E. Albert Reece

obnews@elsevier.com

It is well recognized that the complications and adverse perinatal outcomes associated with gestational diabetes and type 2 diabetes in pregnancy are glucose dependent. The main question in medical management, therefore, is how to maximize glycemic control.

The choice of medication should be determined by the ability of the drug to achieve the targeted level of glycemic control. For some patients, oral antihyperglycemic agents will be the drug of choice while in others combination therapy and/or insulin should be used.

For years, pharmacologic therapy for diabetes in pregnancy was limited to insulin. Obstetricians feared that oral antihyperglycemic agents, as an alternative to insulin therapy, could cause adverse pregnancy outcomes, particularly congenital anomalies and metabolic complications. Because of these concerns, sulfonylurea drugs were contraindicated in pregnancy.

These recommendations were founded, however, on anecdotal reports and poorly designed retrospective studies that were performed prior to the availability of second-generation sulfonylureas such as glyburide.

Today, there is clear evidence from in vivo and in vitro studies that glyburide does not cross the placenta in any appreciable quantity while metformin, another oral glucose-lowering agent, crosses the placenta freely.

Several randomized studies (five glyburide and two metformin studies), as well as other well-designed studies published over the last decade, also have demonstrated that glyburide is as effective and safe as insulin therapy for glycemic control during pregnancy.

Research has shown, moreover, that it's the blood glucose levels—not the drugs themselves—that cause adverse outcomes.

This is good news, because the use of oral antihyperglycemic agents enhances drug compliance for the patient.

Taking a tablet once in the morning and once in the evening is easier, more convenient, and less expensive than giving oneself insulin injections several times a day. Given the choice of insulin injections versus tablets, almost all women will opt for the latter.

Offering glyburide as a safe and effective alternative to insulin has been recommended by several editorials and professional organizations. Indeed, the use of glyburide has become the standard of care in the management of gestational diabetes mellitus (GDM) in many centers and private practices throughout the United States.

It is important to appreciate, however, that in general, as disease severity increases, there is diminishing success in achieving the desired levels of glycemic control.

Although the majority of women with gestational diabetes will benefit from the use of these drugs (approximately 80%), fewer women with type 2 diabetes will be able to achieve optimal glycemic control.

The emphasis overall in diabetes management must therefore be on the level of glycemic control achieved by the patient, with the failure of a drug signaling the need to change the drug algorithm.

Safety, Efficacy of Glyburide

Oral antihyperglycemic drugs—most commonly glyburide and metformin—are the first-line drugs for treating nonpregnant women with type 2 diabetes. These patients are typically older and suffer from greater disease severity (higher fasting and postprandial blood glucose levels and a decreased pancreatic reserve of 50%-80%). They therefore are not comparable to patients with gestational diabetes who are relatively younger and have greater pancreatic reserve.

This begs the following question: If the oral antihyperglycemic drugs are in fact safe for the fetus and can potentially optimize glycemic control—enabling patients to reach targeted levels of glucose control in pregnancy with the same efficacy as insulin—why should GDM patients who represent the milder form of intolerance on the glucose continuum not be treated with these drugs?

In the early 1990s, my colleagues and I evaluated the potential of first-generation and second-generation sulfonylureas to cross the placenta. Using the single-cotyledon placental model—a model that is widely used to characterize the transport and metabolism of drugs and nutrients—we found only minimal transport of glyburide in either the maternal-fetal or the fetal-maternal direction (Am. J. Obstet. Gynecol. 1991;165:807-12).

The transfer of glyburide remained negligible even when we varied the albumin concentration and increased maternal glyburide levels to 100 times the therapeutic level. In no case was there any appreciable metabolism of the agent. First-generation sulfonylureas, on the other hand, crossed the placenta in this model. Metformin did as well, almost freely.

Thereafter, several studies from different centers confirmed that glyburide does not cross the placenta significantly. The studies demonstrated, for instance, that 99.8% of the glyburide is bound to albumin, that the agent has a short elimination half-life, and that effluxes are affected from the fetal-maternal direction. Research also confirmed that metformin does cross the placenta.

In a later prospective, randomized trial comparing glyburide and insulin in 404 women with GDM, my colleagues and I found no significant differences in either the degree of glycemic control or perinatal outcomes (N. Engl. J. Med. 2000;343:1134-8). Target levels of glycemic control were achieved in 82% of the patients receiving glyburide and 88% of those receiving insulin.

There were no significant differences between the groups in the rate of infants who were large for gestational age or who had macrosomia, a ponderal index greater than 2.85, lung complications, hypoglycemia, or fetal anomalies.

We also tested the cord serum at delivery and found similar cord-serum insulin concentrations in the two groups. Glyburide was not detected in the cord serum above the level of 10 ng/mL.

Since 2000, more than 20 studies (4 of them randomized) have been published that show similar success rates with glyburide and insulin in achieving good glycemic control in gestational diabetes as well as similar perinatal outcomes. Most of the studies have been small and not randomized. Oftentimes, however, well-designed retrospective or case-control studies can be just as reliable. In this case, the studies collectively provide a solid basis for evaluation.

In a meta-analysis published last year, investigators concluded that the studies suggest there are no increased perinatal risks with glyburide compared with insulin for the treatment of GDM (Ann. Pharmacotherapy 2008;42:483-90).

Nine studies met the inclusion criteria for the analysis, which totaled 745 glyburide-exposed pregnancies and 637 insulin-exposed pregnancies. Women were typically treated starting at 24 weeks of gestation.

The use of glyburide was not associated, the investigators said, with risk of macrosomia, differences in birth weight, rate of large-for-gestational-age births, differences in gestational age at birth, ICU admission, or risk of neonatal hypoglycemia.

Metformin as an Option

Glyburide and metformin have different mechanisms of action. Glyburide works on the pancreas to stimulate insulin secretion. Metformin, which belongs to the class of oral antihyperglycemic agents known as the biguanides, lowers glucose levels by decreasing hepatic glucose production and decreasing peripheral insulin resistance.

Some have suggested that because metformin does not stimulate insulin secretion, it is less likely than glyburide to cause hypoglycemia and may be the preferable choice for treating diabetes in pregnancy.

While we have not directly compared metformin and glyburide in this regard, our data and data from other studies demonstrate that the rate of maternal hypoglycemia is significantly higher with insulin than with glyburide therapy. In one study using continuous blood glucose measurements, we showed that the maternal rate of hypoglycemic episodes was five times higher in insulin-treated patients than in glyburide-treated patients (Obstet. Gynecol. 2004;104:88-93).

Earlier findings suggesting the opposite—that glyburide is more likely to cause hypoglycemia than is insulin therapy—were from studies in much older, nonpregnant women. Diabetes in patients who are in their 50s through their 80s cannot be compared, in general, to the less severe disease in younger women of reproductive age.

Metformin, like glyburide, has been shown in numerous studies to have no adverse effect in pregnancy in terms of anomalies. The first large randomized, controlled trial to assess the safety and efficacy of metformin versus insulin—published last year—found similar efficacy in achieving target levels of glucose control and no difference in perinatal outcomes among 751 women randomized to one of the two groups (N. Engl. J. Med. 2008;358:2003-15).

Like glyburide, metformin is a class B drug. Because metformin crosses the placenta, physicians must take this into consideration when deciding which oral antihyperglycemic agent to choose. Even if a drug crosses the placenta, however, it should not automatically be considered contraindicated for use in pregnancy because the majority of drugs used in pregnancy cross the placenta without adverse effect to the fetus.

Also of possible concern is the fact that the rate of large-for-gestational-age infants in the New England Journal of Medicine (NEJM) metformin-versus-insulin study was twice the rate of large-for-gestational-age infants in our NEJM study comparing glyburide with insulin. This suggests that the rate of success in achieving glycemic control in pregnancy may be lower with metformin than with glyburide.

We need other studies, however, that directly compare glyburide with metformin (rather than comparing each with insulin), and the resultant perinatal outcomes and glycemic control, in order to address this issue.

Metformin is a popular drug for the treatment of polycystic ovary syndrome (PCOS), which presents the question of whether patients on metformin for PCOS should conceive while on the drug, or halt the drug if they unexpectedly conceive.

The answers in these cases call for individual judgment. In my opinion, metformin is a drug that can be used in pregnancy, as long as one keeps in the back of one's mind the fact that it does cross the placenta. One must also consider that although recent retrospective and prospective trials have shown no adverse effects of metformin in terms of anomalies, no published randomized study has evaluated pregnancy outcomes when patients were treated with the drug from preconception throughout gestation.

With respect to continuing either metformin or glyburide throughout pregnancy for those patients who are treated with these drugs during the preconception stage, the main concern in my opinion is whether the drugs can achieve the levels of glycemic control desired in pregnant women with type 2 diabetes. Because current data have shown that the level of glycemia—and not the drug—is associated with any increased rate of anomalies, I believe patients can remain on these drugs as long as the targeted level of glycemic control is maintained.

Overall, considering that we have a more extensive, more conclusive body of evidence for glyburide than metformin—and considering that glyburide does not cross the placenta—metformin is generally a second choice for me.

Pearls of Management

GDM and type 2 diabetes are essentially the same disease. They are similar in risk factors and in metabolic and endocrine abnormalities. Both are characterized by peripheral insulin resistance, decreased insulin secretion (reflecting declining beta-cell function), and impaired regulation of hepatic glucose.

GDM represents an early stage of the deterioration continuum toward type 2 diabetes. It is characterized by a milder glycemic profile. As I alluded to in a previous Master Class installment (“How Type 2 Diabetes Complicates Pregnancy,” September 2009, p. 28), though, it is increasingly believed that many of the women who are diagnosed with gestational diabetes actually meet the criteria for type 2 diabetes.

Because oral antihyperglycemic agents are the gold standard for therapy in type 2 in the general population—the landmark U.K. Prospective Diabetes Study (UKPDS) of type 2 diabetes showed that 70% of patients achieved desirable levels of glucose control with the use of glyburide—it is sensible to assume that women with GDM or early type 2 diabetes will respond to oral therapy with even greater success.

In general, oral glucose-lowering agents will decrease HbA_1c levels by 1%-2% (insulin, by 1%-2.5%). This roughly corresponds to a drop in fasting blood glucose levels of 30-60 mg/dL.

Oral therapy should be initiated when women cannot achieve fasting blood glucose levels of 95 mg/dL or less, or postprandial levels of 120 mg/dL or less after 2 hours. Diet and exercise can be recommended first for many of our patients, of course, but we must do so with careful consideration of the time that we have to meet target levels of control and prevent macrosomia and other adverse outcomes. Research has shown that at least 60% of patients with GDM eventually will require pharmacologic therapy.

Any pharmacologic therapy necessitates frequent dose adjustment to obtain the desired effect of the drug. Oral antihyperglycemic drugs should be increased only to the maximum dose allowed (20 mg daily in the case of glyburide).

The maximal dose of a drug and steady state are different in nonpregnant and pregnant patients, of course, because drug clearance is higher during pregnancy. However, in order to minimize any potential for complications like maternal hypoglycemia, our aim in diabetes management is to provide the minimal dose that will result in a desirable level of glycemic control.

Different oral antihyperglycemic agents act through diverse mechanisms, and the drugs' characteristics provide a physiological approach to the treatment of type 2 diabetes and GDM. Combination therapies will enhance the effect of these drugs on glucose metabolism, and “whole” patient care (including glucose monitoring, education, and diet adherence) will determine overall success in managing this disease and maximizing the quality of perinatal outcomes.

When insulin is added for the patient treated with oral agents, a single dose at bedtime can be sufficient in many cases. One of the benefits of this combination is the need for a lower dose of insulin. Insulin therapy alone should be used when other combinations have failed and is not limited by a maximum dose.

In obstetrics, we've lagged at least 2 decades behind the field of diabetes management in the general population. Now, however, we should be embracing the use of oral antihyperglycemic agents as the standard of care. We may find with further research that other drugs may have a greater therapeutic effect, but for now glyburide is the best front-line choice for glycemic control.

Glyburide Management

1. Start with 2.5 mg in the morning. If needed, drug titration should occur every 3-7 days.

2. Increase the morning dose by 2.5 mg.

3. Add the evening dose of 5 mg.

4. Increase the morning dose by 5 mg to 10 mg.

5. Increase the evening dose by 5 mg to 10 mg.

Note: The maximal dose is 20 mg daily.

Source: Dr. Langer

Key Points

▸ The level of glycemic control achieved—not the mode of therapy—is the key to improving outcomes in GDM and type 2 diabetes in pregnancy.

▸ Medical therapy with oral agents should be reserved for patients whose fasting plasma glucose levels remain above 95 mg/dL (or whose postprandial levels remain above 120 mg/dL) despite diet therapy and for those who are not appropriate candidates for diet therapy alone.

▸ The aim of therapy is to provide the minimal dose that will result in a desirable level of glycemic control and the least amount of complications for the mother.

▸ Well-designed studies have shown no association between oral antihyperglycemic agents and congenital malformations.

▸ Glyburide, metformin, and insulin are equally effective for GDM treatment at all disease severity levels.

▸ Glyburide is as effective as insulin for the treatment of obese GDM patients.

▸ Combination therapy or insulin therapy should be initiated if desired levels of glucose control are not achieved with one oral agent.

▸ Medication is just one component of intensive therapy. “Whole” patient care is also important.

Source: Dr. Langer

Treating Gestational Diabetes

Ob.Gyn

Within our society there are several conditions that are currently demanding a significant amount of our attention. Among them are obesity and diabetes.

In certain populations—in ethnic minority groups and among Native Americans in particular—there has clearly been a rise in gestational diabetes. There is also an association between the increased incidence of diabetes in pregnancy and an increasingly obese population. The two problems, we are learning, are truly entwined.

In the Master Class published in September, we addressed the diabetes pandemic, which some refer to as “diabesity” because of its association with obesity, and how diabetes complicates pregnancy for the mother and threatens fetal development and outcome.

Sometimes diabetes during pregnancy is of the type 2 variety. Gestational diabetes and type 2 diabetes are sometimes confused in their presentation and hence their diagnosis, however. Admittedly, a precise diagnosis of type 2 diabetes is often made in retrospect following the conclusion of the pregnancy. The diagnostic distinction is important, however, as a diagnosis of type 2 diabetes often drives a more serious approach to glycemic control.

In light of the increasing incidence of diabetes in pregnancy, the age-old problem of optimum treatment takes on even more significance.

Diet is still a mainstay. Insulin therapy remains difficult for patients to accept because it requires injections on a daily basis. Oral agents have been avoided for years because of concerns about safety and the lack of well-controlled data to establish whether such agents cross the placenta and may be potentially harmful to the fetus.

We are now at a juncture in our therapeutic maturity, however, where an increasing amount of information and data are available on the use of therapeutic options such as oral antidiabetic agents.

In light of this crossroads—the convergence of significantly more knowledge and a significantly higher prevalence of diabetes—we thought it high time to review the subject of gestational diabetes, and particularly the contemporary therapeutic options that are now available and can be applied in pregnancy.

I have again invited Oded Langer, M.D., Ph.D., who in September discussed why diabetes must be detected early and treated seriously, to discuss the latest research on oral antidiabetic agents in pregnancy and provide some useful perspective on diabetes management in our patient population.

Dr. Langer is an internationally recognized expert on diabetes in pregnancy who has written and lectured extensively on this subject. He is the Babcock Professor and chairman of the department of obstetrics and gynecology at St. Luke's–Roosevelt Hospital Center, a hospital affiliated with Columbia University in New York.

obnews@elsevier.com

It is well recognized that the complications and adverse perinatal outcomes associated with gestational diabetes and type 2 diabetes in pregnancy are glucose dependent. The main question in medical management, therefore, is how to maximize glycemic control.

The choice of medication should be determined by the ability of the drug to achieve the targeted level of glycemic control. For some patients, oral antihyperglycemic agents will be the drug of choice while in others combination therapy and/or insulin should be used.

For years, pharmacologic therapy for diabetes in pregnancy was limited to insulin. Obstetricians feared that oral antihyperglycemic agents, as an alternative to insulin therapy, could cause adverse pregnancy outcomes, particularly congenital anomalies and metabolic complications. Because of these concerns, sulfonylurea drugs were contraindicated in pregnancy.

These recommendations were founded, however, on anecdotal reports and poorly designed retrospective studies that were performed prior to the availability of second-generation sulfonylureas such as glyburide.

Today, there is clear evidence from in vivo and in vitro studies that glyburide does not cross the placenta in any appreciable quantity while metformin, another oral glucose-lowering agent, crosses the placenta freely.

Several randomized studies (five glyburide and two metformin studies), as well as other well-designed studies published over the last decade, also have demonstrated that glyburide is as effective and safe as insulin therapy for glycemic control during pregnancy.

Research has shown, moreover, that it's the blood glucose levels—not the drugs themselves—that cause adverse outcomes.

This is good news, because the use of oral antihyperglycemic agents enhances drug compliance for the patient.

Taking a tablet once in the morning and once in the evening is easier, more convenient, and less expensive than giving oneself insulin injections several times a day. Given the choice of insulin injections versus tablets, almost all women will opt for the latter.

Offering glyburide as a safe and effective alternative to insulin has been recommended by several editorials and professional organizations. Indeed, the use of glyburide has become the standard of care in the management of gestational diabetes mellitus (GDM) in many centers and private practices throughout the United States.

It is important to appreciate, however, that in general, as disease severity increases, there is diminishing success in achieving the desired levels of glycemic control.

Although the majority of women with gestational diabetes will benefit from the use of these drugs (approximately 80%), fewer women with type 2 diabetes will be able to achieve optimal glycemic control.

The emphasis overall in diabetes management must therefore be on the level of glycemic control achieved by the patient, with the failure of a drug signaling the need to change the drug algorithm.

Safety, Efficacy of Glyburide

Oral antihyperglycemic drugs—most commonly glyburide and metformin—are the first-line drugs for treating nonpregnant women with type 2 diabetes. These patients are typically older and suffer from greater disease severity (higher fasting and postprandial blood glucose levels and a decreased pancreatic reserve of 50%-80%). They therefore are not comparable to patients with gestational diabetes who are relatively younger and have greater pancreatic reserve.

This begs the following question: If the oral antihyperglycemic drugs are in fact safe for the fetus and can potentially optimize glycemic control—enabling patients to reach targeted levels of glucose control in pregnancy with the same efficacy as insulin—why should GDM patients who represent the milder form of intolerance on the glucose continuum not be treated with these drugs?

In the early 1990s, my colleagues and I evaluated the potential of first-generation and second-generation sulfonylureas to cross the placenta. Using the single-cotyledon placental model—a model that is widely used to characterize the transport and metabolism of drugs and nutrients—we found only minimal transport of glyburide in either the maternal-fetal or the fetal-maternal direction (Am. J. Obstet. Gynecol. 1991;165:807-12).

The transfer of glyburide remained negligible even when we varied the albumin concentration and increased maternal glyburide levels to 100 times the therapeutic level. In no case was there any appreciable metabolism of the agent. First-generation sulfonylureas, on the other hand, crossed the placenta in this model. Metformin did as well, almost freely.

Thereafter, several studies from different centers confirmed that glyburide does not cross the placenta significantly. The studies demonstrated, for instance, that 99.8% of the glyburide is bound to albumin, that the agent has a short elimination half-life, and that effluxes are affected from the fetal-maternal direction. Research also confirmed that metformin does cross the placenta.

In a later prospective, randomized trial comparing glyburide and insulin in 404 women with GDM, my colleagues and I found no significant differences in either the degree of glycemic control or perinatal outcomes (N. Engl. J. Med. 2000;343:1134-8). Target levels of glycemic control were achieved in 82% of the patients receiving glyburide and 88% of those receiving insulin.

There were no significant differences between the groups in the rate of infants who were large for gestational age or who had macrosomia, a ponderal index greater than 2.85, lung complications, hypoglycemia, or fetal anomalies.

We also tested the cord serum at delivery and found similar cord-serum insulin concentrations in the two groups. Glyburide was not detected in the cord serum above the level of 10 ng/mL.

Since 2000, more than 20 studies (4 of them randomized) have been published that show similar success rates with glyburide and insulin in achieving good glycemic control in gestational diabetes as well as similar perinatal outcomes. Most of the studies have been small and not randomized. Oftentimes, however, well-designed retrospective or case-control studies can be just as reliable. In this case, the studies collectively provide a solid basis for evaluation.

In a meta-analysis published last year, investigators concluded that the studies suggest there are no increased perinatal risks with glyburide compared with insulin for the treatment of GDM (Ann. Pharmacotherapy 2008;42:483-90).

Nine studies met the inclusion criteria for the analysis, which totaled 745 glyburide-exposed pregnancies and 637 insulin-exposed pregnancies. Women were typically treated starting at 24 weeks of gestation.

The use of glyburide was not associated, the investigators said, with risk of macrosomia, differences in birth weight, rate of large-for-gestational-age births, differences in gestational age at birth, ICU admission, or risk of neonatal hypoglycemia.

Metformin as an Option

Glyburide and metformin have different mechanisms of action. Glyburide works on the pancreas to stimulate insulin secretion. Metformin, which belongs to the class of oral antihyperglycemic agents known as the biguanides, lowers glucose levels by decreasing hepatic glucose production and decreasing peripheral insulin resistance.

Some have suggested that because metformin does not stimulate insulin secretion, it is less likely than glyburide to cause hypoglycemia and may be the preferable choice for treating diabetes in pregnancy.

While we have not directly compared metformin and glyburide in this regard, our data and data from other studies demonstrate that the rate of maternal hypoglycemia is significantly higher with insulin than with glyburide therapy. In one study using continuous blood glucose measurements, we showed that the maternal rate of hypoglycemic episodes was five times higher in insulin-treated patients than in glyburide-treated patients (Obstet. Gynecol. 2004;104:88-93).

Earlier findings suggesting the opposite—that glyburide is more likely to cause hypoglycemia than is insulin therapy—were from studies in much older, nonpregnant women. Diabetes in patients who are in their 50s through their 80s cannot be compared, in general, to the less severe disease in younger women of reproductive age.

Metformin, like glyburide, has been shown in numerous studies to have no adverse effect in pregnancy in terms of anomalies. The first large randomized, controlled trial to assess the safety and efficacy of metformin versus insulin—published last year—found similar efficacy in achieving target levels of glucose control and no difference in perinatal outcomes among 751 women randomized to one of the two groups (N. Engl. J. Med. 2008;358:2003-15).

Like glyburide, metformin is a class B drug. Because metformin crosses the placenta, physicians must take this into consideration when deciding which oral antihyperglycemic agent to choose. Even if a drug crosses the placenta, however, it should not automatically be considered contraindicated for use in pregnancy because the majority of drugs used in pregnancy cross the placenta without adverse effect to the fetus.

Also of possible concern is the fact that the rate of large-for-gestational-age infants in the New England Journal of Medicine (NEJM) metformin-versus-insulin study was twice the rate of large-for-gestational-age infants in our NEJM study comparing glyburide with insulin. This suggests that the rate of success in achieving glycemic control in pregnancy may be lower with metformin than with glyburide.

We need other studies, however, that directly compare glyburide with metformin (rather than comparing each with insulin), and the resultant perinatal outcomes and glycemic control, in order to address this issue.

Metformin is a popular drug for the treatment of polycystic ovary syndrome (PCOS), which presents the question of whether patients on metformin for PCOS should conceive while on the drug, or halt the drug if they unexpectedly conceive.

The answers in these cases call for individual judgment. In my opinion, metformin is a drug that can be used in pregnancy, as long as one keeps in the back of one's mind the fact that it does cross the placenta. One must also consider that although recent retrospective and prospective trials have shown no adverse effects of metformin in terms of anomalies, no published randomized study has evaluated pregnancy outcomes when patients were treated with the drug from preconception throughout gestation.

With respect to continuing either metformin or glyburide throughout pregnancy for those patients who are treated with these drugs during the preconception stage, the main concern in my opinion is whether the drugs can achieve the levels of glycemic control desired in pregnant women with type 2 diabetes. Because current data have shown that the level of glycemia—and not the drug—is associated with any increased rate of anomalies, I believe patients can remain on these drugs as long as the targeted level of glycemic control is maintained.

Overall, considering that we have a more extensive, more conclusive body of evidence for glyburide than metformin—and considering that glyburide does not cross the placenta—metformin is generally a second choice for me.

Pearls of Management

GDM and type 2 diabetes are essentially the same disease. They are similar in risk factors and in metabolic and endocrine abnormalities. Both are characterized by peripheral insulin resistance, decreased insulin secretion (reflecting declining beta-cell function), and impaired regulation of hepatic glucose.

GDM represents an early stage of the deterioration continuum toward type 2 diabetes. It is characterized by a milder glycemic profile. As I alluded to in a previous Master Class installment (“How Type 2 Diabetes Complicates Pregnancy,” September 2009, p. 28), though, it is increasingly believed that many of the women who are diagnosed with gestational diabetes actually meet the criteria for type 2 diabetes.

Because oral antihyperglycemic agents are the gold standard for therapy in type 2 in the general population—the landmark U.K. Prospective Diabetes Study (UKPDS) of type 2 diabetes showed that 70% of patients achieved desirable levels of glucose control with the use of glyburide—it is sensible to assume that women with GDM or early type 2 diabetes will respond to oral therapy with even greater success.

In general, oral glucose-lowering agents will decrease HbA_1c levels by 1%-2% (insulin, by 1%-2.5%). This roughly corresponds to a drop in fasting blood glucose levels of 30-60 mg/dL.

Oral therapy should be initiated when women cannot achieve fasting blood glucose levels of 95 mg/dL or less, or postprandial levels of 120 mg/dL or less after 2 hours. Diet and exercise can be recommended first for many of our patients, of course, but we must do so with careful consideration of the time that we have to meet target levels of control and prevent macrosomia and other adverse outcomes. Research has shown that at least 60% of patients with GDM eventually will require pharmacologic therapy.

Any pharmacologic therapy necessitates frequent dose adjustment to obtain the desired effect of the drug. Oral antihyperglycemic drugs should be increased only to the maximum dose allowed (20 mg daily in the case of glyburide).

The maximal dose of a drug and steady state are different in nonpregnant and pregnant patients, of course, because drug clearance is higher during pregnancy. However, in order to minimize any potential for complications like maternal hypoglycemia, our aim in diabetes management is to provide the minimal dose that will result in a desirable level of glycemic control.

Different oral antihyperglycemic agents act through diverse mechanisms, and the drugs' characteristics provide a physiological approach to the treatment of type 2 diabetes and GDM. Combination therapies will enhance the effect of these drugs on glucose metabolism, and “whole” patient care (including glucose monitoring, education, and diet adherence) will determine overall success in managing this disease and maximizing the quality of perinatal outcomes.

When insulin is added for the patient treated with oral agents, a single dose at bedtime can be sufficient in many cases. One of the benefits of this combination is the need for a lower dose of insulin. Insulin therapy alone should be used when other combinations have failed and is not limited by a maximum dose.

In obstetrics, we've lagged at least 2 decades behind the field of diabetes management in the general population. Now, however, we should be embracing the use of oral antihyperglycemic agents as the standard of care. We may find with further research that other drugs may have a greater therapeutic effect, but for now glyburide is the best front-line choice for glycemic control.

Glyburide Management

1. Start with 2.5 mg in the morning. If needed, drug titration should occur every 3-7 days.

2. Increase the morning dose by 2.5 mg.

3. Add the evening dose of 5 mg.

4. Increase the morning dose by 5 mg to 10 mg.

5. Increase the evening dose by 5 mg to 10 mg.

Note: The maximal dose is 20 mg daily.

Source: Dr. Langer

Key Points

▸ The level of glycemic control achieved—not the mode of therapy—is the key to improving outcomes in GDM and type 2 diabetes in pregnancy.

▸ Medical therapy with oral agents should be reserved for patients whose fasting plasma glucose levels remain above 95 mg/dL (or whose postprandial levels remain above 120 mg/dL) despite diet therapy and for those who are not appropriate candidates for diet therapy alone.

▸ The aim of therapy is to provide the minimal dose that will result in a desirable level of glycemic control and the least amount of complications for the mother.

▸ Well-designed studies have shown no association between oral antihyperglycemic agents and congenital malformations.

▸ Glyburide, metformin, and insulin are equally effective for GDM treatment at all disease severity levels.

▸ Glyburide is as effective as insulin for the treatment of obese GDM patients.

▸ Combination therapy or insulin therapy should be initiated if desired levels of glucose control are not achieved with one oral agent.

▸ Medication is just one component of intensive therapy. “Whole” patient care is also important.

Source: Dr. Langer

Treating Gestational Diabetes

Ob.Gyn

Within our society there are several conditions that are currently demanding a significant amount of our attention. Among them are obesity and diabetes.

In certain populations—in ethnic minority groups and among Native Americans in particular—there has clearly been a rise in gestational diabetes. There is also an association between the increased incidence of diabetes in pregnancy and an increasingly obese population. The two problems, we are learning, are truly entwined.

In the Master Class published in September, we addressed the diabetes pandemic, which some refer to as “diabesity” because of its association with obesity, and how diabetes complicates pregnancy for the mother and threatens fetal development and outcome.

Sometimes diabetes during pregnancy is of the type 2 variety. Gestational diabetes and type 2 diabetes are sometimes confused in their presentation and hence their diagnosis, however. Admittedly, a precise diagnosis of type 2 diabetes is often made in retrospect following the conclusion of the pregnancy. The diagnostic distinction is important, however, as a diagnosis of type 2 diabetes often drives a more serious approach to glycemic control.

In light of the increasing incidence of diabetes in pregnancy, the age-old problem of optimum treatment takes on even more significance.

Diet is still a mainstay. Insulin therapy remains difficult for patients to accept because it requires injections on a daily basis. Oral agents have been avoided for years because of concerns about safety and the lack of well-controlled data to establish whether such agents cross the placenta and may be potentially harmful to the fetus.

We are now at a juncture in our therapeutic maturity, however, where an increasing amount of information and data are available on the use of therapeutic options such as oral antidiabetic agents.

In light of this crossroads—the convergence of significantly more knowledge and a significantly higher prevalence of diabetes—we thought it high time to review the subject of gestational diabetes, and particularly the contemporary therapeutic options that are now available and can be applied in pregnancy.

I have again invited Oded Langer, M.D., Ph.D., who in September discussed why diabetes must be detected early and treated seriously, to discuss the latest research on oral antidiabetic agents in pregnancy and provide some useful perspective on diabetes management in our patient population.

Dr. Langer is an internationally recognized expert on diabetes in pregnancy who has written and lectured extensively on this subject. He is the Babcock Professor and chairman of the department of obstetrics and gynecology at St. Luke's–Roosevelt Hospital Center, a hospital affiliated with Columbia University in New York.

obnews@elsevier.com

It is well recognized that the complications and adverse perinatal outcomes associated with gestational diabetes and type 2 diabetes in pregnancy are glucose dependent. The main question in medical management, therefore, is how to maximize glycemic control.

The choice of medication should be determined by the ability of the drug to achieve the targeted level of glycemic control. For some patients, oral antihyperglycemic agents will be the drug of choice while in others combination therapy and/or insulin should be used.

For years, pharmacologic therapy for diabetes in pregnancy was limited to insulin. Obstetricians feared that oral antihyperglycemic agents, as an alternative to insulin therapy, could cause adverse pregnancy outcomes, particularly congenital anomalies and metabolic complications. Because of these concerns, sulfonylurea drugs were contraindicated in pregnancy.

These recommendations were founded, however, on anecdotal reports and poorly designed retrospective studies that were performed prior to the availability of second-generation sulfonylureas such as glyburide.

Today, there is clear evidence from in vivo and in vitro studies that glyburide does not cross the placenta in any appreciable quantity while metformin, another oral glucose-lowering agent, crosses the placenta freely.

Several randomized studies (five glyburide and two metformin studies), as well as other well-designed studies published over the last decade, also have demonstrated that glyburide is as effective and safe as insulin therapy for glycemic control during pregnancy.

Research has shown, moreover, that it's the blood glucose levels—not the drugs themselves—that cause adverse outcomes.

This is good news, because the use of oral antihyperglycemic agents enhances drug compliance for the patient.

Taking a tablet once in the morning and once in the evening is easier, more convenient, and less expensive than giving oneself insulin injections several times a day. Given the choice of insulin injections versus tablets, almost all women will opt for the latter.

Offering glyburide as a safe and effective alternative to insulin has been recommended by several editorials and professional organizations. Indeed, the use of glyburide has become the standard of care in the management of gestational diabetes mellitus (GDM) in many centers and private practices throughout the United States.

It is important to appreciate, however, that in general, as disease severity increases, there is diminishing success in achieving the desired levels of glycemic control.

Although the majority of women with gestational diabetes will benefit from the use of these drugs (approximately 80%), fewer women with type 2 diabetes will be able to achieve optimal glycemic control.

The emphasis overall in diabetes management must therefore be on the level of glycemic control achieved by the patient, with the failure of a drug signaling the need to change the drug algorithm.

Safety, Efficacy of Glyburide

Oral antihyperglycemic drugs—most commonly glyburide and metformin—are the first-line drugs for treating nonpregnant women with type 2 diabetes. These patients are typically older and suffer from greater disease severity (higher fasting and postprandial blood glucose levels and a decreased pancreatic reserve of 50%-80%). They therefore are not comparable to patients with gestational diabetes who are relatively younger and have greater pancreatic reserve.

This begs the following question: If the oral antihyperglycemic drugs are in fact safe for the fetus and can potentially optimize glycemic control—enabling patients to reach targeted levels of glucose control in pregnancy with the same efficacy as insulin—why should GDM patients who represent the milder form of intolerance on the glucose continuum not be treated with these drugs?

In the early 1990s, my colleagues and I evaluated the potential of first-generation and second-generation sulfonylureas to cross the placenta. Using the single-cotyledon placental model—a model that is widely used to characterize the transport and metabolism of drugs and nutrients—we found only minimal transport of glyburide in either the maternal-fetal or the fetal-maternal direction (Am. J. Obstet. Gynecol. 1991;165:807-12).

The transfer of glyburide remained negligible even when we varied the albumin concentration and increased maternal glyburide levels to 100 times the therapeutic level. In no case was there any appreciable metabolism of the agent. First-generation sulfonylureas, on the other hand, crossed the placenta in this model. Metformin did as well, almost freely.

Thereafter, several studies from different centers confirmed that glyburide does not cross the placenta significantly. The studies demonstrated, for instance, that 99.8% of the glyburide is bound to albumin, that the agent has a short elimination half-life, and that effluxes are affected from the fetal-maternal direction. Research also confirmed that metformin does cross the placenta.

In a later prospective, randomized trial comparing glyburide and insulin in 404 women with GDM, my colleagues and I found no significant differences in either the degree of glycemic control or perinatal outcomes (N. Engl. J. Med. 2000;343:1134-8). Target levels of glycemic control were achieved in 82% of the patients receiving glyburide and 88% of those receiving insulin.

There were no significant differences between the groups in the rate of infants who were large for gestational age or who had macrosomia, a ponderal index greater than 2.85, lung complications, hypoglycemia, or fetal anomalies.

We also tested the cord serum at delivery and found similar cord-serum insulin concentrations in the two groups. Glyburide was not detected in the cord serum above the level of 10 ng/mL.

Since 2000, more than 20 studies (4 of them randomized) have been published that show similar success rates with glyburide and insulin in achieving good glycemic control in gestational diabetes as well as similar perinatal outcomes. Most of the studies have been small and not randomized. Oftentimes, however, well-designed retrospective or case-control studies can be just as reliable. In this case, the studies collectively provide a solid basis for evaluation.

In a meta-analysis published last year, investigators concluded that the studies suggest there are no increased perinatal risks with glyburide compared with insulin for the treatment of GDM (Ann. Pharmacotherapy 2008;42:483-90).

