Master Class

Dr. Roberto Romero: The common pathway of parturition consists of the anatomical, physiologic, biochemical, and clinical events that occur in the mother and/or fetus in both term and preterm labor. The uterine components of this pathway include increased uterine contractility; cervical ripening (dilatation and effacement); and membrane/decidual activation. In most women, these components are typically activated in a synchronous manner in spontaneous labor at term. Indeed, most women admitted in labor have uterine contractions, cervical changes and—sometimes—rupture of membranes.

However, in some cases the activation of the common pathway may be asynchronous. For example, a patient may have increased uterine contractility, but the cervix undergoes very little change over time. This is what is called a prolonged latent phase of labor. In 10% of cases, patients have spontaneous rupture of membranes without myometrial contractility. This is evidence that membrane/decidual activation has occurred without recruitment of the myometrium.

Asynchronous activation is more common in the preterm gestation. Many patients with suspected preterm labor will present with increased uterine contractility without cervical changes. Others will present with the clinical picture of cervical insufficiency (which used to be called cervical incompetence). Finally, some women will present with preterm premature rupture of the membranes (pPROM), which is premature membrane/decidual activation.

EAR: What is the importance of the concept of the common pathway?

RR: Much of the clinical management and research in understanding the causes of premature labor, treatment, and prevention has been focused on the elements of the common terminal pathway. For example, we have used uterine monitors to detect an increase in uterine contractility and tocolytic agents to treat increased myometrial contractility. We use ultrasound to identify patients with a short cervix who are at risk for preterm delivery. In some cases, we have placed cervical cerclage in patients at risk. Finally, we have used fetal fibronectin to detect decidual/membrane deactivation. A positive fetal fibronectin is an indicator that disruption of the choriodecidual interface has occurred. Yet these interventions aim to treat preterm labor as a symptom, without first identifying and understanding the underlying pathology that sets it in motion. Progress on this front is now being made.

EAR: What is the difference between spontaneous labor at term and preterm labor?

RR: We propose that spontaneous labor at term is the inevitable process that occurs when the capacity of the mother to support the fetus in utero has been reached. In other words, when the fetus has achieved maturity and is ready to face extrauterine life, it signals the onset of labor and engages the cooperation of the mother in this process.

In contrast, we propose that premature labor results from a pathologic insult that activates the common pathway of parturition. Before the development of newborn special care units, extreme prematurity was nearly always lethal. Thus, being born preterm is likely to result from such a severe pathologic process that it threatens the survival of the mother and/or baby.

In summary, spontaneous labor at term results from physiologic activation of the common pathway, whereas preterm labor would result from pathologic activation of the pathway.

EAR: What is the evidence that premature labor is a heterogeneous condition?

RR: My laboratory and other groups have generated evidence that the pattern of uterine gene expression—also known as the transcriptional profile—is different in patients with different causes of premature labor. A transcriptional profile is a snapshot of genes that are being upregulated or downregulated at a particular point in time.

We have demonstrated experimentally that the transcriptional profile in the uteri of mice that go into labor as a result of infection is different from the transcriptional profile of mice that go into labor because of ovariectomy (a model of progesterone withdrawal).

We have also examined the transcriptional profile of the chorioamniotic membranes in women with preterm labor and intact membranes vs. women with pPROM, in each case studying women with and without histologic chorioamnionitis. These studies have demonstrated that the patterns of gene expression are very different in these four groups, even though the clinical presentations are similar.

Collectively, the observations in patients and animals suggest that premature labor is a heterogeneous condition. Although they share a common pathway (uterine contractility and cervical dilatation and/or membrane rupture or activation), there are multiple causes for the preterm parturition syndrome.

Using the tools of high-dimensional biology, we have learned that premature labor is not simply labor before its time, but rather a disease state. It is caused by different pathologic processes with both environmental components and genetic components. For example, in infection-induced preterm labor (OB.GYN. NEWS, July 1, 2006, p. 42), the environmental component is represented by the microorganisms that cause the infection. The genetic component is the factor that predisposes some women to have an intrauterine infection or to respond more severely to that infection.

A prime example of the importance of genetics lies with the fetus. In pregnancy, we have not one patient, but two. Accumulating evidence indicates that the fetus plays a central role in the initiation of labor in both animals and humans. In humans, mothers of fetuses who have mounted a severe fetal inflammatory response are more likely to go into labor than are mothers of fetuses who have not mounted a fetal inflammatory response to infection. The magnitude and severity of the inflammatory response are under genetic control.

Thus, in pregnancy, the genetic makeup of two hosts—mother and child—plays a role in determining the susceptibility and response to infection. It is a unique situation in medicine.

EAR: Why do you call preterm parturition a syndrome?

RR: The current taxonomy of disease in obstetrics is largely based on the symptoms and signs exhibited by the mother, not the mechanisms of disease responsible for the clinical presentations. A syndrome is a combination of symptoms and signs that form a distinct clinical picture indicative of a particular disorder. Implicit in this definition is the fact that a syndrome can have multiple causes. Our emphasis in referring to premature parturition as a syndrome is that it will help both patients and physicians readjust the unreasonable expectation that one test can diagnose or identify all women at risk, and that one treatment will be effective for all women in premature labor, regardless of the cause.

EAR: In the last Master Class, we spoke about the role of infection and inflammation as a cause of premature labor. You have shared with us a figure that shows other causes of preterm parturition. I would like to discuss the other causes with you. Can you tell us how uterine ischemia and/or vascular pathology cause premature labor?

RR: Placental histology suggests that vascular lesions involving maternal or fetal circulation constitute the second most common apparent cause of preterm labor and pPROM, after inflammation.

Research in this area has focused on elevated rates of vascular abnormalities in women with spontaneous preterm labor with intact membranes and pPROM, compared with women who deliver at term. The vascular lesions have been found on both the maternal and fetal side. For example, thrombosis of the decidual vessels attached to the placenta and failure of physiologic transformation in the myometrial segment of the spiral arteries are generally considered maternal lesions. Abnormalities in the fetal circulation linked to preterm labor include a decreased number of arterioles in the villi and fetal arterial thrombosis.

Whereas uteroplacental ischemia is the driver of vascular events, the leading candidate to explain the molecular mechanisms responsible is the renin-angiotensin system; in severe uteroplacental ischemia, the enzyme thrombin is emerging as an important activator of preterm labor associated with vaginal bleeding.

The work of Dr. Mark Phillippe and Dr. Michal Elovitz has demonstrated in animal models and in vivo investigations that whole blood—but not heparinized blood—raises contractile activity of the uterine muscle, and that such increased uterine activity can be blocked with a thrombin antagonist.

Moreover, women with preterm labor have higher concentrations of thrombin-antithrombin (TAT) complexes in amniotic fluid and in maternal plasma than do women without preterm labor. Similarly, Dr. Todd Rosen and Dr. Charles Lockwood have provided evidence that women destined to develop pPROM have higher concentrations of thrombin weeks before the development of complications. Therefore, thrombin is a potential initiator not only of the rupture of membranes (via stromal cells and matrix metalloproteinase 1), but also of uterine contractility and preterm labor.

The thrombin connection would help to explain why retroplacental hematomas in early pregnancy are associated with preterm delivery, and why vaginal bleeding in the first or second trimester is a risk factor for preterm birth with intact or ruptured membranes.

EAR: What is the evidence that uterine overdistention is a cause of preterm parturition?

RR: Obstetricians and midwives know that multiple gestation is a risk factor for preterm delivery, and that the higher the order of multiple gestation, the greater the risk for preterm birth. Patients with polyhydramnios resulting from a congenital fetal anomaly are also at risk for spontaneous preterm labor and delivery. These two conditions are probably mediated by uterine overdistention. It is likely that the same is the case for patients who have müllerian duct abnormalities in which the uterine cavity is small. One example is congenital hypoplastic uterus and another is the abnormal uterus resulting from diethylstilbestrol exposure.

EAR: What is the mechanism linking uterine overdistention with premature labor?

RR: This is an area that requires further work. In general terms, mechanical signals triggered by uterine stretch may lead to preterm labor—as in multiple gestations and polyhydramnios—although the precise mechanisms involved remain unknown.

Experimental distention of the uterus with a saline-filled balloon rapidly prompted regular uterine contractions in women carrying live term fetuses or dead fetuses. All were delivered within 21 hours.

Stephen Lye, Ph.D., and his group at the University of Toronto have found increased expression of oxytocin receptor, connexin 43, and the c-fos mRNA in the myometrium. Gillian Bryant-Greenwood, Ph.D., at the University of Hawaii, Honolulu, has shown that stretching of the chorioamniotic membranes in experimental models can increase the expression of interleukin-8 and also another cytokine called visfatin, which can have important effects on the integrity of the membranes.

EAR: I noticed that cervical pathology is also a potential cause of the preterm parturition syndrome. Is this the same as cervical insufficiency?

RR: Yes. Cervical insufficiency is also a cause of the preterm parturition syndrome and can result from congenital disorders, surgical trauma, trauma, or infection. Although cervical length has been touted as a predictor of preterm birth, it is important to remember that a short cervix is not always a ripe cervix. Once again, more research is needed to identify the events that occur as a result of cervical insufficiency, and the ways these affect the initiation of preterm and term labor.

EAR: What about abnormal allograft reaction?

RR: The fetoplacental unit has been called “nature's most successful transplant,” or—more accurately—a “semiallograft.” The mechanisms that bring about tolerance of this semiallograft are poorly understood. However, transplants of solid organs are tolerated through the establishment of microchimerism in the transplanted organ as well as in the host. Therefore, we consider that microchimerism in pregnancy is probably important for tolerance of the fetoplacental unit. However, I anticipate that under pathologic conditions—just as in the case of transplants—tolerance of the fetoplacental unit may break down, which in turn may lead to a unique form of rejection of the fetoplacental unit. Unraveling the mechanisms of this rejectionlike process is a fascinating challenge. However, ob.gyns. know that the frequency of adverse pregnancy outcomes is higher in mothers who have pregnancies after embryo or egg donation. Under these circumstances, the placenta and fetus are totally foreign because they do not have the normal 50% genetic endowment from the mother. The complications noticed in these pregnancies include not only preeclampsia and growth restriction, but also preterm labor.

EAR: What is the evidence that an allergic phenomenon could be associated with premature labor, and could antihistamines be a treatment for premature labor?

RR: This idea came to me after seeing the relative of an obstetrician who went into premature labor after eating shellfish to which she was allergic. Around that time, we observed that a group of women in premature labor had eosinophils in the amniotic cavity. Eosinophils are associated with an allergiclike phenomenon and are not normally present in the amniotic cavity. The evidence to support biologic plausibility was generated in our work with Dr. Robert Garfield and Dr. Egle Bytautiene. We were able to demonstrate that guinea pigs allergic to egg proteins (ovalbumin) went into premature labor when challenged with the allergen during pregnancy. Premature labor could be prevented by the administration of an antihistamine in these animals.

We have interpreted this as evidence that some patients with premature labor may have an allergiclike reaction or type I hypersensitivity reaction. The nature of the allergen may vary. However, we know that allergens can cross the placenta. For example, dust mite antigen has been demonstrated in the amniotic fluid of women in the midtrimester of pregnancy. Also, there is evidence that the fetus is able to recognize and mount an immune response to allergens in utero.

In response to your question, we have treated with antihistamines some patients who have a typical allergiclike history along with premature labor, and this has resulted in the disappearance of uterine contractions. However, these are anecdotal reports, and I would like to stress that our interest in this mechanism of disease stems from the importance of demonstrating that a common mechanism of disease, such as allergy, can be a cause of the preterm parturition syndrome. This should not be surprising, because the uterus is bestowed with mast cells, the key effector cells of an allergic response, and the uterus has all the components required to generate an allergiclike immune response.

EAR: What is the evidence and importance of hormonal dysfunction in premature parturition?

RR: Progesterone withdrawal and/or deficiency has not yet been specifically demonstrated as an initiator of spontaneous parturition in humans. However, the role of progesterone in maintaining pregnancy is unquestionable.

Indeed, suspension of progesterone action through the administration of progesterone receptor inhibitors and progesterone receptor antagonists can induce activation of the components of the common pathway of parturition in animals and humans.

The progesterone/estradiol and progesterone/estriol ratios in amniotic fluid are lower in laboring than in nonlaboring subjects, and the progesterone/estriol ratio is lower in preterm labor followed by preterm delivery compared with preterm labor followed by term delivery, suggesting that these hormones are important in determining the duration of pregnancy.

Trials of progesterone administration to prevent preterm delivery have shown interesting results. Specifically, two recent randomized clinical trials demonstrated that vaginal suppositories containing natural progesterone, or injections of a progesterone, 17 α-hydroxyprogesterone caproate, to women at risk for preterm delivery seem to reduce the rate of spontaneous preterm delivery. Moreover, in the trial using 17 α-hydroxyprogesterone caproate, infants of mothers treated with this compound had a lower rate of necrotizing enterocolitis, intraventricular hemorrhage, and the need for supplemental oxygen. Further research is needed to identify the ideal progesterone regimen and the patients who may benefit from this intervention.

EAR: What about stress as a cause of premature labor?

RR: Epidemiologic studies have indicated that women exposed to stressful conditions during pregnancy have a mild increase in the rate of spontaneous preterm labor. The work of Dr. Pathik Wadhwa and Dr. Cal Hobel has been seminal in this area.

The precise mechanisms whereby stress causes premature labor implicate corticotropin-releasing hormone (CRH), which is produced by the hypothalamus and—importantly—by the placenta. Dr. Roger Smith's work in Australia has proposed that CRH is the regulator of a placental clock. Dr. Felice Petraglia in Italy has also contributed significantly to establish a link between CRH and premature labor.

The clinical implications of this work are related to the epidemiologic observations reported by Dr. Emile Papiernik in France, noting that women who are prescribed rest during pregnancy had a lower frequency of preterm delivery. This interesting experience has not been explored in the United States.

However, a targeted intervention to the patient at risk—such as the woman who must stand or do significant physical work during pregnancy—may be beneficial. However, bed rest per se is not an effective treatment to prevent all causes of premature labor. It is easy to understand that if the cause of preterm parturition is infection, then bed rest will not cure it.

EAR: What is the final message that you would like the readers of OB.GYN. NEWS take with them?

RR: Preterm labor is not just labor before its time, but is the result of a pathologic process. The challenge for health care providers is to try to identify why a women is in premature labor, what specific mechanism of disease may be involved, how sick the fetus is, and whether the benefits of pregnancy prolongation outweigh the risk of prematurity. The administration of steroids has been demonstrated to reduce the rate of adverse neonatal outcomes, and it is indicated when the patient is at risk for preterm delivery.

Preterm Labor Has Multiple Causes

In July's Master Class, the specific role of infection in preterm labor was discussed at length by Dr. Roberto Romero, chief of the Perinatology Research Branch at the National Institute of Child Health and Human Development, and professor of obstetrics and gynecology at Wayne State University in Detroit.

Although infection is a leading—and perhaps the best understood—cause of spontaneous preterm labor and delivery, it is not the only cause. Research from Dr. Romero's group and others increasingly point to several disease mechanisms with genetic and environmental components that can be responsible for what we now know as the preterm parturition syndrome.

I am pleased to welcome back Dr. Romero, an international authority on the syndrome.

In this month's discussion, Dr. Romero provides an overview of evolving knowledge about the syndrome and details current scientific progress in the understanding of the noninfectious causes that may be important in the process of preterm labor.

Dr. Roberto Romero: The common pathway of parturition consists of the anatomical, physiologic, biochemical, and clinical events that occur in the mother and/or fetus in both term and preterm labor. The uterine components of this pathway include increased uterine contractility; cervical ripening (dilatation and effacement); and membrane/decidual activation. In most women, these components are typically activated in a synchronous manner in spontaneous labor at term. Indeed, most women admitted in labor have uterine contractions, cervical changes and—sometimes—rupture of membranes.

However, in some cases the activation of the common pathway may be asynchronous. For example, a patient may have increased uterine contractility, but the cervix undergoes very little change over time. This is what is called a prolonged latent phase of labor. In 10% of cases, patients have spontaneous rupture of membranes without myometrial contractility. This is evidence that membrane/decidual activation has occurred without recruitment of the myometrium.

Asynchronous activation is more common in the preterm gestation. Many patients with suspected preterm labor will present with increased uterine contractility without cervical changes. Others will present with the clinical picture of cervical insufficiency (which used to be called cervical incompetence). Finally, some women will present with preterm premature rupture of the membranes (pPROM), which is premature membrane/decidual activation.

EAR: What is the importance of the concept of the common pathway?

RR: Much of the clinical management and research in understanding the causes of premature labor, treatment, and prevention has been focused on the elements of the common terminal pathway. For example, we have used uterine monitors to detect an increase in uterine contractility and tocolytic agents to treat increased myometrial contractility. We use ultrasound to identify patients with a short cervix who are at risk for preterm delivery. In some cases, we have placed cervical cerclage in patients at risk. Finally, we have used fetal fibronectin to detect decidual/membrane deactivation. A positive fetal fibronectin is an indicator that disruption of the choriodecidual interface has occurred. Yet these interventions aim to treat preterm labor as a symptom, without first identifying and understanding the underlying pathology that sets it in motion. Progress on this front is now being made.

EAR: What is the difference between spontaneous labor at term and preterm labor?

RR: We propose that spontaneous labor at term is the inevitable process that occurs when the capacity of the mother to support the fetus in utero has been reached. In other words, when the fetus has achieved maturity and is ready to face extrauterine life, it signals the onset of labor and engages the cooperation of the mother in this process.

In contrast, we propose that premature labor results from a pathologic insult that activates the common pathway of parturition. Before the development of newborn special care units, extreme prematurity was nearly always lethal. Thus, being born preterm is likely to result from such a severe pathologic process that it threatens the survival of the mother and/or baby.

In summary, spontaneous labor at term results from physiologic activation of the common pathway, whereas preterm labor would result from pathologic activation of the pathway.

EAR: What is the evidence that premature labor is a heterogeneous condition?

RR: My laboratory and other groups have generated evidence that the pattern of uterine gene expression—also known as the transcriptional profile—is different in patients with different causes of premature labor. A transcriptional profile is a snapshot of genes that are being upregulated or downregulated at a particular point in time.

We have demonstrated experimentally that the transcriptional profile in the uteri of mice that go into labor as a result of infection is different from the transcriptional profile of mice that go into labor because of ovariectomy (a model of progesterone withdrawal).

We have also examined the transcriptional profile of the chorioamniotic membranes in women with preterm labor and intact membranes vs. women with pPROM, in each case studying women with and without histologic chorioamnionitis. These studies have demonstrated that the patterns of gene expression are very different in these four groups, even though the clinical presentations are similar.

Collectively, the observations in patients and animals suggest that premature labor is a heterogeneous condition. Although they share a common pathway (uterine contractility and cervical dilatation and/or membrane rupture or activation), there are multiple causes for the preterm parturition syndrome.

Using the tools of high-dimensional biology, we have learned that premature labor is not simply labor before its time, but rather a disease state. It is caused by different pathologic processes with both environmental components and genetic components. For example, in infection-induced preterm labor (OB.GYN. NEWS, July 1, 2006, p. 42), the environmental component is represented by the microorganisms that cause the infection. The genetic component is the factor that predisposes some women to have an intrauterine infection or to respond more severely to that infection.

A prime example of the importance of genetics lies with the fetus. In pregnancy, we have not one patient, but two. Accumulating evidence indicates that the fetus plays a central role in the initiation of labor in both animals and humans. In humans, mothers of fetuses who have mounted a severe fetal inflammatory response are more likely to go into labor than are mothers of fetuses who have not mounted a fetal inflammatory response to infection. The magnitude and severity of the inflammatory response are under genetic control.

Thus, in pregnancy, the genetic makeup of two hosts—mother and child—plays a role in determining the susceptibility and response to infection. It is a unique situation in medicine.

EAR: Why do you call preterm parturition a syndrome?

RR: The current taxonomy of disease in obstetrics is largely based on the symptoms and signs exhibited by the mother, not the mechanisms of disease responsible for the clinical presentations. A syndrome is a combination of symptoms and signs that form a distinct clinical picture indicative of a particular disorder. Implicit in this definition is the fact that a syndrome can have multiple causes. Our emphasis in referring to premature parturition as a syndrome is that it will help both patients and physicians readjust the unreasonable expectation that one test can diagnose or identify all women at risk, and that one treatment will be effective for all women in premature labor, regardless of the cause.

EAR: In the last Master Class, we spoke about the role of infection and inflammation as a cause of premature labor. You have shared with us a figure that shows other causes of preterm parturition. I would like to discuss the other causes with you. Can you tell us how uterine ischemia and/or vascular pathology cause premature labor?

RR: Placental histology suggests that vascular lesions involving maternal or fetal circulation constitute the second most common apparent cause of preterm labor and pPROM, after inflammation.

Research in this area has focused on elevated rates of vascular abnormalities in women with spontaneous preterm labor with intact membranes and pPROM, compared with women who deliver at term. The vascular lesions have been found on both the maternal and fetal side. For example, thrombosis of the decidual vessels attached to the placenta and failure of physiologic transformation in the myometrial segment of the spiral arteries are generally considered maternal lesions. Abnormalities in the fetal circulation linked to preterm labor include a decreased number of arterioles in the villi and fetal arterial thrombosis.

Whereas uteroplacental ischemia is the driver of vascular events, the leading candidate to explain the molecular mechanisms responsible is the renin-angiotensin system; in severe uteroplacental ischemia, the enzyme thrombin is emerging as an important activator of preterm labor associated with vaginal bleeding.

The work of Dr. Mark Phillippe and Dr. Michal Elovitz has demonstrated in animal models and in vivo investigations that whole blood—but not heparinized blood—raises contractile activity of the uterine muscle, and that such increased uterine activity can be blocked with a thrombin antagonist.

Moreover, women with preterm labor have higher concentrations of thrombin-antithrombin (TAT) complexes in amniotic fluid and in maternal plasma than do women without preterm labor. Similarly, Dr. Todd Rosen and Dr. Charles Lockwood have provided evidence that women destined to develop pPROM have higher concentrations of thrombin weeks before the development of complications. Therefore, thrombin is a potential initiator not only of the rupture of membranes (via stromal cells and matrix metalloproteinase 1), but also of uterine contractility and preterm labor.

The thrombin connection would help to explain why retroplacental hematomas in early pregnancy are associated with preterm delivery, and why vaginal bleeding in the first or second trimester is a risk factor for preterm birth with intact or ruptured membranes.

EAR: What is the evidence that uterine overdistention is a cause of preterm parturition?

RR: Obstetricians and midwives know that multiple gestation is a risk factor for preterm delivery, and that the higher the order of multiple gestation, the greater the risk for preterm birth. Patients with polyhydramnios resulting from a congenital fetal anomaly are also at risk for spontaneous preterm labor and delivery. These two conditions are probably mediated by uterine overdistention. It is likely that the same is the case for patients who have müllerian duct abnormalities in which the uterine cavity is small. One example is congenital hypoplastic uterus and another is the abnormal uterus resulting from diethylstilbestrol exposure.

EAR: What is the mechanism linking uterine overdistention with premature labor?

RR: This is an area that requires further work. In general terms, mechanical signals triggered by uterine stretch may lead to preterm labor—as in multiple gestations and polyhydramnios—although the precise mechanisms involved remain unknown.

Experimental distention of the uterus with a saline-filled balloon rapidly prompted regular uterine contractions in women carrying live term fetuses or dead fetuses. All were delivered within 21 hours.

Stephen Lye, Ph.D., and his group at the University of Toronto have found increased expression of oxytocin receptor, connexin 43, and the c-fos mRNA in the myometrium. Gillian Bryant-Greenwood, Ph.D., at the University of Hawaii, Honolulu, has shown that stretching of the chorioamniotic membranes in experimental models can increase the expression of interleukin-8 and also another cytokine called visfatin, which can have important effects on the integrity of the membranes.

EAR: I noticed that cervical pathology is also a potential cause of the preterm parturition syndrome. Is this the same as cervical insufficiency?

RR: Yes. Cervical insufficiency is also a cause of the preterm parturition syndrome and can result from congenital disorders, surgical trauma, trauma, or infection. Although cervical length has been touted as a predictor of preterm birth, it is important to remember that a short cervix is not always a ripe cervix. Once again, more research is needed to identify the events that occur as a result of cervical insufficiency, and the ways these affect the initiation of preterm and term labor.

EAR: What about abnormal allograft reaction?

RR: The fetoplacental unit has been called “nature's most successful transplant,” or—more accurately—a “semiallograft.” The mechanisms that bring about tolerance of this semiallograft are poorly understood. However, transplants of solid organs are tolerated through the establishment of microchimerism in the transplanted organ as well as in the host. Therefore, we consider that microchimerism in pregnancy is probably important for tolerance of the fetoplacental unit. However, I anticipate that under pathologic conditions—just as in the case of transplants—tolerance of the fetoplacental unit may break down, which in turn may lead to a unique form of rejection of the fetoplacental unit. Unraveling the mechanisms of this rejectionlike process is a fascinating challenge. However, ob.gyns. know that the frequency of adverse pregnancy outcomes is higher in mothers who have pregnancies after embryo or egg donation. Under these circumstances, the placenta and fetus are totally foreign because they do not have the normal 50% genetic endowment from the mother. The complications noticed in these pregnancies include not only preeclampsia and growth restriction, but also preterm labor.

EAR: What is the evidence that an allergic phenomenon could be associated with premature labor, and could antihistamines be a treatment for premature labor?

RR: This idea came to me after seeing the relative of an obstetrician who went into premature labor after eating shellfish to which she was allergic. Around that time, we observed that a group of women in premature labor had eosinophils in the amniotic cavity. Eosinophils are associated with an allergiclike phenomenon and are not normally present in the amniotic cavity. The evidence to support biologic plausibility was generated in our work with Dr. Robert Garfield and Dr. Egle Bytautiene. We were able to demonstrate that guinea pigs allergic to egg proteins (ovalbumin) went into premature labor when challenged with the allergen during pregnancy. Premature labor could be prevented by the administration of an antihistamine in these animals.

We have interpreted this as evidence that some patients with premature labor may have an allergiclike reaction or type I hypersensitivity reaction. The nature of the allergen may vary. However, we know that allergens can cross the placenta. For example, dust mite antigen has been demonstrated in the amniotic fluid of women in the midtrimester of pregnancy. Also, there is evidence that the fetus is able to recognize and mount an immune response to allergens in utero.

In response to your question, we have treated with antihistamines some patients who have a typical allergiclike history along with premature labor, and this has resulted in the disappearance of uterine contractions. However, these are anecdotal reports, and I would like to stress that our interest in this mechanism of disease stems from the importance of demonstrating that a common mechanism of disease, such as allergy, can be a cause of the preterm parturition syndrome. This should not be surprising, because the uterus is bestowed with mast cells, the key effector cells of an allergic response, and the uterus has all the components required to generate an allergiclike immune response.

EAR: What is the evidence and importance of hormonal dysfunction in premature parturition?

RR: Progesterone withdrawal and/or deficiency has not yet been specifically demonstrated as an initiator of spontaneous parturition in humans. However, the role of progesterone in maintaining pregnancy is unquestionable.

Indeed, suspension of progesterone action through the administration of progesterone receptor inhibitors and progesterone receptor antagonists can induce activation of the components of the common pathway of parturition in animals and humans.

The progesterone/estradiol and progesterone/estriol ratios in amniotic fluid are lower in laboring than in nonlaboring subjects, and the progesterone/estriol ratio is lower in preterm labor followed by preterm delivery compared with preterm labor followed by term delivery, suggesting that these hormones are important in determining the duration of pregnancy.

Trials of progesterone administration to prevent preterm delivery have shown interesting results. Specifically, two recent randomized clinical trials demonstrated that vaginal suppositories containing natural progesterone, or injections of a progesterone, 17 α-hydroxyprogesterone caproate, to women at risk for preterm delivery seem to reduce the rate of spontaneous preterm delivery. Moreover, in the trial using 17 α-hydroxyprogesterone caproate, infants of mothers treated with this compound had a lower rate of necrotizing enterocolitis, intraventricular hemorrhage, and the need for supplemental oxygen. Further research is needed to identify the ideal progesterone regimen and the patients who may benefit from this intervention.

EAR: What about stress as a cause of premature labor?

RR: Epidemiologic studies have indicated that women exposed to stressful conditions during pregnancy have a mild increase in the rate of spontaneous preterm labor. The work of Dr. Pathik Wadhwa and Dr. Cal Hobel has been seminal in this area.

The precise mechanisms whereby stress causes premature labor implicate corticotropin-releasing hormone (CRH), which is produced by the hypothalamus and—importantly—by the placenta. Dr. Roger Smith's work in Australia has proposed that CRH is the regulator of a placental clock. Dr. Felice Petraglia in Italy has also contributed significantly to establish a link between CRH and premature labor.

The clinical implications of this work are related to the epidemiologic observations reported by Dr. Emile Papiernik in France, noting that women who are prescribed rest during pregnancy had a lower frequency of preterm delivery. This interesting experience has not been explored in the United States.

However, a targeted intervention to the patient at risk—such as the woman who must stand or do significant physical work during pregnancy—may be beneficial. However, bed rest per se is not an effective treatment to prevent all causes of premature labor. It is easy to understand that if the cause of preterm parturition is infection, then bed rest will not cure it.

EAR: What is the final message that you would like the readers of OB.GYN. NEWS take with them?

RR: Preterm labor is not just labor before its time, but is the result of a pathologic process. The challenge for health care providers is to try to identify why a women is in premature labor, what specific mechanism of disease may be involved, how sick the fetus is, and whether the benefits of pregnancy prolongation outweigh the risk of prematurity. The administration of steroids has been demonstrated to reduce the rate of adverse neonatal outcomes, and it is indicated when the patient is at risk for preterm delivery.

Preterm Labor Has Multiple Causes

In July's Master Class, the specific role of infection in preterm labor was discussed at length by Dr. Roberto Romero, chief of the Perinatology Research Branch at the National Institute of Child Health and Human Development, and professor of obstetrics and gynecology at Wayne State University in Detroit.

Although infection is a leading—and perhaps the best understood—cause of spontaneous preterm labor and delivery, it is not the only cause. Research from Dr. Romero's group and others increasingly point to several disease mechanisms with genetic and environmental components that can be responsible for what we now know as the preterm parturition syndrome.

I am pleased to welcome back Dr. Romero, an international authority on the syndrome.

In this month's discussion, Dr. Romero provides an overview of evolving knowledge about the syndrome and details current scientific progress in the understanding of the noninfectious causes that may be important in the process of preterm labor.

Dr. Roberto Romero: The common pathway of parturition consists of the anatomical, physiologic, biochemical, and clinical events that occur in the mother and/or fetus in both term and preterm labor. The uterine components of this pathway include increased uterine contractility; cervical ripening (dilatation and effacement); and membrane/decidual activation. In most women, these components are typically activated in a synchronous manner in spontaneous labor at term. Indeed, most women admitted in labor have uterine contractions, cervical changes and—sometimes—rupture of membranes.

However, in some cases the activation of the common pathway may be asynchronous. For example, a patient may have increased uterine contractility, but the cervix undergoes very little change over time. This is what is called a prolonged latent phase of labor. In 10% of cases, patients have spontaneous rupture of membranes without myometrial contractility. This is evidence that membrane/decidual activation has occurred without recruitment of the myometrium.

Asynchronous activation is more common in the preterm gestation. Many patients with suspected preterm labor will present with increased uterine contractility without cervical changes. Others will present with the clinical picture of cervical insufficiency (which used to be called cervical incompetence). Finally, some women will present with preterm premature rupture of the membranes (pPROM), which is premature membrane/decidual activation.

EAR: What is the importance of the concept of the common pathway?

RR: Much of the clinical management and research in understanding the causes of premature labor, treatment, and prevention has been focused on the elements of the common terminal pathway. For example, we have used uterine monitors to detect an increase in uterine contractility and tocolytic agents to treat increased myometrial contractility. We use ultrasound to identify patients with a short cervix who are at risk for preterm delivery. In some cases, we have placed cervical cerclage in patients at risk. Finally, we have used fetal fibronectin to detect decidual/membrane deactivation. A positive fetal fibronectin is an indicator that disruption of the choriodecidual interface has occurred. Yet these interventions aim to treat preterm labor as a symptom, without first identifying and understanding the underlying pathology that sets it in motion. Progress on this front is now being made.

EAR: What is the difference between spontaneous labor at term and preterm labor?

RR: We propose that spontaneous labor at term is the inevitable process that occurs when the capacity of the mother to support the fetus in utero has been reached. In other words, when the fetus has achieved maturity and is ready to face extrauterine life, it signals the onset of labor and engages the cooperation of the mother in this process.

In contrast, we propose that premature labor results from a pathologic insult that activates the common pathway of parturition. Before the development of newborn special care units, extreme prematurity was nearly always lethal. Thus, being born preterm is likely to result from such a severe pathologic process that it threatens the survival of the mother and/or baby.

In summary, spontaneous labor at term results from physiologic activation of the common pathway, whereas preterm labor would result from pathologic activation of the pathway.

EAR: What is the evidence that premature labor is a heterogeneous condition?

RR: My laboratory and other groups have generated evidence that the pattern of uterine gene expression—also known as the transcriptional profile—is different in patients with different causes of premature labor. A transcriptional profile is a snapshot of genes that are being upregulated or downregulated at a particular point in time.

We have demonstrated experimentally that the transcriptional profile in the uteri of mice that go into labor as a result of infection is different from the transcriptional profile of mice that go into labor because of ovariectomy (a model of progesterone withdrawal).

We have also examined the transcriptional profile of the chorioamniotic membranes in women with preterm labor and intact membranes vs. women with pPROM, in each case studying women with and without histologic chorioamnionitis. These studies have demonstrated that the patterns of gene expression are very different in these four groups, even though the clinical presentations are similar.

Collectively, the observations in patients and animals suggest that premature labor is a heterogeneous condition. Although they share a common pathway (uterine contractility and cervical dilatation and/or membrane rupture or activation), there are multiple causes for the preterm parturition syndrome.

Using the tools of high-dimensional biology, we have learned that premature labor is not simply labor before its time, but rather a disease state. It is caused by different pathologic processes with both environmental components and genetic components. For example, in infection-induced preterm labor (OB.GYN. NEWS, July 1, 2006, p. 42), the environmental component is represented by the microorganisms that cause the infection. The genetic component is the factor that predisposes some women to have an intrauterine infection or to respond more severely to that infection.

A prime example of the importance of genetics lies with the fetus. In pregnancy, we have not one patient, but two. Accumulating evidence indicates that the fetus plays a central role in the initiation of labor in both animals and humans. In humans, mothers of fetuses who have mounted a severe fetal inflammatory response are more likely to go into labor than are mothers of fetuses who have not mounted a fetal inflammatory response to infection. The magnitude and severity of the inflammatory response are under genetic control.

Thus, in pregnancy, the genetic makeup of two hosts—mother and child—plays a role in determining the susceptibility and response to infection. It is a unique situation in medicine.

EAR: Why do you call preterm parturition a syndrome?

RR: The current taxonomy of disease in obstetrics is largely based on the symptoms and signs exhibited by the mother, not the mechanisms of disease responsible for the clinical presentations. A syndrome is a combination of symptoms and signs that form a distinct clinical picture indicative of a particular disorder. Implicit in this definition is the fact that a syndrome can have multiple causes. Our emphasis in referring to premature parturition as a syndrome is that it will help both patients and physicians readjust the unreasonable expectation that one test can diagnose or identify all women at risk, and that one treatment will be effective for all women in premature labor, regardless of the cause.

