E. Albert 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

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.

Yet we have reasons to be optimistic. When it comes to treating the disease, we're nowhere near where we were 20 years ago—or even 10 years ago. In communities with access to care, prognoses have improved significantly. As obstetricians, we now have the tools that allow us to provide effective care for HIV-infected pregnant women and to reduce perinatal transmission. Because of our increasing use of highly active antiretroviral therapy in addition to zidovudine chemoprophylaxis and the appropriate use of elective cesarean section, we now see only a few hundred HIV-infected newborns a year.

We could reduce perinatal transmission even further with two actions: embracing the Institute of Medicine's simple and practical “opt-out” approach to HIV testing, and using rapid screening tests more frequently. The use of a rapid screening test is an important evolving step, or shift, in the management of the HIV-infected pregnant woman. It is vital that these tests be used when necessary during labor.

Once a diagnosis is made, it is our job to guide the patient through the complex but promising process of treatment and monitoring, including, when necessary, the use of resistance testing. To do this, obstetricians can partner with HIV specialists and access up-to-date, practical treatment information online.

'Opt-Out' Testing, Rapid Tests

Many of the infants born HIV-positive today are infected because their mothers were not tested. Perhaps one in nine HIV-infected pregnant women gets minimal or no prenatal care. A significant number of others do not initiate care until the third trimester.

In 1999, the Institute of Medicine recommended an informed right-of-refusal approach to testing.

In this approach, the physician informs the patient that she is going to be tested for the virus that causes AIDS and that she has the right to refuse the test. She can “opt out” by signing a consent form.

That does not mean that there are fewer safeguards with HIV testing. We're still respecting patients' autonomy. In fact, we are more cautious with this test than with other screening procedures that we routinely perform. For example, we don't have individual, informed opt-out policies for breast exams that may detect cancer. HIV infection is treatable. With early diagnosis and therapy, women have decades to live and babies can be free of the disease.

Obstetricians need to put their imprimatur on the test. That's part of our role in caring for pregnant women. If we say, “You don't need this test, do you?” instead of saying “This is a test that's good for everybody,” we may as well not offer it. The goal simply put is to have HIV status determined as early as possible in all pregnancies.

The focus most recently among scientific and public health experts has been on rapid HIV tests. The Centers for Disease Control and Prevention has recommended that physicians liberalize the use of rapid screening in labor and delivery suites, emergency departments, and other settings.

These tests should be offered to any woman in labor whose serostatus is unknown. Although not as reliable as the standard approach used for prenatal testing, these tests are sensitive enough to identify HIV-infected women, and the results can be used as a basis for offering treatment while confirmatory tests are performed. Obstetricians should not wait for definitive follow-up tests to begin intrapartum and early neonatal prophylaxis. We can tell patients that if confirmatory tests turn out negative, treatment will be discontinued.

Therapy

If a pregnant woman tests positive, it is the obstetrician's job to monitor her immunologic and virologic status. Studies have shown a direct correlation between viral load and perinatal transmission, with transmission lower at any given viral load if antiretroviral therapy is used.

The viral load also can be used to counsel women about the potential utility of cesarean section: With plasma HIV-1 RNA levels higher than 1,000 copies/mL, cesarean section will reduce rates of transmission. Below that level, the additive benefit of cesarean section, beyond that which can be achieved with highly active retroviral therapy, is less certain.

A lot has changed since 1994, when the Pediatric AIDS Clinical Trials Group reported that zidovudine could reduce the risk for mother-to-child transmission 70%. Current interventions for all HIV-infected individuals focus on early initiation of HAART (highly active antiretroviral therapy)—the term used for the more aggressive and more potent combination antiretroviral regimens that can better suppress viral replication, preserve immune function, and minimize the development of resistance.

Although there are special and complex considerations to be made with regard to the choice of HAART agents in pregnancy, pregnancy per se is not a reason to defer what is now standard therapy.

In pregnancy, zidovudine should still be used whenever possible as a component of HAART regimens. Although it is similar in many ways to other nucleoside reverse transcriptase inhibitors, it has the advantage of demonstrated efficacy in preventing perinatal transmission.

