate the formation of blood vessels – it can be employed to predict who will develop early hypertensive complications. And when other factors such as maternal weight and blood pressure at the time of first-trimester assessment are added to the equation, the accuracy of our predictions increases further.

We are proceeding in this area with a bit of caution, as we cannot yet predict the onset of preeclampsia later on in pregnancy. The predictive value of the first-trimester assessment for hypertensive problems that occur closer to term is not very good, so patients with normal early assessments still need careful prenatal care.

Still, in many ways we can tackle the most severe problems through early detection. There is some evidence that the administration of low-dose aspirin can reduce the incidence of hypertension and preeclampsia, as well as complications with the baby's growth, in women with detected placental abnormalities. This means that not only are we able to define and identify those women at highest risk, but we also have the ability to potentially modify the course of placental development and perhaps even eliminate hypertensive complications.

Current research is aimed at defining who will best benefit from this approach, because while low-dose aspirin appears in some research to work when started early in high-risk women, benefits have not been duplicated in other studies.

More broadly, first-trimester assessment of maternal characteristics (such as weight), serum analytes, and ultrasound features set the stage for ongoing maternal evaluation of characteristics such as weight gain during pregnancy to predict her risk of developing preeclampsia, diabetes, and other serious problems, including neonatal concerns requiring specialized newborn care.

The Big Picture

As first-trimester screening evolves with technologic developments to become more comprehensive and precise, one of its ever-important components involves the art of history taking, physician-patient dialogue, and the incorporation of low-tech risk assessments for coping with and possibly preventing preterm labor and delivery.

Measuring the cervix at this very early stage is not a good predictor of its ability to contain the pregnancy for the rest of the gestation or even until a reasonably mature gestation is reached. In the first trimester, the cervix generally is not under enough pressure from the weight of the pregnancy to disclose whether it is a strong or weak cervix or whether it has the potential to shorten in an extreme way or not. This is different from measuring the cervix later in pregnancy when the shortening process has already started, and when intervention is based on proven results.

The first trimester is an excellent time, however, to have the mother recount her history. It is also a good time to make decisions about the use of progesterone, which in weekly injections has been shown to reduce the incidence of preterm delivery, and to institute a serial monitoring program so that any changes may be detected before the patient presents with rapidly advancing preterm labor – i.e., before a clinical emergency.

Such dialogue and interaction emphasizes to me the importance of a team approach to first-trimester screening that involves the ob.gyn. physicians, well-trained sonographers, well-trained perinatal nurses, and perinatologists who specialize in high-risk maternal and fetal complications.

Prenatal screening is no longer an in-and-out assessment of two or three measures. That began to change more than 5 years ago with adoption of the first-trimester screening approach combining biochemistry and imaging. It continues to evolve as prenatal screening provides an even more thorough and comprehensive view of fetal, placental, and maternal function that allows us to thoroughly map out the care of our patients. For women who have normal pregnancies, this is incredibly reassuring. And for those with any kind of outlying results or overt complications, it provides a starting point for making the best of even the most challenging pregnancies.

At left, the narrow nuchal translucency and brightly echogenic nasal bone at 12 weeks' gestation reduce the likelihood of aneuploidy. At right, the fetus has a NT over 4 mm and nonvisualizing nasal bone. CVS on the second fetus revealed Down syndrome.

Source Images courtesy Dr. Christopher R. Harman

In another pair of fetuses appearing at 12 weeks' gestation for nucal translucency screening, tricuspid valve Doppler shows normal flow on the left. The fetus on the right has a large downward jet of tricuspid regurgitation, suggesting possible abnormalities; pulmonary stenosis was later diagnosed.

Source Images courtesy Dr. Christopher R. Harman

3-D blocks analyzed by tomographic section in a systematic approach yield a complete catalogue of anatomic cardiac landmarks in over 80% of fetuses at 12 weeks.

Complete endocardial cushion defect was diagnosed at 12 weeks. First trimester echocardiography was triggered by abnormal ductus venosus alone during routine screening.

Source Elsevier Global Medical News

The Evolution of Prenatal Assessment

obnews@elsevier.com

It is astonishing how much obstetrics and maternal-fetal medicine have grown. There was a time not too long ago when obstetric care was primarily delivered to the mother, with the fetus being a hopeful beneficiary. We could listen to the fetal heart rate using the fetoscope, but access to the fetus for its early developmental analysis was otherwise off-limits; its growth and development were assumed as part of maternal-focused obstetric care.

The introduction of electronic fetal monitoring gave us the opportunity to see a recording of the fetal heart rate pattern – its rhythm, and its quality – and we used that as an indirect measure of fetal well-being. Subsequently, ultrasound became available, and we could then evaluate the anatomy of the fetus – though usually in the latter part of pregnancy – and appreciate the morphology and overall growth performance.

It was not until relatively recently that the focus of prenatal assessment has shifted to the first trimester. In large measure, this change has been consumer driven. Families have become very interested in the development of their unborn children, and that interest increasingly has centered on obtaining more information earlier on. Such demand has pushed physician scientists working in the field to adapt their technologies to the first trimester. Recent research has, in large measure, advanced in response to parental interests.

Fetal diagnosis in the first trimester was thus born of this great desire and has evolved to the point where, as stated in this month's Master Class, it is becoming the standard of care. The field of first-trimester fetal diagnosis now consists of a series of biochemical and biophysical assessments that can truly evaluate fetal well-being at the current time and can contribute to the prediction of later development and later fetal well-being, or more importantly, the loss of fetal well-being.

It is in light of this burgeoning field of first-trimester evaluation that we decided to develop a Master Class to review this new state of the art. I have invited Dr. Christopher R. Harman, an international expert in the field of ultrasound and Doppler technology, to serve as this month's guest professor.

Dr. Harman is professor and interim chair of the department of obstetrics, gynecology, and reproductive sciences at the University of Maryland, Baltimore, as well as director of the school's maternal-fetal medicine division. He will explain how research is honing in on a first-trimester platform of assessments that holds even more potential for predicting risks and complications than we realized with the first-trimester screening algorithm that took hold more than 5 years ago.

It is fairly well appreciated that more than 1.7 million individuals living in the United States are now infected with HIV. What may be less appreciated by patients and physicians is that the impact of the epidemic on women has grown significantly over time.

In 2008, using a new national surveillance system, the Centers for Disease Control and Prevention reported that women comprised more than one-fourth (27%) of the 56,300 people estimated to have been newly infected with HIV in 2006. That is, an estimated 15,000 women were newly infected with HIV in 2006 alone (JAMA 2008;300:520-9).

As ob.gyns., we care for women of all ages, from adolescents through women in their senior years. Therefore, we are in the unique position to be able to identify HIV-infected individuals who could benefit significantly from early monitoring and treatment and to decrease the risk of transmission on a broader level. We can protect our patients, and they in turn can protect their partners and future children. This is a tremendous opportunity that we should not miss.

In 2006, the CDC moved away from HIV testing recommendations that were risk based and advised routine screening for HIV infection for all patients aged 13–64 years. It recommended that physicians notify their patients that testing will be performed unless they decline.

The American College of Obstetricians and Gynecologists weighed in the next year, saying that universal testing with patient notification is more effective in identifying infected patients than is targeted risk-based testing, largely because many women found to be infected with HIV did not consider themselves to have been at risk. Opt-out testing is less cumbersome, ACOG pointed out, because it removes the requirement for lengthy pretest counseling and for detailed, testing-related informed consent.

A 2007 survey of almost 400 medical staff at San Francisco General Hospital, which serves a population with a high HIV prevalence, showed that clinicians in obstetrics/gynecology and HIV infectious disease specialists were significantly more likely to routinely test their patients than were physicians in other specialties (J. Acquir. Immune Defic. Syndr. 2009;50:114-6).

As the authors say, however, this isn't surprising given the fact that ACOG, the CDC, and other national organizations have long called for universal prenatal HIV testing.

Other studies have suggested that compliance with the CDC recommendations is low – that many ob.gyns. as well as other primary care physicians – do not routinely offer HIV testing outside of the prenatal context. Even in high prevalence areas such as New Jersey, we have documented that many providers miss the opportunity to offer the test to all their patients, deeming them unlikely to be infected. This approach hinders early access to care for potentially infected patients and fails to address an unknowing risk of transmission to partners.

We need to think differently.

We do not ask patients: Do you want a chlamydia test? A Pap smear? A cholesterol test? We tell them, instead, that we're going to check their cholesterol levels, or that it's time for their Pap smear, or that we'd recommend a chlamydia test. We need to present HIV testing in the same way – as part of the routine battery of tests that will be performed unless the patient declines. Studies have shown, interestingly, that more patients accept recommended HIV testing when they know it's routinely offered to everyone, without an assessment of risk.

Furthermore, we need to do so in spite of race and in patients of all ages, with all the generations of women whom we see.

As ob.gyns., we must be cognizant of the changing face of HIV infection in women in the last 30 years and realize the unique challenge that we now face as the infection encompasses patients from a broader age spectrum than just those in their reproductive years. We have witnessed both an increased number of HIV infections in the older population and increased survival among individuals on highly active antiretroviral therapy (HAART), including those who were perinatally infected.

We also must appreciate that women who are engaged in a relationship with a known HIV-infected partner, regardless of their age, can prevent acquisition with barrier methods such as condom use or postexposure prophylaxis as delineated by the CDC for serodiscordant couples.

Women Older Than 50

Studies have consistently demonstrated that many women are sexually active into their 60s. Even when we appreciate this, we tend to dismiss the possibility that any of our older patients might have HIV infection. We tend to assume that our patients are in stable relationships and presume there is no value to HIV testing.

It's important to appreciate, however, that the number of people aged 50 years and older who are living with HIV/AIDS has been increasing in recent years. It is estimated that almost one-fourth of all people with HIV/AIDS in the United States are age 50 years and older. While this is partly because HAART has extended the lives of many HIV-infected people, it is also attributed to newly diagnosed infections in people over 50 years.

The 2008 CDC analysis that showed that women comprised more than one-fourth of the individuals newly infected with HIV in 2006 also found that 25% of the new infections were in individuals (men and women) aged 40–49 years (13,900 out of 56,300). Another 10% were in individuals aged 50 years and over (5,800 of 56,300). Approximately 30% of the infections were a result of heterosexual contact. Earlier data from the 1990s similarly showed over 10% of new AIDS cases occurring in people older than age 50 years.

Women of all ages can wrongly believe they are not at risk of contracting HIV. In one recent survey examining patient attitudes about HIV testing and knowledge about their own risk status, only 2% of approximately 850 women of various ages considered themselves at high risk for HIV infection despite the fact that almost half of them reported having had unprotected sex at some point with more than one partner. The women were patients of ob.gyn. members of ACOG's Collaborative Ambulatory Research Network (Matern. Child Health J. 2009;13:355-63).

Older women are generally even less knowledgeable about HIV transmission and how to protect themselves than are younger women, and they are not concerned about undesired pregnancy. For these reasons, many older women may not be practicing safer sex, increasing their risk for HIV and other sexually transmitted infections.

In a nine-question survey of 514 urban women aged 50 years and older (mean age of 62), the majority of women scored poorly, answering four or fewer of the questions correctly. Eighty-four percent correctly identified unprotected heterosexual sex as a moderate- to high-risk activity, but only 13% identified condoms as being very effective in preventing HIV, and 18% said condoms are not at all effective (J. Amer. Geriatr. Soc. 2004;52:1549-53).

In another study aimed at assessing differences in the characteristics of individuals (both men and women) who refuse testing and those who accept it, investigators found that HIV test refusal was associated with female gender, white race, older age, and higher educational level (AIDS Patient Care STDS 2006;20:84-92).

Older women must be educated about their risk of heterosexual transmission and the fact that the risk for HIV acquisition has been increasing since 1994 in the United States. They need to understand that normal physiologic changes in the menopausal period such as thinning of the vaginal mucosa, increased susceptibility to vaginal abrasions during intercourse, and changes in their immune response can make them more vulnerable to disease acquisition or progression.

It also is important to educate them about the effectiveness of condoms and the importance of knowing the HIV status of their partners, because it is estimated that approximately 21% of infected individuals in the United States do not know their HIV status.

Most of all, our patients should understand that 30 years into the epidemic, we have demonstrated excellent survival in individuals on treatment, particularly among those who were diagnosed early and who are receiving HAART. A recent report from the CDC shows that average life expectancy after HIV diagnosis in the general population increased from 10.5 to 22.5 years from 1996 to 2005 (J. Acquir. Immune Defic. Syndr. 2010;53:124-130).

Interestingly, as the report points out, studies have shown that although HIV-infected women had a greater life expectancy to begin with, they showed a lesser magnitude of improvement than did men, particularly white men. (Women's life expectancy changed from 12.6 to 23.6 years.) This observation highlights the importance of earlier diagnosis and link to care.

Knowing about the successes of HAART is important because women are less likely to opt out of HIV testing when they perceive the benefits. We can explain to patients – especially those who are apprehensive about the test – that the test is integrated into the annual health care panel (along with cholesterol and triglyceride testing, and genital cytology), and that, contrary to decades ago, we can treat and control HIV disease once it is diagnosed, which is more than we can do for certain types of cancer.

Our patients need to understand that it can be a manageable chronic disease as long as it is detected and effectively addressed early in the course of their infection. Today, we have access to a wide array of pamphlets and videos that we can offer in the waiting area to help patients understand this and appreciate the value of HIV testing.

Serodiscordant Couples

Thus far, there is limited standardization or consensus on how and when to provide counseling, testing, and prevention strategies for women who are involved in HIV serodiscordant relationships. However, most experts recommend that patients whose partners are HIV positive should be tested for HIV infection annually and encouraged to use effective prevention strategies such as the male or female condom.

Screening and treatment for sexually transmitted diseases should be done annually as coinfection can increase the risk of HIV transmission. In one of the studies demonstrating an impact of STD treatment – a randomized trial conducted more than 15 years ago in rural Tanzania – improved STD education and treatment reduced HIV incidence by about 40% (Lancet 1995;346:530-6).

In cases in which an unplanned sexual encounter with an HIV-positive partner occurs without protection, postexposure prophylaxis should be considered and given as soon as the event is identified, preferably within 48 hours. The CDC's recommendations for the use of antiretroviral postexposure prophylaxis, issued in 2005, call for a 28-day course of HAART (MMWR 2005;54[RR02]:1-20)

Decisions about the optimal postexposure therapy involve various factors, including the partner's antiretroviral history, adherence to the regimen, and most recent viral load. We may need to counsel patients, however, that having undetectable virus in the blood does not necessarily mean there will not be any virus in the genital tract. Discrepancies between serum and genital viral load have been reported among HIV-infected men and women on HAART.

If a woman engages in unprotected sex with a male of unknown serostatus, she can request postexposure prophylaxis. In this case, she should be counseled about the risks and benefits of postexposure HAART, as she may expose herself to unnecessary toxicities.

When faced with these situations we can obtain guidance from, or work in partnership with, the infectious disease provider who is managing the HIV-infected partner, or we can contact state or national phone lines for linkage to immediate care. Some health departments have established nonoccupational postexposure prophylaxis programs in their jurisdictions. Overall, it is important that we be aware of the availability of postexposure HAART and its possible risks and benefits.

In the near future, a woman whose partner is HIV positive should be able to benefit from antiretroviral microbicides used before or after intercourse. In the double-blind, randomized, and well-publicized CAPRISA (Centre for the AIDS Programme of Research in South Africa) 004 trial, a 1% vaginal gel formulation of tenofovir reduced HIV acquisition by approximately 39% overall and by 54% in women with high adherence to the protocol for gel application (Science 2010;329:1168-74). Another phase III trial of tenofovir is ongoing.

The field of safe reproduction for HIV serodiscordant couples also is advancing, such that women and their partners have various options for conceiving with minimal risk of transmitting the infection.

A large body of evidence suggests that reproductive technology – that is, sperm washing and artificial insemination – can help HIV-affected couples safely conceive, and the results of further CDC-sponsored research aimed at evaluating outcomes in couples who have used these techniques to conceive are expected soon. For many couples, however, such technologies are economically inaccessible.

Experts are looking at periconception preexposure prophylaxis as a potential strategy for preventing HIV transmission in couples trying to conceive. Under this approach, the seronegative partner would take antiretroviral drugs during periods of attempted conception, with the goal of preventing initial viral replication. Clinical trials evaluating its safety and efficacy are ongoing.

Other components of a risk-reduction program should include suppressive antiretroviral therapy for the infected partner (who may yet be eligible for such therapy under current recommendations for CD4 cell count), screening and pretreatment for other sexually transmitted infections, and unprotected sexual intercourse that is limited to times of peak fertility (AIDS 2010;24:1975-82).

Perinatally Infected Women

An increasing number of perinatally infected adolescents has been identified and engaged in care throughout the United States. This population is unique in that many were initially exposed to monotherapy or dual antiretroviral regimens and thus have developed resistance to several antiretroviral regimens. In addition, their adherence to HAART is lower than required to avert failure on current regimens.

They are a population that presents a challenge to ob.gyns. because many have high-risk sexual behaviors, and when they become pregnant, they are at high risk for operative delivery due to inadequate viral suppression.

We recently reported on the pregnancy outcomes of 10 perinatally infected adolescents referred to the high-risk obstetric clinic at our institution and delivered between 1997 and 2007. Neonatal outcomes were generally favorable, but these young women had a high rate of operative delivery (62%, compared with our institutional rate of 33%) due to the failure to achieve undetectable viral load (Am. J. Obstet. Gynecol. 2009;200:149.e1-5).

Our goals for these women should therefore include supporting and counseling on treatment adherence and on the selection of well-tolerated HAART regimens that can rapidly suppress viral load. We should also minimize the use of operative deliveries when feasible to avert compromise of their future reproductive health, and provide adequate contraceptive counseling to prevent unplanned pregnancies. We also must engage the partners of these young women in HIV prevention strategies and HIV testing (in our cohort, most of the sexual partners were seronegative males) and work with them in preventing the acquisition of other sexually transmitted infections. Abnormal cervical cytology and STIs affected 80% of the patients in our cohort, and high rates of STIs have been reported in other cohorts of HIV-infected adolescents.

Engaging the patients in care and viral suppression prior to conception and educating their partners to avert HIV acquisition will be among the highest priorities in years to come, especially since this group is more disenfranchised from the health care system and less likely to engage in pregnancy prevention and planning.

Dr. Bardequez said she had no relevant financial disclosures.

Arlene D. Bardeguez, M.D., M.P.H.

Source Courtesy Dr. Arlene D. Bardequez

Source Elsevier Global Medical News

Source Elsevier Global Medical News

HIV and Nonpregnant Women

obnews@elsevier.com

Since the beginning of the HIV/AIDS epidemic in the 1980s, women have been affected with this dreaded disease. Many have been at risk of acquiring the virus, many have become infected, and some consequently have been at risk of transmitting the virus to their offspring.

Ob.gyns. have played a major role in the dramatic decrease in mother-to-child transmission since its peak in 1992; prenatal screening followed by the use of antiretroviral therapy in women found to be HIV infected has reduced the risk of HIV transmission from a woman to her child to less than 2%.

Among nonpregnant women, our frequency of HIV testing has been variable, depending, for many of us, on the prevalence of HIV/AIDS in our communities and on our knowledge and/or perception of each patient's risk level.

In recent years, this selective approach to testing has been deemed faulty. It is an approach that has been subject to our own biases of risk and to misperceptions of many of the women we care for. Moreover, a risk-based approach has increasingly conflicted with the changing face of AIDS/HIV infection – most notably, the rise in heterosexual transmission and the fact that 1 in 5 infected individuals (including our patient's sexual partners) are estimated to be unaware of their infection.

Studies have shown that many women who are found to be HIV positive did not consider themselves to be at risk. Had we seen these women, we might not have considered them to be at risk either. According to the most recent HIV Surveillance Report from the Centers for Disease Control and Prevention, 30% of HIV-positive women were tested for HIV late in their illness (that is, diagnosed with AIDS within 1 year of testing positive). Had they been diagnosed earlier, these women could have had years added to their lives with the early and ongoing use of highly active antiretroviral therapy.

For these and other reasons, there are significant public health advantages to the recommendation issued by the CDC 5 years ago that health care providers routinely test (with patient notification and an opportunity to decline) all patients aged 13–64 years.

As providers for women of all ages, it is important that we are aware of changing trends and issues in the HIV epidemic and that we are attentive to the CDC's recommendations. It is for this reason that I have invited Dr. Arlene D. Bardeguez to address the role that the ob.gyn. plays in HIV prevention and testing in nonpregnant women.

Dr. Bardeguez serves as professor in the department of obstetrics, gynecology and women's health and director of HIV services at the New Jersey Medical School, Newark, N.J. Her special interest and expertise in HIV-infected women is evident in her clinical work and patient care, her research and writing, her teaching, and her work in the policy arena.

Here, she explains why HIV prevention strategies, including HIV pre- or postexposure prophylaxis, should become part of our routine clinical care. She also details how we can care for perinatally infected adolescents and how we must address the risks faced by our older patients. As providers of women's health through the age spectrum, she explains, we have an important role to play in the prevention of HIV acquisition and transmission.

It is fairly well appreciated that more than 1.7 million individuals living in the United States are now infected with HIV. What may be less appreciated by patients and physicians is that the impact of the epidemic on women has grown significantly over time.

In 2008, using a new national surveillance system, the Centers for Disease Control and Prevention reported that women comprised more than one-fourth (27%) of the 56,300 people estimated to have been newly infected with HIV in 2006. That is, an estimated 15,000 women were newly infected with HIV in 2006 alone (JAMA 2008;300:520-9).

As ob.gyns., we care for women of all ages, from adolescents through women in their senior years. Therefore, we are in the unique position to be able to identify HIV-infected individuals who could benefit significantly from early monitoring and treatment and to decrease the risk of transmission on a broader level. We can protect our patients, and they in turn can protect their partners and future children. This is a tremendous opportunity that we should not miss.

In 2006, the CDC moved away from HIV testing recommendations that were risk based and advised routine screening for HIV infection for all patients aged 13–64 years. It recommended that physicians notify their patients that testing will be performed unless they decline.

The American College of Obstetricians and Gynecologists weighed in the next year, saying that universal testing with patient notification is more effective in identifying infected patients than is targeted risk-based testing, largely because many women found to be infected with HIV did not consider themselves to have been at risk. Opt-out testing is less cumbersome, ACOG pointed out, because it removes the requirement for lengthy pretest counseling and for detailed, testing-related informed consent.

A 2007 survey of almost 400 medical staff at San Francisco General Hospital, which serves a population with a high HIV prevalence, showed that clinicians in obstetrics/gynecology and HIV infectious disease specialists were significantly more likely to routinely test their patients than were physicians in other specialties (J. Acquir. Immune Defic. Syndr. 2009;50:114-6).

As the authors say, however, this isn't surprising given the fact that ACOG, the CDC, and other national organizations have long called for universal prenatal HIV testing.

Other studies have suggested that compliance with the CDC recommendations is low – that many ob.gyns. as well as other primary care physicians – do not routinely offer HIV testing outside of the prenatal context. Even in high prevalence areas such as New Jersey, we have documented that many providers miss the opportunity to offer the test to all their patients, deeming them unlikely to be infected. This approach hinders early access to care for potentially infected patients and fails to address an unknowing risk of transmission to partners.

We need to think differently.

We do not ask patients: Do you want a chlamydia test? A Pap smear? A cholesterol test? We tell them, instead, that we're going to check their cholesterol levels, or that it's time for their Pap smear, or that we'd recommend a chlamydia test. We need to present HIV testing in the same way – as part of the routine battery of tests that will be performed unless the patient declines. Studies have shown, interestingly, that more patients accept recommended HIV testing when they know it's routinely offered to everyone, without an assessment of risk.

Furthermore, we need to do so in spite of race and in patients of all ages, with all the generations of women whom we see.

As ob.gyns., we must be cognizant of the changing face of HIV infection in women in the last 30 years and realize the unique challenge that we now face as the infection encompasses patients from a broader age spectrum than just those in their reproductive years. We have witnessed both an increased number of HIV infections in the older population and increased survival among individuals on highly active antiretroviral therapy (HAART), including those who were perinatally infected.

We also must appreciate that women who are engaged in a relationship with a known HIV-infected partner, regardless of their age, can prevent acquisition with barrier methods such as condom use or postexposure prophylaxis as delineated by the CDC for serodiscordant couples.

Women Older Than 50

Studies have consistently demonstrated that many women are sexually active into their 60s. Even when we appreciate this, we tend to dismiss the possibility that any of our older patients might have HIV infection. We tend to assume that our patients are in stable relationships and presume there is no value to HIV testing.

It's important to appreciate, however, that the number of people aged 50 years and older who are living with HIV/AIDS has been increasing in recent years. It is estimated that almost one-fourth of all people with HIV/AIDS in the United States are age 50 years and older. While this is partly because HAART has extended the lives of many HIV-infected people, it is also attributed to newly diagnosed infections in people over 50 years.

The 2008 CDC analysis that showed that women comprised more than one-fourth of the individuals newly infected with HIV in 2006 also found that 25% of the new infections were in individuals (men and women) aged 40–49 years (13,900 out of 56,300). Another 10% were in individuals aged 50 years and over (5,800 of 56,300). Approximately 30% of the infections were a result of heterosexual contact. Earlier data from the 1990s similarly showed over 10% of new AIDS cases occurring in people older than age 50 years.

Women of all ages can wrongly believe they are not at risk of contracting HIV. In one recent survey examining patient attitudes about HIV testing and knowledge about their own risk status, only 2% of approximately 850 women of various ages considered themselves at high risk for HIV infection despite the fact that almost half of them reported having had unprotected sex at some point with more than one partner. The women were patients of ob.gyn. members of ACOG's Collaborative Ambulatory Research Network (Matern. Child Health J. 2009;13:355-63).

Older women are generally even less knowledgeable about HIV transmission and how to protect themselves than are younger women, and they are not concerned about undesired pregnancy. For these reasons, many older women may not be practicing safer sex, increasing their risk for HIV and other sexually transmitted infections.

In a nine-question survey of 514 urban women aged 50 years and older (mean age of 62), the majority of women scored poorly, answering four or fewer of the questions correctly. Eighty-four percent correctly identified unprotected heterosexual sex as a moderate- to high-risk activity, but only 13% identified condoms as being very effective in preventing HIV, and 18% said condoms are not at all effective (J. Amer. Geriatr. Soc. 2004;52:1549-53).

In another study aimed at assessing differences in the characteristics of individuals (both men and women) who refuse testing and those who accept it, investigators found that HIV test refusal was associated with female gender, white race, older age, and higher educational level (AIDS Patient Care STDS 2006;20:84-92).

Older women must be educated about their risk of heterosexual transmission and the fact that the risk for HIV acquisition has been increasing since 1994 in the United States. They need to understand that normal physiologic changes in the menopausal period such as thinning of the vaginal mucosa, increased susceptibility to vaginal abrasions during intercourse, and changes in their immune response can make them more vulnerable to disease acquisition or progression.

It also is important to educate them about the effectiveness of condoms and the importance of knowing the HIV status of their partners, because it is estimated that approximately 21% of infected individuals in the United States do not know their HIV status.

Most of all, our patients should understand that 30 years into the epidemic, we have demonstrated excellent survival in individuals on treatment, particularly among those who were diagnosed early and who are receiving HAART. A recent report from the CDC shows that average life expectancy after HIV diagnosis in the general population increased from 10.5 to 22.5 years from 1996 to 2005 (J. Acquir. Immune Defic. Syndr. 2010;53:124-130).

Interestingly, as the report points out, studies have shown that although HIV-infected women had a greater life expectancy to begin with, they showed a lesser magnitude of improvement than did men, particularly white men. (Women's life expectancy changed from 12.6 to 23.6 years.) This observation highlights the importance of earlier diagnosis and link to care.

Knowing about the successes of HAART is important because women are less likely to opt out of HIV testing when they perceive the benefits. We can explain to patients – especially those who are apprehensive about the test – that the test is integrated into the annual health care panel (along with cholesterol and triglyceride testing, and genital cytology), and that, contrary to decades ago, we can treat and control HIV disease once it is diagnosed, which is more than we can do for certain types of cancer.

Our patients need to understand that it can be a manageable chronic disease as long as it is detected and effectively addressed early in the course of their infection. Today, we have access to a wide array of pamphlets and videos that we can offer in the waiting area to help patients understand this and appreciate the value of HIV testing.

Serodiscordant Couples

Thus far, there is limited standardization or consensus on how and when to provide counseling, testing, and prevention strategies for women who are involved in HIV serodiscordant relationships. However, most experts recommend that patients whose partners are HIV positive should be tested for HIV infection annually and encouraged to use effective prevention strategies such as the male or female condom.

Screening and treatment for sexually transmitted diseases should be done annually as coinfection can increase the risk of HIV transmission. In one of the studies demonstrating an impact of STD treatment – a randomized trial conducted more than 15 years ago in rural Tanzania – improved STD education and treatment reduced HIV incidence by about 40% (Lancet 1995;346:530-6).

In cases in which an unplanned sexual encounter with an HIV-positive partner occurs without protection, postexposure prophylaxis should be considered and given as soon as the event is identified, preferably within 48 hours. The CDC's recommendations for the use of antiretroviral postexposure prophylaxis, issued in 2005, call for a 28-day course of HAART (MMWR 2005;54[RR02]:1-20)

Decisions about the optimal postexposure therapy involve various factors, including the partner's antiretroviral history, adherence to the regimen, and most recent viral load. We may need to counsel patients, however, that having undetectable virus in the blood does not necessarily mean there will not be any virus in the genital tract. Discrepancies between serum and genital viral load have been reported among HIV-infected men and women on HAART.

If a woman engages in unprotected sex with a male of unknown serostatus, she can request postexposure prophylaxis. In this case, she should be counseled about the risks and benefits of postexposure HAART, as she may expose herself to unnecessary toxicities.

When faced with these situations we can obtain guidance from, or work in partnership with, the infectious disease provider who is managing the HIV-infected partner, or we can contact state or national phone lines for linkage to immediate care. Some health departments have established nonoccupational postexposure prophylaxis programs in their jurisdictions. Overall, it is important that we be aware of the availability of postexposure HAART and its possible risks and benefits.

In the near future, a woman whose partner is HIV positive should be able to benefit from antiretroviral microbicides used before or after intercourse. In the double-blind, randomized, and well-publicized CAPRISA (Centre for the AIDS Programme of Research in South Africa) 004 trial, a 1% vaginal gel formulation of tenofovir reduced HIV acquisition by approximately 39% overall and by 54% in women with high adherence to the protocol for gel application (Science 2010;329:1168-74). Another phase III trial of tenofovir is ongoing.

The field of safe reproduction for HIV serodiscordant couples also is advancing, such that women and their partners have various options for conceiving with minimal risk of transmitting the infection.

A large body of evidence suggests that reproductive technology – that is, sperm washing and artificial insemination – can help HIV-affected couples safely conceive, and the results of further CDC-sponsored research aimed at evaluating outcomes in couples who have used these techniques to conceive are expected soon. For many couples, however, such technologies are economically inaccessible.

Experts are looking at periconception preexposure prophylaxis as a potential strategy for preventing HIV transmission in couples trying to conceive. Under this approach, the seronegative partner would take antiretroviral drugs during periods of attempted conception, with the goal of preventing initial viral replication. Clinical trials evaluating its safety and efficacy are ongoing.

Other components of a risk-reduction program should include suppressive antiretroviral therapy for the infected partner (who may yet be eligible for such therapy under current recommendations for CD4 cell count), screening and pretreatment for other sexually transmitted infections, and unprotected sexual intercourse that is limited to times of peak fertility (AIDS 2010;24:1975-82).