EAR: In the last Master Class, we spoke about the role of infection and inflammation as a cause of premature labor. You have shared with us a figure that shows other causes of preterm parturition. I would like to discuss the other causes with you. Can you tell us how uterine ischemia and/or vascular pathology cause premature labor?

RR: Placental histology suggests that vascular lesions involving maternal or fetal circulation constitute the second most common apparent cause of preterm labor and pPROM, after inflammation.

Research in this area has focused on elevated rates of vascular abnormalities in women with spontaneous preterm labor with intact membranes and pPROM, compared with women who deliver at term. The vascular lesions have been found on both the maternal and fetal side. For example, thrombosis of the decidual vessels attached to the placenta and failure of physiologic transformation in the myometrial segment of the spiral arteries are generally considered maternal lesions. Abnormalities in the fetal circulation linked to preterm labor include a decreased number of arterioles in the villi and fetal arterial thrombosis.

Whereas uteroplacental ischemia is the driver of vascular events, the leading candidate to explain the molecular mechanisms responsible is the renin-angiotensin system; in severe uteroplacental ischemia, the enzyme thrombin is emerging as an important activator of preterm labor associated with vaginal bleeding.

The work of Dr. Mark Phillippe and Dr. Michal Elovitz has demonstrated in animal models and in vivo investigations that whole blood—but not heparinized blood—raises contractile activity of the uterine muscle, and that such increased uterine activity can be blocked with a thrombin antagonist.

Moreover, women with preterm labor have higher concentrations of thrombin-antithrombin (TAT) complexes in amniotic fluid and in maternal plasma than do women without preterm labor. Similarly, Dr. Todd Rosen and Dr. Charles Lockwood have provided evidence that women destined to develop pPROM have higher concentrations of thrombin weeks before the development of complications. Therefore, thrombin is a potential initiator not only of the rupture of membranes (via stromal cells and matrix metalloproteinase 1), but also of uterine contractility and preterm labor.

The thrombin connection would help to explain why retroplacental hematomas in early pregnancy are associated with preterm delivery, and why vaginal bleeding in the first or second trimester is a risk factor for preterm birth with intact or ruptured membranes.

EAR: What is the evidence that uterine overdistention is a cause of preterm parturition?

RR: Obstetricians and midwives know that multiple gestation is a risk factor for preterm delivery, and that the higher the order of multiple gestation, the greater the risk for preterm birth. Patients with polyhydramnios resulting from a congenital fetal anomaly are also at risk for spontaneous preterm labor and delivery. These two conditions are probably mediated by uterine overdistention. It is likely that the same is the case for patients who have müllerian duct abnormalities in which the uterine cavity is small. One example is congenital hypoplastic uterus and another is the abnormal uterus resulting from diethylstilbestrol exposure.

EAR: What is the mechanism linking uterine overdistention with premature labor?

RR: This is an area that requires further work. In general terms, mechanical signals triggered by uterine stretch may lead to preterm labor—as in multiple gestations and polyhydramnios—although the precise mechanisms involved remain unknown.

Experimental distention of the uterus with a saline-filled balloon rapidly prompted regular uterine contractions in women carrying live term fetuses or dead fetuses. All were delivered within 21 hours.

Stephen Lye, Ph.D., and his group at the University of Toronto have found increased expression of oxytocin receptor, connexin 43, and the c-fos mRNA in the myometrium. Gillian Bryant-Greenwood, Ph.D., at the University of Hawaii, Honolulu, has shown that stretching of the chorioamniotic membranes in experimental models can increase the expression of interleukin-8 and also another cytokine called visfatin, which can have important effects on the integrity of the membranes.

EAR: I noticed that cervical pathology is also a potential cause of the preterm parturition syndrome. Is this the same as cervical insufficiency?

RR: Yes. Cervical insufficiency is also a cause of the preterm parturition syndrome and can result from congenital disorders, surgical trauma, trauma, or infection. Although cervical length has been touted as a predictor of preterm birth, it is important to remember that a short cervix is not always a ripe cervix. Once again, more research is needed to identify the events that occur as a result of cervical insufficiency, and the ways these affect the initiation of preterm and term labor.

EAR: What about abnormal allograft reaction?

RR: The fetoplacental unit has been called “nature's most successful transplant,” or—more accurately—a “semiallograft.” The mechanisms that bring about tolerance of this semiallograft are poorly understood. However, transplants of solid organs are tolerated through the establishment of microchimerism in the transplanted organ as well as in the host. Therefore, we consider that microchimerism in pregnancy is probably important for tolerance of the fetoplacental unit. However, I anticipate that under pathologic conditions—just as in the case of transplants—tolerance of the fetoplacental unit may break down, which in turn may lead to a unique form of rejection of the fetoplacental unit. Unraveling the mechanisms of this rejectionlike process is a fascinating challenge. However, ob.gyns. know that the frequency of adverse pregnancy outcomes is higher in mothers who have pregnancies after embryo or egg donation. Under these circumstances, the placenta and fetus are totally foreign because they do not have the normal 50% genetic endowment from the mother. The complications noticed in these pregnancies include not only preeclampsia and growth restriction, but also preterm labor.

EAR: What is the evidence that an allergic phenomenon could be associated with premature labor, and could antihistamines be a treatment for premature labor?

RR: This idea came to me after seeing the relative of an obstetrician who went into premature labor after eating shellfish to which she was allergic. Around that time, we observed that a group of women in premature labor had eosinophils in the amniotic cavity. Eosinophils are associated with an allergiclike phenomenon and are not normally present in the amniotic cavity. The evidence to support biologic plausibility was generated in our work with Dr. Robert Garfield and Dr. Egle Bytautiene. We were able to demonstrate that guinea pigs allergic to egg proteins (ovalbumin) went into premature labor when challenged with the allergen during pregnancy. Premature labor could be prevented by the administration of an antihistamine in these animals.

We have interpreted this as evidence that some patients with premature labor may have an allergiclike reaction or type I hypersensitivity reaction. The nature of the allergen may vary. However, we know that allergens can cross the placenta. For example, dust mite antigen has been demonstrated in the amniotic fluid of women in the midtrimester of pregnancy. Also, there is evidence that the fetus is able to recognize and mount an immune response to allergens in utero.

In response to your question, we have treated with antihistamines some patients who have a typical allergiclike history along with premature labor, and this has resulted in the disappearance of uterine contractions. However, these are anecdotal reports, and I would like to stress that our interest in this mechanism of disease stems from the importance of demonstrating that a common mechanism of disease, such as allergy, can be a cause of the preterm parturition syndrome. This should not be surprising, because the uterus is bestowed with mast cells, the key effector cells of an allergic response, and the uterus has all the components required to generate an allergiclike immune response.

EAR: What is the evidence and importance of hormonal dysfunction in premature parturition?

RR: Progesterone withdrawal and/or deficiency has not yet been specifically demonstrated as an initiator of spontaneous parturition in humans. However, the role of progesterone in maintaining pregnancy is unquestionable.

Indeed, suspension of progesterone action through the administration of progesterone receptor inhibitors and progesterone receptor antagonists can induce activation of the components of the common pathway of parturition in animals and humans.

The progesterone/estradiol and progesterone/estriol ratios in amniotic fluid are lower in laboring than in nonlaboring subjects, and the progesterone/estriol ratio is lower in preterm labor followed by preterm delivery compared with preterm labor followed by term delivery, suggesting that these hormones are important in determining the duration of pregnancy.

Trials of progesterone administration to prevent preterm delivery have shown interesting results. Specifically, two recent randomized clinical trials demonstrated that vaginal suppositories containing natural progesterone, or injections of a progesterone, 17 α-hydroxyprogesterone caproate, to women at risk for preterm delivery seem to reduce the rate of spontaneous preterm delivery. Moreover, in the trial using 17 α-hydroxyprogesterone caproate, infants of mothers treated with this compound had a lower rate of necrotizing enterocolitis, intraventricular hemorrhage, and the need for supplemental oxygen. Further research is needed to identify the ideal progesterone regimen and the patients who may benefit from this intervention.

EAR: What about stress as a cause of premature labor?

RR: Epidemiologic studies have indicated that women exposed to stressful conditions during pregnancy have a mild increase in the rate of spontaneous preterm labor. The work of Dr. Pathik Wadhwa and Dr. Cal Hobel has been seminal in this area.

The precise mechanisms whereby stress causes premature labor implicate corticotropin-releasing hormone (CRH), which is produced by the hypothalamus and—importantly—by the placenta. Dr. Roger Smith's work in Australia has proposed that CRH is the regulator of a placental clock. Dr. Felice Petraglia in Italy has also contributed significantly to establish a link between CRH and premature labor.

The clinical implications of this work are related to the epidemiologic observations reported by Dr. Emile Papiernik in France, noting that women who are prescribed rest during pregnancy had a lower frequency of preterm delivery. This interesting experience has not been explored in the United States.

However, a targeted intervention to the patient at risk—such as the woman who must stand or do significant physical work during pregnancy—may be beneficial. However, bed rest per se is not an effective treatment to prevent all causes of premature labor. It is easy to understand that if the cause of preterm parturition is infection, then bed rest will not cure it.

EAR: What is the final message that you would like the readers of OB.GYN. NEWS take with them?

RR: Preterm labor is not just labor before its time, but is the result of a pathologic process. The challenge for health care providers is to try to identify why a women is in premature labor, what specific mechanism of disease may be involved, how sick the fetus is, and whether the benefits of pregnancy prolongation outweigh the risk of prematurity. The administration of steroids has been demonstrated to reduce the rate of adverse neonatal outcomes, and it is indicated when the patient is at risk for preterm delivery.

Preterm Labor Has Multiple Causes

In July's Master Class, the specific role of infection in preterm labor was discussed at length by Dr. Roberto Romero, chief of the Perinatology Research Branch at the National Institute of Child Health and Human Development, and professor of obstetrics and gynecology at Wayne State University in Detroit.

Although infection is a leading—and perhaps the best understood—cause of spontaneous preterm labor and delivery, it is not the only cause. Research from Dr. Romero's group and others increasingly point to several disease mechanisms with genetic and environmental components that can be responsible for what we now know as the preterm parturition syndrome.

I am pleased to welcome back Dr. Romero, an international authority on the syndrome.

In this month's discussion, Dr. Romero provides an overview of evolving knowledge about the syndrome and details current scientific progress in the understanding of the noninfectious causes that may be important in the process of preterm labor.

Today, there are more published studies on the use of tension-free vaginal tape in the treatment of stress urinary incontinence than on any other procedure that has ever been performed for stress incontinence.

When compared with traditional suspensions and slings, TVT has been shown to be at least as—if not more—efficacious for all types of stress urinary incontinence, from incontinence due to anatomical abnormalities to incontinence resulting from intrinsic sphincter deficiency and mixed incontinence.

Added to TVT's efficacy is the fact that the TVT procedure is simpler, shorter in duration (approximately 20 minutes), and less invasive than other procedures, with extremely low complication rates when the appropriate technique is utilized and retropublic anatomy is appreciated.

Clearly, the TVT procedure is a good treatment of choice.

TVT's Origins

The TVT procedure, which was the first use of the synthetic midurethral sling, was first done in this country in 1998.

The history of TVT is interesting because the procedure went against everything we always thought we understood about surgery for SUI: mainly, that the mechanism for continence was at the proximal urethra and bladder neck, and that surgeries for incontinence needed to either elevate or support this area. TVT, on the other hand, uses a midurethral placement. It provides a backboard under a portion of the urethra that has very little mobility.

In addition to processing this major change in thinking, many of us also thought at the time that synthetic materials should be avoided for sling procedures, and few of us could easily grasp the notion of placing a sling without fixing it to anything.

The TVT procedure was first described by Dr. Ulf Ulmsten in 1996. In the mid-1980s, he and his fellow, Dr. Peter Petros, set out to identify and describe a new minimally invasive outpatient procedure for stress incontinence.

They described a series of small studies, exploring what they called the “integral theory,” in which they looked at different slings or meshes placed at different anatomical sites underneath the urethra.

In the end, they determined that a certain type of polypropylene mesh, placed through a vaginal-to-suprapubic route using specially designed, long stainless steel needles that can be passed under local anesthesia, was the best approach.

According to Dr. Ulmsten's theory, the procedure works by reinforcing the pubourethral ligaments and levator ani muscles, as well as increasing the support of the vaginal hammock.

The Entry of Transobturator Slings

The TVT procedure required blind passage of needles through the retropubic space, a process that potentially brings the needle into close proximity with vascular structures as well as bowel and the bladder.

And indeed, there were rare reports of very serious complications related to vascular and bowel injuries.

These complications led a Frenchman, Dr. Emmanuel Delorme, to describe the first transobturator tape (TOT) procedure. The theory behind this technique, which represented a second generation of midurethral slings, was that it avoided the retropubic space and thus avoided these potential vascular, bowel, and bladder injuries.

The procedure became quite popular, and techniques to place the transobturator sling from the vaginal side or from the inner thigh were described. Experience with these modifications has grown over the last few years.

Complication rates with TOT have been low, but some complications, particularly those related to the inner thigh, have been described.

The next generation of synthetic midurethral slings, which will be available in the next year, will be even less invasive than TOT, as the sling will not have an exit site.

To date, we lack data from any long-term, randomized comparison of the two procedures, and we should not draw any conclusions until we have such long-term data. I believe we need to see a minimum follow-up of 2 years.

The data should accumulate quickly, however. In fact, a prospective, randomized comparison of TVT versus TOT has just been completed, so data should be forthcoming.

Regarding TVT specifically, we have long-term data (up to 7 years) showing that TVT maintains its high cure rate of greater than 80%.

I sometimes use TOT in my practice; at this time, it seems especially reasonable in patients at high risk for pelvic adhesions and in patients who have milder degrees of incontinence or SUI that is felt to be occult.

Performing TVT

The TVT procedure begins with the administration of a hemostatic agent and an anesthetic. (We prefer lidocaine with epinephrine.) The anterior vaginal wall is injected at the level of the distal- to midurethra.

It is important to appreciate that this portion of the anterior vaginal wall is fused to the posterior urethra. No clear plane of dissection exists between these two structures.

The tips of the scissors are then used to create two tunnels to the level of the interior pubic ramus. The bladder is emptied and, using a catheter guide, the urethra is deflected in the direction opposite to the direction in which the needle is going to be passed.

The TVT needle is then directed toward the ipsilateral shoulder, and the tip of the needle is used to penetrate the urogenital diaphragm. No more than 0.5–0.75 inch of the needle should be passed in a lateral direction.

Once the urogenital diaphragm has been penetrated, the handle of the needle is dropped, and the tip of the needle is moved in a medial and superior direction. Be certain that the needle tip maintains contact with the back of the pubic bone. This is a very important landmark, and using it will help avoid migration of the needle into dangerous areas.

The next resistance that you will feel at the tip of the needle is the undersurface of the rectus muscle.

The needle is then used to penetrate the anterior abdominal fascia, and the tip comes up through the previously created stab wound. Cystoscopy is performed with the needle in place.

It is very important to overdistend the bladder and make sure that every millimeter of the bladder wall is visualized. Subtle penetrations can be easily missed if the bladder is not overdistended. Once it can be determined for certain that the needle has not penetrated the bladder, the needle is passed and the same procedure is repeated on the opposite side.

With the plastic sheath in place, you can achieve tensioning of the sling either through a cough stress test or suprapubic pressure. Some clinicians—believing that it's unnecessary to perform any sort of stress test—prefer just to place the sling loosely below the urethra, and that's fine.

If at all possible, I like to recreate SUI with suprapubic pressure or a cough, but at times this is not possible. With experience, you'll realize that the sling is placed very loosely most of the time. My end point in the majority of cases is being able to easily pass a right-angled clamp between the sling and the posterior urethra.

Preventing Complications

The most common complication of the TVT procedure is inadvertent penetration of the bladder. However, as long as this is diagnosed and the needle is withdrawn, the bladder emptied, and the needle repassed safely, penetration will rarely, if ever, cause any significant sequelae. In my opinion, these patients really do not even require any prolonged drainage, assuming that the penetration site is in a high, nondependent portion of the bladder.

Vascular injuries occur when the tip of the needle migrates away from the back of the pubic bone. Most commonly, this occurs when the needle is continued in a lateral direction and comes in close proximity with the obturator neurovascular bundle. If the needle is continued in a lateral direction, it may come in close proximity to the external iliac artery and vein.

Regarding bowel injuries, I strongly believe that this procedure should be avoided in patients who are at high risk for significant pelvic adhesions. This category includes patients who have had a ruptured appendix with peritonitis, patients who have had severe endometriosis and are known to have significant pelvic adhesions, and any patient you feel might be at high risk for having bowel adhered very low in the pelvis.

And again, we must not underestimate the importance of maintaining the contact of the needle on the back of the pubic bone. It is attention to specific anatomical landmarks such as this that make the operation both safe and successful.

A small percentage (less than 1%) of patients will have erosion of the tape. This outcome can be easily managed by either excising the eroded part of the tape or re-covering it with healthier tissue.

Rates of partial or complete retention postoperatively—a problem after any operation for SUI—have been very low and can be managed by either stretching or cutting the tape.

MICKEY M. KARRAM M.D.

Emily Brannan, Illustration

Vascular injuries may occur when the needle is continued in a lateral direction and comes in close proximity to the obturator neurovascular bundle. Courtesy Dr. Mickey M. Karram

Stress Urinary Incontinence

Until recently, gynecologists and urologists approached stress urinary incontinence differently. Gynecologists were champions of retropubic colpopexy procedures, while urologists performed sling procedures. Through Dr. Ulf Ulmsten's landmark work on stress urinary incontinence, culminating in the use of tension-free vaginal tape (TVT) in 1996, gynecologists and urologists throughout the world came to agree on a common procedure.

Whereas laparoscopic retropubic colpopexy was the minimally invasive surgical procedure of choice in the late 1990s, the use of TVT has quickly become the preferred minimally invasive technique in the treatment of stress urinary incontinence. The rapid acceptance of the use of tension-free vaginal tape is quite understandable. Few techniques in gynecologic surgery have been as well studied.

Rapidly accumulating data indicate that the long-term results are at least as good as the standard, retropubic colpopexy. In a large, multicenter, prospective, randomized trial for stress urinary incontinence (Am. J. Obstet. Gynecol. 2004;190:324–31), the cure rates at 2 years for TVT and colposuspension were essentially the same (81% vs. 80%).

For this edition of the Master Class, I am proud to have Dr. Mickey M. Karram discussing TVT in the treatment of stress urinary incontinence. As one of the true thought leaders in urogynecology, Dr. Karram helped introduce the use of TVT in the United States.

Dr. Karram is the director of urogynecology and reconstructive pelvic surgery and the director and founder of the fellowship training program in female pelvic medicine and reconstructive surgery in the department of obstetrics and gynecology at Good Samaritan Hospital in Cincinnati. He is also affiliated with the department of obstetrics and gynecology at the University of Cincinnati and is editor-in-chief of the International Urogynecology Journal and Pelvic Floor Dysfunction.

Dr. Karram has authored over 90 peer-reviewed publications and 33 book chapters, and has edited five books. I am truly honored to have Dr. Karram introduce the important topic of synthetic midurethral slings for stress incontinence.

Today, there are more published studies on the use of tension-free vaginal tape in the treatment of stress urinary incontinence than on any other procedure that has ever been performed for stress incontinence.

When compared with traditional suspensions and slings, TVT has been shown to be at least as—if not more—efficacious for all types of stress urinary incontinence, from incontinence due to anatomical abnormalities to incontinence resulting from intrinsic sphincter deficiency and mixed incontinence.

Added to TVT's efficacy is the fact that the TVT procedure is simpler, shorter in duration (approximately 20 minutes), and less invasive than other procedures, with extremely low complication rates when the appropriate technique is utilized and retropublic anatomy is appreciated.

Clearly, the TVT procedure is a good treatment of choice.

TVT's Origins

The TVT procedure, which was the first use of the synthetic midurethral sling, was first done in this country in 1998.

The history of TVT is interesting because the procedure went against everything we always thought we understood about surgery for SUI: mainly, that the mechanism for continence was at the proximal urethra and bladder neck, and that surgeries for incontinence needed to either elevate or support this area. TVT, on the other hand, uses a midurethral placement. It provides a backboard under a portion of the urethra that has very little mobility.

In addition to processing this major change in thinking, many of us also thought at the time that synthetic materials should be avoided for sling procedures, and few of us could easily grasp the notion of placing a sling without fixing it to anything.

The TVT procedure was first described by Dr. Ulf Ulmsten in 1996. In the mid-1980s, he and his fellow, Dr. Peter Petros, set out to identify and describe a new minimally invasive outpatient procedure for stress incontinence.

They described a series of small studies, exploring what they called the “integral theory,” in which they looked at different slings or meshes placed at different anatomical sites underneath the urethra.

In the end, they determined that a certain type of polypropylene mesh, placed through a vaginal-to-suprapubic route using specially designed, long stainless steel needles that can be passed under local anesthesia, was the best approach.

According to Dr. Ulmsten's theory, the procedure works by reinforcing the pubourethral ligaments and levator ani muscles, as well as increasing the support of the vaginal hammock.

The Entry of Transobturator Slings

The TVT procedure required blind passage of needles through the retropubic space, a process that potentially brings the needle into close proximity with vascular structures as well as bowel and the bladder.

And indeed, there were rare reports of very serious complications related to vascular and bowel injuries.

These complications led a Frenchman, Dr. Emmanuel Delorme, to describe the first transobturator tape (TOT) procedure. The theory behind this technique, which represented a second generation of midurethral slings, was that it avoided the retropubic space and thus avoided these potential vascular, bowel, and bladder injuries.

The procedure became quite popular, and techniques to place the transobturator sling from the vaginal side or from the inner thigh were described. Experience with these modifications has grown over the last few years.

Complication rates with TOT have been low, but some complications, particularly those related to the inner thigh, have been described.

The next generation of synthetic midurethral slings, which will be available in the next year, will be even less invasive than TOT, as the sling will not have an exit site.

To date, we lack data from any long-term, randomized comparison of the two procedures, and we should not draw any conclusions until we have such long-term data. I believe we need to see a minimum follow-up of 2 years.

The data should accumulate quickly, however. In fact, a prospective, randomized comparison of TVT versus TOT has just been completed, so data should be forthcoming.

Regarding TVT specifically, we have long-term data (up to 7 years) showing that TVT maintains its high cure rate of greater than 80%.

I sometimes use TOT in my practice; at this time, it seems especially reasonable in patients at high risk for pelvic adhesions and in patients who have milder degrees of incontinence or SUI that is felt to be occult.

Performing TVT

The TVT procedure begins with the administration of a hemostatic agent and an anesthetic. (We prefer lidocaine with epinephrine.) The anterior vaginal wall is injected at the level of the distal- to midurethra.

It is important to appreciate that this portion of the anterior vaginal wall is fused to the posterior urethra. No clear plane of dissection exists between these two structures.

The tips of the scissors are then used to create two tunnels to the level of the interior pubic ramus. The bladder is emptied and, using a catheter guide, the urethra is deflected in the direction opposite to the direction in which the needle is going to be passed.

The TVT needle is then directed toward the ipsilateral shoulder, and the tip of the needle is used to penetrate the urogenital diaphragm. No more than 0.5–0.75 inch of the needle should be passed in a lateral direction.

Once the urogenital diaphragm has been penetrated, the handle of the needle is dropped, and the tip of the needle is moved in a medial and superior direction. Be certain that the needle tip maintains contact with the back of the pubic bone. This is a very important landmark, and using it will help avoid migration of the needle into dangerous areas.

The next resistance that you will feel at the tip of the needle is the undersurface of the rectus muscle.

The needle is then used to penetrate the anterior abdominal fascia, and the tip comes up through the previously created stab wound. Cystoscopy is performed with the needle in place.

It is very important to overdistend the bladder and make sure that every millimeter of the bladder wall is visualized. Subtle penetrations can be easily missed if the bladder is not overdistended. Once it can be determined for certain that the needle has not penetrated the bladder, the needle is passed and the same procedure is repeated on the opposite side.

With the plastic sheath in place, you can achieve tensioning of the sling either through a cough stress test or suprapubic pressure. Some clinicians—believing that it's unnecessary to perform any sort of stress test—prefer just to place the sling loosely below the urethra, and that's fine.

If at all possible, I like to recreate SUI with suprapubic pressure or a cough, but at times this is not possible. With experience, you'll realize that the sling is placed very loosely most of the time. My end point in the majority of cases is being able to easily pass a right-angled clamp between the sling and the posterior urethra.

Preventing Complications

The most common complication of the TVT procedure is inadvertent penetration of the bladder. However, as long as this is diagnosed and the needle is withdrawn, the bladder emptied, and the needle repassed safely, penetration will rarely, if ever, cause any significant sequelae. In my opinion, these patients really do not even require any prolonged drainage, assuming that the penetration site is in a high, nondependent portion of the bladder.

Vascular injuries occur when the tip of the needle migrates away from the back of the pubic bone. Most commonly, this occurs when the needle is continued in a lateral direction and comes in close proximity with the obturator neurovascular bundle. If the needle is continued in a lateral direction, it may come in close proximity to the external iliac artery and vein.

Regarding bowel injuries, I strongly believe that this procedure should be avoided in patients who are at high risk for significant pelvic adhesions. This category includes patients who have had a ruptured appendix with peritonitis, patients who have had severe endometriosis and are known to have significant pelvic adhesions, and any patient you feel might be at high risk for having bowel adhered very low in the pelvis.

And again, we must not underestimate the importance of maintaining the contact of the needle on the back of the pubic bone. It is attention to specific anatomical landmarks such as this that make the operation both safe and successful.

A small percentage (less than 1%) of patients will have erosion of the tape. This outcome can be easily managed by either excising the eroded part of the tape or re-covering it with healthier tissue.

Rates of partial or complete retention postoperatively—a problem after any operation for SUI—have been very low and can be managed by either stretching or cutting the tape.

MICKEY M. KARRAM M.D.

Emily Brannan, Illustration

Vascular injuries may occur when the needle is continued in a lateral direction and comes in close proximity to the obturator neurovascular bundle. Courtesy Dr. Mickey M. Karram

Stress Urinary Incontinence

Until recently, gynecologists and urologists approached stress urinary incontinence differently. Gynecologists were champions of retropubic colpopexy procedures, while urologists performed sling procedures. Through Dr. Ulf Ulmsten's landmark work on stress urinary incontinence, culminating in the use of tension-free vaginal tape (TVT) in 1996, gynecologists and urologists throughout the world came to agree on a common procedure.

Whereas laparoscopic retropubic colpopexy was the minimally invasive surgical procedure of choice in the late 1990s, the use of TVT has quickly become the preferred minimally invasive technique in the treatment of stress urinary incontinence. The rapid acceptance of the use of tension-free vaginal tape is quite understandable. Few techniques in gynecologic surgery have been as well studied.

Rapidly accumulating data indicate that the long-term results are at least as good as the standard, retropubic colpopexy. In a large, multicenter, prospective, randomized trial for stress urinary incontinence (Am. J. Obstet. Gynecol. 2004;190:324–31), the cure rates at 2 years for TVT and colposuspension were essentially the same (81% vs. 80%).

For this edition of the Master Class, I am proud to have Dr. Mickey M. Karram discussing TVT in the treatment of stress urinary incontinence. As one of the true thought leaders in urogynecology, Dr. Karram helped introduce the use of TVT in the United States.

Dr. Karram is the director of urogynecology and reconstructive pelvic surgery and the director and founder of the fellowship training program in female pelvic medicine and reconstructive surgery in the department of obstetrics and gynecology at Good Samaritan Hospital in Cincinnati. He is also affiliated with the department of obstetrics and gynecology at the University of Cincinnati and is editor-in-chief of the International Urogynecology Journal and Pelvic Floor Dysfunction.

Dr. Karram has authored over 90 peer-reviewed publications and 33 book chapters, and has edited five books. I am truly honored to have Dr. Karram introduce the important topic of synthetic midurethral slings for stress incontinence.

Today, there are more published studies on the use of tension-free vaginal tape in the treatment of stress urinary incontinence than on any other procedure that has ever been performed for stress incontinence.

When compared with traditional suspensions and slings, TVT has been shown to be at least as—if not more—efficacious for all types of stress urinary incontinence, from incontinence due to anatomical abnormalities to incontinence resulting from intrinsic sphincter deficiency and mixed incontinence.

Added to TVT's efficacy is the fact that the TVT procedure is simpler, shorter in duration (approximately 20 minutes), and less invasive than other procedures, with extremely low complication rates when the appropriate technique is utilized and retropublic anatomy is appreciated.

Clearly, the TVT procedure is a good treatment of choice.

TVT's Origins

The TVT procedure, which was the first use of the synthetic midurethral sling, was first done in this country in 1998.

The history of TVT is interesting because the procedure went against everything we always thought we understood about surgery for SUI: mainly, that the mechanism for continence was at the proximal urethra and bladder neck, and that surgeries for incontinence needed to either elevate or support this area. TVT, on the other hand, uses a midurethral placement. It provides a backboard under a portion of the urethra that has very little mobility.

In addition to processing this major change in thinking, many of us also thought at the time that synthetic materials should be avoided for sling procedures, and few of us could easily grasp the notion of placing a sling without fixing it to anything.

The TVT procedure was first described by Dr. Ulf Ulmsten in 1996. In the mid-1980s, he and his fellow, Dr. Peter Petros, set out to identify and describe a new minimally invasive outpatient procedure for stress incontinence.

They described a series of small studies, exploring what they called the “integral theory,” in which they looked at different slings or meshes placed at different anatomical sites underneath the urethra.

In the end, they determined that a certain type of polypropylene mesh, placed through a vaginal-to-suprapubic route using specially designed, long stainless steel needles that can be passed under local anesthesia, was the best approach.

According to Dr. Ulmsten's theory, the procedure works by reinforcing the pubourethral ligaments and levator ani muscles, as well as increasing the support of the vaginal hammock.

The Entry of Transobturator Slings

The TVT procedure required blind passage of needles through the retropubic space, a process that potentially brings the needle into close proximity with vascular structures as well as bowel and the bladder.

And indeed, there were rare reports of very serious complications related to vascular and bowel injuries.

These complications led a Frenchman, Dr. Emmanuel Delorme, to describe the first transobturator tape (TOT) procedure. The theory behind this technique, which represented a second generation of midurethral slings, was that it avoided the retropubic space and thus avoided these potential vascular, bowel, and bladder injuries.

The procedure became quite popular, and techniques to place the transobturator sling from the vaginal side or from the inner thigh were described. Experience with these modifications has grown over the last few years.

Complication rates with TOT have been low, but some complications, particularly those related to the inner thigh, have been described.

The next generation of synthetic midurethral slings, which will be available in the next year, will be even less invasive than TOT, as the sling will not have an exit site.

To date, we lack data from any long-term, randomized comparison of the two procedures, and we should not draw any conclusions until we have such long-term data. I believe we need to see a minimum follow-up of 2 years.

The data should accumulate quickly, however. In fact, a prospective, randomized comparison of TVT versus TOT has just been completed, so data should be forthcoming.

Regarding TVT specifically, we have long-term data (up to 7 years) showing that TVT maintains its high cure rate of greater than 80%.

I sometimes use TOT in my practice; at this time, it seems especially reasonable in patients at high risk for pelvic adhesions and in patients who have milder degrees of incontinence or SUI that is felt to be occult.

Performing TVT

The TVT procedure begins with the administration of a hemostatic agent and an anesthetic. (We prefer lidocaine with epinephrine.) The anterior vaginal wall is injected at the level of the distal- to midurethra.

It is important to appreciate that this portion of the anterior vaginal wall is fused to the posterior urethra. No clear plane of dissection exists between these two structures.

The tips of the scissors are then used to create two tunnels to the level of the interior pubic ramus. The bladder is emptied and, using a catheter guide, the urethra is deflected in the direction opposite to the direction in which the needle is going to be passed.

The TVT needle is then directed toward the ipsilateral shoulder, and the tip of the needle is used to penetrate the urogenital diaphragm. No more than 0.5–0.75 inch of the needle should be passed in a lateral direction.

Once the urogenital diaphragm has been penetrated, the handle of the needle is dropped, and the tip of the needle is moved in a medial and superior direction. Be certain that the needle tip maintains contact with the back of the pubic bone. This is a very important landmark, and using it will help avoid migration of the needle into dangerous areas.

The next resistance that you will feel at the tip of the needle is the undersurface of the rectus muscle.

The needle is then used to penetrate the anterior abdominal fascia, and the tip comes up through the previously created stab wound. Cystoscopy is performed with the needle in place.

It is very important to overdistend the bladder and make sure that every millimeter of the bladder wall is visualized. Subtle penetrations can be easily missed if the bladder is not overdistended. Once it can be determined for certain that the needle has not penetrated the bladder, the needle is passed and the same procedure is repeated on the opposite side.

With the plastic sheath in place, you can achieve tensioning of the sling either through a cough stress test or suprapubic pressure. Some clinicians—believing that it's unnecessary to perform any sort of stress test—prefer just to place the sling loosely below the urethra, and that's fine.

If at all possible, I like to recreate SUI with suprapubic pressure or a cough, but at times this is not possible. With experience, you'll realize that the sling is placed very loosely most of the time. My end point in the majority of cases is being able to easily pass a right-angled clamp between the sling and the posterior urethra.

Preventing Complications

The most common complication of the TVT procedure is inadvertent penetration of the bladder. However, as long as this is diagnosed and the needle is withdrawn, the bladder emptied, and the needle repassed safely, penetration will rarely, if ever, cause any significant sequelae. In my opinion, these patients really do not even require any prolonged drainage, assuming that the penetration site is in a high, nondependent portion of the bladder.

Vascular injuries occur when the tip of the needle migrates away from the back of the pubic bone. Most commonly, this occurs when the needle is continued in a lateral direction and comes in close proximity with the obturator neurovascular bundle. If the needle is continued in a lateral direction, it may come in close proximity to the external iliac artery and vein.

Regarding bowel injuries, I strongly believe that this procedure should be avoided in patients who are at high risk for significant pelvic adhesions. This category includes patients who have had a ruptured appendix with peritonitis, patients who have had severe endometriosis and are known to have significant pelvic adhesions, and any patient you feel might be at high risk for having bowel adhered very low in the pelvis.

And again, we must not underestimate the importance of maintaining the contact of the needle on the back of the pubic bone. It is attention to specific anatomical landmarks such as this that make the operation both safe and successful.

A small percentage (less than 1%) of patients will have erosion of the tape. This outcome can be easily managed by either excising the eroded part of the tape or re-covering it with healthier tissue.

Rates of partial or complete retention postoperatively—a problem after any operation for SUI—have been very low and can be managed by either stretching or cutting the tape.

MICKEY M. KARRAM M.D.

Emily Brannan, Illustration

Vascular injuries may occur when the needle is continued in a lateral direction and comes in close proximity to the obturator neurovascular bundle. Courtesy Dr. Mickey M. Karram

Stress Urinary Incontinence

Until recently, gynecologists and urologists approached stress urinary incontinence differently. Gynecologists were champions of retropubic colpopexy procedures, while urologists performed sling procedures. Through Dr. Ulf Ulmsten's landmark work on stress urinary incontinence, culminating in the use of tension-free vaginal tape (TVT) in 1996, gynecologists and urologists throughout the world came to agree on a common procedure.

Whereas laparoscopic retropubic colpopexy was the minimally invasive surgical procedure of choice in the late 1990s, the use of TVT has quickly become the preferred minimally invasive technique in the treatment of stress urinary incontinence. The rapid acceptance of the use of tension-free vaginal tape is quite understandable. Few techniques in gynecologic surgery have been as well studied.