Nine studies met the inclusion criteria for the analysis, which totaled 745 glyburide-exposed pregnancies and 637 insulin-exposed pregnancies. Women were typically treated starting at 24 weeks of gestation.

The use of glyburide was not associated, the investigators said, with risk of macrosomia, differences in birth weight, rate of large-for-gestational-age births, differences in gestational age at birth, ICU admission, or risk of neonatal hypoglycemia.

Metformin as an Option

Glyburide and metformin have different mechanisms of action. Glyburide works on the pancreas to stimulate insulin secretion. Metformin, which belongs to the class of oral antihyperglycemic agents known as the biguanides, lowers glucose levels by decreasing hepatic glucose production and decreasing peripheral insulin resistance.

Some have suggested that because metformin does not stimulate insulin secretion, it is less likely than glyburide to cause hypoglycemia and may be the preferable choice for treating diabetes in pregnancy.

While we have not directly compared metformin and glyburide in this regard, our data and data from other studies demonstrate that the rate of maternal hypoglycemia is significantly higher with insulin than with glyburide therapy. In one study using continuous blood glucose measurements, we showed that the maternal rate of hypoglycemic episodes was five times higher in insulin-treated patients than in glyburide-treated patients (Obstet. Gynecol. 2004;104:88-93).

Earlier findings suggesting the opposite—that glyburide is more likely to cause hypoglycemia than is insulin therapy—were from studies in much older, nonpregnant women. Diabetes in patients who are in their 50s through their 80s cannot be compared, in general, to the less severe disease in younger women of reproductive age.

Metformin, like glyburide, has been shown in numerous studies to have no adverse effect in pregnancy in terms of anomalies. The first large randomized, controlled trial to assess the safety and efficacy of metformin versus insulin—published last year—found similar efficacy in achieving target levels of glucose control and no difference in perinatal outcomes among 751 women randomized to one of the two groups (N. Engl. J. Med. 2008;358:2003-15).

Like glyburide, metformin is a class B drug. Because metformin crosses the placenta, physicians must take this into consideration when deciding which oral antihyperglycemic agent to choose. Even if a drug crosses the placenta, however, it should not automatically be considered contraindicated for use in pregnancy because the majority of drugs used in pregnancy cross the placenta without adverse effect to the fetus.

Also of possible concern is the fact that the rate of large-for-gestational-age infants in the New England Journal of Medicine (NEJM) metformin-versus-insulin study was twice the rate of large-for-gestational-age infants in our NEJM study comparing glyburide with insulin. This suggests that the rate of success in achieving glycemic control in pregnancy may be lower with metformin than with glyburide.

We need other studies, however, that directly compare glyburide with metformin (rather than comparing each with insulin), and the resultant perinatal outcomes and glycemic control, in order to address this issue.

Metformin is a popular drug for the treatment of polycystic ovary syndrome (PCOS), which presents the question of whether patients on metformin for PCOS should conceive while on the drug, or halt the drug if they unexpectedly conceive.

The answers in these cases call for individual judgment. In my opinion, metformin is a drug that can be used in pregnancy, as long as one keeps in the back of one's mind the fact that it does cross the placenta. One must also consider that although recent retrospective and prospective trials have shown no adverse effects of metformin in terms of anomalies, no published randomized study has evaluated pregnancy outcomes when patients were treated with the drug from preconception throughout gestation.

With respect to continuing either metformin or glyburide throughout pregnancy for those patients who are treated with these drugs during the preconception stage, the main concern in my opinion is whether the drugs can achieve the levels of glycemic control desired in pregnant women with type 2 diabetes. Because current data have shown that the level of glycemia—and not the drug—is associated with any increased rate of anomalies, I believe patients can remain on these drugs as long as the targeted level of glycemic control is maintained.

Overall, considering that we have a more extensive, more conclusive body of evidence for glyburide than metformin—and considering that glyburide does not cross the placenta—metformin is generally a second choice for me.

Pearls of Management

GDM and type 2 diabetes are essentially the same disease. They are similar in risk factors and in metabolic and endocrine abnormalities. Both are characterized by peripheral insulin resistance, decreased insulin secretion (reflecting declining beta-cell function), and impaired regulation of hepatic glucose.

GDM represents an early stage of the deterioration continuum toward type 2 diabetes. It is characterized by a milder glycemic profile. As I alluded to in a previous Master Class installment (“How Type 2 Diabetes Complicates Pregnancy,” September 2009, p. 28), though, it is increasingly believed that many of the women who are diagnosed with gestational diabetes actually meet the criteria for type 2 diabetes.

Because oral antihyperglycemic agents are the gold standard for therapy in type 2 in the general population—the landmark U.K. Prospective Diabetes Study (UKPDS) of type 2 diabetes showed that 70% of patients achieved desirable levels of glucose control with the use of glyburide—it is sensible to assume that women with GDM or early type 2 diabetes will respond to oral therapy with even greater success.

In general, oral glucose-lowering agents will decrease HbA_1c levels by 1%-2% (insulin, by 1%-2.5%). This roughly corresponds to a drop in fasting blood glucose levels of 30-60 mg/dL.

Oral therapy should be initiated when women cannot achieve fasting blood glucose levels of 95 mg/dL or less, or postprandial levels of 120 mg/dL or less after 2 hours. Diet and exercise can be recommended first for many of our patients, of course, but we must do so with careful consideration of the time that we have to meet target levels of control and prevent macrosomia and other adverse outcomes. Research has shown that at least 60% of patients with GDM eventually will require pharmacologic therapy.

Any pharmacologic therapy necessitates frequent dose adjustment to obtain the desired effect of the drug. Oral antihyperglycemic drugs should be increased only to the maximum dose allowed (20 mg daily in the case of glyburide).

The maximal dose of a drug and steady state are different in nonpregnant and pregnant patients, of course, because drug clearance is higher during pregnancy. However, in order to minimize any potential for complications like maternal hypoglycemia, our aim in diabetes management is to provide the minimal dose that will result in a desirable level of glycemic control.

Different oral antihyperglycemic agents act through diverse mechanisms, and the drugs' characteristics provide a physiological approach to the treatment of type 2 diabetes and GDM. Combination therapies will enhance the effect of these drugs on glucose metabolism, and “whole” patient care (including glucose monitoring, education, and diet adherence) will determine overall success in managing this disease and maximizing the quality of perinatal outcomes.

When insulin is added for the patient treated with oral agents, a single dose at bedtime can be sufficient in many cases. One of the benefits of this combination is the need for a lower dose of insulin. Insulin therapy alone should be used when other combinations have failed and is not limited by a maximum dose.

In obstetrics, we've lagged at least 2 decades behind the field of diabetes management in the general population. Now, however, we should be embracing the use of oral antihyperglycemic agents as the standard of care. We may find with further research that other drugs may have a greater therapeutic effect, but for now glyburide is the best front-line choice for glycemic control.

Glyburide Management

1. Start with 2.5 mg in the morning. If needed, drug titration should occur every 3-7 days.

2. Increase the morning dose by 2.5 mg.

3. Add the evening dose of 5 mg.

4. Increase the morning dose by 5 mg to 10 mg.

5. Increase the evening dose by 5 mg to 10 mg.

Note: The maximal dose is 20 mg daily.

Source: Dr. Langer

Key Points

▸ The level of glycemic control achieved—not the mode of therapy—is the key to improving outcomes in GDM and type 2 diabetes in pregnancy.

▸ Medical therapy with oral agents should be reserved for patients whose fasting plasma glucose levels remain above 95 mg/dL (or whose postprandial levels remain above 120 mg/dL) despite diet therapy and for those who are not appropriate candidates for diet therapy alone.

▸ The aim of therapy is to provide the minimal dose that will result in a desirable level of glycemic control and the least amount of complications for the mother.

▸ Well-designed studies have shown no association between oral antihyperglycemic agents and congenital malformations.

▸ Glyburide, metformin, and insulin are equally effective for GDM treatment at all disease severity levels.

▸ Glyburide is as effective as insulin for the treatment of obese GDM patients.

▸ Combination therapy or insulin therapy should be initiated if desired levels of glucose control are not achieved with one oral agent.

▸ Medication is just one component of intensive therapy. “Whole” patient care is also important.

Source: Dr. Langer

Treating Gestational Diabetes

Ob.Gyn

Within our society there are several conditions that are currently demanding a significant amount of our attention. Among them are obesity and diabetes.

In certain populations—in ethnic minority groups and among Native Americans in particular—there has clearly been a rise in gestational diabetes. There is also an association between the increased incidence of diabetes in pregnancy and an increasingly obese population. The two problems, we are learning, are truly entwined.

In the Master Class published in September, we addressed the diabetes pandemic, which some refer to as “diabesity” because of its association with obesity, and how diabetes complicates pregnancy for the mother and threatens fetal development and outcome.

Sometimes diabetes during pregnancy is of the type 2 variety. Gestational diabetes and type 2 diabetes are sometimes confused in their presentation and hence their diagnosis, however. Admittedly, a precise diagnosis of type 2 diabetes is often made in retrospect following the conclusion of the pregnancy. The diagnostic distinction is important, however, as a diagnosis of type 2 diabetes often drives a more serious approach to glycemic control.

In light of the increasing incidence of diabetes in pregnancy, the age-old problem of optimum treatment takes on even more significance.

Diet is still a mainstay. Insulin therapy remains difficult for patients to accept because it requires injections on a daily basis. Oral agents have been avoided for years because of concerns about safety and the lack of well-controlled data to establish whether such agents cross the placenta and may be potentially harmful to the fetus.

We are now at a juncture in our therapeutic maturity, however, where an increasing amount of information and data are available on the use of therapeutic options such as oral antidiabetic agents.

In light of this crossroads—the convergence of significantly more knowledge and a significantly higher prevalence of diabetes—we thought it high time to review the subject of gestational diabetes, and particularly the contemporary therapeutic options that are now available and can be applied in pregnancy.

I have again invited Oded Langer, M.D., Ph.D., who in September discussed why diabetes must be detected early and treated seriously, to discuss the latest research on oral antidiabetic agents in pregnancy and provide some useful perspective on diabetes management in our patient population.

Dr. Langer is an internationally recognized expert on diabetes in pregnancy who has written and lectured extensively on this subject. He is the Babcock Professor and chairman of the department of obstetrics and gynecology at St. Luke's–Roosevelt Hospital Center, a hospital affiliated with Columbia University in New York.

obnews@elsevier.com

As obstetricians we stand at the front line of preventing and treating pandemic influenza A(H1N1). Our pregnant patients who become infected with the H1N1 virus will potentially be more likely than the general population to develop severe disease, to be hospitalized, and to die from complications of the infection. They also will be at high risk of having preterm birth and fetal loss.

All this means that we must take an aggressive approach to therapy, treating women at the time they present with symptoms and being honest with them about their risks. Moreover, we must plan and execute infection control protocols and other nonpharmacologic interventions that traditionally have not been part of our armamentarium.

To be prepared, it is important that we understand influenza—why and how seasonal and pandemic influenza occur, how pregnant women have fared in previous pandemics, and what their outcomes have been thus far in the current pandemic. Most of us know little about influenza, but as we now practice on the front line with patients who are highly vulnerable, we must know more.

Understanding Pandemic Influenza

Influenza viruses are RNA viruses composed of eight separate negative-strand RNA segments that code for 11 viral proteins. These viruses regularly mutate while replicating themselves, altering their genome and shuffling their genes enough each year that our immune systems do not recognize them.

These ongoing genetic alterations are what drive annual epidemics of seasonal flu and are what make the influenza virus so different from the varicella-zoster virus (chickenpox) and other familiar viruses that are not RNA viruses. While infection with the varicella-zoster virus, or vaccination against it, gives most of us immunity for life, we are all susceptible to annual occurrences of seasonal influenza, regardless of how healthy we are.

There are three influenza virus types: influenza A, B, and C. Only types A and B cause infection in humans. Influenza A, which has been associated with most major pandemics and causes about two-thirds of seasonal influenza, is subtyped according to two surface proteins/antigens: hemagglutinin (H) and neuraminidase (N). Viruses with three different hemagglutinin subtypes H1, H2, and H3, as well as neuraminidase subtypes N1 and N2, have been previously associated with infections in humans.

The major natural reservoir for influenza A virus subtypes is the intestinal track of birds, particularly ducks, geese, and other water fowl. A significant number of different flu virus variations are normal flora in the intestinal tract of these birds.

While most viral infections that humans occasionally acquire from the birds are self-limited, some infections can be dangerous. If one is unlucky enough to be simultaneously infected with an avian influenza virus and a human influenza virus, the genes in each of these two viruses can randomly reassort, or rearrange themselves, to form a new virus.

This phenomenon, called reassortment, is one of two possible phenomena that lead to “antigen shift,” which results in immunologically unique viruses that produce pandemic influenza strains.

The other phenomenon that produces intermittent pandemic strains is called adaptation. In this scenario, an avian virus mutates enough over time—particularly with respect to its hemagglutinin molecule—that it becomes able to infect humans and to be easily transmissible from person to person.

The 1918 “Spanish” influenza pandemic produced by an H1N1 influenza virus—the most lethal pandemic in recorded history that was responsible for an estimated 50-100 million deaths worldwide—is believed to have resulted from genomic adaptation. An avian virus mutated enough that it spread from birds to humans and was then transmissible from person to person by common methods of viral spread. An attenuated version of this H1N1 virus then recurred annually for almost the next 30 years.

The 1957 “Asian flu” pandemic, on the other hand, emerged as a result of reassortment. A person infected with the then seasonally recurring H1N1 human virus was simultaneously infected with an H2N2 avian virus, and the genes reassorted to produce a new immunologically unique H2N2 virus. Fortunately, this virus did not contain many of the virulence factors that influenza viruses need to be highly lethal, so the 1957 pandemic was far milder than the 1918 pandemic.

A similar reassortment process led to the “Hong Kong flu” pandemic in 1968. It is believed that a person infected with the then seasonal H2N2 virus became infected with an H3 avian virus as well, generating a new H3N2 virus. Again, this virus was not as lethal as the 1918 virus, and after the pandemic subsided, an attenuated version became the annual seasonal influenza strain.

Interestingly, the H1N1 virus suddenly reappeared in the 1970s. Since then, seasonal influenza has been produced by a combination of the H3N2 virus and the H1N1 virus. Thus, annual influenza vaccines target both the seasonal H1N1 virus and the virus derived from the 1969 pandemic, along with the influenza B virus.

Epidemiological data going back over a hundred years show that influenza pandemics occur about every 30 years. Although the reasons for this recurring time interval are not understood, the data are strong enough that, especially since the late 1990s, experts have anticipated the development of the next pandemic.

The H5N1 avian influenza that emerged in Hong Kong in 1997 fortunately has not mutated enough to be easily transmissible among humans. Experts have been concerned, however, that this virus will undergo either adaptation or reassortment and lead to a severe pandemic. Thus far, human infections with the H5N1 avian influenza virus have been associated with an overall mortality of approximately 60%. Of the 433 cases reported to the World Health Organization through June of this year, 262 people had died.

A novel H1N1 influenza A virus containing genes from human, avian, and swine viruses was first identified in pigs in the United States in 1998. Although less significant than birds, pigs play an important role in the spread of influenza because they are susceptible to influenza virus from both birds and humans. Between 2005 and 2009, 11 cases of human infection with this triple-reassortment virus were described in the United States. In March and April of this year, further reassortment of this novel influenza A(H1N1) virus—one with uniquely different hemagglutinin and neuraminidase surface proteins—was identified in patients in Mexico. Transmissibility of the new H1N1 flu virus is high. Since initial cases of the novel H1N1 influenza virus were identified in Mexico, and then in Southern California, the virus has spread rapidly. In June, the WHO declared a pandemic. As of early September, tens of thousands of cases had been reported in the United States, and hundreds of thousands of cases had been reported worldwide.

It is important to appreciate the fact that pandemic influenza can occur in waves, with alternating periods of high infectivity and weeks or months of fewer infections; this pattern was particularly apparent in the 1918 pandemic.

In the 1918 pandemic, the second wave (lasting 8-10 weeks) occurred in the fall and was associated with a much higher mortality (up to 2%) than the first wave that had occurred in the spring. A third wave occurring in the spring of 1919 was similar to the first wave in terms of its high morbidity and relatively lower mortality.

Pandemics and Pregnancy

For reasons that are unclear, pregnant women have been observed to have higher morbidity and mortality compared with nonpregnant patients during influenza infections—seasonal or pandemic.

Observational reports of the 1918 pandemic paint a grim picture. One report published in the Journal of the American Medical Association in 1918, for instance, showed that 52 of 101 pregnant women who were admitted to Cook County Hospital in Chicago during a 2-month period with severe influenza succumbed to the illness. This mortality of 51% in pregnant patients was significantly higher than the observed 33% mortality rate in nonpregnant patients admitted to the hospital (719 of 2,154 nonpregnant patients who were admitted during the same time period died).

Additionally, among the 49 pregnant survivors in this sample, 43% either aborted or delivered prematurely (J. Am. Med. Assoc. 1918:71;1898-99). These are remarkable numbers.

Milder pandemics have had lower mortality overall, but reports have clearly shown that disproportionate numbers of pregnant women—particularly in the third trimester—have succumbed during influenza pandemics compared with the general population. An observational report from the milder 1968 pandemic, for instance, shows that pregnant women still were disproportionately represented among those dying during the pandemic.

Thus far in the current pandemic, the Centers for Disease Control and Prevention has reported similar trends—that pregnant women who contract the virus are significantly more likely to require hospitalization and are disproportionately represented among those who have died from it.

Of 34 cases of confirmed or probable H1N1 influenza in pregnant women that were reported to the CDC during the first month of the pandemic (mid-April to mid-May), 11 (32%) were admitted to the hospital. Dr. Denise Jamieson and her coinvestigators at the CDC noted that this hospitalization rate was four times higher than the hospitalization rate in the nonpregnant population due to influenza infection (Lancet 2009 Aug. 8;

doi:10.1016/S0140-6736[09]61304-0

This report by Dr. Jamieson also noted that the mortality is disproportionately elevated among pregnant women, especially in the third trimester. Four of six relatively healthy pregnant women who died during the first 2 months of the pandemic (mid-April to mid-June) were in the third trimester.

Each of the six women who succumbed developed acute viral pneumonia and subsequent acute respiratory distress syndrome requiring mechanical ventilation. (There were 45 total deaths reported during this period.)

Overall, just as it was in the 1918 pandemic, the highest mortality in the current pandemic appears to be occurring in the healthiest segments of the population—those in their late teens to late 40s—rather than in the very young and elderly (in addition to the chronically ill) as is typical for seasonal influenza. There is some evidence that suggests this increased mortality among the young, healthy population is due to a phenomenon called “cytokine storm,” or cytokine dysregulation. The body launches such a robust, overly exuberant immune response that it becomes self-destructive.

How this relates to pregnant women is unclear, as is their overall higher risk for more severe disease, complications, and death. There is speculation that their higher morbidity and mortality risk with influenza relates to immunologic changes in pregnancy, alterations in their respiratory physiology, and/or the overall greater metabolic demands of pregnancy. At this point, however, the testing of these hypotheses with the necessary animal studies has not been done.

In Practice Today

Therapeutic recommendations are driven by this history of pandemic influenza and the outcomes for pregnant women, as well as experience thus far with the current H1N1 influenza pandemic. Because pregnant women tend to have such a rapid onset and progression of disease, it is important to treat women at the time they present with symptoms, rather than waiting until these patients get worse or until culture results have been obtained.

The CDC has recommended that symptomatic pregnant women be treated with oseltamivir (Tamiflu), an antiviral neuraminidase inhibitor, as soon as possible after the onset of symptoms, and that pregnant women with significant exposure receive a prophylactic course of oseltamivir or zanamivir (Relenza). The benefit is expected to be greatest when treatment is initiated within 48 hours.

(In the CDC's Lancet-published report on H1N1 in pregnancy, the earliest initiation of oseltamivir in the pregnant women who died was 6 days after symptom onset.)

The vast majority of patients who have influenza—at least 80%—will present with a fever. Cough, sore throat, and muscle aches are other common symptoms. Occasionally, patients will have nausea or vomiting. During an active influenza pandemic, if a pregnant patient presents with signs and symptoms consistent with an influenzalike illness, we should err on the side of caution and begin empiric treatment.

In cases in which the diagnosis is unclear—in a patient with new nausea and vomiting but no fever or other symptoms suggestive of influenza, for instance—it is critical that we caution patients to call right away if they develop respiratory symptoms and/or a fever.

Because of concerns regarding the potential side effects of the antiviral medications, pregnant women can be expected to be hesitant about initiating treatment. However, given the increased risks of significant morbidity and mortality associated with untreated influenza infection, the risk-benefit ratio strongly favors the early initiation of effective antiviral medication.

Pregnant women are in the CDC's high-risk category for early vaccination, and certainly this is the best way to prevent their risk of significant morbidity and mortality. It is important that we educate our support staff to encourage patients to receive the vaccine; studies have shown that flu vaccination rates were low when nurses and front office staff were not committed to and invested in the idea.

There is only a small chance that individuals will acquire the seasonal influenza strain, but because pregnant women face increased risks with seasonal influenza as well, the CDC has recommended that they should still receive the seasonal influenza vaccine.

Vaccination also will protect pregnant women against the potential dangers of sequential influenza infections; being compromised with an infection of seasonal flu would potentially further increase a pregnant woman's risk of becoming severely ill with a subsequent pandemic H1N1 infection.

Public health measures call for “social distancing” as a nonpharmacologic method of influenza prevention—that is, these measures recommend limiting the number of people one is surrounded by or exposed to. Such measures have special meaning for us as obstetricians. It is imperative that we see infected and noninfected patients at separate time periods and/or in separate locations, and that we limit the numbers of pregnant women coming into our offices for prenatal care in the midst of a pandemic.

The use of masks and other standard infection control procedures also is imperative, and will help decrease viral transmission. But we must do more. We don't want one infected patient sitting in our waiting room with 10 other noninfected patients. Given what we know about the transmissibility of the virus, at least three or four of them would become infected in such a scenario.

In the middle of an active influenza pandemic, the benefit of having an otherwise healthy woman at midgestation keep her routinely scheduled prenatal visit as opposed to deferring her visit and staying at home (possibly calling in to talk with a triage nurse) will need to be considered.

The alternatives are not perfect, but we certainly do not want to expose healthy pregnant women to a potentially lethal infection in our waiting room or even in the bus or elevator of our office building.

Our other challenge will involve hospital care. As obstetricians we will need to facilitate and lead the development of labor and delivery triage systems aimed at separating infected and noninfected laboring patients.

ELSEVIER GLOBAL MEDICAL NEWS

Pandemic H1N1 Flu and Pregnancy

Our nation is facing an influenza pandemic this fall and winter, adding to the difficulties of dealing with a struggling economy, two foreign wars, and attempts to reform our health care.

Indeed, on June 11, 2009, the World Health Organization announced that a pandemic of influenza A(H1N1) was underway. The U.S. count includes thousands of hospitalizations and more than 350 deaths to date.

Although most people who have become ill with this new virus have recovered without requiring medical treatment, there is great concern regarding the effects of this novel flu virus on vulnerable populations.

Seasonal influenza typically poses the greatest risk to the very young and the very old, but this influenza pandemic poses the greatest risk to young people and to pregnant women, in particular. High rates of severe illnesses and even deaths have been reported among pregnant women during this current outbreak. Thus, this pandemic has to be taken very seriously in obstetrics, and we need to employ all preventive measures possible. If we can do this effectively, we can head off the most significant and severe adverse consequences in our pregnant patients.

In an effort to provide the greatest education for the obstetrical community, and to create the greatest preparedness for managing the H1N1 pandemic, we have chosen to do a comprehensive Master Class on this subject. We have invited Mark Phillippe, M.D., M.H.C.M., to tell us how previous influenza pandemics have affected pregnant women and to discuss what impact the current pandemic is already having. We also have asked him to provide in detail his preparedness plan for practicing obstetricians.

Dr. Phillippe is John Van Sicklen Maeck Professor and Chairman of the department of obstetrics, gynecology, and reproductive sciences at the University of Vermont, Burlington. He is a nationally recognized maternal-fetal medicine expert, and has a research interest in influenza and how and why it impacts maternal mortality and the risk of pregnancy loss.

Key Points

The newly emerged pandemic influenza A(H1N1) virus is expected to present significant challenges to the entire health care system.

The challenges will be especially great for pregnant women and those who provide medical care for them.

Previous influenza pandemics have been notable for increased morbidity and mortality among pregnant women, especially during the third trimester.

In the past, all that could be offered to pregnant women was supportive care. We now have antiviral medications and will soon have a vaccine for the pandemic H1N1 virus.

We need to educate ourselves and our patients about how to use these therapeutic interventions effectively.

Source: Dr. Phillippe

obnews@elsevier.com

As obstetricians we stand at the front line of preventing and treating pandemic influenza A(H1N1). Our pregnant patients who become infected with the H1N1 virus will potentially be more likely than the general population to develop severe disease, to be hospitalized, and to die from complications of the infection. They also will be at high risk of having preterm birth and fetal loss.

All this means that we must take an aggressive approach to therapy, treating women at the time they present with symptoms and being honest with them about their risks. Moreover, we must plan and execute infection control protocols and other nonpharmacologic interventions that traditionally have not been part of our armamentarium.

To be prepared, it is important that we understand influenza—why and how seasonal and pandemic influenza occur, how pregnant women have fared in previous pandemics, and what their outcomes have been thus far in the current pandemic. Most of us know little about influenza, but as we now practice on the front line with patients who are highly vulnerable, we must know more.

Understanding Pandemic Influenza

Influenza viruses are RNA viruses composed of eight separate negative-strand RNA segments that code for 11 viral proteins. These viruses regularly mutate while replicating themselves, altering their genome and shuffling their genes enough each year that our immune systems do not recognize them.

These ongoing genetic alterations are what drive annual epidemics of seasonal flu and are what make the influenza virus so different from the varicella-zoster virus (chickenpox) and other familiar viruses that are not RNA viruses. While infection with the varicella-zoster virus, or vaccination against it, gives most of us immunity for life, we are all susceptible to annual occurrences of seasonal influenza, regardless of how healthy we are.

There are three influenza virus types: influenza A, B, and C. Only types A and B cause infection in humans. Influenza A, which has been associated with most major pandemics and causes about two-thirds of seasonal influenza, is subtyped according to two surface proteins/antigens: hemagglutinin (H) and neuraminidase (N). Viruses with three different hemagglutinin subtypes H1, H2, and H3, as well as neuraminidase subtypes N1 and N2, have been previously associated with infections in humans.

The major natural reservoir for influenza A virus subtypes is the intestinal track of birds, particularly ducks, geese, and other water fowl. A significant number of different flu virus variations are normal flora in the intestinal tract of these birds.

While most viral infections that humans occasionally acquire from the birds are self-limited, some infections can be dangerous. If one is unlucky enough to be simultaneously infected with an avian influenza virus and a human influenza virus, the genes in each of these two viruses can randomly reassort, or rearrange themselves, to form a new virus.

This phenomenon, called reassortment, is one of two possible phenomena that lead to “antigen shift,” which results in immunologically unique viruses that produce pandemic influenza strains.

The other phenomenon that produces intermittent pandemic strains is called adaptation. In this scenario, an avian virus mutates enough over time—particularly with respect to its hemagglutinin molecule—that it becomes able to infect humans and to be easily transmissible from person to person.

The 1918 “Spanish” influenza pandemic produced by an H1N1 influenza virus—the most lethal pandemic in recorded history that was responsible for an estimated 50-100 million deaths worldwide—is believed to have resulted from genomic adaptation. An avian virus mutated enough that it spread from birds to humans and was then transmissible from person to person by common methods of viral spread. An attenuated version of this H1N1 virus then recurred annually for almost the next 30 years.

The 1957 “Asian flu” pandemic, on the other hand, emerged as a result of reassortment. A person infected with the then seasonally recurring H1N1 human virus was simultaneously infected with an H2N2 avian virus, and the genes reassorted to produce a new immunologically unique H2N2 virus. Fortunately, this virus did not contain many of the virulence factors that influenza viruses need to be highly lethal, so the 1957 pandemic was far milder than the 1918 pandemic.

A similar reassortment process led to the “Hong Kong flu” pandemic in 1968. It is believed that a person infected with the then seasonal H2N2 virus became infected with an H3 avian virus as well, generating a new H3N2 virus. Again, this virus was not as lethal as the 1918 virus, and after the pandemic subsided, an attenuated version became the annual seasonal influenza strain.

Interestingly, the H1N1 virus suddenly reappeared in the 1970s. Since then, seasonal influenza has been produced by a combination of the H3N2 virus and the H1N1 virus. Thus, annual influenza vaccines target both the seasonal H1N1 virus and the virus derived from the 1969 pandemic, along with the influenza B virus.

Epidemiological data going back over a hundred years show that influenza pandemics occur about every 30 years. Although the reasons for this recurring time interval are not understood, the data are strong enough that, especially since the late 1990s, experts have anticipated the development of the next pandemic.

The H5N1 avian influenza that emerged in Hong Kong in 1997 fortunately has not mutated enough to be easily transmissible among humans. Experts have been concerned, however, that this virus will undergo either adaptation or reassortment and lead to a severe pandemic. Thus far, human infections with the H5N1 avian influenza virus have been associated with an overall mortality of approximately 60%. Of the 433 cases reported to the World Health Organization through June of this year, 262 people had died.

A novel H1N1 influenza A virus containing genes from human, avian, and swine viruses was first identified in pigs in the United States in 1998. Although less significant than birds, pigs play an important role in the spread of influenza because they are susceptible to influenza virus from both birds and humans. Between 2005 and 2009, 11 cases of human infection with this triple-reassortment virus were described in the United States. In March and April of this year, further reassortment of this novel influenza A(H1N1) virus—one with uniquely different hemagglutinin and neuraminidase surface proteins—was identified in patients in Mexico. Transmissibility of the new H1N1 flu virus is high. Since initial cases of the novel H1N1 influenza virus were identified in Mexico, and then in Southern California, the virus has spread rapidly. In June, the WHO declared a pandemic. As of early September, tens of thousands of cases had been reported in the United States, and hundreds of thousands of cases had been reported worldwide.

It is important to appreciate the fact that pandemic influenza can occur in waves, with alternating periods of high infectivity and weeks or months of fewer infections; this pattern was particularly apparent in the 1918 pandemic.

In the 1918 pandemic, the second wave (lasting 8-10 weeks) occurred in the fall and was associated with a much higher mortality (up to 2%) than the first wave that had occurred in the spring. A third wave occurring in the spring of 1919 was similar to the first wave in terms of its high morbidity and relatively lower mortality.

Pandemics and Pregnancy

For reasons that are unclear, pregnant women have been observed to have higher morbidity and mortality compared with nonpregnant patients during influenza infections—seasonal or pandemic.

Observational reports of the 1918 pandemic paint a grim picture. One report published in the Journal of the American Medical Association in 1918, for instance, showed that 52 of 101 pregnant women who were admitted to Cook County Hospital in Chicago during a 2-month period with severe influenza succumbed to the illness. This mortality of 51% in pregnant patients was significantly higher than the observed 33% mortality rate in nonpregnant patients admitted to the hospital (719 of 2,154 nonpregnant patients who were admitted during the same time period died).

Additionally, among the 49 pregnant survivors in this sample, 43% either aborted or delivered prematurely (J. Am. Med. Assoc. 1918:71;1898-99). These are remarkable numbers.

Milder pandemics have had lower mortality overall, but reports have clearly shown that disproportionate numbers of pregnant women—particularly in the third trimester—have succumbed during influenza pandemics compared with the general population. An observational report from the milder 1968 pandemic, for instance, shows that pregnant women still were disproportionately represented among those dying during the pandemic.

Thus far in the current pandemic, the Centers for Disease Control and Prevention has reported similar trends—that pregnant women who contract the virus are significantly more likely to require hospitalization and are disproportionately represented among those who have died from it.

Of 34 cases of confirmed or probable H1N1 influenza in pregnant women that were reported to the CDC during the first month of the pandemic (mid-April to mid-May), 11 (32%) were admitted to the hospital. Dr. Denise Jamieson and her coinvestigators at the CDC noted that this hospitalization rate was four times higher than the hospitalization rate in the nonpregnant population due to influenza infection (Lancet 2009 Aug. 8;

doi:10.1016/S0140-6736[09]61304-0

This report by Dr. Jamieson also noted that the mortality is disproportionately elevated among pregnant women, especially in the third trimester. Four of six relatively healthy pregnant women who died during the first 2 months of the pandemic (mid-April to mid-June) were in the third trimester.

Each of the six women who succumbed developed acute viral pneumonia and subsequent acute respiratory distress syndrome requiring mechanical ventilation. (There were 45 total deaths reported during this period.)

Overall, just as it was in the 1918 pandemic, the highest mortality in the current pandemic appears to be occurring in the healthiest segments of the population—those in their late teens to late 40s—rather than in the very young and elderly (in addition to the chronically ill) as is typical for seasonal influenza. There is some evidence that suggests this increased mortality among the young, healthy population is due to a phenomenon called “cytokine storm,” or cytokine dysregulation. The body launches such a robust, overly exuberant immune response that it becomes self-destructive.

How this relates to pregnant women is unclear, as is their overall higher risk for more severe disease, complications, and death. There is speculation that their higher morbidity and mortality risk with influenza relates to immunologic changes in pregnancy, alterations in their respiratory physiology, and/or the overall greater metabolic demands of pregnancy. At this point, however, the testing of these hypotheses with the necessary animal studies has not been done.

In Practice Today

Therapeutic recommendations are driven by this history of pandemic influenza and the outcomes for pregnant women, as well as experience thus far with the current H1N1 influenza pandemic. Because pregnant women tend to have such a rapid onset and progression of disease, it is important to treat women at the time they present with symptoms, rather than waiting until these patients get worse or until culture results have been obtained.

The CDC has recommended that symptomatic pregnant women be treated with oseltamivir (Tamiflu), an antiviral neuraminidase inhibitor, as soon as possible after the onset of symptoms, and that pregnant women with significant exposure receive a prophylactic course of oseltamivir or zanamivir (Relenza). The benefit is expected to be greatest when treatment is initiated within 48 hours.

(In the CDC's Lancet-published report on H1N1 in pregnancy, the earliest initiation of oseltamivir in the pregnant women who died was 6 days after symptom onset.)

The vast majority of patients who have influenza—at least 80%—will present with a fever. Cough, sore throat, and muscle aches are other common symptoms. Occasionally, patients will have nausea or vomiting. During an active influenza pandemic, if a pregnant patient presents with signs and symptoms consistent with an influenzalike illness, we should err on the side of caution and begin empiric treatment.

In cases in which the diagnosis is unclear—in a patient with new nausea and vomiting but no fever or other symptoms suggestive of influenza, for instance—it is critical that we caution patients to call right away if they develop respiratory symptoms and/or a fever.

Because of concerns regarding the potential side effects of the antiviral medications, pregnant women can be expected to be hesitant about initiating treatment. However, given the increased risks of significant morbidity and mortality associated with untreated influenza infection, the risk-benefit ratio strongly favors the early initiation of effective antiviral medication.

Pregnant women are in the CDC's high-risk category for early vaccination, and certainly this is the best way to prevent their risk of significant morbidity and mortality. It is important that we educate our support staff to encourage patients to receive the vaccine; studies have shown that flu vaccination rates were low when nurses and front office staff were not committed to and invested in the idea.

There is only a small chance that individuals will acquire the seasonal influenza strain, but because pregnant women face increased risks with seasonal influenza as well, the CDC has recommended that they should still receive the seasonal influenza vaccine.