Perinatally Infected Women

An increasing number of perinatally infected adolescents has been identified and engaged in care throughout the United States. This population is unique in that many were initially exposed to monotherapy or dual antiretroviral regimens and thus have developed resistance to several antiretroviral regimens. In addition, their adherence to HAART is lower than required to avert failure on current regimens.

They are a population that presents a challenge to ob.gyns. because many have high-risk sexual behaviors, and when they become pregnant, they are at high risk for operative delivery due to inadequate viral suppression.

We recently reported on the pregnancy outcomes of 10 perinatally infected adolescents referred to the high-risk obstetric clinic at our institution and delivered between 1997 and 2007. Neonatal outcomes were generally favorable, but these young women had a high rate of operative delivery (62%, compared with our institutional rate of 33%) due to the failure to achieve undetectable viral load (Am. J. Obstet. Gynecol. 2009;200:149.e1-5).

Our goals for these women should therefore include supporting and counseling on treatment adherence and on the selection of well-tolerated HAART regimens that can rapidly suppress viral load. We should also minimize the use of operative deliveries when feasible to avert compromise of their future reproductive health, and provide adequate contraceptive counseling to prevent unplanned pregnancies. We also must engage the partners of these young women in HIV prevention strategies and HIV testing (in our cohort, most of the sexual partners were seronegative males) and work with them in preventing the acquisition of other sexually transmitted infections. Abnormal cervical cytology and STIs affected 80% of the patients in our cohort, and high rates of STIs have been reported in other cohorts of HIV-infected adolescents.

Engaging the patients in care and viral suppression prior to conception and educating their partners to avert HIV acquisition will be among the highest priorities in years to come, especially since this group is more disenfranchised from the health care system and less likely to engage in pregnancy prevention and planning.

Dr. Bardequez said she had no relevant financial disclosures.

Arlene D. Bardeguez, M.D., M.P.H.

Source Courtesy Dr. Arlene D. Bardequez

Source Elsevier Global Medical News

Source Elsevier Global Medical News

HIV and Nonpregnant Women

obnews@elsevier.com

Since the beginning of the HIV/AIDS epidemic in the 1980s, women have been affected with this dreaded disease. Many have been at risk of acquiring the virus, many have become infected, and some consequently have been at risk of transmitting the virus to their offspring.

Ob.gyns. have played a major role in the dramatic decrease in mother-to-child transmission since its peak in 1992; prenatal screening followed by the use of antiretroviral therapy in women found to be HIV infected has reduced the risk of HIV transmission from a woman to her child to less than 2%.

Among nonpregnant women, our frequency of HIV testing has been variable, depending, for many of us, on the prevalence of HIV/AIDS in our communities and on our knowledge and/or perception of each patient's risk level.

In recent years, this selective approach to testing has been deemed faulty. It is an approach that has been subject to our own biases of risk and to misperceptions of many of the women we care for. Moreover, a risk-based approach has increasingly conflicted with the changing face of AIDS/HIV infection – most notably, the rise in heterosexual transmission and the fact that 1 in 5 infected individuals (including our patient's sexual partners) are estimated to be unaware of their infection.

Studies have shown that many women who are found to be HIV positive did not consider themselves to be at risk. Had we seen these women, we might not have considered them to be at risk either. According to the most recent HIV Surveillance Report from the Centers for Disease Control and Prevention, 30% of HIV-positive women were tested for HIV late in their illness (that is, diagnosed with AIDS within 1 year of testing positive). Had they been diagnosed earlier, these women could have had years added to their lives with the early and ongoing use of highly active antiretroviral therapy.

For these and other reasons, there are significant public health advantages to the recommendation issued by the CDC 5 years ago that health care providers routinely test (with patient notification and an opportunity to decline) all patients aged 13–64 years.

As providers for women of all ages, it is important that we are aware of changing trends and issues in the HIV epidemic and that we are attentive to the CDC's recommendations. It is for this reason that I have invited Dr. Arlene D. Bardeguez to address the role that the ob.gyn. plays in HIV prevention and testing in nonpregnant women.

Dr. Bardeguez serves as professor in the department of obstetrics, gynecology and women's health and director of HIV services at the New Jersey Medical School, Newark, N.J. Her special interest and expertise in HIV-infected women is evident in her clinical work and patient care, her research and writing, her teaching, and her work in the policy arena.

Here, she explains why HIV prevention strategies, including HIV pre- or postexposure prophylaxis, should become part of our routine clinical care. She also details how we can care for perinatally infected adolescents and how we must address the risks faced by our older patients. As providers of women's health through the age spectrum, she explains, we have an important role to play in the prevention of HIV acquisition and transmission.

It is fairly well appreciated that more than 1.7 million individuals living in the United States are now infected with HIV. What may be less appreciated by patients and physicians is that the impact of the epidemic on women has grown significantly over time.

In 2008, using a new national surveillance system, the Centers for Disease Control and Prevention reported that women comprised more than one-fourth (27%) of the 56,300 people estimated to have been newly infected with HIV in 2006. That is, an estimated 15,000 women were newly infected with HIV in 2006 alone (JAMA 2008;300:520-9).

As ob.gyns., we care for women of all ages, from adolescents through women in their senior years. Therefore, we are in the unique position to be able to identify HIV-infected individuals who could benefit significantly from early monitoring and treatment and to decrease the risk of transmission on a broader level. We can protect our patients, and they in turn can protect their partners and future children. This is a tremendous opportunity that we should not miss.

In 2006, the CDC moved away from HIV testing recommendations that were risk based and advised routine screening for HIV infection for all patients aged 13–64 years. It recommended that physicians notify their patients that testing will be performed unless they decline.

The American College of Obstetricians and Gynecologists weighed in the next year, saying that universal testing with patient notification is more effective in identifying infected patients than is targeted risk-based testing, largely because many women found to be infected with HIV did not consider themselves to have been at risk. Opt-out testing is less cumbersome, ACOG pointed out, because it removes the requirement for lengthy pretest counseling and for detailed, testing-related informed consent.

A 2007 survey of almost 400 medical staff at San Francisco General Hospital, which serves a population with a high HIV prevalence, showed that clinicians in obstetrics/gynecology and HIV infectious disease specialists were significantly more likely to routinely test their patients than were physicians in other specialties (J. Acquir. Immune Defic. Syndr. 2009;50:114-6).

As the authors say, however, this isn't surprising given the fact that ACOG, the CDC, and other national organizations have long called for universal prenatal HIV testing.

Other studies have suggested that compliance with the CDC recommendations is low – that many ob.gyns. as well as other primary care physicians – do not routinely offer HIV testing outside of the prenatal context. Even in high prevalence areas such as New Jersey, we have documented that many providers miss the opportunity to offer the test to all their patients, deeming them unlikely to be infected. This approach hinders early access to care for potentially infected patients and fails to address an unknowing risk of transmission to partners.

We need to think differently.

We do not ask patients: Do you want a chlamydia test? A Pap smear? A cholesterol test? We tell them, instead, that we're going to check their cholesterol levels, or that it's time for their Pap smear, or that we'd recommend a chlamydia test. We need to present HIV testing in the same way – as part of the routine battery of tests that will be performed unless the patient declines. Studies have shown, interestingly, that more patients accept recommended HIV testing when they know it's routinely offered to everyone, without an assessment of risk.

Furthermore, we need to do so in spite of race and in patients of all ages, with all the generations of women whom we see.

As ob.gyns., we must be cognizant of the changing face of HIV infection in women in the last 30 years and realize the unique challenge that we now face as the infection encompasses patients from a broader age spectrum than just those in their reproductive years. We have witnessed both an increased number of HIV infections in the older population and increased survival among individuals on highly active antiretroviral therapy (HAART), including those who were perinatally infected.

We also must appreciate that women who are engaged in a relationship with a known HIV-infected partner, regardless of their age, can prevent acquisition with barrier methods such as condom use or postexposure prophylaxis as delineated by the CDC for serodiscordant couples.

Women Older Than 50

Studies have consistently demonstrated that many women are sexually active into their 60s. Even when we appreciate this, we tend to dismiss the possibility that any of our older patients might have HIV infection. We tend to assume that our patients are in stable relationships and presume there is no value to HIV testing.

It's important to appreciate, however, that the number of people aged 50 years and older who are living with HIV/AIDS has been increasing in recent years. It is estimated that almost one-fourth of all people with HIV/AIDS in the United States are age 50 years and older. While this is partly because HAART has extended the lives of many HIV-infected people, it is also attributed to newly diagnosed infections in people over 50 years.

The 2008 CDC analysis that showed that women comprised more than one-fourth of the individuals newly infected with HIV in 2006 also found that 25% of the new infections were in individuals (men and women) aged 40–49 years (13,900 out of 56,300). Another 10% were in individuals aged 50 years and over (5,800 of 56,300). Approximately 30% of the infections were a result of heterosexual contact. Earlier data from the 1990s similarly showed over 10% of new AIDS cases occurring in people older than age 50 years.

Women of all ages can wrongly believe they are not at risk of contracting HIV. In one recent survey examining patient attitudes about HIV testing and knowledge about their own risk status, only 2% of approximately 850 women of various ages considered themselves at high risk for HIV infection despite the fact that almost half of them reported having had unprotected sex at some point with more than one partner. The women were patients of ob.gyn. members of ACOG's Collaborative Ambulatory Research Network (Matern. Child Health J. 2009;13:355-63).

Older women are generally even less knowledgeable about HIV transmission and how to protect themselves than are younger women, and they are not concerned about undesired pregnancy. For these reasons, many older women may not be practicing safer sex, increasing their risk for HIV and other sexually transmitted infections.

In a nine-question survey of 514 urban women aged 50 years and older (mean age of 62), the majority of women scored poorly, answering four or fewer of the questions correctly. Eighty-four percent correctly identified unprotected heterosexual sex as a moderate- to high-risk activity, but only 13% identified condoms as being very effective in preventing HIV, and 18% said condoms are not at all effective (J. Amer. Geriatr. Soc. 2004;52:1549-53).

In another study aimed at assessing differences in the characteristics of individuals (both men and women) who refuse testing and those who accept it, investigators found that HIV test refusal was associated with female gender, white race, older age, and higher educational level (AIDS Patient Care STDS 2006;20:84-92).

Older women must be educated about their risk of heterosexual transmission and the fact that the risk for HIV acquisition has been increasing since 1994 in the United States. They need to understand that normal physiologic changes in the menopausal period such as thinning of the vaginal mucosa, increased susceptibility to vaginal abrasions during intercourse, and changes in their immune response can make them more vulnerable to disease acquisition or progression.

It also is important to educate them about the effectiveness of condoms and the importance of knowing the HIV status of their partners, because it is estimated that approximately 21% of infected individuals in the United States do not know their HIV status.

Most of all, our patients should understand that 30 years into the epidemic, we have demonstrated excellent survival in individuals on treatment, particularly among those who were diagnosed early and who are receiving HAART. A recent report from the CDC shows that average life expectancy after HIV diagnosis in the general population increased from 10.5 to 22.5 years from 1996 to 2005 (J. Acquir. Immune Defic. Syndr. 2010;53:124-130).

Interestingly, as the report points out, studies have shown that although HIV-infected women had a greater life expectancy to begin with, they showed a lesser magnitude of improvement than did men, particularly white men. (Women's life expectancy changed from 12.6 to 23.6 years.) This observation highlights the importance of earlier diagnosis and link to care.

Knowing about the successes of HAART is important because women are less likely to opt out of HIV testing when they perceive the benefits. We can explain to patients – especially those who are apprehensive about the test – that the test is integrated into the annual health care panel (along with cholesterol and triglyceride testing, and genital cytology), and that, contrary to decades ago, we can treat and control HIV disease once it is diagnosed, which is more than we can do for certain types of cancer.

Our patients need to understand that it can be a manageable chronic disease as long as it is detected and effectively addressed early in the course of their infection. Today, we have access to a wide array of pamphlets and videos that we can offer in the waiting area to help patients understand this and appreciate the value of HIV testing.

Serodiscordant Couples

Thus far, there is limited standardization or consensus on how and when to provide counseling, testing, and prevention strategies for women who are involved in HIV serodiscordant relationships. However, most experts recommend that patients whose partners are HIV positive should be tested for HIV infection annually and encouraged to use effective prevention strategies such as the male or female condom.

Screening and treatment for sexually transmitted diseases should be done annually as coinfection can increase the risk of HIV transmission. In one of the studies demonstrating an impact of STD treatment – a randomized trial conducted more than 15 years ago in rural Tanzania – improved STD education and treatment reduced HIV incidence by about 40% (Lancet 1995;346:530-6).

In cases in which an unplanned sexual encounter with an HIV-positive partner occurs without protection, postexposure prophylaxis should be considered and given as soon as the event is identified, preferably within 48 hours. The CDC's recommendations for the use of antiretroviral postexposure prophylaxis, issued in 2005, call for a 28-day course of HAART (MMWR 2005;54[RR02]:1-20)

Decisions about the optimal postexposure therapy involve various factors, including the partner's antiretroviral history, adherence to the regimen, and most recent viral load. We may need to counsel patients, however, that having undetectable virus in the blood does not necessarily mean there will not be any virus in the genital tract. Discrepancies between serum and genital viral load have been reported among HIV-infected men and women on HAART.

If a woman engages in unprotected sex with a male of unknown serostatus, she can request postexposure prophylaxis. In this case, she should be counseled about the risks and benefits of postexposure HAART, as she may expose herself to unnecessary toxicities.

When faced with these situations we can obtain guidance from, or work in partnership with, the infectious disease provider who is managing the HIV-infected partner, or we can contact state or national phone lines for linkage to immediate care. Some health departments have established nonoccupational postexposure prophylaxis programs in their jurisdictions. Overall, it is important that we be aware of the availability of postexposure HAART and its possible risks and benefits.

In the near future, a woman whose partner is HIV positive should be able to benefit from antiretroviral microbicides used before or after intercourse. In the double-blind, randomized, and well-publicized CAPRISA (Centre for the AIDS Programme of Research in South Africa) 004 trial, a 1% vaginal gel formulation of tenofovir reduced HIV acquisition by approximately 39% overall and by 54% in women with high adherence to the protocol for gel application (Science 2010;329:1168-74). Another phase III trial of tenofovir is ongoing.

The field of safe reproduction for HIV serodiscordant couples also is advancing, such that women and their partners have various options for conceiving with minimal risk of transmitting the infection.

A large body of evidence suggests that reproductive technology – that is, sperm washing and artificial insemination – can help HIV-affected couples safely conceive, and the results of further CDC-sponsored research aimed at evaluating outcomes in couples who have used these techniques to conceive are expected soon. For many couples, however, such technologies are economically inaccessible.

Experts are looking at periconception preexposure prophylaxis as a potential strategy for preventing HIV transmission in couples trying to conceive. Under this approach, the seronegative partner would take antiretroviral drugs during periods of attempted conception, with the goal of preventing initial viral replication. Clinical trials evaluating its safety and efficacy are ongoing.

Other components of a risk-reduction program should include suppressive antiretroviral therapy for the infected partner (who may yet be eligible for such therapy under current recommendations for CD4 cell count), screening and pretreatment for other sexually transmitted infections, and unprotected sexual intercourse that is limited to times of peak fertility (AIDS 2010;24:1975-82).

Perinatally Infected Women

An increasing number of perinatally infected adolescents has been identified and engaged in care throughout the United States. This population is unique in that many were initially exposed to monotherapy or dual antiretroviral regimens and thus have developed resistance to several antiretroviral regimens. In addition, their adherence to HAART is lower than required to avert failure on current regimens.

They are a population that presents a challenge to ob.gyns. because many have high-risk sexual behaviors, and when they become pregnant, they are at high risk for operative delivery due to inadequate viral suppression.

We recently reported on the pregnancy outcomes of 10 perinatally infected adolescents referred to the high-risk obstetric clinic at our institution and delivered between 1997 and 2007. Neonatal outcomes were generally favorable, but these young women had a high rate of operative delivery (62%, compared with our institutional rate of 33%) due to the failure to achieve undetectable viral load (Am. J. Obstet. Gynecol. 2009;200:149.e1-5).

Our goals for these women should therefore include supporting and counseling on treatment adherence and on the selection of well-tolerated HAART regimens that can rapidly suppress viral load. We should also minimize the use of operative deliveries when feasible to avert compromise of their future reproductive health, and provide adequate contraceptive counseling to prevent unplanned pregnancies. We also must engage the partners of these young women in HIV prevention strategies and HIV testing (in our cohort, most of the sexual partners were seronegative males) and work with them in preventing the acquisition of other sexually transmitted infections. Abnormal cervical cytology and STIs affected 80% of the patients in our cohort, and high rates of STIs have been reported in other cohorts of HIV-infected adolescents.

Engaging the patients in care and viral suppression prior to conception and educating their partners to avert HIV acquisition will be among the highest priorities in years to come, especially since this group is more disenfranchised from the health care system and less likely to engage in pregnancy prevention and planning.

Dr. Bardequez said she had no relevant financial disclosures.

Arlene D. Bardeguez, M.D., M.P.H.

Source Courtesy Dr. Arlene D. Bardequez

Source Elsevier Global Medical News

Source Elsevier Global Medical News

HIV and Nonpregnant Women

obnews@elsevier.com

Since the beginning of the HIV/AIDS epidemic in the 1980s, women have been affected with this dreaded disease. Many have been at risk of acquiring the virus, many have become infected, and some consequently have been at risk of transmitting the virus to their offspring.

Ob.gyns. have played a major role in the dramatic decrease in mother-to-child transmission since its peak in 1992; prenatal screening followed by the use of antiretroviral therapy in women found to be HIV infected has reduced the risk of HIV transmission from a woman to her child to less than 2%.

Among nonpregnant women, our frequency of HIV testing has been variable, depending, for many of us, on the prevalence of HIV/AIDS in our communities and on our knowledge and/or perception of each patient's risk level.

In recent years, this selective approach to testing has been deemed faulty. It is an approach that has been subject to our own biases of risk and to misperceptions of many of the women we care for. Moreover, a risk-based approach has increasingly conflicted with the changing face of AIDS/HIV infection – most notably, the rise in heterosexual transmission and the fact that 1 in 5 infected individuals (including our patient's sexual partners) are estimated to be unaware of their infection.

Studies have shown that many women who are found to be HIV positive did not consider themselves to be at risk. Had we seen these women, we might not have considered them to be at risk either. According to the most recent HIV Surveillance Report from the Centers for Disease Control and Prevention, 30% of HIV-positive women were tested for HIV late in their illness (that is, diagnosed with AIDS within 1 year of testing positive). Had they been diagnosed earlier, these women could have had years added to their lives with the early and ongoing use of highly active antiretroviral therapy.

For these and other reasons, there are significant public health advantages to the recommendation issued by the CDC 5 years ago that health care providers routinely test (with patient notification and an opportunity to decline) all patients aged 13–64 years.

As providers for women of all ages, it is important that we are aware of changing trends and issues in the HIV epidemic and that we are attentive to the CDC's recommendations. It is for this reason that I have invited Dr. Arlene D. Bardeguez to address the role that the ob.gyn. plays in HIV prevention and testing in nonpregnant women.

Dr. Bardeguez serves as professor in the department of obstetrics, gynecology and women's health and director of HIV services at the New Jersey Medical School, Newark, N.J. Her special interest and expertise in HIV-infected women is evident in her clinical work and patient care, her research and writing, her teaching, and her work in the policy arena.

Here, she explains why HIV prevention strategies, including HIV pre- or postexposure prophylaxis, should become part of our routine clinical care. She also details how we can care for perinatally infected adolescents and how we must address the risks faced by our older patients. As providers of women's health through the age spectrum, she explains, we have an important role to play in the prevention of HIV acquisition and transmission.

While infant deaths associated with congenital heart defects have declined substantially over the past 2 decades, congenital heart disease remains the most common fatal congenital anomaly in the first year after birth.

Prematurity is the most significant cause of death in the first week of life, but after that point, birth defects take over as the leading cause of infant mortality (and overall, birth defects are the leading cause of infant mortality). Cardiovascular defects, in turn, are the single largest contributor to infant mortality attributable to birth defects – severe congenital heart disease (CHD) affects approximately 0.5% of all neonates and is responsible for one-third of deaths between birth and 1 year of life.

Prenatal diagnosis of CHD is important because early detection can improve the planning of services and provision of coordinated multidisciplinary care. While most fetal therapy for CHD is investigational and still evolving, studies from all over the world have shown that if a baby is known to have a heart problem and is delivered at a facility that provides definitive care, the baby will likely fare better.

Unfortunately, most infants born with CHD do not have defined risk factors. As obstetricians we must always be alert to the possibility that, even without a clear risk factor, there could be a cardiovascular problem.

It is important to know, on the other hand, who is at increased risk and should be evaluated further, and who is not at increased risk. We know now that certain infants whom we haven't traditionally thought of as being at risk for CHD are indeed at higher risk. Our knowledge of familial contributions to CHD has grown, for instance, giving obstetricians the responsibility to be alert for potential familial genetic patterns so that the proper counseling can be provided.

There are also noninherited risk factors that can be identified and potentially modified. It is unclear what proportion of CHD can be prevented, but at the least, obstetricians should be aware of such risk factors so they can provide guidance to parents and future parents that could reduce the risk of their children having a major cardiovascular malformation, and so they can ensure proper surveillance in any pregnancy.

Familial Risks

Over the past 15 years or so, our understanding of inherited causes of congenital heart defects has increased significantly, and while there is much more to learn, it is now appreciated that genetics plays a greater role in CHD than previously estimated.

Molecular genetics studies in families with multiple affected individuals have even led to the identification of specific genetic abnormalities for several forms of CHD, such as the single gene mutation sometimes seen in tetralogy of Fallot; others are related to mutations in more than one gene.

While most chromosome defects are not inherited, some anomalies or syndromes with cardiac phenotypes – for instance, those involving microdeletions or gonadal mosaicism – can be inherited and play a small but increasingly appreciated role in CHD. The William-Beuren syndrome and the 22q11.2 deletion syndrome, for instance, are microdeletion syndromes that show autosomal dominant inheritance.

Overall, parents of a child with CHD that is not associated with a typical chromosomal aberration have a 2%–3% chance of having another child with CHD; it is estimated that half of affected siblings will be diagnosed with the same lesion, the other half with a different lesion.

Classic Mendelian transmission is occasionally responsible for inherited CHD in families, but recurrence risk is significant only when the family history of CHD involves first- or second-degree relatives.

Fetal echocardiography is definitely warranted when the mother or father – or a sibling – of the fetus has CHD, as well as when CHD has affected a parent's own mother, father, sister, or brother.

Once you get further out in the family history, to cousins and other third-degree and more distant relatives, the risk is not high enough to warrant a more detailed fetal examination. This is important for counseling; parents who are worried about a history of CHD in third-degree relatives should be reassured.

Among the changes in patterns of referral for fetal echocardiography that we detected at Yale-New Haven Hospital from 1985 to 2003 was an 18% increase in referrals for a family history of CHD, including family history in more distant relatives.

This increase was not accompanied by any change in the percentage of structural cardiovascular heart defects consequently detected (J. Ultrasound Med. 2006;25:197-202).

As an increasing number of patients with major congenital cardiac defects have been surviving to adulthood and parenthood, numerous investigators have attempted to identify specific recurrence risks.

One study done in the United Kingdom, for instance, identified 727 adults with surgically modified major heart defects and their 393 live offspring. Of these infants, 16 were born with cardiac malformations, representing a total recurrence risk of 4.1%. Recurrence risk in offspring ranged from 3.1% for tetralogy of Fallot to 7.8% for atrioventricular septal defect (Lancet 1998;351:311-6).

CHD occurred more often in offspring of affected mothers (5.7%) than affected fathers (2.2%). Compared with offspring, sibling risk was significantly lower: 2.1% overall.

A much larger and more recent study done in Denmark again showed strong familial clustering in first-degree relatives for CHDs, particularly for recurrences of the same heart defect. (Very few families experience a second heart defect, the study found.)

The study – a national cohort study of more than 1.7 million people born during a 29-year period – also is one of the largest studies, if not the largest study, to document a decreasing risk as family history gets more distant.

The relative risks of any CHD in singletons were 3.21 for a family history of any CHD in first-degree relatives, 1.78 for a family history involving second-degree relatives, and 1.10 for a family history in third-degree relatives (Circulation 2009;120:295-301).

Only with a history of affected first- and second-degree relatives was there a statistically greater chance of having an affected fetus.

In twins, the relative risks of any CHD were 12.5 for same-sex twins and 6.93 for twins of both sexes, the Danish investigators noted.

And in looking at the contribution of CHD family history to the total number of CHD cases in the population, they found that 2.2% of heart defect cases in the population were attributed to CHD family history in first-degree relatives.

Another notable finding from other studies is that women with cyanotic heart disease have a higher risk of having a baby with CHD than do women with noncyanotic heart disease.

Maternal Risks

Just as we've learned much about inherited causes of congenital heart disease over the past 15 years, there is a growing body of epidemiologic literature on potential fetal exposures – from maternal illnesses to maternal drug exposures – that can alter the risk of CHD.

The risk factors for CHD maternal teratogen exposure are numerous. They include lithium, alcohol, isotretinoin, and various anticonvulsant drugs, and many are well-appreciated by ob.gyns.

Other factors for which risk has been well determined, and can be better appreciated, include:

▸ High vitamin A intake. Findings are not completely consistent, but we have enough data now to suggest that women who take extra-large doses of vitamin A may actually be putting their fetuses at risk of birth defects.

One study worth noting found that among more than 22,000 pregnant women, those who took more than 10,000 IU of vitamin A from supplements were 4.8 times more likely to have babies with birth defects associated with cranial-neural-crest tissue than were women who consumed 5,000 IU or less per day (N. Engl. J. Med. 1995;333:1369-73).

Typical prenatal vitamins have 5,000 IU in each dose. This is one reason that women with twin pregnancies can take extra folic acid, but should not double up on their prenatal multivitamins.

▸ Folate antagonists. Common drugs such as trimethoprim, triamterene, sulfasalazine, phenytoin, phenobarbital, primidone, carbamazepine, and cholestyramine may increase the risk not only of neural-tube defects, but of cardiovascular defects as well, in addition to oral clefts and urinary tract defects.

Fortunately, studies such as one published in 2000 involving thousands of infants show that the folic acid component of prenatal multivitamin supplements can reduce the risks of these defects, just as it reduces the risk of neural-tube defects (N. Engl. J. Med. 2000;343:1608-14).

▸ Paxil (paroxetine). This is the only antidepressant that has been shown in some studies to increase the risk of CHD. Its manufacturer, GlaxoSmithKline, changed the label's pregnancy precaution in 2005 from a Pregnancy Category C to Category D. If a patient becomes pregnant while taking the drug, she should be advised of potential harm to the fetus.

One epidemiologic study showed that women taking Paxil were two times more likely to have an infant with CHD, and 2.2 times more likely to have an infant with any congenital malformation, than were women taking other antidepressants.

▸ Diabetes. The risk of fetal anomalies with maternal diabetes and elevated hemoglobin A_1c in early pregnancy has been known for some time.

In a study published in 1981, for instance, the risk of CHD and other fetal anomalies rose from 5% to 22% as maternal HbA_1c rose from a range of 7%–8.5% to greater than 8.5% (N. Engl. J. Med. 1981;304:1331-4).

We've also known for some time that differences in CHD may exist even with good metabolic control. Studies have documented mild cardiac hypertrophy involving the interventricular septum and the ventricular free walls, for instance, in diabetic mothers with good metabolic control (J. Pediatr. 1991;118:103-7 and Am J. Obstet. Gynecol. 1991;164:837-43). Such growth affects cardiac diastolic function.

With the epidemic of obesity and the increasing prevalence of early type 2 diabetes and glucose intolerance among women of childbearing age, however, this is an increasingly important risk factor to appreciate and counsel about.

The most important message, we've learned, is that there's no such thing as perfect control – that good metabolic control will not necessarily protect diabetic mothers from the higher risk of CHD.

Just as detection and appropriate management of diabetes before and during pregnancy are of utmost importance, so is fetal echocardiography for every pregnant woman who has pregestational diabetes – even diabetes that is well controlled.

Indeed, the same review of all fetal echocardiography performed between 1985 and 2003 at Yale-New Haven Hospital that showed an increase in referrals for family history also showed a 9% increase in the proportion of studies done for pregestational diabetes as the indication. The increase was most striking when it came to women who had recently been diagnosed, compared with long-standing diabetes – a finding that likely reflects the increase in obesity.

▸ Phenylketonuria. Fortunately, strict dietary control before conception and during pregnancy can reduce the increased risk of heart defects faced by women with this disorder. We need to remember that aspartame (NutraSweet) can cause phenylalanine levels to increase in women with PKU, but not in normal women. Women without PKU can be reassured that there is no evidence linking aspartame with birth defects.

Fetal Risks

Among the fetal risk factors important to consider are:

▸ Extracardiac anomalies. The identification of any extracardiac anomaly should raise our level of suspicion for other anomalies, including congenital heart defects. If we see one anomaly – anywhere in the fetus – there often are really two. And if we see two anomalies, there frequently are really three.

▸ Nonimmune hydrops. All fetuses found to have NIH should be evaluated with fetal echocardiography. Structural heart disease in fetuses with NIH is usually indicative of a poor prognosis for survival, but when rhythm disturbances/arrhythmias are detected in association with NIH, there is sometimes an option for prenatal treatment.

▸ Fetal arrhythmias. An irregular heartbeat is usually not a problem, but tachycardia and especially bradycardia are associated with an increased risk of CHD. There may be structural heart defects in as many as half of fetuses with fixed bradycardia (i.e., baseline heart rate less than 100). In general, it is best that all arrhythmias are examined; it is just too hard to tell them apart by auscultation alone.

▸ Nuchal translucency. Numerous studies have shown that elevated first-trimester nuchal translucency (NT) increases the risk of major congenital heart defects in chromosomally normal fetuses, and that risk increases with increasing NT measurement.

In a large prospective multicenter study conducted by the National Institute of Child Health and Human Development, for instance, investigators identified 21 cases of major congenital heart defects in 8,167 chromosomally normal pregnancies. They reported that the incidence of CHD per 1,000 pregnancies rose from 1.9 with an NT measurement of less than 2.0 mm, to 4.8 with an NT measurement of 2.0–2.4 mm, to 6.0 with an NT measurement of 2.5–3.4 mm, to 23 of every 1,000 pregnancies with an NT measurement of 3.5 mm or greater (Am. J. Obstet. Gynecol. 2005;192:1357–61).

If the NT is greater than 3.5 mm, measured by a qualified sonographer or sonologist at 11–14 weeks as part of an aneuploidy risk assessment scan, the patient should be referred for fetal echocardiography.

▸ In vitro fertilization. We recently investigated the prevalence of congenital heart defects among IVF pregnancies at our referral program at Yale, and found that children conceived through IVF were 3–12 times as likely to have CHD as was the general population (J. Ultrasound Med. 2010;29:917-22).

Similar data have come from Australia and Europe, with reported odds ratios for IVF versus natural conception of 3–4. I tell patients, therefore, that it's not just one place or one study suggesting risk. Indeed, it's a meaningful risk factor.

▸ Monochorionic twins. In a systemic literature review we conducted several years ago that included 40 fetuses with CHDs among 830 fetuses from monochorionic/diamniotic twin gestations, the rate of CHDs in these twin gestations was significantly higher than the prevalence rate of CHDs in the general population (J. Ultrasound Med. 2007;26:1491-8).

Congenital heart defects were almost three times as likely to complicate the monochorionic/diamniotic twin gestations affected by twin-to-twin transfusion syndrome (TTTS), compared with those without TTTS, but an increase occurred regardless of the presence of TTTS. Ventricular septal defects were among the most frequent heart defects. Fetal echocardiography may be considered for all monochorionic/diamniotic twin gestations.