Rapidly accumulating data indicate that the long-term results are at least as good as the standard, retropubic colpopexy. In a large, multicenter, prospective, randomized trial for stress urinary incontinence (Am. J. Obstet. Gynecol. 2004;190:324–31), the cure rates at 2 years for TVT and colposuspension were essentially the same (81% vs. 80%).

For this edition of the Master Class, I am proud to have Dr. Mickey M. Karram discussing TVT in the treatment of stress urinary incontinence. As one of the true thought leaders in urogynecology, Dr. Karram helped introduce the use of TVT in the United States.

Dr. Karram is the director of urogynecology and reconstructive pelvic surgery and the director and founder of the fellowship training program in female pelvic medicine and reconstructive surgery in the department of obstetrics and gynecology at Good Samaritan Hospital in Cincinnati. He is also affiliated with the department of obstetrics and gynecology at the University of Cincinnati and is editor-in-chief of the International Urogynecology Journal and Pelvic Floor Dysfunction.

Dr. Karram has authored over 90 peer-reviewed publications and 33 book chapters, and has edited five books. I am truly honored to have Dr. Karram introduce the important topic of synthetic midurethral slings for stress incontinence.

Dr. E. Albert Reece: How important is infection as a mechanism of disease in premature labor?

Dr. Roberto Romero: Intrauterine and systemic infections are a leading cause of spontaneous preterm labor and delivery. Indeed, infections and inflammation are the only mechanisms of disease for which a clear causal link with prematurity has been established. Moreover, a clear molecular pathophysiology has been described.

EAR: How frequent is intrauterine infection in spontaneous preterm birth?

RR: It has been estimated that one of every four preterm births occurs to mothers with intraamniotic infection (defined as a positive amniotic fluid culture for microorganisms). Under normal circumstances, the amniotic cavity does not contain bacteria, just as cerebrospinal fluid does not. However, approximately 12% of women presenting with an episode of preterm labor will have a positive amniotic fluid culture for microorganisms. The organisms most frequently isolated are genital mycoplasmas, particularly Ureaplasma urealyticum. Among women with preterm premature rupture of membranes (PROM), one of every three will have a positive amniotic fluid culture for microorganisms at the time of presentation. U. urealyticum is the most common microorganism isolated from the amniotic cavity.

EAR: Is there a particular subgroup of women in whom intrauterine infection is more prevalent?

RR: The earlier the gestational age at which a patient presents with preterm labor and intact membranes or preterm PROM, the higher the likelihood of a positive amniotic fluid culture. For example, infection and/or inflammation is present in close to 70% of women presenting around 24 weeks of gestation, but is much rarer in patients presenting after 34 weeks.

EAR: Among women who present with a clinical picture of acute cervical insufficiency, also known as an “incompetent cervix,” how common are infections?

RR: Studies by our group and others indicate that approximately 50% of women presenting with a dilated cervix and bulging membranes before 24 weeks of gestation will have a positive amniotic fluid culture for microorganisms. It is important to realize that rupture of membranes after a cervical cerclage may be the result of a subclinical infectious process, rather than the consequence of cerclage placement.

EAR: What proportion of intrauterine infections manifest themselves with clinical chorioamnionitis?

RR: Most intrauterine infections are subclinical in nature. Our work indicates that among women with intraamniotic infection and preterm labor with intact membranes, only 12% will have a positive amniotic fluid culture. Among women with preterm PROM, only 20% will have clinical signs of chorioamnionitis when a positive amniotic fluid culture is present.

EAR: If most infections are subclinical in nature, how can they be detected?

RR: The most accurate method to detect the presence of intraamniotic infection is analysis of amniotic fluid. Amniotic fluid is normally sterile for bacteria. It is possible to isolate some viruses from amniotic fluid, but generally, cultures for viruses are not performed in patients with preterm labor and preterm PROM. Amniotic fluid should be cultured for aerobic and anaerobic bacteria, as well as for Mycoplasma species. Detection of mycoplasmas is important, because they are the most common organisms found in the amniotic fluid. Commercially available systems exist that can be implemented in U.S. laboratories.

EAR: The results of cultures take several days to become available. Thus, rapid tests are required to assess the likelihood of infection or inflammation. What tests would you recommend for this purpose?

RR: A positive Gram stain has 99% specificity, but 20% sensitivity in the detection of intraamniotic infection. The low sensitivity is because the Gram stain cannot detect mycoplasmas since these organisms are too small to be seen with light microscopy. However, the take-home message is that a positive Gram stain is virtually always associated with a positive culture and that false positives are rare. The current approach to the detection of infection and/or inflammation in the amniotic fluid includes other tests that are routinely performed for the analysis of cerebrospinal fluid in all hospitals in the United States. Such tests include a white blood cell (WBC) count of amniotic fluid, and a glucose determination.

EAR: How can the clinician interpret the results of an amniotic fluid WBC and an amniotic fluid glucose determination?

RR: White blood cells—such as neutrophils, monocytes, or eosinophils—are not normally present in the amniotic fluid. Therefore, a high count of white blood cells is an indicator that intraamniotic inflammation is present. We recommend that an amniotic fluid sample be sent to the clinical hematology laboratory, that a WBC count be performed in the standard hemacytometer chamber, and that this be followed by a differential count. When the WBC count is greater than 50 cells/L in patients with intact membranes—or greater than 30 in patients with preterm PROM—the likelihood of a positive amniotic fluid culture is high.

In terms of the amniotic fluid glucose concentration, under normal circumstances glucose is present in the amniotic fluid. The lower the amniotic fluid glucose value, the higher the likelihood of intraamniotic infection or inflammation. For example, glucose values less than 14 mg/dL in women with intact membranes—or less than 10 mg/dL in women with preterm PROM—suggest that intraamniotic infection and/or inflammation is present.

EAR: Are there other tests, such as measurements of cytokines or other proteins, that can be used to detect inflammation in the amniotic fluid?

RR: The concentrations of a cytokine, such as interleukin-6, can be used to detect inflammation. Similarly, we have developed a rapid test that can be used at the bedside to detect inflammation by detecting the concentration of an enzyme produced by neutrophils. This enzyme is MMP-8 (matrix metalloproteinase-8).

These tests can be valuable in the context of midtrimester amniocentesis. The rate of pregnancy loss after a midtrimester amniocentesis has been estimated to be 0.5%–1%; such losses have mistakenly been thought to be always procedure related. However, we have found that among women who have midtrimester amniocenteses, those who have an elevated IL-6 or MMP-8 concentration are more likely to lose their pregnancy or have a spontaneous abortion shortly after the procedure. In these circumstances, determination of IL-6 or MMP-8 in the amniotic fluid stored by the genetic laboratories may be helpful for the patient and physician to identify that intraamniotic inflammation was a cause of the pregnancy loss. This may also have medicolegal implications.

EAR: How common is intraamniotic infection and/or inflammation in women having genetic amniocenteses in the midtrimester of pregnancy?

RR: The frequency of intraamniotic infection has been estimated to be 0.9%; the frequency of intraamniotic inflammation is about 1.2%. The most common organism found in the amniotic fluid is U. urealyticum. Intraamniotic infection and/or inflammation is more common in women who have discolored amniotic fluid at the time of genetic amniocentesis. It is important to realize that these infections are subclinical and that sometimes, patients with these infections rupture their membranes within hours or days of the procedure.

EAR: Can treatment be offered to these patients with midtrimester intraamniotic infections?

RR: Recent evidence from Dr. Sonia Hassan in our group indicates that the administration of antibiotics to the mother can eradicate intraamniotic infection in the midtrimester. Women with a short cervix detected by ultrasound were found to have microorganisms in 9% of cases. Patients were offered treatment with antibiotics and a repeat amniocentesis was performed to be sure that the infections were eradicated. Most women treated in this fashion had eradication of their intraamniotic infection and their pregnancy went to term.

EAR: How frequently are intrauterine infections confined to the amniotic fluid, and how often is the fetus involved?

RR: A study conducted in the United Kingdom in women with preterm PROM indicated that approximately 30% of patients had microorganisms in the amniotic fluid. Of these, 30% had positive fetal blood cultures. This means that 10% of all fetuses with preterm PROM will have fetal bacteremia. Clearly, this represents a minimum estimate of the frequency of fetal infection, a result of the limitations of standard techniques and the difficulties in isolating relevant microorganisms from fetal blood.

EAR: What is the importance of congenital neonatal infections?

RR: Sepsis is a more serious disease in neonates than in adults. Neonates have been generally considered immunosuppressed hosts, and the lethality of sepsis in neonates is high. There is now accumulating evidence that neonates with sepsis are more likely to develop cerebral palsy and bronchopulmonary dysplasia or chronic lung disease.

EAR: How important is intrauterine infection as a cause for cerebral palsy?

RR: It has been estimated that as many as 20% of all cases of cerebral palsy result from infection. Moreover, this applies to term neonates as well as to preterm neonates. Therefore, the traditional paradigm—that intrapartum asphyxia was the leading cause of cerebral palsy—is probably not correct. Obstetricians need to be aware that undiagnosed infections can be a cause for cerebral palsy because this has medicolegal implications.

EAR: What is the link between infection and the brain injury associated with cerebral palsy?

RR: Microorganisms involved in cases of intraamniotic infection can invade the human fetus. When the fetus breathes or swallows infected amniotic fluid, microorganisms may be entering the fetal compartment. Once microorganisms invade the fetus, they elicit a fetal inflammatory response syndrome (FIRS), which is the counterpart of the systemic inflammatory response syndrome (SIRS) in the adult. In FIRS one of the most critical organs affected is the brain. Microorganisms or their products that gain access to the fetal brain can induce damage of neurons or white matter in utero. Damage to the white matter in utero is also known as periventricular leukomalacia (PVL) and is the most important predictor of cerebral palsy. There is evidence that cytokines, chemokines, and other inflammatory products—such as reactive oxygen metabolites—can cause damage to the glia or to neurons, which is responsible for the cognitive abnormalities, including mental retardation.

EAR: If most intrauterine infections are subclinical, how can an obstetrician determine whether or not a neonate had intrauterine infection after birth?

RR: One possibility is to look at the placenta. Inflammation in the placenta can be of maternal origin or of fetal origin. Histologic chorioamnionitis is inflammation of the chorioamniotic membranes caused by maternal cells and is, therefore, a maternal inflammatory response. By contrast, funisitis—inflammation of the umbilical cord—is a fetal inflammatory response. Therefore, the presence of funisitis, diagnosed by examination of the placenta, indicates that the fetus was exposed to microorganisms before birth, or that the fetus mounted a FIRS. This is the reason why we call funisitis the hallmark of FIRS. The practical implication of this is that the examination of the placenta may be helpful in understanding what happened before birth. This is particularly important, given that funisitis has been associated with the subsequent development of cerebral palsy. The medicolegal implications of this are apparent. Because there is no known treatment for funisitis, there is no evidence that any intervention by obstetricians can prevent cerebral palsy associated with or induced by intrauterine infection.

EAR: Do systemic infections cause premature labor?

RR: Systemic clinical infections—such as pyelonephritis, pneumonia, malaria, and appendicitis—have been associated with premature labor and delivery. However, there is recent evidence that subclinical distant infections may also be a cause of premature labor and delivery. Specifically, periodontal disease, which is a chronic inflammatory process, has been associated with the subsequent development of preterm labor as well as with small-for-gestational-age infants.

The Changing Approach to Preterm Labor

Preterm delivery accounts for a significant component of infant mortality in the world. In this, the United States has not been spared; in fact, our country ranks a dismal 21st internationally in infant mortality, with prematurity as a major contributor.

Historically, obstetrics has approached this problem from a therapeutic perspective: If you see a contraction, try to stop it. In large measure, we have been unsuccessful, staving off delivery by a mean of approximately 2 days despite our best efforts. Although this window can allow for the stabilization of patients, arranging for their transfer to appropriate delivery sites, and initiating required medications, it does not solve the problem of prematurity.

By focusing on the symptoms of premature labor, we have not paused sufficiently to ask basic questions about potential causes and triggers that could help us to develop preventive strategies and targeted treatments for what is clearly a multifactorial syndrome.

This is all changing. The National Institutes of Health saw this as such a priority that it formed a Perinatology Research Branch within the National Institute of Child Health and Development and chose international authority Dr. Roberto Romero to lead it. The Centers for Disease Control and Prevention and the March of Dimes have similarly launched research initiatives and made the prevention of prematurity a priority.

Much progress has been made, with Dr. Romero's team taking a role in the forefront. I am very pleased to welcome Dr. Romero, professor of ob.gyn. at Wayne State University in Detroit and chief of the Perinatology Research Branch at NIH, as this month's guest professor. We will review advances in our understanding of the biology of prematurity as a syndrome and offer potential treatment implications, beginning with a focus on infection.

In September, we will similarly review the other contributors to the prematurity syndrome.

Dr. E. Albert Reece: How important is infection as a mechanism of disease in premature labor?

Dr. Roberto Romero: Intrauterine and systemic infections are a leading cause of spontaneous preterm labor and delivery. Indeed, infections and inflammation are the only mechanisms of disease for which a clear causal link with prematurity has been established. Moreover, a clear molecular pathophysiology has been described.

EAR: How frequent is intrauterine infection in spontaneous preterm birth?

RR: It has been estimated that one of every four preterm births occurs to mothers with intraamniotic infection (defined as a positive amniotic fluid culture for microorganisms). Under normal circumstances, the amniotic cavity does not contain bacteria, just as cerebrospinal fluid does not. However, approximately 12% of women presenting with an episode of preterm labor will have a positive amniotic fluid culture for microorganisms. The organisms most frequently isolated are genital mycoplasmas, particularly Ureaplasma urealyticum. Among women with preterm premature rupture of membranes (PROM), one of every three will have a positive amniotic fluid culture for microorganisms at the time of presentation. U. urealyticum is the most common microorganism isolated from the amniotic cavity.

EAR: Is there a particular subgroup of women in whom intrauterine infection is more prevalent?

RR: The earlier the gestational age at which a patient presents with preterm labor and intact membranes or preterm PROM, the higher the likelihood of a positive amniotic fluid culture. For example, infection and/or inflammation is present in close to 70% of women presenting around 24 weeks of gestation, but is much rarer in patients presenting after 34 weeks.

EAR: Among women who present with a clinical picture of acute cervical insufficiency, also known as an “incompetent cervix,” how common are infections?

RR: Studies by our group and others indicate that approximately 50% of women presenting with a dilated cervix and bulging membranes before 24 weeks of gestation will have a positive amniotic fluid culture for microorganisms. It is important to realize that rupture of membranes after a cervical cerclage may be the result of a subclinical infectious process, rather than the consequence of cerclage placement.

EAR: What proportion of intrauterine infections manifest themselves with clinical chorioamnionitis?

RR: Most intrauterine infections are subclinical in nature. Our work indicates that among women with intraamniotic infection and preterm labor with intact membranes, only 12% will have a positive amniotic fluid culture. Among women with preterm PROM, only 20% will have clinical signs of chorioamnionitis when a positive amniotic fluid culture is present.

EAR: If most infections are subclinical in nature, how can they be detected?

RR: The most accurate method to detect the presence of intraamniotic infection is analysis of amniotic fluid. Amniotic fluid is normally sterile for bacteria. It is possible to isolate some viruses from amniotic fluid, but generally, cultures for viruses are not performed in patients with preterm labor and preterm PROM. Amniotic fluid should be cultured for aerobic and anaerobic bacteria, as well as for Mycoplasma species. Detection of mycoplasmas is important, because they are the most common organisms found in the amniotic fluid. Commercially available systems exist that can be implemented in U.S. laboratories.

EAR: The results of cultures take several days to become available. Thus, rapid tests are required to assess the likelihood of infection or inflammation. What tests would you recommend for this purpose?

RR: A positive Gram stain has 99% specificity, but 20% sensitivity in the detection of intraamniotic infection. The low sensitivity is because the Gram stain cannot detect mycoplasmas since these organisms are too small to be seen with light microscopy. However, the take-home message is that a positive Gram stain is virtually always associated with a positive culture and that false positives are rare. The current approach to the detection of infection and/or inflammation in the amniotic fluid includes other tests that are routinely performed for the analysis of cerebrospinal fluid in all hospitals in the United States. Such tests include a white blood cell (WBC) count of amniotic fluid, and a glucose determination.

EAR: How can the clinician interpret the results of an amniotic fluid WBC and an amniotic fluid glucose determination?

RR: White blood cells—such as neutrophils, monocytes, or eosinophils—are not normally present in the amniotic fluid. Therefore, a high count of white blood cells is an indicator that intraamniotic inflammation is present. We recommend that an amniotic fluid sample be sent to the clinical hematology laboratory, that a WBC count be performed in the standard hemacytometer chamber, and that this be followed by a differential count. When the WBC count is greater than 50 cells/L in patients with intact membranes—or greater than 30 in patients with preterm PROM—the likelihood of a positive amniotic fluid culture is high.

In terms of the amniotic fluid glucose concentration, under normal circumstances glucose is present in the amniotic fluid. The lower the amniotic fluid glucose value, the higher the likelihood of intraamniotic infection or inflammation. For example, glucose values less than 14 mg/dL in women with intact membranes—or less than 10 mg/dL in women with preterm PROM—suggest that intraamniotic infection and/or inflammation is present.

EAR: Are there other tests, such as measurements of cytokines or other proteins, that can be used to detect inflammation in the amniotic fluid?

RR: The concentrations of a cytokine, such as interleukin-6, can be used to detect inflammation. Similarly, we have developed a rapid test that can be used at the bedside to detect inflammation by detecting the concentration of an enzyme produced by neutrophils. This enzyme is MMP-8 (matrix metalloproteinase-8).

These tests can be valuable in the context of midtrimester amniocentesis. The rate of pregnancy loss after a midtrimester amniocentesis has been estimated to be 0.5%–1%; such losses have mistakenly been thought to be always procedure related. However, we have found that among women who have midtrimester amniocenteses, those who have an elevated IL-6 or MMP-8 concentration are more likely to lose their pregnancy or have a spontaneous abortion shortly after the procedure. In these circumstances, determination of IL-6 or MMP-8 in the amniotic fluid stored by the genetic laboratories may be helpful for the patient and physician to identify that intraamniotic inflammation was a cause of the pregnancy loss. This may also have medicolegal implications.

EAR: How common is intraamniotic infection and/or inflammation in women having genetic amniocenteses in the midtrimester of pregnancy?

RR: The frequency of intraamniotic infection has been estimated to be 0.9%; the frequency of intraamniotic inflammation is about 1.2%. The most common organism found in the amniotic fluid is U. urealyticum. Intraamniotic infection and/or inflammation is more common in women who have discolored amniotic fluid at the time of genetic amniocentesis. It is important to realize that these infections are subclinical and that sometimes, patients with these infections rupture their membranes within hours or days of the procedure.

EAR: Can treatment be offered to these patients with midtrimester intraamniotic infections?

RR: Recent evidence from Dr. Sonia Hassan in our group indicates that the administration of antibiotics to the mother can eradicate intraamniotic infection in the midtrimester. Women with a short cervix detected by ultrasound were found to have microorganisms in 9% of cases. Patients were offered treatment with antibiotics and a repeat amniocentesis was performed to be sure that the infections were eradicated. Most women treated in this fashion had eradication of their intraamniotic infection and their pregnancy went to term.

EAR: How frequently are intrauterine infections confined to the amniotic fluid, and how often is the fetus involved?

RR: A study conducted in the United Kingdom in women with preterm PROM indicated that approximately 30% of patients had microorganisms in the amniotic fluid. Of these, 30% had positive fetal blood cultures. This means that 10% of all fetuses with preterm PROM will have fetal bacteremia. Clearly, this represents a minimum estimate of the frequency of fetal infection, a result of the limitations of standard techniques and the difficulties in isolating relevant microorganisms from fetal blood.

EAR: What is the importance of congenital neonatal infections?

RR: Sepsis is a more serious disease in neonates than in adults. Neonates have been generally considered immunosuppressed hosts, and the lethality of sepsis in neonates is high. There is now accumulating evidence that neonates with sepsis are more likely to develop cerebral palsy and bronchopulmonary dysplasia or chronic lung disease.

EAR: How important is intrauterine infection as a cause for cerebral palsy?

RR: It has been estimated that as many as 20% of all cases of cerebral palsy result from infection. Moreover, this applies to term neonates as well as to preterm neonates. Therefore, the traditional paradigm—that intrapartum asphyxia was the leading cause of cerebral palsy—is probably not correct. Obstetricians need to be aware that undiagnosed infections can be a cause for cerebral palsy because this has medicolegal implications.

EAR: What is the link between infection and the brain injury associated with cerebral palsy?

RR: Microorganisms involved in cases of intraamniotic infection can invade the human fetus. When the fetus breathes or swallows infected amniotic fluid, microorganisms may be entering the fetal compartment. Once microorganisms invade the fetus, they elicit a fetal inflammatory response syndrome (FIRS), which is the counterpart of the systemic inflammatory response syndrome (SIRS) in the adult. In FIRS one of the most critical organs affected is the brain. Microorganisms or their products that gain access to the fetal brain can induce damage of neurons or white matter in utero. Damage to the white matter in utero is also known as periventricular leukomalacia (PVL) and is the most important predictor of cerebral palsy. There is evidence that cytokines, chemokines, and other inflammatory products—such as reactive oxygen metabolites—can cause damage to the glia or to neurons, which is responsible for the cognitive abnormalities, including mental retardation.

EAR: If most intrauterine infections are subclinical, how can an obstetrician determine whether or not a neonate had intrauterine infection after birth?

RR: One possibility is to look at the placenta. Inflammation in the placenta can be of maternal origin or of fetal origin. Histologic chorioamnionitis is inflammation of the chorioamniotic membranes caused by maternal cells and is, therefore, a maternal inflammatory response. By contrast, funisitis—inflammation of the umbilical cord—is a fetal inflammatory response. Therefore, the presence of funisitis, diagnosed by examination of the placenta, indicates that the fetus was exposed to microorganisms before birth, or that the fetus mounted a FIRS. This is the reason why we call funisitis the hallmark of FIRS. The practical implication of this is that the examination of the placenta may be helpful in understanding what happened before birth. This is particularly important, given that funisitis has been associated with the subsequent development of cerebral palsy. The medicolegal implications of this are apparent. Because there is no known treatment for funisitis, there is no evidence that any intervention by obstetricians can prevent cerebral palsy associated with or induced by intrauterine infection.

EAR: Do systemic infections cause premature labor?

RR: Systemic clinical infections—such as pyelonephritis, pneumonia, malaria, and appendicitis—have been associated with premature labor and delivery. However, there is recent evidence that subclinical distant infections may also be a cause of premature labor and delivery. Specifically, periodontal disease, which is a chronic inflammatory process, has been associated with the subsequent development of preterm labor as well as with small-for-gestational-age infants.

The Changing Approach to Preterm Labor

Preterm delivery accounts for a significant component of infant mortality in the world. In this, the United States has not been spared; in fact, our country ranks a dismal 21st internationally in infant mortality, with prematurity as a major contributor.

Historically, obstetrics has approached this problem from a therapeutic perspective: If you see a contraction, try to stop it. In large measure, we have been unsuccessful, staving off delivery by a mean of approximately 2 days despite our best efforts. Although this window can allow for the stabilization of patients, arranging for their transfer to appropriate delivery sites, and initiating required medications, it does not solve the problem of prematurity.

By focusing on the symptoms of premature labor, we have not paused sufficiently to ask basic questions about potential causes and triggers that could help us to develop preventive strategies and targeted treatments for what is clearly a multifactorial syndrome.

This is all changing. The National Institutes of Health saw this as such a priority that it formed a Perinatology Research Branch within the National Institute of Child Health and Development and chose international authority Dr. Roberto Romero to lead it. The Centers for Disease Control and Prevention and the March of Dimes have similarly launched research initiatives and made the prevention of prematurity a priority.

Much progress has been made, with Dr. Romero's team taking a role in the forefront. I am very pleased to welcome Dr. Romero, professor of ob.gyn. at Wayne State University in Detroit and chief of the Perinatology Research Branch at NIH, as this month's guest professor. We will review advances in our understanding of the biology of prematurity as a syndrome and offer potential treatment implications, beginning with a focus on infection.

In September, we will similarly review the other contributors to the prematurity syndrome.

Dr. E. Albert Reece: How important is infection as a mechanism of disease in premature labor?

Dr. Roberto Romero: Intrauterine and systemic infections are a leading cause of spontaneous preterm labor and delivery. Indeed, infections and inflammation are the only mechanisms of disease for which a clear causal link with prematurity has been established. Moreover, a clear molecular pathophysiology has been described.

EAR: How frequent is intrauterine infection in spontaneous preterm birth?

RR: It has been estimated that one of every four preterm births occurs to mothers with intraamniotic infection (defined as a positive amniotic fluid culture for microorganisms). Under normal circumstances, the amniotic cavity does not contain bacteria, just as cerebrospinal fluid does not. However, approximately 12% of women presenting with an episode of preterm labor will have a positive amniotic fluid culture for microorganisms. The organisms most frequently isolated are genital mycoplasmas, particularly Ureaplasma urealyticum. Among women with preterm premature rupture of membranes (PROM), one of every three will have a positive amniotic fluid culture for microorganisms at the time of presentation. U. urealyticum is the most common microorganism isolated from the amniotic cavity.

EAR: Is there a particular subgroup of women in whom intrauterine infection is more prevalent?

RR: The earlier the gestational age at which a patient presents with preterm labor and intact membranes or preterm PROM, the higher the likelihood of a positive amniotic fluid culture. For example, infection and/or inflammation is present in close to 70% of women presenting around 24 weeks of gestation, but is much rarer in patients presenting after 34 weeks.

EAR: Among women who present with a clinical picture of acute cervical insufficiency, also known as an “incompetent cervix,” how common are infections?

RR: Studies by our group and others indicate that approximately 50% of women presenting with a dilated cervix and bulging membranes before 24 weeks of gestation will have a positive amniotic fluid culture for microorganisms. It is important to realize that rupture of membranes after a cervical cerclage may be the result of a subclinical infectious process, rather than the consequence of cerclage placement.

EAR: What proportion of intrauterine infections manifest themselves with clinical chorioamnionitis?

RR: Most intrauterine infections are subclinical in nature. Our work indicates that among women with intraamniotic infection and preterm labor with intact membranes, only 12% will have a positive amniotic fluid culture. Among women with preterm PROM, only 20% will have clinical signs of chorioamnionitis when a positive amniotic fluid culture is present.

EAR: If most infections are subclinical in nature, how can they be detected?

RR: The most accurate method to detect the presence of intraamniotic infection is analysis of amniotic fluid. Amniotic fluid is normally sterile for bacteria. It is possible to isolate some viruses from amniotic fluid, but generally, cultures for viruses are not performed in patients with preterm labor and preterm PROM. Amniotic fluid should be cultured for aerobic and anaerobic bacteria, as well as for Mycoplasma species. Detection of mycoplasmas is important, because they are the most common organisms found in the amniotic fluid. Commercially available systems exist that can be implemented in U.S. laboratories.

EAR: The results of cultures take several days to become available. Thus, rapid tests are required to assess the likelihood of infection or inflammation. What tests would you recommend for this purpose?

RR: A positive Gram stain has 99% specificity, but 20% sensitivity in the detection of intraamniotic infection. The low sensitivity is because the Gram stain cannot detect mycoplasmas since these organisms are too small to be seen with light microscopy. However, the take-home message is that a positive Gram stain is virtually always associated with a positive culture and that false positives are rare. The current approach to the detection of infection and/or inflammation in the amniotic fluid includes other tests that are routinely performed for the analysis of cerebrospinal fluid in all hospitals in the United States. Such tests include a white blood cell (WBC) count of amniotic fluid, and a glucose determination.

EAR: How can the clinician interpret the results of an amniotic fluid WBC and an amniotic fluid glucose determination?

RR: White blood cells—such as neutrophils, monocytes, or eosinophils—are not normally present in the amniotic fluid. Therefore, a high count of white blood cells is an indicator that intraamniotic inflammation is present. We recommend that an amniotic fluid sample be sent to the clinical hematology laboratory, that a WBC count be performed in the standard hemacytometer chamber, and that this be followed by a differential count. When the WBC count is greater than 50 cells/L in patients with intact membranes—or greater than 30 in patients with preterm PROM—the likelihood of a positive amniotic fluid culture is high.

In terms of the amniotic fluid glucose concentration, under normal circumstances glucose is present in the amniotic fluid. The lower the amniotic fluid glucose value, the higher the likelihood of intraamniotic infection or inflammation. For example, glucose values less than 14 mg/dL in women with intact membranes—or less than 10 mg/dL in women with preterm PROM—suggest that intraamniotic infection and/or inflammation is present.

EAR: Are there other tests, such as measurements of cytokines or other proteins, that can be used to detect inflammation in the amniotic fluid?

RR: The concentrations of a cytokine, such as interleukin-6, can be used to detect inflammation. Similarly, we have developed a rapid test that can be used at the bedside to detect inflammation by detecting the concentration of an enzyme produced by neutrophils. This enzyme is MMP-8 (matrix metalloproteinase-8).

These tests can be valuable in the context of midtrimester amniocentesis. The rate of pregnancy loss after a midtrimester amniocentesis has been estimated to be 0.5%–1%; such losses have mistakenly been thought to be always procedure related. However, we have found that among women who have midtrimester amniocenteses, those who have an elevated IL-6 or MMP-8 concentration are more likely to lose their pregnancy or have a spontaneous abortion shortly after the procedure. In these circumstances, determination of IL-6 or MMP-8 in the amniotic fluid stored by the genetic laboratories may be helpful for the patient and physician to identify that intraamniotic inflammation was a cause of the pregnancy loss. This may also have medicolegal implications.

EAR: How common is intraamniotic infection and/or inflammation in women having genetic amniocenteses in the midtrimester of pregnancy?

RR: The frequency of intraamniotic infection has been estimated to be 0.9%; the frequency of intraamniotic inflammation is about 1.2%. The most common organism found in the amniotic fluid is U. urealyticum. Intraamniotic infection and/or inflammation is more common in women who have discolored amniotic fluid at the time of genetic amniocentesis. It is important to realize that these infections are subclinical and that sometimes, patients with these infections rupture their membranes within hours or days of the procedure.

EAR: Can treatment be offered to these patients with midtrimester intraamniotic infections?

RR: Recent evidence from Dr. Sonia Hassan in our group indicates that the administration of antibiotics to the mother can eradicate intraamniotic infection in the midtrimester. Women with a short cervix detected by ultrasound were found to have microorganisms in 9% of cases. Patients were offered treatment with antibiotics and a repeat amniocentesis was performed to be sure that the infections were eradicated. Most women treated in this fashion had eradication of their intraamniotic infection and their pregnancy went to term.

EAR: How frequently are intrauterine infections confined to the amniotic fluid, and how often is the fetus involved?

RR: A study conducted in the United Kingdom in women with preterm PROM indicated that approximately 30% of patients had microorganisms in the amniotic fluid. Of these, 30% had positive fetal blood cultures. This means that 10% of all fetuses with preterm PROM will have fetal bacteremia. Clearly, this represents a minimum estimate of the frequency of fetal infection, a result of the limitations of standard techniques and the difficulties in isolating relevant microorganisms from fetal blood.

EAR: What is the importance of congenital neonatal infections?

RR: Sepsis is a more serious disease in neonates than in adults. Neonates have been generally considered immunosuppressed hosts, and the lethality of sepsis in neonates is high. There is now accumulating evidence that neonates with sepsis are more likely to develop cerebral palsy and bronchopulmonary dysplasia or chronic lung disease.

EAR: How important is intrauterine infection as a cause for cerebral palsy?

RR: It has been estimated that as many as 20% of all cases of cerebral palsy result from infection. Moreover, this applies to term neonates as well as to preterm neonates. Therefore, the traditional paradigm—that intrapartum asphyxia was the leading cause of cerebral palsy—is probably not correct. Obstetricians need to be aware that undiagnosed infections can be a cause for cerebral palsy because this has medicolegal implications.

EAR: What is the link between infection and the brain injury associated with cerebral palsy?

RR: Microorganisms involved in cases of intraamniotic infection can invade the human fetus. When the fetus breathes or swallows infected amniotic fluid, microorganisms may be entering the fetal compartment. Once microorganisms invade the fetus, they elicit a fetal inflammatory response syndrome (FIRS), which is the counterpart of the systemic inflammatory response syndrome (SIRS) in the adult. In FIRS one of the most critical organs affected is the brain. Microorganisms or their products that gain access to the fetal brain can induce damage of neurons or white matter in utero. Damage to the white matter in utero is also known as periventricular leukomalacia (PVL) and is the most important predictor of cerebral palsy. There is evidence that cytokines, chemokines, and other inflammatory products—such as reactive oxygen metabolites—can cause damage to the glia or to neurons, which is responsible for the cognitive abnormalities, including mental retardation.

EAR: If most intrauterine infections are subclinical, how can an obstetrician determine whether or not a neonate had intrauterine infection after birth?

RR: One possibility is to look at the placenta. Inflammation in the placenta can be of maternal origin or of fetal origin. Histologic chorioamnionitis is inflammation of the chorioamniotic membranes caused by maternal cells and is, therefore, a maternal inflammatory response. By contrast, funisitis—inflammation of the umbilical cord—is a fetal inflammatory response. Therefore, the presence of funisitis, diagnosed by examination of the placenta, indicates that the fetus was exposed to microorganisms before birth, or that the fetus mounted a FIRS. This is the reason why we call funisitis the hallmark of FIRS. The practical implication of this is that the examination of the placenta may be helpful in understanding what happened before birth. This is particularly important, given that funisitis has been associated with the subsequent development of cerebral palsy. The medicolegal implications of this are apparent. Because there is no known treatment for funisitis, there is no evidence that any intervention by obstetricians can prevent cerebral palsy associated with or induced by intrauterine infection.

EAR: Do systemic infections cause premature labor?

RR: Systemic clinical infections—such as pyelonephritis, pneumonia, malaria, and appendicitis—have been associated with premature labor and delivery. However, there is recent evidence that subclinical distant infections may also be a cause of premature labor and delivery. Specifically, periodontal disease, which is a chronic inflammatory process, has been associated with the subsequent development of preterm labor as well as with small-for-gestational-age infants.

The Changing Approach to Preterm Labor

Preterm delivery accounts for a significant component of infant mortality in the world. In this, the United States has not been spared; in fact, our country ranks a dismal 21st internationally in infant mortality, with prematurity as a major contributor.

Historically, obstetrics has approached this problem from a therapeutic perspective: If you see a contraction, try to stop it. In large measure, we have been unsuccessful, staving off delivery by a mean of approximately 2 days despite our best efforts. Although this window can allow for the stabilization of patients, arranging for their transfer to appropriate delivery sites, and initiating required medications, it does not solve the problem of prematurity.

By focusing on the symptoms of premature labor, we have not paused sufficiently to ask basic questions about potential causes and triggers that could help us to develop preventive strategies and targeted treatments for what is clearly a multifactorial syndrome.

This is all changing. The National Institutes of Health saw this as such a priority that it formed a Perinatology Research Branch within the National Institute of Child Health and Development and chose international authority Dr. Roberto Romero to lead it. The Centers for Disease Control and Prevention and the March of Dimes have similarly launched research initiatives and made the prevention of prematurity a priority.