If you don't see a substantial number of HIV-infected women, or if you don't keep up with the ever-expanding body of literature on antiretroviral drugs and patient management, I would advise comanaging your patient with an HIV specialist.

The obstetrician's key role is to ask the consultant what he or she would recommend if the patient were not pregnant, and then to take the lead in evaluating the drugs' benefits, toxicities, and risks. Obstetricians—with their dual roles of optimizing the health of the mother and preventing transmission of the virus to the child, in that order of priority—should be the ones to modify the regimen if necessary.

We often use category C drugs during pregnancy if we know that a drug is much more effective than a category B drug. However, specialists in other disciplines might recommend category B drugs, not because they are better but because of those specialists' unfamiliarity with the care of pregnant women and their fear of using category C drugs. We should be the ones to make that call, and should work with the HIV specialist in balancing efficacy and fetal safety.

The HIV specialists, on the other hand, are going to know all the ins and outs about drug combinations, about acceptable rates of viral load decrease, and about dosing schedules and other logistical details.

In general, the use of two nucleoside reverse transcriptase inhibitors along with a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor is recommended. It also is often useful to choose a regimen that spares one class of antiretroviral agents in case resistance develops. There are choices within each of the three drug categories, but there also are certain medications that should not be used in combination because of overlapping toxicities or diminished efficacy.

There are also certain potential perinatal risks. Nevirapine, for instance, can cause fulminant liver disease in women who have CD4 counts greater than 250 cells/mm

Treatment with efavirenz, for example, should be avoided during the first trimester because the drug has been associated with severe central nervous system anomalies. Overall, it's important to recognize and tell patients that we do not have long-term outcome data on the use during pregnancy of any of the available antiretroviral drugs.

The number of HAART regimens continues to increase, and there may be new reports of problems, so in addition to consulting with HIV specialists, obstetricians should also make use of the Public Health Service's Web site (

www.aidsinfo.nih.gov/guidelines

Prevention of Resistance

Once therapy is underway, viral loads should be checked every month until the viral load is undetectable. At that point, monitoring should be done every 2–3 months. If the viral load is not dropping or does not become undetectable within 6 months, a decision about new therapy will have to be made.

Before therapy is stopped, however, your patient must undergo resistance testing—a practice that has become a standard component of HIV care, mainly for identifying therapies that should not be used in the new regimen.

If you stop therapy first and draw blood just a week later, the wild-type virus (the nonmutant strain) may have overgrown a minority mutant strain, and the resistant virus may not be detected. You must draw blood before discontinuing therapy.

Also remember that second regimens do not work as well as first regimens, so it is important to do everything possible to prevent nonadherence. Patients who are only intermittently adherent—who have intermediate drug levels—are more likely to develop resistance.

Be sure to explain at the start that it is critical for the patient to be committed to therapy and to take drugs in a timely fashion. And if a patient develops nausea and vomiting, have her stop her drug regimen until the symptoms subside.

Mode of Delivery

As a rule, women who have scheduled a cesarean delivery before the onset of labor and before rupture of membranes have a lower rate of perinatal HIV-1 transmission. However, for a patient whose viral load is very low, there really is no evidence that scheduled cesarean delivery can lower the risk of transmission.

In addition, there is some preliminary evidence to support the notion that even some patients whose viral load is not that low—plasma HIV-1 RNA levels higher than 1,000 copies/mL—may not benefit from cesarean delivery if they are being given HAART. Those data remain to be confirmed.

Considering all that is known and unknown, I would advise a cesarean section for women whose viral load is greater than 1,000 copies/mL. When a patient's viral load is low, however, I would tell her that there is no proven benefit to delivering surgically.

Managing HIV in Pregnancy

When the HIV-AIDS epidemic spread across the Western hemisphere and into the United States, we all were petrified. We've made great strides with research and investigation. Today, we have a greater understanding of the biology of the disease, ways to prevent its transmission, and methods of control. Medication development has moved rapidly.