Vaccination also will protect pregnant women against the potential dangers of sequential influenza infections; being compromised with an infection of seasonal flu would potentially further increase a pregnant woman's risk of becoming severely ill with a subsequent pandemic H1N1 infection.

Public health measures call for “social distancing” as a nonpharmacologic method of influenza prevention—that is, these measures recommend limiting the number of people one is surrounded by or exposed to. Such measures have special meaning for us as obstetricians. It is imperative that we see infected and noninfected patients at separate time periods and/or in separate locations, and that we limit the numbers of pregnant women coming into our offices for prenatal care in the midst of a pandemic.

The use of masks and other standard infection control procedures also is imperative, and will help decrease viral transmission. But we must do more. We don't want one infected patient sitting in our waiting room with 10 other noninfected patients. Given what we know about the transmissibility of the virus, at least three or four of them would become infected in such a scenario.

In the middle of an active influenza pandemic, the benefit of having an otherwise healthy woman at midgestation keep her routinely scheduled prenatal visit as opposed to deferring her visit and staying at home (possibly calling in to talk with a triage nurse) will need to be considered.

The alternatives are not perfect, but we certainly do not want to expose healthy pregnant women to a potentially lethal infection in our waiting room or even in the bus or elevator of our office building.

Our other challenge will involve hospital care. As obstetricians we will need to facilitate and lead the development of labor and delivery triage systems aimed at separating infected and noninfected laboring patients.

ELSEVIER GLOBAL MEDICAL NEWS

Pandemic H1N1 Flu and Pregnancy

Our nation is facing an influenza pandemic this fall and winter, adding to the difficulties of dealing with a struggling economy, two foreign wars, and attempts to reform our health care.

Indeed, on June 11, 2009, the World Health Organization announced that a pandemic of influenza A(H1N1) was underway. The U.S. count includes thousands of hospitalizations and more than 350 deaths to date.

Although most people who have become ill with this new virus have recovered without requiring medical treatment, there is great concern regarding the effects of this novel flu virus on vulnerable populations.

Seasonal influenza typically poses the greatest risk to the very young and the very old, but this influenza pandemic poses the greatest risk to young people and to pregnant women, in particular. High rates of severe illnesses and even deaths have been reported among pregnant women during this current outbreak. Thus, this pandemic has to be taken very seriously in obstetrics, and we need to employ all preventive measures possible. If we can do this effectively, we can head off the most significant and severe adverse consequences in our pregnant patients.

In an effort to provide the greatest education for the obstetrical community, and to create the greatest preparedness for managing the H1N1 pandemic, we have chosen to do a comprehensive Master Class on this subject. We have invited Mark Phillippe, M.D., M.H.C.M., to tell us how previous influenza pandemics have affected pregnant women and to discuss what impact the current pandemic is already having. We also have asked him to provide in detail his preparedness plan for practicing obstetricians.

Dr. Phillippe is John Van Sicklen Maeck Professor and Chairman of the department of obstetrics, gynecology, and reproductive sciences at the University of Vermont, Burlington. He is a nationally recognized maternal-fetal medicine expert, and has a research interest in influenza and how and why it impacts maternal mortality and the risk of pregnancy loss.

Key Points

The newly emerged pandemic influenza A(H1N1) virus is expected to present significant challenges to the entire health care system.

The challenges will be especially great for pregnant women and those who provide medical care for them.

Previous influenza pandemics have been notable for increased morbidity and mortality among pregnant women, especially during the third trimester.

In the past, all that could be offered to pregnant women was supportive care. We now have antiviral medications and will soon have a vaccine for the pandemic H1N1 virus.

We need to educate ourselves and our patients about how to use these therapeutic interventions effectively.

Source: Dr. Phillippe

obnews@elsevier.com

As obstetricians we stand at the front line of preventing and treating pandemic influenza A(H1N1). Our pregnant patients who become infected with the H1N1 virus will potentially be more likely than the general population to develop severe disease, to be hospitalized, and to die from complications of the infection. They also will be at high risk of having preterm birth and fetal loss.

All this means that we must take an aggressive approach to therapy, treating women at the time they present with symptoms and being honest with them about their risks. Moreover, we must plan and execute infection control protocols and other nonpharmacologic interventions that traditionally have not been part of our armamentarium.

To be prepared, it is important that we understand influenza—why and how seasonal and pandemic influenza occur, how pregnant women have fared in previous pandemics, and what their outcomes have been thus far in the current pandemic. Most of us know little about influenza, but as we now practice on the front line with patients who are highly vulnerable, we must know more.

Understanding Pandemic Influenza

Influenza viruses are RNA viruses composed of eight separate negative-strand RNA segments that code for 11 viral proteins. These viruses regularly mutate while replicating themselves, altering their genome and shuffling their genes enough each year that our immune systems do not recognize them.

These ongoing genetic alterations are what drive annual epidemics of seasonal flu and are what make the influenza virus so different from the varicella-zoster virus (chickenpox) and other familiar viruses that are not RNA viruses. While infection with the varicella-zoster virus, or vaccination against it, gives most of us immunity for life, we are all susceptible to annual occurrences of seasonal influenza, regardless of how healthy we are.

There are three influenza virus types: influenza A, B, and C. Only types A and B cause infection in humans. Influenza A, which has been associated with most major pandemics and causes about two-thirds of seasonal influenza, is subtyped according to two surface proteins/antigens: hemagglutinin (H) and neuraminidase (N). Viruses with three different hemagglutinin subtypes H1, H2, and H3, as well as neuraminidase subtypes N1 and N2, have been previously associated with infections in humans.

The major natural reservoir for influenza A virus subtypes is the intestinal track of birds, particularly ducks, geese, and other water fowl. A significant number of different flu virus variations are normal flora in the intestinal tract of these birds.

While most viral infections that humans occasionally acquire from the birds are self-limited, some infections can be dangerous. If one is unlucky enough to be simultaneously infected with an avian influenza virus and a human influenza virus, the genes in each of these two viruses can randomly reassort, or rearrange themselves, to form a new virus.

This phenomenon, called reassortment, is one of two possible phenomena that lead to “antigen shift,” which results in immunologically unique viruses that produce pandemic influenza strains.

The other phenomenon that produces intermittent pandemic strains is called adaptation. In this scenario, an avian virus mutates enough over time—particularly with respect to its hemagglutinin molecule—that it becomes able to infect humans and to be easily transmissible from person to person.

The 1918 “Spanish” influenza pandemic produced by an H1N1 influenza virus—the most lethal pandemic in recorded history that was responsible for an estimated 50-100 million deaths worldwide—is believed to have resulted from genomic adaptation. An avian virus mutated enough that it spread from birds to humans and was then transmissible from person to person by common methods of viral spread. An attenuated version of this H1N1 virus then recurred annually for almost the next 30 years.

The 1957 “Asian flu” pandemic, on the other hand, emerged as a result of reassortment. A person infected with the then seasonally recurring H1N1 human virus was simultaneously infected with an H2N2 avian virus, and the genes reassorted to produce a new immunologically unique H2N2 virus. Fortunately, this virus did not contain many of the virulence factors that influenza viruses need to be highly lethal, so the 1957 pandemic was far milder than the 1918 pandemic.

A similar reassortment process led to the “Hong Kong flu” pandemic in 1968. It is believed that a person infected with the then seasonal H2N2 virus became infected with an H3 avian virus as well, generating a new H3N2 virus. Again, this virus was not as lethal as the 1918 virus, and after the pandemic subsided, an attenuated version became the annual seasonal influenza strain.

Interestingly, the H1N1 virus suddenly reappeared in the 1970s. Since then, seasonal influenza has been produced by a combination of the H3N2 virus and the H1N1 virus. Thus, annual influenza vaccines target both the seasonal H1N1 virus and the virus derived from the 1969 pandemic, along with the influenza B virus.

Epidemiological data going back over a hundred years show that influenza pandemics occur about every 30 years. Although the reasons for this recurring time interval are not understood, the data are strong enough that, especially since the late 1990s, experts have anticipated the development of the next pandemic.

The H5N1 avian influenza that emerged in Hong Kong in 1997 fortunately has not mutated enough to be easily transmissible among humans. Experts have been concerned, however, that this virus will undergo either adaptation or reassortment and lead to a severe pandemic. Thus far, human infections with the H5N1 avian influenza virus have been associated with an overall mortality of approximately 60%. Of the 433 cases reported to the World Health Organization through June of this year, 262 people had died.

A novel H1N1 influenza A virus containing genes from human, avian, and swine viruses was first identified in pigs in the United States in 1998. Although less significant than birds, pigs play an important role in the spread of influenza because they are susceptible to influenza virus from both birds and humans. Between 2005 and 2009, 11 cases of human infection with this triple-reassortment virus were described in the United States. In March and April of this year, further reassortment of this novel influenza A(H1N1) virus—one with uniquely different hemagglutinin and neuraminidase surface proteins—was identified in patients in Mexico. Transmissibility of the new H1N1 flu virus is high. Since initial cases of the novel H1N1 influenza virus were identified in Mexico, and then in Southern California, the virus has spread rapidly. In June, the WHO declared a pandemic. As of early September, tens of thousands of cases had been reported in the United States, and hundreds of thousands of cases had been reported worldwide.

It is important to appreciate the fact that pandemic influenza can occur in waves, with alternating periods of high infectivity and weeks or months of fewer infections; this pattern was particularly apparent in the 1918 pandemic.

In the 1918 pandemic, the second wave (lasting 8-10 weeks) occurred in the fall and was associated with a much higher mortality (up to 2%) than the first wave that had occurred in the spring. A third wave occurring in the spring of 1919 was similar to the first wave in terms of its high morbidity and relatively lower mortality.

Pandemics and Pregnancy

For reasons that are unclear, pregnant women have been observed to have higher morbidity and mortality compared with nonpregnant patients during influenza infections—seasonal or pandemic.

Observational reports of the 1918 pandemic paint a grim picture. One report published in the Journal of the American Medical Association in 1918, for instance, showed that 52 of 101 pregnant women who were admitted to Cook County Hospital in Chicago during a 2-month period with severe influenza succumbed to the illness. This mortality of 51% in pregnant patients was significantly higher than the observed 33% mortality rate in nonpregnant patients admitted to the hospital (719 of 2,154 nonpregnant patients who were admitted during the same time period died).

Additionally, among the 49 pregnant survivors in this sample, 43% either aborted or delivered prematurely (J. Am. Med. Assoc. 1918:71;1898-99). These are remarkable numbers.

Milder pandemics have had lower mortality overall, but reports have clearly shown that disproportionate numbers of pregnant women—particularly in the third trimester—have succumbed during influenza pandemics compared with the general population. An observational report from the milder 1968 pandemic, for instance, shows that pregnant women still were disproportionately represented among those dying during the pandemic.

Thus far in the current pandemic, the Centers for Disease Control and Prevention has reported similar trends—that pregnant women who contract the virus are significantly more likely to require hospitalization and are disproportionately represented among those who have died from it.

Of 34 cases of confirmed or probable H1N1 influenza in pregnant women that were reported to the CDC during the first month of the pandemic (mid-April to mid-May), 11 (32%) were admitted to the hospital. Dr. Denise Jamieson and her coinvestigators at the CDC noted that this hospitalization rate was four times higher than the hospitalization rate in the nonpregnant population due to influenza infection (Lancet 2009 Aug. 8;

doi:10.1016/S0140-6736[09]61304-0

This report by Dr. Jamieson also noted that the mortality is disproportionately elevated among pregnant women, especially in the third trimester. Four of six relatively healthy pregnant women who died during the first 2 months of the pandemic (mid-April to mid-June) were in the third trimester.

Each of the six women who succumbed developed acute viral pneumonia and subsequent acute respiratory distress syndrome requiring mechanical ventilation. (There were 45 total deaths reported during this period.)

Overall, just as it was in the 1918 pandemic, the highest mortality in the current pandemic appears to be occurring in the healthiest segments of the population—those in their late teens to late 40s—rather than in the very young and elderly (in addition to the chronically ill) as is typical for seasonal influenza. There is some evidence that suggests this increased mortality among the young, healthy population is due to a phenomenon called “cytokine storm,” or cytokine dysregulation. The body launches such a robust, overly exuberant immune response that it becomes self-destructive.

How this relates to pregnant women is unclear, as is their overall higher risk for more severe disease, complications, and death. There is speculation that their higher morbidity and mortality risk with influenza relates to immunologic changes in pregnancy, alterations in their respiratory physiology, and/or the overall greater metabolic demands of pregnancy. At this point, however, the testing of these hypotheses with the necessary animal studies has not been done.

In Practice Today

Therapeutic recommendations are driven by this history of pandemic influenza and the outcomes for pregnant women, as well as experience thus far with the current H1N1 influenza pandemic. Because pregnant women tend to have such a rapid onset and progression of disease, it is important to treat women at the time they present with symptoms, rather than waiting until these patients get worse or until culture results have been obtained.

The CDC has recommended that symptomatic pregnant women be treated with oseltamivir (Tamiflu), an antiviral neuraminidase inhibitor, as soon as possible after the onset of symptoms, and that pregnant women with significant exposure receive a prophylactic course of oseltamivir or zanamivir (Relenza). The benefit is expected to be greatest when treatment is initiated within 48 hours.

(In the CDC's Lancet-published report on H1N1 in pregnancy, the earliest initiation of oseltamivir in the pregnant women who died was 6 days after symptom onset.)

The vast majority of patients who have influenza—at least 80%—will present with a fever. Cough, sore throat, and muscle aches are other common symptoms. Occasionally, patients will have nausea or vomiting. During an active influenza pandemic, if a pregnant patient presents with signs and symptoms consistent with an influenzalike illness, we should err on the side of caution and begin empiric treatment.

In cases in which the diagnosis is unclear—in a patient with new nausea and vomiting but no fever or other symptoms suggestive of influenza, for instance—it is critical that we caution patients to call right away if they develop respiratory symptoms and/or a fever.

Because of concerns regarding the potential side effects of the antiviral medications, pregnant women can be expected to be hesitant about initiating treatment. However, given the increased risks of significant morbidity and mortality associated with untreated influenza infection, the risk-benefit ratio strongly favors the early initiation of effective antiviral medication.

Pregnant women are in the CDC's high-risk category for early vaccination, and certainly this is the best way to prevent their risk of significant morbidity and mortality. It is important that we educate our support staff to encourage patients to receive the vaccine; studies have shown that flu vaccination rates were low when nurses and front office staff were not committed to and invested in the idea.

There is only a small chance that individuals will acquire the seasonal influenza strain, but because pregnant women face increased risks with seasonal influenza as well, the CDC has recommended that they should still receive the seasonal influenza vaccine.

Vaccination also will protect pregnant women against the potential dangers of sequential influenza infections; being compromised with an infection of seasonal flu would potentially further increase a pregnant woman's risk of becoming severely ill with a subsequent pandemic H1N1 infection.

Public health measures call for “social distancing” as a nonpharmacologic method of influenza prevention—that is, these measures recommend limiting the number of people one is surrounded by or exposed to. Such measures have special meaning for us as obstetricians. It is imperative that we see infected and noninfected patients at separate time periods and/or in separate locations, and that we limit the numbers of pregnant women coming into our offices for prenatal care in the midst of a pandemic.

The use of masks and other standard infection control procedures also is imperative, and will help decrease viral transmission. But we must do more. We don't want one infected patient sitting in our waiting room with 10 other noninfected patients. Given what we know about the transmissibility of the virus, at least three or four of them would become infected in such a scenario.

In the middle of an active influenza pandemic, the benefit of having an otherwise healthy woman at midgestation keep her routinely scheduled prenatal visit as opposed to deferring her visit and staying at home (possibly calling in to talk with a triage nurse) will need to be considered.

The alternatives are not perfect, but we certainly do not want to expose healthy pregnant women to a potentially lethal infection in our waiting room or even in the bus or elevator of our office building.

Our other challenge will involve hospital care. As obstetricians we will need to facilitate and lead the development of labor and delivery triage systems aimed at separating infected and noninfected laboring patients.

ELSEVIER GLOBAL MEDICAL NEWS

Pandemic H1N1 Flu and Pregnancy

Our nation is facing an influenza pandemic this fall and winter, adding to the difficulties of dealing with a struggling economy, two foreign wars, and attempts to reform our health care.

Indeed, on June 11, 2009, the World Health Organization announced that a pandemic of influenza A(H1N1) was underway. The U.S. count includes thousands of hospitalizations and more than 350 deaths to date.

Although most people who have become ill with this new virus have recovered without requiring medical treatment, there is great concern regarding the effects of this novel flu virus on vulnerable populations.

Seasonal influenza typically poses the greatest risk to the very young and the very old, but this influenza pandemic poses the greatest risk to young people and to pregnant women, in particular. High rates of severe illnesses and even deaths have been reported among pregnant women during this current outbreak. Thus, this pandemic has to be taken very seriously in obstetrics, and we need to employ all preventive measures possible. If we can do this effectively, we can head off the most significant and severe adverse consequences in our pregnant patients.

In an effort to provide the greatest education for the obstetrical community, and to create the greatest preparedness for managing the H1N1 pandemic, we have chosen to do a comprehensive Master Class on this subject. We have invited Mark Phillippe, M.D., M.H.C.M., to tell us how previous influenza pandemics have affected pregnant women and to discuss what impact the current pandemic is already having. We also have asked him to provide in detail his preparedness plan for practicing obstetricians.

Dr. Phillippe is John Van Sicklen Maeck Professor and Chairman of the department of obstetrics, gynecology, and reproductive sciences at the University of Vermont, Burlington. He is a nationally recognized maternal-fetal medicine expert, and has a research interest in influenza and how and why it impacts maternal mortality and the risk of pregnancy loss.

Key Points

The newly emerged pandemic influenza A(H1N1) virus is expected to present significant challenges to the entire health care system.

The challenges will be especially great for pregnant women and those who provide medical care for them.

Previous influenza pandemics have been notable for increased morbidity and mortality among pregnant women, especially during the third trimester.

In the past, all that could be offered to pregnant women was supportive care. We now have antiviral medications and will soon have a vaccine for the pandemic H1N1 virus.

We need to educate ourselves and our patients about how to use these therapeutic interventions effectively.

Source: Dr. Phillippe

The world is experiencing a diabetes pandemic, with the incidence projected to double worldwide over current levels by 2030. This extraordinary rise in the rate of diabetes worldwide has been paralleled by a similarly rapid rate of increase in the incidence of obesity. Most of the rise in diabetes rate is occurring in the type 2 category.

As a result of this pandemic in the general population, pregnant women also have a high rate of diabetes. Indeed, some clinics report that as many as 20% or more of their pregnant patients have diabetes. This presents an increasing challenge to the practitioner, especially because these patients present not only with diabetes but its associated complications for the mother and for fetal development and fetal outcome.

If there was ever a time when educating practitioners regarding contemporary methods of managing pregnant patients with diabetes is needed, it is now. Thus, we have decided to dedicate two issues of our Master Class series to the management of diabetes in pregnancy. The first installment, below, addresses how diabetes affects perinatal outcomes and how we can work to detect diabetes early and provide intensive treatment. The second installment, scheduled for the December issue, will delve into the use of oral antidiabetic agents in pregnancy.

Between the two parts of this series will be another Master Class that addresses another very challenging public health problem: the novel influenza A(H1N1) pandemic.

Both topics—diabetes in pregnancy, and influenza in pregnancy—are extremely high priority and highly contemporary, and are worthy of significant attention.

For this Master Class, I have invited Oded Langer, M.D, Ph.D., an internationally recognized expert on diabetes in pregnancy who has written and lectured extensively on this subject. Dr. Langer is the Babcock Professor and chairman of the department of obstetrics and gynecology at St. Luke's-Roosevelt Hospital Center, a university hospital of Columbia University in New York.

The world is experiencing a diabetes pandemic, with the incidence projected to double worldwide over current levels by 2030. This extraordinary rise in the rate of diabetes worldwide has been paralleled by a similarly rapid rate of increase in the incidence of obesity. Most of the rise in diabetes rate is occurring in the type 2 category.

As a result of this pandemic in the general population, pregnant women also have a high rate of diabetes. Indeed, some clinics report that as many as 20% or more of their pregnant patients have diabetes. This presents an increasing challenge to the practitioner, especially because these patients present not only with diabetes but its associated complications for the mother and for fetal development and fetal outcome.

If there was ever a time when educating practitioners regarding contemporary methods of managing pregnant patients with diabetes is needed, it is now. Thus, we have decided to dedicate two issues of our Master Class series to the management of diabetes in pregnancy. The first installment, below, addresses how diabetes affects perinatal outcomes and how we can work to detect diabetes early and provide intensive treatment. The second installment, scheduled for the December issue, will delve into the use of oral antidiabetic agents in pregnancy.

Between the two parts of this series will be another Master Class that addresses another very challenging public health problem: the novel influenza A(H1N1) pandemic.

Both topics—diabetes in pregnancy, and influenza in pregnancy—are extremely high priority and highly contemporary, and are worthy of significant attention.

For this Master Class, I have invited Oded Langer, M.D, Ph.D., an internationally recognized expert on diabetes in pregnancy who has written and lectured extensively on this subject. Dr. Langer is the Babcock Professor and chairman of the department of obstetrics and gynecology at St. Luke's-Roosevelt Hospital Center, a university hospital of Columbia University in New York.

The world is experiencing a diabetes pandemic, with the incidence projected to double worldwide over current levels by 2030. This extraordinary rise in the rate of diabetes worldwide has been paralleled by a similarly rapid rate of increase in the incidence of obesity. Most of the rise in diabetes rate is occurring in the type 2 category.

As a result of this pandemic in the general population, pregnant women also have a high rate of diabetes. Indeed, some clinics report that as many as 20% or more of their pregnant patients have diabetes. This presents an increasing challenge to the practitioner, especially because these patients present not only with diabetes but its associated complications for the mother and for fetal development and fetal outcome.

If there was ever a time when educating practitioners regarding contemporary methods of managing pregnant patients with diabetes is needed, it is now. Thus, we have decided to dedicate two issues of our Master Class series to the management of diabetes in pregnancy. The first installment, below, addresses how diabetes affects perinatal outcomes and how we can work to detect diabetes early and provide intensive treatment. The second installment, scheduled for the December issue, will delve into the use of oral antidiabetic agents in pregnancy.

Between the two parts of this series will be another Master Class that addresses another very challenging public health problem: the novel influenza A(H1N1) pandemic.

Both topics—diabetes in pregnancy, and influenza in pregnancy—are extremely high priority and highly contemporary, and are worthy of significant attention.

For this Master Class, I have invited Oded Langer, M.D, Ph.D., an internationally recognized expert on diabetes in pregnancy who has written and lectured extensively on this subject. Dr. Langer is the Babcock Professor and chairman of the department of obstetrics and gynecology at St. Luke's-Roosevelt Hospital Center, a university hospital of Columbia University in New York.

mikeross@ucla.edu

Electronic fetal monitoring lies at the crux of our efforts to assess fetal well-being and detect intrapartum fetal compromise. Yet making the most of this tool—using it meaningfully to quantify or assess fetal well-being by the heart rate tracing—has been and remains a struggle.

To understand the challenges, one only has to look at the number of groups and individuals who have proposed—and continue to propose—various systems, definitions, and recommendations for assessing fetal heart rate tracings. Finding the best assessment strategies remains a key goal in obstetrics as we work toward realizing the full potential benefits of electronic fetal monitoring.

The report issued last year by a panel convened by the National Institute of Child Health and Human Development, the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine took us a step forward by initiating a consistent nomenclature of normal, abnormal, and indeterminate fetal well-being. This three-tiered system for fetal heart rate interpretation is limited, however, in that it assesses the fetal heart rate only during a discrete window of time, and provides no discrimination as to the degree of “normal.”

We need to think more broadly as we assess fetal heart rate tracings to understand where a fetus is on the spectrum of acidosis. The overall change in fetal metabolic acidosis during labor is what best reflects the risk of hypoxemia-induced organ injury. Although it's not a perfect criterion for predicting fetal well-being, the estimated degree of fetal metabolic acidosis is a much more meaningful predictor than is an estimate of the acute oxygenation status.

When seeing any normal fetal heart rate tracing at a snapshot in time, for instance, we could be dealing with a perfectly normal fetus (that is, one with a low level of acidosis) on the one hand, or we could have a fetus that is precariously close to entering severe acidosis. An abnormal fetal heart rate tracing, similarly, is not in-and-of-itself predictive of fetal metabolic acidosis.

Knowing whether a fetus has only mild acidosis, or severe acidosis, has important implications. A fetus struck with bradycardia, for instance, will tolerate the complication much better if it has mild or no significant acidosis at the start than if it is on the precipice of shifting into severe acidosis. Knowledge of the degree of acidosis equips us to better predict and manage fetal compromise and avoid unnecessary operative deliveries.

Indeed, more research is needed to better understand the change in the level of fetal metabolic acidosis with both the progression of labor and with induced fetal heart rate changes. Yet even as we work to advance our knowledge, we have learned enough about fetal acidosis to be able to seek answers to several questions: Is what's happening to the heart rate affected by hypoxia? Does the tracing reflect the degree of acidosis? Where are we on the spectrum of acidosis?

Changes in Base Deficit

The values termed “base excess” or “base deficit” are used to quantify the magnitude of metabolic acidosis during normal stages of labor. A large positive base deficit—or a large negative base excess—indicates that the body's base buffers have been used up to buffer acids and that metabolic acidosis is present.

A base deficit of 12 mmol/L—or alternatively a base excess of −12 mmol/L—is widely accepted as the threshold for risk of acute brain injury. When we're looking at a tracing, our monitoring and management plans will differ significantly, therefore, for a fetus with a normal tracing and a base deficit of 2 mmol/L compared with a fetus who has a normal tracing and a base deficit of 8 mmol/L.

The average fetus enters labor slightly acidotic with a base deficit of approximately 2 mmol/L. During the latent phase of labor, which typically represents minimal stress, the fetus incurs no real change in base deficit. During the active phase, however, the stress of the labor causes the base deficit to increase by approximately 1 mmol/L every 3-6 hours, and during the second stage, the base deficit increases by approximately 1 mmol/L every hour. This means that by the end of the first stage of labor, the fetus has a base deficit of 4 mmol/L, on average. At the end of the second stage, the average baby is born with a base deficit of approximately 5 mmol/L.

The development of mild acidosis through the stages of normal labor is analogous to an adult walking, jogging, and then sprinting. Most of us would progressively use more oxygen than we can provide as we pick up the pace, spurring a conversion from aerobic to anaerobic metabolism that results in the production of lactic acid and consequent soreness—even aching pain—in our legs. For the fetus, the latent phase of labor is the equivalent of our walking, the active phase represents jogging, and the second stage is equivalent to a sprint.

During labor, lactic acid accumulation can lead to metabolic acidosis and a blunting of the vagal regulation of the fetal heart rate and consequent loss of accelerations, loss of variability between contractions, and other changes with possible long-term sequelae.

In monitoring labor, we want to know where we are on the spectrum of acidosis. Have we gone through the active phase, for example? Where are we in the second stage? Understanding where the fetus is on this spectrum prepares us to manage any changes—any additional acidosis related to fetal heart rate decelerations—that are superimposed on the background stress of the labor process.

Acidosis and Heart Rate Patterns

Research has confirmed not only degrees of hypoxemia and fetal base deficit values during the normal course of labor; it also has provided a window of knowledge into the changes in fetal acidosis in relation to particular fetal heart rate patterns.

Early decelerations are generally well tolerated by the fetus and probably do not result in any additional acidosis. These are believed to result from fetal head compression and a subsequent hormonal or vagal response.

Similarly, mild or moderate variable fetal heart rate decelerations, which are due to modest cord compression, are well tolerated if they occur at a reasonable frequency (such as every 3 minutes). The frequency of variable decelerations is critical as lactic acid generated during the variable deceleration may be cleared across the placenta during the periods between decelerations.

When variable heart rate decelerations are severe and of increasing frequency, however, the fetus can accumulate lactic acid—sometimes rapidly—depending on the frequency. A severe variable deceleration results from complete or near-complete umbilical cord occlusion and is typically defined as one that lasts for at least 60 seconds, during which the heart rate drops below 70 beats per minute

In a study we published this year with colleagues in Canada, we found that severe variable decelerations result in an increase in base deficit of 0.5 mmol/L per minute of cord occlusion. We also found, however, that metabolic acidosis is cleared at a rate of 0.1 mmol/L per minute of recovery, when fetal heart rate is normal and stress is reduced (Am. J. Obstet. Gynecol. 2009;200:200.e1-7).

Given these rates of acid accumulation and normalization, one can understand how acidosis may develop when repetitive, severe variable decelerations occur every 3 minutes, for instance. Past a certain frequency and severity, there simply isn't enough recovery time to allow the fetus to sufficiently correct the base deficit.

Although most of us will not actually be using these acid accumulation and recovery rates to calculate specific base deficits, an awareness of the principles can aid us in assessing fetal acidosis. The concept of recovery time is an important one. Again, knowing where your patient is on the spectrum of acidosis tells you how much “buffer time” you have if something goes wrong.

There is policy, sometimes attributed to midwives, that advocates letting the patient push only during every other contraction. Given what we've learned about the development of acidosis, when pushing is associated with severe variable decelerations, there may be an advantage to pushing every other contraction in order to permit sufficient recovery time and clearance of acid between the decelerations.

One of the signals that acidosis is progressing to a moderate level (approximately 8 mmol/L) is the change in severe variable decelerations from typical (having shoulders, a sharp drop, and a sharp rise) to atypical (a loss of shoulders, a U-shaped variable deceleration, or a slow return to baseline).

Another sign of moderate acidosis is a loss of variability between contractions. These heart rate patterns need more research, but in my experience a prolonged loss of variability between contractions (unrelated to the fetal sleep state) typically does not occur until the base deficit approaches 8 mmol/L or greater. Given that the risk of brain injury begins with a base deficit of 12 mmol/L, an observation of this change provides a buffer zone during which the patient can be even more closely monitored.

It used to be thought that late decelerations were extremely worrisome, but we have learned that these patterns are usually less threatening to the fetus's accumulation of metabolic acidosis than are severe variable decelerations.

When there is good baseline variability between the decelerations, the late deceleration often reflects a vagal-mediated response and probably involves no change in the level of acidosis. When there is a loss of variability between contractions, however, the late deceleration may reflect a hypoxia-induced response. Still, the rate of acidosis accumulation is typically less than it is with severe variable decelerations.

In general, the amount of acid accumulation with late decelerations is dependent on the frequency and severity of the decelerations; the accumulation of acidosis may range from a base deficit increase of 1 mmol/L every 5 minutes to an increase of just 1 mmol/L every 15 minutes.

One of the weak links in our understanding of fetal acidosis today is our inability to recognize preexisting acidosis or preexisting injury. We have little experience in identifying fetal heart rate patterns associated with preexisting hypoxic injuries.

Adding to the challenge is the knowledge that a post-term fetus or one with intrauterine growth restriction may begin labor with a slightly greater level of acidosis. Furthermore, fetuses with true sepsis or severe anemia may accumulate acid at an increased rate compared with normal fetuses.

Where We Stand

Practically, attempting to avoid injury by recognizing mild, moderate, and potentially severe levels of fetal acidosis means that one must carefully examine fetal heart rate tracings, not only for the time we are present in the room, but at least back to the time of our previous assessment. As much as is possible, we should understand what the entirety of the monitoring has shown.

We should attempt to factor in the known changes in fetal acidosis associated with normal stages of labor together with estimated changes in acidosis related to superimposed fetal heart rate decelerations. With an understanding of the progress and stage of labor, the current fetal heart rate pattern, and the approximate level of fetal metabolic acidosis, we will be best prepared to manage the pregnancy for an optimal outcome.

ELSEVIER GLOBAL MEDICAL NEWS

ELSEVIER GLOBAL MEDICAL NEWS

Fetal Heart Rate Monitoring

Over the years, we have endeavored to assess fetal well-being by a number of electronic and nonelectronic means with varying degrees of success. Of all these methods, fetal heart rate monitoring has withstood the test of time.

Our continued use of fetal heart rate monitoring as a means of assessing the fetus's biochemical and biophysical status has contributed much to our understanding of fetal well-being, or lack thereof. More recently, efforts have been made to better correlate variations in fetal heart rate to fetal well-being.

It is well known that the fetus is the final arbiter of intrauterine stress and may respond with compensatory mechanisms that may thwart various types of stresses. In such a scenario, the fetus may not manifest a compromised state, despite potentially harmful stress conditions. On the other hand, another fetus facing similarly stressful intrauterine conditions may struggle, exhibiting fetal distress or worse.

In reality, what matters most is the response of the fetus and not the stressful condition per se. Every attempt to monitor fetal well-being has been focused, therefore, on the response of the fetus to various types of stress. Because we're unable to conduct biochemical testing on a real-time or continuous basis, fetal heart rate monitoring often has been used as a surrogate for the biochemical adaptations by the fetus to intrauterine stress conditions.

Fetal heart rate monitoring, thus, becomes a very important diagnostic tool because the decisions that physicians make and the interventions that they undertake often are based on their interpretation of the fetal heart rate tracings. Such decisions are critical to the overall outcome of the fetus.

It is in this light that we are dedicating a Master Class to the subject of fetal acidosis and fetal heart rate assessment and have invited Dr. Michael G. Ross to serve as our guest professor this month. Dr. Ross is the chair of obstetrics and gynecology at the Harbor-UCLA Medical Center in Torrance, Calif., and professor and vice chair of obstetrics and gynecology at the David Geffen School of Medicine at the University of California, Los Angeles.

Dr. Ross's exceptional article on this topic delineates the mechanisms of fetal metabolic acidosis and its effects on fetal well-being. He also offers valuable insights on how fetal heart rate tracings might be better utilized as a powerful tool for detecting and predicting where a fetus may lie along the acidosis spectrum during various stages of labor so that interventions may be implemented to prevent severe acidosis and associated injury to the fetus.

mikeross@ucla.edu

Electronic fetal monitoring lies at the crux of our efforts to assess fetal well-being and detect intrapartum fetal compromise. Yet making the most of this tool—using it meaningfully to quantify or assess fetal well-being by the heart rate tracing—has been and remains a struggle.

To understand the challenges, one only has to look at the number of groups and individuals who have proposed—and continue to propose—various systems, definitions, and recommendations for assessing fetal heart rate tracings. Finding the best assessment strategies remains a key goal in obstetrics as we work toward realizing the full potential benefits of electronic fetal monitoring.

The report issued last year by a panel convened by the National Institute of Child Health and Human Development, the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine took us a step forward by initiating a consistent nomenclature of normal, abnormal, and indeterminate fetal well-being. This three-tiered system for fetal heart rate interpretation is limited, however, in that it assesses the fetal heart rate only during a discrete window of time, and provides no discrimination as to the degree of “normal.”

We need to think more broadly as we assess fetal heart rate tracings to understand where a fetus is on the spectrum of acidosis. The overall change in fetal metabolic acidosis during labor is what best reflects the risk of hypoxemia-induced organ injury. Although it's not a perfect criterion for predicting fetal well-being, the estimated degree of fetal metabolic acidosis is a much more meaningful predictor than is an estimate of the acute oxygenation status.

When seeing any normal fetal heart rate tracing at a snapshot in time, for instance, we could be dealing with a perfectly normal fetus (that is, one with a low level of acidosis) on the one hand, or we could have a fetus that is precariously close to entering severe acidosis. An abnormal fetal heart rate tracing, similarly, is not in-and-of-itself predictive of fetal metabolic acidosis.