Much progress has been made, with Dr. Romero's team taking a role in the forefront. I am very pleased to welcome Dr. Romero, professor of ob.gyn. at Wayne State University in Detroit and chief of the Perinatology Research Branch at NIH, as this month's guest professor. We will review advances in our understanding of the biology of prematurity as a syndrome and offer potential treatment implications, beginning with a focus on infection.

In September, we will similarly review the other contributors to the prematurity syndrome.

The concept of using grafts or mesh for rectocele repair—as well as for other hernias of pelvic organ support—makes sense. Their use can restore correct anatomical support by recreating and/or augmenting the fascial layer, enabling us to provide additional stability to traditional repairs of the posterior vaginal wall that too often may incorporate weak tissue.

Our general surgery colleagues have reduced their failure rate for hernia treatment by almost 50% by augmenting their procedures with mesh or grafts.

It was reported almost a decade ago that women have an 11% risk of needing surgery for prolapse or urinary incontinence by age 80 years—and that at least one-third will need a second surgery. Over the last 5 years, new surgical procedures for incontinence have raised our incontinence success rates to nearly 90%. Our success rate for prolapse using traditional techniques, meanwhile, remains in the 50%–70% range.

We're looking for a better mousetrap, and mesh or graft augmentation is likely to be it. Certainly, it is worth considering.

The Shortcomings of Our Traditions

Our underlying concepts of prolapse have changed. We used to think of prolapse strictly as the result of weakness in the vaginal wall and subsequent stretching. Our traditional repair technique was, simply put, to tighten the weakened tissue and narrow the vaginal wall.

The next stage in our thinking was that we were actually dealing with hernias—that is, with discrete breaks (site-specific defects) in the tissue. Our practice then progressed to opening up the vaginal mucosa, finding the defect, and closing it. This was the origin of the anterior paravaginal repair for cystocele and the posterior site-specific repair for rectocele.

There are pros and cons to both traditional ways of thinking. For instance, finding the defect and closing it are theoretically fine, but our assumption here is that the intact tissue is strong. That's not always the case. Sometimes it's hard to find the defect. And sometimes we may even create it.

Often when we're looking for better tissue to use for a central repair, we gravitate toward more lateral tissue and end up bringing too much tissue to the midline, causing dyspareunia. Or we move up in our search for tissue—that is, into the enterocele tissue—and we do our best with tissue that often is of poor quality. This may well result in a recurrence, which we often attribute to “poor protoplasm” or failure of the patient to adhere to our postoperative instructions.

And in either case, with traditional plication techniques or traditional site-specific techniques, we usually are not altering the patient's underlying risk factors for prolapse or for recurrence after surgery. Constipation; obesity; nerve or muscle damage; and occupational risk factors, such as heavy lifting are among the many remaining factors that, without strong tissue and stability, can put our repair in jeopardy.

Our most recent evolution in thinking, therefore, has been to look at our general surgeon colleagues' use of mesh and grafts to more successfully treat hernias, and to think that maybe we can do the same thing.

Choosing Donor or Synthetic Grafts

The use of grafts or mesh alleviates many of the challenges we have faced with our traditional techniques. One real benefit, for instance, is that we can extend mesh up into the enterocele and create strong tissue in a place where we previously would have worked with weak peritoneum.

A variety of graft and mesh products is available to the clinician. (See box.) The question of which materials are better is still much debated among physicians, however. The advantage of donor grafts, of course, is that they are biologic, which should significantly alleviate or even eliminate problems of erosion and rejection. The downside is that the materials are expensive and can contract over time. We also do not yet fully understand the in vivo response to these grafts. In some cases, the body may chew up the graft; in other cases, the graft may be encapsulated through an inflammatory reaction.

The advantage of synthetic meshes is that they are readily available, have more consistent material strength, and are permanent. There also is a great variety of materials to choose from—something that we should certainly view as a benefit and take advantage of. Synthetic meshes come in different weaves, with various degrees of pliability, strength, softness, and thickness. Such variables are important to consider, because the mesh we use in the vagina must be both strong enough to maintain the integrity of our repairs and flexible enough to accommodate sexual function.

The downside of synthetic meshes relates to its permanence. The mesh will be with our patient for the rest of her life, during which time rejection, infection, and especially erosion can occur. Whereas dyspareunia and failure are the major complications of traditional repairs, erosion—or exposure, as it is more frequently called today—is the primary complication associated with the use of mesh.

Our Judgment Call

At this time, we do not have enough data on rectocele repair with grafts or mesh to either uniformly recommend or uniformly reject this new type of repair. We need more evidence-based information to document its long-term efficacy.

However, these augmented procedures are now established in many settings—with observed short-term success—and I believe they should be considered for our more challenging cases.

The key to doing good rectocele repair, I believe, is first being able to identify the anatomy, and second, being able to make the clinical judgment about when and when not to use a mesh or graft. In my practice, for instance, we generally use mesh in patients with recurrences, in patients with very advanced prolapse and poor-quality tissue, and in women with a high risk for recurrence, such as those with chronic constipation, obesity, or jobs that require heavy lifting.

With mesh augmentation, we've taken our success rate to 85%–90% for all vaginal wall repairs, and to 90% for rectocele repair. The erosion rate for rectocele repair probably is about 10%. Most erosions can be managed conservatively, and few require reoperation if identified early. The dyspareunia rate is harder to get a handle on and is something we are still evaluating.

Newer Techniques, Getting Started

Some experienced physicians are now using new needle-guided mesh techniques. These procedures are quick, and some physicians value the fact that the materials come in convenient kits.

In these new techniques, needles are inserted through the transobturator approach and brought out near the ischial spine. The needles are then attached to the arms of the mesh, and the mesh is pulled through. The main disadvantage to this technique lies in the blind passage of needles through fairly long distances and critical areas where the potential for complications could include rectal injury, nerve injury, and bleeding. Another disadvantage is that the kits are relatively expensive.

I would rather attach mesh to a suture that I can see, although—in the right hands—needle-guided mesh techniques are probably safe and may result in better mesh application. Certainly you would want substantive experience and a sound knowledge of pelvic anatomy before proceeding.

Needle-guided techniques aside, the skills needed for mesh and graft augmentation of rectocele repair are logical extensions of the ob.gyn's current skill set. It is helpful, though, to revisit the anatomy in a cadaver lab, to talk with physicians who have had experience with grafts and mesh, and even to arrange preceptorships or visit the operating room to see the techniques performed. Then, as with many surgical procedures, success will depend on your skill, comfort level, and clinical judgment.

ELSEVIER GLOBAL MEDICAL NEWS

Mesh or graft placement for rectocele/enterocele repair is shown. Courtesy Dr. Neeraj Kohli/Dr. John R. Miklos

Rectocele Repair Evolves

Unfortunately, as an avid endoscopic surgeon and infertility specialist, I must admit that the most exciting arena in gynecologic surgery at present belongs to the urogynecologist. Until now, there has been little innovation within the subspecialty, even though it was well known that long-term results were compromised by weakened tissue and external factors. However, on the heels of our increased knowledge of the anatomy of the pelvic floor and the pathophysiology of incontinence and prolapse, techniques are being introduced that attempt to increase efficiency and thus decrease recurrence and the necessity of a second surgery.

I have asked Dr. Neeraj Kohli, chief of the urogynecology division at Brigham and Women's Hospital, Boston, to discuss the nuances of the use of mesh or grafts to augment rectocele repairs. A urogynecologist in the department of obstetrics, gynecology, and reproductive biology at Harvard Medical School. Dr. Kohli will make the case for the use of mesh or grafts in selected patients who in the past would have been treated via site-specific defect repair. I am certain that you will find Dr. Kohli's Master Class in gynecologic surgery to be both intriguing and thought provoking.

Tips for Success

The use of mesh or grafts is not without risk, and part of our technique and surgical process should involve a thorough effort to minimize risk. Here are some tips for avoiding complications:

▸ Cut the mesh or graft to an appropriate size and do not lay it in too tightly. Remember that mesh and grafts can contract. Adjust the material loosely and remember that its role is to prevent descent of the prolapse, not to elevate or support the tissue. A little movement of the mesh is preferred and will minimize the risk of erosion and dyspareunia.

▸ Make sure the mesh or graft lies flat, and always consider apical support. Folds in the mesh will increase the risk of erosion. The risk of complications will also increase if too few or too many sutures are used to secure the mesh. The Capio ligature device (Boston Scientific Corp.) is a good tool for placing apical sutures without extensive dissection, but it is just one of a variety of tools you can use.

▸ Ensure good hemostasis. I recommend packing the vagina for 24 hours after a mesh procedure to reduce the risk of hematoma and subsequent abscess or erosion, as well as to help the vaginal epithelium bond to the underlying mesh. We use a standardized vaginal packing with estrogen cream.

▸ Use adequate estrogenation. Both pre- and postoperative vaginal estrogen is recommended. We usually begin vaginal estrogen cream at the 2-week postoperative visit and continue it for at least 3 months.

When you start your dissection, keep it thick. The strength of the repair is dependent on the mesh, not on the patient's own tissue, so it is better to keep a thicker vaginal skin. As a result, you will reduce the risk of erosion.

The concept of using grafts or mesh for rectocele repair—as well as for other hernias of pelvic organ support—makes sense. Their use can restore correct anatomical support by recreating and/or augmenting the fascial layer, enabling us to provide additional stability to traditional repairs of the posterior vaginal wall that too often may incorporate weak tissue.

Our general surgery colleagues have reduced their failure rate for hernia treatment by almost 50% by augmenting their procedures with mesh or grafts.

It was reported almost a decade ago that women have an 11% risk of needing surgery for prolapse or urinary incontinence by age 80 years—and that at least one-third will need a second surgery. Over the last 5 years, new surgical procedures for incontinence have raised our incontinence success rates to nearly 90%. Our success rate for prolapse using traditional techniques, meanwhile, remains in the 50%–70% range.

We're looking for a better mousetrap, and mesh or graft augmentation is likely to be it. Certainly, it is worth considering.

The Shortcomings of Our Traditions

Our underlying concepts of prolapse have changed. We used to think of prolapse strictly as the result of weakness in the vaginal wall and subsequent stretching. Our traditional repair technique was, simply put, to tighten the weakened tissue and narrow the vaginal wall.

The next stage in our thinking was that we were actually dealing with hernias—that is, with discrete breaks (site-specific defects) in the tissue. Our practice then progressed to opening up the vaginal mucosa, finding the defect, and closing it. This was the origin of the anterior paravaginal repair for cystocele and the posterior site-specific repair for rectocele.

There are pros and cons to both traditional ways of thinking. For instance, finding the defect and closing it are theoretically fine, but our assumption here is that the intact tissue is strong. That's not always the case. Sometimes it's hard to find the defect. And sometimes we may even create it.

Often when we're looking for better tissue to use for a central repair, we gravitate toward more lateral tissue and end up bringing too much tissue to the midline, causing dyspareunia. Or we move up in our search for tissue—that is, into the enterocele tissue—and we do our best with tissue that often is of poor quality. This may well result in a recurrence, which we often attribute to “poor protoplasm” or failure of the patient to adhere to our postoperative instructions.

And in either case, with traditional plication techniques or traditional site-specific techniques, we usually are not altering the patient's underlying risk factors for prolapse or for recurrence after surgery. Constipation; obesity; nerve or muscle damage; and occupational risk factors, such as heavy lifting are among the many remaining factors that, without strong tissue and stability, can put our repair in jeopardy.

Our most recent evolution in thinking, therefore, has been to look at our general surgeon colleagues' use of mesh and grafts to more successfully treat hernias, and to think that maybe we can do the same thing.

Choosing Donor or Synthetic Grafts

The use of grafts or mesh alleviates many of the challenges we have faced with our traditional techniques. One real benefit, for instance, is that we can extend mesh up into the enterocele and create strong tissue in a place where we previously would have worked with weak peritoneum.

A variety of graft and mesh products is available to the clinician. (See box.) The question of which materials are better is still much debated among physicians, however. The advantage of donor grafts, of course, is that they are biologic, which should significantly alleviate or even eliminate problems of erosion and rejection. The downside is that the materials are expensive and can contract over time. We also do not yet fully understand the in vivo response to these grafts. In some cases, the body may chew up the graft; in other cases, the graft may be encapsulated through an inflammatory reaction.

The advantage of synthetic meshes is that they are readily available, have more consistent material strength, and are permanent. There also is a great variety of materials to choose from—something that we should certainly view as a benefit and take advantage of. Synthetic meshes come in different weaves, with various degrees of pliability, strength, softness, and thickness. Such variables are important to consider, because the mesh we use in the vagina must be both strong enough to maintain the integrity of our repairs and flexible enough to accommodate sexual function.

The downside of synthetic meshes relates to its permanence. The mesh will be with our patient for the rest of her life, during which time rejection, infection, and especially erosion can occur. Whereas dyspareunia and failure are the major complications of traditional repairs, erosion—or exposure, as it is more frequently called today—is the primary complication associated with the use of mesh.

Our Judgment Call

At this time, we do not have enough data on rectocele repair with grafts or mesh to either uniformly recommend or uniformly reject this new type of repair. We need more evidence-based information to document its long-term efficacy.

However, these augmented procedures are now established in many settings—with observed short-term success—and I believe they should be considered for our more challenging cases.

The key to doing good rectocele repair, I believe, is first being able to identify the anatomy, and second, being able to make the clinical judgment about when and when not to use a mesh or graft. In my practice, for instance, we generally use mesh in patients with recurrences, in patients with very advanced prolapse and poor-quality tissue, and in women with a high risk for recurrence, such as those with chronic constipation, obesity, or jobs that require heavy lifting.

With mesh augmentation, we've taken our success rate to 85%–90% for all vaginal wall repairs, and to 90% for rectocele repair. The erosion rate for rectocele repair probably is about 10%. Most erosions can be managed conservatively, and few require reoperation if identified early. The dyspareunia rate is harder to get a handle on and is something we are still evaluating.

Newer Techniques, Getting Started

Some experienced physicians are now using new needle-guided mesh techniques. These procedures are quick, and some physicians value the fact that the materials come in convenient kits.

In these new techniques, needles are inserted through the transobturator approach and brought out near the ischial spine. The needles are then attached to the arms of the mesh, and the mesh is pulled through. The main disadvantage to this technique lies in the blind passage of needles through fairly long distances and critical areas where the potential for complications could include rectal injury, nerve injury, and bleeding. Another disadvantage is that the kits are relatively expensive.

I would rather attach mesh to a suture that I can see, although—in the right hands—needle-guided mesh techniques are probably safe and may result in better mesh application. Certainly you would want substantive experience and a sound knowledge of pelvic anatomy before proceeding.

Needle-guided techniques aside, the skills needed for mesh and graft augmentation of rectocele repair are logical extensions of the ob.gyn's current skill set. It is helpful, though, to revisit the anatomy in a cadaver lab, to talk with physicians who have had experience with grafts and mesh, and even to arrange preceptorships or visit the operating room to see the techniques performed. Then, as with many surgical procedures, success will depend on your skill, comfort level, and clinical judgment.

ELSEVIER GLOBAL MEDICAL NEWS

Mesh or graft placement for rectocele/enterocele repair is shown. Courtesy Dr. Neeraj Kohli/Dr. John R. Miklos

Rectocele Repair Evolves

Unfortunately, as an avid endoscopic surgeon and infertility specialist, I must admit that the most exciting arena in gynecologic surgery at present belongs to the urogynecologist. Until now, there has been little innovation within the subspecialty, even though it was well known that long-term results were compromised by weakened tissue and external factors. However, on the heels of our increased knowledge of the anatomy of the pelvic floor and the pathophysiology of incontinence and prolapse, techniques are being introduced that attempt to increase efficiency and thus decrease recurrence and the necessity of a second surgery.

I have asked Dr. Neeraj Kohli, chief of the urogynecology division at Brigham and Women's Hospital, Boston, to discuss the nuances of the use of mesh or grafts to augment rectocele repairs. A urogynecologist in the department of obstetrics, gynecology, and reproductive biology at Harvard Medical School. Dr. Kohli will make the case for the use of mesh or grafts in selected patients who in the past would have been treated via site-specific defect repair. I am certain that you will find Dr. Kohli's Master Class in gynecologic surgery to be both intriguing and thought provoking.

Tips for Success

The use of mesh or grafts is not without risk, and part of our technique and surgical process should involve a thorough effort to minimize risk. Here are some tips for avoiding complications:

▸ Cut the mesh or graft to an appropriate size and do not lay it in too tightly. Remember that mesh and grafts can contract. Adjust the material loosely and remember that its role is to prevent descent of the prolapse, not to elevate or support the tissue. A little movement of the mesh is preferred and will minimize the risk of erosion and dyspareunia.

▸ Make sure the mesh or graft lies flat, and always consider apical support. Folds in the mesh will increase the risk of erosion. The risk of complications will also increase if too few or too many sutures are used to secure the mesh. The Capio ligature device (Boston Scientific Corp.) is a good tool for placing apical sutures without extensive dissection, but it is just one of a variety of tools you can use.

▸ Ensure good hemostasis. I recommend packing the vagina for 24 hours after a mesh procedure to reduce the risk of hematoma and subsequent abscess or erosion, as well as to help the vaginal epithelium bond to the underlying mesh. We use a standardized vaginal packing with estrogen cream.

▸ Use adequate estrogenation. Both pre- and postoperative vaginal estrogen is recommended. We usually begin vaginal estrogen cream at the 2-week postoperative visit and continue it for at least 3 months.

When you start your dissection, keep it thick. The strength of the repair is dependent on the mesh, not on the patient's own tissue, so it is better to keep a thicker vaginal skin. As a result, you will reduce the risk of erosion.

The concept of using grafts or mesh for rectocele repair—as well as for other hernias of pelvic organ support—makes sense. Their use can restore correct anatomical support by recreating and/or augmenting the fascial layer, enabling us to provide additional stability to traditional repairs of the posterior vaginal wall that too often may incorporate weak tissue.

Our general surgery colleagues have reduced their failure rate for hernia treatment by almost 50% by augmenting their procedures with mesh or grafts.

It was reported almost a decade ago that women have an 11% risk of needing surgery for prolapse or urinary incontinence by age 80 years—and that at least one-third will need a second surgery. Over the last 5 years, new surgical procedures for incontinence have raised our incontinence success rates to nearly 90%. Our success rate for prolapse using traditional techniques, meanwhile, remains in the 50%–70% range.

We're looking for a better mousetrap, and mesh or graft augmentation is likely to be it. Certainly, it is worth considering.

The Shortcomings of Our Traditions

Our underlying concepts of prolapse have changed. We used to think of prolapse strictly as the result of weakness in the vaginal wall and subsequent stretching. Our traditional repair technique was, simply put, to tighten the weakened tissue and narrow the vaginal wall.

The next stage in our thinking was that we were actually dealing with hernias—that is, with discrete breaks (site-specific defects) in the tissue. Our practice then progressed to opening up the vaginal mucosa, finding the defect, and closing it. This was the origin of the anterior paravaginal repair for cystocele and the posterior site-specific repair for rectocele.

There are pros and cons to both traditional ways of thinking. For instance, finding the defect and closing it are theoretically fine, but our assumption here is that the intact tissue is strong. That's not always the case. Sometimes it's hard to find the defect. And sometimes we may even create it.

Often when we're looking for better tissue to use for a central repair, we gravitate toward more lateral tissue and end up bringing too much tissue to the midline, causing dyspareunia. Or we move up in our search for tissue—that is, into the enterocele tissue—and we do our best with tissue that often is of poor quality. This may well result in a recurrence, which we often attribute to “poor protoplasm” or failure of the patient to adhere to our postoperative instructions.

And in either case, with traditional plication techniques or traditional site-specific techniques, we usually are not altering the patient's underlying risk factors for prolapse or for recurrence after surgery. Constipation; obesity; nerve or muscle damage; and occupational risk factors, such as heavy lifting are among the many remaining factors that, without strong tissue and stability, can put our repair in jeopardy.

Our most recent evolution in thinking, therefore, has been to look at our general surgeon colleagues' use of mesh and grafts to more successfully treat hernias, and to think that maybe we can do the same thing.

Choosing Donor or Synthetic Grafts

The use of grafts or mesh alleviates many of the challenges we have faced with our traditional techniques. One real benefit, for instance, is that we can extend mesh up into the enterocele and create strong tissue in a place where we previously would have worked with weak peritoneum.

A variety of graft and mesh products is available to the clinician. (See box.) The question of which materials are better is still much debated among physicians, however. The advantage of donor grafts, of course, is that they are biologic, which should significantly alleviate or even eliminate problems of erosion and rejection. The downside is that the materials are expensive and can contract over time. We also do not yet fully understand the in vivo response to these grafts. In some cases, the body may chew up the graft; in other cases, the graft may be encapsulated through an inflammatory reaction.

The advantage of synthetic meshes is that they are readily available, have more consistent material strength, and are permanent. There also is a great variety of materials to choose from—something that we should certainly view as a benefit and take advantage of. Synthetic meshes come in different weaves, with various degrees of pliability, strength, softness, and thickness. Such variables are important to consider, because the mesh we use in the vagina must be both strong enough to maintain the integrity of our repairs and flexible enough to accommodate sexual function.

The downside of synthetic meshes relates to its permanence. The mesh will be with our patient for the rest of her life, during which time rejection, infection, and especially erosion can occur. Whereas dyspareunia and failure are the major complications of traditional repairs, erosion—or exposure, as it is more frequently called today—is the primary complication associated with the use of mesh.

Our Judgment Call

At this time, we do not have enough data on rectocele repair with grafts or mesh to either uniformly recommend or uniformly reject this new type of repair. We need more evidence-based information to document its long-term efficacy.

However, these augmented procedures are now established in many settings—with observed short-term success—and I believe they should be considered for our more challenging cases.

The key to doing good rectocele repair, I believe, is first being able to identify the anatomy, and second, being able to make the clinical judgment about when and when not to use a mesh or graft. In my practice, for instance, we generally use mesh in patients with recurrences, in patients with very advanced prolapse and poor-quality tissue, and in women with a high risk for recurrence, such as those with chronic constipation, obesity, or jobs that require heavy lifting.

With mesh augmentation, we've taken our success rate to 85%–90% for all vaginal wall repairs, and to 90% for rectocele repair. The erosion rate for rectocele repair probably is about 10%. Most erosions can be managed conservatively, and few require reoperation if identified early. The dyspareunia rate is harder to get a handle on and is something we are still evaluating.

Newer Techniques, Getting Started

Some experienced physicians are now using new needle-guided mesh techniques. These procedures are quick, and some physicians value the fact that the materials come in convenient kits.

In these new techniques, needles are inserted through the transobturator approach and brought out near the ischial spine. The needles are then attached to the arms of the mesh, and the mesh is pulled through. The main disadvantage to this technique lies in the blind passage of needles through fairly long distances and critical areas where the potential for complications could include rectal injury, nerve injury, and bleeding. Another disadvantage is that the kits are relatively expensive.

I would rather attach mesh to a suture that I can see, although—in the right hands—needle-guided mesh techniques are probably safe and may result in better mesh application. Certainly you would want substantive experience and a sound knowledge of pelvic anatomy before proceeding.

Needle-guided techniques aside, the skills needed for mesh and graft augmentation of rectocele repair are logical extensions of the ob.gyn's current skill set. It is helpful, though, to revisit the anatomy in a cadaver lab, to talk with physicians who have had experience with grafts and mesh, and even to arrange preceptorships or visit the operating room to see the techniques performed. Then, as with many surgical procedures, success will depend on your skill, comfort level, and clinical judgment.

ELSEVIER GLOBAL MEDICAL NEWS

Mesh or graft placement for rectocele/enterocele repair is shown. Courtesy Dr. Neeraj Kohli/Dr. John R. Miklos

Rectocele Repair Evolves

Unfortunately, as an avid endoscopic surgeon and infertility specialist, I must admit that the most exciting arena in gynecologic surgery at present belongs to the urogynecologist. Until now, there has been little innovation within the subspecialty, even though it was well known that long-term results were compromised by weakened tissue and external factors. However, on the heels of our increased knowledge of the anatomy of the pelvic floor and the pathophysiology of incontinence and prolapse, techniques are being introduced that attempt to increase efficiency and thus decrease recurrence and the necessity of a second surgery.

I have asked Dr. Neeraj Kohli, chief of the urogynecology division at Brigham and Women's Hospital, Boston, to discuss the nuances of the use of mesh or grafts to augment rectocele repairs. A urogynecologist in the department of obstetrics, gynecology, and reproductive biology at Harvard Medical School. Dr. Kohli will make the case for the use of mesh or grafts in selected patients who in the past would have been treated via site-specific defect repair. I am certain that you will find Dr. Kohli's Master Class in gynecologic surgery to be both intriguing and thought provoking.

Tips for Success

The use of mesh or grafts is not without risk, and part of our technique and surgical process should involve a thorough effort to minimize risk. Here are some tips for avoiding complications:

▸ Cut the mesh or graft to an appropriate size and do not lay it in too tightly. Remember that mesh and grafts can contract. Adjust the material loosely and remember that its role is to prevent descent of the prolapse, not to elevate or support the tissue. A little movement of the mesh is preferred and will minimize the risk of erosion and dyspareunia.

▸ Make sure the mesh or graft lies flat, and always consider apical support. Folds in the mesh will increase the risk of erosion. The risk of complications will also increase if too few or too many sutures are used to secure the mesh. The Capio ligature device (Boston Scientific Corp.) is a good tool for placing apical sutures without extensive dissection, but it is just one of a variety of tools you can use.

▸ Ensure good hemostasis. I recommend packing the vagina for 24 hours after a mesh procedure to reduce the risk of hematoma and subsequent abscess or erosion, as well as to help the vaginal epithelium bond to the underlying mesh. We use a standardized vaginal packing with estrogen cream.

▸ Use adequate estrogenation. Both pre- and postoperative vaginal estrogen is recommended. We usually begin vaginal estrogen cream at the 2-week postoperative visit and continue it for at least 3 months.

When you start your dissection, keep it thick. The strength of the repair is dependent on the mesh, not on the patient's own tissue, so it is better to keep a thicker vaginal skin. As a result, you will reduce the risk of erosion.

Contrary to what many still believe, hysteroscopic myomectomy can be one of the safest, mostly easily learned surgical procedures in gynecology. It is certainly underutilized and continues to be offered and performed by relatively few gynecologists.

With proper training and attention to the preoperative evaluation, surgical technique, and strict fluid management, we can offer patients a treatment for submucous fibroids that is superior in most cases both to other surgical options—such as hysterectomy, open myomectomy, and uterine artery embolization—and to nonsurgical treatments.

The resection of submucosal myomas transcervically is a less invasive approach than are other surgical procedures. We can achieve excellent outcomes in terms of both fertility and the resolution of abnormal uterine bleeding and other symptoms. And we can do so with rates of complications, recurrence, and repeat resection that are much lower than commonly expected.

The Preoperative Evaluation

A comprehensive preoperative evaluation is critical. We want the best possible assessment of the size and location of the fibroid or fibroids, as well as the depth and even the vascularity of each fibroid.

We want to know how deeply each fibroid penetrates into the myometrium and whether it is resectable with the hysteroscope. With such an assessment, we can make a sound decision about whether the fibroid can be treated hysteroscopically and whether we, individually, have the expertise to do it. In general, the risk of fluid absorption, bleeding, and uterine perforation increases as the percentage of fibroid extending into the myometrium increases.

Diagnostic hysteroscopy, sonohysterography, transvaginal ultrasonography, and—in some cases—MRI may be used for this evaluation.

Just Before Surgery

The creation of false passages at the time of cervical dilation, cervical tears, and uterine perforation all are common to hysteroscopy performed with a stenotic, or unripe, cervix. It is therefore important that we consider administering a cervical-ripening agent as a prelude to surgery.

Some institutions and physicians will administer a cervical-ripening agent to women deemed to be at high risk of having cervical stenosis, such as patients who are nulliparous or who have had a cone biopsy. In other institutions, every patient undergoes a preoperative cervical-softening procedure.

One protocol worth serious consideration is the routine oral administration of 200 mcg of misoprostol (Cytotec) 8–12 hours before surgery for all patients, with high-risk patients receiving an additional dose 2 days before surgery. The protocol will result in a cervix that is softer, significantly less likely to tear, and certainly more easily dilated. This can be achieved with few and infrequent side effects, sometimes including some cramping, fever, or vaginal bleeding. Some, but not all, pharmacies will dispense the drug in single or double tablets; it is worth knowing where to refer patients.

Hysteroscopes and Fluid Management

Gynecologic surgeons today have a choice of three different types of instruments for resecting myomas hysteroscopically, and their relative popularity probably varies by region. The longest-standing option is a monopolar hysteroscope, which uses monopolar radiofrequency current in a wire loop. The bipolar scope, which employs bipolar energy in a wire loop, was introduced about 10 years ago.

The Smith & Nephew rotating resectoscope is the newest addition, having been available for almost a year. It differs from classic resectoscopes in two ways: The system converts electrical energy into mechanical energy to remove the fibroid, and it immediately evacuates the fibroid segments.

The uterine-distention medium used will vary by modality. Operative hysteroscopy that is performed in a monopolar environment, for instance, requires a hypotonic electrolyte-free solution, such as 1.5% glycine, 3% sorbitol, and 5% mannitol. Bipolar operative hysteroscopy can be performed using an isotonic, electrolyte-containing solution like saline or Ringer's lactate solution. The rotating resectoscope requires normal saline.

In any case, regardless of the chosen modality, fluid management is critical for intraoperative safety. It demands meticulous attention and vigilance. The exact inflow and outflow of any fluid must be monitored to prevent the complications that can result from excess fluid absorption and subsequent hyponatremia (with an electrolyte-free solution) or fluid overload.

A good fluid management system, which is essential to all operative hysteroscopy, will rapidly and continuously measure fluid input and output, and will provide a real-time assessment of the fluid deficit. Each hospital should have a protocol for fluid management that specifies, among other things, a fluid deficit at which surgery using each modality should be stopped.

We should be operating, in other words, with a set maximum allowable limit of fluid absorption. If we discontinue surgery when the fluid volume reaches this predetermined level, we can avoid major fluid-related complications.

As a general rule of thumb, monopolar systems using nonelectrolyte solutions must be stopped earlier to avoid hyponatremia.

There are variations in practice, particularly among gynecologists with significant hysteroscopy experience, but experts typically recommend a threshold of no more than 1,000 cc for monopolar systems, and a threshold of no more than 2,000 cc when electrolyte solutions are used with a bipolar system.

Particularly with larger fibroids, which require more time and more fluid, consider injecting dilute vasopressin into the cervical stroma at the start of the surgery. Several studies have shown that vasopressin reduces intravasation of the fluid, makes the cervix easier to dilate, and decreases intraoperative bleeding.

Surgical Technique

Some surgeons prefer to insert the hysteroscope into the cervix blindly, whereas many prefer to advance it under direct visualization. Some prefer mono- or bipolar scopes with a 12-degree angle, whereas others like to work with 25- or 30-degree hysteroscopes. The Smith & Nephew system uses a 0-degree scope.

There are, however, some givens. With any system, a fibroid should never be removed at its base because a free-floating fibroid is difficult to retrieve. Each fibroid should be shaved down in strips, the number of which depends largely on the size of the loop (if the monopolar or bipolar hysteroscope is being used) and the percentage of fibroid that is in the cavity.

When using the monopolar and bipolar hysteroscopes, place the loop in contact with the fibroid and then apply a minimal amount of tension going back toward the cervix before activating the electrode. Do not activate the electrode until you have the loop coming back toward the cervix.

This process must be deliberate and precise, because once the loop is activated, there is little tactile sensation. Then shave the fibroid down in strips until the myometrium is reached. With the morcellator, the rotary blade must run in contact with the fibroid.

At that point, intentionally let the endocavity deflate and the myometrium decompress. Quite often, you will find that the intramural portion of the fibroid now protrudes into the cavity, having been pushed outward as a result of the myometrial decompression and the decrease in endocavity pressure. It can then be shaved down more.

If you can see the pseudocapsule between the muscle and fibroid, you can also then use your wire loop to “massage out” any remaining portion of the fibroid. Often, if the maximum fluid absorption has not been reached, you will be able to massage it out, shave it down, massage it out more, and so forth, to the extent that you can actually resect the deep intramural portion of the myoma. If you cannot see the pseudocapsule, it is time to stop the surgery.

Some surgeons may opt at this point to proceed laparoscopically to retrieve the remaining intramural portion of the fibroid, particularly if they estimate that more than 10%–15% of the fibroid remains, and if they are operating on patients with infertility concerns or patients who are planning to undergo in-vitro fertilization. Or they may chose to come back later for a repeat procedure.

Other surgeons prefer a less aggressive approach—in which the patient's symptoms are monitored, and she returns to the office in 2–3 weeks for a flexible diagnostic hysteroscopy—particularly when dealing with patients whose symptoms do not include infertility. More often than not, any remaining portion of the fibroid will appear white and avascular and will not cause any further trouble for the patient.

The bottom line, regardless, is that hysteroscopic surgery is successful if the presenting problem is safely eradicated. Your level of aggressiveness will be determined largely by your patient's symptoms and individual situation. With a careful preoperative evaluation of the fibroids and the use of sound judgment early on about the appropriateness of the procedure and your own skills, repeat procedures will and should be unusual.

The Nuances of Intrauterine Pressure

Remember that as uterine distention pressure rises higher than the mean arterial or venous pressure, fluid absorption also rises. There is an advantage, therefore, to maintaining the lowest intrauterine pressure possible; also, more of the fibroid will protrude into the cavity. On the other hand, the greater visibility gained with greater distention makes it advantageous to work under higher pressures.

Some surgeons work at 100 mm of pressure consistently and believe they can work quickly because they can see well; others start surgery at 50–60 mm of pressure and gradually increase the pressure to achieve greater distention and visibility as needed.

Each surgeon develops his or her own technique, with the underlying goal being to maintain a balance between a pressure that gives adequate flow, distention, and visualization, and a pressure that minimizes fluid absorption. With an understanding of the underlying principles and the importance of fluid management, you will find an approach that keeps you from getting frustrated and leads to good outcomes.

Use of the Morcellation System

The new fibroid morcellation system offers some advantages—particularly when the surgeon is new to hysteroscopic procedures—because it continuously suctions away fibroid strips and eliminates the need to remove debris and redistend the cavity.

Its disadvantage, however, is that it does not allow the same breadth of surgery as can be performed with a wire loop. Generally, the new system is to be used to resect fibroids that are completely or mainly in the uterine cavity. Type II myomas, as well as large fibroids, are very difficult to deal with using this technique.

Starting Out

With any of the available devices and systems, hysteroscopic myomectomy is not nearly as technically challenging as other procedures gynecologists do. In our experience, it is not difficult to teach residents. To start, beginners should work with other physicians and remove smaller fibroids until they gain confidence. They could even start with polyps, which are easier to remove.

Those new to this procedure will soon appreciate the fact that the fears of complications are unfounded. The overall complication rate is less than 3%–-no higher, and probably lower, than the rate for other procedures like endometrial ablation—and rates of infections, hematomas, and other injuries are significantly lower than those for other procedures.

Uterine artery embolization has been gaining popularity for treatment of symptomatic uterine fibroids, and it is a procedure that patients will probably want to discuss. In many institutions, however, the procedure is not even an option for submucous fibroids, because the fibroids can separate, subsequently blocking the cervix, going through necrosis, and eventually causing sepsis and other complications. In fact, at least two deaths have been reported.

In general, patients' symptoms tend to continue after uterine artery embolization, and patients often ultimately require hysteroscopic resection.