Dr. Copel disclosed that he has received research support from Philips Healthcare and Siemens Healthcare. Both companies manufacture echocardiography and other ultrasound systems.

A two-dimensional four-chamber view of a normal fetal heart (left). Fetal image of a complete atrioventricular septal defect with large atrial (**) and ventricular (*) septal defects (right).

Source Images: © Elsevier Inc.

Diagnosing Birth Defects

Birth defects continue to account for the majority of infant deaths, and their biologic basis continues to present a mixed picture, with the majority of causes still unknown. Cardiac defects – the most common type of birth defect – result in varying types of morbidity, but remain the most severe and disabling of all birth defects. As our guest author points out below, cardiovascular defects are the single largest contributor to birth defect–attributable infant mortality.

What is clear is the fact that when birth defects are identified prenatally, decisions can be made regarding the timing and route of delivery and even the facility where delivery occurs. We know that such decision making can be highly influential on the ultimate outcome of the infant.

Fortunately, there has been improvement in recent years in diagnostic technology that enables more prenatal diagnosis of congenital heart disease, and certain conditions that in the past went unknown or undiagnosed are now being identified early so that specialists can intervene in a timely manner.

While certain pregnancies are clearly at higher risk – those involving mothers who have pregestational diabetes, for instance, or mothers with exposure to particular toxins – there are other scenarios and factors that increase risk of which we should be aware.

It's a tricky evaluative process, for, as our guest author points out, most infants born with congenital heart disease do not have defined risk factors. At the least, however, we can be aware of the familial, maternal, and fetal factors that are known to increase risk and then ensure that all at-risk pregnancies are properly evaluated – often with fetal echocardiography – to determine if a cardiac defect is present and, if so, to plan the delivery-related issues of timing, mode, and facility.

In light of the importance of this subject and the role that ultrasound scanning, genetic counseling, and early decision making and planning can play in the ultimate outcome of the fetus, we decided to do a Master Class on congenital heart defects. We have invited Dr. Joshua A. Copel, professor of obstetrics, gynecology, and reproductive services, and of pediatrics, and vice chair of obstetrics at Yale University, New Haven, Conn., to serve as our guest professor.

Dr. Copel has written and lectured extensively on fetal arrhythmias, fetal cardiac anomalies and congenital heart disease, and sonographic monitoring and fetal echocardiography. Here he discusses what we should know about both familial contributions to congenital heart disease and various noninherited risk factors.

While infant deaths associated with congenital heart defects have declined substantially over the past 2 decades, congenital heart disease remains the most common fatal congenital anomaly in the first year after birth.

Prematurity is the most significant cause of death in the first week of life, but after that point, birth defects take over as the leading cause of infant mortality (and overall, birth defects are the leading cause of infant mortality). Cardiovascular defects, in turn, are the single largest contributor to infant mortality attributable to birth defects – severe congenital heart disease (CHD) affects approximately 0.5% of all neonates and is responsible for one-third of deaths between birth and 1 year of life.

Prenatal diagnosis of CHD is important because early detection can improve the planning of services and provision of coordinated multidisciplinary care. While most fetal therapy for CHD is investigational and still evolving, studies from all over the world have shown that if a baby is known to have a heart problem and is delivered at a facility that provides definitive care, the baby will likely fare better.

Unfortunately, most infants born with CHD do not have defined risk factors. As obstetricians we must always be alert to the possibility that, even without a clear risk factor, there could be a cardiovascular problem.

It is important to know, on the other hand, who is at increased risk and should be evaluated further, and who is not at increased risk. We know now that certain infants whom we haven't traditionally thought of as being at risk for CHD are indeed at higher risk. Our knowledge of familial contributions to CHD has grown, for instance, giving obstetricians the responsibility to be alert for potential familial genetic patterns so that the proper counseling can be provided.

There are also noninherited risk factors that can be identified and potentially modified. It is unclear what proportion of CHD can be prevented, but at the least, obstetricians should be aware of such risk factors so they can provide guidance to parents and future parents that could reduce the risk of their children having a major cardiovascular malformation, and so they can ensure proper surveillance in any pregnancy.

Familial Risks

Over the past 15 years or so, our understanding of inherited causes of congenital heart defects has increased significantly, and while there is much more to learn, it is now appreciated that genetics plays a greater role in CHD than previously estimated.

Molecular genetics studies in families with multiple affected individuals have even led to the identification of specific genetic abnormalities for several forms of CHD, such as the single gene mutation sometimes seen in tetralogy of Fallot; others are related to mutations in more than one gene.

While most chromosome defects are not inherited, some anomalies or syndromes with cardiac phenotypes – for instance, those involving microdeletions or gonadal mosaicism – can be inherited and play a small but increasingly appreciated role in CHD. The William-Beuren syndrome and the 22q11.2 deletion syndrome, for instance, are microdeletion syndromes that show autosomal dominant inheritance.

Overall, parents of a child with CHD that is not associated with a typical chromosomal aberration have a 2%–3% chance of having another child with CHD; it is estimated that half of affected siblings will be diagnosed with the same lesion, the other half with a different lesion.

Classic Mendelian transmission is occasionally responsible for inherited CHD in families, but recurrence risk is significant only when the family history of CHD involves first- or second-degree relatives.

Fetal echocardiography is definitely warranted when the mother or father – or a sibling – of the fetus has CHD, as well as when CHD has affected a parent's own mother, father, sister, or brother.

Once you get further out in the family history, to cousins and other third-degree and more distant relatives, the risk is not high enough to warrant a more detailed fetal examination. This is important for counseling; parents who are worried about a history of CHD in third-degree relatives should be reassured.

Among the changes in patterns of referral for fetal echocardiography that we detected at Yale-New Haven Hospital from 1985 to 2003 was an 18% increase in referrals for a family history of CHD, including family history in more distant relatives.

This increase was not accompanied by any change in the percentage of structural cardiovascular heart defects consequently detected (J. Ultrasound Med. 2006;25:197-202).

As an increasing number of patients with major congenital cardiac defects have been surviving to adulthood and parenthood, numerous investigators have attempted to identify specific recurrence risks.

One study done in the United Kingdom, for instance, identified 727 adults with surgically modified major heart defects and their 393 live offspring. Of these infants, 16 were born with cardiac malformations, representing a total recurrence risk of 4.1%. Recurrence risk in offspring ranged from 3.1% for tetralogy of Fallot to 7.8% for atrioventricular septal defect (Lancet 1998;351:311-6).

CHD occurred more often in offspring of affected mothers (5.7%) than affected fathers (2.2%). Compared with offspring, sibling risk was significantly lower: 2.1% overall.

A much larger and more recent study done in Denmark again showed strong familial clustering in first-degree relatives for CHDs, particularly for recurrences of the same heart defect. (Very few families experience a second heart defect, the study found.)

The study – a national cohort study of more than 1.7 million people born during a 29-year period – also is one of the largest studies, if not the largest study, to document a decreasing risk as family history gets more distant.

The relative risks of any CHD in singletons were 3.21 for a family history of any CHD in first-degree relatives, 1.78 for a family history involving second-degree relatives, and 1.10 for a family history in third-degree relatives (Circulation 2009;120:295-301).

Only with a history of affected first- and second-degree relatives was there a statistically greater chance of having an affected fetus.

In twins, the relative risks of any CHD were 12.5 for same-sex twins and 6.93 for twins of both sexes, the Danish investigators noted.

And in looking at the contribution of CHD family history to the total number of CHD cases in the population, they found that 2.2% of heart defect cases in the population were attributed to CHD family history in first-degree relatives.

Another notable finding from other studies is that women with cyanotic heart disease have a higher risk of having a baby with CHD than do women with noncyanotic heart disease.

Maternal Risks

Just as we've learned much about inherited causes of congenital heart disease over the past 15 years, there is a growing body of epidemiologic literature on potential fetal exposures – from maternal illnesses to maternal drug exposures – that can alter the risk of CHD.

The risk factors for CHD maternal teratogen exposure are numerous. They include lithium, alcohol, isotretinoin, and various anticonvulsant drugs, and many are well-appreciated by ob.gyns.

Other factors for which risk has been well determined, and can be better appreciated, include:

▸ High vitamin A intake. Findings are not completely consistent, but we have enough data now to suggest that women who take extra-large doses of vitamin A may actually be putting their fetuses at risk of birth defects.

One study worth noting found that among more than 22,000 pregnant women, those who took more than 10,000 IU of vitamin A from supplements were 4.8 times more likely to have babies with birth defects associated with cranial-neural-crest tissue than were women who consumed 5,000 IU or less per day (N. Engl. J. Med. 1995;333:1369-73).

Typical prenatal vitamins have 5,000 IU in each dose. This is one reason that women with twin pregnancies can take extra folic acid, but should not double up on their prenatal multivitamins.

▸ Folate antagonists. Common drugs such as trimethoprim, triamterene, sulfasalazine, phenytoin, phenobarbital, primidone, carbamazepine, and cholestyramine may increase the risk not only of neural-tube defects, but of cardiovascular defects as well, in addition to oral clefts and urinary tract defects.

Fortunately, studies such as one published in 2000 involving thousands of infants show that the folic acid component of prenatal multivitamin supplements can reduce the risks of these defects, just as it reduces the risk of neural-tube defects (N. Engl. J. Med. 2000;343:1608-14).

▸ Paxil (paroxetine). This is the only antidepressant that has been shown in some studies to increase the risk of CHD. Its manufacturer, GlaxoSmithKline, changed the label's pregnancy precaution in 2005 from a Pregnancy Category C to Category D. If a patient becomes pregnant while taking the drug, she should be advised of potential harm to the fetus.

One epidemiologic study showed that women taking Paxil were two times more likely to have an infant with CHD, and 2.2 times more likely to have an infant with any congenital malformation, than were women taking other antidepressants.

▸ Diabetes. The risk of fetal anomalies with maternal diabetes and elevated hemoglobin A_1c in early pregnancy has been known for some time.

In a study published in 1981, for instance, the risk of CHD and other fetal anomalies rose from 5% to 22% as maternal HbA_1c rose from a range of 7%–8.5% to greater than 8.5% (N. Engl. J. Med. 1981;304:1331-4).

We've also known for some time that differences in CHD may exist even with good metabolic control. Studies have documented mild cardiac hypertrophy involving the interventricular septum and the ventricular free walls, for instance, in diabetic mothers with good metabolic control (J. Pediatr. 1991;118:103-7 and Am J. Obstet. Gynecol. 1991;164:837-43). Such growth affects cardiac diastolic function.

With the epidemic of obesity and the increasing prevalence of early type 2 diabetes and glucose intolerance among women of childbearing age, however, this is an increasingly important risk factor to appreciate and counsel about.

The most important message, we've learned, is that there's no such thing as perfect control – that good metabolic control will not necessarily protect diabetic mothers from the higher risk of CHD.

Just as detection and appropriate management of diabetes before and during pregnancy are of utmost importance, so is fetal echocardiography for every pregnant woman who has pregestational diabetes – even diabetes that is well controlled.

Indeed, the same review of all fetal echocardiography performed between 1985 and 2003 at Yale-New Haven Hospital that showed an increase in referrals for family history also showed a 9% increase in the proportion of studies done for pregestational diabetes as the indication. The increase was most striking when it came to women who had recently been diagnosed, compared with long-standing diabetes – a finding that likely reflects the increase in obesity.

▸ Phenylketonuria. Fortunately, strict dietary control before conception and during pregnancy can reduce the increased risk of heart defects faced by women with this disorder. We need to remember that aspartame (NutraSweet) can cause phenylalanine levels to increase in women with PKU, but not in normal women. Women without PKU can be reassured that there is no evidence linking aspartame with birth defects.

Fetal Risks

Among the fetal risk factors important to consider are:

▸ Extracardiac anomalies. The identification of any extracardiac anomaly should raise our level of suspicion for other anomalies, including congenital heart defects. If we see one anomaly – anywhere in the fetus – there often are really two. And if we see two anomalies, there frequently are really three.

▸ Nonimmune hydrops. All fetuses found to have NIH should be evaluated with fetal echocardiography. Structural heart disease in fetuses with NIH is usually indicative of a poor prognosis for survival, but when rhythm disturbances/arrhythmias are detected in association with NIH, there is sometimes an option for prenatal treatment.

▸ Fetal arrhythmias. An irregular heartbeat is usually not a problem, but tachycardia and especially bradycardia are associated with an increased risk of CHD. There may be structural heart defects in as many as half of fetuses with fixed bradycardia (i.e., baseline heart rate less than 100). In general, it is best that all arrhythmias are examined; it is just too hard to tell them apart by auscultation alone.

▸ Nuchal translucency. Numerous studies have shown that elevated first-trimester nuchal translucency (NT) increases the risk of major congenital heart defects in chromosomally normal fetuses, and that risk increases with increasing NT measurement.

In a large prospective multicenter study conducted by the National Institute of Child Health and Human Development, for instance, investigators identified 21 cases of major congenital heart defects in 8,167 chromosomally normal pregnancies. They reported that the incidence of CHD per 1,000 pregnancies rose from 1.9 with an NT measurement of less than 2.0 mm, to 4.8 with an NT measurement of 2.0–2.4 mm, to 6.0 with an NT measurement of 2.5–3.4 mm, to 23 of every 1,000 pregnancies with an NT measurement of 3.5 mm or greater (Am. J. Obstet. Gynecol. 2005;192:1357–61).

If the NT is greater than 3.5 mm, measured by a qualified sonographer or sonologist at 11–14 weeks as part of an aneuploidy risk assessment scan, the patient should be referred for fetal echocardiography.

▸ In vitro fertilization. We recently investigated the prevalence of congenital heart defects among IVF pregnancies at our referral program at Yale, and found that children conceived through IVF were 3–12 times as likely to have CHD as was the general population (J. Ultrasound Med. 2010;29:917-22).

Similar data have come from Australia and Europe, with reported odds ratios for IVF versus natural conception of 3–4. I tell patients, therefore, that it's not just one place or one study suggesting risk. Indeed, it's a meaningful risk factor.

▸ Monochorionic twins. In a systemic literature review we conducted several years ago that included 40 fetuses with CHDs among 830 fetuses from monochorionic/diamniotic twin gestations, the rate of CHDs in these twin gestations was significantly higher than the prevalence rate of CHDs in the general population (J. Ultrasound Med. 2007;26:1491-8).

Congenital heart defects were almost three times as likely to complicate the monochorionic/diamniotic twin gestations affected by twin-to-twin transfusion syndrome (TTTS), compared with those without TTTS, but an increase occurred regardless of the presence of TTTS. Ventricular septal defects were among the most frequent heart defects. Fetal echocardiography may be considered for all monochorionic/diamniotic twin gestations.

Dr. Copel disclosed that he has received research support from Philips Healthcare and Siemens Healthcare. Both companies manufacture echocardiography and other ultrasound systems.

A two-dimensional four-chamber view of a normal fetal heart (left). Fetal image of a complete atrioventricular septal defect with large atrial (**) and ventricular (*) septal defects (right).

Source Images: © Elsevier Inc.

Diagnosing Birth Defects

Birth defects continue to account for the majority of infant deaths, and their biologic basis continues to present a mixed picture, with the majority of causes still unknown. Cardiac defects – the most common type of birth defect – result in varying types of morbidity, but remain the most severe and disabling of all birth defects. As our guest author points out below, cardiovascular defects are the single largest contributor to birth defect–attributable infant mortality.

What is clear is the fact that when birth defects are identified prenatally, decisions can be made regarding the timing and route of delivery and even the facility where delivery occurs. We know that such decision making can be highly influential on the ultimate outcome of the infant.

Fortunately, there has been improvement in recent years in diagnostic technology that enables more prenatal diagnosis of congenital heart disease, and certain conditions that in the past went unknown or undiagnosed are now being identified early so that specialists can intervene in a timely manner.

While certain pregnancies are clearly at higher risk – those involving mothers who have pregestational diabetes, for instance, or mothers with exposure to particular toxins – there are other scenarios and factors that increase risk of which we should be aware.

It's a tricky evaluative process, for, as our guest author points out, most infants born with congenital heart disease do not have defined risk factors. At the least, however, we can be aware of the familial, maternal, and fetal factors that are known to increase risk and then ensure that all at-risk pregnancies are properly evaluated – often with fetal echocardiography – to determine if a cardiac defect is present and, if so, to plan the delivery-related issues of timing, mode, and facility.

In light of the importance of this subject and the role that ultrasound scanning, genetic counseling, and early decision making and planning can play in the ultimate outcome of the fetus, we decided to do a Master Class on congenital heart defects. We have invited Dr. Joshua A. Copel, professor of obstetrics, gynecology, and reproductive services, and of pediatrics, and vice chair of obstetrics at Yale University, New Haven, Conn., to serve as our guest professor.

Dr. Copel has written and lectured extensively on fetal arrhythmias, fetal cardiac anomalies and congenital heart disease, and sonographic monitoring and fetal echocardiography. Here he discusses what we should know about both familial contributions to congenital heart disease and various noninherited risk factors.

While infant deaths associated with congenital heart defects have declined substantially over the past 2 decades, congenital heart disease remains the most common fatal congenital anomaly in the first year after birth.

Prematurity is the most significant cause of death in the first week of life, but after that point, birth defects take over as the leading cause of infant mortality (and overall, birth defects are the leading cause of infant mortality). Cardiovascular defects, in turn, are the single largest contributor to infant mortality attributable to birth defects – severe congenital heart disease (CHD) affects approximately 0.5% of all neonates and is responsible for one-third of deaths between birth and 1 year of life.

Prenatal diagnosis of CHD is important because early detection can improve the planning of services and provision of coordinated multidisciplinary care. While most fetal therapy for CHD is investigational and still evolving, studies from all over the world have shown that if a baby is known to have a heart problem and is delivered at a facility that provides definitive care, the baby will likely fare better.

Unfortunately, most infants born with CHD do not have defined risk factors. As obstetricians we must always be alert to the possibility that, even without a clear risk factor, there could be a cardiovascular problem.

It is important to know, on the other hand, who is at increased risk and should be evaluated further, and who is not at increased risk. We know now that certain infants whom we haven't traditionally thought of as being at risk for CHD are indeed at higher risk. Our knowledge of familial contributions to CHD has grown, for instance, giving obstetricians the responsibility to be alert for potential familial genetic patterns so that the proper counseling can be provided.

There are also noninherited risk factors that can be identified and potentially modified. It is unclear what proportion of CHD can be prevented, but at the least, obstetricians should be aware of such risk factors so they can provide guidance to parents and future parents that could reduce the risk of their children having a major cardiovascular malformation, and so they can ensure proper surveillance in any pregnancy.

Familial Risks

Over the past 15 years or so, our understanding of inherited causes of congenital heart defects has increased significantly, and while there is much more to learn, it is now appreciated that genetics plays a greater role in CHD than previously estimated.

Molecular genetics studies in families with multiple affected individuals have even led to the identification of specific genetic abnormalities for several forms of CHD, such as the single gene mutation sometimes seen in tetralogy of Fallot; others are related to mutations in more than one gene.

While most chromosome defects are not inherited, some anomalies or syndromes with cardiac phenotypes – for instance, those involving microdeletions or gonadal mosaicism – can be inherited and play a small but increasingly appreciated role in CHD. The William-Beuren syndrome and the 22q11.2 deletion syndrome, for instance, are microdeletion syndromes that show autosomal dominant inheritance.

Overall, parents of a child with CHD that is not associated with a typical chromosomal aberration have a 2%–3% chance of having another child with CHD; it is estimated that half of affected siblings will be diagnosed with the same lesion, the other half with a different lesion.

Classic Mendelian transmission is occasionally responsible for inherited CHD in families, but recurrence risk is significant only when the family history of CHD involves first- or second-degree relatives.

Fetal echocardiography is definitely warranted when the mother or father – or a sibling – of the fetus has CHD, as well as when CHD has affected a parent's own mother, father, sister, or brother.

Once you get further out in the family history, to cousins and other third-degree and more distant relatives, the risk is not high enough to warrant a more detailed fetal examination. This is important for counseling; parents who are worried about a history of CHD in third-degree relatives should be reassured.

Among the changes in patterns of referral for fetal echocardiography that we detected at Yale-New Haven Hospital from 1985 to 2003 was an 18% increase in referrals for a family history of CHD, including family history in more distant relatives.

This increase was not accompanied by any change in the percentage of structural cardiovascular heart defects consequently detected (J. Ultrasound Med. 2006;25:197-202).

As an increasing number of patients with major congenital cardiac defects have been surviving to adulthood and parenthood, numerous investigators have attempted to identify specific recurrence risks.

One study done in the United Kingdom, for instance, identified 727 adults with surgically modified major heart defects and their 393 live offspring. Of these infants, 16 were born with cardiac malformations, representing a total recurrence risk of 4.1%. Recurrence risk in offspring ranged from 3.1% for tetralogy of Fallot to 7.8% for atrioventricular septal defect (Lancet 1998;351:311-6).

CHD occurred more often in offspring of affected mothers (5.7%) than affected fathers (2.2%). Compared with offspring, sibling risk was significantly lower: 2.1% overall.

A much larger and more recent study done in Denmark again showed strong familial clustering in first-degree relatives for CHDs, particularly for recurrences of the same heart defect. (Very few families experience a second heart defect, the study found.)

The study – a national cohort study of more than 1.7 million people born during a 29-year period – also is one of the largest studies, if not the largest study, to document a decreasing risk as family history gets more distant.

The relative risks of any CHD in singletons were 3.21 for a family history of any CHD in first-degree relatives, 1.78 for a family history involving second-degree relatives, and 1.10 for a family history in third-degree relatives (Circulation 2009;120:295-301).

Only with a history of affected first- and second-degree relatives was there a statistically greater chance of having an affected fetus.

In twins, the relative risks of any CHD were 12.5 for same-sex twins and 6.93 for twins of both sexes, the Danish investigators noted.

And in looking at the contribution of CHD family history to the total number of CHD cases in the population, they found that 2.2% of heart defect cases in the population were attributed to CHD family history in first-degree relatives.

Another notable finding from other studies is that women with cyanotic heart disease have a higher risk of having a baby with CHD than do women with noncyanotic heart disease.

Maternal Risks

Just as we've learned much about inherited causes of congenital heart disease over the past 15 years, there is a growing body of epidemiologic literature on potential fetal exposures – from maternal illnesses to maternal drug exposures – that can alter the risk of CHD.

The risk factors for CHD maternal teratogen exposure are numerous. They include lithium, alcohol, isotretinoin, and various anticonvulsant drugs, and many are well-appreciated by ob.gyns.

Other factors for which risk has been well determined, and can be better appreciated, include:

▸ High vitamin A intake. Findings are not completely consistent, but we have enough data now to suggest that women who take extra-large doses of vitamin A may actually be putting their fetuses at risk of birth defects.

One study worth noting found that among more than 22,000 pregnant women, those who took more than 10,000 IU of vitamin A from supplements were 4.8 times more likely to have babies with birth defects associated with cranial-neural-crest tissue than were women who consumed 5,000 IU or less per day (N. Engl. J. Med. 1995;333:1369-73).

Typical prenatal vitamins have 5,000 IU in each dose. This is one reason that women with twin pregnancies can take extra folic acid, but should not double up on their prenatal multivitamins.

▸ Folate antagonists. Common drugs such as trimethoprim, triamterene, sulfasalazine, phenytoin, phenobarbital, primidone, carbamazepine, and cholestyramine may increase the risk not only of neural-tube defects, but of cardiovascular defects as well, in addition to oral clefts and urinary tract defects.

Fortunately, studies such as one published in 2000 involving thousands of infants show that the folic acid component of prenatal multivitamin supplements can reduce the risks of these defects, just as it reduces the risk of neural-tube defects (N. Engl. J. Med. 2000;343:1608-14).

▸ Paxil (paroxetine). This is the only antidepressant that has been shown in some studies to increase the risk of CHD. Its manufacturer, GlaxoSmithKline, changed the label's pregnancy precaution in 2005 from a Pregnancy Category C to Category D. If a patient becomes pregnant while taking the drug, she should be advised of potential harm to the fetus.

One epidemiologic study showed that women taking Paxil were two times more likely to have an infant with CHD, and 2.2 times more likely to have an infant with any congenital malformation, than were women taking other antidepressants.

▸ Diabetes. The risk of fetal anomalies with maternal diabetes and elevated hemoglobin A_1c in early pregnancy has been known for some time.

In a study published in 1981, for instance, the risk of CHD and other fetal anomalies rose from 5% to 22% as maternal HbA_1c rose from a range of 7%–8.5% to greater than 8.5% (N. Engl. J. Med. 1981;304:1331-4).

We've also known for some time that differences in CHD may exist even with good metabolic control. Studies have documented mild cardiac hypertrophy involving the interventricular septum and the ventricular free walls, for instance, in diabetic mothers with good metabolic control (J. Pediatr. 1991;118:103-7 and Am J. Obstet. Gynecol. 1991;164:837-43). Such growth affects cardiac diastolic function.

With the epidemic of obesity and the increasing prevalence of early type 2 diabetes and glucose intolerance among women of childbearing age, however, this is an increasingly important risk factor to appreciate and counsel about.

The most important message, we've learned, is that there's no such thing as perfect control – that good metabolic control will not necessarily protect diabetic mothers from the higher risk of CHD.

Just as detection and appropriate management of diabetes before and during pregnancy are of utmost importance, so is fetal echocardiography for every pregnant woman who has pregestational diabetes – even diabetes that is well controlled.

Indeed, the same review of all fetal echocardiography performed between 1985 and 2003 at Yale-New Haven Hospital that showed an increase in referrals for family history also showed a 9% increase in the proportion of studies done for pregestational diabetes as the indication. The increase was most striking when it came to women who had recently been diagnosed, compared with long-standing diabetes – a finding that likely reflects the increase in obesity.

▸ Phenylketonuria. Fortunately, strict dietary control before conception and during pregnancy can reduce the increased risk of heart defects faced by women with this disorder. We need to remember that aspartame (NutraSweet) can cause phenylalanine levels to increase in women with PKU, but not in normal women. Women without PKU can be reassured that there is no evidence linking aspartame with birth defects.

Fetal Risks

Among the fetal risk factors important to consider are:

▸ Extracardiac anomalies. The identification of any extracardiac anomaly should raise our level of suspicion for other anomalies, including congenital heart defects. If we see one anomaly – anywhere in the fetus – there often are really two. And if we see two anomalies, there frequently are really three.

▸ Nonimmune hydrops. All fetuses found to have NIH should be evaluated with fetal echocardiography. Structural heart disease in fetuses with NIH is usually indicative of a poor prognosis for survival, but when rhythm disturbances/arrhythmias are detected in association with NIH, there is sometimes an option for prenatal treatment.

▸ Fetal arrhythmias. An irregular heartbeat is usually not a problem, but tachycardia and especially bradycardia are associated with an increased risk of CHD. There may be structural heart defects in as many as half of fetuses with fixed bradycardia (i.e., baseline heart rate less than 100). In general, it is best that all arrhythmias are examined; it is just too hard to tell them apart by auscultation alone.

▸ Nuchal translucency. Numerous studies have shown that elevated first-trimester nuchal translucency (NT) increases the risk of major congenital heart defects in chromosomally normal fetuses, and that risk increases with increasing NT measurement.

In a large prospective multicenter study conducted by the National Institute of Child Health and Human Development, for instance, investigators identified 21 cases of major congenital heart defects in 8,167 chromosomally normal pregnancies. They reported that the incidence of CHD per 1,000 pregnancies rose from 1.9 with an NT measurement of less than 2.0 mm, to 4.8 with an NT measurement of 2.0–2.4 mm, to 6.0 with an NT measurement of 2.5–3.4 mm, to 23 of every 1,000 pregnancies with an NT measurement of 3.5 mm or greater (Am. J. Obstet. Gynecol. 2005;192:1357–61).

If the NT is greater than 3.5 mm, measured by a qualified sonographer or sonologist at 11–14 weeks as part of an aneuploidy risk assessment scan, the patient should be referred for fetal echocardiography.

▸ In vitro fertilization. We recently investigated the prevalence of congenital heart defects among IVF pregnancies at our referral program at Yale, and found that children conceived through IVF were 3–12 times as likely to have CHD as was the general population (J. Ultrasound Med. 2010;29:917-22).

Similar data have come from Australia and Europe, with reported odds ratios for IVF versus natural conception of 3–4. I tell patients, therefore, that it's not just one place or one study suggesting risk. Indeed, it's a meaningful risk factor.

▸ Monochorionic twins. In a systemic literature review we conducted several years ago that included 40 fetuses with CHDs among 830 fetuses from monochorionic/diamniotic twin gestations, the rate of CHDs in these twin gestations was significantly higher than the prevalence rate of CHDs in the general population (J. Ultrasound Med. 2007;26:1491-8).

Congenital heart defects were almost three times as likely to complicate the monochorionic/diamniotic twin gestations affected by twin-to-twin transfusion syndrome (TTTS), compared with those without TTTS, but an increase occurred regardless of the presence of TTTS. Ventricular septal defects were among the most frequent heart defects. Fetal echocardiography may be considered for all monochorionic/diamniotic twin gestations.

Dr. Copel disclosed that he has received research support from Philips Healthcare and Siemens Healthcare. Both companies manufacture echocardiography and other ultrasound systems.

A two-dimensional four-chamber view of a normal fetal heart (left). Fetal image of a complete atrioventricular septal defect with large atrial (**) and ventricular (*) septal defects (right).

Source Images: © Elsevier Inc.

Diagnosing Birth Defects

Birth defects continue to account for the majority of infant deaths, and their biologic basis continues to present a mixed picture, with the majority of causes still unknown. Cardiac defects – the most common type of birth defect – result in varying types of morbidity, but remain the most severe and disabling of all birth defects. As our guest author points out below, cardiovascular defects are the single largest contributor to birth defect–attributable infant mortality.

What is clear is the fact that when birth defects are identified prenatally, decisions can be made regarding the timing and route of delivery and even the facility where delivery occurs. We know that such decision making can be highly influential on the ultimate outcome of the infant.

Fortunately, there has been improvement in recent years in diagnostic technology that enables more prenatal diagnosis of congenital heart disease, and certain conditions that in the past went unknown or undiagnosed are now being identified early so that specialists can intervene in a timely manner.

While certain pregnancies are clearly at higher risk – those involving mothers who have pregestational diabetes, for instance, or mothers with exposure to particular toxins – there are other scenarios and factors that increase risk of which we should be aware.

It's a tricky evaluative process, for, as our guest author points out, most infants born with congenital heart disease do not have defined risk factors. At the least, however, we can be aware of the familial, maternal, and fetal factors that are known to increase risk and then ensure that all at-risk pregnancies are properly evaluated – often with fetal echocardiography – to determine if a cardiac defect is present and, if so, to plan the delivery-related issues of timing, mode, and facility.

In light of the importance of this subject and the role that ultrasound scanning, genetic counseling, and early decision making and planning can play in the ultimate outcome of the fetus, we decided to do a Master Class on congenital heart defects. We have invited Dr. Joshua A. Copel, professor of obstetrics, gynecology, and reproductive services, and of pediatrics, and vice chair of obstetrics at Yale University, New Haven, Conn., to serve as our guest professor.

Dr. Copel has written and lectured extensively on fetal arrhythmias, fetal cardiac anomalies and congenital heart disease, and sonographic monitoring and fetal echocardiography. Here he discusses what we should know about both familial contributions to congenital heart disease and various noninherited risk factors.

During the last 10–15 years, in an effort to improve troubling rates of spontaneous preterm delivery and other adverse pregnancy outcomes, investigators have looked at many kinds of clinical and subclinical infections and explored their possible associations to preterm birth.

Bacterial vaginosis is one infection that has been associated in numerous studies with a higher risk of preterm birth. Periodontal disease is another. While not all studies have found an association, there is substantial evidence – mainly from observational and epidemiologic studies – linking periodontal disease to spontaneous preterm birth and identifying the disease as a probable risk factor for preterm delivery.