Knowing whether a fetus has only mild acidosis, or severe acidosis, has important implications. A fetus struck with bradycardia, for instance, will tolerate the complication much better if it has mild or no significant acidosis at the start than if it is on the precipice of shifting into severe acidosis. Knowledge of the degree of acidosis equips us to better predict and manage fetal compromise and avoid unnecessary operative deliveries.

Indeed, more research is needed to better understand the change in the level of fetal metabolic acidosis with both the progression of labor and with induced fetal heart rate changes. Yet even as we work to advance our knowledge, we have learned enough about fetal acidosis to be able to seek answers to several questions: Is what's happening to the heart rate affected by hypoxia? Does the tracing reflect the degree of acidosis? Where are we on the spectrum of acidosis?

Changes in Base Deficit

The values termed “base excess” or “base deficit” are used to quantify the magnitude of metabolic acidosis during normal stages of labor. A large positive base deficit—or a large negative base excess—indicates that the body's base buffers have been used up to buffer acids and that metabolic acidosis is present.

A base deficit of 12 mmol/L—or alternatively a base excess of −12 mmol/L—is widely accepted as the threshold for risk of acute brain injury. When we're looking at a tracing, our monitoring and management plans will differ significantly, therefore, for a fetus with a normal tracing and a base deficit of 2 mmol/L compared with a fetus who has a normal tracing and a base deficit of 8 mmol/L.

The average fetus enters labor slightly acidotic with a base deficit of approximately 2 mmol/L. During the latent phase of labor, which typically represents minimal stress, the fetus incurs no real change in base deficit. During the active phase, however, the stress of the labor causes the base deficit to increase by approximately 1 mmol/L every 3-6 hours, and during the second stage, the base deficit increases by approximately 1 mmol/L every hour. This means that by the end of the first stage of labor, the fetus has a base deficit of 4 mmol/L, on average. At the end of the second stage, the average baby is born with a base deficit of approximately 5 mmol/L.

The development of mild acidosis through the stages of normal labor is analogous to an adult walking, jogging, and then sprinting. Most of us would progressively use more oxygen than we can provide as we pick up the pace, spurring a conversion from aerobic to anaerobic metabolism that results in the production of lactic acid and consequent soreness—even aching pain—in our legs. For the fetus, the latent phase of labor is the equivalent of our walking, the active phase represents jogging, and the second stage is equivalent to a sprint.

During labor, lactic acid accumulation can lead to metabolic acidosis and a blunting of the vagal regulation of the fetal heart rate and consequent loss of accelerations, loss of variability between contractions, and other changes with possible long-term sequelae.

In monitoring labor, we want to know where we are on the spectrum of acidosis. Have we gone through the active phase, for example? Where are we in the second stage? Understanding where the fetus is on this spectrum prepares us to manage any changes—any additional acidosis related to fetal heart rate decelerations—that are superimposed on the background stress of the labor process.

Acidosis and Heart Rate Patterns

Research has confirmed not only degrees of hypoxemia and fetal base deficit values during the normal course of labor; it also has provided a window of knowledge into the changes in fetal acidosis in relation to particular fetal heart rate patterns.

Early decelerations are generally well tolerated by the fetus and probably do not result in any additional acidosis. These are believed to result from fetal head compression and a subsequent hormonal or vagal response.

Similarly, mild or moderate variable fetal heart rate decelerations, which are due to modest cord compression, are well tolerated if they occur at a reasonable frequency (such as every 3 minutes). The frequency of variable decelerations is critical as lactic acid generated during the variable deceleration may be cleared across the placenta during the periods between decelerations.

When variable heart rate decelerations are severe and of increasing frequency, however, the fetus can accumulate lactic acid—sometimes rapidly—depending on the frequency. A severe variable deceleration results from complete or near-complete umbilical cord occlusion and is typically defined as one that lasts for at least 60 seconds, during which the heart rate drops below 70 beats per minute

In a study we published this year with colleagues in Canada, we found that severe variable decelerations result in an increase in base deficit of 0.5 mmol/L per minute of cord occlusion. We also found, however, that metabolic acidosis is cleared at a rate of 0.1 mmol/L per minute of recovery, when fetal heart rate is normal and stress is reduced (Am. J. Obstet. Gynecol. 2009;200:200.e1-7).

Given these rates of acid accumulation and normalization, one can understand how acidosis may develop when repetitive, severe variable decelerations occur every 3 minutes, for instance. Past a certain frequency and severity, there simply isn't enough recovery time to allow the fetus to sufficiently correct the base deficit.

Although most of us will not actually be using these acid accumulation and recovery rates to calculate specific base deficits, an awareness of the principles can aid us in assessing fetal acidosis. The concept of recovery time is an important one. Again, knowing where your patient is on the spectrum of acidosis tells you how much “buffer time” you have if something goes wrong.

There is policy, sometimes attributed to midwives, that advocates letting the patient push only during every other contraction. Given what we've learned about the development of acidosis, when pushing is associated with severe variable decelerations, there may be an advantage to pushing every other contraction in order to permit sufficient recovery time and clearance of acid between the decelerations.

One of the signals that acidosis is progressing to a moderate level (approximately 8 mmol/L) is the change in severe variable decelerations from typical (having shoulders, a sharp drop, and a sharp rise) to atypical (a loss of shoulders, a U-shaped variable deceleration, or a slow return to baseline).

Another sign of moderate acidosis is a loss of variability between contractions. These heart rate patterns need more research, but in my experience a prolonged loss of variability between contractions (unrelated to the fetal sleep state) typically does not occur until the base deficit approaches 8 mmol/L or greater. Given that the risk of brain injury begins with a base deficit of 12 mmol/L, an observation of this change provides a buffer zone during which the patient can be even more closely monitored.

It used to be thought that late decelerations were extremely worrisome, but we have learned that these patterns are usually less threatening to the fetus's accumulation of metabolic acidosis than are severe variable decelerations.

When there is good baseline variability between the decelerations, the late deceleration often reflects a vagal-mediated response and probably involves no change in the level of acidosis. When there is a loss of variability between contractions, however, the late deceleration may reflect a hypoxia-induced response. Still, the rate of acidosis accumulation is typically less than it is with severe variable decelerations.

In general, the amount of acid accumulation with late decelerations is dependent on the frequency and severity of the decelerations; the accumulation of acidosis may range from a base deficit increase of 1 mmol/L every 5 minutes to an increase of just 1 mmol/L every 15 minutes.

One of the weak links in our understanding of fetal acidosis today is our inability to recognize preexisting acidosis or preexisting injury. We have little experience in identifying fetal heart rate patterns associated with preexisting hypoxic injuries.

Adding to the challenge is the knowledge that a post-term fetus or one with intrauterine growth restriction may begin labor with a slightly greater level of acidosis. Furthermore, fetuses with true sepsis or severe anemia may accumulate acid at an increased rate compared with normal fetuses.

Where We Stand

Practically, attempting to avoid injury by recognizing mild, moderate, and potentially severe levels of fetal acidosis means that one must carefully examine fetal heart rate tracings, not only for the time we are present in the room, but at least back to the time of our previous assessment. As much as is possible, we should understand what the entirety of the monitoring has shown.

We should attempt to factor in the known changes in fetal acidosis associated with normal stages of labor together with estimated changes in acidosis related to superimposed fetal heart rate decelerations. With an understanding of the progress and stage of labor, the current fetal heart rate pattern, and the approximate level of fetal metabolic acidosis, we will be best prepared to manage the pregnancy for an optimal outcome.

ELSEVIER GLOBAL MEDICAL NEWS

ELSEVIER GLOBAL MEDICAL NEWS

Fetal Heart Rate Monitoring

Over the years, we have endeavored to assess fetal well-being by a number of electronic and nonelectronic means with varying degrees of success. Of all these methods, fetal heart rate monitoring has withstood the test of time.

Our continued use of fetal heart rate monitoring as a means of assessing the fetus's biochemical and biophysical status has contributed much to our understanding of fetal well-being, or lack thereof. More recently, efforts have been made to better correlate variations in fetal heart rate to fetal well-being.

It is well known that the fetus is the final arbiter of intrauterine stress and may respond with compensatory mechanisms that may thwart various types of stresses. In such a scenario, the fetus may not manifest a compromised state, despite potentially harmful stress conditions. On the other hand, another fetus facing similarly stressful intrauterine conditions may struggle, exhibiting fetal distress or worse.

In reality, what matters most is the response of the fetus and not the stressful condition per se. Every attempt to monitor fetal well-being has been focused, therefore, on the response of the fetus to various types of stress. Because we're unable to conduct biochemical testing on a real-time or continuous basis, fetal heart rate monitoring often has been used as a surrogate for the biochemical adaptations by the fetus to intrauterine stress conditions.

Fetal heart rate monitoring, thus, becomes a very important diagnostic tool because the decisions that physicians make and the interventions that they undertake often are based on their interpretation of the fetal heart rate tracings. Such decisions are critical to the overall outcome of the fetus.

It is in this light that we are dedicating a Master Class to the subject of fetal acidosis and fetal heart rate assessment and have invited Dr. Michael G. Ross to serve as our guest professor this month. Dr. Ross is the chair of obstetrics and gynecology at the Harbor-UCLA Medical Center in Torrance, Calif., and professor and vice chair of obstetrics and gynecology at the David Geffen School of Medicine at the University of California, Los Angeles.

Dr. Ross's exceptional article on this topic delineates the mechanisms of fetal metabolic acidosis and its effects on fetal well-being. He also offers valuable insights on how fetal heart rate tracings might be better utilized as a powerful tool for detecting and predicting where a fetus may lie along the acidosis spectrum during various stages of labor so that interventions may be implemented to prevent severe acidosis and associated injury to the fetus.

mikeross@ucla.edu

Electronic fetal monitoring lies at the crux of our efforts to assess fetal well-being and detect intrapartum fetal compromise. Yet making the most of this tool—using it meaningfully to quantify or assess fetal well-being by the heart rate tracing—has been and remains a struggle.

To understand the challenges, one only has to look at the number of groups and individuals who have proposed—and continue to propose—various systems, definitions, and recommendations for assessing fetal heart rate tracings. Finding the best assessment strategies remains a key goal in obstetrics as we work toward realizing the full potential benefits of electronic fetal monitoring.

The report issued last year by a panel convened by the National Institute of Child Health and Human Development, the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine took us a step forward by initiating a consistent nomenclature of normal, abnormal, and indeterminate fetal well-being. This three-tiered system for fetal heart rate interpretation is limited, however, in that it assesses the fetal heart rate only during a discrete window of time, and provides no discrimination as to the degree of “normal.”

We need to think more broadly as we assess fetal heart rate tracings to understand where a fetus is on the spectrum of acidosis. The overall change in fetal metabolic acidosis during labor is what best reflects the risk of hypoxemia-induced organ injury. Although it's not a perfect criterion for predicting fetal well-being, the estimated degree of fetal metabolic acidosis is a much more meaningful predictor than is an estimate of the acute oxygenation status.

When seeing any normal fetal heart rate tracing at a snapshot in time, for instance, we could be dealing with a perfectly normal fetus (that is, one with a low level of acidosis) on the one hand, or we could have a fetus that is precariously close to entering severe acidosis. An abnormal fetal heart rate tracing, similarly, is not in-and-of-itself predictive of fetal metabolic acidosis.

Knowing whether a fetus has only mild acidosis, or severe acidosis, has important implications. A fetus struck with bradycardia, for instance, will tolerate the complication much better if it has mild or no significant acidosis at the start than if it is on the precipice of shifting into severe acidosis. Knowledge of the degree of acidosis equips us to better predict and manage fetal compromise and avoid unnecessary operative deliveries.

Indeed, more research is needed to better understand the change in the level of fetal metabolic acidosis with both the progression of labor and with induced fetal heart rate changes. Yet even as we work to advance our knowledge, we have learned enough about fetal acidosis to be able to seek answers to several questions: Is what's happening to the heart rate affected by hypoxia? Does the tracing reflect the degree of acidosis? Where are we on the spectrum of acidosis?

Changes in Base Deficit

The values termed “base excess” or “base deficit” are used to quantify the magnitude of metabolic acidosis during normal stages of labor. A large positive base deficit—or a large negative base excess—indicates that the body's base buffers have been used up to buffer acids and that metabolic acidosis is present.

A base deficit of 12 mmol/L—or alternatively a base excess of −12 mmol/L—is widely accepted as the threshold for risk of acute brain injury. When we're looking at a tracing, our monitoring and management plans will differ significantly, therefore, for a fetus with a normal tracing and a base deficit of 2 mmol/L compared with a fetus who has a normal tracing and a base deficit of 8 mmol/L.

The average fetus enters labor slightly acidotic with a base deficit of approximately 2 mmol/L. During the latent phase of labor, which typically represents minimal stress, the fetus incurs no real change in base deficit. During the active phase, however, the stress of the labor causes the base deficit to increase by approximately 1 mmol/L every 3-6 hours, and during the second stage, the base deficit increases by approximately 1 mmol/L every hour. This means that by the end of the first stage of labor, the fetus has a base deficit of 4 mmol/L, on average. At the end of the second stage, the average baby is born with a base deficit of approximately 5 mmol/L.

The development of mild acidosis through the stages of normal labor is analogous to an adult walking, jogging, and then sprinting. Most of us would progressively use more oxygen than we can provide as we pick up the pace, spurring a conversion from aerobic to anaerobic metabolism that results in the production of lactic acid and consequent soreness—even aching pain—in our legs. For the fetus, the latent phase of labor is the equivalent of our walking, the active phase represents jogging, and the second stage is equivalent to a sprint.

During labor, lactic acid accumulation can lead to metabolic acidosis and a blunting of the vagal regulation of the fetal heart rate and consequent loss of accelerations, loss of variability between contractions, and other changes with possible long-term sequelae.

In monitoring labor, we want to know where we are on the spectrum of acidosis. Have we gone through the active phase, for example? Where are we in the second stage? Understanding where the fetus is on this spectrum prepares us to manage any changes—any additional acidosis related to fetal heart rate decelerations—that are superimposed on the background stress of the labor process.

Acidosis and Heart Rate Patterns

Research has confirmed not only degrees of hypoxemia and fetal base deficit values during the normal course of labor; it also has provided a window of knowledge into the changes in fetal acidosis in relation to particular fetal heart rate patterns.

Early decelerations are generally well tolerated by the fetus and probably do not result in any additional acidosis. These are believed to result from fetal head compression and a subsequent hormonal or vagal response.

Similarly, mild or moderate variable fetal heart rate decelerations, which are due to modest cord compression, are well tolerated if they occur at a reasonable frequency (such as every 3 minutes). The frequency of variable decelerations is critical as lactic acid generated during the variable deceleration may be cleared across the placenta during the periods between decelerations.

When variable heart rate decelerations are severe and of increasing frequency, however, the fetus can accumulate lactic acid—sometimes rapidly—depending on the frequency. A severe variable deceleration results from complete or near-complete umbilical cord occlusion and is typically defined as one that lasts for at least 60 seconds, during which the heart rate drops below 70 beats per minute

In a study we published this year with colleagues in Canada, we found that severe variable decelerations result in an increase in base deficit of 0.5 mmol/L per minute of cord occlusion. We also found, however, that metabolic acidosis is cleared at a rate of 0.1 mmol/L per minute of recovery, when fetal heart rate is normal and stress is reduced (Am. J. Obstet. Gynecol. 2009;200:200.e1-7).

Given these rates of acid accumulation and normalization, one can understand how acidosis may develop when repetitive, severe variable decelerations occur every 3 minutes, for instance. Past a certain frequency and severity, there simply isn't enough recovery time to allow the fetus to sufficiently correct the base deficit.

Although most of us will not actually be using these acid accumulation and recovery rates to calculate specific base deficits, an awareness of the principles can aid us in assessing fetal acidosis. The concept of recovery time is an important one. Again, knowing where your patient is on the spectrum of acidosis tells you how much “buffer time” you have if something goes wrong.

There is policy, sometimes attributed to midwives, that advocates letting the patient push only during every other contraction. Given what we've learned about the development of acidosis, when pushing is associated with severe variable decelerations, there may be an advantage to pushing every other contraction in order to permit sufficient recovery time and clearance of acid between the decelerations.

One of the signals that acidosis is progressing to a moderate level (approximately 8 mmol/L) is the change in severe variable decelerations from typical (having shoulders, a sharp drop, and a sharp rise) to atypical (a loss of shoulders, a U-shaped variable deceleration, or a slow return to baseline).

Another sign of moderate acidosis is a loss of variability between contractions. These heart rate patterns need more research, but in my experience a prolonged loss of variability between contractions (unrelated to the fetal sleep state) typically does not occur until the base deficit approaches 8 mmol/L or greater. Given that the risk of brain injury begins with a base deficit of 12 mmol/L, an observation of this change provides a buffer zone during which the patient can be even more closely monitored.

It used to be thought that late decelerations were extremely worrisome, but we have learned that these patterns are usually less threatening to the fetus's accumulation of metabolic acidosis than are severe variable decelerations.

When there is good baseline variability between the decelerations, the late deceleration often reflects a vagal-mediated response and probably involves no change in the level of acidosis. When there is a loss of variability between contractions, however, the late deceleration may reflect a hypoxia-induced response. Still, the rate of acidosis accumulation is typically less than it is with severe variable decelerations.

In general, the amount of acid accumulation with late decelerations is dependent on the frequency and severity of the decelerations; the accumulation of acidosis may range from a base deficit increase of 1 mmol/L every 5 minutes to an increase of just 1 mmol/L every 15 minutes.

One of the weak links in our understanding of fetal acidosis today is our inability to recognize preexisting acidosis or preexisting injury. We have little experience in identifying fetal heart rate patterns associated with preexisting hypoxic injuries.

Adding to the challenge is the knowledge that a post-term fetus or one with intrauterine growth restriction may begin labor with a slightly greater level of acidosis. Furthermore, fetuses with true sepsis or severe anemia may accumulate acid at an increased rate compared with normal fetuses.

Where We Stand

Practically, attempting to avoid injury by recognizing mild, moderate, and potentially severe levels of fetal acidosis means that one must carefully examine fetal heart rate tracings, not only for the time we are present in the room, but at least back to the time of our previous assessment. As much as is possible, we should understand what the entirety of the monitoring has shown.

We should attempt to factor in the known changes in fetal acidosis associated with normal stages of labor together with estimated changes in acidosis related to superimposed fetal heart rate decelerations. With an understanding of the progress and stage of labor, the current fetal heart rate pattern, and the approximate level of fetal metabolic acidosis, we will be best prepared to manage the pregnancy for an optimal outcome.

ELSEVIER GLOBAL MEDICAL NEWS

ELSEVIER GLOBAL MEDICAL NEWS

Fetal Heart Rate Monitoring

Over the years, we have endeavored to assess fetal well-being by a number of electronic and nonelectronic means with varying degrees of success. Of all these methods, fetal heart rate monitoring has withstood the test of time.

Our continued use of fetal heart rate monitoring as a means of assessing the fetus's biochemical and biophysical status has contributed much to our understanding of fetal well-being, or lack thereof. More recently, efforts have been made to better correlate variations in fetal heart rate to fetal well-being.

It is well known that the fetus is the final arbiter of intrauterine stress and may respond with compensatory mechanisms that may thwart various types of stresses. In such a scenario, the fetus may not manifest a compromised state, despite potentially harmful stress conditions. On the other hand, another fetus facing similarly stressful intrauterine conditions may struggle, exhibiting fetal distress or worse.

In reality, what matters most is the response of the fetus and not the stressful condition per se. Every attempt to monitor fetal well-being has been focused, therefore, on the response of the fetus to various types of stress. Because we're unable to conduct biochemical testing on a real-time or continuous basis, fetal heart rate monitoring often has been used as a surrogate for the biochemical adaptations by the fetus to intrauterine stress conditions.

Fetal heart rate monitoring, thus, becomes a very important diagnostic tool because the decisions that physicians make and the interventions that they undertake often are based on their interpretation of the fetal heart rate tracings. Such decisions are critical to the overall outcome of the fetus.

It is in this light that we are dedicating a Master Class to the subject of fetal acidosis and fetal heart rate assessment and have invited Dr. Michael G. Ross to serve as our guest professor this month. Dr. Ross is the chair of obstetrics and gynecology at the Harbor-UCLA Medical Center in Torrance, Calif., and professor and vice chair of obstetrics and gynecology at the David Geffen School of Medicine at the University of California, Los Angeles.

Dr. Ross's exceptional article on this topic delineates the mechanisms of fetal metabolic acidosis and its effects on fetal well-being. He also offers valuable insights on how fetal heart rate tracings might be better utilized as a powerful tool for detecting and predicting where a fetus may lie along the acidosis spectrum during various stages of labor so that interventions may be implemented to prevent severe acidosis and associated injury to the fetus.

We now know enough about the development and potential complications associated with monochorionic twin pregnancies that the term “twin pregnancy” is no longer precise enough to be used as a medical term. We must distinguish between monochorionic and dichorionic twins.

Monochorionic twin pregnancies have unique features that substantially increase the risk of fetal death, growth restriction, and other complications. The twins share a single placenta, and their circulations are essentially linked to each other through their placental anastomoses. These linked circulations allow blood to be redirected—sometimes very rapidly—toward one twin or the other. This is not typically the case in dichorionic pregnancies.

Thus, we must always take both fetuses in a monochorionic twin pregnancy into consideration, because when one fetus is in jeopardy, the other typically is as well. This interdependency is fundamentally different from the less-entwined relationship of dichorionic twins, and makes monitoring more complicated and all the more important.

We must make the distinction between monochorionic and dichorionic twins early on—optimally, in the first trimester. With the opportunity to make this critical distinction—as well as improvements in fetal therapy and advances in ultrasound assessment that allow us to detect potential problems early—we can lay the foundation for the effective, proactive management of these at-risk pregnancies from the first trimester on.

Once the diagnosis of chorionicity is made, medical reports should specify the type of twin pregnancy that is present, rather than using what should now be considered the layman's term “twin pregnancy.”

The Potential Risks

The potential risks of monochorionic pregnancies stem from:

▸ Unequal placenta sharing. In an ideal world, the twins' single placenta is equally shared. However, it is often the case that one twin will have just 30%–40% of the monochorionic placenta, while the other fetus has the much larger portion. Such unequal placenta sharing leads to an unequal sharing of nutrients, which can lead to growth restriction and severe low birth weight in one of the fetuses.

This type of growth restriction—known as selective intrauterine growth restriction (IUGR)—affects about 10% of all identical twins. It happens quite early in pregnancy and, as we know from singleton growth-restricted fetuses, can lead to a host of troubling complications.

That is why the fetuses in a monochorionic pregnancy can never be treated in isolation. With the early onset of growth restriction in a monochorionic pregnancy, for example, the twin with this complication faces a higher risk of in utero death—an outcome that always negatively impacts the other fetus as well.

In a dichorionic pregnancy, if a co-twin weighs 320 g at 26 weeks and is at high risk of in utero death, we typically would advise the parents to delay delivery. The extremely high likelihood of fetal death of the growth-restricted twin would not justify exposing the otherwise normally grown healthy twin to the risks of prematurity. Accepting the fetal death of the growth-restricted twin and allowing pregnancy to continue gives the larger fetus a very good chance of being healthy at birth rather than being born premature with a significant risk of prematurity-related complications.

However, in a monochorionic pregnancy, intrauterine demise of the smaller fetus could put the healthy co-twin at a significant risk for acute severe hemorrhage into the placenta and circulation of the growth-restricted twin. This carries the risk of brain, renal, and cardiac damage—or even death—of the co-twin. The option of delaying delivery beyond the point of demise of the smaller twin, therefore, is unacceptable in this setting.

Rather, the fetuses would need intensive monitoring by experts who are alert to all the potential signs of fetal deterioration. Additional options, including fetal therapy, might require even more subspecialty evaluation.

▸ Unequal blood volume. Blood volume also may be unequally shared. In uncomplicated pregnancies, blood is exchanged equally through the vascular anastomoses that characterize all monochorionic pregnancies. Sometimes, however, the exchange is unbalanced and blood is shunted in one direction without adequate return.

Anastomoses that are between artery and vein act as one-way valves and can lead to significant differences in volume. Artery-to-artery and vein-to-vein connections allow direct exchange in either direction, with the direction of blood flow determined by the difference in blood pressure on either side.

If one fetus develops an unstable circulation or dies, the instability or resultant drop in blood pressure causes the healthy or surviving twin to lose a large amount of blood volume across the connecting vessels and into the sick or dying twin. This is why, when one fetus dies, the risk of death for the co-twin can be as high as 60%. It also explains why a surviving co-twin has a significant risk of brain injury.

The intertwin anastomoses account for a range of other pregnancy complications. When placenta sharing is equal but there is a significant mismatch in blood flow and blood volume, twin-to-twin syndrome (TTTS) can develop. In this scenario, the imbalance progresses to the extent that one twin becomes a “donor” of blood volume and the other twin becomes the “recipient.”

A decline in blood volume for the donor twin leads to decreased urine output to the extent that bladder filling virtually ceases and oligohydramnios may progress to anhydramnios. The recipient twin, in the meantime, urinates excessively, leading to polyhydramnios and possibly preterm labor.

TTTS develops in about 10%–15% of monochorionic pregnancies. Overall, however—if you add the approximately 10% that are affected by selective IUGR, and an unknown percentage of pregnancies that may have a bit of both problems or are complicated in other ways to this 10%–15%—I estimate that as many as one-third of monochorionic twins have some kind of significant complication.

For TTTS, endoscopic laser ablation (or laser coagulation) of placental anastomoses has been shown to be an effective treatment and a preferable first-line approach for severe cases diagnosed before 26 weeks. These therapies, however, are available only at specialized centers—a fact that adds to the value of early diagnosis of chorionicity and prospective monitoring for complications.

The Need for Early Diagnosis

We cannot attempt to alleviate complications and improve survival unless a diagnosis of monochorionicity is made early. The diagnosis of chorionicity certainly is more difficult in the second trimester.

However, if a patient has not had a first-trimester scan, a diagnosis should still be attempted.

Monochorionic twin pregnancies remain largely unpredictable. At 12 weeks' gestation, however, if we have diagnosed identical twins, there are several ultrasound parameters we can measure to begin to predict how the pregnancy will proceed and what fetal complications might develop.

Some studies have shown, for instance, that a discrepancy in nuchal translucency between the co-twins of more than 60% means that there is a 60%–70% chance that TTTS will develop.

There also may be some discrepancies in size of other structures that are apparent in the first trimester, such as differences in abdominal circumference, for example, as well as differences in amniotic fluid volume, or bladder size that might be helpful in planning fetal surveillance.

After initial evaluation, we generally recommend that monochorionic twins be evaluated again at 16 weeks, based on research by Dr. Liesbeth Lewi of the University Hospitals in Leuven, Belgium, showing that a combined risk assessment in the first trimester and at 16 weeks can predict selective IUGR or TTTS with greater than 80% accuracy.

In a study of 200 monochorionic diamniotic twin pregnancies, Dr. Lewi found that significant predictors of TTTS, selective IUGR, or intrauterine death in the first trimester were crown-rump length and discordant amniotic fluid volume. At 16 weeks, significant predictors were the differences between the co-twins in abdominal circumference, amniotic fluid volume, and the site of cord insertions. [The site of cord insertion was classified as velamentous, eccentric (more than 2 cm from the placental edge), or marginal (less than 2 cm from the placental edge), and a discordant cord insertion was considered to be the combination of a velamentous cord insertion in one fetus and an eccentric cord insertion in the other fetus.]

The differences between the co-twins in the ultrasound parameters were additive when measured in the first trimester and at 16 weeks. Combined risk assessment detected 58% of the fetal complications by classifying 21% of the 200 pregnancies as high risk, with a false-positive rate of 8%, while the predictive value of one assessment alone was significantly lower (Am. J. Obstet. Gynecol. 2008;199:493.e1–7).

Dr. Lewi's research was among the literature considered recently by a panel of experts assembled by the North American Fetal Therapy Network. The panel has been working on a consensus statement that, when finalized, will make recommendations for early diagnosis of monochorionicity and basic combined risk assessment.

Doppler ultrasound (US) measurements of the umbilical arteries, which depict resistance in the blood vessels and resultant blood flow, also may be helpful. Just as with singleton pregnancies, Doppler US provides information in the monochorionic pregnancy about the vasculature of the placenta and the amount of placenta the fetuses have available for nutrient exchange.

In monochorionic pregnancies, however, Doppler US has the added benefit of being key to diagnosing and evaluating hemodynamically significant arterio-arterial anastomoses that induce variations in diastolic velocity not seen in singleton pregnancies.

The imbalance in blood flow exchange between the co-twins' circulations—again, the primary contributor to the development of TTTS—also can be examined using Doppler assessments of two additional vascular beds: the middle cerebral artery (MCA) and the ductus venosus.

The MCA peak systolic velocity reflects how fast blood is flowing in the brain. Large differences in the MCA can point to TTTS. The ductus venosus, a unique fetal vessel that funnels a proportion of nutrient-rich umbilical venous return directly into the right atrium, similarly can be used to evaluate cardiac status. Doppler screening of the ductus venosus and MCA has its most useful role early in pregnancy.

Again, because most of the amniotic fluid from 16 weeks on is due to fetal urination, and because changes in urine output reflect changes in blood volume status, the assessment of bladder filling and amniotic fluid volume reveals much about blood volume status and possible TTTS.

Whenever we see a monochorionic twin pregnancy, therefore, we face a range of questions: What are the sizes of the fetuses? Is there a discrepancy? What is the ultrasound end-diastolic velocity in each twin? Is it normal? Or, is there variability in the waveform, which is indicative of hemodynamically significant arterio-arterial anastomoses? Is the amniotic fluid volume normal? What do the bladders look like? Does one fetus have a bladder that's barely filling?

By regularly asking these questions—and using the pregnancy as its own control—we will be alert to the potential problems associated with monochorionicity and more able to proactively plan our monitoring schedules.

A new discrepancy or a change from a previous exam might mean seeing the patient weekly as opposed to every 2 or 3 weeks.

Frequent monitoring is prudent throughout pregnancy as severe TTTS can develop until 22–23 weeks' gestation, even when findings are normal at 18 weeks.

Moreover, milder forms of TTTS, as well as milder forms of selective IUGR, can develop even later.

Umbilical artery Doppler shows significant variation in end-diastolic velocity from positive/absent to markedly reversed, as well as scalloping of the waveform. This indicates the presence of hemodynamically significant arterio-arterial anastomoses.

At left, the presence of chorionic tissue between the layers of amnion from the two sacs produces a “Lambda” sign (circle) that indicates a dichorionic diamniotic pregnancy. At right, the absence of this sign (arrow) indicates monochorionic placentation.

The fetus on the left has a larger abdominal circumference and a higher maximum vertical amniotic fluid pocket, which can point to unequal placenta sharing and/or unequal blood volume and requires follow-up evaluation. Images courtesy Dr. Ahmet A. Baschat

The Complexity of Multiple Gestation

Multiple gestation is an obstetric condition that confronts every obstetrician at some point. Twin pregnancies, for one, are quite frequent, occurring in 3.2% of all pregnancies. Because of this frequency, it is important that we spend some time reviewing the various presentations of twin pregnancies as well as the potential complications.

Twin pregnancies are not a monolithic condition. As we know, twin pregnancies can present in a two-placenta double-membrane sac (dichorionic diamniotic), in a single-placenta double-membrane sac (monochorionic diamniotic), or in some version thereof.

The clinical presentation of twin pregnancies and the potential complications will vary widely, making it of utmost importance to diagnose chorionicity early on. The simple term “twin pregnancy” is not, as our guest author says, a term that is precise enough, in and of itself, to ensure optimal management. A distinction between monochorionic and dichorionic twins must be made.

The complications that are of greatest concern in monochorionic pregnancies involve the anastomoses between the twins' two vasculatures.

In uncomplicated pregnancies, blood is exchanged equally through these anastomoses.

In some pregnancies, however, blood flow becomes unbalanced to the extent that one or both fetuses are compromised.

The management options for complications such as twin-to-twin transfusion syndrome (TTTS) have traditionally been quite limited.

Until recently, management for TTTS involved observation or the removal of excess amniotic fluid.

More recently, however, surgical interventions have been employed with variable success.

Although every obstetrician may not possess the mastery of fetal surgery in these conditions, it is important that all obstetricians nevertheless understand the options that are available and be able to make accurate diagnoses, offer appropriate counseling, and make referrals if appropriate.

Thus, I believe the focus of this Master Class—monochorionicity, its features, and the facets of good management—will be of significant value to the clinician.

We have invited Dr. Ahmet A. Baschat of the department of obstetrics, gynecology, and reproductive sciences at the University of Maryland, Baltimore, to be our guest professor this month. Dr. Baschat is a recognized national expert in fetal therapy, including various intrauterine surgical procedures.

Key Points

▸ Making an accurate diagnosis of chorionicity early in a twin pregnancy is crucial for the prospective management of potential complications. This is because monochorionic twins have unique features that can lead to unequal placenta sharing and unequal blood volume, increasing the risk of fetal death, growth restriction, and other complications. Early in the first trimester is the optimal time to verify chorionicity.

▸ Estimating fetal growth by measuring head diameter, abdominal circumference, and femur length is an important aspect of assessing placenta sharing and the availability of nutrients. The abdominal circumference is the single best measurement of fetal nutrient status; a discrepancy at 16 weeks increases the risk for subsequent complications.

▸ Evaluating bladder filling in combination with amniotic fluid volume is an important element of estimating fetal blood volume status.

▸ Research shows that a combined risk assessment in the first trimester and at 16 weeks can predict selective intrauterine growth restriction and twin-to-twin transfusion syndrome—two of the major complications of monochorionic pregnancies—with greater than 80% accuracy.

▸ Doppler ultrasound of the umbilical artery is important for assessing placenta sharing and the presence of hemodynamically significant arterio-arterial anastomoses.

We now know enough about the development and potential complications associated with monochorionic twin pregnancies that the term “twin pregnancy” is no longer precise enough to be used as a medical term. We must distinguish between monochorionic and dichorionic twins.

Monochorionic twin pregnancies have unique features that substantially increase the risk of fetal death, growth restriction, and other complications. The twins share a single placenta, and their circulations are essentially linked to each other through their placental anastomoses. These linked circulations allow blood to be redirected—sometimes very rapidly—toward one twin or the other. This is not typically the case in dichorionic pregnancies.

Thus, we must always take both fetuses in a monochorionic twin pregnancy into consideration, because when one fetus is in jeopardy, the other typically is as well. This interdependency is fundamentally different from the less-entwined relationship of dichorionic twins, and makes monitoring more complicated and all the more important.

We must make the distinction between monochorionic and dichorionic twins early on—optimally, in the first trimester. With the opportunity to make this critical distinction—as well as improvements in fetal therapy and advances in ultrasound assessment that allow us to detect potential problems early—we can lay the foundation for the effective, proactive management of these at-risk pregnancies from the first trimester on.

Once the diagnosis of chorionicity is made, medical reports should specify the type of twin pregnancy that is present, rather than using what should now be considered the layman's term “twin pregnancy.”

The Potential Risks

The potential risks of monochorionic pregnancies stem from:

▸ Unequal placenta sharing. In an ideal world, the twins' single placenta is equally shared. However, it is often the case that one twin will have just 30%–40% of the monochorionic placenta, while the other fetus has the much larger portion. Such unequal placenta sharing leads to an unequal sharing of nutrients, which can lead to growth restriction and severe low birth weight in one of the fetuses.

This type of growth restriction—known as selective intrauterine growth restriction (IUGR)—affects about 10% of all identical twins. It happens quite early in pregnancy and, as we know from singleton growth-restricted fetuses, can lead to a host of troubling complications.

That is why the fetuses in a monochorionic pregnancy can never be treated in isolation. With the early onset of growth restriction in a monochorionic pregnancy, for example, the twin with this complication faces a higher risk of in utero death—an outcome that always negatively impacts the other fetus as well.