Hysteroscopy, on the other hand, has it all for most patients: low invasiveness, high efficacy, extremely low recurrence, and excellent patient safety.

A 2-cm intracavitary fibroid is shown before surgery.

Versapoint 4-mm wire loop approaches the fibroid.

The 4-mm wire loop is placed behind the fibroid.

The postoperative resection bed is shown here. Photos courtesy Dr. Linda Bradley

Submucous Uterine Fibroids

Uterine fibroids are the most common benign tumor of the female genital tract. Almost 40% of the 600,000 hysterectomies performed each year in the United States are performed for symptomatic fibroids. Given the fact that many fibroids occur in women who want to maintain fertility, have serious health concerns, or desire the most minimally invasive option, hysterectomy often cannot be considered. When the fibroid is submucous in location, a hysteroscopic approach to myomectomy is the procedure of choice. Despite this, few gynecologists maintain this technique in their surgical armamentarium.

It is my desire that this article will spur many readers to safely proceed with hysteroscopic myomectomy. In order to accomplish this, I have asked Dr. Linda Bradley, director of hysteroscopic services at the Cleveland Clinic, and Dr. Keith Isaacson, medical director of the center for minimally invasive gynecologic surgery at Newton-Wellesley Hospital in Newton, Mass., to join me in a discussion on the advantages of the hysteroscopic approach to myomectomy.

Both Dr. Bradley and Dr. Isaacson are noted internationally for their expertise in hysteroscopic surgery. Not only are they gifted hysteroscopic surgeons, but they have written, lectured, and been principal researchers in this area as well.

On that note, let us proceed.

Contrary to what many still believe, hysteroscopic myomectomy can be one of the safest, mostly easily learned surgical procedures in gynecology. It is certainly underutilized and continues to be offered and performed by relatively few gynecologists.

With proper training and attention to the preoperative evaluation, surgical technique, and strict fluid management, we can offer patients a treatment for submucous fibroids that is superior in most cases both to other surgical options—such as hysterectomy, open myomectomy, and uterine artery embolization—and to nonsurgical treatments.

The resection of submucosal myomas transcervically is a less invasive approach than are other surgical procedures. We can achieve excellent outcomes in terms of both fertility and the resolution of abnormal uterine bleeding and other symptoms. And we can do so with rates of complications, recurrence, and repeat resection that are much lower than commonly expected.

The Preoperative Evaluation

A comprehensive preoperative evaluation is critical. We want the best possible assessment of the size and location of the fibroid or fibroids, as well as the depth and even the vascularity of each fibroid.

We want to know how deeply each fibroid penetrates into the myometrium and whether it is resectable with the hysteroscope. With such an assessment, we can make a sound decision about whether the fibroid can be treated hysteroscopically and whether we, individually, have the expertise to do it. In general, the risk of fluid absorption, bleeding, and uterine perforation increases as the percentage of fibroid extending into the myometrium increases.

Diagnostic hysteroscopy, sonohysterography, transvaginal ultrasonography, and—in some cases—MRI may be used for this evaluation.

Just Before Surgery

The creation of false passages at the time of cervical dilation, cervical tears, and uterine perforation all are common to hysteroscopy performed with a stenotic, or unripe, cervix. It is therefore important that we consider administering a cervical-ripening agent as a prelude to surgery.

Some institutions and physicians will administer a cervical-ripening agent to women deemed to be at high risk of having cervical stenosis, such as patients who are nulliparous or who have had a cone biopsy. In other institutions, every patient undergoes a preoperative cervical-softening procedure.

One protocol worth serious consideration is the routine oral administration of 200 mcg of misoprostol (Cytotec) 8–12 hours before surgery for all patients, with high-risk patients receiving an additional dose 2 days before surgery. The protocol will result in a cervix that is softer, significantly less likely to tear, and certainly more easily dilated. This can be achieved with few and infrequent side effects, sometimes including some cramping, fever, or vaginal bleeding. Some, but not all, pharmacies will dispense the drug in single or double tablets; it is worth knowing where to refer patients.

Hysteroscopes and Fluid Management

Gynecologic surgeons today have a choice of three different types of instruments for resecting myomas hysteroscopically, and their relative popularity probably varies by region. The longest-standing option is a monopolar hysteroscope, which uses monopolar radiofrequency current in a wire loop. The bipolar scope, which employs bipolar energy in a wire loop, was introduced about 10 years ago.

The Smith & Nephew rotating resectoscope is the newest addition, having been available for almost a year. It differs from classic resectoscopes in two ways: The system converts electrical energy into mechanical energy to remove the fibroid, and it immediately evacuates the fibroid segments.

The uterine-distention medium used will vary by modality. Operative hysteroscopy that is performed in a monopolar environment, for instance, requires a hypotonic electrolyte-free solution, such as 1.5% glycine, 3% sorbitol, and 5% mannitol. Bipolar operative hysteroscopy can be performed using an isotonic, electrolyte-containing solution like saline or Ringer's lactate solution. The rotating resectoscope requires normal saline.

In any case, regardless of the chosen modality, fluid management is critical for intraoperative safety. It demands meticulous attention and vigilance. The exact inflow and outflow of any fluid must be monitored to prevent the complications that can result from excess fluid absorption and subsequent hyponatremia (with an electrolyte-free solution) or fluid overload.

A good fluid management system, which is essential to all operative hysteroscopy, will rapidly and continuously measure fluid input and output, and will provide a real-time assessment of the fluid deficit. Each hospital should have a protocol for fluid management that specifies, among other things, a fluid deficit at which surgery using each modality should be stopped.

We should be operating, in other words, with a set maximum allowable limit of fluid absorption. If we discontinue surgery when the fluid volume reaches this predetermined level, we can avoid major fluid-related complications.

As a general rule of thumb, monopolar systems using nonelectrolyte solutions must be stopped earlier to avoid hyponatremia.

There are variations in practice, particularly among gynecologists with significant hysteroscopy experience, but experts typically recommend a threshold of no more than 1,000 cc for monopolar systems, and a threshold of no more than 2,000 cc when electrolyte solutions are used with a bipolar system.

Particularly with larger fibroids, which require more time and more fluid, consider injecting dilute vasopressin into the cervical stroma at the start of the surgery. Several studies have shown that vasopressin reduces intravasation of the fluid, makes the cervix easier to dilate, and decreases intraoperative bleeding.

Surgical Technique

Some surgeons prefer to insert the hysteroscope into the cervix blindly, whereas many prefer to advance it under direct visualization. Some prefer mono- or bipolar scopes with a 12-degree angle, whereas others like to work with 25- or 30-degree hysteroscopes. The Smith & Nephew system uses a 0-degree scope.

There are, however, some givens. With any system, a fibroid should never be removed at its base because a free-floating fibroid is difficult to retrieve. Each fibroid should be shaved down in strips, the number of which depends largely on the size of the loop (if the monopolar or bipolar hysteroscope is being used) and the percentage of fibroid that is in the cavity.

When using the monopolar and bipolar hysteroscopes, place the loop in contact with the fibroid and then apply a minimal amount of tension going back toward the cervix before activating the electrode. Do not activate the electrode until you have the loop coming back toward the cervix.

This process must be deliberate and precise, because once the loop is activated, there is little tactile sensation. Then shave the fibroid down in strips until the myometrium is reached. With the morcellator, the rotary blade must run in contact with the fibroid.

At that point, intentionally let the endocavity deflate and the myometrium decompress. Quite often, you will find that the intramural portion of the fibroid now protrudes into the cavity, having been pushed outward as a result of the myometrial decompression and the decrease in endocavity pressure. It can then be shaved down more.

If you can see the pseudocapsule between the muscle and fibroid, you can also then use your wire loop to “massage out” any remaining portion of the fibroid. Often, if the maximum fluid absorption has not been reached, you will be able to massage it out, shave it down, massage it out more, and so forth, to the extent that you can actually resect the deep intramural portion of the myoma. If you cannot see the pseudocapsule, it is time to stop the surgery.

Some surgeons may opt at this point to proceed laparoscopically to retrieve the remaining intramural portion of the fibroid, particularly if they estimate that more than 10%–15% of the fibroid remains, and if they are operating on patients with infertility concerns or patients who are planning to undergo in-vitro fertilization. Or they may chose to come back later for a repeat procedure.

Other surgeons prefer a less aggressive approach—in which the patient's symptoms are monitored, and she returns to the office in 2–3 weeks for a flexible diagnostic hysteroscopy—particularly when dealing with patients whose symptoms do not include infertility. More often than not, any remaining portion of the fibroid will appear white and avascular and will not cause any further trouble for the patient.

The bottom line, regardless, is that hysteroscopic surgery is successful if the presenting problem is safely eradicated. Your level of aggressiveness will be determined largely by your patient's symptoms and individual situation. With a careful preoperative evaluation of the fibroids and the use of sound judgment early on about the appropriateness of the procedure and your own skills, repeat procedures will and should be unusual.

The Nuances of Intrauterine Pressure

Remember that as uterine distention pressure rises higher than the mean arterial or venous pressure, fluid absorption also rises. There is an advantage, therefore, to maintaining the lowest intrauterine pressure possible; also, more of the fibroid will protrude into the cavity. On the other hand, the greater visibility gained with greater distention makes it advantageous to work under higher pressures.

Some surgeons work at 100 mm of pressure consistently and believe they can work quickly because they can see well; others start surgery at 50–60 mm of pressure and gradually increase the pressure to achieve greater distention and visibility as needed.

Each surgeon develops his or her own technique, with the underlying goal being to maintain a balance between a pressure that gives adequate flow, distention, and visualization, and a pressure that minimizes fluid absorption. With an understanding of the underlying principles and the importance of fluid management, you will find an approach that keeps you from getting frustrated and leads to good outcomes.

Use of the Morcellation System

The new fibroid morcellation system offers some advantages—particularly when the surgeon is new to hysteroscopic procedures—because it continuously suctions away fibroid strips and eliminates the need to remove debris and redistend the cavity.

Its disadvantage, however, is that it does not allow the same breadth of surgery as can be performed with a wire loop. Generally, the new system is to be used to resect fibroids that are completely or mainly in the uterine cavity. Type II myomas, as well as large fibroids, are very difficult to deal with using this technique.

Starting Out

With any of the available devices and systems, hysteroscopic myomectomy is not nearly as technically challenging as other procedures gynecologists do. In our experience, it is not difficult to teach residents. To start, beginners should work with other physicians and remove smaller fibroids until they gain confidence. They could even start with polyps, which are easier to remove.

Those new to this procedure will soon appreciate the fact that the fears of complications are unfounded. The overall complication rate is less than 3%–-no higher, and probably lower, than the rate for other procedures like endometrial ablation—and rates of infections, hematomas, and other injuries are significantly lower than those for other procedures.

Uterine artery embolization has been gaining popularity for treatment of symptomatic uterine fibroids, and it is a procedure that patients will probably want to discuss. In many institutions, however, the procedure is not even an option for submucous fibroids, because the fibroids can separate, subsequently blocking the cervix, going through necrosis, and eventually causing sepsis and other complications. In fact, at least two deaths have been reported.

In general, patients' symptoms tend to continue after uterine artery embolization, and patients often ultimately require hysteroscopic resection.

Hysteroscopy, on the other hand, has it all for most patients: low invasiveness, high efficacy, extremely low recurrence, and excellent patient safety.

A 2-cm intracavitary fibroid is shown before surgery.

Versapoint 4-mm wire loop approaches the fibroid.

The 4-mm wire loop is placed behind the fibroid.

The postoperative resection bed is shown here. Photos courtesy Dr. Linda Bradley

Submucous Uterine Fibroids

Uterine fibroids are the most common benign tumor of the female genital tract. Almost 40% of the 600,000 hysterectomies performed each year in the United States are performed for symptomatic fibroids. Given the fact that many fibroids occur in women who want to maintain fertility, have serious health concerns, or desire the most minimally invasive option, hysterectomy often cannot be considered. When the fibroid is submucous in location, a hysteroscopic approach to myomectomy is the procedure of choice. Despite this, few gynecologists maintain this technique in their surgical armamentarium.

It is my desire that this article will spur many readers to safely proceed with hysteroscopic myomectomy. In order to accomplish this, I have asked Dr. Linda Bradley, director of hysteroscopic services at the Cleveland Clinic, and Dr. Keith Isaacson, medical director of the center for minimally invasive gynecologic surgery at Newton-Wellesley Hospital in Newton, Mass., to join me in a discussion on the advantages of the hysteroscopic approach to myomectomy.

Both Dr. Bradley and Dr. Isaacson are noted internationally for their expertise in hysteroscopic surgery. Not only are they gifted hysteroscopic surgeons, but they have written, lectured, and been principal researchers in this area as well.

On that note, let us proceed.

Contrary to what many still believe, hysteroscopic myomectomy can be one of the safest, mostly easily learned surgical procedures in gynecology. It is certainly underutilized and continues to be offered and performed by relatively few gynecologists.

With proper training and attention to the preoperative evaluation, surgical technique, and strict fluid management, we can offer patients a treatment for submucous fibroids that is superior in most cases both to other surgical options—such as hysterectomy, open myomectomy, and uterine artery embolization—and to nonsurgical treatments.

The resection of submucosal myomas transcervically is a less invasive approach than are other surgical procedures. We can achieve excellent outcomes in terms of both fertility and the resolution of abnormal uterine bleeding and other symptoms. And we can do so with rates of complications, recurrence, and repeat resection that are much lower than commonly expected.

The Preoperative Evaluation

A comprehensive preoperative evaluation is critical. We want the best possible assessment of the size and location of the fibroid or fibroids, as well as the depth and even the vascularity of each fibroid.

We want to know how deeply each fibroid penetrates into the myometrium and whether it is resectable with the hysteroscope. With such an assessment, we can make a sound decision about whether the fibroid can be treated hysteroscopically and whether we, individually, have the expertise to do it. In general, the risk of fluid absorption, bleeding, and uterine perforation increases as the percentage of fibroid extending into the myometrium increases.

Diagnostic hysteroscopy, sonohysterography, transvaginal ultrasonography, and—in some cases—MRI may be used for this evaluation.

Just Before Surgery

The creation of false passages at the time of cervical dilation, cervical tears, and uterine perforation all are common to hysteroscopy performed with a stenotic, or unripe, cervix. It is therefore important that we consider administering a cervical-ripening agent as a prelude to surgery.

Some institutions and physicians will administer a cervical-ripening agent to women deemed to be at high risk of having cervical stenosis, such as patients who are nulliparous or who have had a cone biopsy. In other institutions, every patient undergoes a preoperative cervical-softening procedure.

One protocol worth serious consideration is the routine oral administration of 200 mcg of misoprostol (Cytotec) 8–12 hours before surgery for all patients, with high-risk patients receiving an additional dose 2 days before surgery. The protocol will result in a cervix that is softer, significantly less likely to tear, and certainly more easily dilated. This can be achieved with few and infrequent side effects, sometimes including some cramping, fever, or vaginal bleeding. Some, but not all, pharmacies will dispense the drug in single or double tablets; it is worth knowing where to refer patients.

Hysteroscopes and Fluid Management

Gynecologic surgeons today have a choice of three different types of instruments for resecting myomas hysteroscopically, and their relative popularity probably varies by region. The longest-standing option is a monopolar hysteroscope, which uses monopolar radiofrequency current in a wire loop. The bipolar scope, which employs bipolar energy in a wire loop, was introduced about 10 years ago.

The Smith & Nephew rotating resectoscope is the newest addition, having been available for almost a year. It differs from classic resectoscopes in two ways: The system converts electrical energy into mechanical energy to remove the fibroid, and it immediately evacuates the fibroid segments.

The uterine-distention medium used will vary by modality. Operative hysteroscopy that is performed in a monopolar environment, for instance, requires a hypotonic electrolyte-free solution, such as 1.5% glycine, 3% sorbitol, and 5% mannitol. Bipolar operative hysteroscopy can be performed using an isotonic, electrolyte-containing solution like saline or Ringer's lactate solution. The rotating resectoscope requires normal saline.

In any case, regardless of the chosen modality, fluid management is critical for intraoperative safety. It demands meticulous attention and vigilance. The exact inflow and outflow of any fluid must be monitored to prevent the complications that can result from excess fluid absorption and subsequent hyponatremia (with an electrolyte-free solution) or fluid overload.

A good fluid management system, which is essential to all operative hysteroscopy, will rapidly and continuously measure fluid input and output, and will provide a real-time assessment of the fluid deficit. Each hospital should have a protocol for fluid management that specifies, among other things, a fluid deficit at which surgery using each modality should be stopped.

We should be operating, in other words, with a set maximum allowable limit of fluid absorption. If we discontinue surgery when the fluid volume reaches this predetermined level, we can avoid major fluid-related complications.

As a general rule of thumb, monopolar systems using nonelectrolyte solutions must be stopped earlier to avoid hyponatremia.

There are variations in practice, particularly among gynecologists with significant hysteroscopy experience, but experts typically recommend a threshold of no more than 1,000 cc for monopolar systems, and a threshold of no more than 2,000 cc when electrolyte solutions are used with a bipolar system.

Particularly with larger fibroids, which require more time and more fluid, consider injecting dilute vasopressin into the cervical stroma at the start of the surgery. Several studies have shown that vasopressin reduces intravasation of the fluid, makes the cervix easier to dilate, and decreases intraoperative bleeding.

Surgical Technique

Some surgeons prefer to insert the hysteroscope into the cervix blindly, whereas many prefer to advance it under direct visualization. Some prefer mono- or bipolar scopes with a 12-degree angle, whereas others like to work with 25- or 30-degree hysteroscopes. The Smith & Nephew system uses a 0-degree scope.

There are, however, some givens. With any system, a fibroid should never be removed at its base because a free-floating fibroid is difficult to retrieve. Each fibroid should be shaved down in strips, the number of which depends largely on the size of the loop (if the monopolar or bipolar hysteroscope is being used) and the percentage of fibroid that is in the cavity.

When using the monopolar and bipolar hysteroscopes, place the loop in contact with the fibroid and then apply a minimal amount of tension going back toward the cervix before activating the electrode. Do not activate the electrode until you have the loop coming back toward the cervix.

This process must be deliberate and precise, because once the loop is activated, there is little tactile sensation. Then shave the fibroid down in strips until the myometrium is reached. With the morcellator, the rotary blade must run in contact with the fibroid.

At that point, intentionally let the endocavity deflate and the myometrium decompress. Quite often, you will find that the intramural portion of the fibroid now protrudes into the cavity, having been pushed outward as a result of the myometrial decompression and the decrease in endocavity pressure. It can then be shaved down more.

If you can see the pseudocapsule between the muscle and fibroid, you can also then use your wire loop to “massage out” any remaining portion of the fibroid. Often, if the maximum fluid absorption has not been reached, you will be able to massage it out, shave it down, massage it out more, and so forth, to the extent that you can actually resect the deep intramural portion of the myoma. If you cannot see the pseudocapsule, it is time to stop the surgery.

Some surgeons may opt at this point to proceed laparoscopically to retrieve the remaining intramural portion of the fibroid, particularly if they estimate that more than 10%–15% of the fibroid remains, and if they are operating on patients with infertility concerns or patients who are planning to undergo in-vitro fertilization. Or they may chose to come back later for a repeat procedure.

Other surgeons prefer a less aggressive approach—in which the patient's symptoms are monitored, and she returns to the office in 2–3 weeks for a flexible diagnostic hysteroscopy—particularly when dealing with patients whose symptoms do not include infertility. More often than not, any remaining portion of the fibroid will appear white and avascular and will not cause any further trouble for the patient.

The bottom line, regardless, is that hysteroscopic surgery is successful if the presenting problem is safely eradicated. Your level of aggressiveness will be determined largely by your patient's symptoms and individual situation. With a careful preoperative evaluation of the fibroids and the use of sound judgment early on about the appropriateness of the procedure and your own skills, repeat procedures will and should be unusual.

The Nuances of Intrauterine Pressure

Remember that as uterine distention pressure rises higher than the mean arterial or venous pressure, fluid absorption also rises. There is an advantage, therefore, to maintaining the lowest intrauterine pressure possible; also, more of the fibroid will protrude into the cavity. On the other hand, the greater visibility gained with greater distention makes it advantageous to work under higher pressures.

Some surgeons work at 100 mm of pressure consistently and believe they can work quickly because they can see well; others start surgery at 50–60 mm of pressure and gradually increase the pressure to achieve greater distention and visibility as needed.

Each surgeon develops his or her own technique, with the underlying goal being to maintain a balance between a pressure that gives adequate flow, distention, and visualization, and a pressure that minimizes fluid absorption. With an understanding of the underlying principles and the importance of fluid management, you will find an approach that keeps you from getting frustrated and leads to good outcomes.

Use of the Morcellation System

The new fibroid morcellation system offers some advantages—particularly when the surgeon is new to hysteroscopic procedures—because it continuously suctions away fibroid strips and eliminates the need to remove debris and redistend the cavity.

Its disadvantage, however, is that it does not allow the same breadth of surgery as can be performed with a wire loop. Generally, the new system is to be used to resect fibroids that are completely or mainly in the uterine cavity. Type II myomas, as well as large fibroids, are very difficult to deal with using this technique.

Starting Out

With any of the available devices and systems, hysteroscopic myomectomy is not nearly as technically challenging as other procedures gynecologists do. In our experience, it is not difficult to teach residents. To start, beginners should work with other physicians and remove smaller fibroids until they gain confidence. They could even start with polyps, which are easier to remove.

Those new to this procedure will soon appreciate the fact that the fears of complications are unfounded. The overall complication rate is less than 3%–-no higher, and probably lower, than the rate for other procedures like endometrial ablation—and rates of infections, hematomas, and other injuries are significantly lower than those for other procedures.

Uterine artery embolization has been gaining popularity for treatment of symptomatic uterine fibroids, and it is a procedure that patients will probably want to discuss. In many institutions, however, the procedure is not even an option for submucous fibroids, because the fibroids can separate, subsequently blocking the cervix, going through necrosis, and eventually causing sepsis and other complications. In fact, at least two deaths have been reported.

In general, patients' symptoms tend to continue after uterine artery embolization, and patients often ultimately require hysteroscopic resection.

Hysteroscopy, on the other hand, has it all for most patients: low invasiveness, high efficacy, extremely low recurrence, and excellent patient safety.

A 2-cm intracavitary fibroid is shown before surgery.

Versapoint 4-mm wire loop approaches the fibroid.

The 4-mm wire loop is placed behind the fibroid.

The postoperative resection bed is shown here. Photos courtesy Dr. Linda Bradley

Submucous Uterine Fibroids

Uterine fibroids are the most common benign tumor of the female genital tract. Almost 40% of the 600,000 hysterectomies performed each year in the United States are performed for symptomatic fibroids. Given the fact that many fibroids occur in women who want to maintain fertility, have serious health concerns, or desire the most minimally invasive option, hysterectomy often cannot be considered. When the fibroid is submucous in location, a hysteroscopic approach to myomectomy is the procedure of choice. Despite this, few gynecologists maintain this technique in their surgical armamentarium.

It is my desire that this article will spur many readers to safely proceed with hysteroscopic myomectomy. In order to accomplish this, I have asked Dr. Linda Bradley, director of hysteroscopic services at the Cleveland Clinic, and Dr. Keith Isaacson, medical director of the center for minimally invasive gynecologic surgery at Newton-Wellesley Hospital in Newton, Mass., to join me in a discussion on the advantages of the hysteroscopic approach to myomectomy.

Both Dr. Bradley and Dr. Isaacson are noted internationally for their expertise in hysteroscopic surgery. Not only are they gifted hysteroscopic surgeons, but they have written, lectured, and been principal researchers in this area as well.

On that note, let us proceed.

Dr. Reece, who specializes in maternal-fetal medicine, is the vice chancellor and dean of the college of medicine at the University of Arkansas in Little Rock. He has studied various aspects of diabetes-related birth defects from causation to treatment strategies aimed at achieving euglycemia during early pregnancy and—better yet—before pregnancy.

This month, he will address the toll that poorly controlled maternal diabetes takes on the developing fetus and the responsibility of ob.gyns. to address the problem. He will tell us how ob.gyns. can reduce the rates of diabetes-related birth defects and, in the process, help to improve our infant mortality rate.

The World Health Organization judges the health of a country largely by its infant mortality rate. On this measure, the United States ranks 21st in the world. If we intend to improve the health of the nation, we must aggressively focus on reducing the two most significant contributors to infant mortality: prematurity and birth defects.

One of our efforts should focus on the fact that diabetes-related birth defects occur at a rate of 6%–10% among infants of diabetic mothers—a rate that is two to five times higher than the background rate of the general population.

These birth defects are often multiple and involve multiple organ systems, but the anomalies that usually are the most serious, disabling, and that may even be associated with death, include those affecting the central nervous system (neural tube defects or spina bifida of various types) and the cardiovascular system.

Hyperglycemia: A Teratogen

The causation of these anomalies has been studied in my laboratory and by many other groups around the world. It is clear, based on scientific findings, that hyperglycemia is a teratogen and causes direct injury to early embryonic tissue in the same way that any other teratogen, such as thalidomide or radiation, inflicts injury on a developing tissue.

The injurious effect of hyperglycemia is mediated by the induction or the production of free radicals and—simultaneously—by reductions in the body's natural glutathione antioxidant defense capacity. This results in excess free radicals which relentlessly target various tissues in the midst of early organogenesis. (See chart.)

With this knowledge of the biology of birth defect causation, we now know that by avoiding hyperglycemia during early pregnancy (the first 8 weeks), we can reduce the incidence of birth defects among diabetic offspring to mirror the incidence found within the nondiabetic population. This has been shown in clinical trials throughout the world.

Preconception Programs and Therapies

It has also been shown that patients who enter controlled, preconception counseling programs, who achieve euglycemia prior to pregnancy, and who maintain that euglycemia through the first trimester will benefit from an outcome rate similar to that of the nondiabetic population.

In some countries outside the United States, information on the avoidance of hyperglycemia during early fetal development appears to be better known or better incorporated into practice habits than it is here at home. Moreover, in certain countries in Europe, 50%–75% of diabetic women enter preconception programs prior to pregnancy, whereas only 10%–30% of women in the United States do so.

Admittedly, euglycemia is both difficult to achieve and difficult to maintain. We must not shy away from the responsibility, however. Although it is not a simple exercise, we must at least get to the first step of increasing the numbers of preconception programs and elevating their stature. In addition, we must encourage diabetic women to enter and follow through with these programs, so that efforts can be made to achieve euglycemia before early pregnancy.

We also must lower our threshold for diabetes screening among obese and overweight women who may be contemplating pregnancy. With the rise in obesity throughout North America, there has been a concomitant rise in the incidence of type 2 and gestational diabetes. Obese or overweight women may have undiagnosed diabetes that, if left unchecked and untreated, may well harm their infants.

Preconception programs will vary by institution and community. The programs should provide screening for a variety of possible medical disorders—such as thyroid, hematologic, and metabolic disorders—and should treat diagnosed conditions and achieve stability prior to pregnancy. Euglycemia should be achieved through a combination of diet therapy, which typically is 35 calories per ideal of body weight, and the use of insulin therapy and/or oral hypoglycemic agents, such as glyburide.

Although patients in these programs will be nonpregnant, it nevertheless is preferable to use human insulin. Short-acting and intermediate-acting insulins should be used in combination, and in the mornings and afternoons as necessary and appropriate; these parameters should be adjusted accordingly to achieve euglycemia. Additional strategies may include the newer insulin analogues—lispro or aspart, in particular—as a substitute for regular insulin. Other insulin analogues are not well studied and should not be routinely used in pregnancy.

The Power of Supplements

Based on our laboratory work demonstrating that hyperglycemia depletes inherent and natural antioxidant defense mechanisms, we have also demonstrated that by supplementing diets with antioxidants and polyunsaturated fatty acids, we can reduce the incidence of birth defects in animals.

More recently, studies from the Centers for Disease Control and Prevention have confirmed our own laboratory's work showing that diabetic women taking multivitamins with folic acid are able to lower birth defect rates accordingly.

Although the specific amounts, the specific quantity, and the specific types of antioxidants and other substances are not known at this time—and although there is not a defined correlation regarding intake of multivitamins and specific outcome variables—we do know with certainty that the usage of multivitamins containing folic acid has been shown clinically to improve outcomes.

Given the public health problems of diabetes and obesity, obstetricians and primary care providers must encourage—and require to the extent possible—all diabetic patients to enter preconception care when they are contemplating pregnancies, and to undergo multivitamin therapy containing folic acid. It is, simply, a responsibility we hold. With such efforts, we can have a tremendous effect on pregnancy outcome and the reduction of birth defects.

Diabetic Embryopathy

▸ The overall incidence of diabetic embryopathy is 6%–10%, which is five times higher than in nondiabetics.

▸ Diabetic embryopathy accounts for about 40% of deaths of infants of diabetic mothers.

▸ CNS and cardiovascular malformations are the most common and most serious effects.

▸ Neural tube defects are present in infants of diabetic mothers at a rate of 10–20 per 1,000 live births vs. 1–2 per 1,000 live births in the general population.

Source: Dr. Reece

Dr. Reece, who specializes in maternal-fetal medicine, is the vice chancellor and dean of the college of medicine at the University of Arkansas in Little Rock. He has studied various aspects of diabetes-related birth defects from causation to treatment strategies aimed at achieving euglycemia during early pregnancy and—better yet—before pregnancy.

This month, he will address the toll that poorly controlled maternal diabetes takes on the developing fetus and the responsibility of ob.gyns. to address the problem. He will tell us how ob.gyns. can reduce the rates of diabetes-related birth defects and, in the process, help to improve our infant mortality rate.

The World Health Organization judges the health of a country largely by its infant mortality rate. On this measure, the United States ranks 21st in the world. If we intend to improve the health of the nation, we must aggressively focus on reducing the two most significant contributors to infant mortality: prematurity and birth defects.

One of our efforts should focus on the fact that diabetes-related birth defects occur at a rate of 6%–10% among infants of diabetic mothers—a rate that is two to five times higher than the background rate of the general population.

These birth defects are often multiple and involve multiple organ systems, but the anomalies that usually are the most serious, disabling, and that may even be associated with death, include those affecting the central nervous system (neural tube defects or spina bifida of various types) and the cardiovascular system.

Hyperglycemia: A Teratogen

The causation of these anomalies has been studied in my laboratory and by many other groups around the world. It is clear, based on scientific findings, that hyperglycemia is a teratogen and causes direct injury to early embryonic tissue in the same way that any other teratogen, such as thalidomide or radiation, inflicts injury on a developing tissue.

The injurious effect of hyperglycemia is mediated by the induction or the production of free radicals and—simultaneously—by reductions in the body's natural glutathione antioxidant defense capacity. This results in excess free radicals which relentlessly target various tissues in the midst of early organogenesis. (See chart.)

With this knowledge of the biology of birth defect causation, we now know that by avoiding hyperglycemia during early pregnancy (the first 8 weeks), we can reduce the incidence of birth defects among diabetic offspring to mirror the incidence found within the nondiabetic population. This has been shown in clinical trials throughout the world.

Preconception Programs and Therapies

It has also been shown that patients who enter controlled, preconception counseling programs, who achieve euglycemia prior to pregnancy, and who maintain that euglycemia through the first trimester will benefit from an outcome rate similar to that of the nondiabetic population.

In some countries outside the United States, information on the avoidance of hyperglycemia during early fetal development appears to be better known or better incorporated into practice habits than it is here at home. Moreover, in certain countries in Europe, 50%–75% of diabetic women enter preconception programs prior to pregnancy, whereas only 10%–30% of women in the United States do so.

Admittedly, euglycemia is both difficult to achieve and difficult to maintain. We must not shy away from the responsibility, however. Although it is not a simple exercise, we must at least get to the first step of increasing the numbers of preconception programs and elevating their stature. In addition, we must encourage diabetic women to enter and follow through with these programs, so that efforts can be made to achieve euglycemia before early pregnancy.

We also must lower our threshold for diabetes screening among obese and overweight women who may be contemplating pregnancy. With the rise in obesity throughout North America, there has been a concomitant rise in the incidence of type 2 and gestational diabetes. Obese or overweight women may have undiagnosed diabetes that, if left unchecked and untreated, may well harm their infants.

Preconception programs will vary by institution and community. The programs should provide screening for a variety of possible medical disorders—such as thyroid, hematologic, and metabolic disorders—and should treat diagnosed conditions and achieve stability prior to pregnancy. Euglycemia should be achieved through a combination of diet therapy, which typically is 35 calories per ideal of body weight, and the use of insulin therapy and/or oral hypoglycemic agents, such as glyburide.

Although patients in these programs will be nonpregnant, it nevertheless is preferable to use human insulin. Short-acting and intermediate-acting insulins should be used in combination, and in the mornings and afternoons as necessary and appropriate; these parameters should be adjusted accordingly to achieve euglycemia. Additional strategies may include the newer insulin analogues—lispro or aspart, in particular—as a substitute for regular insulin. Other insulin analogues are not well studied and should not be routinely used in pregnancy.

The Power of Supplements

Based on our laboratory work demonstrating that hyperglycemia depletes inherent and natural antioxidant defense mechanisms, we have also demonstrated that by supplementing diets with antioxidants and polyunsaturated fatty acids, we can reduce the incidence of birth defects in animals.

More recently, studies from the Centers for Disease Control and Prevention have confirmed our own laboratory's work showing that diabetic women taking multivitamins with folic acid are able to lower birth defect rates accordingly.

Although the specific amounts, the specific quantity, and the specific types of antioxidants and other substances are not known at this time—and although there is not a defined correlation regarding intake of multivitamins and specific outcome variables—we do know with certainty that the usage of multivitamins containing folic acid has been shown clinically to improve outcomes.

Given the public health problems of diabetes and obesity, obstetricians and primary care providers must encourage—and require to the extent possible—all diabetic patients to enter preconception care when they are contemplating pregnancies, and to undergo multivitamin therapy containing folic acid. It is, simply, a responsibility we hold. With such efforts, we can have a tremendous effect on pregnancy outcome and the reduction of birth defects.

Diabetic Embryopathy

▸ The overall incidence of diabetic embryopathy is 6%–10%, which is five times higher than in nondiabetics.

▸ Diabetic embryopathy accounts for about 40% of deaths of infants of diabetic mothers.

▸ CNS and cardiovascular malformations are the most common and most serious effects.

▸ Neural tube defects are present in infants of diabetic mothers at a rate of 10–20 per 1,000 live births vs. 1–2 per 1,000 live births in the general population.

Source: Dr. Reece

Dr. Reece, who specializes in maternal-fetal medicine, is the vice chancellor and dean of the college of medicine at the University of Arkansas in Little Rock. He has studied various aspects of diabetes-related birth defects from causation to treatment strategies aimed at achieving euglycemia during early pregnancy and—better yet—before pregnancy.

This month, he will address the toll that poorly controlled maternal diabetes takes on the developing fetus and the responsibility of ob.gyns. to address the problem. He will tell us how ob.gyns. can reduce the rates of diabetes-related birth defects and, in the process, help to improve our infant mortality rate.

The World Health Organization judges the health of a country largely by its infant mortality rate. On this measure, the United States ranks 21st in the world. If we intend to improve the health of the nation, we must aggressively focus on reducing the two most significant contributors to infant mortality: prematurity and birth defects.

One of our efforts should focus on the fact that diabetes-related birth defects occur at a rate of 6%–10% among infants of diabetic mothers—a rate that is two to five times higher than the background rate of the general population.

These birth defects are often multiple and involve multiple organ systems, but the anomalies that usually are the most serious, disabling, and that may even be associated with death, include those affecting the central nervous system (neural tube defects or spina bifida of various types) and the cardiovascular system.