One of the larger studies was a prospective cohort study involving more than 1,300 pregnant women who were enrolled at 21–24 weeks' gestation and provided information on various possible risk factors for preterm birth. Later analyses showed that women with moderate to severe periodontal disease were 4.5 times as likely to deliver spontaneously before 37 weeks' gestation, 5.3 times as likely to deliver before 35 weeks' gestation, and 7.1 times as likely to deliver before 32 weeks (J. Am. Dent. Assoc. 2001;132:875–80).

Other published studies report lower levels of risk, and a more recent meta-analysis that included 17 studies and more than 7,000 women suggested a 2.8-fold increased risk of preterm birth in women with periodontal disease (Am J. Obstet. Gynecol. 2007;196:135.e1–7).

Today, interestingly, we know that bacterial vaginosis and periodontal disease each present our patients with a similar magnitude of increased risk for preterm delivery: a two- to threefold increased risk.

Unfortunately, hopes that identifying and treating the conditions could reduce risk and improve pregnancy outcomes have been dashed – in both cases. In the case of periodontal disease, three major randomized controlled trials in the United States – including the Periodontal Infections and Prematurity Study (PIPS) published in February of this year – have provided evidence that screening and treating periodontal disease during pregnancy are not likely to reduce rates of preterm birth.

This does not mean, however, that we should ignore the problem of periodontal disease. It is a huge problem, affecting up to 40% of pregnant women according to most reports, and there is no evidence to suggest that dental examinations or treatment are deleterious during pregnancy. In all the studies that have been done over the last decade or so, there is nothing to suggest that we shouldn't look for periodontal disease and treat it.

Periodontal disease is clearly associated with other poor health outcomes, in addition to its association with preterm birth, and study after study has shown that good oral health is important for good overall health.

Despite our inability to reduce preterm birth rates with periodontal treatment, it is important to recognize the value of good oral health for all adults, including pregnant women.

The Disease and Its Effects

Periodontal disease often evolves from untreated gingivitis, which causes the gums to redden, swell, and bleed more easily. Bacterial plaque on the surface of the teeth spreads and grows below the gum line (dentistry speaks of a subgingival biofilm), adding to progressive gram-negative anaerobic infection of the mouth and inflammatory responses that ultimately lead to the destruction of tissue and bone.

As Dr. Kim A. Boggess has described in numerous articles on periodontal disease in pregnancy, damage occurs both directly from bacteria in plaque and indirectly through bacterial stimulation of local and systemic inflammatory and immune responses.

Interestingly, there is no single validated definition of periodontal disease. Instead, the clinical criteria used to define periodontal disease have varied among studies, which can make all the data difficult to interpret. Some investigators have focused on the magnitude and extent of attachment loss or other clinical measures of periodontal disease, whereas others hone in on measures of infection and host response to oral bacteria. There are commonly agreed upon clinical markers, however, including gingival recession, tooth attachment loss, and bleeding on gingival probing.

Much of the research into the role of maternal oral health in pregnancy outcomes has been driven by appreciation of the importance that oral health plays in overall general health, and by a growing recognition that periodontal disease can trigger chronic, systemic inflammation, which in turn can drive various disease processes.

The conditions most often associated with periodontal disease are cardiovascular disease and diabetes. Some studies published in the last decade have shown, for instance, that individuals with periodontal disease have at least a 1.5-fold increased risk of developing cardiovascular disease. There also is some evidence that treating periodontal disease can improve various measures of cardiovascular function – such as blood pressure and levels of inflammatory cytokines. In addition, some data suggest that periodontal treatment results in better diabetic control.

Maternal periodontal disease also has been associated with other adverse pregnancy outcomes such as preeclampsia, gestational diabetes, fetal loss, and low birth weight. In a “clinical expert series” on maternal oral health in pregnancy published in 2008, Dr. Boggess provides a comprehensive summary of the literature on these associations, and details why good oral health should be a goal for all individuals, including pregnant women (Obstet. Gynecol. 2008;111:976–86).

Treatment and Preterm Birth

While some of the initial studies of periodontal treatment in pregnancy were promising, suggesting that treatment may reduce the risk for preterm birth, we now have three large studies in the United States that have been negative. Each has involved randomization to active treatment with scaling and root planing or placebo treatment, and each has shown no significant difference in preterm birth between the two groups.

In the multicenter Periodontal Infections and Prematurity Study (PIPS) trial reported early this year, we screened more than 3,500 women between 6 and 20 weeks' gestation and found a prevalence of periodontal disease of 50%. (We defined periodontal disease as attachment loss of at least 3 mm on at least three teeth. Moderate to severe disease was defined as attachment loss of 5 mm or more on three or more teeth.)

The 756 women with periodontal disease who returned for the scheduled treatment visit were then randomly assigned in a 1:1 ratio to active treatment or placebo (superficial cleaning). The mean gestational age at screening was 13.1 weeks, and the mean gestational age at treatment was 16.5 weeks. The groups were balanced with respect to gestational age, periodontal disease severity, and history of preterm delivery (Am. J. Obstet. Gynecol. 2010;202:147.e1–8).

There was no significant difference between the two treatment groups in the incidence of spontaneous preterm birth at less than 35 weeks' gestation (our primary end point) or at less than 37 weeks' gestation. We also saw no difference in mean birth weight or the proportion of low-birth-weight or very-low-birth-weight newborns. There also was no difference in composite neonatal morbidity/mortality between the groups.

These findings are largely concordant with those of two other recent studies. In one study published in 2006, more than 800 women were randomly assigned to receive either antepartum periodontal treatment (before 21 weeks' gestation) or postpartum treatment (control). Periodontal treatment improved measures of periodontitis but did not significantly alter the risk of preterm delivery at less than 37 weeks' gestation (N. Engl. J. Med. 2006;355: 1885–94).

The other study – coined the MOTOR study (Maternal Oral Therapy to Reduce Obstetric Risk) – randomized more than 1,800 patients at three sites to periodontal treatment early in the second trimester or delayed treatment after delivery. Again, investigators demonstrated improvements in oral health after treatment, but found no significant reduction in preterm birth at less than 37 weeks of gestation (Obstet. Gynecol. 2009;114:551–9).

Current Thinking

What should we do in the wake of these negative findings?

First, we must realize that periodontal treatment in these trials improved the oral health of pregnant women, and that the benefits of good oral health cannot be disputed. Secondly, we must still appreciate – and share with our patients – that periodontal disease is very common and does appear to be associated with preterm birth (and possibly other adverse pregnancy outcomes), as well as with other negative health outcomes such as cardiovascular disease and diabetes.

We should be careful, however, and be sure to tell patients that treatment of periodontal disease alone does not appear to reduce the risk of preterm birth.

We need to study these associations further and better understand the mechanisms of periodontal disease–associated preterm birth. There also are unanswered questions about treatment. For example, is it possible that treatment prior to pregnancy may reduce the risk of preterm birth? Is it possible that using adjuvant antibiotic mouthwash may improve pregnancy outcomes? Questions such as these should be answered with additional clinical trials.

We also must better understand and delineate reported disparities in oral health. Periodontal disease disproportionately affects racial and ethnic minorities and those of low socioeconomic status. While differences in access to care and other behaviors and practices likely play a role in these disparities, experts believe that there also may be population differences in oral microbiology or inflammatory responses to bacterial colonization.

As we wait for more information, we can tell our patients about the importance of good oral health, and we can reassure them that periodontal disease treatment in pregnancy appears to be safe. We are not ready, however, to recommend routine screening and treatment of periodontal disease in pregnancy to improve pregnancy outcomes.

DR. MACONES said he has no disclosures relevant to this article. E-mail him at

obnews@elsevier.com

Infection's Relationship to Prematurity

The United States spends almost 18% of its gross domestic product on health care, yet its infant mortality rate is higher than that in most other developed countries. The latest available data show the United States ranking 29th in the world in infant mortality.

One may ask why the United States continues to have this asynchrony between its investments and such an adverse health outcome. One way to assess this is to examine the factors that contribute most significantly to infant mortality: prematurity and birth defects. Prematurity remains a vexing problem in the United States – one for which the mechanism and the treatment remain, at best, elusive.

Infection or inflammation is considered to play a dominant role in the pathogenesis of prematurity. Data to support this role have been generated from a number of controlled, uncontrolled, and even laboratory studies. Most recently, additional studies have shown that inflammation or infection occurring within body cavities, including the vagina (bacterial vaginosis) or the oral cavity (periodontal disease) are associated with increased rates of prematurity.

The conundrum that we find ourselves in at this point is that there does not appear to be an effective means of altering the status of infection or inflammation in order to have a direct impact on prematurity rates. The studies so far have been controversial, leaving obstetricians very confused as to how they can best intervene and improve the perinatal outcome.

It is because of this very difficult situation that we believe it is important to have a Master Class that examines the relationship between infection – most significantly, periodontal infection – and the outcome of prematurity, and the options that can be exercised at this time with regard to oral health, prenatal care, and management pending definitive answers.

We have invited Dr. George A. Macones, an expert in maternal-fetal medicine who has extensively studied the prediction and prevention of prematurity, to serve as our guest author. Dr. Macones is the Mitchell and Elaine Yanow Professor and chair of the department of obstetrics and gynecology at Washington University, St. Louis. In this column, Dr. Macones details the value of counseling our patients about good oral health.

During the last 10–15 years, in an effort to improve troubling rates of spontaneous preterm delivery and other adverse pregnancy outcomes, investigators have looked at many kinds of clinical and subclinical infections and explored their possible associations to preterm birth.

Bacterial vaginosis is one infection that has been associated in numerous studies with a higher risk of preterm birth. Periodontal disease is another. While not all studies have found an association, there is substantial evidence – mainly from observational and epidemiologic studies – linking periodontal disease to spontaneous preterm birth and identifying the disease as a probable risk factor for preterm delivery.

One of the larger studies was a prospective cohort study involving more than 1,300 pregnant women who were enrolled at 21–24 weeks' gestation and provided information on various possible risk factors for preterm birth. Later analyses showed that women with moderate to severe periodontal disease were 4.5 times as likely to deliver spontaneously before 37 weeks' gestation, 5.3 times as likely to deliver before 35 weeks' gestation, and 7.1 times as likely to deliver before 32 weeks (J. Am. Dent. Assoc. 2001;132:875–80).

Other published studies report lower levels of risk, and a more recent meta-analysis that included 17 studies and more than 7,000 women suggested a 2.8-fold increased risk of preterm birth in women with periodontal disease (Am J. Obstet. Gynecol. 2007;196:135.e1–7).

Today, interestingly, we know that bacterial vaginosis and periodontal disease each present our patients with a similar magnitude of increased risk for preterm delivery: a two- to threefold increased risk.

Unfortunately, hopes that identifying and treating the conditions could reduce risk and improve pregnancy outcomes have been dashed – in both cases. In the case of periodontal disease, three major randomized controlled trials in the United States – including the Periodontal Infections and Prematurity Study (PIPS) published in February of this year – have provided evidence that screening and treating periodontal disease during pregnancy are not likely to reduce rates of preterm birth.

This does not mean, however, that we should ignore the problem of periodontal disease. It is a huge problem, affecting up to 40% of pregnant women according to most reports, and there is no evidence to suggest that dental examinations or treatment are deleterious during pregnancy. In all the studies that have been done over the last decade or so, there is nothing to suggest that we shouldn't look for periodontal disease and treat it.

Periodontal disease is clearly associated with other poor health outcomes, in addition to its association with preterm birth, and study after study has shown that good oral health is important for good overall health.

Despite our inability to reduce preterm birth rates with periodontal treatment, it is important to recognize the value of good oral health for all adults, including pregnant women.

The Disease and Its Effects

Periodontal disease often evolves from untreated gingivitis, which causes the gums to redden, swell, and bleed more easily. Bacterial plaque on the surface of the teeth spreads and grows below the gum line (dentistry speaks of a subgingival biofilm), adding to progressive gram-negative anaerobic infection of the mouth and inflammatory responses that ultimately lead to the destruction of tissue and bone.

As Dr. Kim A. Boggess has described in numerous articles on periodontal disease in pregnancy, damage occurs both directly from bacteria in plaque and indirectly through bacterial stimulation of local and systemic inflammatory and immune responses.

Interestingly, there is no single validated definition of periodontal disease. Instead, the clinical criteria used to define periodontal disease have varied among studies, which can make all the data difficult to interpret. Some investigators have focused on the magnitude and extent of attachment loss or other clinical measures of periodontal disease, whereas others hone in on measures of infection and host response to oral bacteria. There are commonly agreed upon clinical markers, however, including gingival recession, tooth attachment loss, and bleeding on gingival probing.

Much of the research into the role of maternal oral health in pregnancy outcomes has been driven by appreciation of the importance that oral health plays in overall general health, and by a growing recognition that periodontal disease can trigger chronic, systemic inflammation, which in turn can drive various disease processes.

The conditions most often associated with periodontal disease are cardiovascular disease and diabetes. Some studies published in the last decade have shown, for instance, that individuals with periodontal disease have at least a 1.5-fold increased risk of developing cardiovascular disease. There also is some evidence that treating periodontal disease can improve various measures of cardiovascular function – such as blood pressure and levels of inflammatory cytokines. In addition, some data suggest that periodontal treatment results in better diabetic control.

Maternal periodontal disease also has been associated with other adverse pregnancy outcomes such as preeclampsia, gestational diabetes, fetal loss, and low birth weight. In a “clinical expert series” on maternal oral health in pregnancy published in 2008, Dr. Boggess provides a comprehensive summary of the literature on these associations, and details why good oral health should be a goal for all individuals, including pregnant women (Obstet. Gynecol. 2008;111:976–86).

Treatment and Preterm Birth

While some of the initial studies of periodontal treatment in pregnancy were promising, suggesting that treatment may reduce the risk for preterm birth, we now have three large studies in the United States that have been negative. Each has involved randomization to active treatment with scaling and root planing or placebo treatment, and each has shown no significant difference in preterm birth between the two groups.

In the multicenter Periodontal Infections and Prematurity Study (PIPS) trial reported early this year, we screened more than 3,500 women between 6 and 20 weeks' gestation and found a prevalence of periodontal disease of 50%. (We defined periodontal disease as attachment loss of at least 3 mm on at least three teeth. Moderate to severe disease was defined as attachment loss of 5 mm or more on three or more teeth.)

The 756 women with periodontal disease who returned for the scheduled treatment visit were then randomly assigned in a 1:1 ratio to active treatment or placebo (superficial cleaning). The mean gestational age at screening was 13.1 weeks, and the mean gestational age at treatment was 16.5 weeks. The groups were balanced with respect to gestational age, periodontal disease severity, and history of preterm delivery (Am. J. Obstet. Gynecol. 2010;202:147.e1–8).

There was no significant difference between the two treatment groups in the incidence of spontaneous preterm birth at less than 35 weeks' gestation (our primary end point) or at less than 37 weeks' gestation. We also saw no difference in mean birth weight or the proportion of low-birth-weight or very-low-birth-weight newborns. There also was no difference in composite neonatal morbidity/mortality between the groups.

These findings are largely concordant with those of two other recent studies. In one study published in 2006, more than 800 women were randomly assigned to receive either antepartum periodontal treatment (before 21 weeks' gestation) or postpartum treatment (control). Periodontal treatment improved measures of periodontitis but did not significantly alter the risk of preterm delivery at less than 37 weeks' gestation (N. Engl. J. Med. 2006;355: 1885–94).

The other study – coined the MOTOR study (Maternal Oral Therapy to Reduce Obstetric Risk) – randomized more than 1,800 patients at three sites to periodontal treatment early in the second trimester or delayed treatment after delivery. Again, investigators demonstrated improvements in oral health after treatment, but found no significant reduction in preterm birth at less than 37 weeks of gestation (Obstet. Gynecol. 2009;114:551–9).

Current Thinking

What should we do in the wake of these negative findings?

First, we must realize that periodontal treatment in these trials improved the oral health of pregnant women, and that the benefits of good oral health cannot be disputed. Secondly, we must still appreciate – and share with our patients – that periodontal disease is very common and does appear to be associated with preterm birth (and possibly other adverse pregnancy outcomes), as well as with other negative health outcomes such as cardiovascular disease and diabetes.

We should be careful, however, and be sure to tell patients that treatment of periodontal disease alone does not appear to reduce the risk of preterm birth.

We need to study these associations further and better understand the mechanisms of periodontal disease–associated preterm birth. There also are unanswered questions about treatment. For example, is it possible that treatment prior to pregnancy may reduce the risk of preterm birth? Is it possible that using adjuvant antibiotic mouthwash may improve pregnancy outcomes? Questions such as these should be answered with additional clinical trials.

We also must better understand and delineate reported disparities in oral health. Periodontal disease disproportionately affects racial and ethnic minorities and those of low socioeconomic status. While differences in access to care and other behaviors and practices likely play a role in these disparities, experts believe that there also may be population differences in oral microbiology or inflammatory responses to bacterial colonization.

As we wait for more information, we can tell our patients about the importance of good oral health, and we can reassure them that periodontal disease treatment in pregnancy appears to be safe. We are not ready, however, to recommend routine screening and treatment of periodontal disease in pregnancy to improve pregnancy outcomes.

DR. MACONES said he has no disclosures relevant to this article. E-mail him at

obnews@elsevier.com

Infection's Relationship to Prematurity

The United States spends almost 18% of its gross domestic product on health care, yet its infant mortality rate is higher than that in most other developed countries. The latest available data show the United States ranking 29th in the world in infant mortality.

One may ask why the United States continues to have this asynchrony between its investments and such an adverse health outcome. One way to assess this is to examine the factors that contribute most significantly to infant mortality: prematurity and birth defects. Prematurity remains a vexing problem in the United States – one for which the mechanism and the treatment remain, at best, elusive.

Infection or inflammation is considered to play a dominant role in the pathogenesis of prematurity. Data to support this role have been generated from a number of controlled, uncontrolled, and even laboratory studies. Most recently, additional studies have shown that inflammation or infection occurring within body cavities, including the vagina (bacterial vaginosis) or the oral cavity (periodontal disease) are associated with increased rates of prematurity.

The conundrum that we find ourselves in at this point is that there does not appear to be an effective means of altering the status of infection or inflammation in order to have a direct impact on prematurity rates. The studies so far have been controversial, leaving obstetricians very confused as to how they can best intervene and improve the perinatal outcome.

It is because of this very difficult situation that we believe it is important to have a Master Class that examines the relationship between infection – most significantly, periodontal infection – and the outcome of prematurity, and the options that can be exercised at this time with regard to oral health, prenatal care, and management pending definitive answers.

We have invited Dr. George A. Macones, an expert in maternal-fetal medicine who has extensively studied the prediction and prevention of prematurity, to serve as our guest author. Dr. Macones is the Mitchell and Elaine Yanow Professor and chair of the department of obstetrics and gynecology at Washington University, St. Louis. In this column, Dr. Macones details the value of counseling our patients about good oral health.

During the last 10–15 years, in an effort to improve troubling rates of spontaneous preterm delivery and other adverse pregnancy outcomes, investigators have looked at many kinds of clinical and subclinical infections and explored their possible associations to preterm birth.

Bacterial vaginosis is one infection that has been associated in numerous studies with a higher risk of preterm birth. Periodontal disease is another. While not all studies have found an association, there is substantial evidence – mainly from observational and epidemiologic studies – linking periodontal disease to spontaneous preterm birth and identifying the disease as a probable risk factor for preterm delivery.

One of the larger studies was a prospective cohort study involving more than 1,300 pregnant women who were enrolled at 21–24 weeks' gestation and provided information on various possible risk factors for preterm birth. Later analyses showed that women with moderate to severe periodontal disease were 4.5 times as likely to deliver spontaneously before 37 weeks' gestation, 5.3 times as likely to deliver before 35 weeks' gestation, and 7.1 times as likely to deliver before 32 weeks (J. Am. Dent. Assoc. 2001;132:875–80).

Other published studies report lower levels of risk, and a more recent meta-analysis that included 17 studies and more than 7,000 women suggested a 2.8-fold increased risk of preterm birth in women with periodontal disease (Am J. Obstet. Gynecol. 2007;196:135.e1–7).

Today, interestingly, we know that bacterial vaginosis and periodontal disease each present our patients with a similar magnitude of increased risk for preterm delivery: a two- to threefold increased risk.

Unfortunately, hopes that identifying and treating the conditions could reduce risk and improve pregnancy outcomes have been dashed – in both cases. In the case of periodontal disease, three major randomized controlled trials in the United States – including the Periodontal Infections and Prematurity Study (PIPS) published in February of this year – have provided evidence that screening and treating periodontal disease during pregnancy are not likely to reduce rates of preterm birth.

This does not mean, however, that we should ignore the problem of periodontal disease. It is a huge problem, affecting up to 40% of pregnant women according to most reports, and there is no evidence to suggest that dental examinations or treatment are deleterious during pregnancy. In all the studies that have been done over the last decade or so, there is nothing to suggest that we shouldn't look for periodontal disease and treat it.

Periodontal disease is clearly associated with other poor health outcomes, in addition to its association with preterm birth, and study after study has shown that good oral health is important for good overall health.

Despite our inability to reduce preterm birth rates with periodontal treatment, it is important to recognize the value of good oral health for all adults, including pregnant women.

The Disease and Its Effects

Periodontal disease often evolves from untreated gingivitis, which causes the gums to redden, swell, and bleed more easily. Bacterial plaque on the surface of the teeth spreads and grows below the gum line (dentistry speaks of a subgingival biofilm), adding to progressive gram-negative anaerobic infection of the mouth and inflammatory responses that ultimately lead to the destruction of tissue and bone.

As Dr. Kim A. Boggess has described in numerous articles on periodontal disease in pregnancy, damage occurs both directly from bacteria in plaque and indirectly through bacterial stimulation of local and systemic inflammatory and immune responses.

Interestingly, there is no single validated definition of periodontal disease. Instead, the clinical criteria used to define periodontal disease have varied among studies, which can make all the data difficult to interpret. Some investigators have focused on the magnitude and extent of attachment loss or other clinical measures of periodontal disease, whereas others hone in on measures of infection and host response to oral bacteria. There are commonly agreed upon clinical markers, however, including gingival recession, tooth attachment loss, and bleeding on gingival probing.

Much of the research into the role of maternal oral health in pregnancy outcomes has been driven by appreciation of the importance that oral health plays in overall general health, and by a growing recognition that periodontal disease can trigger chronic, systemic inflammation, which in turn can drive various disease processes.

The conditions most often associated with periodontal disease are cardiovascular disease and diabetes. Some studies published in the last decade have shown, for instance, that individuals with periodontal disease have at least a 1.5-fold increased risk of developing cardiovascular disease. There also is some evidence that treating periodontal disease can improve various measures of cardiovascular function – such as blood pressure and levels of inflammatory cytokines. In addition, some data suggest that periodontal treatment results in better diabetic control.

Maternal periodontal disease also has been associated with other adverse pregnancy outcomes such as preeclampsia, gestational diabetes, fetal loss, and low birth weight. In a “clinical expert series” on maternal oral health in pregnancy published in 2008, Dr. Boggess provides a comprehensive summary of the literature on these associations, and details why good oral health should be a goal for all individuals, including pregnant women (Obstet. Gynecol. 2008;111:976–86).

Treatment and Preterm Birth

While some of the initial studies of periodontal treatment in pregnancy were promising, suggesting that treatment may reduce the risk for preterm birth, we now have three large studies in the United States that have been negative. Each has involved randomization to active treatment with scaling and root planing or placebo treatment, and each has shown no significant difference in preterm birth between the two groups.

In the multicenter Periodontal Infections and Prematurity Study (PIPS) trial reported early this year, we screened more than 3,500 women between 6 and 20 weeks' gestation and found a prevalence of periodontal disease of 50%. (We defined periodontal disease as attachment loss of at least 3 mm on at least three teeth. Moderate to severe disease was defined as attachment loss of 5 mm or more on three or more teeth.)

The 756 women with periodontal disease who returned for the scheduled treatment visit were then randomly assigned in a 1:1 ratio to active treatment or placebo (superficial cleaning). The mean gestational age at screening was 13.1 weeks, and the mean gestational age at treatment was 16.5 weeks. The groups were balanced with respect to gestational age, periodontal disease severity, and history of preterm delivery (Am. J. Obstet. Gynecol. 2010;202:147.e1–8).

There was no significant difference between the two treatment groups in the incidence of spontaneous preterm birth at less than 35 weeks' gestation (our primary end point) or at less than 37 weeks' gestation. We also saw no difference in mean birth weight or the proportion of low-birth-weight or very-low-birth-weight newborns. There also was no difference in composite neonatal morbidity/mortality between the groups.

These findings are largely concordant with those of two other recent studies. In one study published in 2006, more than 800 women were randomly assigned to receive either antepartum periodontal treatment (before 21 weeks' gestation) or postpartum treatment (control). Periodontal treatment improved measures of periodontitis but did not significantly alter the risk of preterm delivery at less than 37 weeks' gestation (N. Engl. J. Med. 2006;355: 1885–94).

The other study – coined the MOTOR study (Maternal Oral Therapy to Reduce Obstetric Risk) – randomized more than 1,800 patients at three sites to periodontal treatment early in the second trimester or delayed treatment after delivery. Again, investigators demonstrated improvements in oral health after treatment, but found no significant reduction in preterm birth at less than 37 weeks of gestation (Obstet. Gynecol. 2009;114:551–9).

Current Thinking

What should we do in the wake of these negative findings?

First, we must realize that periodontal treatment in these trials improved the oral health of pregnant women, and that the benefits of good oral health cannot be disputed. Secondly, we must still appreciate – and share with our patients – that periodontal disease is very common and does appear to be associated with preterm birth (and possibly other adverse pregnancy outcomes), as well as with other negative health outcomes such as cardiovascular disease and diabetes.

We should be careful, however, and be sure to tell patients that treatment of periodontal disease alone does not appear to reduce the risk of preterm birth.

We need to study these associations further and better understand the mechanisms of periodontal disease–associated preterm birth. There also are unanswered questions about treatment. For example, is it possible that treatment prior to pregnancy may reduce the risk of preterm birth? Is it possible that using adjuvant antibiotic mouthwash may improve pregnancy outcomes? Questions such as these should be answered with additional clinical trials.

We also must better understand and delineate reported disparities in oral health. Periodontal disease disproportionately affects racial and ethnic minorities and those of low socioeconomic status. While differences in access to care and other behaviors and practices likely play a role in these disparities, experts believe that there also may be population differences in oral microbiology or inflammatory responses to bacterial colonization.

As we wait for more information, we can tell our patients about the importance of good oral health, and we can reassure them that periodontal disease treatment in pregnancy appears to be safe. We are not ready, however, to recommend routine screening and treatment of periodontal disease in pregnancy to improve pregnancy outcomes.

DR. MACONES said he has no disclosures relevant to this article. E-mail him at

obnews@elsevier.com

Infection's Relationship to Prematurity

The United States spends almost 18% of its gross domestic product on health care, yet its infant mortality rate is higher than that in most other developed countries. The latest available data show the United States ranking 29th in the world in infant mortality.

One may ask why the United States continues to have this asynchrony between its investments and such an adverse health outcome. One way to assess this is to examine the factors that contribute most significantly to infant mortality: prematurity and birth defects. Prematurity remains a vexing problem in the United States – one for which the mechanism and the treatment remain, at best, elusive.

Infection or inflammation is considered to play a dominant role in the pathogenesis of prematurity. Data to support this role have been generated from a number of controlled, uncontrolled, and even laboratory studies. Most recently, additional studies have shown that inflammation or infection occurring within body cavities, including the vagina (bacterial vaginosis) or the oral cavity (periodontal disease) are associated with increased rates of prematurity.

The conundrum that we find ourselves in at this point is that there does not appear to be an effective means of altering the status of infection or inflammation in order to have a direct impact on prematurity rates. The studies so far have been controversial, leaving obstetricians very confused as to how they can best intervene and improve the perinatal outcome.

It is because of this very difficult situation that we believe it is important to have a Master Class that examines the relationship between infection – most significantly, periodontal infection – and the outcome of prematurity, and the options that can be exercised at this time with regard to oral health, prenatal care, and management pending definitive answers.

We have invited Dr. George A. Macones, an expert in maternal-fetal medicine who has extensively studied the prediction and prevention of prematurity, to serve as our guest author. Dr. Macones is the Mitchell and Elaine Yanow Professor and chair of the department of obstetrics and gynecology at Washington University, St. Louis. In this column, Dr. Macones details the value of counseling our patients about good oral health.

Inherited thrombophilia and its association with both maternal thrombosis and adverse pregnancy outcomes is an issue that has come to the forefront over the past few years.

The association between inherited thrombophilia and maternal thrombosis appears to be fairly robust. Collectively, these thrombophilias account for 50%-70% of all maternal venous thrombotic events in pregnancy. Knowledge of the thrombophilic status of a patient can, therefore, have a significant impact on her clinical care. We understand better today, however, that personal and family history plays a critical role in assessing maternal thrombotic risk.

By contrast, the precise nature of the link between inherited thrombophilia and adverse pregnancy outcomes is still unclear. Over the past decade, the number of negative reports—those showing a lack of association—has increased significantly, and multiple prospective cohort studies have failed to consistently demonstrate the associations suggested by prior case-control studies that were smaller and mainly retrospective.

Collectively, this new landscape of research findings suggests that we should stop screening for inherited thrombophilia in patients with adverse pregnancy outcomes except in the setting of institutional review board–approved studies, and that we should better focus our approach to preventing maternal thrombosis through more careful, individualized risk assessment and through targeted use of antithrombotic therapy.

A New Evidence Base

Initial reports of associations between inherited thrombophilia and adverse pregnancy outcomes such as fetal loss, preeclampsia, fetal growth restriction, and abruptio placentae made some biological sense, but were based largely on small retrospective case-control studies with often inconsistent or contradictory findings.

In the case of fetal loss, numerous studies published in the 1990s and into the next decade showed a moderate association between inherited thrombophilia and stillbirth in particular.

A European retrospective cohort study published in 1996, for instance, found that the increased risk of loss among women with thrombophilia was greater after 28 weeks (odds ratio 3.6) than at or before 28 weeks (OR 1.4), and that the highest risk for stillbirth was associated with combined thrombophilic defects and antithrombin and protein C deficiencies (Lancet 1996;348:913-6).

This confusingly named study—the European Prospective Cohort on Thrombophilia (EPCOT)—involved 571 women with thrombophilia having 1,524 pregnancies, and 395 controls having 1,019 pregnancies.

In 2005, investigators of a larger case-control study nested within the 32,683-patient Nimes Obstetricians and Haematologist cohort reported an association between the factor V Leiden (FVL) mutation and pregnancy loss after 10 weeks (OR 3.5) but not between 3 and 9 weeks (J. Thromb. Haemost. 2005;3:2178-84)

A retrospective cohort study published in 2004 of 491 patients with a history of adverse pregnancy outcomes suggested, moreover, that one or more thrombophilia were actually protective of recurrent fetal losses at less than 10 weeks (Thromb. Haemost. 2004;91:290-5). However, the association of any one thrombophilia with later fetal losses was less significant in this study than in other studies (OR 1.76).

And an earlier meta-analysis of 31 studies looking at fetal loss and various thrombophilic disorders (most of them small case-control studies) concluded that FVL was associated with first-trimester pregnancy loss (OR 2.0) as well as later loss, although the association was much stronger (OR 3.3) with late, nonrecurrent fetal loss (Lancet 2003;361:901-8).

Although these and other studies suggested a link between FVL and stillbirth (and perhaps other thrombophilias and stillbirth), the absolute magnitude of the association (i.e., the absolute risk) was still very small. Moreover, over the past decade, the number of negative reports, especially amongst prospective studies, has increased—a temporal dichotomy that strongly suggests an initial bias toward positive studies and a growing comfort in reporting negative studies.