In a dichorionic pregnancy, if a co-twin weighs 320 g at 26 weeks and is at high risk of in utero death, we typically would advise the parents to delay delivery. The extremely high likelihood of fetal death of the growth-restricted twin would not justify exposing the otherwise normally grown healthy twin to the risks of prematurity. Accepting the fetal death of the growth-restricted twin and allowing pregnancy to continue gives the larger fetus a very good chance of being healthy at birth rather than being born premature with a significant risk of prematurity-related complications.

However, in a monochorionic pregnancy, intrauterine demise of the smaller fetus could put the healthy co-twin at a significant risk for acute severe hemorrhage into the placenta and circulation of the growth-restricted twin. This carries the risk of brain, renal, and cardiac damage—or even death—of the co-twin. The option of delaying delivery beyond the point of demise of the smaller twin, therefore, is unacceptable in this setting.

Rather, the fetuses would need intensive monitoring by experts who are alert to all the potential signs of fetal deterioration. Additional options, including fetal therapy, might require even more subspecialty evaluation.

▸ Unequal blood volume. Blood volume also may be unequally shared. In uncomplicated pregnancies, blood is exchanged equally through the vascular anastomoses that characterize all monochorionic pregnancies. Sometimes, however, the exchange is unbalanced and blood is shunted in one direction without adequate return.

Anastomoses that are between artery and vein act as one-way valves and can lead to significant differences in volume. Artery-to-artery and vein-to-vein connections allow direct exchange in either direction, with the direction of blood flow determined by the difference in blood pressure on either side.

If one fetus develops an unstable circulation or dies, the instability or resultant drop in blood pressure causes the healthy or surviving twin to lose a large amount of blood volume across the connecting vessels and into the sick or dying twin. This is why, when one fetus dies, the risk of death for the co-twin can be as high as 60%. It also explains why a surviving co-twin has a significant risk of brain injury.

The intertwin anastomoses account for a range of other pregnancy complications. When placenta sharing is equal but there is a significant mismatch in blood flow and blood volume, twin-to-twin syndrome (TTTS) can develop. In this scenario, the imbalance progresses to the extent that one twin becomes a “donor” of blood volume and the other twin becomes the “recipient.”

A decline in blood volume for the donor twin leads to decreased urine output to the extent that bladder filling virtually ceases and oligohydramnios may progress to anhydramnios. The recipient twin, in the meantime, urinates excessively, leading to polyhydramnios and possibly preterm labor.

TTTS develops in about 10%–15% of monochorionic pregnancies. Overall, however—if you add the approximately 10% that are affected by selective IUGR, and an unknown percentage of pregnancies that may have a bit of both problems or are complicated in other ways to this 10%–15%—I estimate that as many as one-third of monochorionic twins have some kind of significant complication.

For TTTS, endoscopic laser ablation (or laser coagulation) of placental anastomoses has been shown to be an effective treatment and a preferable first-line approach for severe cases diagnosed before 26 weeks. These therapies, however, are available only at specialized centers—a fact that adds to the value of early diagnosis of chorionicity and prospective monitoring for complications.

The Need for Early Diagnosis

We cannot attempt to alleviate complications and improve survival unless a diagnosis of monochorionicity is made early. The diagnosis of chorionicity certainly is more difficult in the second trimester.

However, if a patient has not had a first-trimester scan, a diagnosis should still be attempted.

Monochorionic twin pregnancies remain largely unpredictable. At 12 weeks' gestation, however, if we have diagnosed identical twins, there are several ultrasound parameters we can measure to begin to predict how the pregnancy will proceed and what fetal complications might develop.

Some studies have shown, for instance, that a discrepancy in nuchal translucency between the co-twins of more than 60% means that there is a 60%–70% chance that TTTS will develop.

There also may be some discrepancies in size of other structures that are apparent in the first trimester, such as differences in abdominal circumference, for example, as well as differences in amniotic fluid volume, or bladder size that might be helpful in planning fetal surveillance.

After initial evaluation, we generally recommend that monochorionic twins be evaluated again at 16 weeks, based on research by Dr. Liesbeth Lewi of the University Hospitals in Leuven, Belgium, showing that a combined risk assessment in the first trimester and at 16 weeks can predict selective IUGR or TTTS with greater than 80% accuracy.

In a study of 200 monochorionic diamniotic twin pregnancies, Dr. Lewi found that significant predictors of TTTS, selective IUGR, or intrauterine death in the first trimester were crown-rump length and discordant amniotic fluid volume. At 16 weeks, significant predictors were the differences between the co-twins in abdominal circumference, amniotic fluid volume, and the site of cord insertions. [The site of cord insertion was classified as velamentous, eccentric (more than 2 cm from the placental edge), or marginal (less than 2 cm from the placental edge), and a discordant cord insertion was considered to be the combination of a velamentous cord insertion in one fetus and an eccentric cord insertion in the other fetus.]

The differences between the co-twins in the ultrasound parameters were additive when measured in the first trimester and at 16 weeks. Combined risk assessment detected 58% of the fetal complications by classifying 21% of the 200 pregnancies as high risk, with a false-positive rate of 8%, while the predictive value of one assessment alone was significantly lower (Am. J. Obstet. Gynecol. 2008;199:493.e1–7).

Dr. Lewi's research was among the literature considered recently by a panel of experts assembled by the North American Fetal Therapy Network. The panel has been working on a consensus statement that, when finalized, will make recommendations for early diagnosis of monochorionicity and basic combined risk assessment.

Doppler ultrasound (US) measurements of the umbilical arteries, which depict resistance in the blood vessels and resultant blood flow, also may be helpful. Just as with singleton pregnancies, Doppler US provides information in the monochorionic pregnancy about the vasculature of the placenta and the amount of placenta the fetuses have available for nutrient exchange.

In monochorionic pregnancies, however, Doppler US has the added benefit of being key to diagnosing and evaluating hemodynamically significant arterio-arterial anastomoses that induce variations in diastolic velocity not seen in singleton pregnancies.

The imbalance in blood flow exchange between the co-twins' circulations—again, the primary contributor to the development of TTTS—also can be examined using Doppler assessments of two additional vascular beds: the middle cerebral artery (MCA) and the ductus venosus.

The MCA peak systolic velocity reflects how fast blood is flowing in the brain. Large differences in the MCA can point to TTTS. The ductus venosus, a unique fetal vessel that funnels a proportion of nutrient-rich umbilical venous return directly into the right atrium, similarly can be used to evaluate cardiac status. Doppler screening of the ductus venosus and MCA has its most useful role early in pregnancy.

Again, because most of the amniotic fluid from 16 weeks on is due to fetal urination, and because changes in urine output reflect changes in blood volume status, the assessment of bladder filling and amniotic fluid volume reveals much about blood volume status and possible TTTS.

Whenever we see a monochorionic twin pregnancy, therefore, we face a range of questions: What are the sizes of the fetuses? Is there a discrepancy? What is the ultrasound end-diastolic velocity in each twin? Is it normal? Or, is there variability in the waveform, which is indicative of hemodynamically significant arterio-arterial anastomoses? Is the amniotic fluid volume normal? What do the bladders look like? Does one fetus have a bladder that's barely filling?

By regularly asking these questions—and using the pregnancy as its own control—we will be alert to the potential problems associated with monochorionicity and more able to proactively plan our monitoring schedules.

A new discrepancy or a change from a previous exam might mean seeing the patient weekly as opposed to every 2 or 3 weeks.

Frequent monitoring is prudent throughout pregnancy as severe TTTS can develop until 22–23 weeks' gestation, even when findings are normal at 18 weeks.

Moreover, milder forms of TTTS, as well as milder forms of selective IUGR, can develop even later.

Umbilical artery Doppler shows significant variation in end-diastolic velocity from positive/absent to markedly reversed, as well as scalloping of the waveform. This indicates the presence of hemodynamically significant arterio-arterial anastomoses.

At left, the presence of chorionic tissue between the layers of amnion from the two sacs produces a “Lambda” sign (circle) that indicates a dichorionic diamniotic pregnancy. At right, the absence of this sign (arrow) indicates monochorionic placentation.

The fetus on the left has a larger abdominal circumference and a higher maximum vertical amniotic fluid pocket, which can point to unequal placenta sharing and/or unequal blood volume and requires follow-up evaluation. Images courtesy Dr. Ahmet A. Baschat

The Complexity of Multiple Gestation

Multiple gestation is an obstetric condition that confronts every obstetrician at some point. Twin pregnancies, for one, are quite frequent, occurring in 3.2% of all pregnancies. Because of this frequency, it is important that we spend some time reviewing the various presentations of twin pregnancies as well as the potential complications.

Twin pregnancies are not a monolithic condition. As we know, twin pregnancies can present in a two-placenta double-membrane sac (dichorionic diamniotic), in a single-placenta double-membrane sac (monochorionic diamniotic), or in some version thereof.

The clinical presentation of twin pregnancies and the potential complications will vary widely, making it of utmost importance to diagnose chorionicity early on. The simple term “twin pregnancy” is not, as our guest author says, a term that is precise enough, in and of itself, to ensure optimal management. A distinction between monochorionic and dichorionic twins must be made.

The complications that are of greatest concern in monochorionic pregnancies involve the anastomoses between the twins' two vasculatures.

In uncomplicated pregnancies, blood is exchanged equally through these anastomoses.

In some pregnancies, however, blood flow becomes unbalanced to the extent that one or both fetuses are compromised.

The management options for complications such as twin-to-twin transfusion syndrome (TTTS) have traditionally been quite limited.

Until recently, management for TTTS involved observation or the removal of excess amniotic fluid.

More recently, however, surgical interventions have been employed with variable success.

Although every obstetrician may not possess the mastery of fetal surgery in these conditions, it is important that all obstetricians nevertheless understand the options that are available and be able to make accurate diagnoses, offer appropriate counseling, and make referrals if appropriate.

Thus, I believe the focus of this Master Class—monochorionicity, its features, and the facets of good management—will be of significant value to the clinician.

We have invited Dr. Ahmet A. Baschat of the department of obstetrics, gynecology, and reproductive sciences at the University of Maryland, Baltimore, to be our guest professor this month. Dr. Baschat is a recognized national expert in fetal therapy, including various intrauterine surgical procedures.

Key Points

▸ Making an accurate diagnosis of chorionicity early in a twin pregnancy is crucial for the prospective management of potential complications. This is because monochorionic twins have unique features that can lead to unequal placenta sharing and unequal blood volume, increasing the risk of fetal death, growth restriction, and other complications. Early in the first trimester is the optimal time to verify chorionicity.

▸ Estimating fetal growth by measuring head diameter, abdominal circumference, and femur length is an important aspect of assessing placenta sharing and the availability of nutrients. The abdominal circumference is the single best measurement of fetal nutrient status; a discrepancy at 16 weeks increases the risk for subsequent complications.

▸ Evaluating bladder filling in combination with amniotic fluid volume is an important element of estimating fetal blood volume status.

▸ Research shows that a combined risk assessment in the first trimester and at 16 weeks can predict selective intrauterine growth restriction and twin-to-twin transfusion syndrome—two of the major complications of monochorionic pregnancies—with greater than 80% accuracy.

▸ Doppler ultrasound of the umbilical artery is important for assessing placenta sharing and the presence of hemodynamically significant arterio-arterial anastomoses.

We now know enough about the development and potential complications associated with monochorionic twin pregnancies that the term “twin pregnancy” is no longer precise enough to be used as a medical term. We must distinguish between monochorionic and dichorionic twins.

Monochorionic twin pregnancies have unique features that substantially increase the risk of fetal death, growth restriction, and other complications. The twins share a single placenta, and their circulations are essentially linked to each other through their placental anastomoses. These linked circulations allow blood to be redirected—sometimes very rapidly—toward one twin or the other. This is not typically the case in dichorionic pregnancies.

Thus, we must always take both fetuses in a monochorionic twin pregnancy into consideration, because when one fetus is in jeopardy, the other typically is as well. This interdependency is fundamentally different from the less-entwined relationship of dichorionic twins, and makes monitoring more complicated and all the more important.

We must make the distinction between monochorionic and dichorionic twins early on—optimally, in the first trimester. With the opportunity to make this critical distinction—as well as improvements in fetal therapy and advances in ultrasound assessment that allow us to detect potential problems early—we can lay the foundation for the effective, proactive management of these at-risk pregnancies from the first trimester on.

Once the diagnosis of chorionicity is made, medical reports should specify the type of twin pregnancy that is present, rather than using what should now be considered the layman's term “twin pregnancy.”

The Potential Risks

The potential risks of monochorionic pregnancies stem from:

▸ Unequal placenta sharing. In an ideal world, the twins' single placenta is equally shared. However, it is often the case that one twin will have just 30%–40% of the monochorionic placenta, while the other fetus has the much larger portion. Such unequal placenta sharing leads to an unequal sharing of nutrients, which can lead to growth restriction and severe low birth weight in one of the fetuses.

This type of growth restriction—known as selective intrauterine growth restriction (IUGR)—affects about 10% of all identical twins. It happens quite early in pregnancy and, as we know from singleton growth-restricted fetuses, can lead to a host of troubling complications.

That is why the fetuses in a monochorionic pregnancy can never be treated in isolation. With the early onset of growth restriction in a monochorionic pregnancy, for example, the twin with this complication faces a higher risk of in utero death—an outcome that always negatively impacts the other fetus as well.

In a dichorionic pregnancy, if a co-twin weighs 320 g at 26 weeks and is at high risk of in utero death, we typically would advise the parents to delay delivery. The extremely high likelihood of fetal death of the growth-restricted twin would not justify exposing the otherwise normally grown healthy twin to the risks of prematurity. Accepting the fetal death of the growth-restricted twin and allowing pregnancy to continue gives the larger fetus a very good chance of being healthy at birth rather than being born premature with a significant risk of prematurity-related complications.

However, in a monochorionic pregnancy, intrauterine demise of the smaller fetus could put the healthy co-twin at a significant risk for acute severe hemorrhage into the placenta and circulation of the growth-restricted twin. This carries the risk of brain, renal, and cardiac damage—or even death—of the co-twin. The option of delaying delivery beyond the point of demise of the smaller twin, therefore, is unacceptable in this setting.

Rather, the fetuses would need intensive monitoring by experts who are alert to all the potential signs of fetal deterioration. Additional options, including fetal therapy, might require even more subspecialty evaluation.

▸ Unequal blood volume. Blood volume also may be unequally shared. In uncomplicated pregnancies, blood is exchanged equally through the vascular anastomoses that characterize all monochorionic pregnancies. Sometimes, however, the exchange is unbalanced and blood is shunted in one direction without adequate return.

Anastomoses that are between artery and vein act as one-way valves and can lead to significant differences in volume. Artery-to-artery and vein-to-vein connections allow direct exchange in either direction, with the direction of blood flow determined by the difference in blood pressure on either side.

If one fetus develops an unstable circulation or dies, the instability or resultant drop in blood pressure causes the healthy or surviving twin to lose a large amount of blood volume across the connecting vessels and into the sick or dying twin. This is why, when one fetus dies, the risk of death for the co-twin can be as high as 60%. It also explains why a surviving co-twin has a significant risk of brain injury.

The intertwin anastomoses account for a range of other pregnancy complications. When placenta sharing is equal but there is a significant mismatch in blood flow and blood volume, twin-to-twin syndrome (TTTS) can develop. In this scenario, the imbalance progresses to the extent that one twin becomes a “donor” of blood volume and the other twin becomes the “recipient.”

A decline in blood volume for the donor twin leads to decreased urine output to the extent that bladder filling virtually ceases and oligohydramnios may progress to anhydramnios. The recipient twin, in the meantime, urinates excessively, leading to polyhydramnios and possibly preterm labor.

TTTS develops in about 10%–15% of monochorionic pregnancies. Overall, however—if you add the approximately 10% that are affected by selective IUGR, and an unknown percentage of pregnancies that may have a bit of both problems or are complicated in other ways to this 10%–15%—I estimate that as many as one-third of monochorionic twins have some kind of significant complication.

For TTTS, endoscopic laser ablation (or laser coagulation) of placental anastomoses has been shown to be an effective treatment and a preferable first-line approach for severe cases diagnosed before 26 weeks. These therapies, however, are available only at specialized centers—a fact that adds to the value of early diagnosis of chorionicity and prospective monitoring for complications.

The Need for Early Diagnosis

We cannot attempt to alleviate complications and improve survival unless a diagnosis of monochorionicity is made early. The diagnosis of chorionicity certainly is more difficult in the second trimester.

However, if a patient has not had a first-trimester scan, a diagnosis should still be attempted.

Monochorionic twin pregnancies remain largely unpredictable. At 12 weeks' gestation, however, if we have diagnosed identical twins, there are several ultrasound parameters we can measure to begin to predict how the pregnancy will proceed and what fetal complications might develop.

Some studies have shown, for instance, that a discrepancy in nuchal translucency between the co-twins of more than 60% means that there is a 60%–70% chance that TTTS will develop.

There also may be some discrepancies in size of other structures that are apparent in the first trimester, such as differences in abdominal circumference, for example, as well as differences in amniotic fluid volume, or bladder size that might be helpful in planning fetal surveillance.

After initial evaluation, we generally recommend that monochorionic twins be evaluated again at 16 weeks, based on research by Dr. Liesbeth Lewi of the University Hospitals in Leuven, Belgium, showing that a combined risk assessment in the first trimester and at 16 weeks can predict selective IUGR or TTTS with greater than 80% accuracy.

In a study of 200 monochorionic diamniotic twin pregnancies, Dr. Lewi found that significant predictors of TTTS, selective IUGR, or intrauterine death in the first trimester were crown-rump length and discordant amniotic fluid volume. At 16 weeks, significant predictors were the differences between the co-twins in abdominal circumference, amniotic fluid volume, and the site of cord insertions. [The site of cord insertion was classified as velamentous, eccentric (more than 2 cm from the placental edge), or marginal (less than 2 cm from the placental edge), and a discordant cord insertion was considered to be the combination of a velamentous cord insertion in one fetus and an eccentric cord insertion in the other fetus.]

The differences between the co-twins in the ultrasound parameters were additive when measured in the first trimester and at 16 weeks. Combined risk assessment detected 58% of the fetal complications by classifying 21% of the 200 pregnancies as high risk, with a false-positive rate of 8%, while the predictive value of one assessment alone was significantly lower (Am. J. Obstet. Gynecol. 2008;199:493.e1–7).

Dr. Lewi's research was among the literature considered recently by a panel of experts assembled by the North American Fetal Therapy Network. The panel has been working on a consensus statement that, when finalized, will make recommendations for early diagnosis of monochorionicity and basic combined risk assessment.

Doppler ultrasound (US) measurements of the umbilical arteries, which depict resistance in the blood vessels and resultant blood flow, also may be helpful. Just as with singleton pregnancies, Doppler US provides information in the monochorionic pregnancy about the vasculature of the placenta and the amount of placenta the fetuses have available for nutrient exchange.

In monochorionic pregnancies, however, Doppler US has the added benefit of being key to diagnosing and evaluating hemodynamically significant arterio-arterial anastomoses that induce variations in diastolic velocity not seen in singleton pregnancies.

The imbalance in blood flow exchange between the co-twins' circulations—again, the primary contributor to the development of TTTS—also can be examined using Doppler assessments of two additional vascular beds: the middle cerebral artery (MCA) and the ductus venosus.

The MCA peak systolic velocity reflects how fast blood is flowing in the brain. Large differences in the MCA can point to TTTS. The ductus venosus, a unique fetal vessel that funnels a proportion of nutrient-rich umbilical venous return directly into the right atrium, similarly can be used to evaluate cardiac status. Doppler screening of the ductus venosus and MCA has its most useful role early in pregnancy.

Again, because most of the amniotic fluid from 16 weeks on is due to fetal urination, and because changes in urine output reflect changes in blood volume status, the assessment of bladder filling and amniotic fluid volume reveals much about blood volume status and possible TTTS.

Whenever we see a monochorionic twin pregnancy, therefore, we face a range of questions: What are the sizes of the fetuses? Is there a discrepancy? What is the ultrasound end-diastolic velocity in each twin? Is it normal? Or, is there variability in the waveform, which is indicative of hemodynamically significant arterio-arterial anastomoses? Is the amniotic fluid volume normal? What do the bladders look like? Does one fetus have a bladder that's barely filling?

By regularly asking these questions—and using the pregnancy as its own control—we will be alert to the potential problems associated with monochorionicity and more able to proactively plan our monitoring schedules.

A new discrepancy or a change from a previous exam might mean seeing the patient weekly as opposed to every 2 or 3 weeks.

Frequent monitoring is prudent throughout pregnancy as severe TTTS can develop until 22–23 weeks' gestation, even when findings are normal at 18 weeks.

Moreover, milder forms of TTTS, as well as milder forms of selective IUGR, can develop even later.

Umbilical artery Doppler shows significant variation in end-diastolic velocity from positive/absent to markedly reversed, as well as scalloping of the waveform. This indicates the presence of hemodynamically significant arterio-arterial anastomoses.

At left, the presence of chorionic tissue between the layers of amnion from the two sacs produces a “Lambda” sign (circle) that indicates a dichorionic diamniotic pregnancy. At right, the absence of this sign (arrow) indicates monochorionic placentation.

The fetus on the left has a larger abdominal circumference and a higher maximum vertical amniotic fluid pocket, which can point to unequal placenta sharing and/or unequal blood volume and requires follow-up evaluation. Images courtesy Dr. Ahmet A. Baschat

The Complexity of Multiple Gestation

Multiple gestation is an obstetric condition that confronts every obstetrician at some point. Twin pregnancies, for one, are quite frequent, occurring in 3.2% of all pregnancies. Because of this frequency, it is important that we spend some time reviewing the various presentations of twin pregnancies as well as the potential complications.

Twin pregnancies are not a monolithic condition. As we know, twin pregnancies can present in a two-placenta double-membrane sac (dichorionic diamniotic), in a single-placenta double-membrane sac (monochorionic diamniotic), or in some version thereof.

The clinical presentation of twin pregnancies and the potential complications will vary widely, making it of utmost importance to diagnose chorionicity early on. The simple term “twin pregnancy” is not, as our guest author says, a term that is precise enough, in and of itself, to ensure optimal management. A distinction between monochorionic and dichorionic twins must be made.

The complications that are of greatest concern in monochorionic pregnancies involve the anastomoses between the twins' two vasculatures.

In uncomplicated pregnancies, blood is exchanged equally through these anastomoses.

In some pregnancies, however, blood flow becomes unbalanced to the extent that one or both fetuses are compromised.

The management options for complications such as twin-to-twin transfusion syndrome (TTTS) have traditionally been quite limited.

Until recently, management for TTTS involved observation or the removal of excess amniotic fluid.

More recently, however, surgical interventions have been employed with variable success.

Although every obstetrician may not possess the mastery of fetal surgery in these conditions, it is important that all obstetricians nevertheless understand the options that are available and be able to make accurate diagnoses, offer appropriate counseling, and make referrals if appropriate.

Thus, I believe the focus of this Master Class—monochorionicity, its features, and the facets of good management—will be of significant value to the clinician.

We have invited Dr. Ahmet A. Baschat of the department of obstetrics, gynecology, and reproductive sciences at the University of Maryland, Baltimore, to be our guest professor this month. Dr. Baschat is a recognized national expert in fetal therapy, including various intrauterine surgical procedures.

Key Points

▸ Making an accurate diagnosis of chorionicity early in a twin pregnancy is crucial for the prospective management of potential complications. This is because monochorionic twins have unique features that can lead to unequal placenta sharing and unequal blood volume, increasing the risk of fetal death, growth restriction, and other complications. Early in the first trimester is the optimal time to verify chorionicity.

▸ Estimating fetal growth by measuring head diameter, abdominal circumference, and femur length is an important aspect of assessing placenta sharing and the availability of nutrients. The abdominal circumference is the single best measurement of fetal nutrient status; a discrepancy at 16 weeks increases the risk for subsequent complications.

▸ Evaluating bladder filling in combination with amniotic fluid volume is an important element of estimating fetal blood volume status.

▸ Research shows that a combined risk assessment in the first trimester and at 16 weeks can predict selective intrauterine growth restriction and twin-to-twin transfusion syndrome—two of the major complications of monochorionic pregnancies—with greater than 80% accuracy.

▸ Doppler ultrasound of the umbilical artery is important for assessing placenta sharing and the presence of hemodynamically significant arterio-arterial anastomoses.

There is a widespread consensus that ultrasound is the clinical standard for the diagnosis of fetal anomalies, and a constellation of factors will ensure its central role into the foreseeable future.

Most importantly, both ultrasound technology and the expertise to perform and interpret it are now widely available. The technology also remains relatively inexpensive, compared with other modalities; its safety has been well established through both study and long-term experience; and it provides real-time visualization, as opposed to images acquired at a particular point in time. Overall, ultrasound should be the first technology employed in the evaluation of the fetal anomaly.

Still, there are well-recognized limitations to sonographic evaluation.

The ability to visualize structures—and thus, the accuracy of a diagnosis—is significantly compromised, for instance, in women who are obese. This is far from a trivial concern today, as the rate of obesity in the United States is high and climbing.

Sonographic evaluation also may be limited by fetal position. Even in an average-size woman, for instance, suboptimal fetal positioning can impair proper visualization of structures.

Another common limitation is the descent of the fetal head into the maternal pelvis. Transvaginal ultrasound is an alternative approach, but the physics of the transvaginal transducer often prevents us from seeing in as many planes as would normally be desirable.

Ultrasound tends to be optimal during midpregnancy. Beyond this point, calcification of the fetal bone structure intensifies. Cranial ossification, for example, can substantially obscure the visualization of intracranial structures.

Finally, effective ultrasound evaluation requires fluid around the fetus. With oligohydramnios, the quality of the sonographic images is significantly compromised.

All told, these limitations are not infrequent or inconsequential. Clinicians commonly encounter such situations during the course of their work.

MRI Technique and Safety

Fetal magnetic resonance imaging provides excellent tissue contrast and is not limited by maternal obesity, skull calcification, or fetal position. It can image the fetus in multiple planes and accomplish this with a large field of view.

MRI can therefore play a valuable role when the findings from ultrasound are unclear or incomplete, or when there is potential for other anomalies that cannot be sufficiently visualized with ultrasound.

MRI relies on the presence of the high water content of tissues, and on the magnetic qualities of the constituent hydrogen nuclei. When tissue is placed in the strong magnetic field of an MRI machine, the hydrogen nuclei or protons move into particular alignments with the applied magnetic field.

Once the protons are lined up, radio frequency pulses are applied, causing the protons to absorb additional energy and spin on their axes of alignment. When the radio frequency pulses are discontinued, the additional energy that the protons had previously absorbed is released. It is this released energy that is transformed into an image. The quantity of energy released will vary depending on the tissue characteristics, such as the relative water and fat content.

Unlike x-ray and CT scans, MRI does not use ionizing radiation. Numerous studies and reports, including studies of MRI technicians who become pregnant, have demonstrated the safety of MRI and the lack of adverse clinical effects. The American College of Radiology published a series of white papers from 1993 to 2004 outlining MRI's safety. Thus, although the safety of MRI continues to be studied, there is no evidence to date that MRI produces harmful effects on human embryos or fetuses.

To be exceedingly cautious, most authorities and practitioners of MRI advise that it not be done in the first trimester.

Even without this extra caution, however, MRI would likely be discouraged in the first trimester because the increased noise-to-signal ratio from imaging such a small structure limits its benefit. It isn't until later in the second trimester, with increased fetal size and fat content, that the quality and resolution of the images achieve a threshold that conveys clinical benefit.

MRI's Leading Indications

MRI is indicated when there is potential for significant change in diagnosis or in patient management beyond the initial ultrasound.

Several studies from both the United States and Europe have demonstrated the clear capability of MRI to significantly modify or alter diagnosis, patient counseling, and management.

In one study of 124 fetuses with central nervous system anomalies detected initially by ultrasound, Dr. Deborah Levine of Harvard Medical School and her colleagues showed that fetal MRI led to 49 major changes in diagnosis and 27 clear changes in management, compared with prior ultrasound.

Suspected central nervous system anomalies—particularly brain anomalies—are, in fact, the most common indication for fetal MRI. There is some literature to support benefits of fetal MRI for other anatomical defects, but the literature provides the strongest evidence of MRI's additional benefit for CNS anomalies. Beyond the CNS, the other two main clinical indications for fetal MRI are for evaluation of the fetal neck and chest.

Among the anomalies and conditions best evaluated by fetal MRI are the following:

▸ Ventriculomegaly. Dilatation of the cerebral ventricles is a relatively common finding by prenatal diagnosticians. Although it is usually well visualized with ultrasound, ventriculomegaly may be accompanied by other associated abnormalities that may remain undetected with sonographic evaluation.

When ventriculomegaly is isolated with no other accompanying anatomical defects, the long-term prognosis is excellent. If there are associated abnormalities, however, the prognosis is significantly compromised, with much worse neurodevelopmental outcomes.

Fetal MRI can help identify those additional abnormalities. Studies from Europe and in the United States have documented significant percentages of cases in which apparently isolated ventriculomegaly was identified on the ultrasound, but was then found to be associated with additional anomalies on the follow-up MRI.

Even in cases with borderline ventricular dilatation, subtle but significant developmental abnormalities are frequently overlooked by ultrasound. MRI diagnosis can facilitate better counseling and prognostication regarding outcome, and can aid in the timely development of management strategies.

▸ Other brain anomalies. MRI can be advantageous for precisely visualizing deep structures of the brain, especially as gestational age advances and the skull becomes calcified. Sometimes, MRI enables visualization of deeper structures—such as the optic chiasma, pituitary stalk, and the pituitary—that are not visible on ultrasound.

Fetal MRI is also advantageous for visualizing subtle lesions of the brain, such as parenchymal infarcts and hemorrhage, and other abnormalities of cortical development. Such subtle anomalies can nevertheless be very consequential to long-term neurologic performance.

In our institution, we order an MRI whenever we see an anomaly of the brain. A persistently and significantly small fetal head with normal-appearing sonographic anatomy may, for example, reveal a lissencephaly syndrome on MRI exam. In patients with a significant family history of brain abnormalities, a confirmatory MRI of the fetal brain, despite a normal sonographic appearance, may be justifiable.

▸ Masses in the neck. MRI is thought to be particularly useful in assessing masses of the fetal neck and the potential for airway obstruction. Limitations of tissue differentiation on ultrasound may preclude a determination of the extent of infiltration of a neck mass. The panoramic view and tissue differentiation of the MRI may overcome this limitation.

These qualities are used to good advantage in determining whether a neck mass is infiltrating or obstructing the fetal airway, and whether it has the potential to prevent spontaneous breathing at delivery. Should such a situation be confirmed prenatally, an EXIT (ex utero intrapartum treatment) procedure can be planned. In this procedure, the fetus's head and shoulders are delivered and the placenta is left attached (maintaining umbilical circulation and fetal oxygenation) while a surgical intubation or tracheoscopy procedure is performed.

▸ Diaphragmatic hernia. Congenital diaphragmatic hernia is among the most common congenital thoracic lesions. Herniation of the abdominal viscus and organs into the chest can lead to compression of the lungs and lung hypoplasia at birth, precluding normal respiration. When the liver is also herniated into the chest, the chances of survival are sharply reduced.

Although possible, it can be difficult to determine herniation of the liver into the chest with ultrasound. MRI easily identifies thoracic displacement of the liver and therefore has prognostic value in congenital diaphragmatic hernia.

Limitations, Future Promise

Prenatal MRI does, however, have limitations. Because the technique is based on contrast between water and fat/lipids, it generally does not provide good quality images before about 24 weeks of gestation—a time period in which neurons, for instance, have not yet undergone significant myelination. Ultrasound, in contrast, tends to be quite effective earlier in pregnancy, which is a distinct advantage.

Availability of MRI technology and specific interest and expertise in fetal MRI also are significantly restricted, compared with ultrasound. Furthermore, MRI technology is significantly more costly than ultrasound at this time.

None of these limitations is immutable. All will likely be addressed or at least attenuated with the passage of time.

Just as important will be the development of a team approach to the use of MRI for fetal anomaly detection. Such an approach would involve embracing the expertise of the obstetrician in fetal anatomy and fetal anomalies in general. The interpretation of fetal MRI images should involve not only radiologists and pediatric subspecialists, such as pediatric neurologists, but also fetal medicine specialists working together.

The greatest promise of fetal MRI lies with further advances in so-called functional MRI. This has the potential to provide information not only about structural features of the anatomy, but about the function of various tissues as well. MRI studies could capitalize, for instance, on the fact that tissue that is injured or developmentally abnormal will have differences in metabolism, compared with normal tissue.

For example, animal studies have shown that the MRI signal of oxygenated hemoglobin is different from the MRI signal of deoxygenated hemoglobin. Utilizing such differences in fetal MRI imaging could enable us to identify oxygen deprivation in fetal and placental tissues.

Advances with MRI spectroscopy, moreover, could provide us with further detailed information on tissue metabolism. Collectively, such advances in MRI could revolutionize research and ultimately clinical assessment of the fetus.

Know the Fetus

The driving force in contemporary times behind the need to evaluate the fetus is the desire of parents to know the most about their fetus as early as possible. Medical indications also may dictate when fetal evaluation is conducted and fetal development assessed.

Prior to the development of ultrasound, such assessment was not possible. However, with the advent of ultrasound technology and other developments that have progressively increased its sophistication, ultrasound imaging has become a reality and an increasingly useful tool. It has been advancing at such a rapid rate that fetal imaging has moved from the third trimester to the second, and even to the first. Not only is fetal growth assessed, but some of the intricacies of fetal development are evaluated as well.

The invasive method of fetal evaluation has taken a similar pathway, expanding from amniocentesis to embryofetoscopy to chorionic-villus sampling to analyte markers in maternal blood. The desire to know more continues to drive the field.

Parents and their physicians call for the greatest possible degree of accuracy and information on the developing fetus.

Fetal MRI technology is an additional tool that is fast evolving in fetal medicine to meet this desire.

At the same time, many have appreciated the limitations of ultrasound technology, which are based upon maternal obesity, fetal position, gestational age, and developmental status of the fetus.

Because of its unique technology, MRI is able to provide added value and new information that was not heretofore possible using current ultrasound technology.

It is in this light that we believe that a Master Class addressing this newest evolving technology is in order.

We have invited Dr. Ray Bahado-Singh, a professor of maternal-fetal medicine at Wayne State University in Detroit and an expert in genetics and prenatal diagnosis, to discuss fetal MRI in detail and to highlight how this new technology may further advance the diagnosis of fetal anomalies.

Key Points

▸ MRI is a rapidly developing technology for fetal diagnosis, and maternal-fetal medicine specialists should develop expertise and collaboration with radiologists.

▸ Substantial clinical and research data demonstrate improvement of CNS diagnoses when MRI is performed after targeted ultrasound.

▸ Emerging data suggest improvement in diagnosis when MRI is used for neck and thoracic abnormalities, excluding the heart.

There is a widespread consensus that ultrasound is the clinical standard for the diagnosis of fetal anomalies, and a constellation of factors will ensure its central role into the foreseeable future.

Most importantly, both ultrasound technology and the expertise to perform and interpret it are now widely available. The technology also remains relatively inexpensive, compared with other modalities; its safety has been well established through both study and long-term experience; and it provides real-time visualization, as opposed to images acquired at a particular point in time. Overall, ultrasound should be the first technology employed in the evaluation of the fetal anomaly.

Still, there are well-recognized limitations to sonographic evaluation.

The ability to visualize structures—and thus, the accuracy of a diagnosis—is significantly compromised, for instance, in women who are obese. This is far from a trivial concern today, as the rate of obesity in the United States is high and climbing.