However, in concert with this good news, patients have become less anxious and, to some extent, have let their guards down. The scare factor seems to have decreased among women and their partners. As a consequence, the rapid decline in incidence that we had hoped for has not materialized.

The number of reported HIV cases in the United States now exceeds 1 million, and the Centers for Disease Control and Prevention estimates that about 25% of those living with HIV are unaware that they have the infection. Increasingly, women are at risk; the CDC reports that from 1999 to 2003, the estimate of AIDS cases increased by 15% among females and 1% among males.

Physicians will therefore continue to be confronted with women who are HIV infected. Like other women, these patients want to have children and provide for their families, so a thorough discussion of the management of HIV in pregnancy is most appropriate at this time. It is particularly important for obstetricians in urban areas, where the presentation of HIV-infected women can be higher. But it is also certainly important in suburban areas, which will see their share of pregnancies in HIV-infected women. Nobody is immune and no community is spared.

I am very pleased to have Howard L. Minkoff, M.D., as my Master Class guest professor this month. He is currently a distinguished professor of ob.gyn. at the State University of New York, and is chair of the department of ob.gyn. at Maimonides Medical Center, both in Brooklyn. Dr. Minkoff has done extensive research and has published widely on the topic of HIV in pregnancy.

Yet we have reasons to be optimistic. When it comes to treating the disease, we're nowhere near where we were 20 years ago—or even 10 years ago. In communities with access to care, prognoses have improved significantly. As obstetricians, we now have the tools that allow us to provide effective care for HIV-infected pregnant women and to reduce perinatal transmission. Because of our increasing use of highly active antiretroviral therapy in addition to zidovudine chemoprophylaxis and the appropriate use of elective cesarean section, we now see only a few hundred HIV-infected newborns a year.

We could reduce perinatal transmission even further with two actions: embracing the Institute of Medicine's simple and practical “opt-out” approach to HIV testing, and using rapid screening tests more frequently. The use of a rapid screening test is an important evolving step, or shift, in the management of the HIV-infected pregnant woman. It is vital that these tests be used when necessary during labor.

Once a diagnosis is made, it is our job to guide the patient through the complex but promising process of treatment and monitoring, including, when necessary, the use of resistance testing. To do this, obstetricians can partner with HIV specialists and access up-to-date, practical treatment information online.

'Opt-Out' Testing, Rapid Tests

Many of the infants born HIV-positive today are infected because their mothers were not tested. Perhaps one in nine HIV-infected pregnant women gets minimal or no prenatal care. A significant number of others do not initiate care until the third trimester.

In 1999, the Institute of Medicine recommended an informed right-of-refusal approach to testing.

In this approach, the physician informs the patient that she is going to be tested for the virus that causes AIDS and that she has the right to refuse the test. She can “opt out” by signing a consent form.

That does not mean that there are fewer safeguards with HIV testing. We're still respecting patients' autonomy. In fact, we are more cautious with this test than with other screening procedures that we routinely perform. For example, we don't have individual, informed opt-out policies for breast exams that may detect cancer. HIV infection is treatable. With early diagnosis and therapy, women have decades to live and babies can be free of the disease.

Obstetricians need to put their imprimatur on the test. That's part of our role in caring for pregnant women. If we say, “You don't need this test, do you?” instead of saying “This is a test that's good for everybody,” we may as well not offer it. The goal simply put is to have HIV status determined as early as possible in all pregnancies.

The focus most recently among scientific and public health experts has been on rapid HIV tests. The Centers for Disease Control and Prevention has recommended that physicians liberalize the use of rapid screening in labor and delivery suites, emergency departments, and other settings.

These tests should be offered to any woman in labor whose serostatus is unknown. Although not as reliable as the standard approach used for prenatal testing, these tests are sensitive enough to identify HIV-infected women, and the results can be used as a basis for offering treatment while confirmatory tests are performed. Obstetricians should not wait for definitive follow-up tests to begin intrapartum and early neonatal prophylaxis. We can tell patients that if confirmatory tests turn out negative, treatment will be discontinued.