The larger prospective cohort studies reported over the last 5 years or so enerally have not found an association between inherited thrombophilia and stillbirth—or other adverse pregnancy outcomes for that matter.

For example, a 2005 study conducted by the Eunice Kennedy Shriver National Institute of Child Health and Human Development's Maternal-Fetal Medicine Units Network identified 134 FVL mutation carriers among nearly 4,900 gravidas in their first trimester of pregnancy and found no increase in fetal loss, preeclampsia, abruption, or intrauterine growth retardation (IUGR). A secondary analysis these data published earlier this year similarly found no association between the prothrombin gene G20210A mutation (PGM) and adverse pregnancy outcomes (Obstet. Gynecol. 2005;106:517-24 and Obstet. Gynecol. 2010;115:14-20).

Another prospective study of 4,250 unselected pregnancies also found no significant associations between FVL and preeclampsia, IUGR, and pregnancy loss (Br. J. Haematol. 2008;140:236-40).

Some of these findings are similar to previous reports from smaller prospective cohort studies. Investigators reported in 1999, for instance, no association between activated protein C resistance and fetal loss, preeclampsia, and IUGR. And in 2000, investigators had similarly reported a lack of association between FVL and methylenetetrahydrofolate reductase (MTHFR) polymorphism and preeclampsia or IUGR.

In general, the reported linkage between inherited thrombophilia and adverse outcomes other than stillbirth was always more tenuous. In the case of preeclampsia, however, meta-analyses of studies done before 2000 showed a fairly strong association between thrombophilia and preeclampsia, while studies published in and after 2001 found no such association.

There are a few exceptions to the lack of association found in larger prospective cohort studies. Most notably, an Australian study published this year of nulliparous women was suggestive of a weak association between the PGM and a composite index of adverse pregnancy outcomes (Obstet. Gynecol. 2010;115:5-13).

However, when investigators analyzed individual outcomes, they found that the only statistically significant associations were between the PGM and placental abruption, and between FVL and stillbirth. These associations, moreover, were based on very small sample size (nine and six patients, respectively). The investigators concluded that “the majority of asymptomatic women who carry an inherited thrombophilia polymorphism have a successful pregnancy outcome.”

There also is, at best, conflicting evidence in the literature of any benefit to heparin therapy for recurrent fetal loss.

A New Outlook on Screening

Given the evolving body of literature, it now seems wholly unjustified to screen low-risk populations. Knowing whether or not the patient has inherited thrombophilia, particularly in the nulliparous state, does not appear to be important for predicting outcomes.

There are questions that remain, however—most notably the question of whether women who have repetitive fetal losses or repetitive preeclampsia or abruptions should be screened and treated for inherited thrombophilia. Certainly, the failure of large prospective cohort studies to demonstrate any consistent association dampens our enthusiasm for the idea that inherited thrombophilia are to blame.

My opinion on this topic has evolved considerably over the last 10 years. I now believe that while screening for antiphospholipid syndrome is still warranted, screening for inherited thrombophilia in women having recurrent adverse pregnancy outcomes should occur only in the setting of an institutional review board–approved study in which ascertainment is done before a subsequent pregnancy and the patient's thrombophilia status is correlated with subsequent outcome (i.e., live birth, miscarriage, stillbirth, fetal growth restriction, preeclampsia, or abruption).

Furthermore, until we have established a definitive link between inherited thrombophilia and adverse pregnancy outcomes, we shouldn't even begin to think about clinical trials of thromboprophylaxis for affected women.

A particularly thorny question that has been raised concerns the issue of early fetal loss. Some have argued that the latest prospective cohort studies involved blood collection at or after 10 weeks' gestation and, therefore, are not relevant to conclusions drawn about the association (or lack thereof) between inherited thrombophilia and embryonic fetal loss.

However, I believe there are several reasons why we can conclude that thrombophilia and embryonic fetal losses are not linked. For one, there are enough data available from negative retrospective studies in which blood was obtained right after the pregnancy was completed. Secondly, there is no correlation between inherited thrombophilia and subsequent in vitro fertilization (IVF) failures in almost a dozen published studies. In fact, there is actually some evidence that FVL is associated with IVF success.

Lastly, we now know there is very little blood flow to the placenta before 10 weeks' gestation. There is some evidence, in fact, that hypoxia is the normal state of the embryo and may even be the preferred condition for culturing embryos in IVF.

Again, this issue requires prospective studies amongst patients with recurrent loss in which ascertainment occurs before the pregnancy commences.

Maternal Thrombotic Risk

While it's fair to say that, in general, inherited thrombophilia modestly increases the risk of maternal venous thrombotic events (VTE), it is critical to appreciate the role that a personal or strong family history of thrombosis (i.e., an affected first-degree relative) plays in determining a mother's risk.

Most women (greater than 93%) without a personal or strong family history of VTE will have uneventful pregnancies even when highly thrombogenic mutations are present. Once a personal or family history is factored in, however, the risk of VTE increases dramatically.

In the absence of a personal history of VTE or such an episode in a first-degree relative, heterozygosity for FVL or PGM is associated with a risk of thrombosis in pregnancy of well under 1% (0.2% and 0.5%, respectively). Similarly, protein C and protein S deficiencies are associated with a VTE risk under 1% in the absence of a personal or close family history.

In contrast, with a positive personal or family history, the risk of VTE in pregnancy increases to 10% in women who have heterozygosity for FVL, greater than 10% for women who have heterozygosity for PGM, 4%-17% in cases of protein C deficiency, and potentially up to 22% in cases of protein S deficiency.

Without a personal or family history, therefore, women with these lower-risk thrombophilia do not require anticoagulation during pregnancy unless they have other risk factors for thrombosis, such as significant obesity or orders for bed rest.

Patients with known inherited thrombophilia and a positive history, on the other hand, should receive antepartum thromboprophylaxis followed by postpartum anticoagulation. (Women who have a cesarean delivery should receive postpartum anticoagulation whether they have a personal or family history or not.)

Anticoagulation during pregnancy is also warranted—regardless of personal or family history—in the rare cases in which a patient is known to have homozygosity for FVL or homozygosity for PGM, or if a patient is known to have “double heterozygosity” for both FVL and PGM. Antithrombin deficiency, the most thrombogenic of all the inherited thrombophilias, also warrants antepartum anticoagulation as well as antithrombin infusions during labor and delivery.

To date, two studies have attempted to determine the value of screening for inherited thrombophilia based on a family history of prior VTE, and neither has shown that widespread screening would be particularly useful or cost effective in this setting. One certainly can argue, on the other hand, in favor of screening for thrombophilia in women who have a strong family history of VTE coupled with other risk factors.

Individualized risk assessment is always valuable. A woman with multiple risk factors—one who is obese, smokes, and is being put on bed rest, for instance—is a candidate for low-molecular-weight heparin (LMWH) therapy, for instance, even without a history of thrombosis and regardless of her thrombophilia status. If such a patient also has hypertension or preeclampsia, however, I'd be reluctant to give her either heparin or LMWH, for fear of abruption or even intracranial hemorrhage.

In what other circumstances is screening for thrombophilia warranted?

It can be justified when there is a personal history of VTE associated with a risk factor that is not recurrent. In this case, the absence of a thrombophilia reduces the risk of occurrence/recurrence of VTE during pregnancy to a very low level, while the presence of a thrombophilia would mandate antepartum anticoagulation. In any case, she should receive postpartum prophylaxis since 75%-80% of fatal pulmonary emboli in pregnancy occur after cesarean delivery.

For instance, screening is valuable in a woman who had a VTE earlier in her life when she was on oral contraception and was put in a cast after a skiing accident. If she does not have a documented thrombophilia, you will not need to give her anticoagulation during the pregnancy—only post partum.

The Work-Up

When screening for inherited thrombophilia is warranted, I recommend limiting it to FVL, PGM, protein C deficiency, antithrombin deficiency, and protein S deficiency. (See table, p. 20.)

Screening for FVL, even during pregnancy, can be done with a second-generation screening test for active protein C resistance, or by polymerase chain reaction (PCR).

Screening for the PGM should be done by PCR, and I recommend getting an antithrombin activity level and a protein C activity level to screen for antithrombin deficiency and protein C deficiency, respectively.

Screening for protein S deficiency is trickier, since circulating protein S activity levels can vary dramatically in pregnancy (i.e., various conditions from infections to surgery to hormonal status can affect activity levels of protein S).

I recommend first assessing the protein S free antigen level. In nonpregnant patients, a free antigen level less than 55% indicates risk for deficiency. Free antigen levels drop significantly in pregnancy, however, making a level at or below 29% in the first and second trimesters, and a level at or below 24% in the third trimester, indicative of risk. Such levels can be accepted as indicating protein S deficiency, or deficiency can be confirmed by then measuring the protein S activity level.

I do not recommend screening for MTHFR mutations or hyperhomocysteinemia. There does not appear to be any association between MTHFR mutations and adverse pregnancy outcomes, and the probable association between hyperhomocysteinemia and maternal venous thrombotic events that exists in general is of far less concern in the United States since grains are fortified with folate. If there is any concern, extra folic acid supplementation should be protective.

Source Elsevier Global Medical News

Key Points

▸ Most positive associations between inherited thrombophilia and adverse pregnancy outcomes were derived from small case-control studies. Many studies are contradictory.

▸ Large prospective cohort studies have failed to demonstrate any consistent association between inherited thrombophilia and adverse pregnancy outcomes.

▸ There appears to be a modest association between thrombophilia and fetal loss after 10 weeks in retrospective, but not most prospective, studies.

▸ There is no current support for screening for inherited thrombophilia in women experiencing recurrent unexplained fetal loss or other adverse pregnancy outcomes. Diagnosis and treatment regimens should occur only in the context of an institutional review board–approved research protocol.

▸ Patients with known inherited thrombophilia and a personal or family history of prior VTE should receive antepartum thromboprophylaxis followed by postpartum anticoagulation.

▸ Unless they have additional, significant risk factors, women with lower-risk thrombophilias (i.e., heterozygotes for FVL, PGM, protein C deficiency, or protein S deficiency) and no history of prior VTE or an affected first-degree relative do not require antepartum thromboprophylaxis.

▸ Women who have a personal history of VTE associated with a nonrecurrent risk factor should be screened.

Source: Dr. Lockwood

Thrombophilia and Adverse Outcomes

Adverse pregnancy outcomes are among the most perplexing pregnancy-related problems because we still have little precise knowledge about the etiology—and often, the mechanisms—associated with them. Over time, a number of causes have been identified and suggested, and some potential therapeutic agents have been proposed.

The relationship between thrombophilia and adverse outcomes has been a long-term association. A number of experiential reports and uncontrolled trials have endorsed this relationship. In fact, experimental therapeutic trials with heparin and other agents have attempted to improve outcomes and have reported incremental benefits when these agents have been used.

This has further galvanized the belief that thrombophilia may in fact be strongly etiologic in the pathophysiology of some adverse pregnancy outcomes. Thus, interventions based on a presumed mechanistic basis have been supported. However, newer data have seemed not to bear out this long-held association between thrombophilia and adverse outcomes, and the implied treatment.

It is in light of this controversy and the conflicting positions that we have decided to do a Master Class to thoroughly review the subject, to look at what data exist that can help unravel this relationship, and to examine whether screening patients for thrombophilia and treating it as a basis for improving pregnancy outcomes is warranted.

We have invited Dr. Charles J. Lockwood to address the topic. Dr. Lockwood is the Anita O'Keeffe Young Professor of Women's Health and chair of the department of obstetrics, gynecology, and reproductive sciences at Yale University, New Haven, Conn., and chief of obstetrics and gynecology at Yale–New Haven Hospital.

Dr. Lockwood has studied and thought a great deal about the association between inherited thrombophilia and adverse pregnancy outcomes, as well as the association between thrombophilia and maternal thrombosis. He urges us to step back and, in light of a “new landscape of research findings,” take a more careful approach to assessment and screening.

Inherited thrombophilia and its association with both maternal thrombosis and adverse pregnancy outcomes is an issue that has come to the forefront over the past few years.

The association between inherited thrombophilia and maternal thrombosis appears to be fairly robust. Collectively, these thrombophilias account for 50%-70% of all maternal venous thrombotic events in pregnancy. Knowledge of the thrombophilic status of a patient can, therefore, have a significant impact on her clinical care. We understand better today, however, that personal and family history plays a critical role in assessing maternal thrombotic risk.

By contrast, the precise nature of the link between inherited thrombophilia and adverse pregnancy outcomes is still unclear. Over the past decade, the number of negative reports—those showing a lack of association—has increased significantly, and multiple prospective cohort studies have failed to consistently demonstrate the associations suggested by prior case-control studies that were smaller and mainly retrospective.

Collectively, this new landscape of research findings suggests that we should stop screening for inherited thrombophilia in patients with adverse pregnancy outcomes except in the setting of institutional review board–approved studies, and that we should better focus our approach to preventing maternal thrombosis through more careful, individualized risk assessment and through targeted use of antithrombotic therapy.

A New Evidence Base

Initial reports of associations between inherited thrombophilia and adverse pregnancy outcomes such as fetal loss, preeclampsia, fetal growth restriction, and abruptio placentae made some biological sense, but were based largely on small retrospective case-control studies with often inconsistent or contradictory findings.

In the case of fetal loss, numerous studies published in the 1990s and into the next decade showed a moderate association between inherited thrombophilia and stillbirth in particular.

A European retrospective cohort study published in 1996, for instance, found that the increased risk of loss among women with thrombophilia was greater after 28 weeks (odds ratio 3.6) than at or before 28 weeks (OR 1.4), and that the highest risk for stillbirth was associated with combined thrombophilic defects and antithrombin and protein C deficiencies (Lancet 1996;348:913-6).

This confusingly named study—the European Prospective Cohort on Thrombophilia (EPCOT)—involved 571 women with thrombophilia having 1,524 pregnancies, and 395 controls having 1,019 pregnancies.

In 2005, investigators of a larger case-control study nested within the 32,683-patient Nimes Obstetricians and Haematologist cohort reported an association between the factor V Leiden (FVL) mutation and pregnancy loss after 10 weeks (OR 3.5) but not between 3 and 9 weeks (J. Thromb. Haemost. 2005;3:2178-84)

A retrospective cohort study published in 2004 of 491 patients with a history of adverse pregnancy outcomes suggested, moreover, that one or more thrombophilia were actually protective of recurrent fetal losses at less than 10 weeks (Thromb. Haemost. 2004;91:290-5). However, the association of any one thrombophilia with later fetal losses was less significant in this study than in other studies (OR 1.76).

And an earlier meta-analysis of 31 studies looking at fetal loss and various thrombophilic disorders (most of them small case-control studies) concluded that FVL was associated with first-trimester pregnancy loss (OR 2.0) as well as later loss, although the association was much stronger (OR 3.3) with late, nonrecurrent fetal loss (Lancet 2003;361:901-8).

Although these and other studies suggested a link between FVL and stillbirth (and perhaps other thrombophilias and stillbirth), the absolute magnitude of the association (i.e., the absolute risk) was still very small. Moreover, over the past decade, the number of negative reports, especially amongst prospective studies, has increased—a temporal dichotomy that strongly suggests an initial bias toward positive studies and a growing comfort in reporting negative studies.

The larger prospective cohort studies reported over the last 5 years or so enerally have not found an association between inherited thrombophilia and stillbirth—or other adverse pregnancy outcomes for that matter.

For example, a 2005 study conducted by the Eunice Kennedy Shriver National Institute of Child Health and Human Development's Maternal-Fetal Medicine Units Network identified 134 FVL mutation carriers among nearly 4,900 gravidas in their first trimester of pregnancy and found no increase in fetal loss, preeclampsia, abruption, or intrauterine growth retardation (IUGR). A secondary analysis these data published earlier this year similarly found no association between the prothrombin gene G20210A mutation (PGM) and adverse pregnancy outcomes (Obstet. Gynecol. 2005;106:517-24 and Obstet. Gynecol. 2010;115:14-20).

Another prospective study of 4,250 unselected pregnancies also found no significant associations between FVL and preeclampsia, IUGR, and pregnancy loss (Br. J. Haematol. 2008;140:236-40).

Some of these findings are similar to previous reports from smaller prospective cohort studies. Investigators reported in 1999, for instance, no association between activated protein C resistance and fetal loss, preeclampsia, and IUGR. And in 2000, investigators had similarly reported a lack of association between FVL and methylenetetrahydrofolate reductase (MTHFR) polymorphism and preeclampsia or IUGR.

In general, the reported linkage between inherited thrombophilia and adverse outcomes other than stillbirth was always more tenuous. In the case of preeclampsia, however, meta-analyses of studies done before 2000 showed a fairly strong association between thrombophilia and preeclampsia, while studies published in and after 2001 found no such association.

There are a few exceptions to the lack of association found in larger prospective cohort studies. Most notably, an Australian study published this year of nulliparous women was suggestive of a weak association between the PGM and a composite index of adverse pregnancy outcomes (Obstet. Gynecol. 2010;115:5-13).

However, when investigators analyzed individual outcomes, they found that the only statistically significant associations were between the PGM and placental abruption, and between FVL and stillbirth. These associations, moreover, were based on very small sample size (nine and six patients, respectively). The investigators concluded that “the majority of asymptomatic women who carry an inherited thrombophilia polymorphism have a successful pregnancy outcome.”

There also is, at best, conflicting evidence in the literature of any benefit to heparin therapy for recurrent fetal loss.

A New Outlook on Screening

Given the evolving body of literature, it now seems wholly unjustified to screen low-risk populations. Knowing whether or not the patient has inherited thrombophilia, particularly in the nulliparous state, does not appear to be important for predicting outcomes.

There are questions that remain, however—most notably the question of whether women who have repetitive fetal losses or repetitive preeclampsia or abruptions should be screened and treated for inherited thrombophilia. Certainly, the failure of large prospective cohort studies to demonstrate any consistent association dampens our enthusiasm for the idea that inherited thrombophilia are to blame.

My opinion on this topic has evolved considerably over the last 10 years. I now believe that while screening for antiphospholipid syndrome is still warranted, screening for inherited thrombophilia in women having recurrent adverse pregnancy outcomes should occur only in the setting of an institutional review board–approved study in which ascertainment is done before a subsequent pregnancy and the patient's thrombophilia status is correlated with subsequent outcome (i.e., live birth, miscarriage, stillbirth, fetal growth restriction, preeclampsia, or abruption).

Furthermore, until we have established a definitive link between inherited thrombophilia and adverse pregnancy outcomes, we shouldn't even begin to think about clinical trials of thromboprophylaxis for affected women.

A particularly thorny question that has been raised concerns the issue of early fetal loss. Some have argued that the latest prospective cohort studies involved blood collection at or after 10 weeks' gestation and, therefore, are not relevant to conclusions drawn about the association (or lack thereof) between inherited thrombophilia and embryonic fetal loss.

However, I believe there are several reasons why we can conclude that thrombophilia and embryonic fetal losses are not linked. For one, there are enough data available from negative retrospective studies in which blood was obtained right after the pregnancy was completed. Secondly, there is no correlation between inherited thrombophilia and subsequent in vitro fertilization (IVF) failures in almost a dozen published studies. In fact, there is actually some evidence that FVL is associated with IVF success.

Lastly, we now know there is very little blood flow to the placenta before 10 weeks' gestation. There is some evidence, in fact, that hypoxia is the normal state of the embryo and may even be the preferred condition for culturing embryos in IVF.

Again, this issue requires prospective studies amongst patients with recurrent loss in which ascertainment occurs before the pregnancy commences.

Maternal Thrombotic Risk

While it's fair to say that, in general, inherited thrombophilia modestly increases the risk of maternal venous thrombotic events (VTE), it is critical to appreciate the role that a personal or strong family history of thrombosis (i.e., an affected first-degree relative) plays in determining a mother's risk.

Most women (greater than 93%) without a personal or strong family history of VTE will have uneventful pregnancies even when highly thrombogenic mutations are present. Once a personal or family history is factored in, however, the risk of VTE increases dramatically.

In the absence of a personal history of VTE or such an episode in a first-degree relative, heterozygosity for FVL or PGM is associated with a risk of thrombosis in pregnancy of well under 1% (0.2% and 0.5%, respectively). Similarly, protein C and protein S deficiencies are associated with a VTE risk under 1% in the absence of a personal or close family history.

In contrast, with a positive personal or family history, the risk of VTE in pregnancy increases to 10% in women who have heterozygosity for FVL, greater than 10% for women who have heterozygosity for PGM, 4%-17% in cases of protein C deficiency, and potentially up to 22% in cases of protein S deficiency.

Without a personal or family history, therefore, women with these lower-risk thrombophilia do not require anticoagulation during pregnancy unless they have other risk factors for thrombosis, such as significant obesity or orders for bed rest.

Patients with known inherited thrombophilia and a positive history, on the other hand, should receive antepartum thromboprophylaxis followed by postpartum anticoagulation. (Women who have a cesarean delivery should receive postpartum anticoagulation whether they have a personal or family history or not.)

Anticoagulation during pregnancy is also warranted—regardless of personal or family history—in the rare cases in which a patient is known to have homozygosity for FVL or homozygosity for PGM, or if a patient is known to have “double heterozygosity” for both FVL and PGM. Antithrombin deficiency, the most thrombogenic of all the inherited thrombophilias, also warrants antepartum anticoagulation as well as antithrombin infusions during labor and delivery.

To date, two studies have attempted to determine the value of screening for inherited thrombophilia based on a family history of prior VTE, and neither has shown that widespread screening would be particularly useful or cost effective in this setting. One certainly can argue, on the other hand, in favor of screening for thrombophilia in women who have a strong family history of VTE coupled with other risk factors.

Individualized risk assessment is always valuable. A woman with multiple risk factors—one who is obese, smokes, and is being put on bed rest, for instance—is a candidate for low-molecular-weight heparin (LMWH) therapy, for instance, even without a history of thrombosis and regardless of her thrombophilia status. If such a patient also has hypertension or preeclampsia, however, I'd be reluctant to give her either heparin or LMWH, for fear of abruption or even intracranial hemorrhage.

In what other circumstances is screening for thrombophilia warranted?

It can be justified when there is a personal history of VTE associated with a risk factor that is not recurrent. In this case, the absence of a thrombophilia reduces the risk of occurrence/recurrence of VTE during pregnancy to a very low level, while the presence of a thrombophilia would mandate antepartum anticoagulation. In any case, she should receive postpartum prophylaxis since 75%-80% of fatal pulmonary emboli in pregnancy occur after cesarean delivery.

For instance, screening is valuable in a woman who had a VTE earlier in her life when she was on oral contraception and was put in a cast after a skiing accident. If she does not have a documented thrombophilia, you will not need to give her anticoagulation during the pregnancy—only post partum.

The Work-Up

When screening for inherited thrombophilia is warranted, I recommend limiting it to FVL, PGM, protein C deficiency, antithrombin deficiency, and protein S deficiency. (See table, p. 20.)

Screening for FVL, even during pregnancy, can be done with a second-generation screening test for active protein C resistance, or by polymerase chain reaction (PCR).

Screening for the PGM should be done by PCR, and I recommend getting an antithrombin activity level and a protein C activity level to screen for antithrombin deficiency and protein C deficiency, respectively.

Screening for protein S deficiency is trickier, since circulating protein S activity levels can vary dramatically in pregnancy (i.e., various conditions from infections to surgery to hormonal status can affect activity levels of protein S).

I recommend first assessing the protein S free antigen level. In nonpregnant patients, a free antigen level less than 55% indicates risk for deficiency. Free antigen levels drop significantly in pregnancy, however, making a level at or below 29% in the first and second trimesters, and a level at or below 24% in the third trimester, indicative of risk. Such levels can be accepted as indicating protein S deficiency, or deficiency can be confirmed by then measuring the protein S activity level.

I do not recommend screening for MTHFR mutations or hyperhomocysteinemia. There does not appear to be any association between MTHFR mutations and adverse pregnancy outcomes, and the probable association between hyperhomocysteinemia and maternal venous thrombotic events that exists in general is of far less concern in the United States since grains are fortified with folate. If there is any concern, extra folic acid supplementation should be protective.

Source Elsevier Global Medical News

Key Points

▸ Most positive associations between inherited thrombophilia and adverse pregnancy outcomes were derived from small case-control studies. Many studies are contradictory.

▸ Large prospective cohort studies have failed to demonstrate any consistent association between inherited thrombophilia and adverse pregnancy outcomes.

▸ There appears to be a modest association between thrombophilia and fetal loss after 10 weeks in retrospective, but not most prospective, studies.

▸ There is no current support for screening for inherited thrombophilia in women experiencing recurrent unexplained fetal loss or other adverse pregnancy outcomes. Diagnosis and treatment regimens should occur only in the context of an institutional review board–approved research protocol.

▸ Patients with known inherited thrombophilia and a personal or family history of prior VTE should receive antepartum thromboprophylaxis followed by postpartum anticoagulation.

▸ Unless they have additional, significant risk factors, women with lower-risk thrombophilias (i.e., heterozygotes for FVL, PGM, protein C deficiency, or protein S deficiency) and no history of prior VTE or an affected first-degree relative do not require antepartum thromboprophylaxis.

▸ Women who have a personal history of VTE associated with a nonrecurrent risk factor should be screened.

Source: Dr. Lockwood

Thrombophilia and Adverse Outcomes

Adverse pregnancy outcomes are among the most perplexing pregnancy-related problems because we still have little precise knowledge about the etiology—and often, the mechanisms—associated with them. Over time, a number of causes have been identified and suggested, and some potential therapeutic agents have been proposed.

The relationship between thrombophilia and adverse outcomes has been a long-term association. A number of experiential reports and uncontrolled trials have endorsed this relationship. In fact, experimental therapeutic trials with heparin and other agents have attempted to improve outcomes and have reported incremental benefits when these agents have been used.

This has further galvanized the belief that thrombophilia may in fact be strongly etiologic in the pathophysiology of some adverse pregnancy outcomes. Thus, interventions based on a presumed mechanistic basis have been supported. However, newer data have seemed not to bear out this long-held association between thrombophilia and adverse outcomes, and the implied treatment.

It is in light of this controversy and the conflicting positions that we have decided to do a Master Class to thoroughly review the subject, to look at what data exist that can help unravel this relationship, and to examine whether screening patients for thrombophilia and treating it as a basis for improving pregnancy outcomes is warranted.

We have invited Dr. Charles J. Lockwood to address the topic. Dr. Lockwood is the Anita O'Keeffe Young Professor of Women's Health and chair of the department of obstetrics, gynecology, and reproductive sciences at Yale University, New Haven, Conn., and chief of obstetrics and gynecology at Yale–New Haven Hospital.

Dr. Lockwood has studied and thought a great deal about the association between inherited thrombophilia and adverse pregnancy outcomes, as well as the association between thrombophilia and maternal thrombosis. He urges us to step back and, in light of a “new landscape of research findings,” take a more careful approach to assessment and screening.

Inherited thrombophilia and its association with both maternal thrombosis and adverse pregnancy outcomes is an issue that has come to the forefront over the past few years.

The association between inherited thrombophilia and maternal thrombosis appears to be fairly robust. Collectively, these thrombophilias account for 50%-70% of all maternal venous thrombotic events in pregnancy. Knowledge of the thrombophilic status of a patient can, therefore, have a significant impact on her clinical care. We understand better today, however, that personal and family history plays a critical role in assessing maternal thrombotic risk.

By contrast, the precise nature of the link between inherited thrombophilia and adverse pregnancy outcomes is still unclear. Over the past decade, the number of negative reports—those showing a lack of association—has increased significantly, and multiple prospective cohort studies have failed to consistently demonstrate the associations suggested by prior case-control studies that were smaller and mainly retrospective.

Collectively, this new landscape of research findings suggests that we should stop screening for inherited thrombophilia in patients with adverse pregnancy outcomes except in the setting of institutional review board–approved studies, and that we should better focus our approach to preventing maternal thrombosis through more careful, individualized risk assessment and through targeted use of antithrombotic therapy.

A New Evidence Base

Initial reports of associations between inherited thrombophilia and adverse pregnancy outcomes such as fetal loss, preeclampsia, fetal growth restriction, and abruptio placentae made some biological sense, but were based largely on small retrospective case-control studies with often inconsistent or contradictory findings.

In the case of fetal loss, numerous studies published in the 1990s and into the next decade showed a moderate association between inherited thrombophilia and stillbirth in particular.

A European retrospective cohort study published in 1996, for instance, found that the increased risk of loss among women with thrombophilia was greater after 28 weeks (odds ratio 3.6) than at or before 28 weeks (OR 1.4), and that the highest risk for stillbirth was associated with combined thrombophilic defects and antithrombin and protein C deficiencies (Lancet 1996;348:913-6).

This confusingly named study—the European Prospective Cohort on Thrombophilia (EPCOT)—involved 571 women with thrombophilia having 1,524 pregnancies, and 395 controls having 1,019 pregnancies.

In 2005, investigators of a larger case-control study nested within the 32,683-patient Nimes Obstetricians and Haematologist cohort reported an association between the factor V Leiden (FVL) mutation and pregnancy loss after 10 weeks (OR 3.5) but not between 3 and 9 weeks (J. Thromb. Haemost. 2005;3:2178-84)

A retrospective cohort study published in 2004 of 491 patients with a history of adverse pregnancy outcomes suggested, moreover, that one or more thrombophilia were actually protective of recurrent fetal losses at less than 10 weeks (Thromb. Haemost. 2004;91:290-5). However, the association of any one thrombophilia with later fetal losses was less significant in this study than in other studies (OR 1.76).

And an earlier meta-analysis of 31 studies looking at fetal loss and various thrombophilic disorders (most of them small case-control studies) concluded that FVL was associated with first-trimester pregnancy loss (OR 2.0) as well as later loss, although the association was much stronger (OR 3.3) with late, nonrecurrent fetal loss (Lancet 2003;361:901-8).

Although these and other studies suggested a link between FVL and stillbirth (and perhaps other thrombophilias and stillbirth), the absolute magnitude of the association (i.e., the absolute risk) was still very small. Moreover, over the past decade, the number of negative reports, especially amongst prospective studies, has increased—a temporal dichotomy that strongly suggests an initial bias toward positive studies and a growing comfort in reporting negative studies.

The larger prospective cohort studies reported over the last 5 years or so enerally have not found an association between inherited thrombophilia and stillbirth—or other adverse pregnancy outcomes for that matter.

For example, a 2005 study conducted by the Eunice Kennedy Shriver National Institute of Child Health and Human Development's Maternal-Fetal Medicine Units Network identified 134 FVL mutation carriers among nearly 4,900 gravidas in their first trimester of pregnancy and found no increase in fetal loss, preeclampsia, abruption, or intrauterine growth retardation (IUGR). A secondary analysis these data published earlier this year similarly found no association between the prothrombin gene G20210A mutation (PGM) and adverse pregnancy outcomes (Obstet. Gynecol. 2005;106:517-24 and Obstet. Gynecol. 2010;115:14-20).

Another prospective study of 4,250 unselected pregnancies also found no significant associations between FVL and preeclampsia, IUGR, and pregnancy loss (Br. J. Haematol. 2008;140:236-40).

Some of these findings are similar to previous reports from smaller prospective cohort studies. Investigators reported in 1999, for instance, no association between activated protein C resistance and fetal loss, preeclampsia, and IUGR. And in 2000, investigators had similarly reported a lack of association between FVL and methylenetetrahydrofolate reductase (MTHFR) polymorphism and preeclampsia or IUGR.

In general, the reported linkage between inherited thrombophilia and adverse outcomes other than stillbirth was always more tenuous. In the case of preeclampsia, however, meta-analyses of studies done before 2000 showed a fairly strong association between thrombophilia and preeclampsia, while studies published in and after 2001 found no such association.