Sonographic evaluation also may be limited by fetal position. Even in an average-size woman, for instance, suboptimal fetal positioning can impair proper visualization of structures.

Another common limitation is the descent of the fetal head into the maternal pelvis. Transvaginal ultrasound is an alternative approach, but the physics of the transvaginal transducer often prevents us from seeing in as many planes as would normally be desirable.

Ultrasound tends to be optimal during midpregnancy. Beyond this point, calcification of the fetal bone structure intensifies. Cranial ossification, for example, can substantially obscure the visualization of intracranial structures.

Finally, effective ultrasound evaluation requires fluid around the fetus. With oligohydramnios, the quality of the sonographic images is significantly compromised.

All told, these limitations are not infrequent or inconsequential. Clinicians commonly encounter such situations during the course of their work.

MRI Technique and Safety

Fetal magnetic resonance imaging provides excellent tissue contrast and is not limited by maternal obesity, skull calcification, or fetal position. It can image the fetus in multiple planes and accomplish this with a large field of view.

MRI can therefore play a valuable role when the findings from ultrasound are unclear or incomplete, or when there is potential for other anomalies that cannot be sufficiently visualized with ultrasound.

MRI relies on the presence of the high water content of tissues, and on the magnetic qualities of the constituent hydrogen nuclei. When tissue is placed in the strong magnetic field of an MRI machine, the hydrogen nuclei or protons move into particular alignments with the applied magnetic field.

Once the protons are lined up, radio frequency pulses are applied, causing the protons to absorb additional energy and spin on their axes of alignment. When the radio frequency pulses are discontinued, the additional energy that the protons had previously absorbed is released. It is this released energy that is transformed into an image. The quantity of energy released will vary depending on the tissue characteristics, such as the relative water and fat content.

Unlike x-ray and CT scans, MRI does not use ionizing radiation. Numerous studies and reports, including studies of MRI technicians who become pregnant, have demonstrated the safety of MRI and the lack of adverse clinical effects. The American College of Radiology published a series of white papers from 1993 to 2004 outlining MRI's safety. Thus, although the safety of MRI continues to be studied, there is no evidence to date that MRI produces harmful effects on human embryos or fetuses.

To be exceedingly cautious, most authorities and practitioners of MRI advise that it not be done in the first trimester.

Even without this extra caution, however, MRI would likely be discouraged in the first trimester because the increased noise-to-signal ratio from imaging such a small structure limits its benefit. It isn't until later in the second trimester, with increased fetal size and fat content, that the quality and resolution of the images achieve a threshold that conveys clinical benefit.

MRI's Leading Indications

MRI is indicated when there is potential for significant change in diagnosis or in patient management beyond the initial ultrasound.

Several studies from both the United States and Europe have demonstrated the clear capability of MRI to significantly modify or alter diagnosis, patient counseling, and management.

In one study of 124 fetuses with central nervous system anomalies detected initially by ultrasound, Dr. Deborah Levine of Harvard Medical School and her colleagues showed that fetal MRI led to 49 major changes in diagnosis and 27 clear changes in management, compared with prior ultrasound.

Suspected central nervous system anomalies—particularly brain anomalies—are, in fact, the most common indication for fetal MRI. There is some literature to support benefits of fetal MRI for other anatomical defects, but the literature provides the strongest evidence of MRI's additional benefit for CNS anomalies. Beyond the CNS, the other two main clinical indications for fetal MRI are for evaluation of the fetal neck and chest.

Among the anomalies and conditions best evaluated by fetal MRI are the following:

▸ Ventriculomegaly. Dilatation of the cerebral ventricles is a relatively common finding by prenatal diagnosticians. Although it is usually well visualized with ultrasound, ventriculomegaly may be accompanied by other associated abnormalities that may remain undetected with sonographic evaluation.

When ventriculomegaly is isolated with no other accompanying anatomical defects, the long-term prognosis is excellent. If there are associated abnormalities, however, the prognosis is significantly compromised, with much worse neurodevelopmental outcomes.

Fetal MRI can help identify those additional abnormalities. Studies from Europe and in the United States have documented significant percentages of cases in which apparently isolated ventriculomegaly was identified on the ultrasound, but was then found to be associated with additional anomalies on the follow-up MRI.

Even in cases with borderline ventricular dilatation, subtle but significant developmental abnormalities are frequently overlooked by ultrasound. MRI diagnosis can facilitate better counseling and prognostication regarding outcome, and can aid in the timely development of management strategies.

▸ Other brain anomalies. MRI can be advantageous for precisely visualizing deep structures of the brain, especially as gestational age advances and the skull becomes calcified. Sometimes, MRI enables visualization of deeper structures—such as the optic chiasma, pituitary stalk, and the pituitary—that are not visible on ultrasound.

Fetal MRI is also advantageous for visualizing subtle lesions of the brain, such as parenchymal infarcts and hemorrhage, and other abnormalities of cortical development. Such subtle anomalies can nevertheless be very consequential to long-term neurologic performance.

In our institution, we order an MRI whenever we see an anomaly of the brain. A persistently and significantly small fetal head with normal-appearing sonographic anatomy may, for example, reveal a lissencephaly syndrome on MRI exam. In patients with a significant family history of brain abnormalities, a confirmatory MRI of the fetal brain, despite a normal sonographic appearance, may be justifiable.

▸ Masses in the neck. MRI is thought to be particularly useful in assessing masses of the fetal neck and the potential for airway obstruction. Limitations of tissue differentiation on ultrasound may preclude a determination of the extent of infiltration of a neck mass. The panoramic view and tissue differentiation of the MRI may overcome this limitation.

These qualities are used to good advantage in determining whether a neck mass is infiltrating or obstructing the fetal airway, and whether it has the potential to prevent spontaneous breathing at delivery. Should such a situation be confirmed prenatally, an EXIT (ex utero intrapartum treatment) procedure can be planned. In this procedure, the fetus's head and shoulders are delivered and the placenta is left attached (maintaining umbilical circulation and fetal oxygenation) while a surgical intubation or tracheoscopy procedure is performed.

▸ Diaphragmatic hernia. Congenital diaphragmatic hernia is among the most common congenital thoracic lesions. Herniation of the abdominal viscus and organs into the chest can lead to compression of the lungs and lung hypoplasia at birth, precluding normal respiration. When the liver is also herniated into the chest, the chances of survival are sharply reduced.

Although possible, it can be difficult to determine herniation of the liver into the chest with ultrasound. MRI easily identifies thoracic displacement of the liver and therefore has prognostic value in congenital diaphragmatic hernia.

Limitations, Future Promise

Prenatal MRI does, however, have limitations. Because the technique is based on contrast between water and fat/lipids, it generally does not provide good quality images before about 24 weeks of gestation—a time period in which neurons, for instance, have not yet undergone significant myelination. Ultrasound, in contrast, tends to be quite effective earlier in pregnancy, which is a distinct advantage.

Availability of MRI technology and specific interest and expertise in fetal MRI also are significantly restricted, compared with ultrasound. Furthermore, MRI technology is significantly more costly than ultrasound at this time.

None of these limitations is immutable. All will likely be addressed or at least attenuated with the passage of time.

Just as important will be the development of a team approach to the use of MRI for fetal anomaly detection. Such an approach would involve embracing the expertise of the obstetrician in fetal anatomy and fetal anomalies in general. The interpretation of fetal MRI images should involve not only radiologists and pediatric subspecialists, such as pediatric neurologists, but also fetal medicine specialists working together.

The greatest promise of fetal MRI lies with further advances in so-called functional MRI. This has the potential to provide information not only about structural features of the anatomy, but about the function of various tissues as well. MRI studies could capitalize, for instance, on the fact that tissue that is injured or developmentally abnormal will have differences in metabolism, compared with normal tissue.

For example, animal studies have shown that the MRI signal of oxygenated hemoglobin is different from the MRI signal of deoxygenated hemoglobin. Utilizing such differences in fetal MRI imaging could enable us to identify oxygen deprivation in fetal and placental tissues.

Advances with MRI spectroscopy, moreover, could provide us with further detailed information on tissue metabolism. Collectively, such advances in MRI could revolutionize research and ultimately clinical assessment of the fetus.

Know the Fetus

The driving force in contemporary times behind the need to evaluate the fetus is the desire of parents to know the most about their fetus as early as possible. Medical indications also may dictate when fetal evaluation is conducted and fetal development assessed.

Prior to the development of ultrasound, such assessment was not possible. However, with the advent of ultrasound technology and other developments that have progressively increased its sophistication, ultrasound imaging has become a reality and an increasingly useful tool. It has been advancing at such a rapid rate that fetal imaging has moved from the third trimester to the second, and even to the first. Not only is fetal growth assessed, but some of the intricacies of fetal development are evaluated as well.

The invasive method of fetal evaluation has taken a similar pathway, expanding from amniocentesis to embryofetoscopy to chorionic-villus sampling to analyte markers in maternal blood. The desire to know more continues to drive the field.

Parents and their physicians call for the greatest possible degree of accuracy and information on the developing fetus.

Fetal MRI technology is an additional tool that is fast evolving in fetal medicine to meet this desire.

At the same time, many have appreciated the limitations of ultrasound technology, which are based upon maternal obesity, fetal position, gestational age, and developmental status of the fetus.

Because of its unique technology, MRI is able to provide added value and new information that was not heretofore possible using current ultrasound technology.

It is in this light that we believe that a Master Class addressing this newest evolving technology is in order.

We have invited Dr. Ray Bahado-Singh, a professor of maternal-fetal medicine at Wayne State University in Detroit and an expert in genetics and prenatal diagnosis, to discuss fetal MRI in detail and to highlight how this new technology may further advance the diagnosis of fetal anomalies.

Key Points

▸ MRI is a rapidly developing technology for fetal diagnosis, and maternal-fetal medicine specialists should develop expertise and collaboration with radiologists.

▸ Substantial clinical and research data demonstrate improvement of CNS diagnoses when MRI is performed after targeted ultrasound.

▸ Emerging data suggest improvement in diagnosis when MRI is used for neck and thoracic abnormalities, excluding the heart.

There is a widespread consensus that ultrasound is the clinical standard for the diagnosis of fetal anomalies, and a constellation of factors will ensure its central role into the foreseeable future.

Most importantly, both ultrasound technology and the expertise to perform and interpret it are now widely available. The technology also remains relatively inexpensive, compared with other modalities; its safety has been well established through both study and long-term experience; and it provides real-time visualization, as opposed to images acquired at a particular point in time. Overall, ultrasound should be the first technology employed in the evaluation of the fetal anomaly.

Still, there are well-recognized limitations to sonographic evaluation.

The ability to visualize structures—and thus, the accuracy of a diagnosis—is significantly compromised, for instance, in women who are obese. This is far from a trivial concern today, as the rate of obesity in the United States is high and climbing.

Sonographic evaluation also may be limited by fetal position. Even in an average-size woman, for instance, suboptimal fetal positioning can impair proper visualization of structures.

Another common limitation is the descent of the fetal head into the maternal pelvis. Transvaginal ultrasound is an alternative approach, but the physics of the transvaginal transducer often prevents us from seeing in as many planes as would normally be desirable.

Ultrasound tends to be optimal during midpregnancy. Beyond this point, calcification of the fetal bone structure intensifies. Cranial ossification, for example, can substantially obscure the visualization of intracranial structures.

Finally, effective ultrasound evaluation requires fluid around the fetus. With oligohydramnios, the quality of the sonographic images is significantly compromised.

All told, these limitations are not infrequent or inconsequential. Clinicians commonly encounter such situations during the course of their work.

MRI Technique and Safety

Fetal magnetic resonance imaging provides excellent tissue contrast and is not limited by maternal obesity, skull calcification, or fetal position. It can image the fetus in multiple planes and accomplish this with a large field of view.

MRI can therefore play a valuable role when the findings from ultrasound are unclear or incomplete, or when there is potential for other anomalies that cannot be sufficiently visualized with ultrasound.

MRI relies on the presence of the high water content of tissues, and on the magnetic qualities of the constituent hydrogen nuclei. When tissue is placed in the strong magnetic field of an MRI machine, the hydrogen nuclei or protons move into particular alignments with the applied magnetic field.

Once the protons are lined up, radio frequency pulses are applied, causing the protons to absorb additional energy and spin on their axes of alignment. When the radio frequency pulses are discontinued, the additional energy that the protons had previously absorbed is released. It is this released energy that is transformed into an image. The quantity of energy released will vary depending on the tissue characteristics, such as the relative water and fat content.

Unlike x-ray and CT scans, MRI does not use ionizing radiation. Numerous studies and reports, including studies of MRI technicians who become pregnant, have demonstrated the safety of MRI and the lack of adverse clinical effects. The American College of Radiology published a series of white papers from 1993 to 2004 outlining MRI's safety. Thus, although the safety of MRI continues to be studied, there is no evidence to date that MRI produces harmful effects on human embryos or fetuses.

To be exceedingly cautious, most authorities and practitioners of MRI advise that it not be done in the first trimester.

Even without this extra caution, however, MRI would likely be discouraged in the first trimester because the increased noise-to-signal ratio from imaging such a small structure limits its benefit. It isn't until later in the second trimester, with increased fetal size and fat content, that the quality and resolution of the images achieve a threshold that conveys clinical benefit.

MRI's Leading Indications

MRI is indicated when there is potential for significant change in diagnosis or in patient management beyond the initial ultrasound.

Several studies from both the United States and Europe have demonstrated the clear capability of MRI to significantly modify or alter diagnosis, patient counseling, and management.

In one study of 124 fetuses with central nervous system anomalies detected initially by ultrasound, Dr. Deborah Levine of Harvard Medical School and her colleagues showed that fetal MRI led to 49 major changes in diagnosis and 27 clear changes in management, compared with prior ultrasound.

Suspected central nervous system anomalies—particularly brain anomalies—are, in fact, the most common indication for fetal MRI. There is some literature to support benefits of fetal MRI for other anatomical defects, but the literature provides the strongest evidence of MRI's additional benefit for CNS anomalies. Beyond the CNS, the other two main clinical indications for fetal MRI are for evaluation of the fetal neck and chest.

Among the anomalies and conditions best evaluated by fetal MRI are the following:

▸ Ventriculomegaly. Dilatation of the cerebral ventricles is a relatively common finding by prenatal diagnosticians. Although it is usually well visualized with ultrasound, ventriculomegaly may be accompanied by other associated abnormalities that may remain undetected with sonographic evaluation.

When ventriculomegaly is isolated with no other accompanying anatomical defects, the long-term prognosis is excellent. If there are associated abnormalities, however, the prognosis is significantly compromised, with much worse neurodevelopmental outcomes.

Fetal MRI can help identify those additional abnormalities. Studies from Europe and in the United States have documented significant percentages of cases in which apparently isolated ventriculomegaly was identified on the ultrasound, but was then found to be associated with additional anomalies on the follow-up MRI.

Even in cases with borderline ventricular dilatation, subtle but significant developmental abnormalities are frequently overlooked by ultrasound. MRI diagnosis can facilitate better counseling and prognostication regarding outcome, and can aid in the timely development of management strategies.

▸ Other brain anomalies. MRI can be advantageous for precisely visualizing deep structures of the brain, especially as gestational age advances and the skull becomes calcified. Sometimes, MRI enables visualization of deeper structures—such as the optic chiasma, pituitary stalk, and the pituitary—that are not visible on ultrasound.

Fetal MRI is also advantageous for visualizing subtle lesions of the brain, such as parenchymal infarcts and hemorrhage, and other abnormalities of cortical development. Such subtle anomalies can nevertheless be very consequential to long-term neurologic performance.

In our institution, we order an MRI whenever we see an anomaly of the brain. A persistently and significantly small fetal head with normal-appearing sonographic anatomy may, for example, reveal a lissencephaly syndrome on MRI exam. In patients with a significant family history of brain abnormalities, a confirmatory MRI of the fetal brain, despite a normal sonographic appearance, may be justifiable.

▸ Masses in the neck. MRI is thought to be particularly useful in assessing masses of the fetal neck and the potential for airway obstruction. Limitations of tissue differentiation on ultrasound may preclude a determination of the extent of infiltration of a neck mass. The panoramic view and tissue differentiation of the MRI may overcome this limitation.

These qualities are used to good advantage in determining whether a neck mass is infiltrating or obstructing the fetal airway, and whether it has the potential to prevent spontaneous breathing at delivery. Should such a situation be confirmed prenatally, an EXIT (ex utero intrapartum treatment) procedure can be planned. In this procedure, the fetus's head and shoulders are delivered and the placenta is left attached (maintaining umbilical circulation and fetal oxygenation) while a surgical intubation or tracheoscopy procedure is performed.

▸ Diaphragmatic hernia. Congenital diaphragmatic hernia is among the most common congenital thoracic lesions. Herniation of the abdominal viscus and organs into the chest can lead to compression of the lungs and lung hypoplasia at birth, precluding normal respiration. When the liver is also herniated into the chest, the chances of survival are sharply reduced.

Although possible, it can be difficult to determine herniation of the liver into the chest with ultrasound. MRI easily identifies thoracic displacement of the liver and therefore has prognostic value in congenital diaphragmatic hernia.

Limitations, Future Promise

Prenatal MRI does, however, have limitations. Because the technique is based on contrast between water and fat/lipids, it generally does not provide good quality images before about 24 weeks of gestation—a time period in which neurons, for instance, have not yet undergone significant myelination. Ultrasound, in contrast, tends to be quite effective earlier in pregnancy, which is a distinct advantage.

Availability of MRI technology and specific interest and expertise in fetal MRI also are significantly restricted, compared with ultrasound. Furthermore, MRI technology is significantly more costly than ultrasound at this time.

None of these limitations is immutable. All will likely be addressed or at least attenuated with the passage of time.

Just as important will be the development of a team approach to the use of MRI for fetal anomaly detection. Such an approach would involve embracing the expertise of the obstetrician in fetal anatomy and fetal anomalies in general. The interpretation of fetal MRI images should involve not only radiologists and pediatric subspecialists, such as pediatric neurologists, but also fetal medicine specialists working together.

The greatest promise of fetal MRI lies with further advances in so-called functional MRI. This has the potential to provide information not only about structural features of the anatomy, but about the function of various tissues as well. MRI studies could capitalize, for instance, on the fact that tissue that is injured or developmentally abnormal will have differences in metabolism, compared with normal tissue.

For example, animal studies have shown that the MRI signal of oxygenated hemoglobin is different from the MRI signal of deoxygenated hemoglobin. Utilizing such differences in fetal MRI imaging could enable us to identify oxygen deprivation in fetal and placental tissues.

Advances with MRI spectroscopy, moreover, could provide us with further detailed information on tissue metabolism. Collectively, such advances in MRI could revolutionize research and ultimately clinical assessment of the fetus.

Know the Fetus

The driving force in contemporary times behind the need to evaluate the fetus is the desire of parents to know the most about their fetus as early as possible. Medical indications also may dictate when fetal evaluation is conducted and fetal development assessed.

Prior to the development of ultrasound, such assessment was not possible. However, with the advent of ultrasound technology and other developments that have progressively increased its sophistication, ultrasound imaging has become a reality and an increasingly useful tool. It has been advancing at such a rapid rate that fetal imaging has moved from the third trimester to the second, and even to the first. Not only is fetal growth assessed, but some of the intricacies of fetal development are evaluated as well.

The invasive method of fetal evaluation has taken a similar pathway, expanding from amniocentesis to embryofetoscopy to chorionic-villus sampling to analyte markers in maternal blood. The desire to know more continues to drive the field.

Parents and their physicians call for the greatest possible degree of accuracy and information on the developing fetus.

Fetal MRI technology is an additional tool that is fast evolving in fetal medicine to meet this desire.

At the same time, many have appreciated the limitations of ultrasound technology, which are based upon maternal obesity, fetal position, gestational age, and developmental status of the fetus.

Because of its unique technology, MRI is able to provide added value and new information that was not heretofore possible using current ultrasound technology.

It is in this light that we believe that a Master Class addressing this newest evolving technology is in order.

We have invited Dr. Ray Bahado-Singh, a professor of maternal-fetal medicine at Wayne State University in Detroit and an expert in genetics and prenatal diagnosis, to discuss fetal MRI in detail and to highlight how this new technology may further advance the diagnosis of fetal anomalies.

Key Points

▸ MRI is a rapidly developing technology for fetal diagnosis, and maternal-fetal medicine specialists should develop expertise and collaboration with radiologists.

▸ Substantial clinical and research data demonstrate improvement of CNS diagnoses when MRI is performed after targeted ultrasound.

▸ Emerging data suggest improvement in diagnosis when MRI is used for neck and thoracic abnormalities, excluding the heart.

Hospital safety issues have been widely reported and have received significant attention recently. However, solutions have been slow in coming. Thus, the ongoing challenge of creating the safest labor and delivery environments possible has been left with obstetricians. Although the problem is daunting, there are many steps that obstetric and gynecologic practices can take on their own that will reduce adverse events in labor and delivery as well as optimize maternal-fetal outcomes.

Separate reports published almost a decade ago by the Institute of Medicine and the American Hospital Association estimated that 44,000–98,000 patients die each year from errors made during hospital stays.

That higher death rate accounts for almost double the number of people who die in motor vehicle accidents each year in this country, and double the number of women who die annually from breast cancer, according to the Centers for Disease Control and Prevention.

The problem is so severe that Dr. Mark R. Chassin, president of the Joint Commission (an independent, not-for-profit organization that accredits and certifies more than 15,000 health care organizations and programs in the United States), noted recently that the chance of any of us being injured from simply being in a hospital and not as the result of an illness is 40% greater than the likelihood of an airline mishandling our luggage.

The problem of inconsistent and dysfunctional clinical patterns of care in both the inpatient and outpatient settings is even more alarming. One large study involving the review of 18,000 patient charts found that only 55% of patients received care in keeping with current best practices (“Epidemic of Care: A Call for Safer, Better, and More Accountable Health Care.” San Francisco: Jossey-Bass, 2003).

Approximately 5 years ago, the Joint Commission examined all perinatal “sentinel” events across the country in all types of institutions, and found that 72% of such events were linked to breakdowns in communication.

Other identified root causes included staff competency (47%), staff orientation and training (40%), inadequate fetal monitoring (34%), unavailable equipment or drugs (30%), and physician-credentialing issues (30%).

Major issues of concern in the labor and delivery setting involve the fetal heart rate tracing, iatrogenic prematurity, shoulder dystocia, and operative delivery, as well as all the verbal and written communications that are involved with each of these areas.

An American College of Obstetricians and Gynecologists survey noted that the fetal heart tracing accounts for the majority of liability claims pertaining to labor and delivery.

Labor and delivery safety programs should therefore focus primarily on these issues, and on the following:

▸ Simplifying and standardizing protocols for care.

▸ Adopting evidence-based practices.

▸ Relying more on simulation and training.

▸ Working together as a team to accomplish defined goals.

Near-Miss Reporting

The real crux of any patient safety initiative—and the element that goes hand-in-hand with each of these aspects of a program—is a “near-miss” reporting system. This is a concept that medicine borrowed from the airline industry; it involves reporting any occurrence that could have resulted in an adverse event.

A near-miss reporting program is nonpunitive, and empowers everyone involved in the care of a patient to report events and happenings that they believe have the potential to cause problems for patients. Reports are made before injury happens and are reviewed in a blame-free environment. Systems can then be analyzed and modified to minimize recurrence of these events.

In fall 2005, a collaborative effort among the academic faculty at Eastern Virginia Medical School (EVMS) in Norfolk, the obstetric community faculty in that city, and Sentara Healthcare established the OB Right program, with the mission of minimizing iatrogenic injury to the mother and infant and reducing adverse patient safety events at labor and delivery. The “near-miss report form” used by the patient safety program at EVMS and Sentara Healthcare asks for descriptions of events that were “out of the ordinary” or “made you uncomfortable.” It also asks for suggested solutions.

The program has been enormously successful. Over the past 3 years, almost 230 near-misses have been reported by our physicians, residents, and nurses. Echoing the 2004 Joint Commission report, our near-miss reports have shown us that communication issues account for at as many as 60% of these potentially dangerous situations. These reports also have helped solidify a patient safety approach that gives special attention to fetal heart rate monitoring, shoulder dystocia, iatrogenic prematurity, and operative deliveries.

Setting Up a Program

At the time the OB Right program was established, it encompassed two hospitals in the Sentara Healthcare System: Sentara Norfolk General Hospital (the academic tertiary hospital of EVMS) and Sentara Leigh Hospital, (a community hospital in Norfolk that has no 24-hour in-house obstetric coverage). The purpose of including both hospitals was to ensure that the program is successful in both settings.

A steering committee was established immediately to oversee the program, and a clinical nurse specialist was recruited to coordinate program activities and serve as the link between the program and the staff. One of the nurse specialist's first tasks was identifying ways of communicating with physicians and staff, and later, letting them know early on of program successes.

The steering committee included physician leaders from the academic and community obstetric faculty, neonatology and anesthesiology physicians, nurse leaders, hospital administrators, risk managers, and representatives from liability insurance companies.

An education and practice committee was formed to review and recommend educational modules for physicians and staff, to research and develop protocols on best practices, to review practice patterns and recommend changes, to establish a simulation lab, and to implement emergency drills.

A data committee was established to identify retrospective and prospective variables for data collection, as well as data collection methods. Its members were also assigned the jobs of conducting patient and physician satisfaction surveys and of developing a system to collect, report, and debrief faculty and staff on reported near-misses.

Members of the technology committee led an effort to identify and develop technology that would improve patient safety at labor and delivery.

Building the Program

A critical look at all available protocols is a key component of a safety initiative. Simplifying and standardizing the oxytocin order set, for instance, was something we did early on.

It's important to ensure that everyone is speaking the same language. We were particularly struck by the importance of common language and common understanding in fetal heart rate monitoring. For example, early on we surveyed EVMS residents and labor and delivery nurses about how they defined uterine tachysystole. Responses were all over the board, with more than 20 different definitions.

Without a common definition, we realized, we would have not only varying recognition of the problem at labor and delivery, but also poor communication among health team members and the potential for harming the patient.

To prevent errors of mistaking fetal heart rate for maternal heart rate during labor, we adopted the National Institute for Child Health and Human Development's definitions of uterine tachysystole and fetal heart rate patterns. This was an important precursor to the development of protocols for addressing tachysystole and enhancing communication.

We also established universal monitoring of maternal and fetal heart rates. The maternal heart rate is continuously displayed on the fetal heart rate monitor, which substantially reduces the chance for error.

In addition, we studied our cesarean section response time and developed new response time guidelines that enabled us to clearly and efficiently communicate with anesthesiology regarding the various levels of urgency involved. Ultimately, we created four cesarean section categories that provided clear communication among health care teams and allowed for data collection and review. (See box above.)

To significantly reduce unnecessary prematurity and its associated morbidity, we implemented elective induction and cesarean section bundles that require either a gestational age of at least 39 weeks or documented fetal lung maturity.

These criteria are currently part of the national voluntary consensus standards for perinatal care in 2008 that were developed by a committee of the National Quality Forum.

Following much debate, we also implemented, at both hospitals, the universal collection of arterial and venous cord pH with every delivery. We have found this practice to be cost effective and to provide objective documentation of fetal intrapartum oxygenation. It also identifies neonates for targeted resuscitation and is a mechanism for continuous quality improvement. Given its potential controversy, however, this practice should not be at the top of the list for safety initiatives at labor and delivery.

Plans in the immediate future include a focus on shoulder dystocia, operative delivery, and triage of patients at labor and delivery.

Given the early success of OB Right, we decided to expand this program to the five other Sentara Healthcare hospitals that provide obstetric services in southeastern Virginia.

In order to achieve this goal, we have created a Clinical Effectiveness Council with physician/nurse team representation from each of the hospitals. The council meets monthly and is currently in the process of implementing key components of the OB Right program.

Keys to Success

We have learned that “buy-in” is key to an effective patient safety initiative. Hospital administration must devote the resources necessary for the success of the program, and both physicians and nurses must be at the table together and be involved as a team with a common safety goal.

A clinical safety coordinator is also essential to the success of a program. This person provides the consistency required and plays a critical role in communicating with the staff in the trenches.

Additionally, it is important to establish methods of communication early on, and to deliver and communicate tangible successes as soon as possible.

The OB Right program communicates with the health care team through posters on labor and delivery, and a newsletter that reports every 3 months on the issues and successes of the program. It also has a Web site with educational modules, near-miss reporting, meeting schedules and minutes, and other interactive tools.

Since OB Right began, we've almost eliminated elective deliveries at less than 39 weeks' gestation, and have achieved an almost-universal compliance with simultaneous maternal and fetal heart rate tracing and measurement of arterial and venous cord pH at both hospitals.

One of the major liability insurance companies sends a representative to the OB Right steering committee meetings and provides premium discounts for physician participation in the OB Right program.

As reported in the Institute of Medicine report “Crossing the Quality Chasm: A New Health System for the 21st Century,” the biggest challenge to moving toward a safer health system is changing the culture from one of blaming individuals for errors to one in which errors are treated not as personal failures but as opportunities to improve the system and prevent harm.

ELSEVIER GLOBAL MEDICAL NEWS

Quality of Care in Obstetrics

Patient safety has become an emphasized area of medicine in recent years. This is not to suggest that the issue of patient safety is new to medicine. Historically, it has been assumed to be a natural part of good medicine and the provision of good medical care.

In 1999, the Institute of Medicine released shocking statistics, estimating that as many as 98,000 people die in any given year as a result of medical errors that occur in hospitals. In the now well-cited report “To Err Is Human: Building a Safer Health Care System,” the IOM asserted that errors occur because good physicians and health care providers work within a bad system. It set a minimum goal of reducing errors by 50% over the next 5 years, and laid out a national agenda for improving patient safety.

This report was followed up by another IOM report published in 2001, “Crossing the Quality Chasm: A New Health Care System for the 21st Century.” This report further defined what kind of change is needed to “close the quality gap.” It provided overarching principles for clinicians, among others, and looked at how systems approaches can be used to implement change.

With both reports—two of many IOM studies and publications aimed at improving the nation's quality of care—a light has been shown nationally and internationally on the importance of not simply assuming that good quality care is part of medicine but, instead, emphasizing and critically analyzing the state of affairs relative to patient safety and quality of care.

Most of our institutions by now have implemented major organizational and structural changes aimed specifically at introducing safety and quality measures. These changes and structures—and the ensuing outcomes—must be monitored so that deviations from the currently available national best practices and standards of care can be identified and corrected.

In obstetrics in particular, where the litigious environment is so challenging, patient safety initiatives become even more important. For this reason, we believe that a Master Class highlighting a particular safety and quality of care initiative in obstetrics may both provide guidance and serve as a catalyst for other centers to emulate.

We have invited Dr. Alfred Z. Abuhamad to be our guest professor. Dr. Abuhamad serves as chairman of the department of ob.gyn. at the Eastern Virginia Medical School, Norfolk, and is the Mason C. Andrews Professor of Obstetrics and Gynecology there. He has played a key role in establishing a patient safety initiative in labor and delivery at EVMS and Sentara Healthcare, and will share, in detail, what he and his colleagues have learned in implementing this initiative.

Key Points About Patient Safety

▸ An estimated 44,000–98,000 patients die each year from errors made during hospital stays.

▸ Two-thirds of perinatal sentinel events are primarily linked to communication issues.

▸ Experience with the OB Right patient safety initiative at Eastern Virginia Medical School and Sentara Healthcare has demonstrated the importance of common language and common understanding when it comes to fetal heart rate monitoring.

▸ To significantly diminish unnecessary prematurity and its associated morbidity, patient safety initiatives should include elective induction and C-section bundles that require either a gestational age of at least 39 weeks or documented fetal lung maturity.

Hospital safety issues have been widely reported and have received significant attention recently. However, solutions have been slow in coming. Thus, the ongoing challenge of creating the safest labor and delivery environments possible has been left with obstetricians. Although the problem is daunting, there are many steps that obstetric and gynecologic practices can take on their own that will reduce adverse events in labor and delivery as well as optimize maternal-fetal outcomes.

Separate reports published almost a decade ago by the Institute of Medicine and the American Hospital Association estimated that 44,000–98,000 patients die each year from errors made during hospital stays.

That higher death rate accounts for almost double the number of people who die in motor vehicle accidents each year in this country, and double the number of women who die annually from breast cancer, according to the Centers for Disease Control and Prevention.

The problem is so severe that Dr. Mark R. Chassin, president of the Joint Commission (an independent, not-for-profit organization that accredits and certifies more than 15,000 health care organizations and programs in the United States), noted recently that the chance of any of us being injured from simply being in a hospital and not as the result of an illness is 40% greater than the likelihood of an airline mishandling our luggage.

The problem of inconsistent and dysfunctional clinical patterns of care in both the inpatient and outpatient settings is even more alarming. One large study involving the review of 18,000 patient charts found that only 55% of patients received care in keeping with current best practices (“Epidemic of Care: A Call for Safer, Better, and More Accountable Health Care.” San Francisco: Jossey-Bass, 2003).

Approximately 5 years ago, the Joint Commission examined all perinatal “sentinel” events across the country in all types of institutions, and found that 72% of such events were linked to breakdowns in communication.

Other identified root causes included staff competency (47%), staff orientation and training (40%), inadequate fetal monitoring (34%), unavailable equipment or drugs (30%), and physician-credentialing issues (30%).

Major issues of concern in the labor and delivery setting involve the fetal heart rate tracing, iatrogenic prematurity, shoulder dystocia, and operative delivery, as well as all the verbal and written communications that are involved with each of these areas.

An American College of Obstetricians and Gynecologists survey noted that the fetal heart tracing accounts for the majority of liability claims pertaining to labor and delivery.

Labor and delivery safety programs should therefore focus primarily on these issues, and on the following:

▸ Simplifying and standardizing protocols for care.

▸ Adopting evidence-based practices.

▸ Relying more on simulation and training.

▸ Working together as a team to accomplish defined goals.

Near-Miss Reporting

The real crux of any patient safety initiative—and the element that goes hand-in-hand with each of these aspects of a program—is a “near-miss” reporting system. This is a concept that medicine borrowed from the airline industry; it involves reporting any occurrence that could have resulted in an adverse event.

A near-miss reporting program is nonpunitive, and empowers everyone involved in the care of a patient to report events and happenings that they believe have the potential to cause problems for patients. Reports are made before injury happens and are reviewed in a blame-free environment. Systems can then be analyzed and modified to minimize recurrence of these events.

In fall 2005, a collaborative effort among the academic faculty at Eastern Virginia Medical School (EVMS) in Norfolk, the obstetric community faculty in that city, and Sentara Healthcare established the OB Right program, with the mission of minimizing iatrogenic injury to the mother and infant and reducing adverse patient safety events at labor and delivery. The “near-miss report form” used by the patient safety program at EVMS and Sentara Healthcare asks for descriptions of events that were “out of the ordinary” or “made you uncomfortable.” It also asks for suggested solutions.

The program has been enormously successful. Over the past 3 years, almost 230 near-misses have been reported by our physicians, residents, and nurses. Echoing the 2004 Joint Commission report, our near-miss reports have shown us that communication issues account for at as many as 60% of these potentially dangerous situations. These reports also have helped solidify a patient safety approach that gives special attention to fetal heart rate monitoring, shoulder dystocia, iatrogenic prematurity, and operative deliveries.

Setting Up a Program

At the time the OB Right program was established, it encompassed two hospitals in the Sentara Healthcare System: Sentara Norfolk General Hospital (the academic tertiary hospital of EVMS) and Sentara Leigh Hospital, (a community hospital in Norfolk that has no 24-hour in-house obstetric coverage). The purpose of including both hospitals was to ensure that the program is successful in both settings.