Therapy

If a pregnant woman tests positive, it is the obstetrician's job to monitor her immunologic and virologic status. Studies have shown a direct correlation between viral load and perinatal transmission, with transmission lower at any given viral load if antiretroviral therapy is used.

The viral load also can be used to counsel women about the potential utility of cesarean section: With plasma HIV-1 RNA levels higher than 1,000 copies/mL, cesarean section will reduce rates of transmission. Below that level, the additive benefit of cesarean section, beyond that which can be achieved with highly active retroviral therapy, is less certain.

A lot has changed since 1994, when the Pediatric AIDS Clinical Trials Group reported that zidovudine could reduce the risk for mother-to-child transmission 70%. Current interventions for all HIV-infected individuals focus on early initiation of HAART (highly active antiretroviral therapy)—the term used for the more aggressive and more potent combination antiretroviral regimens that can better suppress viral replication, preserve immune function, and minimize the development of resistance.

Although there are special and complex considerations to be made with regard to the choice of HAART agents in pregnancy, pregnancy per se is not a reason to defer what is now standard therapy.

In pregnancy, zidovudine should still be used whenever possible as a component of HAART regimens. Although it is similar in many ways to other nucleoside reverse transcriptase inhibitors, it has the advantage of demonstrated efficacy in preventing perinatal transmission.

If you don't see a substantial number of HIV-infected women, or if you don't keep up with the ever-expanding body of literature on antiretroviral drugs and patient management, I would advise comanaging your patient with an HIV specialist.

The obstetrician's key role is to ask the consultant what he or she would recommend if the patient were not pregnant, and then to take the lead in evaluating the drugs' benefits, toxicities, and risks. Obstetricians—with their dual roles of optimizing the health of the mother and preventing transmission of the virus to the child, in that order of priority—should be the ones to modify the regimen if necessary.

We often use category C drugs during pregnancy if we know that a drug is much more effective than a category B drug. However, specialists in other disciplines might recommend category B drugs, not because they are better but because of those specialists' unfamiliarity with the care of pregnant women and their fear of using category C drugs. We should be the ones to make that call, and should work with the HIV specialist in balancing efficacy and fetal safety.

The HIV specialists, on the other hand, are going to know all the ins and outs about drug combinations, about acceptable rates of viral load decrease, and about dosing schedules and other logistical details.

In general, the use of two nucleoside reverse transcriptase inhibitors along with a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor is recommended. It also is often useful to choose a regimen that spares one class of antiretroviral agents in case resistance develops. There are choices within each of the three drug categories, but there also are certain medications that should not be used in combination because of overlapping toxicities or diminished efficacy.

There are also certain potential perinatal risks. Nevirapine, for instance, can cause fulminant liver disease in women who have CD4 counts greater than 250 cells/mm

Treatment with efavirenz, for example, should be avoided during the first trimester because the drug has been associated with severe central nervous system anomalies. Overall, it's important to recognize and tell patients that we do not have long-term outcome data on the use during pregnancy of any of the available antiretroviral drugs.

The number of HAART regimens continues to increase, and there may be new reports of problems, so in addition to consulting with HIV specialists, obstetricians should also make use of the Public Health Service's Web site (

www.aidsinfo.nih.gov/guidelines

Prevention of Resistance

Once therapy is underway, viral loads should be checked every month until the viral load is undetectable. At that point, monitoring should be done every 2–3 months. If the viral load is not dropping or does not become undetectable within 6 months, a decision about new therapy will have to be made.

Before therapy is stopped, however, your patient must undergo resistance testing—a practice that has become a standard component of HIV care, mainly for identifying therapies that should not be used in the new regimen.

If you stop therapy first and draw blood just a week later, the wild-type virus (the nonmutant strain) may have overgrown a minority mutant strain, and the resistant virus may not be detected. You must draw blood before discontinuing therapy.

Also remember that second regimens do not work as well as first regimens, so it is important to do everything possible to prevent nonadherence. Patients who are only intermittently adherent—who have intermediate drug levels—are more likely to develop resistance.

Be sure to explain at the start that it is critical for the patient to be committed to therapy and to take drugs in a timely fashion. And if a patient develops nausea and vomiting, have her stop her drug regimen until the symptoms subside.