Hyperglycemia: A Teratogen

The causation of these anomalies has been studied in my laboratory and by many other groups around the world. It is clear, based on scientific findings, that hyperglycemia is a teratogen and causes direct injury to early embryonic tissue in the same way that any other teratogen, such as thalidomide or radiation, inflicts injury on a developing tissue.

The injurious effect of hyperglycemia is mediated by the induction or the production of free radicals and—simultaneously—by reductions in the body's natural glutathione antioxidant defense capacity. This results in excess free radicals which relentlessly target various tissues in the midst of early organogenesis. (See chart.)

With this knowledge of the biology of birth defect causation, we now know that by avoiding hyperglycemia during early pregnancy (the first 8 weeks), we can reduce the incidence of birth defects among diabetic offspring to mirror the incidence found within the nondiabetic population. This has been shown in clinical trials throughout the world.

Preconception Programs and Therapies

It has also been shown that patients who enter controlled, preconception counseling programs, who achieve euglycemia prior to pregnancy, and who maintain that euglycemia through the first trimester will benefit from an outcome rate similar to that of the nondiabetic population.

In some countries outside the United States, information on the avoidance of hyperglycemia during early fetal development appears to be better known or better incorporated into practice habits than it is here at home. Moreover, in certain countries in Europe, 50%–75% of diabetic women enter preconception programs prior to pregnancy, whereas only 10%–30% of women in the United States do so.

Admittedly, euglycemia is both difficult to achieve and difficult to maintain. We must not shy away from the responsibility, however. Although it is not a simple exercise, we must at least get to the first step of increasing the numbers of preconception programs and elevating their stature. In addition, we must encourage diabetic women to enter and follow through with these programs, so that efforts can be made to achieve euglycemia before early pregnancy.

We also must lower our threshold for diabetes screening among obese and overweight women who may be contemplating pregnancy. With the rise in obesity throughout North America, there has been a concomitant rise in the incidence of type 2 and gestational diabetes. Obese or overweight women may have undiagnosed diabetes that, if left unchecked and untreated, may well harm their infants.

Preconception programs will vary by institution and community. The programs should provide screening for a variety of possible medical disorders—such as thyroid, hematologic, and metabolic disorders—and should treat diagnosed conditions and achieve stability prior to pregnancy. Euglycemia should be achieved through a combination of diet therapy, which typically is 35 calories per ideal of body weight, and the use of insulin therapy and/or oral hypoglycemic agents, such as glyburide.

Although patients in these programs will be nonpregnant, it nevertheless is preferable to use human insulin. Short-acting and intermediate-acting insulins should be used in combination, and in the mornings and afternoons as necessary and appropriate; these parameters should be adjusted accordingly to achieve euglycemia. Additional strategies may include the newer insulin analogues—lispro or aspart, in particular—as a substitute for regular insulin. Other insulin analogues are not well studied and should not be routinely used in pregnancy.

The Power of Supplements

Based on our laboratory work demonstrating that hyperglycemia depletes inherent and natural antioxidant defense mechanisms, we have also demonstrated that by supplementing diets with antioxidants and polyunsaturated fatty acids, we can reduce the incidence of birth defects in animals.

More recently, studies from the Centers for Disease Control and Prevention have confirmed our own laboratory's work showing that diabetic women taking multivitamins with folic acid are able to lower birth defect rates accordingly.

Although the specific amounts, the specific quantity, and the specific types of antioxidants and other substances are not known at this time—and although there is not a defined correlation regarding intake of multivitamins and specific outcome variables—we do know with certainty that the usage of multivitamins containing folic acid has been shown clinically to improve outcomes.

Given the public health problems of diabetes and obesity, obstetricians and primary care providers must encourage—and require to the extent possible—all diabetic patients to enter preconception care when they are contemplating pregnancies, and to undergo multivitamin therapy containing folic acid. It is, simply, a responsibility we hold. With such efforts, we can have a tremendous effect on pregnancy outcome and the reduction of birth defects.

Diabetic Embryopathy

▸ The overall incidence of diabetic embryopathy is 6%–10%, which is five times higher than in nondiabetics.

▸ Diabetic embryopathy accounts for about 40% of deaths of infants of diabetic mothers.

▸ CNS and cardiovascular malformations are the most common and most serious effects.

▸ Neural tube defects are present in infants of diabetic mothers at a rate of 10–20 per 1,000 live births vs. 1–2 per 1,000 live births in the general population.

Source: Dr. Reece

We are in the midst of a significant shift in our approach to prenatal screening for Down syndrome and other major chromosomal abnormalities. We now know, without doubt, that first-trimester screening that combines maternal serum free β-human chorionic gonadotropin and pregnancy-associated plasma protein-A with fetal nuchal translucency measurement is better than second-trimester screening, and we must embrace this new knowledge.

A host of studies, conducted at the front lines of clinical practice as well as at major medical centers, has provided more-than-sufficient evidence that first-trimester screening is ready for implementation in obstetric practice. Major organizations—such as the American College of Obstetricians and Gynecologists, the Society for Maternal-Fetal Medicine, and the National Institutes of Health—are supportive of the shift. For our own patients and as part of an overall public health strategy, we should be rapidly moving away from second-trimester screening and away from using advanced maternal age as the main criterion for deciding who is at risk; instead, we should move toward incorporating the tests and referrals necessary for effective first-trimester screening.

In our practice, we see hundreds of patients who, in previous pregnancies, did not learn until the 18th, 19th, or 20th weeks that they had a baby with a serious problem. They had to go through emotionally wrenching experiences regardless of what they chose to do. With their new pregnancies, they want answers, privately and urgently.

Giving our patients the opportunity to get information and make decisions privately, at a time when their pregnancies are not yet obvious, was always one of the principal driving forces behind the desire for earlier prenatal screening. Now, with first-trimester screening a reality, obstetricians need to be even better prepared to counsel patients and to accept and fully respect their various opinions and decisions.

To effectively incorporate first-trimester screening into practice, we face two other responsibilities. First, we must appreciate—and reassure patients of—the fact that, when done by experienced physicians and at the proper gestational age, chorionic villi sampling (CVS) is safe. When it is done beyond 9 weeks' gestation, the incidence of birth defects after CVS is the same as it is in patients who had no procedure. Second, we must ensure the quality of obstetric ultrasound and, specifically, the measuring of nuchal translucency.

The Road to First-Trimester Screening

We have come a long way in the past 40 years. Once, the best we could do was tell a woman that, as she got older, she had an increased risk of having a baby with a chromosomal abnormality. Then we began to understand that levels of risk were generally clumped together into 5-year cohorts, with a big jump in risk occurring between the 30− to 34-year-old cohort and the 35− to 39-year-olds. As we looked further, we saw that the slope of the curve begins to go up at about age 32 years.

Once amniocentesis was developed, it evolved from a procedure offered only to women at the very highest risk—mainly those who were older than 40 or who had a child with an abnormality—to one that was offered widely to women older than 35 years. In the 1980s, however, it took almost a month for results to come back. By that time, at 21–22 weeks, patients were visibly pregnant, and the bonding process had accelerated.

The angst faced by women at this point in their pregnancies led to the notion of trying to move prenatal diagnosis into the first trimester with CVS. By the end of the 1980s, the procedure was deemed safe and effective. We were stymied, unfortunately, by the limb reduction scare of the early 1990s—an assertion that babies born after CVS had a higher risk of certain limb defects. When this procedure is done in experienced hands and later than 9 weeks' gestation, however, the procedure carries no such risks. The quality of chromosomal study with CVS, moreover, is virtually identical to that with amniocentesis. The risk of miscarriage is also the same.

If all we did was offer CVS and amniocentesis to women aged 35 years and older, however, we would detect only about one-third of the babies born with chromosomal anomalies like Down syndrome. Significantly more pregnancies occur among younger women, and the vast majority of chromosomal abnormalities therefore occur in this “low-risk” group. For this reason—and in an effort to avoid invasive procedures when possible and when desired among older women—physicians and patients clamored for an effective screening test.

Our first obstetric prenatal screening test—the measurement of maternal serum alpha fetoprotein (AFP)—enabled us to detect about one-third of the chromosomal anomalies in women under 35.

The addition of human chorionic gonadotropin and sometimes unconjugated estriol levels measured at 15–18 weeks (the double- and triple-screening protocols) raised the detection rate to approximately 50% in women younger than 35. Yet another measurement—inhibin A—later raised it even more, although we know now that the detection rate is still not as high as that achieved with the first-trimester screening protocol.

These were second-trimester screening tests, however, so women faced the often difficult choice of either having a first-trimester diagnosis by CVS or waiting for screening.

Biochemists experimented with first-trimester measurements and found that AFP and estriol were useless when measured this early. Free β-HCG, however, showed promise, as did measurement of another analyte, pregnancy-associated plasma protein-A (PAPP-A).

(There are two ways of measuring HCG, however, and it is important to understand that virtually all studies done on first-trimester biochemistry have used the so-called free β subunit of HCG—the dissociated part of HCG's β chain. Despite the fact that measurement of the intact β chain is not nearly as useful or accurate, some laboratories still market total β-HCG measurements. It is free β-HCG that we need to measure.)

Meanwhile, ultrasound had become more sophisticated, and it also became apparent that nuchal translucency (the thickness of the back of the fetal neck) in the late first trimester was the strongest indicator of fetal abnormalities identified thus far. It was clear that the bigger the NT measurement, the larger the risk of major chromosomal anomalies.

Because ultrasound and biochemistry are independent markers, a consensus quickly developed that first-trimester screening should utilize both.

It is interesting to note that biochemistry alone is problematic because it does not work as well with multiples and because values are commonly dependent upon gestational age, the determination of which really requires ultrasound. In fact, the late first-trimester ultrasound is the most accurate indicator of gestational age, and in this sense, it offers tremendous obstetric advantages.

We also now know that if NT values are increased and there is not a chromosomal etiology, there may be other congenital problems, principally cardiac anomalies. Early detection of such problems allows not only for reproductive choice but also for planned delivery in appropriate facilities with the best subspecialists.

The Evidence

The person who deserves the lion's share of credit for our shift to first-trimester screening is Dr. Kypros Nicolaides of Kings' College London. Through the second half of the 1990s and continuing on to this point, his group has repeatedly shown that when ultrasound is done correctly and is combined with the proper biochemistry, about 90% of fetuses with trisomy 21 syndrome and other major chromosomal abnormalities can be identified with a 5% false-positive rate.

Investigators of the main American trial on first-trimester screening, called the BUN (Biochemistry, Ultrasound, Nuchal Translucency) study, reported an 83% detection rate with an 8% false-positive rate. Detection rates were similar—even higher—in the FASTER (First- and Second-Trimester Evaluation of Risk) trial published late last year.

In addition to examining first-trimester screening, the FASTER trial addressed the idea of integrating first- and second-trimester screening results. Everyone agrees that the FASTER trial results showed that first-trimester screening works far better than second-trimester screening, and that some patients can modify their first-trimester risk by adding second-trimester protocols. My interpretation, however, is that the vast majority of patients do not need to wait for additional screening. They can have superb results in the first trimester.

Biochemistry can be done anytime between 9 and 13 weeks, but it is best done at weeks 9 or 10. Nuchal translucency, on the other hand, is only interpretable during weeks 11, 12, or 13. Before week 11 or after week 13, we cannot use the data.

Some experts have pointed to the possible added value of the fetal nasal bone measurement, but it is a much harder measurement to perform, and I believe it is unlikely that a large percentage of physicians will be able to do it competently. When it can be correctly obtained, however, it can be a good adjunct to the risk calculation. I consider it a second-line screening test that can be used if there is confusion or ambiguity about the first round of tests.

Ultrasound Quality

Successful first-trimester screening is contingent upon accurate nuchal translucency measurement. There are a number of ways to do the measurement, and frankly, the way in which a standard method was chosen was, in essence, arbitrary. Standardization is necessary, however. NT measurement is not an art.

If we're going to use ultrasound numbers in an algorithm—as we are in our new screening protocols—we must employ the same quality control we expect of any other laboratory measurement. Although the issue of ultrasound certification as a prerequisite of the performance of NT measurement has been debated, several organizations perform quality review.

Nuchal translucency measurement will not be a procedure that everyone does in his or her own office. I see more of a “centers of excellence” model or process evolving, in which a patient who is 9–10 weeks pregnant has blood drawn in her obstetrician's office and then goes to another specialized center for the NT measurement. There, the specialist retrieves the lab results electronically, plugs the NT measurement and lab results into the algorithm, and then—on the spot—tells the patient what her risk is. If the patient decides she wants CVS, the procedure could even be done that day.

As in many other parts of health care, patients in rural areas can be at a disadvantage. To physicians in remote areas, I would say, rely on the biochemistry as a first step.

“Accept and Respect”

As a geneticist, I tell all patients that we try to provide information only, and that what they choose to do with that information is their decision. Faced with screening information and the fact that it adjusts odds and does not provide definitive answers, many patients will decide they are happy with an odds adjustment. Others will say, “I don't care what the risk is, I want a definitive answer.”

Both decisions have to be equally respected. With prenatal screening undergoing such significant change, it is all the more important that we accept the fact that intelligent and reasonable people will look at the same data and reach opposing conclusions. We have to accept and respect this diversity.

During my 25 years in the field, I have found that what patients actually do when they are faced with information is often diametrically the opposite—in both directions—of what they thought they would do if confronted with a problem. That's why I believe that one of the most important things we can do is to reassure patients that everything—any decision—is fine.

A trisomy 18 fetus with enlarged nuchal translucency is seen on ultrasound. Courtesy Dr. Mark I. Evans

Prenatal Screening

There was a time when pregnancy and its outcome were clouded in mystery, when fetal outcome was known only at birth. Over many years, that mystery has dissipated as an evolution of technological developments occurred, eventually leading to the discipline of prenatal diagnosis.

In the 1800s, fetal assessment using the Pinard stethoscope was introduced. This was followed by the introduction and use of more refined instruments that similarly focused on assessment of fetal movement and the fetal heart rate. In 1958, Dr. E.H. Hon introduced electronic fetal monitoring—a technology that enabled us to attempt to assess fetal well-being by attributing illness or lack of health to significant changes in the heart rate. After Dr. Ian Donald of the United Kingdom introduced obstetric ultrasound in the late 1950s and early 1960s, we began using more sophisticated technology to assess the global appearance of the in utero environment.

As this succession of technological innovations occurred, the desire of parents and families to know about the well-being of the fetus grew. Parents welcomed the development of more sophisticated ultrasound and their new ability to scrutinize the fetus in even greater detail, assessing not only its anatomical development but also its behavioral and functional states.

Other methods of fetal assessment were introduced, including biochemical analysis of the maternal and fetal blood. We soon reached the point at which we could use an algorithm that incorporated the biophysical findings of ultrasound and the biochemical assessment of maternal blood to gain significant insight about fetal status very early in gestation.

The culmination of this technological evolution has been the development of first-trimester fetal screening. Using various algorithms, we are now able to gain a significant amount of information on fetal development and outcomes early on.

Our guest professor for Master Class this month, Dr. Mark I. Evans, will elucidate the application of first-trimester prenatal diagnosis. Dr. Evans is professor of obstetrics and gynecology at the Mount Sinai School of Medicine, New York, and president of the Fetal Medicine Foundation of America. He is a national leader in prenatal diagnosis and genetics.

We are in the midst of a significant shift in our approach to prenatal screening for Down syndrome and other major chromosomal abnormalities. We now know, without doubt, that first-trimester screening that combines maternal serum free β-human chorionic gonadotropin and pregnancy-associated plasma protein-A with fetal nuchal translucency measurement is better than second-trimester screening, and we must embrace this new knowledge.

A host of studies, conducted at the front lines of clinical practice as well as at major medical centers, has provided more-than-sufficient evidence that first-trimester screening is ready for implementation in obstetric practice. Major organizations—such as the American College of Obstetricians and Gynecologists, the Society for Maternal-Fetal Medicine, and the National Institutes of Health—are supportive of the shift. For our own patients and as part of an overall public health strategy, we should be rapidly moving away from second-trimester screening and away from using advanced maternal age as the main criterion for deciding who is at risk; instead, we should move toward incorporating the tests and referrals necessary for effective first-trimester screening.

In our practice, we see hundreds of patients who, in previous pregnancies, did not learn until the 18th, 19th, or 20th weeks that they had a baby with a serious problem. They had to go through emotionally wrenching experiences regardless of what they chose to do. With their new pregnancies, they want answers, privately and urgently.

Giving our patients the opportunity to get information and make decisions privately, at a time when their pregnancies are not yet obvious, was always one of the principal driving forces behind the desire for earlier prenatal screening. Now, with first-trimester screening a reality, obstetricians need to be even better prepared to counsel patients and to accept and fully respect their various opinions and decisions.

To effectively incorporate first-trimester screening into practice, we face two other responsibilities. First, we must appreciate—and reassure patients of—the fact that, when done by experienced physicians and at the proper gestational age, chorionic villi sampling (CVS) is safe. When it is done beyond 9 weeks' gestation, the incidence of birth defects after CVS is the same as it is in patients who had no procedure. Second, we must ensure the quality of obstetric ultrasound and, specifically, the measuring of nuchal translucency.

The Road to First-Trimester Screening

We have come a long way in the past 40 years. Once, the best we could do was tell a woman that, as she got older, she had an increased risk of having a baby with a chromosomal abnormality. Then we began to understand that levels of risk were generally clumped together into 5-year cohorts, with a big jump in risk occurring between the 30− to 34-year-old cohort and the 35− to 39-year-olds. As we looked further, we saw that the slope of the curve begins to go up at about age 32 years.

Once amniocentesis was developed, it evolved from a procedure offered only to women at the very highest risk—mainly those who were older than 40 or who had a child with an abnormality—to one that was offered widely to women older than 35 years. In the 1980s, however, it took almost a month for results to come back. By that time, at 21–22 weeks, patients were visibly pregnant, and the bonding process had accelerated.

The angst faced by women at this point in their pregnancies led to the notion of trying to move prenatal diagnosis into the first trimester with CVS. By the end of the 1980s, the procedure was deemed safe and effective. We were stymied, unfortunately, by the limb reduction scare of the early 1990s—an assertion that babies born after CVS had a higher risk of certain limb defects. When this procedure is done in experienced hands and later than 9 weeks' gestation, however, the procedure carries no such risks. The quality of chromosomal study with CVS, moreover, is virtually identical to that with amniocentesis. The risk of miscarriage is also the same.

If all we did was offer CVS and amniocentesis to women aged 35 years and older, however, we would detect only about one-third of the babies born with chromosomal anomalies like Down syndrome. Significantly more pregnancies occur among younger women, and the vast majority of chromosomal abnormalities therefore occur in this “low-risk” group. For this reason—and in an effort to avoid invasive procedures when possible and when desired among older women—physicians and patients clamored for an effective screening test.

Our first obstetric prenatal screening test—the measurement of maternal serum alpha fetoprotein (AFP)—enabled us to detect about one-third of the chromosomal anomalies in women under 35.

The addition of human chorionic gonadotropin and sometimes unconjugated estriol levels measured at 15–18 weeks (the double- and triple-screening protocols) raised the detection rate to approximately 50% in women younger than 35. Yet another measurement—inhibin A—later raised it even more, although we know now that the detection rate is still not as high as that achieved with the first-trimester screening protocol.

These were second-trimester screening tests, however, so women faced the often difficult choice of either having a first-trimester diagnosis by CVS or waiting for screening.

Biochemists experimented with first-trimester measurements and found that AFP and estriol were useless when measured this early. Free β-HCG, however, showed promise, as did measurement of another analyte, pregnancy-associated plasma protein-A (PAPP-A).

(There are two ways of measuring HCG, however, and it is important to understand that virtually all studies done on first-trimester biochemistry have used the so-called free β subunit of HCG—the dissociated part of HCG's β chain. Despite the fact that measurement of the intact β chain is not nearly as useful or accurate, some laboratories still market total β-HCG measurements. It is free β-HCG that we need to measure.)

Meanwhile, ultrasound had become more sophisticated, and it also became apparent that nuchal translucency (the thickness of the back of the fetal neck) in the late first trimester was the strongest indicator of fetal abnormalities identified thus far. It was clear that the bigger the NT measurement, the larger the risk of major chromosomal anomalies.

Because ultrasound and biochemistry are independent markers, a consensus quickly developed that first-trimester screening should utilize both.

It is interesting to note that biochemistry alone is problematic because it does not work as well with multiples and because values are commonly dependent upon gestational age, the determination of which really requires ultrasound. In fact, the late first-trimester ultrasound is the most accurate indicator of gestational age, and in this sense, it offers tremendous obstetric advantages.

We also now know that if NT values are increased and there is not a chromosomal etiology, there may be other congenital problems, principally cardiac anomalies. Early detection of such problems allows not only for reproductive choice but also for planned delivery in appropriate facilities with the best subspecialists.

The Evidence

The person who deserves the lion's share of credit for our shift to first-trimester screening is Dr. Kypros Nicolaides of Kings' College London. Through the second half of the 1990s and continuing on to this point, his group has repeatedly shown that when ultrasound is done correctly and is combined with the proper biochemistry, about 90% of fetuses with trisomy 21 syndrome and other major chromosomal abnormalities can be identified with a 5% false-positive rate.

Investigators of the main American trial on first-trimester screening, called the BUN (Biochemistry, Ultrasound, Nuchal Translucency) study, reported an 83% detection rate with an 8% false-positive rate. Detection rates were similar—even higher—in the FASTER (First- and Second-Trimester Evaluation of Risk) trial published late last year.

In addition to examining first-trimester screening, the FASTER trial addressed the idea of integrating first- and second-trimester screening results. Everyone agrees that the FASTER trial results showed that first-trimester screening works far better than second-trimester screening, and that some patients can modify their first-trimester risk by adding second-trimester protocols. My interpretation, however, is that the vast majority of patients do not need to wait for additional screening. They can have superb results in the first trimester.

Biochemistry can be done anytime between 9 and 13 weeks, but it is best done at weeks 9 or 10. Nuchal translucency, on the other hand, is only interpretable during weeks 11, 12, or 13. Before week 11 or after week 13, we cannot use the data.

Some experts have pointed to the possible added value of the fetal nasal bone measurement, but it is a much harder measurement to perform, and I believe it is unlikely that a large percentage of physicians will be able to do it competently. When it can be correctly obtained, however, it can be a good adjunct to the risk calculation. I consider it a second-line screening test that can be used if there is confusion or ambiguity about the first round of tests.

Ultrasound Quality

Successful first-trimester screening is contingent upon accurate nuchal translucency measurement. There are a number of ways to do the measurement, and frankly, the way in which a standard method was chosen was, in essence, arbitrary. Standardization is necessary, however. NT measurement is not an art.

If we're going to use ultrasound numbers in an algorithm—as we are in our new screening protocols—we must employ the same quality control we expect of any other laboratory measurement. Although the issue of ultrasound certification as a prerequisite of the performance of NT measurement has been debated, several organizations perform quality review.

Nuchal translucency measurement will not be a procedure that everyone does in his or her own office. I see more of a “centers of excellence” model or process evolving, in which a patient who is 9–10 weeks pregnant has blood drawn in her obstetrician's office and then goes to another specialized center for the NT measurement. There, the specialist retrieves the lab results electronically, plugs the NT measurement and lab results into the algorithm, and then—on the spot—tells the patient what her risk is. If the patient decides she wants CVS, the procedure could even be done that day.

As in many other parts of health care, patients in rural areas can be at a disadvantage. To physicians in remote areas, I would say, rely on the biochemistry as a first step.

“Accept and Respect”

As a geneticist, I tell all patients that we try to provide information only, and that what they choose to do with that information is their decision. Faced with screening information and the fact that it adjusts odds and does not provide definitive answers, many patients will decide they are happy with an odds adjustment. Others will say, “I don't care what the risk is, I want a definitive answer.”

Both decisions have to be equally respected. With prenatal screening undergoing such significant change, it is all the more important that we accept the fact that intelligent and reasonable people will look at the same data and reach opposing conclusions. We have to accept and respect this diversity.

During my 25 years in the field, I have found that what patients actually do when they are faced with information is often diametrically the opposite—in both directions—of what they thought they would do if confronted with a problem. That's why I believe that one of the most important things we can do is to reassure patients that everything—any decision—is fine.

A trisomy 18 fetus with enlarged nuchal translucency is seen on ultrasound. Courtesy Dr. Mark I. Evans

Prenatal Screening

There was a time when pregnancy and its outcome were clouded in mystery, when fetal outcome was known only at birth. Over many years, that mystery has dissipated as an evolution of technological developments occurred, eventually leading to the discipline of prenatal diagnosis.

In the 1800s, fetal assessment using the Pinard stethoscope was introduced. This was followed by the introduction and use of more refined instruments that similarly focused on assessment of fetal movement and the fetal heart rate. In 1958, Dr. E.H. Hon introduced electronic fetal monitoring—a technology that enabled us to attempt to assess fetal well-being by attributing illness or lack of health to significant changes in the heart rate. After Dr. Ian Donald of the United Kingdom introduced obstetric ultrasound in the late 1950s and early 1960s, we began using more sophisticated technology to assess the global appearance of the in utero environment.

As this succession of technological innovations occurred, the desire of parents and families to know about the well-being of the fetus grew. Parents welcomed the development of more sophisticated ultrasound and their new ability to scrutinize the fetus in even greater detail, assessing not only its anatomical development but also its behavioral and functional states.

Other methods of fetal assessment were introduced, including biochemical analysis of the maternal and fetal blood. We soon reached the point at which we could use an algorithm that incorporated the biophysical findings of ultrasound and the biochemical assessment of maternal blood to gain significant insight about fetal status very early in gestation.

The culmination of this technological evolution has been the development of first-trimester fetal screening. Using various algorithms, we are now able to gain a significant amount of information on fetal development and outcomes early on.

Our guest professor for Master Class this month, Dr. Mark I. Evans, will elucidate the application of first-trimester prenatal diagnosis. Dr. Evans is professor of obstetrics and gynecology at the Mount Sinai School of Medicine, New York, and president of the Fetal Medicine Foundation of America. He is a national leader in prenatal diagnosis and genetics.

We are in the midst of a significant shift in our approach to prenatal screening for Down syndrome and other major chromosomal abnormalities. We now know, without doubt, that first-trimester screening that combines maternal serum free β-human chorionic gonadotropin and pregnancy-associated plasma protein-A with fetal nuchal translucency measurement is better than second-trimester screening, and we must embrace this new knowledge.

A host of studies, conducted at the front lines of clinical practice as well as at major medical centers, has provided more-than-sufficient evidence that first-trimester screening is ready for implementation in obstetric practice. Major organizations—such as the American College of Obstetricians and Gynecologists, the Society for Maternal-Fetal Medicine, and the National Institutes of Health—are supportive of the shift. For our own patients and as part of an overall public health strategy, we should be rapidly moving away from second-trimester screening and away from using advanced maternal age as the main criterion for deciding who is at risk; instead, we should move toward incorporating the tests and referrals necessary for effective first-trimester screening.

In our practice, we see hundreds of patients who, in previous pregnancies, did not learn until the 18th, 19th, or 20th weeks that they had a baby with a serious problem. They had to go through emotionally wrenching experiences regardless of what they chose to do. With their new pregnancies, they want answers, privately and urgently.

Giving our patients the opportunity to get information and make decisions privately, at a time when their pregnancies are not yet obvious, was always one of the principal driving forces behind the desire for earlier prenatal screening. Now, with first-trimester screening a reality, obstetricians need to be even better prepared to counsel patients and to accept and fully respect their various opinions and decisions.

To effectively incorporate first-trimester screening into practice, we face two other responsibilities. First, we must appreciate—and reassure patients of—the fact that, when done by experienced physicians and at the proper gestational age, chorionic villi sampling (CVS) is safe. When it is done beyond 9 weeks' gestation, the incidence of birth defects after CVS is the same as it is in patients who had no procedure. Second, we must ensure the quality of obstetric ultrasound and, specifically, the measuring of nuchal translucency.

The Road to First-Trimester Screening

We have come a long way in the past 40 years. Once, the best we could do was tell a woman that, as she got older, she had an increased risk of having a baby with a chromosomal abnormality. Then we began to understand that levels of risk were generally clumped together into 5-year cohorts, with a big jump in risk occurring between the 30− to 34-year-old cohort and the 35− to 39-year-olds. As we looked further, we saw that the slope of the curve begins to go up at about age 32 years.

Once amniocentesis was developed, it evolved from a procedure offered only to women at the very highest risk—mainly those who were older than 40 or who had a child with an abnormality—to one that was offered widely to women older than 35 years. In the 1980s, however, it took almost a month for results to come back. By that time, at 21–22 weeks, patients were visibly pregnant, and the bonding process had accelerated.

The angst faced by women at this point in their pregnancies led to the notion of trying to move prenatal diagnosis into the first trimester with CVS. By the end of the 1980s, the procedure was deemed safe and effective. We were stymied, unfortunately, by the limb reduction scare of the early 1990s—an assertion that babies born after CVS had a higher risk of certain limb defects. When this procedure is done in experienced hands and later than 9 weeks' gestation, however, the procedure carries no such risks. The quality of chromosomal study with CVS, moreover, is virtually identical to that with amniocentesis. The risk of miscarriage is also the same.

If all we did was offer CVS and amniocentesis to women aged 35 years and older, however, we would detect only about one-third of the babies born with chromosomal anomalies like Down syndrome. Significantly more pregnancies occur among younger women, and the vast majority of chromosomal abnormalities therefore occur in this “low-risk” group. For this reason—and in an effort to avoid invasive procedures when possible and when desired among older women—physicians and patients clamored for an effective screening test.

Our first obstetric prenatal screening test—the measurement of maternal serum alpha fetoprotein (AFP)—enabled us to detect about one-third of the chromosomal anomalies in women under 35.

The addition of human chorionic gonadotropin and sometimes unconjugated estriol levels measured at 15–18 weeks (the double- and triple-screening protocols) raised the detection rate to approximately 50% in women younger than 35. Yet another measurement—inhibin A—later raised it even more, although we know now that the detection rate is still not as high as that achieved with the first-trimester screening protocol.

These were second-trimester screening tests, however, so women faced the often difficult choice of either having a first-trimester diagnosis by CVS or waiting for screening.

Biochemists experimented with first-trimester measurements and found that AFP and estriol were useless when measured this early. Free β-HCG, however, showed promise, as did measurement of another analyte, pregnancy-associated plasma protein-A (PAPP-A).

(There are two ways of measuring HCG, however, and it is important to understand that virtually all studies done on first-trimester biochemistry have used the so-called free β subunit of HCG—the dissociated part of HCG's β chain. Despite the fact that measurement of the intact β chain is not nearly as useful or accurate, some laboratories still market total β-HCG measurements. It is free β-HCG that we need to measure.)

Meanwhile, ultrasound had become more sophisticated, and it also became apparent that nuchal translucency (the thickness of the back of the fetal neck) in the late first trimester was the strongest indicator of fetal abnormalities identified thus far. It was clear that the bigger the NT measurement, the larger the risk of major chromosomal anomalies.

Because ultrasound and biochemistry are independent markers, a consensus quickly developed that first-trimester screening should utilize both.

It is interesting to note that biochemistry alone is problematic because it does not work as well with multiples and because values are commonly dependent upon gestational age, the determination of which really requires ultrasound. In fact, the late first-trimester ultrasound is the most accurate indicator of gestational age, and in this sense, it offers tremendous obstetric advantages.

We also now know that if NT values are increased and there is not a chromosomal etiology, there may be other congenital problems, principally cardiac anomalies. Early detection of such problems allows not only for reproductive choice but also for planned delivery in appropriate facilities with the best subspecialists.

The Evidence

The person who deserves the lion's share of credit for our shift to first-trimester screening is Dr. Kypros Nicolaides of Kings' College London. Through the second half of the 1990s and continuing on to this point, his group has repeatedly shown that when ultrasound is done correctly and is combined with the proper biochemistry, about 90% of fetuses with trisomy 21 syndrome and other major chromosomal abnormalities can be identified with a 5% false-positive rate.

Investigators of the main American trial on first-trimester screening, called the BUN (Biochemistry, Ultrasound, Nuchal Translucency) study, reported an 83% detection rate with an 8% false-positive rate. Detection rates were similar—even higher—in the FASTER (First- and Second-Trimester Evaluation of Risk) trial published late last year.

In addition to examining first-trimester screening, the FASTER trial addressed the idea of integrating first- and second-trimester screening results. Everyone agrees that the FASTER trial results showed that first-trimester screening works far better than second-trimester screening, and that some patients can modify their first-trimester risk by adding second-trimester protocols. My interpretation, however, is that the vast majority of patients do not need to wait for additional screening. They can have superb results in the first trimester.

Biochemistry can be done anytime between 9 and 13 weeks, but it is best done at weeks 9 or 10. Nuchal translucency, on the other hand, is only interpretable during weeks 11, 12, or 13. Before week 11 or after week 13, we cannot use the data.

Some experts have pointed to the possible added value of the fetal nasal bone measurement, but it is a much harder measurement to perform, and I believe it is unlikely that a large percentage of physicians will be able to do it competently. When it can be correctly obtained, however, it can be a good adjunct to the risk calculation. I consider it a second-line screening test that can be used if there is confusion or ambiguity about the first round of tests.

Ultrasound Quality

Successful first-trimester screening is contingent upon accurate nuchal translucency measurement. There are a number of ways to do the measurement, and frankly, the way in which a standard method was chosen was, in essence, arbitrary. Standardization is necessary, however. NT measurement is not an art.

If we're going to use ultrasound numbers in an algorithm—as we are in our new screening protocols—we must employ the same quality control we expect of any other laboratory measurement. Although the issue of ultrasound certification as a prerequisite of the performance of NT measurement has been debated, several organizations perform quality review.

Nuchal translucency measurement will not be a procedure that everyone does in his or her own office. I see more of a “centers of excellence” model or process evolving, in which a patient who is 9–10 weeks pregnant has blood drawn in her obstetrician's office and then goes to another specialized center for the NT measurement. There, the specialist retrieves the lab results electronically, plugs the NT measurement and lab results into the algorithm, and then—on the spot—tells the patient what her risk is. If the patient decides she wants CVS, the procedure could even be done that day.

As in many other parts of health care, patients in rural areas can be at a disadvantage. To physicians in remote areas, I would say, rely on the biochemistry as a first step.

“Accept and Respect”

As a geneticist, I tell all patients that we try to provide information only, and that what they choose to do with that information is their decision. Faced with screening information and the fact that it adjusts odds and does not provide definitive answers, many patients will decide they are happy with an odds adjustment. Others will say, “I don't care what the risk is, I want a definitive answer.”

Both decisions have to be equally respected. With prenatal screening undergoing such significant change, it is all the more important that we accept the fact that intelligent and reasonable people will look at the same data and reach opposing conclusions. We have to accept and respect this diversity.

During my 25 years in the field, I have found that what patients actually do when they are faced with information is often diametrically the opposite—in both directions—of what they thought they would do if confronted with a problem. That's why I believe that one of the most important things we can do is to reassure patients that everything—any decision—is fine.

A trisomy 18 fetus with enlarged nuchal translucency is seen on ultrasound. Courtesy Dr. Mark I. Evans

Prenatal Screening

There was a time when pregnancy and its outcome were clouded in mystery, when fetal outcome was known only at birth. Over many years, that mystery has dissipated as an evolution of technological developments occurred, eventually leading to the discipline of prenatal diagnosis.