A steering committee was established immediately to oversee the program, and a clinical nurse specialist was recruited to coordinate program activities and serve as the link between the program and the staff. One of the nurse specialist's first tasks was identifying ways of communicating with physicians and staff, and later, letting them know early on of program successes.

The steering committee included physician leaders from the academic and community obstetric faculty, neonatology and anesthesiology physicians, nurse leaders, hospital administrators, risk managers, and representatives from liability insurance companies.

An education and practice committee was formed to review and recommend educational modules for physicians and staff, to research and develop protocols on best practices, to review practice patterns and recommend changes, to establish a simulation lab, and to implement emergency drills.

A data committee was established to identify retrospective and prospective variables for data collection, as well as data collection methods. Its members were also assigned the jobs of conducting patient and physician satisfaction surveys and of developing a system to collect, report, and debrief faculty and staff on reported near-misses.

Members of the technology committee led an effort to identify and develop technology that would improve patient safety at labor and delivery.

Building the Program

A critical look at all available protocols is a key component of a safety initiative. Simplifying and standardizing the oxytocin order set, for instance, was something we did early on.

It's important to ensure that everyone is speaking the same language. We were particularly struck by the importance of common language and common understanding in fetal heart rate monitoring. For example, early on we surveyed EVMS residents and labor and delivery nurses about how they defined uterine tachysystole. Responses were all over the board, with more than 20 different definitions.

Without a common definition, we realized, we would have not only varying recognition of the problem at labor and delivery, but also poor communication among health team members and the potential for harming the patient.

To prevent errors of mistaking fetal heart rate for maternal heart rate during labor, we adopted the National Institute for Child Health and Human Development's definitions of uterine tachysystole and fetal heart rate patterns. This was an important precursor to the development of protocols for addressing tachysystole and enhancing communication.

We also established universal monitoring of maternal and fetal heart rates. The maternal heart rate is continuously displayed on the fetal heart rate monitor, which substantially reduces the chance for error.

In addition, we studied our cesarean section response time and developed new response time guidelines that enabled us to clearly and efficiently communicate with anesthesiology regarding the various levels of urgency involved. Ultimately, we created four cesarean section categories that provided clear communication among health care teams and allowed for data collection and review. (See box above.)

To significantly reduce unnecessary prematurity and its associated morbidity, we implemented elective induction and cesarean section bundles that require either a gestational age of at least 39 weeks or documented fetal lung maturity.

These criteria are currently part of the national voluntary consensus standards for perinatal care in 2008 that were developed by a committee of the National Quality Forum.

Following much debate, we also implemented, at both hospitals, the universal collection of arterial and venous cord pH with every delivery. We have found this practice to be cost effective and to provide objective documentation of fetal intrapartum oxygenation. It also identifies neonates for targeted resuscitation and is a mechanism for continuous quality improvement. Given its potential controversy, however, this practice should not be at the top of the list for safety initiatives at labor and delivery.

Plans in the immediate future include a focus on shoulder dystocia, operative delivery, and triage of patients at labor and delivery.

Given the early success of OB Right, we decided to expand this program to the five other Sentara Healthcare hospitals that provide obstetric services in southeastern Virginia.

In order to achieve this goal, we have created a Clinical Effectiveness Council with physician/nurse team representation from each of the hospitals. The council meets monthly and is currently in the process of implementing key components of the OB Right program.

Keys to Success

We have learned that “buy-in” is key to an effective patient safety initiative. Hospital administration must devote the resources necessary for the success of the program, and both physicians and nurses must be at the table together and be involved as a team with a common safety goal.

A clinical safety coordinator is also essential to the success of a program. This person provides the consistency required and plays a critical role in communicating with the staff in the trenches.

Additionally, it is important to establish methods of communication early on, and to deliver and communicate tangible successes as soon as possible.

The OB Right program communicates with the health care team through posters on labor and delivery, and a newsletter that reports every 3 months on the issues and successes of the program. It also has a Web site with educational modules, near-miss reporting, meeting schedules and minutes, and other interactive tools.

Since OB Right began, we've almost eliminated elective deliveries at less than 39 weeks' gestation, and have achieved an almost-universal compliance with simultaneous maternal and fetal heart rate tracing and measurement of arterial and venous cord pH at both hospitals.

One of the major liability insurance companies sends a representative to the OB Right steering committee meetings and provides premium discounts for physician participation in the OB Right program.

As reported in the Institute of Medicine report “Crossing the Quality Chasm: A New Health System for the 21st Century,” the biggest challenge to moving toward a safer health system is changing the culture from one of blaming individuals for errors to one in which errors are treated not as personal failures but as opportunities to improve the system and prevent harm.

ELSEVIER GLOBAL MEDICAL NEWS

Quality of Care in Obstetrics

Patient safety has become an emphasized area of medicine in recent years. This is not to suggest that the issue of patient safety is new to medicine. Historically, it has been assumed to be a natural part of good medicine and the provision of good medical care.

In 1999, the Institute of Medicine released shocking statistics, estimating that as many as 98,000 people die in any given year as a result of medical errors that occur in hospitals. In the now well-cited report “To Err Is Human: Building a Safer Health Care System,” the IOM asserted that errors occur because good physicians and health care providers work within a bad system. It set a minimum goal of reducing errors by 50% over the next 5 years, and laid out a national agenda for improving patient safety.

This report was followed up by another IOM report published in 2001, “Crossing the Quality Chasm: A New Health Care System for the 21st Century.” This report further defined what kind of change is needed to “close the quality gap.” It provided overarching principles for clinicians, among others, and looked at how systems approaches can be used to implement change.

With both reports—two of many IOM studies and publications aimed at improving the nation's quality of care—a light has been shown nationally and internationally on the importance of not simply assuming that good quality care is part of medicine but, instead, emphasizing and critically analyzing the state of affairs relative to patient safety and quality of care.

Most of our institutions by now have implemented major organizational and structural changes aimed specifically at introducing safety and quality measures. These changes and structures—and the ensuing outcomes—must be monitored so that deviations from the currently available national best practices and standards of care can be identified and corrected.

In obstetrics in particular, where the litigious environment is so challenging, patient safety initiatives become even more important. For this reason, we believe that a Master Class highlighting a particular safety and quality of care initiative in obstetrics may both provide guidance and serve as a catalyst for other centers to emulate.

We have invited Dr. Alfred Z. Abuhamad to be our guest professor. Dr. Abuhamad serves as chairman of the department of ob.gyn. at the Eastern Virginia Medical School, Norfolk, and is the Mason C. Andrews Professor of Obstetrics and Gynecology there. He has played a key role in establishing a patient safety initiative in labor and delivery at EVMS and Sentara Healthcare, and will share, in detail, what he and his colleagues have learned in implementing this initiative.

Key Points About Patient Safety

▸ An estimated 44,000–98,000 patients die each year from errors made during hospital stays.

▸ Two-thirds of perinatal sentinel events are primarily linked to communication issues.

▸ Experience with the OB Right patient safety initiative at Eastern Virginia Medical School and Sentara Healthcare has demonstrated the importance of common language and common understanding when it comes to fetal heart rate monitoring.

▸ To significantly diminish unnecessary prematurity and its associated morbidity, patient safety initiatives should include elective induction and C-section bundles that require either a gestational age of at least 39 weeks or documented fetal lung maturity.

Hospital safety issues have been widely reported and have received significant attention recently. However, solutions have been slow in coming. Thus, the ongoing challenge of creating the safest labor and delivery environments possible has been left with obstetricians. Although the problem is daunting, there are many steps that obstetric and gynecologic practices can take on their own that will reduce adverse events in labor and delivery as well as optimize maternal-fetal outcomes.

Separate reports published almost a decade ago by the Institute of Medicine and the American Hospital Association estimated that 44,000–98,000 patients die each year from errors made during hospital stays.

That higher death rate accounts for almost double the number of people who die in motor vehicle accidents each year in this country, and double the number of women who die annually from breast cancer, according to the Centers for Disease Control and Prevention.

The problem is so severe that Dr. Mark R. Chassin, president of the Joint Commission (an independent, not-for-profit organization that accredits and certifies more than 15,000 health care organizations and programs in the United States), noted recently that the chance of any of us being injured from simply being in a hospital and not as the result of an illness is 40% greater than the likelihood of an airline mishandling our luggage.

The problem of inconsistent and dysfunctional clinical patterns of care in both the inpatient and outpatient settings is even more alarming. One large study involving the review of 18,000 patient charts found that only 55% of patients received care in keeping with current best practices (“Epidemic of Care: A Call for Safer, Better, and More Accountable Health Care.” San Francisco: Jossey-Bass, 2003).

Approximately 5 years ago, the Joint Commission examined all perinatal “sentinel” events across the country in all types of institutions, and found that 72% of such events were linked to breakdowns in communication.

Other identified root causes included staff competency (47%), staff orientation and training (40%), inadequate fetal monitoring (34%), unavailable equipment or drugs (30%), and physician-credentialing issues (30%).

Major issues of concern in the labor and delivery setting involve the fetal heart rate tracing, iatrogenic prematurity, shoulder dystocia, and operative delivery, as well as all the verbal and written communications that are involved with each of these areas.

An American College of Obstetricians and Gynecologists survey noted that the fetal heart tracing accounts for the majority of liability claims pertaining to labor and delivery.

Labor and delivery safety programs should therefore focus primarily on these issues, and on the following:

▸ Simplifying and standardizing protocols for care.

▸ Adopting evidence-based practices.

▸ Relying more on simulation and training.

▸ Working together as a team to accomplish defined goals.

Near-Miss Reporting

The real crux of any patient safety initiative—and the element that goes hand-in-hand with each of these aspects of a program—is a “near-miss” reporting system. This is a concept that medicine borrowed from the airline industry; it involves reporting any occurrence that could have resulted in an adverse event.

A near-miss reporting program is nonpunitive, and empowers everyone involved in the care of a patient to report events and happenings that they believe have the potential to cause problems for patients. Reports are made before injury happens and are reviewed in a blame-free environment. Systems can then be analyzed and modified to minimize recurrence of these events.

In fall 2005, a collaborative effort among the academic faculty at Eastern Virginia Medical School (EVMS) in Norfolk, the obstetric community faculty in that city, and Sentara Healthcare established the OB Right program, with the mission of minimizing iatrogenic injury to the mother and infant and reducing adverse patient safety events at labor and delivery. The “near-miss report form” used by the patient safety program at EVMS and Sentara Healthcare asks for descriptions of events that were “out of the ordinary” or “made you uncomfortable.” It also asks for suggested solutions.

The program has been enormously successful. Over the past 3 years, almost 230 near-misses have been reported by our physicians, residents, and nurses. Echoing the 2004 Joint Commission report, our near-miss reports have shown us that communication issues account for at as many as 60% of these potentially dangerous situations. These reports also have helped solidify a patient safety approach that gives special attention to fetal heart rate monitoring, shoulder dystocia, iatrogenic prematurity, and operative deliveries.

Setting Up a Program

At the time the OB Right program was established, it encompassed two hospitals in the Sentara Healthcare System: Sentara Norfolk General Hospital (the academic tertiary hospital of EVMS) and Sentara Leigh Hospital, (a community hospital in Norfolk that has no 24-hour in-house obstetric coverage). The purpose of including both hospitals was to ensure that the program is successful in both settings.

A steering committee was established immediately to oversee the program, and a clinical nurse specialist was recruited to coordinate program activities and serve as the link between the program and the staff. One of the nurse specialist's first tasks was identifying ways of communicating with physicians and staff, and later, letting them know early on of program successes.

The steering committee included physician leaders from the academic and community obstetric faculty, neonatology and anesthesiology physicians, nurse leaders, hospital administrators, risk managers, and representatives from liability insurance companies.

An education and practice committee was formed to review and recommend educational modules for physicians and staff, to research and develop protocols on best practices, to review practice patterns and recommend changes, to establish a simulation lab, and to implement emergency drills.

A data committee was established to identify retrospective and prospective variables for data collection, as well as data collection methods. Its members were also assigned the jobs of conducting patient and physician satisfaction surveys and of developing a system to collect, report, and debrief faculty and staff on reported near-misses.

Members of the technology committee led an effort to identify and develop technology that would improve patient safety at labor and delivery.

Building the Program

A critical look at all available protocols is a key component of a safety initiative. Simplifying and standardizing the oxytocin order set, for instance, was something we did early on.

It's important to ensure that everyone is speaking the same language. We were particularly struck by the importance of common language and common understanding in fetal heart rate monitoring. For example, early on we surveyed EVMS residents and labor and delivery nurses about how they defined uterine tachysystole. Responses were all over the board, with more than 20 different definitions.

Without a common definition, we realized, we would have not only varying recognition of the problem at labor and delivery, but also poor communication among health team members and the potential for harming the patient.

To prevent errors of mistaking fetal heart rate for maternal heart rate during labor, we adopted the National Institute for Child Health and Human Development's definitions of uterine tachysystole and fetal heart rate patterns. This was an important precursor to the development of protocols for addressing tachysystole and enhancing communication.

We also established universal monitoring of maternal and fetal heart rates. The maternal heart rate is continuously displayed on the fetal heart rate monitor, which substantially reduces the chance for error.

In addition, we studied our cesarean section response time and developed new response time guidelines that enabled us to clearly and efficiently communicate with anesthesiology regarding the various levels of urgency involved. Ultimately, we created four cesarean section categories that provided clear communication among health care teams and allowed for data collection and review. (See box above.)

To significantly reduce unnecessary prematurity and its associated morbidity, we implemented elective induction and cesarean section bundles that require either a gestational age of at least 39 weeks or documented fetal lung maturity.

These criteria are currently part of the national voluntary consensus standards for perinatal care in 2008 that were developed by a committee of the National Quality Forum.

Following much debate, we also implemented, at both hospitals, the universal collection of arterial and venous cord pH with every delivery. We have found this practice to be cost effective and to provide objective documentation of fetal intrapartum oxygenation. It also identifies neonates for targeted resuscitation and is a mechanism for continuous quality improvement. Given its potential controversy, however, this practice should not be at the top of the list for safety initiatives at labor and delivery.

Plans in the immediate future include a focus on shoulder dystocia, operative delivery, and triage of patients at labor and delivery.

Given the early success of OB Right, we decided to expand this program to the five other Sentara Healthcare hospitals that provide obstetric services in southeastern Virginia.

In order to achieve this goal, we have created a Clinical Effectiveness Council with physician/nurse team representation from each of the hospitals. The council meets monthly and is currently in the process of implementing key components of the OB Right program.

Keys to Success

We have learned that “buy-in” is key to an effective patient safety initiative. Hospital administration must devote the resources necessary for the success of the program, and both physicians and nurses must be at the table together and be involved as a team with a common safety goal.

A clinical safety coordinator is also essential to the success of a program. This person provides the consistency required and plays a critical role in communicating with the staff in the trenches.

Additionally, it is important to establish methods of communication early on, and to deliver and communicate tangible successes as soon as possible.

The OB Right program communicates with the health care team through posters on labor and delivery, and a newsletter that reports every 3 months on the issues and successes of the program. It also has a Web site with educational modules, near-miss reporting, meeting schedules and minutes, and other interactive tools.

Since OB Right began, we've almost eliminated elective deliveries at less than 39 weeks' gestation, and have achieved an almost-universal compliance with simultaneous maternal and fetal heart rate tracing and measurement of arterial and venous cord pH at both hospitals.

One of the major liability insurance companies sends a representative to the OB Right steering committee meetings and provides premium discounts for physician participation in the OB Right program.

As reported in the Institute of Medicine report “Crossing the Quality Chasm: A New Health System for the 21st Century,” the biggest challenge to moving toward a safer health system is changing the culture from one of blaming individuals for errors to one in which errors are treated not as personal failures but as opportunities to improve the system and prevent harm.

ELSEVIER GLOBAL MEDICAL NEWS

Quality of Care in Obstetrics

Patient safety has become an emphasized area of medicine in recent years. This is not to suggest that the issue of patient safety is new to medicine. Historically, it has been assumed to be a natural part of good medicine and the provision of good medical care.

In 1999, the Institute of Medicine released shocking statistics, estimating that as many as 98,000 people die in any given year as a result of medical errors that occur in hospitals. In the now well-cited report “To Err Is Human: Building a Safer Health Care System,” the IOM asserted that errors occur because good physicians and health care providers work within a bad system. It set a minimum goal of reducing errors by 50% over the next 5 years, and laid out a national agenda for improving patient safety.

This report was followed up by another IOM report published in 2001, “Crossing the Quality Chasm: A New Health Care System for the 21st Century.” This report further defined what kind of change is needed to “close the quality gap.” It provided overarching principles for clinicians, among others, and looked at how systems approaches can be used to implement change.

With both reports—two of many IOM studies and publications aimed at improving the nation's quality of care—a light has been shown nationally and internationally on the importance of not simply assuming that good quality care is part of medicine but, instead, emphasizing and critically analyzing the state of affairs relative to patient safety and quality of care.

Most of our institutions by now have implemented major organizational and structural changes aimed specifically at introducing safety and quality measures. These changes and structures—and the ensuing outcomes—must be monitored so that deviations from the currently available national best practices and standards of care can be identified and corrected.

In obstetrics in particular, where the litigious environment is so challenging, patient safety initiatives become even more important. For this reason, we believe that a Master Class highlighting a particular safety and quality of care initiative in obstetrics may both provide guidance and serve as a catalyst for other centers to emulate.

We have invited Dr. Alfred Z. Abuhamad to be our guest professor. Dr. Abuhamad serves as chairman of the department of ob.gyn. at the Eastern Virginia Medical School, Norfolk, and is the Mason C. Andrews Professor of Obstetrics and Gynecology there. He has played a key role in establishing a patient safety initiative in labor and delivery at EVMS and Sentara Healthcare, and will share, in detail, what he and his colleagues have learned in implementing this initiative.

Key Points About Patient Safety

▸ An estimated 44,000–98,000 patients die each year from errors made during hospital stays.

▸ Two-thirds of perinatal sentinel events are primarily linked to communication issues.

▸ Experience with the OB Right patient safety initiative at Eastern Virginia Medical School and Sentara Healthcare has demonstrated the importance of common language and common understanding when it comes to fetal heart rate monitoring.

▸ To significantly diminish unnecessary prematurity and its associated morbidity, patient safety initiatives should include elective induction and C-section bundles that require either a gestational age of at least 39 weeks or documented fetal lung maturity.

Despite several decades of extensive research into its pathogenesis, preeclampsia continues to be a syndrome of unknown etiology.

Several theories on the mechanisms leading to preeclampsia have been proposed, all based on numerous pathophysiological abnormalities reported in association with the heterogeneous disorder.

These theories, which have been developed largely during the past 2 decades, involve abnormalities such as impaired trophoblast differentiation and invasion, placental and endothelial dysfunction, immune maladaptation to paternal antigens, an exaggerated systemic inflammatory response, and a state of imbalance between proangiogenic and antiangiogenic factors.

As evidence for these theories has unfolded, investigators have identified numerous risk factors for preeclampsia. Most of them are preexisting risk factors that can be identified either before a patient becomes pregnant or early in the pregnancy. (See box below.)

The disorder's pathogenesis can vary in women with different risk factors or different times of onset. In women with previous preeclampsia, for example, the risk for developing recurrent preeclampsia varies depending on the underlying mechanism and the outcome in the previous pregnancy.

What this means is that even as investigators work to improve our understanding of the disorder, we as clinicians have an immediate opportunity—and responsibility—to identify patients who are at risk for preeclampsia, or recurrent preeclampsia, during preconception counseling or early in gestation.

We can then work with at-risk patients to optimize their health before conception and to carefully manage maternal and fetal well-being during pregnancy.

Women with a history of previous preeclampsia—even those who suffered serious adverse outcomes—should be counseled about their risks and reassured about our ability to optimize outcomes through vigilant monitoring, early detection of complications, and timely delivery.

And in an effort to improve their long-term health, these women should also be counseled about an increased risk for cardiovascular disease and ischemic stroke later in their lives.

Common Scenarios

A healthy 22-year-old woman with an ideal body weight and no preexisting medical risk factors who plans to become pregnant for the first time.

This patient's risk for preeclampsia is low (only 1%-2%). If preeclampsia occurs, it is likely to be mild, with an onset near term or intrapartum, and with generally good outcomes.

Nevertheless, it is important to inquire about any family history of preeclampsia or cardiovascular disease in this type of patient, and to be aware that women who themselves were born small for gestational age have an increased risk for preeclampsia, as does any woman whose husband or partner fathered a preeclamptic pregnancy in another woman.

Certain changes and events can also occur during pregnancy that will increase her risk. If, during antenatal care, ultrasound reveals multifetal gestation or unexplained fetal growth restriction, for instance, her risk of preeclampsia will increase substantially. (See box, page 9, top right.)

Likewise, if she develops gestational hypertension, her risk will increase to 25%-50% based on gestational age at the time the hypertension developed.

Several recently published studies have reported an association between maternal infections and an increased risk of preeclampsia as well. (Infections probably increase a maternal inflammatory response that already is engendered by the pregnancy itself.)

A systematic review published in 2006 found that the odds ratio for preeclampsia was 1.57 in women with urinary tract infections, and 1.76 in women with periodontal disease (N. Engl. J. Med. 2006;355:992-1005).

Unfortunately, the various biomarkers that have been proposed to predict which women are likely to develop preeclampsia—from serum placental growth factor to asymmetric dimethylarginine—have not been shown to be reliable and are not predictive or specific enough for use in clinical practice.

Likewise, supplementation with fish oil, vitamin E, vitamin C, low-dose aspirin, or calcium is not recommended for the prevention of preeclampsia in the young woman with no risk factors.

A 42-year-old who is trying to become pregnant for the first time.

This patient's older age is itself a risk factor for preeclampsia. An older age also often means more body weight and a higher likelihood of chronic hypertension or diabetes, as well as an increased likelihood that donated gametes were used, all of which can significantly increase risk.

As in the case of the younger patient, risk evaluation and management should begin before conception. Family history, personal birth history, and the history of the patient's husband or partner should be explored.

And because a high body mass index is a proven risk factor—as is insulin resistance, which is often linked with obesity—patients who are overweight or obese should be encouraged to lose weight and achieve a healthy BMI.

The risks associated with preexisting medical conditions like hypertension and diabetes vary depending on the conditions' severity.

Studies show, for instance, that women with mild hypertension before conception or early in pregnancy have a 15% rate of preeclampsia, whereas women with severe prepregnancy hypertension have a nearly 50% risk.

In all cases, women with chronic hypertension or diabetes should have their blood pressure and glucose levels optimized before conception, and then controlled throughout their pregnancy.

When assisted reproductive technology is planned, a discussion about the increased risk for preeclampsia that is caused by donated gametes is important, because donor insemination or the use of donated oocytes affects the maternal-fetal immune interaction and increases the risk of preeclampsia to as much as 35%.

Because multifetal gestation is more common with ART than with natural birth and is another risk factor for preeclampsia, this patient's overall risk can also be minimized by reducing the number of transferred embryos and by avoiding hyperstimulation when ovulation induction is required.

Just as in the case of the younger woman, unfortunately, we have little if anything else to offer this patient for the prevention of preeclampsia.

These women can be offered calcium, however. A recent review by the Food and Drug Administration concluded that any benefit with respect to preeclampsia is inconclusive and “unlikely” (Nutr. Rev. 2007;65:78-87).

However, in a 2007 Cochrane review of 12 clinical studies, calcium supplementation was associated with a reduction in the rate of preeclampsia, particularly in populations at high risk and in those with diets deficient in calcium (BJOG 2007;114:933-43).

Management should include a baseline metabolic profile and complete blood count, as well as baseline urinalysis; this information can be helpful if later laboratory studies are needed to assess the function of organ systems likely to be affected by preeclampsia.

Serial ultrasonography as well as uterine Doppler studies at 18-20 weeks should also be employed. The Doppler studies are a useful tool for assessing the velocity of the uterine artery blood flow.

An increased resistance index and/or the presence of uterine artery diastolic notching suggests an increased risk of preeclampsia (as much as a sixfold increased risk) and the need for more vigilant monitoring and care.

A woman who developed severe preeclampsia at 26 weeks' gestation in her first pregnancy. She wants a child but is afraid—terribly and understandably frightened—of a second pregnancy because her first baby was born prematurely and died after about 100 days in the NICU.

We can and should reassure this patient that her loss does not mean she should forego becoming pregnant again, and that with proper monitoring, she has a significant chance of having a healthy baby.

A woman's risk of preeclampsia recurrence will depend on whether or not she has any preexisting risk factors, as well as the gestational age at the time of onset of preeclampsia in her first pregnancy.

The reported rate of recurrent preeclampsia ranges from 11.5% to 65%, with the highest rates being reported in women whose previous preeclampsia occurred in the second trimester. This patient's risk of recurrent preeclampsia is about 50%.

In general, recurrent preeclampsia is more likely to be severe and to develop preterm than is first-time preeclampsia. We can reassure this patient, however, that an early onset of preeclampsia in the first pregnancy does not necessarily mean that the disorder will have an early onset in the second pregnancy.

In a study published in 1991, among women with previous preeclampsia in the second trimester, preeclampsia recurred in the second trimester in 21%, at 28-36 weeks in 21%, and at term in 23% (Am. J. Obstet. Gynecol. 1991;165:1408-12).

Women with a history of eclampsia have a rate of recurrence of 1%-2% and a rate of subsequent preeclampsia of 22%-35%. Women with a history of HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome have a rate of preeclampsia in subsequent pregnancies of 16%-52% and, according to the most reliable data, a rate of recurrent HELLP syndrome of less than 5%.

Management for this patient ideally begins before conception, with an extensive evaluation and an in-depth history to uncover preexisting risk factors and/or medical conditions associated with the disorder.

This will allow proper counseling about the magnitude of risk for preeclampsia recurrence, and will guide you as you manage the pregnancy. (See box, bottom left.)

Knowing when she developed preeclampsia is important, as are details about maternal complications such as HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome, pulmonary edema, or renal failure, for instance; about fetal complications, such as fetal growth restriction; and about previous laboratory test results, as well as placental pathology.

The status of any comorbidities, such as high BMI or high blood pressure, should be optimized before conception, and vigilant monitoring—including early and serial ultrasonography, uterine Doppler assessment at 18-20 weeks, and laboratory testing as indicated—should be instituted to minimize and manage her risk.

By detecting complications early and monitoring for signs and symptoms of preeclampsia—and then hospitalizing her if you detect severe gestational hypertension, fetal growth restriction, or recurrent preeclampsia—you can ensure optimal outcomes.

This patient will probably want to know about the value of various biomarkers and supplements, such as fish oil and vitamins C and E, and again, we need to explain that the best studies have shown minimal to no benefit and do not support their use.

The three large randomized trials looking at vitamin E supplementation, for example, showed no effect on the rate of preeclampsia, its severity, or the rate of adverse neonatal outcomes.

None of the randomized trials on calcium supplementation included women with a previous history of preeclampsia, so the benefit for this indication remains unclear. Nevertheless, because calcium is beneficial for any pregnancy, we recommend it.

The greatest benefits of low-dose aspirin may come for this patient. A recent meta-analysis of 31 randomized trials found a 14% reduction in recurrent preeclampsia—higher than that seen for first-time preeclampsia (Lancet 2007;369:1791-8). Low-dose aspirin has also proved to be safe. We recommend 81 mg daily beginning at 12 weeks' gestation, and suggest discontinuing aspirin with the development of preeclampsia.

If the patient has documented evidence of antiphospholipid antibody syndrome, she should receive prophylactic-dose heparin in addition to low-dose aspirin once fetal viability is confirmed.

A woman who had late-occurring mild preeclampsia in her first pregnancy, and is planning a second child.

This patient experienced the most common presentation of preeclampsia, and fortunately has a fairly low risk for recurrence (about 10%). Chances are also likely that if preeclampsia recurs, it will recur at term.

This risk can be minimized and a good outcome ensured by following the same approach to history taking, counseling, and optimizing health before conception, as well as careful monitoring during pregnancy to detect complications early.

Risks Later in Life

Today, counseling women with a history of preeclampsia involves more than assessing and minimizing risks for recurrence of the disorder. It also involves discussing the now-substantial body of literature that suggests that women whose pregnancies are complicated by preeclampsia and/or fetal growth restriction have an increased risk for future cardiovascular disease and ischemic stroke.

These women require close follow-up after their pregnancies so that their long-term risks can be reduced or avoided through the use of preventive strategies and approaches to care.

Preeclampsia and fetal growth restriction are both vascular-related pregnancy complications, and they share similar risk factors and pathophysiological abnormalities, such as endothelial dysfunction.

It's unclear exactly what mechanisms account for the relationship among these complications and the increased risk of subsequent cardiovascular disease, but it increasingly seems likely that these women have a predisposition to vascular and metabolic disease: a constitutional risk.

Epidemiologic and case-control studies published in the last 10 years—many of them in the nonobstetric literature—have evaluated the associations, and last year a systematic review and meta-analysis of these studies reported a relative risk for chronic hypertension of 3.7 after approximately 14 years of average follow-up, a relative risk of 2.16 for ischemic heart disease after about 11 years of follow-up, and a relative risk of 1.8 for ischemic stroke after about 10 years (BMJ 2007;335:974-85).

In addition, overall mortality after preeclampsia was increased by a relative risk of approximately 1.5 after 14.5 years of follow-up.

In a recently published intergenerational case-control study, Dutch investigators looked at 106 women whose pregnancies were complicated by preeclampsia or fetal growth restriction, a control group of 106 women with normal pregnancies, and each woman's mother and father.

They found significant intergenerational similarities in cardiovascular risk profiles between the women after preeclampsia or fetal growth restriction and their parents, such as higher fasting glucose levels that could not be explained by differences in BMI.

Intergenerational similarities were also found for hypertension, waist circumference, and metabolic syndrome (Hypertension 2008;51:1034-41).

ELSEVIER GLOBAL MEDICAL NEWS

Preeclampsia, Part 3

The exact incidence of preeclampsia is unknown, but in its mild form it is estimated to affect up to 10% of all pregnancies. Indeed, it is one of the most common complications of pregnancy. In a smaller number of cases (just under 1% of pregnancies), the disorder develops as severe preeclampsia.

In the past two Master Class installments on preeclampsia, we have discussed how the disorder presents in various ways, afflicting women of different age groups, of varying parity, and with associated medical complications or the lack thereof.

We have also discussed appropriate evaluation and management protocols. The spectrum of disease is such that it spans the very mild (requiring modest intervention) to the very severe (requiring immediate and aggressive intervention strategies). As we saw in the last installment, it is important to view preeclampsia as a multifaceted disease continuum in which designations of “mild” and “severe” are not necessarily fixed.

The variable presentation of the disorder—and the fact that it cannot be precisely predicted or prevented—may in itself be challenging to the practitioner, as he or she counsels patients who are contemplating pregnancies and may be at risk for preeclampsia.

There are certain predisposing medical and sociodemographic factors, however, that are clearly important and that can be useful if they are integrated into an evaluation and management algorithm. Integrating our knowledge of risk factors allows for the most appropriate counseling to be delivered, and the most appropriate management plan to be developed, on a case-by-case basis.

I have invited Dr. Baha Sibai to once again address the topic of preeclampsia in this third and final installment of our series on the disorder. Dr. Sibai is professor of obstetrics and gynecology at the University of Cincinnati and an international expert on preeclampsia and eclampsia, as well as a leader in both clinical care and research in this area.

In this case, we've taken a different approach to presenting the material. We think our case-by-case format will be practical and applicable to the practitioner who is counseling a number of patients who present with varying histories and risk factors.

How to Manage Recurrence Risk

Preconception

▸ Identify risk factors.

▸ Review outcome of previous pregnancy.

▸ Optimize maternal health.

First Trimester

▸ Perform ultrasonography for dating and assessing fetal number.

▸ Order baseline metabolic profile and complete blood count.

▸ Perform baseline urinalysis.

▸ Offer first-trimester combined screening.

▸ If antiphospholipid syndrome is documented, start low-dose aspirin and heparin. Otherwise, offer low-dose aspirin therapy at 12 weeks' gestation.

Second Trimester

▸ Monitor for signs and symptoms of preeclampsia.

▸ Perform ultrasonography at 18-22 weeks' gestation for fetal anomaly evaluation and to rule out molar gestation.

▸ Perform uterine Doppler studies at 18-20 weeks.

Third Trimester

▸ Monitor for signs and symptoms of preeclampsia.

▸ As indicated by the clinical situation, perform laboratory testing, serial ultrasonography (for fetal growth and amniotic fluid assessment), and umbilical artery Doppler with a nonstress test and/or biophysical profile.

▸ Hospitalize for severe gestational hypertension, fetal growth restriction, or recurrent preeclampsia.

Post Partum

▸ Counsel patient about an increased risk for cardiovascular disease and ischemic stroke.

▸ Encourage close follow-up and prevention.

Source: Adapted from Obstet. Gynecol. 2008;112:359-72

Risk Factors for Preeclampsia

The magnitude of risk depends on the number of factors, which include the following:

▸ Multifetal gestation.

▸ Unexplained fetal growth restriction.

▸ Gestational hypertension.

▸ Hydrops/hydropic degeneration of placenta (triploidy, trisomy 13).

▸ Urinary-tract and periodontal infections.

▸ Biophysical and biochemical markers.

Source: Adapted from Obstet. Gynecol. 2008;112:359-72

Despite several decades of extensive research into its pathogenesis, preeclampsia continues to be a syndrome of unknown etiology.

Several theories on the mechanisms leading to preeclampsia have been proposed, all based on numerous pathophysiological abnormalities reported in association with the heterogeneous disorder.

These theories, which have been developed largely during the past 2 decades, involve abnormalities such as impaired trophoblast differentiation and invasion, placental and endothelial dysfunction, immune maladaptation to paternal antigens, an exaggerated systemic inflammatory response, and a state of imbalance between proangiogenic and antiangiogenic factors.

As evidence for these theories has unfolded, investigators have identified numerous risk factors for preeclampsia. Most of them are preexisting risk factors that can be identified either before a patient becomes pregnant or early in the pregnancy. (See box below.)

The disorder's pathogenesis can vary in women with different risk factors or different times of onset. In women with previous preeclampsia, for example, the risk for developing recurrent preeclampsia varies depending on the underlying mechanism and the outcome in the previous pregnancy.

What this means is that even as investigators work to improve our understanding of the disorder, we as clinicians have an immediate opportunity—and responsibility—to identify patients who are at risk for preeclampsia, or recurrent preeclampsia, during preconception counseling or early in gestation.

We can then work with at-risk patients to optimize their health before conception and to carefully manage maternal and fetal well-being during pregnancy.

Women with a history of previous preeclampsia—even those who suffered serious adverse outcomes—should be counseled about their risks and reassured about our ability to optimize outcomes through vigilant monitoring, early detection of complications, and timely delivery.

And in an effort to improve their long-term health, these women should also be counseled about an increased risk for cardiovascular disease and ischemic stroke later in their lives.

Common Scenarios

A healthy 22-year-old woman with an ideal body weight and no preexisting medical risk factors who plans to become pregnant for the first time.

This patient's risk for preeclampsia is low (only 1%-2%). If preeclampsia occurs, it is likely to be mild, with an onset near term or intrapartum, and with generally good outcomes.

Nevertheless, it is important to inquire about any family history of preeclampsia or cardiovascular disease in this type of patient, and to be aware that women who themselves were born small for gestational age have an increased risk for preeclampsia, as does any woman whose husband or partner fathered a preeclamptic pregnancy in another woman.

Certain changes and events can also occur during pregnancy that will increase her risk. If, during antenatal care, ultrasound reveals multifetal gestation or unexplained fetal growth restriction, for instance, her risk of preeclampsia will increase substantially. (See box, page 9, top right.)