Mode of Delivery

As a rule, women who have scheduled a cesarean delivery before the onset of labor and before rupture of membranes have a lower rate of perinatal HIV-1 transmission. However, for a patient whose viral load is very low, there really is no evidence that scheduled cesarean delivery can lower the risk of transmission.

In addition, there is some preliminary evidence to support the notion that even some patients whose viral load is not that low—plasma HIV-1 RNA levels higher than 1,000 copies/mL—may not benefit from cesarean delivery if they are being given HAART. Those data remain to be confirmed.

Considering all that is known and unknown, I would advise a cesarean section for women whose viral load is greater than 1,000 copies/mL. When a patient's viral load is low, however, I would tell her that there is no proven benefit to delivering surgically.

Managing HIV in Pregnancy

When the HIV-AIDS epidemic spread across the Western hemisphere and into the United States, we all were petrified. We've made great strides with research and investigation. Today, we have a greater understanding of the biology of the disease, ways to prevent its transmission, and methods of control. Medication development has moved rapidly.

However, in concert with this good news, patients have become less anxious and, to some extent, have let their guards down. The scare factor seems to have decreased among women and their partners. As a consequence, the rapid decline in incidence that we had hoped for has not materialized.

The number of reported HIV cases in the United States now exceeds 1 million, and the Centers for Disease Control and Prevention estimates that about 25% of those living with HIV are unaware that they have the infection. Increasingly, women are at risk; the CDC reports that from 1999 to 2003, the estimate of AIDS cases increased by 15% among females and 1% among males.

Physicians will therefore continue to be confronted with women who are HIV infected. Like other women, these patients want to have children and provide for their families, so a thorough discussion of the management of HIV in pregnancy is most appropriate at this time. It is particularly important for obstetricians in urban areas, where the presentation of HIV-infected women can be higher. But it is also certainly important in suburban areas, which will see their share of pregnancies in HIV-infected women. Nobody is immune and no community is spared.

I am very pleased to have Howard L. Minkoff, M.D., as my Master Class guest professor this month. He is currently a distinguished professor of ob.gyn. at the State University of New York, and is chair of the department of ob.gyn. at Maimonides Medical Center, both in Brooklyn. Dr. Minkoff has done extensive research and has published widely on the topic of HIV in pregnancy.

Yet we have reasons to be optimistic. When it comes to treating the disease, we're nowhere near where we were 20 years ago—or even 10 years ago. In communities with access to care, prognoses have improved significantly. As obstetricians, we now have the tools that allow us to provide effective care for HIV-infected pregnant women and to reduce perinatal transmission. Because of our increasing use of highly active antiretroviral therapy in addition to zidovudine chemoprophylaxis and the appropriate use of elective cesarean section, we now see only a few hundred HIV-infected newborns a year.

We could reduce perinatal transmission even further with two actions: embracing the Institute of Medicine's simple and practical “opt-out” approach to HIV testing, and using rapid screening tests more frequently. The use of a rapid screening test is an important evolving step, or shift, in the management of the HIV-infected pregnant woman. It is vital that these tests be used when necessary during labor.

Once a diagnosis is made, it is our job to guide the patient through the complex but promising process of treatment and monitoring, including, when necessary, the use of resistance testing. To do this, obstetricians can partner with HIV specialists and access up-to-date, practical treatment information online.

'Opt-Out' Testing, Rapid Tests

Many of the infants born HIV-positive today are infected because their mothers were not tested. Perhaps one in nine HIV-infected pregnant women gets minimal or no prenatal care. A significant number of others do not initiate care until the third trimester.

In 1999, the Institute of Medicine recommended an informed right-of-refusal approach to testing.

In this approach, the physician informs the patient that she is going to be tested for the virus that causes AIDS and that she has the right to refuse the test. She can “opt out” by signing a consent form.

That does not mean that there are fewer safeguards with HIV testing. We're still respecting patients' autonomy. In fact, we are more cautious with this test than with other screening procedures that we routinely perform. For example, we don't have individual, informed opt-out policies for breast exams that may detect cancer. HIV infection is treatable. With early diagnosis and therapy, women have decades to live and babies can be free of the disease.