In the 1800s, fetal assessment using the Pinard stethoscope was introduced. This was followed by the introduction and use of more refined instruments that similarly focused on assessment of fetal movement and the fetal heart rate. In 1958, Dr. E.H. Hon introduced electronic fetal monitoring—a technology that enabled us to attempt to assess fetal well-being by attributing illness or lack of health to significant changes in the heart rate. After Dr. Ian Donald of the United Kingdom introduced obstetric ultrasound in the late 1950s and early 1960s, we began using more sophisticated technology to assess the global appearance of the in utero environment.

As this succession of technological innovations occurred, the desire of parents and families to know about the well-being of the fetus grew. Parents welcomed the development of more sophisticated ultrasound and their new ability to scrutinize the fetus in even greater detail, assessing not only its anatomical development but also its behavioral and functional states.

Other methods of fetal assessment were introduced, including biochemical analysis of the maternal and fetal blood. We soon reached the point at which we could use an algorithm that incorporated the biophysical findings of ultrasound and the biochemical assessment of maternal blood to gain significant insight about fetal status very early in gestation.

The culmination of this technological evolution has been the development of first-trimester fetal screening. Using various algorithms, we are now able to gain a significant amount of information on fetal development and outcomes early on.

Our guest professor for Master Class this month, Dr. Mark I. Evans, will elucidate the application of first-trimester prenatal diagnosis. Dr. Evans is professor of obstetrics and gynecology at the Mount Sinai School of Medicine, New York, and president of the Fetal Medicine Foundation of America. He is a national leader in prenatal diagnosis and genetics.

Prior to the introduction of laparoscopic assistance, vaginal hysterectomy (VH) was the only minimally invasive option for removing the uterus, and for decades studies have shown that vaginal hysterectomy results in significantly less morbidity than does abdominal hysterectomy. Most recently, investigators who reviewed randomized, controlled trials of hysterectomy for the international Cochrane Collaboration concluded that traditional vaginal hysterectomies should be performed “whenever technically feasible”—even in a world of increasingly popular laparoscopic approaches.

In recent years, technologic advances have resulted in innovative approaches for hysterectomy, including laparoscopically assisted vaginal hysterectomy (LAVH), laparoscopic supracervical hysterectomy (LSH), and total laparoscopic hysterectomy. Despite multiple options for minimally invasive hysterectomy and the evidence suggesting that vaginal hysterectomy should be performed whenever feasible, the majority of hysterectomies in the United States are performed abdominally, and the overall rate of vaginal hysterectomy has held steady.

Comfort level is a major determinant of the type of hysterectomy performed. Many surgeons have not performed sufficient laparoscopic surgeries during residency and do not have the opportunity to receive the appropriate additional training needed to perform laparoscopic techniques requiring advanced skills. Moreover, gynecologic surgeons who have been trained in residency to perform basic vaginal hysterectomy too often dismiss this option because of uterine enlargement or other factors, such as nulliparity, endometriosis, or prior pelvic surgery. In the end, too many patients are denied an attempt at a minimally invasive approach and undergo abdominal hysterectomy.

In many of these cases, a traditional, minimally invasive vaginal approach is achievable. By thoroughly evaluating uterine mobility—ideally, in the operating room—and by more frequently using the relatively simple technique of morcellation to remove the large uterus (which is common among patients needing hysterectomies), we can markedly reduce the rate of abdominal hysterectomy and its ensuing morbidities.

Because it is a relatively straightforward, natural extension of a core procedure for many gynecologists, morcellation can be more quickly and universally applied in practice than are the advanced laparoscopic techniques that many of us strive to learn.

Assessing Uterine Mobility

For successful vaginal hysterectomy with morcellation, the lower uterine segment must be mobile enough to allow control of the uterine arteries and entry into the anterior and posterior cul-de-sacs. These are the essential prerequisites for morcellation; once the cul-de-sacs are entered and the uterine vessels are controlled, we will be able to complete the majority of cases regardless of uterine size.

We should assess uterine mobility in every patient, regardless of the presence or absence of presumptive risk factors such as nulliparity, endometriosis, or pelvic adhesions. In general, mobility is sufficient if we are able to pull the cervix down to the lower third of the vagina.

We can assess the patient's uterine mobility during the office visit to have some assurance of the likelihood of being able to perform vaginal hysterectomy. In general, however, mobility will be notably greater once the patient is under anesthesia, and we really should assess it in the operating room in any case. In a broader sense, performing an examination under anesthesia of uterine mobility, vaginal anatomy, and support to the cervix affords us the opportunity to individualize the hysterectomy and determine the best approach for the patient, rather than pigeonhole the patient into any one particular procedure.

In the patient with uterine enlargement, we should aim to be prepared to perform vaginal hysterectomy with morcellation whenever feasible. If uterine support is normal and vaginal hysterectomy is not technically feasible, laparoscopic assistance should be considered. Although there are no studies directly comparing vaginal hysterectomy and LSH, these two procedures may be the best options for the patient with uterine enlargement. The determining factor between these two approaches should be the presence or absence of uterine mobility, and this should be assessed intraoperatively.

This valuable course of intraoperative decision making begins, of course, with a discussion with the patient about the various options, about the goal of performing an appropriate procedure with the least morbidity, and about her preferences on whether her cervix should stay in or not. In essence, we want to be able to involve the patient beforehand and then tell her that “no matter what, when you're in the recovery room, we will have completed the hysterectomy that is best for you.” Often, we will find that vaginal hysterectomy with morcellation is a viable option when we evaluate the patient under anesthesia.

Performing Morcellation

There are two basic types of morcellation: the wedge technique, and the intramyometrial-coring (also known as the Lash) technique.

In the wedge technique, the cervix is bivalved in the anteroposterior plane to the level of the lower uterine segment. Occasionally, this step alone will result in sufficient mobility to allow delivery of the uterine fundus. Once the cervix is bisected, use a clamp—I prefer a Lahey goiter clamp—to grasp the anterior or posterior uterine wall from endometrium to serosa, and excise a wedge-shaped portion of the uterine wall.

Continue this process until the uterine fundus can be delivered and the remaining pedicles clamped and cut to allow removal of the uterus. Typically, you will encounter individual myomas and can remove these separately.

The Lash technique—or intramyometrial coring—involves a circular incision in the myometrium at the level of the upper cervix. Make successive circumferential incisions, and you will essentially core out the myometrium while the integrity of the endometrial cavity is maintained.

Because the coring technique allows the removal of an intact endometrium, it may be an advantage if you are concerned about unexpected endometrial pathology. With office biopsies and modern imaging techniques, the chance of an unexpected finding of significant pathology should be minimal. Overall, I believe, the wedge technique is technically easier.

In either case, morcellation follows entry into both the anterior and posterior cul-de-sacs and control of the uterine vessels. Generally, I attempt anterior entry first, which allows me to palpate the ureters prior to clamping and cutting the pedicles. Other surgeons advocate entering the posterior cul-de-sac first, because the inability to enter posteriorly is generally considered an indication to abandon the vaginal approach. Regardless of order, both cul-de-sacs must be entered and the uterine vasculare pedicles controlled before proceeding with morcellation.

While at the Mayo Clinic a decade ago, my colleagues and I reviewed the hysterectomies performed over a 2-year period in patients with a uterine weight of 200–600 g. Patients with adnexal masses and malignancy were excluded.

Of 298 patients who were evaluated in the operating room, nearly half (48%) of those with a uterine weight of 200–400 g were deemed to be candidates for vaginal hysterectomy, based on the presence of sufficient uterine mobility. Even in the group with uterine weights of 400–600 g, 11% of patients had sufficient mobility to allow a vaginal approach. This included nulliparous patients and those with previous pelvic surgery and endometriosis.

Vaginal hysterectomy was successful in 97% of these patients, and its complication rate was significantly lower than that of abdominal hysterectomy, regardless of uterine weight. Morcellation, we found, was required in approximately 70%.

The study showed that although uterine size limits its use, the most important factor in deciding to perform vaginal hysterectomy was the presence of uterine mobility and accessibility. It also showed that because some patients with nulliparity, previous pelvic surgery, and endometriosis will still have sufficient mobility, these factors should not be considered as contraindications to the vaginal approach.

Incorporating Laparoscopy

Over the past decade, rates of LAVH have risen significantly, while the overall rate of vaginal hysterectomy has remained stable. This is concerning because, undoubtedly, many of these patients are candidates for traditional vaginal hysterectomy. Numerous studies, including the recent Cochrane Collaboration review, have shown that LAVH does not improve morbidity over traditional vaginal hysterectomy, and is more time consuming and costly.

Ideally, the use of the laparoscope should allow abdominal hysterectomy to be converted to a minimally invasive procedure. As I see it, the laparoscope can be used to address situations that result in uterine immobility, such as nulliparity, adhesions, and endometriosis, thus allowing conversion of these cases to LAVH.

Additionally, we can use laparoscopy to ensure ovarian removal at the time of vaginal hysterectomy, although some would suggest proceeding with traditional vaginal hysterectomy first and only employing laparoscopy if you're having technical difficulty removing the ovaries vaginally. Multiple studies report more than 90% success in removing ovaries at the time of vaginal hysterectomy, suggesting that laparoscopic assistance for ovarian removal should be required in less than 10% of cases.

My own experience with ovarian removal is similar to these studies, so I prefer to attempt vaginal removal first and reserve the use of the laparoscope for the few patients in whom I find it necessary.

Total vs. Supracervical Hysterectomy

The recent introduction of the laparoscopic morcellator allows removal of an enlarged uterus with a laparoscopic approach and has resulted in an increased use of LSH for patients with uterine enlargement.

Although some surgeons counsel patients that keeping their cervix will result in improved pelvic support and sexual function, studies comparing total hysterectomy with supracervical hysterectomy have shown no difference in bladder function and sexual function and support the premise that it's the anatomy of the vagina, and not the presence of the cervix, that is important. (We still need well-designed randomized, controlled trials that compare the morbidities and outcomes of LSH with LAVH and vaginal hysterectomy.)

In patients who already have normal pelvic support, LSH utilizing the laparoscopic morcellator may offer the best option for removal of the enlarged uterus, whereas those patients with uterine mobility are best treated by vaginal hysterectomy with traditional morcellation.

Ideally, we should be in a position to offer both approaches to the patient and should decide which to use based on examination under anesthesia in the operating room. If neither can be achieved, the patient may require abdominal hysterectomy, but at least we will have made an appropriate attempt at a less invasive procedure.

Until we have data pointing us elsewhere, we should embrace the minimally invasive gold standard of vaginal hysterectomy, employing morcellation for the larger uterus more often and turning to laparoscopy when necessary. Hysterectomies are most commonly done in reproductive-age women with fibroids or bleeding, a significant number of whom have enlarged uteri, so our ability to reduce the rate of abdominal hysterectomy—and increase the rate of the less morbid vaginal approach—is significant.

On the left, a wedge is excised from the posterior uterus. On the right, individual myomas are removed as they are encountered during morcellation. Photos courtesy Dr. Michael Moen

Size Doesn't Have to Count

Despite a trend toward minimally invasive gynecologic surgery, nearly 75% of hysterectomies in the United States are still performed via open laparotomy. The most common reason an open approach is selected by the gynecologic surgeon is concern about uterine size.

As editor of the Master Class columns on gynecologic surgery, I have enlisted Dr. Michael Moen to discuss the technique enabling removal of the larger uterus via a vaginal route.

Dr. Moen directs the division of urogynecology at Advocate Lutheran General Hospital in Park Ridge, Ill. He is also affiliated with the department of ob.gyn. at the University of Illinois at Chicago, and is a cofounder of Illinois Urogynecology Ltd. Dr. Moen is a fellow of both the American College of Obstetricians and Gynecologists and the American College of Surgeons, and is a member of the American Urogynecologic Society, the International Urogynecological Association, the Society of Gynecologic Surgeons, and the American Association of Gynecologic Laparoscopists.

While at the Mayo Clinic in Rochester, Minn., Dr. Moen was the lead author of an article on vaginal hysterectomy in patients with benign uterine enlargement for the Journal of Pelvic Surgery, along with his mentor, Dr. Raymond Lee.

Key Points: Vaginal Morcellation

▸ Ensure uterine mobility.

▸ Control uterine vessels.

▸ Proceed with morcellation of uterus.

Option 1: Wedge Technique

Divide cervix in anteroposterior plane to lower uterine segment.

Excise wedge-shaped portions of uterus.

Option 2: Lash Technique (Intramyometrial Coring)

Make successive circular incisions in myometrium to core it out.

Source: Dr. Miller

Prior to the introduction of laparoscopic assistance, vaginal hysterectomy (VH) was the only minimally invasive option for removing the uterus, and for decades studies have shown that vaginal hysterectomy results in significantly less morbidity than does abdominal hysterectomy. Most recently, investigators who reviewed randomized, controlled trials of hysterectomy for the international Cochrane Collaboration concluded that traditional vaginal hysterectomies should be performed “whenever technically feasible”—even in a world of increasingly popular laparoscopic approaches.

In recent years, technologic advances have resulted in innovative approaches for hysterectomy, including laparoscopically assisted vaginal hysterectomy (LAVH), laparoscopic supracervical hysterectomy (LSH), and total laparoscopic hysterectomy. Despite multiple options for minimally invasive hysterectomy and the evidence suggesting that vaginal hysterectomy should be performed whenever feasible, the majority of hysterectomies in the United States are performed abdominally, and the overall rate of vaginal hysterectomy has held steady.

Comfort level is a major determinant of the type of hysterectomy performed. Many surgeons have not performed sufficient laparoscopic surgeries during residency and do not have the opportunity to receive the appropriate additional training needed to perform laparoscopic techniques requiring advanced skills. Moreover, gynecologic surgeons who have been trained in residency to perform basic vaginal hysterectomy too often dismiss this option because of uterine enlargement or other factors, such as nulliparity, endometriosis, or prior pelvic surgery. In the end, too many patients are denied an attempt at a minimally invasive approach and undergo abdominal hysterectomy.

In many of these cases, a traditional, minimally invasive vaginal approach is achievable. By thoroughly evaluating uterine mobility—ideally, in the operating room—and by more frequently using the relatively simple technique of morcellation to remove the large uterus (which is common among patients needing hysterectomies), we can markedly reduce the rate of abdominal hysterectomy and its ensuing morbidities.

Because it is a relatively straightforward, natural extension of a core procedure for many gynecologists, morcellation can be more quickly and universally applied in practice than are the advanced laparoscopic techniques that many of us strive to learn.

Assessing Uterine Mobility

For successful vaginal hysterectomy with morcellation, the lower uterine segment must be mobile enough to allow control of the uterine arteries and entry into the anterior and posterior cul-de-sacs. These are the essential prerequisites for morcellation; once the cul-de-sacs are entered and the uterine vessels are controlled, we will be able to complete the majority of cases regardless of uterine size.

We should assess uterine mobility in every patient, regardless of the presence or absence of presumptive risk factors such as nulliparity, endometriosis, or pelvic adhesions. In general, mobility is sufficient if we are able to pull the cervix down to the lower third of the vagina.

We can assess the patient's uterine mobility during the office visit to have some assurance of the likelihood of being able to perform vaginal hysterectomy. In general, however, mobility will be notably greater once the patient is under anesthesia, and we really should assess it in the operating room in any case. In a broader sense, performing an examination under anesthesia of uterine mobility, vaginal anatomy, and support to the cervix affords us the opportunity to individualize the hysterectomy and determine the best approach for the patient, rather than pigeonhole the patient into any one particular procedure.

In the patient with uterine enlargement, we should aim to be prepared to perform vaginal hysterectomy with morcellation whenever feasible. If uterine support is normal and vaginal hysterectomy is not technically feasible, laparoscopic assistance should be considered. Although there are no studies directly comparing vaginal hysterectomy and LSH, these two procedures may be the best options for the patient with uterine enlargement. The determining factor between these two approaches should be the presence or absence of uterine mobility, and this should be assessed intraoperatively.

This valuable course of intraoperative decision making begins, of course, with a discussion with the patient about the various options, about the goal of performing an appropriate procedure with the least morbidity, and about her preferences on whether her cervix should stay in or not. In essence, we want to be able to involve the patient beforehand and then tell her that “no matter what, when you're in the recovery room, we will have completed the hysterectomy that is best for you.” Often, we will find that vaginal hysterectomy with morcellation is a viable option when we evaluate the patient under anesthesia.

Performing Morcellation

There are two basic types of morcellation: the wedge technique, and the intramyometrial-coring (also known as the Lash) technique.

In the wedge technique, the cervix is bivalved in the anteroposterior plane to the level of the lower uterine segment. Occasionally, this step alone will result in sufficient mobility to allow delivery of the uterine fundus. Once the cervix is bisected, use a clamp—I prefer a Lahey goiter clamp—to grasp the anterior or posterior uterine wall from endometrium to serosa, and excise a wedge-shaped portion of the uterine wall.

Continue this process until the uterine fundus can be delivered and the remaining pedicles clamped and cut to allow removal of the uterus. Typically, you will encounter individual myomas and can remove these separately.

The Lash technique—or intramyometrial coring—involves a circular incision in the myometrium at the level of the upper cervix. Make successive circumferential incisions, and you will essentially core out the myometrium while the integrity of the endometrial cavity is maintained.

Because the coring technique allows the removal of an intact endometrium, it may be an advantage if you are concerned about unexpected endometrial pathology. With office biopsies and modern imaging techniques, the chance of an unexpected finding of significant pathology should be minimal. Overall, I believe, the wedge technique is technically easier.

In either case, morcellation follows entry into both the anterior and posterior cul-de-sacs and control of the uterine vessels. Generally, I attempt anterior entry first, which allows me to palpate the ureters prior to clamping and cutting the pedicles. Other surgeons advocate entering the posterior cul-de-sac first, because the inability to enter posteriorly is generally considered an indication to abandon the vaginal approach. Regardless of order, both cul-de-sacs must be entered and the uterine vasculare pedicles controlled before proceeding with morcellation.

While at the Mayo Clinic a decade ago, my colleagues and I reviewed the hysterectomies performed over a 2-year period in patients with a uterine weight of 200–600 g. Patients with adnexal masses and malignancy were excluded.

Of 298 patients who were evaluated in the operating room, nearly half (48%) of those with a uterine weight of 200–400 g were deemed to be candidates for vaginal hysterectomy, based on the presence of sufficient uterine mobility. Even in the group with uterine weights of 400–600 g, 11% of patients had sufficient mobility to allow a vaginal approach. This included nulliparous patients and those with previous pelvic surgery and endometriosis.

Vaginal hysterectomy was successful in 97% of these patients, and its complication rate was significantly lower than that of abdominal hysterectomy, regardless of uterine weight. Morcellation, we found, was required in approximately 70%.

The study showed that although uterine size limits its use, the most important factor in deciding to perform vaginal hysterectomy was the presence of uterine mobility and accessibility. It also showed that because some patients with nulliparity, previous pelvic surgery, and endometriosis will still have sufficient mobility, these factors should not be considered as contraindications to the vaginal approach.

Incorporating Laparoscopy

Over the past decade, rates of LAVH have risen significantly, while the overall rate of vaginal hysterectomy has remained stable. This is concerning because, undoubtedly, many of these patients are candidates for traditional vaginal hysterectomy. Numerous studies, including the recent Cochrane Collaboration review, have shown that LAVH does not improve morbidity over traditional vaginal hysterectomy, and is more time consuming and costly.

Ideally, the use of the laparoscope should allow abdominal hysterectomy to be converted to a minimally invasive procedure. As I see it, the laparoscope can be used to address situations that result in uterine immobility, such as nulliparity, adhesions, and endometriosis, thus allowing conversion of these cases to LAVH.

Additionally, we can use laparoscopy to ensure ovarian removal at the time of vaginal hysterectomy, although some would suggest proceeding with traditional vaginal hysterectomy first and only employing laparoscopy if you're having technical difficulty removing the ovaries vaginally. Multiple studies report more than 90% success in removing ovaries at the time of vaginal hysterectomy, suggesting that laparoscopic assistance for ovarian removal should be required in less than 10% of cases.

My own experience with ovarian removal is similar to these studies, so I prefer to attempt vaginal removal first and reserve the use of the laparoscope for the few patients in whom I find it necessary.

Total vs. Supracervical Hysterectomy

The recent introduction of the laparoscopic morcellator allows removal of an enlarged uterus with a laparoscopic approach and has resulted in an increased use of LSH for patients with uterine enlargement.

Although some surgeons counsel patients that keeping their cervix will result in improved pelvic support and sexual function, studies comparing total hysterectomy with supracervical hysterectomy have shown no difference in bladder function and sexual function and support the premise that it's the anatomy of the vagina, and not the presence of the cervix, that is important. (We still need well-designed randomized, controlled trials that compare the morbidities and outcomes of LSH with LAVH and vaginal hysterectomy.)

In patients who already have normal pelvic support, LSH utilizing the laparoscopic morcellator may offer the best option for removal of the enlarged uterus, whereas those patients with uterine mobility are best treated by vaginal hysterectomy with traditional morcellation.

Ideally, we should be in a position to offer both approaches to the patient and should decide which to use based on examination under anesthesia in the operating room. If neither can be achieved, the patient may require abdominal hysterectomy, but at least we will have made an appropriate attempt at a less invasive procedure.

Until we have data pointing us elsewhere, we should embrace the minimally invasive gold standard of vaginal hysterectomy, employing morcellation for the larger uterus more often and turning to laparoscopy when necessary. Hysterectomies are most commonly done in reproductive-age women with fibroids or bleeding, a significant number of whom have enlarged uteri, so our ability to reduce the rate of abdominal hysterectomy—and increase the rate of the less morbid vaginal approach—is significant.

On the left, a wedge is excised from the posterior uterus. On the right, individual myomas are removed as they are encountered during morcellation. Photos courtesy Dr. Michael Moen

Size Doesn't Have to Count

Despite a trend toward minimally invasive gynecologic surgery, nearly 75% of hysterectomies in the United States are still performed via open laparotomy. The most common reason an open approach is selected by the gynecologic surgeon is concern about uterine size.

As editor of the Master Class columns on gynecologic surgery, I have enlisted Dr. Michael Moen to discuss the technique enabling removal of the larger uterus via a vaginal route.

Dr. Moen directs the division of urogynecology at Advocate Lutheran General Hospital in Park Ridge, Ill. He is also affiliated with the department of ob.gyn. at the University of Illinois at Chicago, and is a cofounder of Illinois Urogynecology Ltd. Dr. Moen is a fellow of both the American College of Obstetricians and Gynecologists and the American College of Surgeons, and is a member of the American Urogynecologic Society, the International Urogynecological Association, the Society of Gynecologic Surgeons, and the American Association of Gynecologic Laparoscopists.

While at the Mayo Clinic in Rochester, Minn., Dr. Moen was the lead author of an article on vaginal hysterectomy in patients with benign uterine enlargement for the Journal of Pelvic Surgery, along with his mentor, Dr. Raymond Lee.

Key Points: Vaginal Morcellation

▸ Ensure uterine mobility.

▸ Control uterine vessels.

▸ Proceed with morcellation of uterus.

Option 1: Wedge Technique

Divide cervix in anteroposterior plane to lower uterine segment.

Excise wedge-shaped portions of uterus.

Option 2: Lash Technique (Intramyometrial Coring)

Make successive circular incisions in myometrium to core it out.

Source: Dr. Miller

Prior to the introduction of laparoscopic assistance, vaginal hysterectomy (VH) was the only minimally invasive option for removing the uterus, and for decades studies have shown that vaginal hysterectomy results in significantly less morbidity than does abdominal hysterectomy. Most recently, investigators who reviewed randomized, controlled trials of hysterectomy for the international Cochrane Collaboration concluded that traditional vaginal hysterectomies should be performed “whenever technically feasible”—even in a world of increasingly popular laparoscopic approaches.

In recent years, technologic advances have resulted in innovative approaches for hysterectomy, including laparoscopically assisted vaginal hysterectomy (LAVH), laparoscopic supracervical hysterectomy (LSH), and total laparoscopic hysterectomy. Despite multiple options for minimally invasive hysterectomy and the evidence suggesting that vaginal hysterectomy should be performed whenever feasible, the majority of hysterectomies in the United States are performed abdominally, and the overall rate of vaginal hysterectomy has held steady.

Comfort level is a major determinant of the type of hysterectomy performed. Many surgeons have not performed sufficient laparoscopic surgeries during residency and do not have the opportunity to receive the appropriate additional training needed to perform laparoscopic techniques requiring advanced skills. Moreover, gynecologic surgeons who have been trained in residency to perform basic vaginal hysterectomy too often dismiss this option because of uterine enlargement or other factors, such as nulliparity, endometriosis, or prior pelvic surgery. In the end, too many patients are denied an attempt at a minimally invasive approach and undergo abdominal hysterectomy.

In many of these cases, a traditional, minimally invasive vaginal approach is achievable. By thoroughly evaluating uterine mobility—ideally, in the operating room—and by more frequently using the relatively simple technique of morcellation to remove the large uterus (which is common among patients needing hysterectomies), we can markedly reduce the rate of abdominal hysterectomy and its ensuing morbidities.

Because it is a relatively straightforward, natural extension of a core procedure for many gynecologists, morcellation can be more quickly and universally applied in practice than are the advanced laparoscopic techniques that many of us strive to learn.

Assessing Uterine Mobility

For successful vaginal hysterectomy with morcellation, the lower uterine segment must be mobile enough to allow control of the uterine arteries and entry into the anterior and posterior cul-de-sacs. These are the essential prerequisites for morcellation; once the cul-de-sacs are entered and the uterine vessels are controlled, we will be able to complete the majority of cases regardless of uterine size.

We should assess uterine mobility in every patient, regardless of the presence or absence of presumptive risk factors such as nulliparity, endometriosis, or pelvic adhesions. In general, mobility is sufficient if we are able to pull the cervix down to the lower third of the vagina.

We can assess the patient's uterine mobility during the office visit to have some assurance of the likelihood of being able to perform vaginal hysterectomy. In general, however, mobility will be notably greater once the patient is under anesthesia, and we really should assess it in the operating room in any case. In a broader sense, performing an examination under anesthesia of uterine mobility, vaginal anatomy, and support to the cervix affords us the opportunity to individualize the hysterectomy and determine the best approach for the patient, rather than pigeonhole the patient into any one particular procedure.

In the patient with uterine enlargement, we should aim to be prepared to perform vaginal hysterectomy with morcellation whenever feasible. If uterine support is normal and vaginal hysterectomy is not technically feasible, laparoscopic assistance should be considered. Although there are no studies directly comparing vaginal hysterectomy and LSH, these two procedures may be the best options for the patient with uterine enlargement. The determining factor between these two approaches should be the presence or absence of uterine mobility, and this should be assessed intraoperatively.

This valuable course of intraoperative decision making begins, of course, with a discussion with the patient about the various options, about the goal of performing an appropriate procedure with the least morbidity, and about her preferences on whether her cervix should stay in or not. In essence, we want to be able to involve the patient beforehand and then tell her that “no matter what, when you're in the recovery room, we will have completed the hysterectomy that is best for you.” Often, we will find that vaginal hysterectomy with morcellation is a viable option when we evaluate the patient under anesthesia.

Performing Morcellation

There are two basic types of morcellation: the wedge technique, and the intramyometrial-coring (also known as the Lash) technique.

In the wedge technique, the cervix is bivalved in the anteroposterior plane to the level of the lower uterine segment. Occasionally, this step alone will result in sufficient mobility to allow delivery of the uterine fundus. Once the cervix is bisected, use a clamp—I prefer a Lahey goiter clamp—to grasp the anterior or posterior uterine wall from endometrium to serosa, and excise a wedge-shaped portion of the uterine wall.

Continue this process until the uterine fundus can be delivered and the remaining pedicles clamped and cut to allow removal of the uterus. Typically, you will encounter individual myomas and can remove these separately.

The Lash technique—or intramyometrial coring—involves a circular incision in the myometrium at the level of the upper cervix. Make successive circumferential incisions, and you will essentially core out the myometrium while the integrity of the endometrial cavity is maintained.

Because the coring technique allows the removal of an intact endometrium, it may be an advantage if you are concerned about unexpected endometrial pathology. With office biopsies and modern imaging techniques, the chance of an unexpected finding of significant pathology should be minimal. Overall, I believe, the wedge technique is technically easier.

In either case, morcellation follows entry into both the anterior and posterior cul-de-sacs and control of the uterine vessels. Generally, I attempt anterior entry first, which allows me to palpate the ureters prior to clamping and cutting the pedicles. Other surgeons advocate entering the posterior cul-de-sac first, because the inability to enter posteriorly is generally considered an indication to abandon the vaginal approach. Regardless of order, both cul-de-sacs must be entered and the uterine vasculare pedicles controlled before proceeding with morcellation.

While at the Mayo Clinic a decade ago, my colleagues and I reviewed the hysterectomies performed over a 2-year period in patients with a uterine weight of 200–600 g. Patients with adnexal masses and malignancy were excluded.

Of 298 patients who were evaluated in the operating room, nearly half (48%) of those with a uterine weight of 200–400 g were deemed to be candidates for vaginal hysterectomy, based on the presence of sufficient uterine mobility. Even in the group with uterine weights of 400–600 g, 11% of patients had sufficient mobility to allow a vaginal approach. This included nulliparous patients and those with previous pelvic surgery and endometriosis.

Vaginal hysterectomy was successful in 97% of these patients, and its complication rate was significantly lower than that of abdominal hysterectomy, regardless of uterine weight. Morcellation, we found, was required in approximately 70%.

The study showed that although uterine size limits its use, the most important factor in deciding to perform vaginal hysterectomy was the presence of uterine mobility and accessibility. It also showed that because some patients with nulliparity, previous pelvic surgery, and endometriosis will still have sufficient mobility, these factors should not be considered as contraindications to the vaginal approach.

Incorporating Laparoscopy

Over the past decade, rates of LAVH have risen significantly, while the overall rate of vaginal hysterectomy has remained stable. This is concerning because, undoubtedly, many of these patients are candidates for traditional vaginal hysterectomy. Numerous studies, including the recent Cochrane Collaboration review, have shown that LAVH does not improve morbidity over traditional vaginal hysterectomy, and is more time consuming and costly.

Ideally, the use of the laparoscope should allow abdominal hysterectomy to be converted to a minimally invasive procedure. As I see it, the laparoscope can be used to address situations that result in uterine immobility, such as nulliparity, adhesions, and endometriosis, thus allowing conversion of these cases to LAVH.

Additionally, we can use laparoscopy to ensure ovarian removal at the time of vaginal hysterectomy, although some would suggest proceeding with traditional vaginal hysterectomy first and only employing laparoscopy if you're having technical difficulty removing the ovaries vaginally. Multiple studies report more than 90% success in removing ovaries at the time of vaginal hysterectomy, suggesting that laparoscopic assistance for ovarian removal should be required in less than 10% of cases.

My own experience with ovarian removal is similar to these studies, so I prefer to attempt vaginal removal first and reserve the use of the laparoscope for the few patients in whom I find it necessary.

Total vs. Supracervical Hysterectomy

The recent introduction of the laparoscopic morcellator allows removal of an enlarged uterus with a laparoscopic approach and has resulted in an increased use of LSH for patients with uterine enlargement.

Although some surgeons counsel patients that keeping their cervix will result in improved pelvic support and sexual function, studies comparing total hysterectomy with supracervical hysterectomy have shown no difference in bladder function and sexual function and support the premise that it's the anatomy of the vagina, and not the presence of the cervix, that is important. (We still need well-designed randomized, controlled trials that compare the morbidities and outcomes of LSH with LAVH and vaginal hysterectomy.)

In patients who already have normal pelvic support, LSH utilizing the laparoscopic morcellator may offer the best option for removal of the enlarged uterus, whereas those patients with uterine mobility are best treated by vaginal hysterectomy with traditional morcellation.

Ideally, we should be in a position to offer both approaches to the patient and should decide which to use based on examination under anesthesia in the operating room. If neither can be achieved, the patient may require abdominal hysterectomy, but at least we will have made an appropriate attempt at a less invasive procedure.

Until we have data pointing us elsewhere, we should embrace the minimally invasive gold standard of vaginal hysterectomy, employing morcellation for the larger uterus more often and turning to laparoscopy when necessary. Hysterectomies are most commonly done in reproductive-age women with fibroids or bleeding, a significant number of whom have enlarged uteri, so our ability to reduce the rate of abdominal hysterectomy—and increase the rate of the less morbid vaginal approach—is significant.

On the left, a wedge is excised from the posterior uterus. On the right, individual myomas are removed as they are encountered during morcellation. Photos courtesy Dr. Michael Moen

Size Doesn't Have to Count

Despite a trend toward minimally invasive gynecologic surgery, nearly 75% of hysterectomies in the United States are still performed via open laparotomy. The most common reason an open approach is selected by the gynecologic surgeon is concern about uterine size.

As editor of the Master Class columns on gynecologic surgery, I have enlisted Dr. Michael Moen to discuss the technique enabling removal of the larger uterus via a vaginal route.

Dr. Moen directs the division of urogynecology at Advocate Lutheran General Hospital in Park Ridge, Ill. He is also affiliated with the department of ob.gyn. at the University of Illinois at Chicago, and is a cofounder of Illinois Urogynecology Ltd. Dr. Moen is a fellow of both the American College of Obstetricians and Gynecologists and the American College of Surgeons, and is a member of the American Urogynecologic Society, the International Urogynecological Association, the Society of Gynecologic Surgeons, and the American Association of Gynecologic Laparoscopists.

While at the Mayo Clinic in Rochester, Minn., Dr. Moen was the lead author of an article on vaginal hysterectomy in patients with benign uterine enlargement for the Journal of Pelvic Surgery, along with his mentor, Dr. Raymond Lee.

Key Points: Vaginal Morcellation

▸ Ensure uterine mobility.

▸ Control uterine vessels.

▸ Proceed with morcellation of uterus.

Option 1: Wedge Technique

Divide cervix in anteroposterior plane to lower uterine segment.

Excise wedge-shaped portions of uterus.

Option 2: Lash Technique (Intramyometrial Coring)

Make successive circular incisions in myometrium to core it out.

Source: Dr. Miller

The most common complication of assisted reproductive technologies is multiple gestation, particularly triplet and higher-order pregnancy. As we all know, multiple gestation leads to an increased risk of complications in both the fetuses and the mother.

Ovulation induction results in a 20% increase in multiples, the majority of which are twins. In vitro fertilization (IVF) results in a 40% increase in multiples; 32% of these are twins. Unfortunately, we're not making progress in decreasing these rates. Knowing that most patients look at two things—pregnancy rates and cost—when they choose an infertility clinic, many competitive clinics are implanting more than the recommended number of embryos in order to achieve the highest pregnancy rates.

At any opportunity along the spectrum of general to specialized ob.gyn. care, we need to educate and encourage patients to look beyond the pregnancy rates and instead focus on the numbers of embryos transferred and the implantation rates. If we are successful, we could probably make some progress in decreasing the multiple pregnancies associated with assisted reproductive technology (ART). At a basic level, we can ensure that infertility evaluations and treatments are timely, thorough, individualized, and well explained to our patients. In doing so, we will provide good care, and perhaps we can keep the patients' feelings of desperation, which are valid and understandable, somewhat in check.

Infertility Diagnosis, Work-Up

A diagnosis of infertility is usually made when couples have been trying for more than 1 year to become pregnant. Fecundity drops after the age of 27 years, more significantly after the age of 35 years, and dramatically after 40 years. I recommend that, for women older than age 35, we not wait until a year is up, but rather begin a basic infertility work-up after 6 months. These women deserve a more aggressive approach.