There are a few exceptions to the lack of association found in larger prospective cohort studies. Most notably, an Australian study published this year of nulliparous women was suggestive of a weak association between the PGM and a composite index of adverse pregnancy outcomes (Obstet. Gynecol. 2010;115:5-13).

However, when investigators analyzed individual outcomes, they found that the only statistically significant associations were between the PGM and placental abruption, and between FVL and stillbirth. These associations, moreover, were based on very small sample size (nine and six patients, respectively). The investigators concluded that “the majority of asymptomatic women who carry an inherited thrombophilia polymorphism have a successful pregnancy outcome.”

There also is, at best, conflicting evidence in the literature of any benefit to heparin therapy for recurrent fetal loss.

A New Outlook on Screening

Given the evolving body of literature, it now seems wholly unjustified to screen low-risk populations. Knowing whether or not the patient has inherited thrombophilia, particularly in the nulliparous state, does not appear to be important for predicting outcomes.

There are questions that remain, however—most notably the question of whether women who have repetitive fetal losses or repetitive preeclampsia or abruptions should be screened and treated for inherited thrombophilia. Certainly, the failure of large prospective cohort studies to demonstrate any consistent association dampens our enthusiasm for the idea that inherited thrombophilia are to blame.

My opinion on this topic has evolved considerably over the last 10 years. I now believe that while screening for antiphospholipid syndrome is still warranted, screening for inherited thrombophilia in women having recurrent adverse pregnancy outcomes should occur only in the setting of an institutional review board–approved study in which ascertainment is done before a subsequent pregnancy and the patient's thrombophilia status is correlated with subsequent outcome (i.e., live birth, miscarriage, stillbirth, fetal growth restriction, preeclampsia, or abruption).

Furthermore, until we have established a definitive link between inherited thrombophilia and adverse pregnancy outcomes, we shouldn't even begin to think about clinical trials of thromboprophylaxis for affected women.

A particularly thorny question that has been raised concerns the issue of early fetal loss. Some have argued that the latest prospective cohort studies involved blood collection at or after 10 weeks' gestation and, therefore, are not relevant to conclusions drawn about the association (or lack thereof) between inherited thrombophilia and embryonic fetal loss.

However, I believe there are several reasons why we can conclude that thrombophilia and embryonic fetal losses are not linked. For one, there are enough data available from negative retrospective studies in which blood was obtained right after the pregnancy was completed. Secondly, there is no correlation between inherited thrombophilia and subsequent in vitro fertilization (IVF) failures in almost a dozen published studies. In fact, there is actually some evidence that FVL is associated with IVF success.

Lastly, we now know there is very little blood flow to the placenta before 10 weeks' gestation. There is some evidence, in fact, that hypoxia is the normal state of the embryo and may even be the preferred condition for culturing embryos in IVF.

Again, this issue requires prospective studies amongst patients with recurrent loss in which ascertainment occurs before the pregnancy commences.

Maternal Thrombotic Risk

While it's fair to say that, in general, inherited thrombophilia modestly increases the risk of maternal venous thrombotic events (VTE), it is critical to appreciate the role that a personal or strong family history of thrombosis (i.e., an affected first-degree relative) plays in determining a mother's risk.

Most women (greater than 93%) without a personal or strong family history of VTE will have uneventful pregnancies even when highly thrombogenic mutations are present. Once a personal or family history is factored in, however, the risk of VTE increases dramatically.

In the absence of a personal history of VTE or such an episode in a first-degree relative, heterozygosity for FVL or PGM is associated with a risk of thrombosis in pregnancy of well under 1% (0.2% and 0.5%, respectively). Similarly, protein C and protein S deficiencies are associated with a VTE risk under 1% in the absence of a personal or close family history.

In contrast, with a positive personal or family history, the risk of VTE in pregnancy increases to 10% in women who have heterozygosity for FVL, greater than 10% for women who have heterozygosity for PGM, 4%-17% in cases of protein C deficiency, and potentially up to 22% in cases of protein S deficiency.

Without a personal or family history, therefore, women with these lower-risk thrombophilia do not require anticoagulation during pregnancy unless they have other risk factors for thrombosis, such as significant obesity or orders for bed rest.

Patients with known inherited thrombophilia and a positive history, on the other hand, should receive antepartum thromboprophylaxis followed by postpartum anticoagulation. (Women who have a cesarean delivery should receive postpartum anticoagulation whether they have a personal or family history or not.)

Anticoagulation during pregnancy is also warranted—regardless of personal or family history—in the rare cases in which a patient is known to have homozygosity for FVL or homozygosity for PGM, or if a patient is known to have “double heterozygosity” for both FVL and PGM. Antithrombin deficiency, the most thrombogenic of all the inherited thrombophilias, also warrants antepartum anticoagulation as well as antithrombin infusions during labor and delivery.

To date, two studies have attempted to determine the value of screening for inherited thrombophilia based on a family history of prior VTE, and neither has shown that widespread screening would be particularly useful or cost effective in this setting. One certainly can argue, on the other hand, in favor of screening for thrombophilia in women who have a strong family history of VTE coupled with other risk factors.

Individualized risk assessment is always valuable. A woman with multiple risk factors—one who is obese, smokes, and is being put on bed rest, for instance—is a candidate for low-molecular-weight heparin (LMWH) therapy, for instance, even without a history of thrombosis and regardless of her thrombophilia status. If such a patient also has hypertension or preeclampsia, however, I'd be reluctant to give her either heparin or LMWH, for fear of abruption or even intracranial hemorrhage.

In what other circumstances is screening for thrombophilia warranted?

It can be justified when there is a personal history of VTE associated with a risk factor that is not recurrent. In this case, the absence of a thrombophilia reduces the risk of occurrence/recurrence of VTE during pregnancy to a very low level, while the presence of a thrombophilia would mandate antepartum anticoagulation. In any case, she should receive postpartum prophylaxis since 75%-80% of fatal pulmonary emboli in pregnancy occur after cesarean delivery.

For instance, screening is valuable in a woman who had a VTE earlier in her life when she was on oral contraception and was put in a cast after a skiing accident. If she does not have a documented thrombophilia, you will not need to give her anticoagulation during the pregnancy—only post partum.

The Work-Up

When screening for inherited thrombophilia is warranted, I recommend limiting it to FVL, PGM, protein C deficiency, antithrombin deficiency, and protein S deficiency. (See table, p. 20.)

Screening for FVL, even during pregnancy, can be done with a second-generation screening test for active protein C resistance, or by polymerase chain reaction (PCR).

Screening for the PGM should be done by PCR, and I recommend getting an antithrombin activity level and a protein C activity level to screen for antithrombin deficiency and protein C deficiency, respectively.

Screening for protein S deficiency is trickier, since circulating protein S activity levels can vary dramatically in pregnancy (i.e., various conditions from infections to surgery to hormonal status can affect activity levels of protein S).

I recommend first assessing the protein S free antigen level. In nonpregnant patients, a free antigen level less than 55% indicates risk for deficiency. Free antigen levels drop significantly in pregnancy, however, making a level at or below 29% in the first and second trimesters, and a level at or below 24% in the third trimester, indicative of risk. Such levels can be accepted as indicating protein S deficiency, or deficiency can be confirmed by then measuring the protein S activity level.

I do not recommend screening for MTHFR mutations or hyperhomocysteinemia. There does not appear to be any association between MTHFR mutations and adverse pregnancy outcomes, and the probable association between hyperhomocysteinemia and maternal venous thrombotic events that exists in general is of far less concern in the United States since grains are fortified with folate. If there is any concern, extra folic acid supplementation should be protective.

Source Elsevier Global Medical News

Key Points

▸ Most positive associations between inherited thrombophilia and adverse pregnancy outcomes were derived from small case-control studies. Many studies are contradictory.

▸ Large prospective cohort studies have failed to demonstrate any consistent association between inherited thrombophilia and adverse pregnancy outcomes.

▸ There appears to be a modest association between thrombophilia and fetal loss after 10 weeks in retrospective, but not most prospective, studies.

▸ There is no current support for screening for inherited thrombophilia in women experiencing recurrent unexplained fetal loss or other adverse pregnancy outcomes. Diagnosis and treatment regimens should occur only in the context of an institutional review board–approved research protocol.

▸ Patients with known inherited thrombophilia and a personal or family history of prior VTE should receive antepartum thromboprophylaxis followed by postpartum anticoagulation.

▸ Unless they have additional, significant risk factors, women with lower-risk thrombophilias (i.e., heterozygotes for FVL, PGM, protein C deficiency, or protein S deficiency) and no history of prior VTE or an affected first-degree relative do not require antepartum thromboprophylaxis.

▸ Women who have a personal history of VTE associated with a nonrecurrent risk factor should be screened.

Source: Dr. Lockwood

Thrombophilia and Adverse Outcomes

Adverse pregnancy outcomes are among the most perplexing pregnancy-related problems because we still have little precise knowledge about the etiology—and often, the mechanisms—associated with them. Over time, a number of causes have been identified and suggested, and some potential therapeutic agents have been proposed.

The relationship between thrombophilia and adverse outcomes has been a long-term association. A number of experiential reports and uncontrolled trials have endorsed this relationship. In fact, experimental therapeutic trials with heparin and other agents have attempted to improve outcomes and have reported incremental benefits when these agents have been used.

This has further galvanized the belief that thrombophilia may in fact be strongly etiologic in the pathophysiology of some adverse pregnancy outcomes. Thus, interventions based on a presumed mechanistic basis have been supported. However, newer data have seemed not to bear out this long-held association between thrombophilia and adverse outcomes, and the implied treatment.

It is in light of this controversy and the conflicting positions that we have decided to do a Master Class to thoroughly review the subject, to look at what data exist that can help unravel this relationship, and to examine whether screening patients for thrombophilia and treating it as a basis for improving pregnancy outcomes is warranted.

We have invited Dr. Charles J. Lockwood to address the topic. Dr. Lockwood is the Anita O'Keeffe Young Professor of Women's Health and chair of the department of obstetrics, gynecology, and reproductive sciences at Yale University, New Haven, Conn., and chief of obstetrics and gynecology at Yale–New Haven Hospital.

Dr. Lockwood has studied and thought a great deal about the association between inherited thrombophilia and adverse pregnancy outcomes, as well as the association between thrombophilia and maternal thrombosis. He urges us to step back and, in light of a “new landscape of research findings,” take a more careful approach to assessment and screening.

Obesity is a worldwide epidemic with management implications that are more urgent than ever for obstetrics. The latest data from the Centers for Disease Control and Prevention show a prevalence of obesity that surpasses 35% in U.S. women of reproductive age.

Implications of Obesity

The potential maternal, fetal, peripartum, and neonatal complications in our obese pregnant patients are numerous. Studies have shown that the obese woman has a significantly increased risk of early miscarriage (an odds ratio of 1.2) and recurrent miscarriage (OR of 3.5), compared with a normal-weight woman after natural conception (Hum. Reprod. 2004;19:1644-6). The risk of congenital anomalies also rises in obese women. In a recent meta-analysis, obese mothers were at significantly increased risk of having a child affected by a neural tube defect (OR 1.9), spina bifida (OR 2.2), cardiovascular anomalies (OR 1.3), and other anomalies, compared with body mass index (BMI)–appropriate mothers (JAMA 2009;301:636-50). In a prospective, multicenter study of more than 16,000 women, obese women and morbidly obese women were 2.5 and 3.2 times, respectively, more likely to develop gestational hypertension than nonobese women. They also were 1.6 and 3.3 times more likely, respectively, to develop preeclampsia. Gestational diabetes was 2.6 and 4 times more likely to occur in obese and morbidly obese women, compared with normal-weight pregnant women (Am. J. Obstet. Gynecol. 2004;190:1091-7).

Obesity also increases the risk of indicated preterm delivery, caused by complications such as preeclampsia and diabetes. The risk of cesarean delivery and associated morbidities increases as well, as does the risk of macrosomia and fetal overgrowth (an increase in adipose tissue rather than lean body mass).

Macrosomia then perpetuates the problem of obesity in the offspring. Evidence clearly points toward an increase in adolescent and adult obesity in infants who are born either large for gestational age or who are macrosomic.

Excess maternal weight gain, particularly in average-weight women, is also a risk factor for excess birth weight (Obstet. Gynecol. 2008;112:999-1006).

There has been increasing awareness over the past decade, moreover, of the role that maternal obesity may play in unexplained antepartum fetal death. At least two studies—one in a Canadian population and one in a Danish National Birth Cohort — have shown that maternal pregravid weight increased the risk of unexplained fetal death, even in women without medical or obstetric complications (Obstet. Gynecol. 2000;95:215-21, and Obstet. Gynecol. 2005;106:250-9).

Managing the Obese Patient

Vigilant management of the obese pregnant woman is critical not only for the woman and her baby, but for future generations as well. We must increase our attentiveness to and surveillance for all the risks that obesity poses during pregnancy, and must think preventively during comprehensive preconceptional and postpartum care, with the goal of breaking the vicious cycle of obesity.

Until we gain a better understanding of underlying genetic predispositions, physiology, and mechanisms relating to maternal and fetoplacental interactions that affect fetal growth and development, all treatments in obese pregnant women must be empiric. However, we need to build upon the information we currently possess because waiting may not be an option.

Here are some of the key components of effective obesity management in pregnancy:

▸ Appreciate that obesity is treatable. Certainly, women should aim to conceive while at a normal body mass index (BMI). Our ability to manage obesity preconceptually is constrained by the fact that many pregnancies are unplanned. However, when given the opportunity, we must encourage and help facilitate weight loss before pregnancy.

With proper counseling, some obese women can indeed achieve meaningful weight loss before conception. We know that lifestyle measures involving both nutritional counseling and exercise are more beneficial than either approach alone. The American College of Obstetricians and Gynecologists has practical guidelines on how to assess and manage obesity in the nonpregnant woman (“The Role of the Obstetrician Gynecologist in the Assessment and Management of Obesity,” Committee Opinion Number 319, October 2005).

We also must treat obesity as a problem itself, with an individualized, patient-centered approach. This point was stressed in the report on weight gain in pregnancy issued last year by the Institute of Medicine and National Research Council (

www.nap.edu

As obstetricians we tend to home in during pregnancy on the complications of obesity while overlooking the underlying problem. We also are less likely to think about individualized, patient-centered treatment for a woman who is overweight or obese as we would for a woman with a more straightforward problem like gestational diabetes. We need a change of mind set.

If a woman enters pregnancy obese, limiting her weight gain to recommended levels will help lower her risk of various complications and reduce postpartum weight retention. Exercise and other lifestyle changes will also improve insulin use in women with diabetes.

In the postpartum period, we must help women meet the important goal of returning to their prepregnancy weight, and then encourage them to lower their weight before the next pregnancy, referring them to specialists if necessary to break the cycle of obesity.

Breastfeeding is an important tool to reducing postpartum weight retention—it increases caloric utilization by 500-800 calories per day and has short- and long-term benefits for both the mother and the baby. We must appreciate, however, that it is technically more difficult for an obese woman to breastfeed, compared to a nonobese woman. The obese patient may need special help from a lactation consultant.

▸ Think inflammation and insulin resistance. In the pregravid state, an obese woman has increased inflammation and more insulin resistance to begin with. Her inflammatory profile and level of insulin resistance then only increases in pregnancy. (There are significant 50%-60% decreases in maternal insulin sensitivity by the end of the third trimester.)

Increased insulin resistance in pregnancy, studies show, can drive an excess flow of nutrients to the fetus and lead to macrosomia. Insulin resistance also may increase the risk of preeclampsia and gestational diabetes.

Although insulin sensitizers such as metformin or thiazolidinediones theoretically may be useful for increasing insulin sensitivity, these agents cross the placenta and their fetal safety has not been documented. This brings us back to lifestyle interventions to improve insulin resistance—a calorie-appropriate diet that is low in saturated fat and high in complex carbohydrates, for instance, along with exercise that uses large skeletal muscles, such as walking and swimming.

The role of dietary supplements such as fish oil and vitamin D in decreasing inflammation and improving metabolic function are currently under investigation. While we do not believe either causes any harm, it is too early to make official recommendations. At this point, we must focus on lifestyle interventions as our primary management approach.

▸ Pursue early glucose testing, and tight glucose control in patients with gestational diabetes mellitus (GDM). Women who are obese should be considered for early glucose screening rather than waiting until the 24- to 28-week standard screening period. Such early screening enables the detection of undiagnosed type 2 diabetes, or overt diabetes, and is the new recommendation of the International Association of Diabetes and Pregnancy Study Groups (IADPSG) for the diagnosis of GDM (Diabetes Care 2010;33:676-82).

When results from early screening are normal, testing should be repeated later. If either pregestational diabetes or gestational diabetes is detected, tight glucose control should be the goal.

A recent paper from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study suggests there are strong independent associations of fasting C-peptide (an index of insulin sensitivity) and BMI with preeclampsia. Maternal glucose levels in this study (levels below those found in diabetes mellitus) had weaker associations with preeclampsia (Am. J. Obstet. Gynecol. 2010;202:255.e1-7).

Other data show that tight glucose control in obese women with diabetes may decrease the risk of preeclampsia and other complications.

▸ Limit weight gain in pregnancy. Although pregravid weight, rather than weight gain during pregnancy, has the strongest correlation with the complications of maternal obesity in pregnancy and with birth weight, maternal weight gain during gestation still is positively correlated with excess birth weight and with various complications.

At minimum, we can work with women on limiting weight gain in pregnancy and following the new guidelines published last year by the Institute of Medicine and National Research Council. The report, which updates the previously published guidelines from 1990, specifies a new weight gain range for obese women, limiting their gain to 11-20 pounds during pregnancy.

Studies published after the previous guidelines were released in 1990 have consistently shown that women who gain weight within the recommended amounts have better outcomes. Women who do not gain excess weight also are less likely to retain extra pounds after birth.

Research also has shown, however, that a high proportion of women report that they were either given no advice on how much weight to gain or were advised to gain outside of their recommended range.

Indeed, an increasingly large proportion of women has gained in excess of the recommendations: From 1993 to 2003, the proportion of overweight women gaining in excess of the 1990 IOM recommendations increased to approximately 63%; approximately 46% of obese women gained excess weight.

Given the IOM's lower weight gain recommendation for obese women, such proportions will likely rise unless we increase the counseling we give patients on weight, diet, and exercise, and unless we routinely record and discuss patients' weight, height, and BMI.

More recent studies have focused on interventions to help women limit their weight gain during pregnancy. Although none of the four trials conducted in North American populations and reviewed by the IOM was completely successful in helping women limit their gestational weight gain and adhere to the 1990 guidelines, two European studies demonstrate that it's possible to motivate obese pregnant women to limit their weight gain during pregnancy to 6-7 kg. The interventions involved individual dietary or motivational counseling, and in one of the studies, the provision of specially designed aqua aerobics classes.

In general, interventions described in the literature have included counseling, the provision of unique physical activity classes, dietary prescription, and even daily recording of dietary intake.

▸ But do not encourage weight loss. Some investigators have recently proposed that obese women should consider weight loss during pregnancy in order to decrease adverse perinatal outcomes. It is my opinion that while women should avoid excessive weight gain, they should not be advised to lose weight until additional investigation shows that there are benefits and no adverse consequences to the mother and/or fetus.

There are obligatory physiological changes that for most women result in a “net maternal weight gain”: on average, 4-5 kg of weight at term represents the fetus, the placenta, and amniotic fluid.

For reasons that we don't fully understand, some obese women do not gain weight during pregnancy, or may actually lose weight, and still have a healthy baby. These women may have a decrease in energy expenditure in pregnancy and a subsequent decrease in intake, and/or there may be other physiologic issues at work.

As long as such a patient is eating well, seeing a nutritionist, and does not have ketonemia/ketonuria, and her baby is growing well, I would not encourage excessive intake in order to meet a particular weight gain target. I would just monitor her carefully.

The bottom line: Until we learn more about the safety of intentional weight loss during pregnancy, we face a delicate balancing task. On one hand, we need to appreciate that some women do not gain weight during pregnancy and should not necessarily be urged to gain an arbitrary amount while, on the other hand, we should not encourage these women to lose weight.

▸ Consider bariatric surgery to be a tool in your armamentarium. Population studies and reports of long-term outcomes from the United States and Scandinavia suggest that bariatric surgery has potential long-term benefits—in terms of weight loss and improvement in metabolic function—for women of reproductive age who do not have success with lifestyle measures and medical treatments.

In our practice, we often refer women after delivery to see our obesity specialist, who institutes medical therapy and will move on to consideration of bariatric surgery if the medical therapy is not successful. Experts have determined that bariatric surgery may be considered in women with a BMI greater than 35 (class II obesity) who have significant medical problems such as hypertension or diabetes, or in women who have a BMI greater than 40 (class III obesity) and no obvious medical complications.

ACOG's committee opinion No. 315 from 2005 includes various recommendations about how long to delay pregnancy after surgery (12-18 months after laparoscopic adjustable gastric banding, for example), and what vitamin supplementation is necessary. Women who have laparoscopic adjustable gastric banding should be monitored by both their obstetrician and bariatric surgeon during pregnancy, according to the ACOG committee's recommendations (Obstet. Gynecol. 2005;106:671-5).

▸ Don't “miss the forest for the trees.” When encountering various complaints and problems during pregnancy, think of the underlying obesity and not only the effects of pregnancy. Because obese women have an increased risk of developing or having manifestations of the metabolic syndrome—hypertension, proteinuria, dyslipidemia, and diabetes—we are seeing an increase in medical problems that in the past have been diagnosed primarily in older nonpregnant patients. Sleep apnea and nonalcoholic fatty liver disease are examples.

A woman who has shortness of breath or declining levels of oxygen saturation post partum, particularly after a cesarean delivery, may actually have sleep apnea, for instance, rather than a pulmonary embolism or pregnancy-related changes in tidal volume.

Similarly, elevated liver function tests may be an indication of nonalcoholic fatty liver disease rather than a manifestation of severe preeclampsia or the HELP syndrome. Non-alcoholic fatty liver disease is actually the most common reason today for a woman of reproductive age to have elevated liver function tests. Increasingly, it is becoming a more common diagnosis in the obese patient. Obesity, increased estrogen concentrations, elevated lipids, and increased insulin resistance have all been recognized as factors contributing to the development of non-alcoholic fatty liver disease.

▸ Up the ante on kick counts. Because the risk of stillbirth is significantly increased in the obese pregnant woman (even the patients without hypertensive disorders or other complications), fetal monitoring with kick counts is all the more important.

The cost/potential benefit of more extensive evaluation is unclear for the obese woman without any medical or obstetric complications (and fetal assessment is more difficult in the obese patient), but certainly a lower threshold for more formal testing should be considered for women who do have complications and for women in whom a “red flag” is raised.

A patient whose baby appears to be very large on ultrasound or in the clinical exam, for instance, or a patient whose baby is well above the 90th percentile too early in gestation might benefit from more formal evaluation of fetal well-being, even if glucose and blood pressure tests are normal.

Vitals

Source Elsevier Global Medical News

Source Elsevier Global Medical News

Complications of Obesity in Pregnancy

Obesity is one of the world's fastest growing and most insidious pandemics. At least 400 million adults worldwide, and one-third of adult Americans fit the criteria for obesity (JAMA 2010;303:235-41). Indeed, obesity is increasingly being diagnosed at earlier ages; it is estimated that between 16% and 33% of U.S. children and adolescents are obese.

It is particularly distressing when obesity impacts women of child-bearing age because they, along with their offspring, are the populations most vulnerable to the consequences of obesity. There are many long-term, downstream consequences of obesity for pregnant women, including a significantly higher risk of developing type 2 diabetes, hypertension, and cardiovascular disease. Additionally, the offspring of these women face significant health consequences in utero, during birth, as well as for many years afterward. Children born to obese women are more likely to be large for gestational age, delivered by cesarean section, or have birth defects and are at significantly greater risk of becoming obese and developing obesity-related complications, such as type 2 diabetes, in adolescence and adulthood.

Because obesity is so prevalent among women of child-bearing age, we have decided to devote a Master Class to discussing the potential complications of obesity during pregnancy and how best to manage and/or prevent those complications. The goal is to give practitioners the basic knowledge they need to identify those at-risk obese patients so they can institute appropriate preventive and therapeutic measures.

Patrick Catalano, M.D., professor and chair of the department of reproductive biology at Case Western Reserve University, is one of the world's leading experts on the short- and long-term consequences of obesity for pregnant women and their offspring. He served on the Institute of Medicine committee that in 2009 reexamined guidelines on weight gain during pregnancy. He also is leading the effort to inform physicians and the public about the costly complications of obesity in pregnancy and in finding ways to prevent these complications from occurring in the first place. Dr. Catalano's research focus is on insulin resistance and glucose metabolism in pregnancy and the role of placental cytokines in the regulation of fetal growth and adiposity.

Obesity is a worldwide epidemic with management implications that are more urgent than ever for obstetrics. The latest data from the Centers for Disease Control and Prevention show a prevalence of obesity that surpasses 35% in U.S. women of reproductive age.

Implications of Obesity

The potential maternal, fetal, peripartum, and neonatal complications in our obese pregnant patients are numerous. Studies have shown that the obese woman has a significantly increased risk of early miscarriage (an odds ratio of 1.2) and recurrent miscarriage (OR of 3.5), compared with a normal-weight woman after natural conception (Hum. Reprod. 2004;19:1644-6). The risk of congenital anomalies also rises in obese women. In a recent meta-analysis, obese mothers were at significantly increased risk of having a child affected by a neural tube defect (OR 1.9), spina bifida (OR 2.2), cardiovascular anomalies (OR 1.3), and other anomalies, compared with body mass index (BMI)–appropriate mothers (JAMA 2009;301:636-50). In a prospective, multicenter study of more than 16,000 women, obese women and morbidly obese women were 2.5 and 3.2 times, respectively, more likely to develop gestational hypertension than nonobese women. They also were 1.6 and 3.3 times more likely, respectively, to develop preeclampsia. Gestational diabetes was 2.6 and 4 times more likely to occur in obese and morbidly obese women, compared with normal-weight pregnant women (Am. J. Obstet. Gynecol. 2004;190:1091-7).

Obesity also increases the risk of indicated preterm delivery, caused by complications such as preeclampsia and diabetes. The risk of cesarean delivery and associated morbidities increases as well, as does the risk of macrosomia and fetal overgrowth (an increase in adipose tissue rather than lean body mass).

Macrosomia then perpetuates the problem of obesity in the offspring. Evidence clearly points toward an increase in adolescent and adult obesity in infants who are born either large for gestational age or who are macrosomic.

Excess maternal weight gain, particularly in average-weight women, is also a risk factor for excess birth weight (Obstet. Gynecol. 2008;112:999-1006).

There has been increasing awareness over the past decade, moreover, of the role that maternal obesity may play in unexplained antepartum fetal death. At least two studies—one in a Canadian population and one in a Danish National Birth Cohort — have shown that maternal pregravid weight increased the risk of unexplained fetal death, even in women without medical or obstetric complications (Obstet. Gynecol. 2000;95:215-21, and Obstet. Gynecol. 2005;106:250-9).

Managing the Obese Patient

Vigilant management of the obese pregnant woman is critical not only for the woman and her baby, but for future generations as well. We must increase our attentiveness to and surveillance for all the risks that obesity poses during pregnancy, and must think preventively during comprehensive preconceptional and postpartum care, with the goal of breaking the vicious cycle of obesity.

Until we gain a better understanding of underlying genetic predispositions, physiology, and mechanisms relating to maternal and fetoplacental interactions that affect fetal growth and development, all treatments in obese pregnant women must be empiric. However, we need to build upon the information we currently possess because waiting may not be an option.

Here are some of the key components of effective obesity management in pregnancy:

▸ Appreciate that obesity is treatable. Certainly, women should aim to conceive while at a normal body mass index (BMI). Our ability to manage obesity preconceptually is constrained by the fact that many pregnancies are unplanned. However, when given the opportunity, we must encourage and help facilitate weight loss before pregnancy.

With proper counseling, some obese women can indeed achieve meaningful weight loss before conception. We know that lifestyle measures involving both nutritional counseling and exercise are more beneficial than either approach alone. The American College of Obstetricians and Gynecologists has practical guidelines on how to assess and manage obesity in the nonpregnant woman (“The Role of the Obstetrician Gynecologist in the Assessment and Management of Obesity,” Committee Opinion Number 319, October 2005).

We also must treat obesity as a problem itself, with an individualized, patient-centered approach. This point was stressed in the report on weight gain in pregnancy issued last year by the Institute of Medicine and National Research Council (

www.nap.edu

As obstetricians we tend to home in during pregnancy on the complications of obesity while overlooking the underlying problem. We also are less likely to think about individualized, patient-centered treatment for a woman who is overweight or obese as we would for a woman with a more straightforward problem like gestational diabetes. We need a change of mind set.

If a woman enters pregnancy obese, limiting her weight gain to recommended levels will help lower her risk of various complications and reduce postpartum weight retention. Exercise and other lifestyle changes will also improve insulin use in women with diabetes.

In the postpartum period, we must help women meet the important goal of returning to their prepregnancy weight, and then encourage them to lower their weight before the next pregnancy, referring them to specialists if necessary to break the cycle of obesity.

Breastfeeding is an important tool to reducing postpartum weight retention—it increases caloric utilization by 500-800 calories per day and has short- and long-term benefits for both the mother and the baby. We must appreciate, however, that it is technically more difficult for an obese woman to breastfeed, compared to a nonobese woman. The obese patient may need special help from a lactation consultant.

▸ Think inflammation and insulin resistance. In the pregravid state, an obese woman has increased inflammation and more insulin resistance to begin with. Her inflammatory profile and level of insulin resistance then only increases in pregnancy. (There are significant 50%-60% decreases in maternal insulin sensitivity by the end of the third trimester.)

Increased insulin resistance in pregnancy, studies show, can drive an excess flow of nutrients to the fetus and lead to macrosomia. Insulin resistance also may increase the risk of preeclampsia and gestational diabetes.

Although insulin sensitizers such as metformin or thiazolidinediones theoretically may be useful for increasing insulin sensitivity, these agents cross the placenta and their fetal safety has not been documented. This brings us back to lifestyle interventions to improve insulin resistance—a calorie-appropriate diet that is low in saturated fat and high in complex carbohydrates, for instance, along with exercise that uses large skeletal muscles, such as walking and swimming.

The role of dietary supplements such as fish oil and vitamin D in decreasing inflammation and improving metabolic function are currently under investigation. While we do not believe either causes any harm, it is too early to make official recommendations. At this point, we must focus on lifestyle interventions as our primary management approach.

▸ Pursue early glucose testing, and tight glucose control in patients with gestational diabetes mellitus (GDM). Women who are obese should be considered for early glucose screening rather than waiting until the 24- to 28-week standard screening period. Such early screening enables the detection of undiagnosed type 2 diabetes, or overt diabetes, and is the new recommendation of the International Association of Diabetes and Pregnancy Study Groups (IADPSG) for the diagnosis of GDM (Diabetes Care 2010;33:676-82).

When results from early screening are normal, testing should be repeated later. If either pregestational diabetes or gestational diabetes is detected, tight glucose control should be the goal.

A recent paper from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study suggests there are strong independent associations of fasting C-peptide (an index of insulin sensitivity) and BMI with preeclampsia. Maternal glucose levels in this study (levels below those found in diabetes mellitus) had weaker associations with preeclampsia (Am. J. Obstet. Gynecol. 2010;202:255.e1-7).

Other data show that tight glucose control in obese women with diabetes may decrease the risk of preeclampsia and other complications.

▸ Limit weight gain in pregnancy. Although pregravid weight, rather than weight gain during pregnancy, has the strongest correlation with the complications of maternal obesity in pregnancy and with birth weight, maternal weight gain during gestation still is positively correlated with excess birth weight and with various complications.