Likewise, if she develops gestational hypertension, her risk will increase to 25%-50% based on gestational age at the time the hypertension developed.

Several recently published studies have reported an association between maternal infections and an increased risk of preeclampsia as well. (Infections probably increase a maternal inflammatory response that already is engendered by the pregnancy itself.)

A systematic review published in 2006 found that the odds ratio for preeclampsia was 1.57 in women with urinary tract infections, and 1.76 in women with periodontal disease (N. Engl. J. Med. 2006;355:992-1005).

Unfortunately, the various biomarkers that have been proposed to predict which women are likely to develop preeclampsia—from serum placental growth factor to asymmetric dimethylarginine—have not been shown to be reliable and are not predictive or specific enough for use in clinical practice.

Likewise, supplementation with fish oil, vitamin E, vitamin C, low-dose aspirin, or calcium is not recommended for the prevention of preeclampsia in the young woman with no risk factors.

A 42-year-old who is trying to become pregnant for the first time.

This patient's older age is itself a risk factor for preeclampsia. An older age also often means more body weight and a higher likelihood of chronic hypertension or diabetes, as well as an increased likelihood that donated gametes were used, all of which can significantly increase risk.

As in the case of the younger patient, risk evaluation and management should begin before conception. Family history, personal birth history, and the history of the patient's husband or partner should be explored.

And because a high body mass index is a proven risk factor—as is insulin resistance, which is often linked with obesity—patients who are overweight or obese should be encouraged to lose weight and achieve a healthy BMI.

The risks associated with preexisting medical conditions like hypertension and diabetes vary depending on the conditions' severity.

Studies show, for instance, that women with mild hypertension before conception or early in pregnancy have a 15% rate of preeclampsia, whereas women with severe prepregnancy hypertension have a nearly 50% risk.

In all cases, women with chronic hypertension or diabetes should have their blood pressure and glucose levels optimized before conception, and then controlled throughout their pregnancy.

When assisted reproductive technology is planned, a discussion about the increased risk for preeclampsia that is caused by donated gametes is important, because donor insemination or the use of donated oocytes affects the maternal-fetal immune interaction and increases the risk of preeclampsia to as much as 35%.

Because multifetal gestation is more common with ART than with natural birth and is another risk factor for preeclampsia, this patient's overall risk can also be minimized by reducing the number of transferred embryos and by avoiding hyperstimulation when ovulation induction is required.

Just as in the case of the younger woman, unfortunately, we have little if anything else to offer this patient for the prevention of preeclampsia.

These women can be offered calcium, however. A recent review by the Food and Drug Administration concluded that any benefit with respect to preeclampsia is inconclusive and “unlikely” (Nutr. Rev. 2007;65:78-87).

However, in a 2007 Cochrane review of 12 clinical studies, calcium supplementation was associated with a reduction in the rate of preeclampsia, particularly in populations at high risk and in those with diets deficient in calcium (BJOG 2007;114:933-43).

Management should include a baseline metabolic profile and complete blood count, as well as baseline urinalysis; this information can be helpful if later laboratory studies are needed to assess the function of organ systems likely to be affected by preeclampsia.

Serial ultrasonography as well as uterine Doppler studies at 18-20 weeks should also be employed. The Doppler studies are a useful tool for assessing the velocity of the uterine artery blood flow.

An increased resistance index and/or the presence of uterine artery diastolic notching suggests an increased risk of preeclampsia (as much as a sixfold increased risk) and the need for more vigilant monitoring and care.

A woman who developed severe preeclampsia at 26 weeks' gestation in her first pregnancy. She wants a child but is afraid—terribly and understandably frightened—of a second pregnancy because her first baby was born prematurely and died after about 100 days in the NICU.

We can and should reassure this patient that her loss does not mean she should forego becoming pregnant again, and that with proper monitoring, she has a significant chance of having a healthy baby.

A woman's risk of preeclampsia recurrence will depend on whether or not she has any preexisting risk factors, as well as the gestational age at the time of onset of preeclampsia in her first pregnancy.

The reported rate of recurrent preeclampsia ranges from 11.5% to 65%, with the highest rates being reported in women whose previous preeclampsia occurred in the second trimester. This patient's risk of recurrent preeclampsia is about 50%.

In general, recurrent preeclampsia is more likely to be severe and to develop preterm than is first-time preeclampsia. We can reassure this patient, however, that an early onset of preeclampsia in the first pregnancy does not necessarily mean that the disorder will have an early onset in the second pregnancy.

In a study published in 1991, among women with previous preeclampsia in the second trimester, preeclampsia recurred in the second trimester in 21%, at 28-36 weeks in 21%, and at term in 23% (Am. J. Obstet. Gynecol. 1991;165:1408-12).

Women with a history of eclampsia have a rate of recurrence of 1%-2% and a rate of subsequent preeclampsia of 22%-35%. Women with a history of HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome have a rate of preeclampsia in subsequent pregnancies of 16%-52% and, according to the most reliable data, a rate of recurrent HELLP syndrome of less than 5%.

Management for this patient ideally begins before conception, with an extensive evaluation and an in-depth history to uncover preexisting risk factors and/or medical conditions associated with the disorder.

This will allow proper counseling about the magnitude of risk for preeclampsia recurrence, and will guide you as you manage the pregnancy. (See box, bottom left.)

Knowing when she developed preeclampsia is important, as are details about maternal complications such as HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome, pulmonary edema, or renal failure, for instance; about fetal complications, such as fetal growth restriction; and about previous laboratory test results, as well as placental pathology.

The status of any comorbidities, such as high BMI or high blood pressure, should be optimized before conception, and vigilant monitoring—including early and serial ultrasonography, uterine Doppler assessment at 18-20 weeks, and laboratory testing as indicated—should be instituted to minimize and manage her risk.

By detecting complications early and monitoring for signs and symptoms of preeclampsia—and then hospitalizing her if you detect severe gestational hypertension, fetal growth restriction, or recurrent preeclampsia—you can ensure optimal outcomes.

This patient will probably want to know about the value of various biomarkers and supplements, such as fish oil and vitamins C and E, and again, we need to explain that the best studies have shown minimal to no benefit and do not support their use.

The three large randomized trials looking at vitamin E supplementation, for example, showed no effect on the rate of preeclampsia, its severity, or the rate of adverse neonatal outcomes.

None of the randomized trials on calcium supplementation included women with a previous history of preeclampsia, so the benefit for this indication remains unclear. Nevertheless, because calcium is beneficial for any pregnancy, we recommend it.

The greatest benefits of low-dose aspirin may come for this patient. A recent meta-analysis of 31 randomized trials found a 14% reduction in recurrent preeclampsia—higher than that seen for first-time preeclampsia (Lancet 2007;369:1791-8). Low-dose aspirin has also proved to be safe. We recommend 81 mg daily beginning at 12 weeks' gestation, and suggest discontinuing aspirin with the development of preeclampsia.

If the patient has documented evidence of antiphospholipid antibody syndrome, she should receive prophylactic-dose heparin in addition to low-dose aspirin once fetal viability is confirmed.

A woman who had late-occurring mild preeclampsia in her first pregnancy, and is planning a second child.

This patient experienced the most common presentation of preeclampsia, and fortunately has a fairly low risk for recurrence (about 10%). Chances are also likely that if preeclampsia recurs, it will recur at term.

This risk can be minimized and a good outcome ensured by following the same approach to history taking, counseling, and optimizing health before conception, as well as careful monitoring during pregnancy to detect complications early.

Risks Later in Life

Today, counseling women with a history of preeclampsia involves more than assessing and minimizing risks for recurrence of the disorder. It also involves discussing the now-substantial body of literature that suggests that women whose pregnancies are complicated by preeclampsia and/or fetal growth restriction have an increased risk for future cardiovascular disease and ischemic stroke.

These women require close follow-up after their pregnancies so that their long-term risks can be reduced or avoided through the use of preventive strategies and approaches to care.

Preeclampsia and fetal growth restriction are both vascular-related pregnancy complications, and they share similar risk factors and pathophysiological abnormalities, such as endothelial dysfunction.

It's unclear exactly what mechanisms account for the relationship among these complications and the increased risk of subsequent cardiovascular disease, but it increasingly seems likely that these women have a predisposition to vascular and metabolic disease: a constitutional risk.

Epidemiologic and case-control studies published in the last 10 years—many of them in the nonobstetric literature—have evaluated the associations, and last year a systematic review and meta-analysis of these studies reported a relative risk for chronic hypertension of 3.7 after approximately 14 years of average follow-up, a relative risk of 2.16 for ischemic heart disease after about 11 years of follow-up, and a relative risk of 1.8 for ischemic stroke after about 10 years (BMJ 2007;335:974-85).

In addition, overall mortality after preeclampsia was increased by a relative risk of approximately 1.5 after 14.5 years of follow-up.

In a recently published intergenerational case-control study, Dutch investigators looked at 106 women whose pregnancies were complicated by preeclampsia or fetal growth restriction, a control group of 106 women with normal pregnancies, and each woman's mother and father.

They found significant intergenerational similarities in cardiovascular risk profiles between the women after preeclampsia or fetal growth restriction and their parents, such as higher fasting glucose levels that could not be explained by differences in BMI.

Intergenerational similarities were also found for hypertension, waist circumference, and metabolic syndrome (Hypertension 2008;51:1034-41).

ELSEVIER GLOBAL MEDICAL NEWS

Preeclampsia, Part 3

The exact incidence of preeclampsia is unknown, but in its mild form it is estimated to affect up to 10% of all pregnancies. Indeed, it is one of the most common complications of pregnancy. In a smaller number of cases (just under 1% of pregnancies), the disorder develops as severe preeclampsia.

In the past two Master Class installments on preeclampsia, we have discussed how the disorder presents in various ways, afflicting women of different age groups, of varying parity, and with associated medical complications or the lack thereof.

We have also discussed appropriate evaluation and management protocols. The spectrum of disease is such that it spans the very mild (requiring modest intervention) to the very severe (requiring immediate and aggressive intervention strategies). As we saw in the last installment, it is important to view preeclampsia as a multifaceted disease continuum in which designations of “mild” and “severe” are not necessarily fixed.

The variable presentation of the disorder—and the fact that it cannot be precisely predicted or prevented—may in itself be challenging to the practitioner, as he or she counsels patients who are contemplating pregnancies and may be at risk for preeclampsia.

There are certain predisposing medical and sociodemographic factors, however, that are clearly important and that can be useful if they are integrated into an evaluation and management algorithm. Integrating our knowledge of risk factors allows for the most appropriate counseling to be delivered, and the most appropriate management plan to be developed, on a case-by-case basis.

I have invited Dr. Baha Sibai to once again address the topic of preeclampsia in this third and final installment of our series on the disorder. Dr. Sibai is professor of obstetrics and gynecology at the University of Cincinnati and an international expert on preeclampsia and eclampsia, as well as a leader in both clinical care and research in this area.

In this case, we've taken a different approach to presenting the material. We think our case-by-case format will be practical and applicable to the practitioner who is counseling a number of patients who present with varying histories and risk factors.

How to Manage Recurrence Risk

Preconception

▸ Identify risk factors.

▸ Review outcome of previous pregnancy.

▸ Optimize maternal health.

First Trimester

▸ Perform ultrasonography for dating and assessing fetal number.

▸ Order baseline metabolic profile and complete blood count.

▸ Perform baseline urinalysis.

▸ Offer first-trimester combined screening.

▸ If antiphospholipid syndrome is documented, start low-dose aspirin and heparin. Otherwise, offer low-dose aspirin therapy at 12 weeks' gestation.

Second Trimester

▸ Monitor for signs and symptoms of preeclampsia.

▸ Perform ultrasonography at 18-22 weeks' gestation for fetal anomaly evaluation and to rule out molar gestation.

▸ Perform uterine Doppler studies at 18-20 weeks.

Third Trimester

▸ Monitor for signs and symptoms of preeclampsia.

▸ As indicated by the clinical situation, perform laboratory testing, serial ultrasonography (for fetal growth and amniotic fluid assessment), and umbilical artery Doppler with a nonstress test and/or biophysical profile.

▸ Hospitalize for severe gestational hypertension, fetal growth restriction, or recurrent preeclampsia.

Post Partum

▸ Counsel patient about an increased risk for cardiovascular disease and ischemic stroke.

▸ Encourage close follow-up and prevention.

Source: Adapted from Obstet. Gynecol. 2008;112:359-72

Risk Factors for Preeclampsia

The magnitude of risk depends on the number of factors, which include the following:

▸ Multifetal gestation.

▸ Unexplained fetal growth restriction.

▸ Gestational hypertension.

▸ Hydrops/hydropic degeneration of placenta (triploidy, trisomy 13).

▸ Urinary-tract and periodontal infections.

▸ Biophysical and biochemical markers.

Source: Adapted from Obstet. Gynecol. 2008;112:359-72

Despite several decades of extensive research into its pathogenesis, preeclampsia continues to be a syndrome of unknown etiology.

Several theories on the mechanisms leading to preeclampsia have been proposed, all based on numerous pathophysiological abnormalities reported in association with the heterogeneous disorder.

These theories, which have been developed largely during the past 2 decades, involve abnormalities such as impaired trophoblast differentiation and invasion, placental and endothelial dysfunction, immune maladaptation to paternal antigens, an exaggerated systemic inflammatory response, and a state of imbalance between proangiogenic and antiangiogenic factors.

As evidence for these theories has unfolded, investigators have identified numerous risk factors for preeclampsia. Most of them are preexisting risk factors that can be identified either before a patient becomes pregnant or early in the pregnancy. (See box below.)

The disorder's pathogenesis can vary in women with different risk factors or different times of onset. In women with previous preeclampsia, for example, the risk for developing recurrent preeclampsia varies depending on the underlying mechanism and the outcome in the previous pregnancy.

What this means is that even as investigators work to improve our understanding of the disorder, we as clinicians have an immediate opportunity—and responsibility—to identify patients who are at risk for preeclampsia, or recurrent preeclampsia, during preconception counseling or early in gestation.

We can then work with at-risk patients to optimize their health before conception and to carefully manage maternal and fetal well-being during pregnancy.

Women with a history of previous preeclampsia—even those who suffered serious adverse outcomes—should be counseled about their risks and reassured about our ability to optimize outcomes through vigilant monitoring, early detection of complications, and timely delivery.

And in an effort to improve their long-term health, these women should also be counseled about an increased risk for cardiovascular disease and ischemic stroke later in their lives.

Common Scenarios

A healthy 22-year-old woman with an ideal body weight and no preexisting medical risk factors who plans to become pregnant for the first time.

This patient's risk for preeclampsia is low (only 1%-2%). If preeclampsia occurs, it is likely to be mild, with an onset near term or intrapartum, and with generally good outcomes.

Nevertheless, it is important to inquire about any family history of preeclampsia or cardiovascular disease in this type of patient, and to be aware that women who themselves were born small for gestational age have an increased risk for preeclampsia, as does any woman whose husband or partner fathered a preeclamptic pregnancy in another woman.

Certain changes and events can also occur during pregnancy that will increase her risk. If, during antenatal care, ultrasound reveals multifetal gestation or unexplained fetal growth restriction, for instance, her risk of preeclampsia will increase substantially. (See box, page 9, top right.)

Likewise, if she develops gestational hypertension, her risk will increase to 25%-50% based on gestational age at the time the hypertension developed.

Several recently published studies have reported an association between maternal infections and an increased risk of preeclampsia as well. (Infections probably increase a maternal inflammatory response that already is engendered by the pregnancy itself.)

A systematic review published in 2006 found that the odds ratio for preeclampsia was 1.57 in women with urinary tract infections, and 1.76 in women with periodontal disease (N. Engl. J. Med. 2006;355:992-1005).

Unfortunately, the various biomarkers that have been proposed to predict which women are likely to develop preeclampsia—from serum placental growth factor to asymmetric dimethylarginine—have not been shown to be reliable and are not predictive or specific enough for use in clinical practice.

Likewise, supplementation with fish oil, vitamin E, vitamin C, low-dose aspirin, or calcium is not recommended for the prevention of preeclampsia in the young woman with no risk factors.

A 42-year-old who is trying to become pregnant for the first time.

This patient's older age is itself a risk factor for preeclampsia. An older age also often means more body weight and a higher likelihood of chronic hypertension or diabetes, as well as an increased likelihood that donated gametes were used, all of which can significantly increase risk.

As in the case of the younger patient, risk evaluation and management should begin before conception. Family history, personal birth history, and the history of the patient's husband or partner should be explored.

And because a high body mass index is a proven risk factor—as is insulin resistance, which is often linked with obesity—patients who are overweight or obese should be encouraged to lose weight and achieve a healthy BMI.

The risks associated with preexisting medical conditions like hypertension and diabetes vary depending on the conditions' severity.

Studies show, for instance, that women with mild hypertension before conception or early in pregnancy have a 15% rate of preeclampsia, whereas women with severe prepregnancy hypertension have a nearly 50% risk.

In all cases, women with chronic hypertension or diabetes should have their blood pressure and glucose levels optimized before conception, and then controlled throughout their pregnancy.

When assisted reproductive technology is planned, a discussion about the increased risk for preeclampsia that is caused by donated gametes is important, because donor insemination or the use of donated oocytes affects the maternal-fetal immune interaction and increases the risk of preeclampsia to as much as 35%.

Because multifetal gestation is more common with ART than with natural birth and is another risk factor for preeclampsia, this patient's overall risk can also be minimized by reducing the number of transferred embryos and by avoiding hyperstimulation when ovulation induction is required.

Just as in the case of the younger woman, unfortunately, we have little if anything else to offer this patient for the prevention of preeclampsia.

These women can be offered calcium, however. A recent review by the Food and Drug Administration concluded that any benefit with respect to preeclampsia is inconclusive and “unlikely” (Nutr. Rev. 2007;65:78-87).

However, in a 2007 Cochrane review of 12 clinical studies, calcium supplementation was associated with a reduction in the rate of preeclampsia, particularly in populations at high risk and in those with diets deficient in calcium (BJOG 2007;114:933-43).

Management should include a baseline metabolic profile and complete blood count, as well as baseline urinalysis; this information can be helpful if later laboratory studies are needed to assess the function of organ systems likely to be affected by preeclampsia.

Serial ultrasonography as well as uterine Doppler studies at 18-20 weeks should also be employed. The Doppler studies are a useful tool for assessing the velocity of the uterine artery blood flow.

An increased resistance index and/or the presence of uterine artery diastolic notching suggests an increased risk of preeclampsia (as much as a sixfold increased risk) and the need for more vigilant monitoring and care.

A woman who developed severe preeclampsia at 26 weeks' gestation in her first pregnancy. She wants a child but is afraid—terribly and understandably frightened—of a second pregnancy because her first baby was born prematurely and died after about 100 days in the NICU.

We can and should reassure this patient that her loss does not mean she should forego becoming pregnant again, and that with proper monitoring, she has a significant chance of having a healthy baby.

A woman's risk of preeclampsia recurrence will depend on whether or not she has any preexisting risk factors, as well as the gestational age at the time of onset of preeclampsia in her first pregnancy.

The reported rate of recurrent preeclampsia ranges from 11.5% to 65%, with the highest rates being reported in women whose previous preeclampsia occurred in the second trimester. This patient's risk of recurrent preeclampsia is about 50%.

In general, recurrent preeclampsia is more likely to be severe and to develop preterm than is first-time preeclampsia. We can reassure this patient, however, that an early onset of preeclampsia in the first pregnancy does not necessarily mean that the disorder will have an early onset in the second pregnancy.

In a study published in 1991, among women with previous preeclampsia in the second trimester, preeclampsia recurred in the second trimester in 21%, at 28-36 weeks in 21%, and at term in 23% (Am. J. Obstet. Gynecol. 1991;165:1408-12).

Women with a history of eclampsia have a rate of recurrence of 1%-2% and a rate of subsequent preeclampsia of 22%-35%. Women with a history of HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome have a rate of preeclampsia in subsequent pregnancies of 16%-52% and, according to the most reliable data, a rate of recurrent HELLP syndrome of less than 5%.

Management for this patient ideally begins before conception, with an extensive evaluation and an in-depth history to uncover preexisting risk factors and/or medical conditions associated with the disorder.

This will allow proper counseling about the magnitude of risk for preeclampsia recurrence, and will guide you as you manage the pregnancy. (See box, bottom left.)

Knowing when she developed preeclampsia is important, as are details about maternal complications such as HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome, pulmonary edema, or renal failure, for instance; about fetal complications, such as fetal growth restriction; and about previous laboratory test results, as well as placental pathology.

The status of any comorbidities, such as high BMI or high blood pressure, should be optimized before conception, and vigilant monitoring—including early and serial ultrasonography, uterine Doppler assessment at 18-20 weeks, and laboratory testing as indicated—should be instituted to minimize and manage her risk.

By detecting complications early and monitoring for signs and symptoms of preeclampsia—and then hospitalizing her if you detect severe gestational hypertension, fetal growth restriction, or recurrent preeclampsia—you can ensure optimal outcomes.

This patient will probably want to know about the value of various biomarkers and supplements, such as fish oil and vitamins C and E, and again, we need to explain that the best studies have shown minimal to no benefit and do not support their use.

The three large randomized trials looking at vitamin E supplementation, for example, showed no effect on the rate of preeclampsia, its severity, or the rate of adverse neonatal outcomes.

None of the randomized trials on calcium supplementation included women with a previous history of preeclampsia, so the benefit for this indication remains unclear. Nevertheless, because calcium is beneficial for any pregnancy, we recommend it.

The greatest benefits of low-dose aspirin may come for this patient. A recent meta-analysis of 31 randomized trials found a 14% reduction in recurrent preeclampsia—higher than that seen for first-time preeclampsia (Lancet 2007;369:1791-8). Low-dose aspirin has also proved to be safe. We recommend 81 mg daily beginning at 12 weeks' gestation, and suggest discontinuing aspirin with the development of preeclampsia.

If the patient has documented evidence of antiphospholipid antibody syndrome, she should receive prophylactic-dose heparin in addition to low-dose aspirin once fetal viability is confirmed.

A woman who had late-occurring mild preeclampsia in her first pregnancy, and is planning a second child.

This patient experienced the most common presentation of preeclampsia, and fortunately has a fairly low risk for recurrence (about 10%). Chances are also likely that if preeclampsia recurs, it will recur at term.

This risk can be minimized and a good outcome ensured by following the same approach to history taking, counseling, and optimizing health before conception, as well as careful monitoring during pregnancy to detect complications early.

Risks Later in Life

Today, counseling women with a history of preeclampsia involves more than assessing and minimizing risks for recurrence of the disorder. It also involves discussing the now-substantial body of literature that suggests that women whose pregnancies are complicated by preeclampsia and/or fetal growth restriction have an increased risk for future cardiovascular disease and ischemic stroke.

These women require close follow-up after their pregnancies so that their long-term risks can be reduced or avoided through the use of preventive strategies and approaches to care.

Preeclampsia and fetal growth restriction are both vascular-related pregnancy complications, and they share similar risk factors and pathophysiological abnormalities, such as endothelial dysfunction.

It's unclear exactly what mechanisms account for the relationship among these complications and the increased risk of subsequent cardiovascular disease, but it increasingly seems likely that these women have a predisposition to vascular and metabolic disease: a constitutional risk.

Epidemiologic and case-control studies published in the last 10 years—many of them in the nonobstetric literature—have evaluated the associations, and last year a systematic review and meta-analysis of these studies reported a relative risk for chronic hypertension of 3.7 after approximately 14 years of average follow-up, a relative risk of 2.16 for ischemic heart disease after about 11 years of follow-up, and a relative risk of 1.8 for ischemic stroke after about 10 years (BMJ 2007;335:974-85).

In addition, overall mortality after preeclampsia was increased by a relative risk of approximately 1.5 after 14.5 years of follow-up.

In a recently published intergenerational case-control study, Dutch investigators looked at 106 women whose pregnancies were complicated by preeclampsia or fetal growth restriction, a control group of 106 women with normal pregnancies, and each woman's mother and father.

They found significant intergenerational similarities in cardiovascular risk profiles between the women after preeclampsia or fetal growth restriction and their parents, such as higher fasting glucose levels that could not be explained by differences in BMI.

Intergenerational similarities were also found for hypertension, waist circumference, and metabolic syndrome (Hypertension 2008;51:1034-41).

ELSEVIER GLOBAL MEDICAL NEWS

Preeclampsia, Part 3

The exact incidence of preeclampsia is unknown, but in its mild form it is estimated to affect up to 10% of all pregnancies. Indeed, it is one of the most common complications of pregnancy. In a smaller number of cases (just under 1% of pregnancies), the disorder develops as severe preeclampsia.

In the past two Master Class installments on preeclampsia, we have discussed how the disorder presents in various ways, afflicting women of different age groups, of varying parity, and with associated medical complications or the lack thereof.

We have also discussed appropriate evaluation and management protocols. The spectrum of disease is such that it spans the very mild (requiring modest intervention) to the very severe (requiring immediate and aggressive intervention strategies). As we saw in the last installment, it is important to view preeclampsia as a multifaceted disease continuum in which designations of “mild” and “severe” are not necessarily fixed.

The variable presentation of the disorder—and the fact that it cannot be precisely predicted or prevented—may in itself be challenging to the practitioner, as he or she counsels patients who are contemplating pregnancies and may be at risk for preeclampsia.

There are certain predisposing medical and sociodemographic factors, however, that are clearly important and that can be useful if they are integrated into an evaluation and management algorithm. Integrating our knowledge of risk factors allows for the most appropriate counseling to be delivered, and the most appropriate management plan to be developed, on a case-by-case basis.

I have invited Dr. Baha Sibai to once again address the topic of preeclampsia in this third and final installment of our series on the disorder. Dr. Sibai is professor of obstetrics and gynecology at the University of Cincinnati and an international expert on preeclampsia and eclampsia, as well as a leader in both clinical care and research in this area.

In this case, we've taken a different approach to presenting the material. We think our case-by-case format will be practical and applicable to the practitioner who is counseling a number of patients who present with varying histories and risk factors.

How to Manage Recurrence Risk

Preconception

▸ Identify risk factors.

▸ Review outcome of previous pregnancy.

▸ Optimize maternal health.

First Trimester

▸ Perform ultrasonography for dating and assessing fetal number.

▸ Order baseline metabolic profile and complete blood count.

▸ Perform baseline urinalysis.

▸ Offer first-trimester combined screening.

▸ If antiphospholipid syndrome is documented, start low-dose aspirin and heparin. Otherwise, offer low-dose aspirin therapy at 12 weeks' gestation.

Second Trimester

▸ Monitor for signs and symptoms of preeclampsia.

▸ Perform ultrasonography at 18-22 weeks' gestation for fetal anomaly evaluation and to rule out molar gestation.

▸ Perform uterine Doppler studies at 18-20 weeks.

Third Trimester

▸ Monitor for signs and symptoms of preeclampsia.

▸ As indicated by the clinical situation, perform laboratory testing, serial ultrasonography (for fetal growth and amniotic fluid assessment), and umbilical artery Doppler with a nonstress test and/or biophysical profile.

▸ Hospitalize for severe gestational hypertension, fetal growth restriction, or recurrent preeclampsia.

Post Partum

▸ Counsel patient about an increased risk for cardiovascular disease and ischemic stroke.

▸ Encourage close follow-up and prevention.

Source: Adapted from Obstet. Gynecol. 2008;112:359-72

Risk Factors for Preeclampsia

The magnitude of risk depends on the number of factors, which include the following:

▸ Multifetal gestation.

▸ Unexplained fetal growth restriction.

▸ Gestational hypertension.

▸ Hydrops/hydropic degeneration of placenta (triploidy, trisomy 13).

▸ Urinary-tract and periodontal infections.

▸ Biophysical and biochemical markers.

Source: Adapted from Obstet. Gynecol. 2008;112:359-72

This Master Class is the second in a three-part series on the topic of preeclampsia, which is a relatively common complication of pregnancy that can result in severe morbidity and mortality if not well managed. In light of this, we have decided to dedicate a significant amount of coverage to this topic.

In the previous Master Class article, we covered one end of the spectrum—severe preeclampsia. This Master Class focuses on the more common presentation of mild preeclampsia, which sometimes presents in a manner similar to that of gestational hypertension alone.

Mild gestational hypertension-preeclampsia affects up to 10% of all pregnancies. Because it is a relatively common complication of pregnancy, it is critically important that the practitioner develops a clinical algorithm for diagnosis—one that distinguishes mild gestational hypertension-preeclampsia from gestational hypertension alone—and institutes an appropriate management protocol.

Dr. Baha M. Sibai, our guest professor previously on the topic of severe preeclampsia, will help us with this Master Class. He focuses here on the salient differences between gestational hypertension and mild preeclampsia and how these conditions should be managed in the antepartum, intrapartum, and postpartum periods.

Dr. Sibai is an international expert on preeclampsia and eclampsia and a world leader in clinical care and research in this field. He is professor of obstetrics and gynecology at the University of Cincinnati, and has contributed to more than 350 studies in peer-reviewed journals on these topics.

In the third and final part of the series on preeclampsia, Dr. Sibai will address the risk of recurrent preeclampsia and how subsequent pregnancies in women with a history of previous preeclampsia should be managed.

This Master Class is the second in a three-part series on the topic of preeclampsia, which is a relatively common complication of pregnancy that can result in severe morbidity and mortality if not well managed. In light of this, we have decided to dedicate a significant amount of coverage to this topic.

In the previous Master Class article, we covered one end of the spectrum—severe preeclampsia. This Master Class focuses on the more common presentation of mild preeclampsia, which sometimes presents in a manner similar to that of gestational hypertension alone.

Mild gestational hypertension-preeclampsia affects up to 10% of all pregnancies. Because it is a relatively common complication of pregnancy, it is critically important that the practitioner develops a clinical algorithm for diagnosis—one that distinguishes mild gestational hypertension-preeclampsia from gestational hypertension alone—and institutes an appropriate management protocol.

Dr. Baha M. Sibai, our guest professor previously on the topic of severe preeclampsia, will help us with this Master Class. He focuses here on the salient differences between gestational hypertension and mild preeclampsia and how these conditions should be managed in the antepartum, intrapartum, and postpartum periods.

Dr. Sibai is an international expert on preeclampsia and eclampsia and a world leader in clinical care and research in this field. He is professor of obstetrics and gynecology at the University of Cincinnati, and has contributed to more than 350 studies in peer-reviewed journals on these topics.

In the third and final part of the series on preeclampsia, Dr. Sibai will address the risk of recurrent preeclampsia and how subsequent pregnancies in women with a history of previous preeclampsia should be managed.

This Master Class is the second in a three-part series on the topic of preeclampsia, which is a relatively common complication of pregnancy that can result in severe morbidity and mortality if not well managed. In light of this, we have decided to dedicate a significant amount of coverage to this topic.

In the previous Master Class article, we covered one end of the spectrum—severe preeclampsia. This Master Class focuses on the more common presentation of mild preeclampsia, which sometimes presents in a manner similar to that of gestational hypertension alone.

Mild gestational hypertension-preeclampsia affects up to 10% of all pregnancies. Because it is a relatively common complication of pregnancy, it is critically important that the practitioner develops a clinical algorithm for diagnosis—one that distinguishes mild gestational hypertension-preeclampsia from gestational hypertension alone—and institutes an appropriate management protocol.

Dr. Baha M. Sibai, our guest professor previously on the topic of severe preeclampsia, will help us with this Master Class. He focuses here on the salient differences between gestational hypertension and mild preeclampsia and how these conditions should be managed in the antepartum, intrapartum, and postpartum periods.

Dr. Sibai is an international expert on preeclampsia and eclampsia and a world leader in clinical care and research in this field. He is professor of obstetrics and gynecology at the University of Cincinnati, and has contributed to more than 350 studies in peer-reviewed journals on these topics.

In the third and final part of the series on preeclampsia, Dr. Sibai will address the risk of recurrent preeclampsia and how subsequent pregnancies in women with a history of previous preeclampsia should be managed.

Preeclampsia is one of the most challenging and high-risk conditions that obstetric specialists will confront in their clinical practices.

This condition continues to be a vexing problem because the etiology remains evasive, not only in its onset, but often in its manifestations and complications as well.

Patients who develop preeclampsia fall into three categories. One subset of patients develops preeclampsia that remains mild and does not cause any major complications. Another subset develops a more advanced preeclampsia with some complications that are usually manageable, often without grave risk to the pregnancy.

The third subset of patients develops a severe form of preeclampsia based on precise, defined criteria. This form of preeclampsia may present in premature pregnancies, where the condition creates the greatest challenge and raises a clinical conundrum: Is it best to deliver the patient, or to embrace expectant management?

Because the severe form of preeclampsia is such a difficult problem and the outcome of the pregnancy hinges on the clinician's choice of the right approach, we thought it was important to dedicate a Master Class to the management of these high-risk patients.

I have invited Dr. Baha M. Sibai, an international expert on preeclampsia and eclampsia and a world leader in both clinical care and research in this field, to provide a thorough discussion of this difficult topic.

Dr. Sibai is professor of obstetrics and gynecology at the University of Cincinnati and has contributed to more than 350 studies in peer-reviewed journals on the subject of preeclampsia and eclampsia.

Preeclampsia is one of the most challenging and high-risk conditions that obstetric specialists will confront in their clinical practices.

This condition continues to be a vexing problem because the etiology remains evasive, not only in its onset, but often in its manifestations and complications as well.

Patients who develop preeclampsia fall into three categories. One subset of patients develops preeclampsia that remains mild and does not cause any major complications. Another subset develops a more advanced preeclampsia with some complications that are usually manageable, often without grave risk to the pregnancy.

The third subset of patients develops a severe form of preeclampsia based on precise, defined criteria. This form of preeclampsia may present in premature pregnancies, where the condition creates the greatest challenge and raises a clinical conundrum: Is it best to deliver the patient, or to embrace expectant management?

Because the severe form of preeclampsia is such a difficult problem and the outcome of the pregnancy hinges on the clinician's choice of the right approach, we thought it was important to dedicate a Master Class to the management of these high-risk patients.

I have invited Dr. Baha M. Sibai, an international expert on preeclampsia and eclampsia and a world leader in both clinical care and research in this field, to provide a thorough discussion of this difficult topic.

Dr. Sibai is professor of obstetrics and gynecology at the University of Cincinnati and has contributed to more than 350 studies in peer-reviewed journals on the subject of preeclampsia and eclampsia.

Preeclampsia is one of the most challenging and high-risk conditions that obstetric specialists will confront in their clinical practices.

This condition continues to be a vexing problem because the etiology remains evasive, not only in its onset, but often in its manifestations and complications as well.

Patients who develop preeclampsia fall into three categories. One subset of patients develops preeclampsia that remains mild and does not cause any major complications. Another subset develops a more advanced preeclampsia with some complications that are usually manageable, often without grave risk to the pregnancy.

The third subset of patients develops a severe form of preeclampsia based on precise, defined criteria. This form of preeclampsia may present in premature pregnancies, where the condition creates the greatest challenge and raises a clinical conundrum: Is it best to deliver the patient, or to embrace expectant management?

Because the severe form of preeclampsia is such a difficult problem and the outcome of the pregnancy hinges on the clinician's choice of the right approach, we thought it was important to dedicate a Master Class to the management of these high-risk patients.

I have invited Dr. Baha M. Sibai, an international expert on preeclampsia and eclampsia and a world leader in both clinical care and research in this field, to provide a thorough discussion of this difficult topic.

Dr. Sibai is professor of obstetrics and gynecology at the University of Cincinnati and has contributed to more than 350 studies in peer-reviewed journals on the subject of preeclampsia and eclampsia.