After 6 months in a patient who is older than 35, or after 1 year in younger patients, we should provide the basics: blood testing to check ovarian reserve, a hysterosalpingogram to ensure that the uterus is normal and that tubes are patent, and a semen analysis. It is important to use an infertility laboratory for the semen analysis. Regular laboratories usually do not check for Kruger morphology, which is critical.

Examinations should include a check on thyroid function. Approximately 2% of women in the reproductive age group have hypothyroidism or subclinical hypothyroidism, which can affect fertility but is treatable. It's also important to know if a woman has had endometriosis or previous pelvic surgeries. Diagnostic operative laparoscopies can be performed by general ob.gyns. to rule out or treat endometriosis if they feel comfortable doing the procedure.

When you take the patient's history, certain questions—such as “When did your mother enter menopause?”—are critical because they may lead to an early diagnosis and, appropriately, to a more aggressive treatment approach. Perimenopause—during which time ovarian reserve is compromised—usually begins 5-10 years earlier than menopause. If I know that a patient's mother went into menopause at age 40, I will work through infertility treatment more quickly, as I would with older patients. Testing for ovarian reserve in women younger than 35 is too often dismissed. It shouldn't be.

It's well known that smoking and exposure to secondhand smoke decrease fecundity. They increase rates of abnormal ovarian reserve, oocyte atresia, and miscarriage. In IVF patients, they increase IVF failure and the number of IVF cycles needed to conceive. One prospective study showed that for each year of active smoking, there is a 9% decrease in the success of ART. Smoking also affects the sperm cell. Even if sperm look normal, smoking has been shown to lead to damage of the genetic material, causing abnormalities in sperm count, motility, morphology, and function.

The good news is that many of the effects of smoking are reversible. The duration of smoking may affect the degree of reversibility, but certainly we have the opportunity to improve fecundity and the success of fertility treatment if we identify smokers and work hard to help them with cessation.

Starting Treatment

If all of these basic work-ups are normal and the patient is younger than 32 years of age we can proceed with a trial of Clomid (clomiphene citrate). I recommend treatment with Clomid for 3-4 months, because most patients who will achieve pregnancy will do so within the first three to four cycles. After several months, the chances of a pregnancy are significantly decreased, and other treatment options need to be considered. Treatment with Clomid alone for longer than 6 months really isn't fair to the patient, and neither is the use of Clomid in patients older than age 37.

Keep in mind that even in small doses, Clomid can have a negative effect on the endometrium. I recommend ultrasonography to check for normal follicular development and to check the lining. If the lining is thin, the implantation rate will be low.

You may decide, after 2 months of Clomid treatment, to try another two to three cycles along with intrauterine insemination. You may also decide that ovulation induction or IVF is more appropriate.

If you are a general ob.gyn. who is performing superovulation induction with hormones, my advice is to judge your comfort level with hormonal stimulation, and to establish and maintain a good relationship with an infertility clinic.

Controlling Multiples

With both ovulation induction/enhancement and IVF, there are ways to control the rate of multiple gestations. Your degree of control is less with ovarian stimulation and intrauterine insemination, but you do have some control and it is important to proceed cautiously. If you see that a patient has more than two or three mature follicles and that her estradiol is elevated above the appropriate level at day 3, it's often best to cancel that cycle. The patient may prefer to proceed knowing the risks, but at least she is being counseled.

The guidelines of the Society for Assisted Reproductive Technology and the American Society for Reproductive Medicine are age based, and are meant to help determine the appropriate number of cleavage-stage embryos to transfer.

According to the guidelines, no more than two good-quality embryos should be transferred in patients under age 35. If the embryos are not necessarily of good quality as judged by morphologic criteria, I believe a third embryo can be considered; but in no case should more than three be transferred.

The guidelines also say that for patients with a favorable prognosis, such as those with good-quality embryos or previous successes with IVF, consideration should be given to transferring only a single embryo. I do believe that if embryos are of excellent quality and the patient is young, and especially if the embryos can be cultured to the blastocyst stage and then transferred, it is worth pushing for a single embryo transfer, which dramatically decreases the risk of multiple births.

For patients aged 35-37, the guidelines are that no more than two good-quality embryos—and no more than three in any other case—should be transferred. Patients who are 38-40 years old should receive no more than three good-quality embryos, and no more than four in any other case.

For patients older than age 40, the guidelines state that no more than five embryos should be transferred. And I would recommend that no more than four be transferred in many cases. All these numbers should be decreased, of course, when embryos are transferred as blastocysts.

European specialists routinely transfer no more than two embryos. They usually transfer embryos at the more advanced blastocyst stage, and because they work in systems of socialized medicine, it doesn't matter whether the patient gets pregnant after just one cycle or more. In the United States, a cycle costs $10,000-$15,000, and patients want to get pregnant the first time.

I encourage my patients who have come for ART consultations to visit the neonatal ICU. The visits give them some perspective on the complications associated with higher-order births. I will often raise the issue of selective fetal reduction—posing it as theoretical—when I see a patient for an IVF consultation. Asking patients how they would feel about this possibility prompts them to think and be prepared for it. It also impresses upon patients that the risk of multiples is real if too many embryos are implanted. Selective fetal reduction is an option, but it has its own complications and risks. We always prefer not to reach that point.

One of the most important things we can do to reduce the rate of multiple gestations is to ensure that we work with an experienced laboratory staffed with excellent embryologists and an excellent director. Certain elements of the visual inspection of embryos are standard and reliably consistent, whereas other elements are more subjective. To some extent, each laboratory director has his or her own way of grading embryos, so our attentiveness to outcomes is critical.

Preimplantation genetic diagnosis (PGD) is typically not performed unless a patient requests it. It is recommended for patients who are older or who have certain chromosomal or genetic abnormalities. It is also recommended in some patients with repeat pregnancy wastage. Single cells can be sent out on day 3 of embryo culture and results can be obtained within 24 hours, in time for embryo transfer at day 5.

The other step we can routinely take is to encourage our patients to thoroughly examine the Society for Assisted Reproductive Technology's clinic-specific IVF data. Asking patients to step back and look at more than pregnancy rates could be the biggest key to reducing multiple gestations with IVF.

Multiples and Mortality

Infant mortality is a problem of major concern to the industrialized world, and it continues to be an important marker for assessing the health and welfare of countries. Despite the fact that the United States spends 15% of its gross national product on health care, it ranks 21st in the world in its infant mortality rate, below countries that spend much less.

The causes of our high infant mortality rate are complex and multifaceted, and we will not attempt in Master Class to address them all. We will, however, address one component: the rising rate of multiple gestations.

Between 1996 and 2002, multiple births in the United States increased more than 22%, from 2.7% to 3.3% of all live births. In 2002, the preterm birth rate among multiple deliveries was approximately 60%, six times higher than the preterm birth rate among singleton births, according to the National Center for Health Statistics. In its preliminary report on births for 2004, the NCHS said that increases in multiple births “have strongly influenced recent upswings” in preterm and low-birth-weight births.

Assisted reproduction plays a role. There is evidence that the percentage of higher-order pregnancies resulting from assisted reproductive technology has been decreasing, but multiple pregnancies with ART remain a problem.

One has to ask whether, with greater care and improved protocols in assisted reproduction, we wouldn't be able to address the continuing effect that infertility treatment has on the rate of multiple pregnancies.

It is a subject that has caught national attention and has been addressed in many quarters. The Society for Assisted Reproductive Technology, an affiliate of the American Society for Reproductive Medicine has examined the issue and made recommendations for improved practice (see sidebar).

My guest professor this month is Dr. Aida Shanti, who is the director of the division of reproductive endocrinology and infertility at the University of Arkansas, Little Rock. She will address these contemporary recommendations and explore how such guidance can potentially have a real impact.

Age-Based Embryo Transfer Guidelines

▸ In patients under the age of 35, no more than two embryos should be transferred in the absence of extraor-dinary circumstances. For patients with the most favorable prognosis, consideration should be given to transferring only a single embryo. Patients having the most favorable prognosis include those who are un-dergoing their first cycle of IVF, have good-quality embryos as judged by morphologic criteria, and have ex-cess of embryos of sufficient quality to warrant cryopreservation. Patients who have had previous success with IVF should also be considered in the most favorable prognostic category.

▸ For patients between 35 and 37 years of age having a more favorable prognosis, no more than two em-bryos should be transferred. All oth-ers in this age group should have no more than three embryos transferred.

▸ For patients between 38 and 40 years of age, no more than four em-bryos should be transferred. For pa-tients in this age group having a more favorable prognosis, considera-tion should be given to transfer of no more than three embryos.

▸ For most patients greater than 40 years of age, no more than five em-bryos should be transferred.

▸ For patients with two or more pre-vious failed IVF cycles and those hav-ing a less favorable prognosis, addi-tional embryos may be transferred according to individual circumstances after appropriate consultation.

▸ In donor egg cycles, the donor's age should determine the appropriate number of embryos to transfer.

Since all oocytes may not fertilize when GIFT is performed, one more oocyte than embryo may be trans-ferred for each prognostic category.

Source: Fertil. Steril. 2004;82:773-4.

The most common complication of assisted reproductive technologies is multiple gestation, particularly triplet and higher-order pregnancy. As we all know, multiple gestation leads to an increased risk of complications in both the fetuses and the mother.

Ovulation induction results in a 20% increase in multiples, the majority of which are twins. In vitro fertilization (IVF) results in a 40% increase in multiples; 32% of these are twins. Unfortunately, we're not making progress in decreasing these rates. Knowing that most patients look at two things—pregnancy rates and cost—when they choose an infertility clinic, many competitive clinics are implanting more than the recommended number of embryos in order to achieve the highest pregnancy rates.

At any opportunity along the spectrum of general to specialized ob.gyn. care, we need to educate and encourage patients to look beyond the pregnancy rates and instead focus on the numbers of embryos transferred and the implantation rates. If we are successful, we could probably make some progress in decreasing the multiple pregnancies associated with assisted reproductive technology (ART). At a basic level, we can ensure that infertility evaluations and treatments are timely, thorough, individualized, and well explained to our patients. In doing so, we will provide good care, and perhaps we can keep the patients' feelings of desperation, which are valid and understandable, somewhat in check.

Infertility Diagnosis, Work-Up

A diagnosis of infertility is usually made when couples have been trying for more than 1 year to become pregnant. Fecundity drops after the age of 27 years, more significantly after the age of 35 years, and dramatically after 40 years. I recommend that, for women older than age 35, we not wait until a year is up, but rather begin a basic infertility work-up after 6 months. These women deserve a more aggressive approach.

After 6 months in a patient who is older than 35, or after 1 year in younger patients, we should provide the basics: blood testing to check ovarian reserve, a hysterosalpingogram to ensure that the uterus is normal and that tubes are patent, and a semen analysis. It is important to use an infertility laboratory for the semen analysis. Regular laboratories usually do not check for Kruger morphology, which is critical.

Examinations should include a check on thyroid function. Approximately 2% of women in the reproductive age group have hypothyroidism or subclinical hypothyroidism, which can affect fertility but is treatable. It's also important to know if a woman has had endometriosis or previous pelvic surgeries. Diagnostic operative laparoscopies can be performed by general ob.gyns. to rule out or treat endometriosis if they feel comfortable doing the procedure.

When you take the patient's history, certain questions—such as “When did your mother enter menopause?”—are critical because they may lead to an early diagnosis and, appropriately, to a more aggressive treatment approach. Perimenopause—during which time ovarian reserve is compromised—usually begins 5-10 years earlier than menopause. If I know that a patient's mother went into menopause at age 40, I will work through infertility treatment more quickly, as I would with older patients. Testing for ovarian reserve in women younger than 35 is too often dismissed. It shouldn't be.

It's well known that smoking and exposure to secondhand smoke decrease fecundity. They increase rates of abnormal ovarian reserve, oocyte atresia, and miscarriage. In IVF patients, they increase IVF failure and the number of IVF cycles needed to conceive. One prospective study showed that for each year of active smoking, there is a 9% decrease in the success of ART. Smoking also affects the sperm cell. Even if sperm look normal, smoking has been shown to lead to damage of the genetic material, causing abnormalities in sperm count, motility, morphology, and function.

The good news is that many of the effects of smoking are reversible. The duration of smoking may affect the degree of reversibility, but certainly we have the opportunity to improve fecundity and the success of fertility treatment if we identify smokers and work hard to help them with cessation.

Starting Treatment

If all of these basic work-ups are normal and the patient is younger than 32 years of age we can proceed with a trial of Clomid (clomiphene citrate). I recommend treatment with Clomid for 3-4 months, because most patients who will achieve pregnancy will do so within the first three to four cycles. After several months, the chances of a pregnancy are significantly decreased, and other treatment options need to be considered. Treatment with Clomid alone for longer than 6 months really isn't fair to the patient, and neither is the use of Clomid in patients older than age 37.

Keep in mind that even in small doses, Clomid can have a negative effect on the endometrium. I recommend ultrasonography to check for normal follicular development and to check the lining. If the lining is thin, the implantation rate will be low.

You may decide, after 2 months of Clomid treatment, to try another two to three cycles along with intrauterine insemination. You may also decide that ovulation induction or IVF is more appropriate.

If you are a general ob.gyn. who is performing superovulation induction with hormones, my advice is to judge your comfort level with hormonal stimulation, and to establish and maintain a good relationship with an infertility clinic.

Controlling Multiples

With both ovulation induction/enhancement and IVF, there are ways to control the rate of multiple gestations. Your degree of control is less with ovarian stimulation and intrauterine insemination, but you do have some control and it is important to proceed cautiously. If you see that a patient has more than two or three mature follicles and that her estradiol is elevated above the appropriate level at day 3, it's often best to cancel that cycle. The patient may prefer to proceed knowing the risks, but at least she is being counseled.

The guidelines of the Society for Assisted Reproductive Technology and the American Society for Reproductive Medicine are age based, and are meant to help determine the appropriate number of cleavage-stage embryos to transfer.

According to the guidelines, no more than two good-quality embryos should be transferred in patients under age 35. If the embryos are not necessarily of good quality as judged by morphologic criteria, I believe a third embryo can be considered; but in no case should more than three be transferred.

The guidelines also say that for patients with a favorable prognosis, such as those with good-quality embryos or previous successes with IVF, consideration should be given to transferring only a single embryo. I do believe that if embryos are of excellent quality and the patient is young, and especially if the embryos can be cultured to the blastocyst stage and then transferred, it is worth pushing for a single embryo transfer, which dramatically decreases the risk of multiple births.

For patients aged 35-37, the guidelines are that no more than two good-quality embryos—and no more than three in any other case—should be transferred. Patients who are 38-40 years old should receive no more than three good-quality embryos, and no more than four in any other case.

For patients older than age 40, the guidelines state that no more than five embryos should be transferred. And I would recommend that no more than four be transferred in many cases. All these numbers should be decreased, of course, when embryos are transferred as blastocysts.

European specialists routinely transfer no more than two embryos. They usually transfer embryos at the more advanced blastocyst stage, and because they work in systems of socialized medicine, it doesn't matter whether the patient gets pregnant after just one cycle or more. In the United States, a cycle costs $10,000-$15,000, and patients want to get pregnant the first time.

I encourage my patients who have come for ART consultations to visit the neonatal ICU. The visits give them some perspective on the complications associated with higher-order births. I will often raise the issue of selective fetal reduction—posing it as theoretical—when I see a patient for an IVF consultation. Asking patients how they would feel about this possibility prompts them to think and be prepared for it. It also impresses upon patients that the risk of multiples is real if too many embryos are implanted. Selective fetal reduction is an option, but it has its own complications and risks. We always prefer not to reach that point.

One of the most important things we can do to reduce the rate of multiple gestations is to ensure that we work with an experienced laboratory staffed with excellent embryologists and an excellent director. Certain elements of the visual inspection of embryos are standard and reliably consistent, whereas other elements are more subjective. To some extent, each laboratory director has his or her own way of grading embryos, so our attentiveness to outcomes is critical.

Preimplantation genetic diagnosis (PGD) is typically not performed unless a patient requests it. It is recommended for patients who are older or who have certain chromosomal or genetic abnormalities. It is also recommended in some patients with repeat pregnancy wastage. Single cells can be sent out on day 3 of embryo culture and results can be obtained within 24 hours, in time for embryo transfer at day 5.

The other step we can routinely take is to encourage our patients to thoroughly examine the Society for Assisted Reproductive Technology's clinic-specific IVF data. Asking patients to step back and look at more than pregnancy rates could be the biggest key to reducing multiple gestations with IVF.

Multiples and Mortality

Infant mortality is a problem of major concern to the industrialized world, and it continues to be an important marker for assessing the health and welfare of countries. Despite the fact that the United States spends 15% of its gross national product on health care, it ranks 21st in the world in its infant mortality rate, below countries that spend much less.

The causes of our high infant mortality rate are complex and multifaceted, and we will not attempt in Master Class to address them all. We will, however, address one component: the rising rate of multiple gestations.

Between 1996 and 2002, multiple births in the United States increased more than 22%, from 2.7% to 3.3% of all live births. In 2002, the preterm birth rate among multiple deliveries was approximately 60%, six times higher than the preterm birth rate among singleton births, according to the National Center for Health Statistics. In its preliminary report on births for 2004, the NCHS said that increases in multiple births “have strongly influenced recent upswings” in preterm and low-birth-weight births.

Assisted reproduction plays a role. There is evidence that the percentage of higher-order pregnancies resulting from assisted reproductive technology has been decreasing, but multiple pregnancies with ART remain a problem.

One has to ask whether, with greater care and improved protocols in assisted reproduction, we wouldn't be able to address the continuing effect that infertility treatment has on the rate of multiple pregnancies.

It is a subject that has caught national attention and has been addressed in many quarters. The Society for Assisted Reproductive Technology, an affiliate of the American Society for Reproductive Medicine has examined the issue and made recommendations for improved practice (see sidebar).

My guest professor this month is Dr. Aida Shanti, who is the director of the division of reproductive endocrinology and infertility at the University of Arkansas, Little Rock. She will address these contemporary recommendations and explore how such guidance can potentially have a real impact.

Age-Based Embryo Transfer Guidelines

▸ In patients under the age of 35, no more than two embryos should be transferred in the absence of extraor-dinary circumstances. For patients with the most favorable prognosis, consideration should be given to transferring only a single embryo. Patients having the most favorable prognosis include those who are un-dergoing their first cycle of IVF, have good-quality embryos as judged by morphologic criteria, and have ex-cess of embryos of sufficient quality to warrant cryopreservation. Patients who have had previous success with IVF should also be considered in the most favorable prognostic category.

▸ For patients between 35 and 37 years of age having a more favorable prognosis, no more than two em-bryos should be transferred. All oth-ers in this age group should have no more than three embryos transferred.

▸ For patients between 38 and 40 years of age, no more than four em-bryos should be transferred. For pa-tients in this age group having a more favorable prognosis, considera-tion should be given to transfer of no more than three embryos.

▸ For most patients greater than 40 years of age, no more than five em-bryos should be transferred.

▸ For patients with two or more pre-vious failed IVF cycles and those hav-ing a less favorable prognosis, addi-tional embryos may be transferred according to individual circumstances after appropriate consultation.

▸ In donor egg cycles, the donor's age should determine the appropriate number of embryos to transfer.

Since all oocytes may not fertilize when GIFT is performed, one more oocyte than embryo may be trans-ferred for each prognostic category.

Source: Fertil. Steril. 2004;82:773-4.

The most common complication of assisted reproductive technologies is multiple gestation, particularly triplet and higher-order pregnancy. As we all know, multiple gestation leads to an increased risk of complications in both the fetuses and the mother.

Ovulation induction results in a 20% increase in multiples, the majority of which are twins. In vitro fertilization (IVF) results in a 40% increase in multiples; 32% of these are twins. Unfortunately, we're not making progress in decreasing these rates. Knowing that most patients look at two things—pregnancy rates and cost—when they choose an infertility clinic, many competitive clinics are implanting more than the recommended number of embryos in order to achieve the highest pregnancy rates.

At any opportunity along the spectrum of general to specialized ob.gyn. care, we need to educate and encourage patients to look beyond the pregnancy rates and instead focus on the numbers of embryos transferred and the implantation rates. If we are successful, we could probably make some progress in decreasing the multiple pregnancies associated with assisted reproductive technology (ART). At a basic level, we can ensure that infertility evaluations and treatments are timely, thorough, individualized, and well explained to our patients. In doing so, we will provide good care, and perhaps we can keep the patients' feelings of desperation, which are valid and understandable, somewhat in check.

Infertility Diagnosis, Work-Up

A diagnosis of infertility is usually made when couples have been trying for more than 1 year to become pregnant. Fecundity drops after the age of 27 years, more significantly after the age of 35 years, and dramatically after 40 years. I recommend that, for women older than age 35, we not wait until a year is up, but rather begin a basic infertility work-up after 6 months. These women deserve a more aggressive approach.

After 6 months in a patient who is older than 35, or after 1 year in younger patients, we should provide the basics: blood testing to check ovarian reserve, a hysterosalpingogram to ensure that the uterus is normal and that tubes are patent, and a semen analysis. It is important to use an infertility laboratory for the semen analysis. Regular laboratories usually do not check for Kruger morphology, which is critical.

Examinations should include a check on thyroid function. Approximately 2% of women in the reproductive age group have hypothyroidism or subclinical hypothyroidism, which can affect fertility but is treatable. It's also important to know if a woman has had endometriosis or previous pelvic surgeries. Diagnostic operative laparoscopies can be performed by general ob.gyns. to rule out or treat endometriosis if they feel comfortable doing the procedure.

When you take the patient's history, certain questions—such as “When did your mother enter menopause?”—are critical because they may lead to an early diagnosis and, appropriately, to a more aggressive treatment approach. Perimenopause—during which time ovarian reserve is compromised—usually begins 5-10 years earlier than menopause. If I know that a patient's mother went into menopause at age 40, I will work through infertility treatment more quickly, as I would with older patients. Testing for ovarian reserve in women younger than 35 is too often dismissed. It shouldn't be.

It's well known that smoking and exposure to secondhand smoke decrease fecundity. They increase rates of abnormal ovarian reserve, oocyte atresia, and miscarriage. In IVF patients, they increase IVF failure and the number of IVF cycles needed to conceive. One prospective study showed that for each year of active smoking, there is a 9% decrease in the success of ART. Smoking also affects the sperm cell. Even if sperm look normal, smoking has been shown to lead to damage of the genetic material, causing abnormalities in sperm count, motility, morphology, and function.

The good news is that many of the effects of smoking are reversible. The duration of smoking may affect the degree of reversibility, but certainly we have the opportunity to improve fecundity and the success of fertility treatment if we identify smokers and work hard to help them with cessation.

Starting Treatment

If all of these basic work-ups are normal and the patient is younger than 32 years of age we can proceed with a trial of Clomid (clomiphene citrate). I recommend treatment with Clomid for 3-4 months, because most patients who will achieve pregnancy will do so within the first three to four cycles. After several months, the chances of a pregnancy are significantly decreased, and other treatment options need to be considered. Treatment with Clomid alone for longer than 6 months really isn't fair to the patient, and neither is the use of Clomid in patients older than age 37.

Keep in mind that even in small doses, Clomid can have a negative effect on the endometrium. I recommend ultrasonography to check for normal follicular development and to check the lining. If the lining is thin, the implantation rate will be low.

You may decide, after 2 months of Clomid treatment, to try another two to three cycles along with intrauterine insemination. You may also decide that ovulation induction or IVF is more appropriate.

If you are a general ob.gyn. who is performing superovulation induction with hormones, my advice is to judge your comfort level with hormonal stimulation, and to establish and maintain a good relationship with an infertility clinic.

Controlling Multiples

With both ovulation induction/enhancement and IVF, there are ways to control the rate of multiple gestations. Your degree of control is less with ovarian stimulation and intrauterine insemination, but you do have some control and it is important to proceed cautiously. If you see that a patient has more than two or three mature follicles and that her estradiol is elevated above the appropriate level at day 3, it's often best to cancel that cycle. The patient may prefer to proceed knowing the risks, but at least she is being counseled.

The guidelines of the Society for Assisted Reproductive Technology and the American Society for Reproductive Medicine are age based, and are meant to help determine the appropriate number of cleavage-stage embryos to transfer.

According to the guidelines, no more than two good-quality embryos should be transferred in patients under age 35. If the embryos are not necessarily of good quality as judged by morphologic criteria, I believe a third embryo can be considered; but in no case should more than three be transferred.

The guidelines also say that for patients with a favorable prognosis, such as those with good-quality embryos or previous successes with IVF, consideration should be given to transferring only a single embryo. I do believe that if embryos are of excellent quality and the patient is young, and especially if the embryos can be cultured to the blastocyst stage and then transferred, it is worth pushing for a single embryo transfer, which dramatically decreases the risk of multiple births.

For patients aged 35-37, the guidelines are that no more than two good-quality embryos—and no more than three in any other case—should be transferred. Patients who are 38-40 years old should receive no more than three good-quality embryos, and no more than four in any other case.

For patients older than age 40, the guidelines state that no more than five embryos should be transferred. And I would recommend that no more than four be transferred in many cases. All these numbers should be decreased, of course, when embryos are transferred as blastocysts.

European specialists routinely transfer no more than two embryos. They usually transfer embryos at the more advanced blastocyst stage, and because they work in systems of socialized medicine, it doesn't matter whether the patient gets pregnant after just one cycle or more. In the United States, a cycle costs $10,000-$15,000, and patients want to get pregnant the first time.

I encourage my patients who have come for ART consultations to visit the neonatal ICU. The visits give them some perspective on the complications associated with higher-order births. I will often raise the issue of selective fetal reduction—posing it as theoretical—when I see a patient for an IVF consultation. Asking patients how they would feel about this possibility prompts them to think and be prepared for it. It also impresses upon patients that the risk of multiples is real if too many embryos are implanted. Selective fetal reduction is an option, but it has its own complications and risks. We always prefer not to reach that point.

One of the most important things we can do to reduce the rate of multiple gestations is to ensure that we work with an experienced laboratory staffed with excellent embryologists and an excellent director. Certain elements of the visual inspection of embryos are standard and reliably consistent, whereas other elements are more subjective. To some extent, each laboratory director has his or her own way of grading embryos, so our attentiveness to outcomes is critical.

Preimplantation genetic diagnosis (PGD) is typically not performed unless a patient requests it. It is recommended for patients who are older or who have certain chromosomal or genetic abnormalities. It is also recommended in some patients with repeat pregnancy wastage. Single cells can be sent out on day 3 of embryo culture and results can be obtained within 24 hours, in time for embryo transfer at day 5.

The other step we can routinely take is to encourage our patients to thoroughly examine the Society for Assisted Reproductive Technology's clinic-specific IVF data. Asking patients to step back and look at more than pregnancy rates could be the biggest key to reducing multiple gestations with IVF.

Multiples and Mortality

Infant mortality is a problem of major concern to the industrialized world, and it continues to be an important marker for assessing the health and welfare of countries. Despite the fact that the United States spends 15% of its gross national product on health care, it ranks 21st in the world in its infant mortality rate, below countries that spend much less.

The causes of our high infant mortality rate are complex and multifaceted, and we will not attempt in Master Class to address them all. We will, however, address one component: the rising rate of multiple gestations.

Between 1996 and 2002, multiple births in the United States increased more than 22%, from 2.7% to 3.3% of all live births. In 2002, the preterm birth rate among multiple deliveries was approximately 60%, six times higher than the preterm birth rate among singleton births, according to the National Center for Health Statistics. In its preliminary report on births for 2004, the NCHS said that increases in multiple births “have strongly influenced recent upswings” in preterm and low-birth-weight births.

Assisted reproduction plays a role. There is evidence that the percentage of higher-order pregnancies resulting from assisted reproductive technology has been decreasing, but multiple pregnancies with ART remain a problem.

One has to ask whether, with greater care and improved protocols in assisted reproduction, we wouldn't be able to address the continuing effect that infertility treatment has on the rate of multiple pregnancies.

It is a subject that has caught national attention and has been addressed in many quarters. The Society for Assisted Reproductive Technology, an affiliate of the American Society for Reproductive Medicine has examined the issue and made recommendations for improved practice (see sidebar).

My guest professor this month is Dr. Aida Shanti, who is the director of the division of reproductive endocrinology and infertility at the University of Arkansas, Little Rock. She will address these contemporary recommendations and explore how such guidance can potentially have a real impact.

Age-Based Embryo Transfer Guidelines

▸ In patients under the age of 35, no more than two embryos should be transferred in the absence of extraor-dinary circumstances. For patients with the most favorable prognosis, consideration should be given to transferring only a single embryo. Patients having the most favorable prognosis include those who are un-dergoing their first cycle of IVF, have good-quality embryos as judged by morphologic criteria, and have ex-cess of embryos of sufficient quality to warrant cryopreservation. Patients who have had previous success with IVF should also be considered in the most favorable prognostic category.

▸ For patients between 35 and 37 years of age having a more favorable prognosis, no more than two em-bryos should be transferred. All oth-ers in this age group should have no more than three embryos transferred.

▸ For patients between 38 and 40 years of age, no more than four em-bryos should be transferred. For pa-tients in this age group having a more favorable prognosis, considera-tion should be given to transfer of no more than three embryos.

▸ For most patients greater than 40 years of age, no more than five em-bryos should be transferred.

▸ For patients with two or more pre-vious failed IVF cycles and those hav-ing a less favorable prognosis, addi-tional embryos may be transferred according to individual circumstances after appropriate consultation.

▸ In donor egg cycles, the donor's age should determine the appropriate number of embryos to transfer.

Since all oocytes may not fertilize when GIFT is performed, one more oocyte than embryo may be trans-ferred for each prognostic category.

Source: Fertil. Steril. 2004;82:773-4.

SAN DIEGO — Thermal balloon endometrial ablation is a safe and effective option for the treatment of women with idiopathic menorrhagia, results from a 3-year study of 330 women have shown.

“The procedure is simple, does not require additional training in operative hysterectomy, and compares favorably with other ablative techniques,” Stefanos Chandakas, M.D., Ph.D., reported at an international congress of the Society of Laparoendoscopic Surgeons. “These good results, however, need to be confirmed in a randomized, controlled trial.”

He and his associates used a 6-mm diameter Cavaterm Plus thermoablation system in 330 women with a mean age of 42 years. All participants had experienced heavy menstrual bleeding, failed medical treatment for the condition, and otherwise would have required hysterectomy, endometrial laser ablation, or endometrial resection.

The outpatient procedures were performed from January 2001 to June 2004 at Princess Royal University Hospital and Farnborough Hospital, Orpington, England. Contraindications included undiagnosed uterine bleeding, pregnancy or the desire to become pregnant, atypical endometrial cells, cervical length greater than 6 mm, a uterine cavity less than 4 cm or greater than 10 cm, uterine wall weakness, and ongoing infection.

No endometrial preparation was used. Each ablation lasted 10 minutes at a temperature of 78° C. Follow-up occurred at intervals of 3, 6, 12, 24, and 36 months, for a mean of 22 months.

Nearly half of the participants (48%) were amenorrheic after 1 year, while the rates of amenorrhea were 39% and 38% after 2 and 3 years, respectively. (See chart.)

The majority of women (83%) reported a reduction in dysmenorrhea and premenstrual symptoms at 1 year, “which is a recognized and consistent finding following endometrial destructive procedures,” said Dr. Chandakas of the minimal access unit in the department of obstetrics and gynecology at Princess Royal.

At 3 years, 73% of women reported a reduction in dysmenorrhea and premenstrual symptoms. No balloons failed, and no major complications were noted.

Dr. Chandakas disclosed that he has no financial interest in Wallsten Medical, the Swiss manufacturer of Cavaterm Plus.

SAN DIEGO — Thermal balloon endometrial ablation is a safe and effective option for the treatment of women with idiopathic menorrhagia, results from a 3-year study of 330 women have shown.

“The procedure is simple, does not require additional training in operative hysterectomy, and compares favorably with other ablative techniques,” Stefanos Chandakas, M.D., Ph.D., reported at an international congress of the Society of Laparoendoscopic Surgeons. “These good results, however, need to be confirmed in a randomized, controlled trial.”

He and his associates used a 6-mm diameter Cavaterm Plus thermoablation system in 330 women with a mean age of 42 years. All participants had experienced heavy menstrual bleeding, failed medical treatment for the condition, and otherwise would have required hysterectomy, endometrial laser ablation, or endometrial resection.

The outpatient procedures were performed from January 2001 to June 2004 at Princess Royal University Hospital and Farnborough Hospital, Orpington, England. Contraindications included undiagnosed uterine bleeding, pregnancy or the desire to become pregnant, atypical endometrial cells, cervical length greater than 6 mm, a uterine cavity less than 4 cm or greater than 10 cm, uterine wall weakness, and ongoing infection.

No endometrial preparation was used. Each ablation lasted 10 minutes at a temperature of 78° C. Follow-up occurred at intervals of 3, 6, 12, 24, and 36 months, for a mean of 22 months.

Nearly half of the participants (48%) were amenorrheic after 1 year, while the rates of amenorrhea were 39% and 38% after 2 and 3 years, respectively. (See chart.)

The majority of women (83%) reported a reduction in dysmenorrhea and premenstrual symptoms at 1 year, “which is a recognized and consistent finding following endometrial destructive procedures,” said Dr. Chandakas of the minimal access unit in the department of obstetrics and gynecology at Princess Royal.

At 3 years, 73% of women reported a reduction in dysmenorrhea and premenstrual symptoms. No balloons failed, and no major complications were noted.

Dr. Chandakas disclosed that he has no financial interest in Wallsten Medical, the Swiss manufacturer of Cavaterm Plus.

SAN DIEGO — Thermal balloon endometrial ablation is a safe and effective option for the treatment of women with idiopathic menorrhagia, results from a 3-year study of 330 women have shown.

“The procedure is simple, does not require additional training in operative hysterectomy, and compares favorably with other ablative techniques,” Stefanos Chandakas, M.D., Ph.D., reported at an international congress of the Society of Laparoendoscopic Surgeons. “These good results, however, need to be confirmed in a randomized, controlled trial.”

He and his associates used a 6-mm diameter Cavaterm Plus thermoablation system in 330 women with a mean age of 42 years. All participants had experienced heavy menstrual bleeding, failed medical treatment for the condition, and otherwise would have required hysterectomy, endometrial laser ablation, or endometrial resection.

The outpatient procedures were performed from January 2001 to June 2004 at Princess Royal University Hospital and Farnborough Hospital, Orpington, England. Contraindications included undiagnosed uterine bleeding, pregnancy or the desire to become pregnant, atypical endometrial cells, cervical length greater than 6 mm, a uterine cavity less than 4 cm or greater than 10 cm, uterine wall weakness, and ongoing infection.

No endometrial preparation was used. Each ablation lasted 10 minutes at a temperature of 78° C. Follow-up occurred at intervals of 3, 6, 12, 24, and 36 months, for a mean of 22 months.

Nearly half of the participants (48%) were amenorrheic after 1 year, while the rates of amenorrhea were 39% and 38% after 2 and 3 years, respectively. (See chart.)

The majority of women (83%) reported a reduction in dysmenorrhea and premenstrual symptoms at 1 year, “which is a recognized and consistent finding following endometrial destructive procedures,” said Dr. Chandakas of the minimal access unit in the department of obstetrics and gynecology at Princess Royal.

At 3 years, 73% of women reported a reduction in dysmenorrhea and premenstrual symptoms. No balloons failed, and no major complications were noted.

Dr. Chandakas disclosed that he has no financial interest in Wallsten Medical, the Swiss manufacturer of Cavaterm Plus.