At minimum, we can work with women on limiting weight gain in pregnancy and following the new guidelines published last year by the Institute of Medicine and National Research Council. The report, which updates the previously published guidelines from 1990, specifies a new weight gain range for obese women, limiting their gain to 11-20 pounds during pregnancy.

Studies published after the previous guidelines were released in 1990 have consistently shown that women who gain weight within the recommended amounts have better outcomes. Women who do not gain excess weight also are less likely to retain extra pounds after birth.

Research also has shown, however, that a high proportion of women report that they were either given no advice on how much weight to gain or were advised to gain outside of their recommended range.

Indeed, an increasingly large proportion of women has gained in excess of the recommendations: From 1993 to 2003, the proportion of overweight women gaining in excess of the 1990 IOM recommendations increased to approximately 63%; approximately 46% of obese women gained excess weight.

Given the IOM's lower weight gain recommendation for obese women, such proportions will likely rise unless we increase the counseling we give patients on weight, diet, and exercise, and unless we routinely record and discuss patients' weight, height, and BMI.

More recent studies have focused on interventions to help women limit their weight gain during pregnancy. Although none of the four trials conducted in North American populations and reviewed by the IOM was completely successful in helping women limit their gestational weight gain and adhere to the 1990 guidelines, two European studies demonstrate that it's possible to motivate obese pregnant women to limit their weight gain during pregnancy to 6-7 kg. The interventions involved individual dietary or motivational counseling, and in one of the studies, the provision of specially designed aqua aerobics classes.

In general, interventions described in the literature have included counseling, the provision of unique physical activity classes, dietary prescription, and even daily recording of dietary intake.

▸ But do not encourage weight loss. Some investigators have recently proposed that obese women should consider weight loss during pregnancy in order to decrease adverse perinatal outcomes. It is my opinion that while women should avoid excessive weight gain, they should not be advised to lose weight until additional investigation shows that there are benefits and no adverse consequences to the mother and/or fetus.

There are obligatory physiological changes that for most women result in a “net maternal weight gain”: on average, 4-5 kg of weight at term represents the fetus, the placenta, and amniotic fluid.

For reasons that we don't fully understand, some obese women do not gain weight during pregnancy, or may actually lose weight, and still have a healthy baby. These women may have a decrease in energy expenditure in pregnancy and a subsequent decrease in intake, and/or there may be other physiologic issues at work.

As long as such a patient is eating well, seeing a nutritionist, and does not have ketonemia/ketonuria, and her baby is growing well, I would not encourage excessive intake in order to meet a particular weight gain target. I would just monitor her carefully.

The bottom line: Until we learn more about the safety of intentional weight loss during pregnancy, we face a delicate balancing task. On one hand, we need to appreciate that some women do not gain weight during pregnancy and should not necessarily be urged to gain an arbitrary amount while, on the other hand, we should not encourage these women to lose weight.

▸ Consider bariatric surgery to be a tool in your armamentarium. Population studies and reports of long-term outcomes from the United States and Scandinavia suggest that bariatric surgery has potential long-term benefits—in terms of weight loss and improvement in metabolic function—for women of reproductive age who do not have success with lifestyle measures and medical treatments.

In our practice, we often refer women after delivery to see our obesity specialist, who institutes medical therapy and will move on to consideration of bariatric surgery if the medical therapy is not successful. Experts have determined that bariatric surgery may be considered in women with a BMI greater than 35 (class II obesity) who have significant medical problems such as hypertension or diabetes, or in women who have a BMI greater than 40 (class III obesity) and no obvious medical complications.

ACOG's committee opinion No. 315 from 2005 includes various recommendations about how long to delay pregnancy after surgery (12-18 months after laparoscopic adjustable gastric banding, for example), and what vitamin supplementation is necessary. Women who have laparoscopic adjustable gastric banding should be monitored by both their obstetrician and bariatric surgeon during pregnancy, according to the ACOG committee's recommendations (Obstet. Gynecol. 2005;106:671-5).

▸ Don't “miss the forest for the trees.” When encountering various complaints and problems during pregnancy, think of the underlying obesity and not only the effects of pregnancy. Because obese women have an increased risk of developing or having manifestations of the metabolic syndrome—hypertension, proteinuria, dyslipidemia, and diabetes—we are seeing an increase in medical problems that in the past have been diagnosed primarily in older nonpregnant patients. Sleep apnea and nonalcoholic fatty liver disease are examples.

A woman who has shortness of breath or declining levels of oxygen saturation post partum, particularly after a cesarean delivery, may actually have sleep apnea, for instance, rather than a pulmonary embolism or pregnancy-related changes in tidal volume.

Similarly, elevated liver function tests may be an indication of nonalcoholic fatty liver disease rather than a manifestation of severe preeclampsia or the HELP syndrome. Non-alcoholic fatty liver disease is actually the most common reason today for a woman of reproductive age to have elevated liver function tests. Increasingly, it is becoming a more common diagnosis in the obese patient. Obesity, increased estrogen concentrations, elevated lipids, and increased insulin resistance have all been recognized as factors contributing to the development of non-alcoholic fatty liver disease.

▸ Up the ante on kick counts. Because the risk of stillbirth is significantly increased in the obese pregnant woman (even the patients without hypertensive disorders or other complications), fetal monitoring with kick counts is all the more important.

The cost/potential benefit of more extensive evaluation is unclear for the obese woman without any medical or obstetric complications (and fetal assessment is more difficult in the obese patient), but certainly a lower threshold for more formal testing should be considered for women who do have complications and for women in whom a “red flag” is raised.

A patient whose baby appears to be very large on ultrasound or in the clinical exam, for instance, or a patient whose baby is well above the 90th percentile too early in gestation might benefit from more formal evaluation of fetal well-being, even if glucose and blood pressure tests are normal.

Vitals

Source Elsevier Global Medical News

Source Elsevier Global Medical News

Complications of Obesity in Pregnancy

Obesity is one of the world's fastest growing and most insidious pandemics. At least 400 million adults worldwide, and one-third of adult Americans fit the criteria for obesity (JAMA 2010;303:235-41). Indeed, obesity is increasingly being diagnosed at earlier ages; it is estimated that between 16% and 33% of U.S. children and adolescents are obese.

It is particularly distressing when obesity impacts women of child-bearing age because they, along with their offspring, are the populations most vulnerable to the consequences of obesity. There are many long-term, downstream consequences of obesity for pregnant women, including a significantly higher risk of developing type 2 diabetes, hypertension, and cardiovascular disease. Additionally, the offspring of these women face significant health consequences in utero, during birth, as well as for many years afterward. Children born to obese women are more likely to be large for gestational age, delivered by cesarean section, or have birth defects and are at significantly greater risk of becoming obese and developing obesity-related complications, such as type 2 diabetes, in adolescence and adulthood.

Because obesity is so prevalent among women of child-bearing age, we have decided to devote a Master Class to discussing the potential complications of obesity during pregnancy and how best to manage and/or prevent those complications. The goal is to give practitioners the basic knowledge they need to identify those at-risk obese patients so they can institute appropriate preventive and therapeutic measures.

Patrick Catalano, M.D., professor and chair of the department of reproductive biology at Case Western Reserve University, is one of the world's leading experts on the short- and long-term consequences of obesity for pregnant women and their offspring. He served on the Institute of Medicine committee that in 2009 reexamined guidelines on weight gain during pregnancy. He also is leading the effort to inform physicians and the public about the costly complications of obesity in pregnancy and in finding ways to prevent these complications from occurring in the first place. Dr. Catalano's research focus is on insulin resistance and glucose metabolism in pregnancy and the role of placental cytokines in the regulation of fetal growth and adiposity.

Obesity is a worldwide epidemic with management implications that are more urgent than ever for obstetrics. The latest data from the Centers for Disease Control and Prevention show a prevalence of obesity that surpasses 35% in U.S. women of reproductive age.

Implications of Obesity

The potential maternal, fetal, peripartum, and neonatal complications in our obese pregnant patients are numerous. Studies have shown that the obese woman has a significantly increased risk of early miscarriage (an odds ratio of 1.2) and recurrent miscarriage (OR of 3.5), compared with a normal-weight woman after natural conception (Hum. Reprod. 2004;19:1644-6). The risk of congenital anomalies also rises in obese women. In a recent meta-analysis, obese mothers were at significantly increased risk of having a child affected by a neural tube defect (OR 1.9), spina bifida (OR 2.2), cardiovascular anomalies (OR 1.3), and other anomalies, compared with body mass index (BMI)–appropriate mothers (JAMA 2009;301:636-50). In a prospective, multicenter study of more than 16,000 women, obese women and morbidly obese women were 2.5 and 3.2 times, respectively, more likely to develop gestational hypertension than nonobese women. They also were 1.6 and 3.3 times more likely, respectively, to develop preeclampsia. Gestational diabetes was 2.6 and 4 times more likely to occur in obese and morbidly obese women, compared with normal-weight pregnant women (Am. J. Obstet. Gynecol. 2004;190:1091-7).

Obesity also increases the risk of indicated preterm delivery, caused by complications such as preeclampsia and diabetes. The risk of cesarean delivery and associated morbidities increases as well, as does the risk of macrosomia and fetal overgrowth (an increase in adipose tissue rather than lean body mass).

Macrosomia then perpetuates the problem of obesity in the offspring. Evidence clearly points toward an increase in adolescent and adult obesity in infants who are born either large for gestational age or who are macrosomic.

Excess maternal weight gain, particularly in average-weight women, is also a risk factor for excess birth weight (Obstet. Gynecol. 2008;112:999-1006).

There has been increasing awareness over the past decade, moreover, of the role that maternal obesity may play in unexplained antepartum fetal death. At least two studies—one in a Canadian population and one in a Danish National Birth Cohort — have shown that maternal pregravid weight increased the risk of unexplained fetal death, even in women without medical or obstetric complications (Obstet. Gynecol. 2000;95:215-21, and Obstet. Gynecol. 2005;106:250-9).

Managing the Obese Patient

Vigilant management of the obese pregnant woman is critical not only for the woman and her baby, but for future generations as well. We must increase our attentiveness to and surveillance for all the risks that obesity poses during pregnancy, and must think preventively during comprehensive preconceptional and postpartum care, with the goal of breaking the vicious cycle of obesity.

Until we gain a better understanding of underlying genetic predispositions, physiology, and mechanisms relating to maternal and fetoplacental interactions that affect fetal growth and development, all treatments in obese pregnant women must be empiric. However, we need to build upon the information we currently possess because waiting may not be an option.

Here are some of the key components of effective obesity management in pregnancy:

▸ Appreciate that obesity is treatable. Certainly, women should aim to conceive while at a normal body mass index (BMI). Our ability to manage obesity preconceptually is constrained by the fact that many pregnancies are unplanned. However, when given the opportunity, we must encourage and help facilitate weight loss before pregnancy.

With proper counseling, some obese women can indeed achieve meaningful weight loss before conception. We know that lifestyle measures involving both nutritional counseling and exercise are more beneficial than either approach alone. The American College of Obstetricians and Gynecologists has practical guidelines on how to assess and manage obesity in the nonpregnant woman (“The Role of the Obstetrician Gynecologist in the Assessment and Management of Obesity,” Committee Opinion Number 319, October 2005).

We also must treat obesity as a problem itself, with an individualized, patient-centered approach. This point was stressed in the report on weight gain in pregnancy issued last year by the Institute of Medicine and National Research Council (

www.nap.edu

As obstetricians we tend to home in during pregnancy on the complications of obesity while overlooking the underlying problem. We also are less likely to think about individualized, patient-centered treatment for a woman who is overweight or obese as we would for a woman with a more straightforward problem like gestational diabetes. We need a change of mind set.

If a woman enters pregnancy obese, limiting her weight gain to recommended levels will help lower her risk of various complications and reduce postpartum weight retention. Exercise and other lifestyle changes will also improve insulin use in women with diabetes.

In the postpartum period, we must help women meet the important goal of returning to their prepregnancy weight, and then encourage them to lower their weight before the next pregnancy, referring them to specialists if necessary to break the cycle of obesity.

Breastfeeding is an important tool to reducing postpartum weight retention—it increases caloric utilization by 500-800 calories per day and has short- and long-term benefits for both the mother and the baby. We must appreciate, however, that it is technically more difficult for an obese woman to breastfeed, compared to a nonobese woman. The obese patient may need special help from a lactation consultant.

▸ Think inflammation and insulin resistance. In the pregravid state, an obese woman has increased inflammation and more insulin resistance to begin with. Her inflammatory profile and level of insulin resistance then only increases in pregnancy. (There are significant 50%-60% decreases in maternal insulin sensitivity by the end of the third trimester.)

Increased insulin resistance in pregnancy, studies show, can drive an excess flow of nutrients to the fetus and lead to macrosomia. Insulin resistance also may increase the risk of preeclampsia and gestational diabetes.

Although insulin sensitizers such as metformin or thiazolidinediones theoretically may be useful for increasing insulin sensitivity, these agents cross the placenta and their fetal safety has not been documented. This brings us back to lifestyle interventions to improve insulin resistance—a calorie-appropriate diet that is low in saturated fat and high in complex carbohydrates, for instance, along with exercise that uses large skeletal muscles, such as walking and swimming.

The role of dietary supplements such as fish oil and vitamin D in decreasing inflammation and improving metabolic function are currently under investigation. While we do not believe either causes any harm, it is too early to make official recommendations. At this point, we must focus on lifestyle interventions as our primary management approach.

▸ Pursue early glucose testing, and tight glucose control in patients with gestational diabetes mellitus (GDM). Women who are obese should be considered for early glucose screening rather than waiting until the 24- to 28-week standard screening period. Such early screening enables the detection of undiagnosed type 2 diabetes, or overt diabetes, and is the new recommendation of the International Association of Diabetes and Pregnancy Study Groups (IADPSG) for the diagnosis of GDM (Diabetes Care 2010;33:676-82).

When results from early screening are normal, testing should be repeated later. If either pregestational diabetes or gestational diabetes is detected, tight glucose control should be the goal.

A recent paper from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study suggests there are strong independent associations of fasting C-peptide (an index of insulin sensitivity) and BMI with preeclampsia. Maternal glucose levels in this study (levels below those found in diabetes mellitus) had weaker associations with preeclampsia (Am. J. Obstet. Gynecol. 2010;202:255.e1-7).

Other data show that tight glucose control in obese women with diabetes may decrease the risk of preeclampsia and other complications.

▸ Limit weight gain in pregnancy. Although pregravid weight, rather than weight gain during pregnancy, has the strongest correlation with the complications of maternal obesity in pregnancy and with birth weight, maternal weight gain during gestation still is positively correlated with excess birth weight and with various complications.

At minimum, we can work with women on limiting weight gain in pregnancy and following the new guidelines published last year by the Institute of Medicine and National Research Council. The report, which updates the previously published guidelines from 1990, specifies a new weight gain range for obese women, limiting their gain to 11-20 pounds during pregnancy.

Studies published after the previous guidelines were released in 1990 have consistently shown that women who gain weight within the recommended amounts have better outcomes. Women who do not gain excess weight also are less likely to retain extra pounds after birth.

Research also has shown, however, that a high proportion of women report that they were either given no advice on how much weight to gain or were advised to gain outside of their recommended range.

Indeed, an increasingly large proportion of women has gained in excess of the recommendations: From 1993 to 2003, the proportion of overweight women gaining in excess of the 1990 IOM recommendations increased to approximately 63%; approximately 46% of obese women gained excess weight.

Given the IOM's lower weight gain recommendation for obese women, such proportions will likely rise unless we increase the counseling we give patients on weight, diet, and exercise, and unless we routinely record and discuss patients' weight, height, and BMI.

More recent studies have focused on interventions to help women limit their weight gain during pregnancy. Although none of the four trials conducted in North American populations and reviewed by the IOM was completely successful in helping women limit their gestational weight gain and adhere to the 1990 guidelines, two European studies demonstrate that it's possible to motivate obese pregnant women to limit their weight gain during pregnancy to 6-7 kg. The interventions involved individual dietary or motivational counseling, and in one of the studies, the provision of specially designed aqua aerobics classes.

In general, interventions described in the literature have included counseling, the provision of unique physical activity classes, dietary prescription, and even daily recording of dietary intake.

▸ But do not encourage weight loss. Some investigators have recently proposed that obese women should consider weight loss during pregnancy in order to decrease adverse perinatal outcomes. It is my opinion that while women should avoid excessive weight gain, they should not be advised to lose weight until additional investigation shows that there are benefits and no adverse consequences to the mother and/or fetus.

There are obligatory physiological changes that for most women result in a “net maternal weight gain”: on average, 4-5 kg of weight at term represents the fetus, the placenta, and amniotic fluid.

For reasons that we don't fully understand, some obese women do not gain weight during pregnancy, or may actually lose weight, and still have a healthy baby. These women may have a decrease in energy expenditure in pregnancy and a subsequent decrease in intake, and/or there may be other physiologic issues at work.

As long as such a patient is eating well, seeing a nutritionist, and does not have ketonemia/ketonuria, and her baby is growing well, I would not encourage excessive intake in order to meet a particular weight gain target. I would just monitor her carefully.

The bottom line: Until we learn more about the safety of intentional weight loss during pregnancy, we face a delicate balancing task. On one hand, we need to appreciate that some women do not gain weight during pregnancy and should not necessarily be urged to gain an arbitrary amount while, on the other hand, we should not encourage these women to lose weight.

▸ Consider bariatric surgery to be a tool in your armamentarium. Population studies and reports of long-term outcomes from the United States and Scandinavia suggest that bariatric surgery has potential long-term benefits—in terms of weight loss and improvement in metabolic function—for women of reproductive age who do not have success with lifestyle measures and medical treatments.

In our practice, we often refer women after delivery to see our obesity specialist, who institutes medical therapy and will move on to consideration of bariatric surgery if the medical therapy is not successful. Experts have determined that bariatric surgery may be considered in women with a BMI greater than 35 (class II obesity) who have significant medical problems such as hypertension or diabetes, or in women who have a BMI greater than 40 (class III obesity) and no obvious medical complications.

ACOG's committee opinion No. 315 from 2005 includes various recommendations about how long to delay pregnancy after surgery (12-18 months after laparoscopic adjustable gastric banding, for example), and what vitamin supplementation is necessary. Women who have laparoscopic adjustable gastric banding should be monitored by both their obstetrician and bariatric surgeon during pregnancy, according to the ACOG committee's recommendations (Obstet. Gynecol. 2005;106:671-5).

▸ Don't “miss the forest for the trees.” When encountering various complaints and problems during pregnancy, think of the underlying obesity and not only the effects of pregnancy. Because obese women have an increased risk of developing or having manifestations of the metabolic syndrome—hypertension, proteinuria, dyslipidemia, and diabetes—we are seeing an increase in medical problems that in the past have been diagnosed primarily in older nonpregnant patients. Sleep apnea and nonalcoholic fatty liver disease are examples.

A woman who has shortness of breath or declining levels of oxygen saturation post partum, particularly after a cesarean delivery, may actually have sleep apnea, for instance, rather than a pulmonary embolism or pregnancy-related changes in tidal volume.

Similarly, elevated liver function tests may be an indication of nonalcoholic fatty liver disease rather than a manifestation of severe preeclampsia or the HELP syndrome. Non-alcoholic fatty liver disease is actually the most common reason today for a woman of reproductive age to have elevated liver function tests. Increasingly, it is becoming a more common diagnosis in the obese patient. Obesity, increased estrogen concentrations, elevated lipids, and increased insulin resistance have all been recognized as factors contributing to the development of non-alcoholic fatty liver disease.

▸ Up the ante on kick counts. Because the risk of stillbirth is significantly increased in the obese pregnant woman (even the patients without hypertensive disorders or other complications), fetal monitoring with kick counts is all the more important.

The cost/potential benefit of more extensive evaluation is unclear for the obese woman without any medical or obstetric complications (and fetal assessment is more difficult in the obese patient), but certainly a lower threshold for more formal testing should be considered for women who do have complications and for women in whom a “red flag” is raised.

A patient whose baby appears to be very large on ultrasound or in the clinical exam, for instance, or a patient whose baby is well above the 90th percentile too early in gestation might benefit from more formal evaluation of fetal well-being, even if glucose and blood pressure tests are normal.

Vitals

Source Elsevier Global Medical News

Source Elsevier Global Medical News

Complications of Obesity in Pregnancy

Obesity is one of the world's fastest growing and most insidious pandemics. At least 400 million adults worldwide, and one-third of adult Americans fit the criteria for obesity (JAMA 2010;303:235-41). Indeed, obesity is increasingly being diagnosed at earlier ages; it is estimated that between 16% and 33% of U.S. children and adolescents are obese.

It is particularly distressing when obesity impacts women of child-bearing age because they, along with their offspring, are the populations most vulnerable to the consequences of obesity. There are many long-term, downstream consequences of obesity for pregnant women, including a significantly higher risk of developing type 2 diabetes, hypertension, and cardiovascular disease. Additionally, the offspring of these women face significant health consequences in utero, during birth, as well as for many years afterward. Children born to obese women are more likely to be large for gestational age, delivered by cesarean section, or have birth defects and are at significantly greater risk of becoming obese and developing obesity-related complications, such as type 2 diabetes, in adolescence and adulthood.

Because obesity is so prevalent among women of child-bearing age, we have decided to devote a Master Class to discussing the potential complications of obesity during pregnancy and how best to manage and/or prevent those complications. The goal is to give practitioners the basic knowledge they need to identify those at-risk obese patients so they can institute appropriate preventive and therapeutic measures.

Patrick Catalano, M.D., professor and chair of the department of reproductive biology at Case Western Reserve University, is one of the world's leading experts on the short- and long-term consequences of obesity for pregnant women and their offspring. He served on the Institute of Medicine committee that in 2009 reexamined guidelines on weight gain during pregnancy. He also is leading the effort to inform physicians and the public about the costly complications of obesity in pregnancy and in finding ways to prevent these complications from occurring in the first place. Dr. Catalano's research focus is on insulin resistance and glucose metabolism in pregnancy and the role of placental cytokines in the regulation of fetal growth and adiposity.

obnews@elsevier.com

Vaginal birth after cesarean gained widespread acceptance in the 1980s after a National Institutes of Health Consensus Development Conference panel questioned the necessity of routine repeat cesarean deliveries and described situations in which a VBAC should be offered. Some insurers even mandated that physicians attempt a VBAC prior to a repeat cesarean delivery.

Since 1996, however, the VBAC rate has dropped substantially while cesarean delivery rates have risen steadily. The overall cesarean delivery rate was approximately 32% when last measured in 2007, up from 21% in 1996. The VBAC rate was less than 10% in 2007, compared with 28% in 1996, according to the Centers for Disease Control and Prevention.

Indeed, pregnant women now have limited access to VBAC services, and many are not even offered the option of having a trial of labor after cesarean. Some hospitals have declined to provide VBAC services, and the most recent medical liability survey conducted by the American College of Obstetricians and Gynecologists showed that almost 20% of responding fellows stopped offering or performing VBACs between 2006 and 2008. (In the prior survey, completed in 2006, these numbers were even higher—upward of 26%.)

The exact causes of the decline in VBAC deliveries are unclear, but the shift likely involves a mix of concerns about the possibility of uterine rupture, patient preferences, medicolegal pressures, guidelines that call for the immediate availability of personnel to perform an emergency cesarean, and other clinical and nonclinical factors.

It is a complex and concerning trend—one considered important enough to the health of women in the United States for the NIH to recently convene another Consensus Development Conference panel on the topic. The panel was asked to examine the causes of VBAC decline as well as the available research on the benefits and harms of attempting a trial of labor after a patient has had a cesarean delivery.

In a draft statement titled, “Vaginal Birth After Cesarean: New Insights,” released in March, the panel affirmed that a trial of labor is a reasonable option for many women with a prior cesarean delivery. It also urged that current VBAC guidelines be reconsidered and more research conducted.

Although guidelines are being revisited and research ensues, we owe it to the patients in our own practices to thoroughly consider what is known about the short- and long-term safety of VBAC, the selection of candidates, and the most reasonable approaches to intrapartum management.

Short-Term Safety of VBAC

In the past decade, there have been two large observational studies in the United States that have shed much light on the efficacy and safety of a trial of labor after cesarean. Both studies involved upwards of 20,000 women, and both showed rates of uterine rupture under 1%. This finding is significant, because some have suggested that uterine rupture is on the rise in the United States.

In one of these studies—a prospective cohort study conducted from 1999 through 2002 at 19 academic medical centers belonging to the National Institute of Child Health and Human Development Maternal-Fetal Medicine Units (MFMU) Network—there were 124 cases of uterine rupture among 17,898 women who underwent a trial of labor after cesarean, and no cases of uterine rupture among 15,801 women who underwent elective repeat cesarean delivery.

The rate of uterine rupture was 0.7% for women with a prior low transverse incision, 2.0% for those with a prior low vertical incision, and 0.5% for those with an unknown type of prior incision. Overall, the rate of uterine rupture in this study was 0.7% (N. Engl. J. Med. 2004;351:2581-9).

The second study, which I led, revealed a rate of uterine rupture in women who attempted VBAC of 0.9%, compared with a rate of 0.004% in women who underwent elective repeat cesarean section. This study was a multicenter observational study in which records of approximately 25,000 women with a prior low-transverse cesarean section were reviewed (Am. J. Obstet. Gynecol. 2005;193:1656-62).

Just as uterine rupture is more common in women who have a VBAC attempt than in those who choose elective repeat cesarean section, so are adverse perinatal outcomes. The MFMU study found 12 cases of hypoxic ischemic encephalopathy (HIE) among the term infants whose mothers underwent trials of labor. Seven of the cases of HIE were associated with uterine rupture.

Perspective is important. Although uterine rupture and HIE—the complications of most concern—are higher among those who attempt VBAC, the absolute rates are quite low and are comparable to, if not lower than, the complication rates of most other obstetrical procedures we perform on a daily basis.

Considering that the risks of pregnancy and childbirth overall are often underappreciated, it is important to share these data with patients and explain that the risks of VBAC are similar in magnitude to complications observed with any vaginal delivery. Certainly, these large observational studies—which provide a broader, more representative look at outcomes than prior studies—provide short-term safety evidence that overall favors VBAC as a standard part of practice.

Selecting Candidates

Patient selection is important, as most of the major complications in women who attempt a trial of labor occur in association with a failed VBAC attempt.

At least several investigators, myself included, have attempted to develop models or scoring systems to predict which women are most likely to be delivered vaginally with a VBAC attempt. Many of these models have incorporated factors that can be ascertained early in prenatal care as well as those that are not known until admission for delivery. Other models focus on factors available at the first prenatal visit, such as maternal age, prepregnancy body mass index, ethnicity, and prior vaginal delivery.

Unfortunately, these models have not been shown to accurately predict who is going to succeed and who is going to fail in a VBAC attempt.

Thus far, the one clinically useful predictive factor we have for VBAC success is prior vaginal delivery, whether it's a prior successful VBAC attempt or a vaginal delivery that predated a cesarean section. Indeed, numerous studies have supported the predictive value of a prior vaginal delivery.

In 2005, for instance, the MFMU reported that a previous vaginal delivery was the most significant predictor of VBAC delivery success in a cohort of 29,661 women with a history of one prior cesarean delivery. Women with a prior vaginal birth had a VBAC delivery success rate of 86.6%, compared with 60.9% in women without a prior vaginal delivery (Am. J. Obstet. Gynecol. 2005;193:1016-23).

A secondary analysis of our large, retrospective observational study on maternal complications with VBAC (discussed above) similarly showed that VBAC candidates with a prior vaginal birth were significantly more successful in achieving vaginal delivery than women with no prior vaginal delivery. The success rate was 89.9%, compared with 67% (Am. J. Obstet. Gynecol. 2006;195:1143-7).

Women with a history of vaginal delivery also appear to have lower rates of major complications, making a VBAC attempt safer in these patients than a planned repeat cesarean section (whether the attempt is successful or not). In our observational study, a prior vaginal delivery was associated with significant reductions in major morbidity.

Clearly, not all women with a history of cesarean delivery are the same, and women with a prior vaginal delivery should be counseled about their more favorable benefit-risk ratio.

Overall, the vaginal delivery rate after a trial of labor is high in women who have had prior cesareans. In our large observational study, the vaginal delivery rate among those women who attempted VBAC was 75.5%. Furthermore, in the draft of its consensus development conference statement, the NIH panel reported that there is a “high grade of evidence” showing that a trial of labor is successful in nearly 75% of cases.

Even in the least favorable groups—among women who might appear to have unfavorable risk profiles for VBAC attempts—the success rate for VBAC is consistently higher than 50%.

Intrapartum Management

We can make a relatively safe and reasonable process even safer by carefully and conservatively managing the intrapartum period in women attempting VBAC.

Here are several tips for managing a trial of labor after cesarean:

▸ Induce labor only when absolutely necessary. Research from both large observational studies on a trial of labor after cesarean has shown that the risk of uterine rupture is two- to threefold higher in women who have their labor induced than in women who are delivered spontaneously. We should therefore refrain from inducing labor unless we have solid medical reasons to do so.

▸ Try to avoid the use of multiple induction agents. If you're considering induction for a VBAC candidate who has an unfavorable cervical exam, reconsider it. Research has also shown that women who require multiple agents for induction have the highest rates of uterine rupture—rates that are almost four- to fivefold higher than those for women who labor spontaneously.

▸ Avoid higher doses of oxytocin. There does not appear to be an increased risk of rupture with oxytocin augmentation of spontaneous labor—unless the dose is in excess of 20 mU/min. An analysis by Dr. A.G. Cahill (Am. J. Obstet. Gynecol. 2007;197:495.e1-5), for example, found a dose-response relationship of maximum oxytocin administration and uterine rupture. Some institutions have already decided not to go above this amount in women attempting VBAC.

If your institution allows higher levels, be extra vigilant as the dosage increases.

▸ Be leery of intrauterine pressure catheters. Old data had suggested that intrauterine pressure catheters could be useful for predicting uterine rupture during trials of labor after cesarean. However, these data have not been supported by further research. I do not recommend the routine use of these catheters to try to predict uterine rupture in women attempting VBAC.

▸ Be aware of signs of possible rupture. Clinical suspicion should be high in women who have unusual pain when epidural anesthesia is already in place and in women who need frequent epidural dosing during a VBAC trial.

Research has shown that both conditions are markers for possible impending uterine rupture during VBAC attempts. An analysis of 504 women who had epidural anesthetic during attempted VBAC, for instance, showed that women who had a uterine rupture received more epidural doses on average, especially during the final 90 minutes of labor, than women who did not have a uterine rupture (Am. J. Obstet. Gynecol. 2010;202:355.e1-5).

▸ Keep patients informed. Keeping your patient informed and comfortable with her options for delivery after cesarean section involves counseling throughout the course of prenatal care and could even include the use of an actual informed consent form for a trial of labor, which can help facilitate thorough discussions about the risks and benefits of attempting VBAC. Informed consent should extend into labor, however. Patients can be told that it is acceptable to inquire about stopping a trial of labor at any point. Giving patients the opportunity to “opt out” can be a good thing; it gives them more control over what's happening.

Consequences of Not Doing VBACs

There is a danger to too easily dismissing VBAC. Although most research has focused on uterine rupture and the index pregnancy, there is also research that clearly shows that serious maternal morbidity increases progressively with each repeat cesarean delivery. With multiple cesareans, each delivery becomes more complicated and carries more risk. The effect on maternal health can be profound.

A prospective observational study of approximately 30,000 women who had cesarean delivery without labor showed that the risks of cystotomy, bowel injury, ureteral injury, hysterectomy, and the need for postoperative ventilation, intensive care unit admission, and significant blood transfusion all were significantly increased with increasing numbers of cesarean deliveries (Obstet. Gynecol. 2006;107:1226-32).

Even more concerning is the risk of abnormal placentation. In this study, placenta accreta occurred in 0.24%, 0.31%, 0.57%, 2.13%, 2.33%, and 6.74% of women who were undergoing their first, second, third, fourth, fifth, and sixth or more cesarean deliveries. In women with placenta previa, the risk for placenta accreta rose progressively with each cesarean delivery—3.3% with the first cesarean, 11% with the second, 40% with the third, 61% with the fifth, and up to 67% with the fifth and sixth cesareans.

Because the rates of abnormal placentation are rising in the United States, it is extremely important that we consider not only the short-term complications of VBAC, such as uterine rupture, but also the long-term consequences of multiple repeat cesarean deliveries.

This part of the overall safety profile of VBAC is discussed in the NIH's draft consensus conference statement. The statement points out that women who have had VBAC have reduced abnormalities of placental growth and position in subsequent pregnancies, and that the incidence of placenta previa significantly increases in women with each additional cesarean delivery.

In counseling about elective repeat cesarean delivery versus a trial of labor, I often talk with women about the number of children they intend to have. If a woman has had a prior cesarean delivery and desires a large family, I am very inclined to strongly encourage her to pursue a trial of labor.

Vitals

Source Elsevier Global Medical News

Key Points

Dr. Macones offered these take-home points:

▸ Rates of uterine rupture and hypoxic ischemic encephalopathy are higher in women who attempt VBAC, but the absolute rates are quite low and similar to the complication rates of most other obstetrical procedures we do.

▸ Prior vaginal delivery is the only clinically useful predictive factor for VBAC success.

▸ VBAC outcomes can be maximized by inducing labor only when necessary, avoiding the use of multiple induction agents, avoiding higher doses of oxytocin, and being aware of signs of possible rupture.

▸ The long-term impact of multiple repeat cesareans should be factored into decision making, as serious maternal morbidity increases with each repeat cesarean delivery.

VBAC: Should We or Shouldn't We?

The surgical approach to infant delivery is not new. Indeed, a variety of approaches have been used to extract fetuses from the uterus when, for various reasons, a vaginal delivery is not possible.

The old notion that “once a cesarean section, always a cesarean section,” moreover, has been a dogma that has existed in obstetrics and medicine for decades. Although this has worked well, many a time, for the convenience of the mother or the physician, it is also problematic. Over time, multiple repeat cesarean sections can pose a hazard, either because the scar becomes weak and at risk of rupture or because the surgical intervention becomes very challenging.

Concerns about possible rupture with repeat cesarean sections were particularly acute in the early years before it was appreciated that there was a difference between a vertical uterine incision and a transverse uterine incision. Following the realization that the lower uterine segment is less prone to active contraction and therefore less likely to rupture, transverse uterine incisions were encouraged in virtually all circumstances, and rupture of the uterus with repeat cesarean section became less of an issue.

In more recent times, reports of trials of labor following prior cesarean delivery resulting in successful vaginal delivery began to appear, and the notion of vaginal birth after cesarean (VBAC) took off, with a wave of success, across the country and indeed around the world. However, as the number of vaginal deliveries after cesarean sections increased, the rate of uterine rupture increased as well.

The rate of uterine rupture has remained low. Still, no matter when it occurs, uterine rupture is always a challenge—a challenge to the surgeon, a problem for the mother or baby, and unfortunately, sometimes a cause of litigation. Because of this complicating set of circumstances, the issue of advisability of VBAC has become a real medical dilemma.

Should we do them? Or should we not? If we should, when should we do them? Are there any guidelines? These are just some of the questions that have arisen over the years that we have had to grapple with. It is in this light that a Master Class to address these issues seemed appropriate. We have invited Dr. George A. Macones, an expert in maternal-fetal medicine who has studied VBAC for many years, to serve as our guest author.

Dr. Macones is the Mitchell and Elaine Yanow Professor and chair of the department of obstetrics and gynecology at Washington University in St. Louis. He recently was invited to speak at a National Institutes of Health consensus development conference on VBAC. In this column, he offers us some insight into why VBAC is a reasonable option for many women, how we can select candidates and counsel our patients, and what we can do to effectively manage our patients' attempts to achieve vaginal delivery after cesarean.

obnews@elsevier.com

Vaginal birth after cesarean gained widespread acceptance in the 1980s after a National Institutes of Health Consensus Development Conference panel questioned the necessity of routine repeat cesarean deliveries and described situations in which a VBAC should be offered. Some insurers even mandated that physicians attempt a VBAC prior to a repeat cesarean delivery.

Since 1996, however, the VBAC rate has dropped substantially while cesarean delivery rates have risen steadily. The overall cesarean delivery rate was approximately 32% when last measured in 2007, up from 21% in 1996. The VBAC rate was less than 10% in 2007, compared with 28% in 1996, according to the Centers for Disease Control and Prevention.

Indeed, pregnant women now have limited access to VBAC services, and many are not even offered the option of having a trial of labor after cesarean. Some hospitals have declined to provide VBAC services, and the most recent medical liability survey conducted by the American College of Obstetricians and Gynecologists showed that almost 20% of responding fellows stopped offering or performing VBACs between 2006 and 2008. (In the prior survey, completed in 2006, these numbers were even higher—upward of 26%.)

The exact causes of the decline in VBAC deliveries are unclear, but the shift likely involves a mix of concerns about the possibility of uterine rupture, patient preferences, medicolegal pressures, guidelines that call for the immediate availability of personnel to perform an emergency cesarean, and other clinical and nonclinical factors.

It is a complex and concerning trend—one considered important enough to the health of women in the United States for the NIH to recently convene another Consensus Development Conference panel on the topic. The panel was asked to examine the causes of VBAC decline as well as the available research on the benefits and harms of attempting a trial of labor after a patient has had a cesarean delivery.

In a draft statement titled, “Vaginal Birth After Cesarean: New Insights,” released in March, the panel affirmed that a trial of labor is a reasonable option for many women with a prior cesarean delivery. It also urged that current VBAC guidelines be reconsidered and more research conducted.

Although guidelines are being revisited and research ensues, we owe it to the patients in our own practices to thoroughly consider what is known about the short- and long-term safety of VBAC, the selection of candidates, and the most reasonable approaches to intrapartum management.

Short-Term Safety of VBAC

In the past decade, there have been two large observational studies in the United States that have shed much light on the efficacy and safety of a trial of labor after cesarean. Both studies involved upwards of 20,000 women, and both showed rates of uterine rupture under 1%. This finding is significant, because some have suggested that uterine rupture is on the rise in the United States.

In one of these studies—a prospective cohort study conducted from 1999 through 2002 at 19 academic medical centers belonging to the National Institute of Child Health and Human Development Maternal-Fetal Medicine Units (MFMU) Network—there were 124 cases of uterine rupture among 17,898 women who underwent a trial of labor after cesarean, and no cases of uterine rupture among 15,801 women who underwent elective repeat cesarean delivery.

The rate of uterine rupture was 0.7% for women with a prior low transverse incision, 2.0% for those with a prior low vertical incision, and 0.5% for those with an unknown type of prior incision. Overall, the rate of uterine rupture in this study was 0.7% (N. Engl. J. Med. 2004;351:2581-9).

The second study, which I led, revealed a rate of uterine rupture in women who attempted VBAC of 0.9%, compared with a rate of 0.004% in women who underwent elective repeat cesarean section. This study was a multicenter observational study in which records of approximately 25,000 women with a prior low-transverse cesarean section were reviewed (Am. J. Obstet. Gynecol. 2005;193:1656-62).

Just as uterine rupture is more common in women who have a VBAC attempt than in those who choose elective repeat cesarean section, so are adverse perinatal outcomes. The MFMU study found 12 cases of hypoxic ischemic encephalopathy (HIE) among the term infants whose mothers underwent trials of labor. Seven of the cases of HIE were associated with uterine rupture.

Perspective is important. Although uterine rupture and HIE—the complications of most concern—are higher among those who attempt VBAC, the absolute rates are quite low and are comparable to, if not lower than, the complication rates of most other obstetrical procedures we perform on a daily basis.

Considering that the risks of pregnancy and childbirth overall are often underappreciated, it is important to share these data with patients and explain that the risks of VBAC are similar in magnitude to complications observed with any vaginal delivery. Certainly, these large observational studies—which provide a broader, more representative look at outcomes than prior studies—provide short-term safety evidence that overall favors VBAC as a standard part of practice.

Selecting Candidates

Patient selection is important, as most of the major complications in women who attempt a trial of labor occur in association with a failed VBAC attempt.

At least several investigators, myself included, have attempted to develop models or scoring systems to predict which women are most likely to be delivered vaginally with a VBAC attempt. Many of these models have incorporated factors that can be ascertained early in prenatal care as well as those that are not known until admission for delivery. Other models focus on factors available at the first prenatal visit, such as maternal age, prepregnancy body mass index, ethnicity, and prior vaginal delivery.

Unfortunately, these models have not been shown to accurately predict who is going to succeed and who is going to fail in a VBAC attempt.

Thus far, the one clinically useful predictive factor we have for VBAC success is prior vaginal delivery, whether it's a prior successful VBAC attempt or a vaginal delivery that predated a cesarean section. Indeed, numerous studies have supported the predictive value of a prior vaginal delivery.

In 2005, for instance, the MFMU reported that a previous vaginal delivery was the most significant predictor of VBAC delivery success in a cohort of 29,661 women with a history of one prior cesarean delivery. Women with a prior vaginal birth had a VBAC delivery success rate of 86.6%, compared with 60.9% in women without a prior vaginal delivery (Am. J. Obstet. Gynecol. 2005;193:1016-23).

A secondary analysis of our large, retrospective observational study on maternal complications with VBAC (discussed above) similarly showed that VBAC candidates with a prior vaginal birth were significantly more successful in achieving vaginal delivery than women with no prior vaginal delivery. The success rate was 89.9%, compared with 67% (Am. J. Obstet. Gynecol. 2006;195:1143-7).

Women with a history of vaginal delivery also appear to have lower rates of major complications, making a VBAC attempt safer in these patients than a planned repeat cesarean section (whether the attempt is successful or not). In our observational study, a prior vaginal delivery was associated with significant reductions in major morbidity.

Clearly, not all women with a history of cesarean delivery are the same, and women with a prior vaginal delivery should be counseled about their more favorable benefit-risk ratio.

Overall, the vaginal delivery rate after a trial of labor is high in women who have had prior cesareans. In our large observational study, the vaginal delivery rate among those women who attempted VBAC was 75.5%. Furthermore, in the draft of its consensus development conference statement, the NIH panel reported that there is a “high grade of evidence” showing that a trial of labor is successful in nearly 75% of cases.

Even in the least favorable groups—among women who might appear to have unfavorable risk profiles for VBAC attempts—the success rate for VBAC is consistently higher than 50%.

Intrapartum Management

We can make a relatively safe and reasonable process even safer by carefully and conservatively managing the intrapartum period in women attempting VBAC.

Here are several tips for managing a trial of labor after cesarean:

▸ Induce labor only when absolutely necessary. Research from both large observational studies on a trial of labor after cesarean has shown that the risk of uterine rupture is two- to threefold higher in women who have their labor induced than in women who are delivered spontaneously. We should therefore refrain from inducing labor unless we have solid medical reasons to do so.

▸ Try to avoid the use of multiple induction agents. If you're considering induction for a VBAC candidate who has an unfavorable cervical exam, reconsider it. Research has also shown that women who require multiple agents for induction have the highest rates of uterine rupture—rates that are almost four- to fivefold higher than those for women who labor spontaneously.

▸ Avoid higher doses of oxytocin. There does not appear to be an increased risk of rupture with oxytocin augmentation of spontaneous labor—unless the dose is in excess of 20 mU/min. An analysis by Dr. A.G. Cahill (Am. J. Obstet. Gynecol. 2007;197:495.e1-5), for example, found a dose-response relationship of maximum oxytocin administration and uterine rupture. Some institutions have already decided not to go above this amount in women attempting VBAC.

If your institution allows higher levels, be extra vigilant as the dosage increases.

▸ Be leery of intrauterine pressure catheters. Old data had suggested that intrauterine pressure catheters could be useful for predicting uterine rupture during trials of labor after cesarean. However, these data have not been supported by further research. I do not recommend the routine use of these catheters to try to predict uterine rupture in women attempting VBAC.

▸ Be aware of signs of possible rupture. Clinical suspicion should be high in women who have unusual pain when epidural anesthesia is already in place and in women who need frequent epidural dosing during a VBAC trial.

Research has shown that both conditions are markers for possible impending uterine rupture during VBAC attempts. An analysis of 504 women who had epidural anesthetic during attempted VBAC, for instance, showed that women who had a uterine rupture received more epidural doses on average, especially during the final 90 minutes of labor, than women who did not have a uterine rupture (Am. J. Obstet. Gynecol. 2010;202:355.e1-5).

▸ Keep patients informed. Keeping your patient informed and comfortable with her options for delivery after cesarean section involves counseling throughout the course of prenatal care and could even include the use of an actual informed consent form for a trial of labor, which can help facilitate thorough discussions about the risks and benefits of attempting VBAC. Informed consent should extend into labor, however. Patients can be told that it is acceptable to inquire about stopping a trial of labor at any point. Giving patients the opportunity to “opt out” can be a good thing; it gives them more control over what's happening.

Consequences of Not Doing VBACs

There is a danger to too easily dismissing VBAC. Although most research has focused on uterine rupture and the index pregnancy, there is also research that clearly shows that serious maternal morbidity increases progressively with each repeat cesarean delivery. With multiple cesareans, each delivery becomes more complicated and carries more risk. The effect on maternal health can be profound.

A prospective observational study of approximately 30,000 women who had cesarean delivery without labor showed that the risks of cystotomy, bowel injury, ureteral injury, hysterectomy, and the need for postoperative ventilation, intensive care unit admission, and significant blood transfusion all were significantly increased with increasing numbers of cesarean deliveries (Obstet. Gynecol. 2006;107:1226-32).

Even more concerning is the risk of abnormal placentation. In this study, placenta accreta occurred in 0.24%, 0.31%, 0.57%, 2.13%, 2.33%, and 6.74% of women who were undergoing their first, second, third, fourth, fifth, and sixth or more cesarean deliveries. In women with placenta previa, the risk for placenta accreta rose progressively with each cesarean delivery—3.3% with the first cesarean, 11% with the second, 40% with the third, 61% with the fifth, and up to 67% with the fifth and sixth cesareans.

Because the rates of abnormal placentation are rising in the United States, it is extremely important that we consider not only the short-term complications of VBAC, such as uterine rupture, but also the long-term consequences of multiple repeat cesarean deliveries.

This part of the overall safety profile of VBAC is discussed in the NIH's draft consensus conference statement. The statement points out that women who have had VBAC have reduced abnormalities of placental growth and position in subsequent pregnancies, and that the incidence of placenta previa significantly increases in women with each additional cesarean delivery.

In counseling about elective repeat cesarean delivery versus a trial of labor, I often talk with women about the number of children they intend to have. If a woman has had a prior cesarean delivery and desires a large family, I am very inclined to strongly encourage her to pursue a trial of labor.

Vitals

Source Elsevier Global Medical News

Key Points

Dr. Macones offered these take-home points:

▸ Rates of uterine rupture and hypoxic ischemic encephalopathy are higher in women who attempt VBAC, but the absolute rates are quite low and similar to the complication rates of most other obstetrical procedures we do.

▸ Prior vaginal delivery is the only clinically useful predictive factor for VBAC success.

▸ VBAC outcomes can be maximized by inducing labor only when necessary, avoiding the use of multiple induction agents, avoiding higher doses of oxytocin, and being aware of signs of possible rupture.

▸ The long-term impact of multiple repeat cesareans should be factored into decision making, as serious maternal morbidity increases with each repeat cesarean delivery.

VBAC: Should We or Shouldn't We?

The surgical approach to infant delivery is not new. Indeed, a variety of approaches have been used to extract fetuses from the uterus when, for various reasons, a vaginal delivery is not possible.

The old notion that “once a cesarean section, always a cesarean section,” moreover, has been a dogma that has existed in obstetrics and medicine for decades. Although this has worked well, many a time, for the convenience of the mother or the physician, it is also problematic. Over time, multiple repeat cesarean sections can pose a hazard, either because the scar becomes weak and at risk of rupture or because the surgical intervention becomes very challenging.

Concerns about possible rupture with repeat cesarean sections were particularly acute in the early years before it was appreciated that there was a difference between a vertical uterine incision and a transverse uterine incision. Following the realization that the lower uterine segment is less prone to active contraction and therefore less likely to rupture, transverse uterine incisions were encouraged in virtually all circumstances, and rupture of the uterus with repeat cesarean section became less of an issue.

In more recent times, reports of trials of labor following prior cesarean delivery resulting in successful vaginal delivery began to appear, and the notion of vaginal birth after cesarean (VBAC) took off, with a wave of success, across the country and indeed around the world. However, as the number of vaginal deliveries after cesarean sections increased, the rate of uterine rupture increased as well.

The rate of uterine rupture has remained low. Still, no matter when it occurs, uterine rupture is always a challenge—a challenge to the surgeon, a problem for the mother or baby, and unfortunately, sometimes a cause of litigation. Because of this complicating set of circumstances, the issue of advisability of VBAC has become a real medical dilemma.

Should we do them? Or should we not? If we should, when should we do them? Are there any guidelines? These are just some of the questions that have arisen over the years that we have had to grapple with. It is in this light that a Master Class to address these issues seemed appropriate. We have invited Dr. George A. Macones, an expert in maternal-fetal medicine who has studied VBAC for many years, to serve as our guest author.

Dr. Macones is the Mitchell and Elaine Yanow Professor and chair of the department of obstetrics and gynecology at Washington University in St. Louis. He recently was invited to speak at a National Institutes of Health consensus development conference on VBAC. In this column, he offers us some insight into why VBAC is a reasonable option for many women, how we can select candidates and counsel our patients, and what we can do to effectively manage our patients' attempts to achieve vaginal delivery after cesarean.

obnews@elsevier.com

Vaginal birth after cesarean gained widespread acceptance in the 1980s after a National Institutes of Health Consensus Development Conference panel questioned the necessity of routine repeat cesarean deliveries and described situations in which a VBAC should be offered. Some insurers even mandated that physicians attempt a VBAC prior to a repeat cesarean delivery.

Since 1996, however, the VBAC rate has dropped substantially while cesarean delivery rates have risen steadily. The overall cesarean delivery rate was approximately 32% when last measured in 2007, up from 21% in 1996. The VBAC rate was less than 10% in 2007, compared with 28% in 1996, according to the Centers for Disease Control and Prevention.

Indeed, pregnant women now have limited access to VBAC services, and many are not even offered the option of having a trial of labor after cesarean. Some hospitals have declined to provide VBAC services, and the most recent medical liability survey conducted by the American College of Obstetricians and Gynecologists showed that almost 20% of responding fellows stopped offering or performing VBACs between 2006 and 2008. (In the prior survey, completed in 2006, these numbers were even higher—upward of 26%.)

The exact causes of the decline in VBAC deliveries are unclear, but the shift likely involves a mix of concerns about the possibility of uterine rupture, patient preferences, medicolegal pressures, guidelines that call for the immediate availability of personnel to perform an emergency cesarean, and other clinical and nonclinical factors.

It is a complex and concerning trend—one considered important enough to the health of women in the United States for the NIH to recently convene another Consensus Development Conference panel on the topic. The panel was asked to examine the causes of VBAC decline as well as the available research on the benefits and harms of attempting a trial of labor after a patient has had a cesarean delivery.

In a draft statement titled, “Vaginal Birth After Cesarean: New Insights,” released in March, the panel affirmed that a trial of labor is a reasonable option for many women with a prior cesarean delivery. It also urged that current VBAC guidelines be reconsidered and more research conducted.

Although guidelines are being revisited and research ensues, we owe it to the patients in our own practices to thoroughly consider what is known about the short- and long-term safety of VBAC, the selection of candidates, and the most reasonable approaches to intrapartum management.

Short-Term Safety of VBAC

In the past decade, there have been two large observational studies in the United States that have shed much light on the efficacy and safety of a trial of labor after cesarean. Both studies involved upwards of 20,000 women, and both showed rates of uterine rupture under 1%. This finding is significant, because some have suggested that uterine rupture is on the rise in the United States.

In one of these studies—a prospective cohort study conducted from 1999 through 2002 at 19 academic medical centers belonging to the National Institute of Child Health and Human Development Maternal-Fetal Medicine Units (MFMU) Network—there were 124 cases of uterine rupture among 17,898 women who underwent a trial of labor after cesarean, and no cases of uterine rupture among 15,801 women who underwent elective repeat cesarean delivery.

The rate of uterine rupture was 0.7% for women with a prior low transverse incision, 2.0% for those with a prior low vertical incision, and 0.5% for those with an unknown type of prior incision. Overall, the rate of uterine rupture in this study was 0.7% (N. Engl. J. Med. 2004;351:2581-9).

The second study, which I led, revealed a rate of uterine rupture in women who attempted VBAC of 0.9%, compared with a rate of 0.004% in women who underwent elective repeat cesarean section. This study was a multicenter observational study in which records of approximately 25,000 women with a prior low-transverse cesarean section were reviewed (Am. J. Obstet. Gynecol. 2005;193:1656-62).

Just as uterine rupture is more common in women who have a VBAC attempt than in those who choose elective repeat cesarean section, so are adverse perinatal outcomes. The MFMU study found 12 cases of hypoxic ischemic encephalopathy (HIE) among the term infants whose mothers underwent trials of labor. Seven of the cases of HIE were associated with uterine rupture.

Perspective is important. Although uterine rupture and HIE—the complications of most concern—are higher among those who attempt VBAC, the absolute rates are quite low and are comparable to, if not lower than, the complication rates of most other obstetrical procedures we perform on a daily basis.

Considering that the risks of pregnancy and childbirth overall are often underappreciated, it is important to share these data with patients and explain that the risks of VBAC are similar in magnitude to complications observed with any vaginal delivery. Certainly, these large observational studies—which provide a broader, more representative look at outcomes than prior studies—provide short-term safety evidence that overall favors VBAC as a standard part of practice.

Selecting Candidates

Patient selection is important, as most of the major complications in women who attempt a trial of labor occur in association with a failed VBAC attempt.

At least several investigators, myself included, have attempted to develop models or scoring systems to predict which women are most likely to be delivered vaginally with a VBAC attempt. Many of these models have incorporated factors that can be ascertained early in prenatal care as well as those that are not known until admission for delivery. Other models focus on factors available at the first prenatal visit, such as maternal age, prepregnancy body mass index, ethnicity, and prior vaginal delivery.

Unfortunately, these models have not been shown to accurately predict who is going to succeed and who is going to fail in a VBAC attempt.

Thus far, the one clinically useful predictive factor we have for VBAC success is prior vaginal delivery, whether it's a prior successful VBAC attempt or a vaginal delivery that predated a cesarean section. Indeed, numerous studies have supported the predictive value of a prior vaginal delivery.

In 2005, for instance, the MFMU reported that a previous vaginal delivery was the most significant predictor of VBAC delivery success in a cohort of 29,661 women with a history of one prior cesarean delivery. Women with a prior vaginal birth had a VBAC delivery success rate of 86.6%, compared with 60.9% in women without a prior vaginal delivery (Am. J. Obstet. Gynecol. 2005;193:1016-23).

A secondary analysis of our large, retrospective observational study on maternal complications with VBAC (discussed above) similarly showed that VBAC candidates with a prior vaginal birth were significantly more successful in achieving vaginal delivery than women with no prior vaginal delivery. The success rate was 89.9%, compared with 67% (Am. J. Obstet. Gynecol. 2006;195:1143-7).

Women with a history of vaginal delivery also appear to have lower rates of major complications, making a VBAC attempt safer in these patients than a planned repeat cesarean section (whether the attempt is successful or not). In our observational study, a prior vaginal delivery was associated with significant reductions in major morbidity.

Clearly, not all women with a history of cesarean delivery are the same, and women with a prior vaginal delivery should be counseled about their more favorable benefit-risk ratio.

Overall, the vaginal delivery rate after a trial of labor is high in women who have had prior cesareans. In our large observational study, the vaginal delivery rate among those women who attempted VBAC was 75.5%. Furthermore, in the draft of its consensus development conference statement, the NIH panel reported that there is a “high grade of evidence” showing that a trial of labor is successful in nearly 75% of cases.

Even in the least favorable groups—among women who might appear to have unfavorable risk profiles for VBAC attempts—the success rate for VBAC is consistently higher than 50%.

Intrapartum Management

We can make a relatively safe and reasonable process even safer by carefully and conservatively managing the intrapartum period in women attempting VBAC.

Here are several tips for managing a trial of labor after cesarean:

▸ Induce labor only when absolutely necessary. Research from both large observational studies on a trial of labor after cesarean has shown that the risk of uterine rupture is two- to threefold higher in women who have their labor induced than in women who are delivered spontaneously. We should therefore refrain from inducing labor unless we have solid medical reasons to do so.

▸ Try to avoid the use of multiple induction agents. If you're considering induction for a VBAC candidate who has an unfavorable cervical exam, reconsider it. Research has also shown that women who require multiple agents for induction have the highest rates of uterine rupture—rates that are almost four- to fivefold higher than those for women who labor spontaneously.

▸ Avoid higher doses of oxytocin. There does not appear to be an increased risk of rupture with oxytocin augmentation of spontaneous labor—unless the dose is in excess of 20 mU/min. An analysis by Dr. A.G. Cahill (Am. J. Obstet. Gynecol. 2007;197:495.e1-5), for example, found a dose-response relationship of maximum oxytocin administration and uterine rupture. Some institutions have already decided not to go above this amount in women attempting VBAC.

If your institution allows higher levels, be extra vigilant as the dosage increases.

▸ Be leery of intrauterine pressure catheters. Old data had suggested that intrauterine pressure catheters could be useful for predicting uterine rupture during trials of labor after cesarean. However, these data have not been supported by further research. I do not recommend the routine use of these catheters to try to predict uterine rupture in women attempting VBAC.

▸ Be aware of signs of possible rupture. Clinical suspicion should be high in women who have unusual pain when epidural anesthesia is already in place and in women who need frequent epidural dosing during a VBAC trial.

Research has shown that both conditions are markers for possible impending uterine rupture during VBAC attempts. An analysis of 504 women who had epidural anesthetic during attempted VBAC, for instance, showed that women who had a uterine rupture received more epidural doses on average, especially during the final 90 minutes of labor, than women who did not have a uterine rupture (Am. J. Obstet. Gynecol. 2010;202:355.e1-5).

▸ Keep patients informed. Keeping your patient informed and comfortable with her options for delivery after cesarean section involves counseling throughout the course of prenatal care and could even include the use of an actual informed consent form for a trial of labor, which can help facilitate thorough discussions about the risks and benefits of attempting VBAC. Informed consent should extend into labor, however. Patients can be told that it is acceptable to inquire about stopping a trial of labor at any point. Giving patients the opportunity to “opt out” can be a good thing; it gives them more control over what's happening.

Consequences of Not Doing VBACs

There is a danger to too easily dismissing VBAC. Although most research has focused on uterine rupture and the index pregnancy, there is also research that clearly shows that serious maternal morbidity increases progressively with each repeat cesarean delivery. With multiple cesareans, each delivery becomes more complicated and carries more risk. The effect on maternal health can be profound.

A prospective observational study of approximately 30,000 women who had cesarean delivery without labor showed that the risks of cystotomy, bowel injury, ureteral injury, hysterectomy, and the need for postoperative ventilation, intensive care unit admission, and significant blood transfusion all were significantly increased with increasing numbers of cesarean deliveries (Obstet. Gynecol. 2006;107:1226-32).

Even more concerning is the risk of abnormal placentation. In this study, placenta accreta occurred in 0.24%, 0.31%, 0.57%, 2.13%, 2.33%, and 6.74% of women who were undergoing their first, second, third, fourth, fifth, and sixth or more cesarean deliveries. In women with placenta previa, the risk for placenta accreta rose progressively with each cesarean delivery—3.3% with the first cesarean, 11% with the second, 40% with the third, 61% with the fifth, and up to 67% with the fifth and sixth cesareans.

Because the rates of abnormal placentation are rising in the United States, it is extremely important that we consider not only the short-term complications of VBAC, such as uterine rupture, but also the long-term consequences of multiple repeat cesarean deliveries.

This part of the overall safety profile of VBAC is discussed in the NIH's draft consensus conference statement. The statement points out that women who have had VBAC have reduced abnormalities of placental growth and position in subsequent pregnancies, and that the incidence of placenta previa significantly increases in women with each additional cesarean delivery.

In counseling about elective repeat cesarean delivery versus a trial of labor, I often talk with women about the number of children they intend to have. If a woman has had a prior cesarean delivery and desires a large family, I am very inclined to strongly encourage her to pursue a trial of labor.

Vitals

Source Elsevier Global Medical News

Key Points

Dr. Macones offered these take-home points:

▸ Rates of uterine rupture and hypoxic ischemic encephalopathy are higher in women who attempt VBAC, but the absolute rates are quite low and similar to the complication rates of most other obstetrical procedures we do.

▸ Prior vaginal delivery is the only clinically useful predictive factor for VBAC success.

▸ VBAC outcomes can be maximized by inducing labor only when necessary, avoiding the use of multiple induction agents, avoiding higher doses of oxytocin, and being aware of signs of possible rupture.

▸ The long-term impact of multiple repeat cesareans should be factored into decision making, as serious maternal morbidity increases with each repeat cesarean delivery.

VBAC: Should We or Shouldn't We?

The surgical approach to infant delivery is not new. Indeed, a variety of approaches have been used to extract fetuses from the uterus when, for various reasons, a vaginal delivery is not possible.

The old notion that “once a cesarean section, always a cesarean section,” moreover, has been a dogma that has existed in obstetrics and medicine for decades. Although this has worked well, many a time, for the convenience of the mother or the physician, it is also problematic. Over time, multiple repeat cesarean sections can pose a hazard, either because the scar becomes weak and at risk of rupture or because the surgical intervention becomes very challenging.

Concerns about possible rupture with repeat cesarean sections were particularly acute in the early years before it was appreciated that there was a difference between a vertical uterine incision and a transverse uterine incision. Following the realization that the lower uterine segment is less prone to active contraction and therefore less likely to rupture, transverse uterine incisions were encouraged in virtually all circumstances, and rupture of the uterus with repeat cesarean section became less of an issue.

In more recent times, reports of trials of labor following prior cesarean delivery resulting in successful vaginal delivery began to appear, and the notion of vaginal birth after cesarean (VBAC) took off, with a wave of success, across the country and indeed around the world. However, as the number of vaginal deliveries after cesarean sections increased, the rate of uterine rupture increased as well.

The rate of uterine rupture has remained low. Still, no matter when it occurs, uterine rupture is always a challenge—a challenge to the surgeon, a problem for the mother or baby, and unfortunately, sometimes a cause of litigation. Because of this complicating set of circumstances, the issue of advisability of VBAC has become a real medical dilemma.

Should we do them? Or should we not? If we should, when should we do them? Are there any guidelines? These are just some of the questions that have arisen over the years that we have had to grapple with. It is in this light that a Master Class to address these issues seemed appropriate. We have invited Dr. George A. Macones, an expert in maternal-fetal medicine who has studied VBAC for many years, to serve as our guest author.

Dr. Macones is the Mitchell and Elaine Yanow Professor and chair of the department of obstetrics and gynecology at Washington University in St. Louis. He recently was invited to speak at a National Institutes of Health consensus development conference on VBAC. In this column, he offers us some insight into why VBAC is a reasonable option for many women, how we can select candidates and counsel our patients, and what we can do to effectively manage our patients' attempts to achieve vaginal delivery after cesarean.