Obstetricians need to put their imprimatur on the test. That's part of our role in caring for pregnant women. If we say, “You don't need this test, do you?” instead of saying “This is a test that's good for everybody,” we may as well not offer it. The goal simply put is to have HIV status determined as early as possible in all pregnancies.

The focus most recently among scientific and public health experts has been on rapid HIV tests. The Centers for Disease Control and Prevention has recommended that physicians liberalize the use of rapid screening in labor and delivery suites, emergency departments, and other settings.

These tests should be offered to any woman in labor whose serostatus is unknown. Although not as reliable as the standard approach used for prenatal testing, these tests are sensitive enough to identify HIV-infected women, and the results can be used as a basis for offering treatment while confirmatory tests are performed. Obstetricians should not wait for definitive follow-up tests to begin intrapartum and early neonatal prophylaxis. We can tell patients that if confirmatory tests turn out negative, treatment will be discontinued.

Therapy

If a pregnant woman tests positive, it is the obstetrician's job to monitor her immunologic and virologic status. Studies have shown a direct correlation between viral load and perinatal transmission, with transmission lower at any given viral load if antiretroviral therapy is used.

The viral load also can be used to counsel women about the potential utility of cesarean section: With plasma HIV-1 RNA levels higher than 1,000 copies/mL, cesarean section will reduce rates of transmission. Below that level, the additive benefit of cesarean section, beyond that which can be achieved with highly active retroviral therapy, is less certain.

A lot has changed since 1994, when the Pediatric AIDS Clinical Trials Group reported that zidovudine could reduce the risk for mother-to-child transmission 70%. Current interventions for all HIV-infected individuals focus on early initiation of HAART (highly active antiretroviral therapy)—the term used for the more aggressive and more potent combination antiretroviral regimens that can better suppress viral replication, preserve immune function, and minimize the development of resistance.

Although there are special and complex considerations to be made with regard to the choice of HAART agents in pregnancy, pregnancy per se is not a reason to defer what is now standard therapy.

In pregnancy, zidovudine should still be used whenever possible as a component of HAART regimens. Although it is similar in many ways to other nucleoside reverse transcriptase inhibitors, it has the advantage of demonstrated efficacy in preventing perinatal transmission.

If you don't see a substantial number of HIV-infected women, or if you don't keep up with the ever-expanding body of literature on antiretroviral drugs and patient management, I would advise comanaging your patient with an HIV specialist.

The obstetrician's key role is to ask the consultant what he or she would recommend if the patient were not pregnant, and then to take the lead in evaluating the drugs' benefits, toxicities, and risks. Obstetricians—with their dual roles of optimizing the health of the mother and preventing transmission of the virus to the child, in that order of priority—should be the ones to modify the regimen if necessary.

We often use category C drugs during pregnancy if we know that a drug is much more effective than a category B drug. However, specialists in other disciplines might recommend category B drugs, not because they are better but because of those specialists' unfamiliarity with the care of pregnant women and their fear of using category C drugs. We should be the ones to make that call, and should work with the HIV specialist in balancing efficacy and fetal safety.

The HIV specialists, on the other hand, are going to know all the ins and outs about drug combinations, about acceptable rates of viral load decrease, and about dosing schedules and other logistical details.

In general, the use of two nucleoside reverse transcriptase inhibitors along with a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor is recommended. It also is often useful to choose a regimen that spares one class of antiretroviral agents in case resistance develops. There are choices within each of the three drug categories, but there also are certain medications that should not be used in combination because of overlapping toxicities or diminished efficacy.

There are also certain potential perinatal risks. Nevirapine, for instance, can cause fulminant liver disease in women who have CD4 counts greater than 250 cells/mm

Treatment with efavirenz, for example, should be avoided during the first trimester because the drug has been associated with severe central nervous system anomalies. Overall, it's important to recognize and tell patients that we do not have long-term outcome data on the use during pregnancy of any of the available antiretroviral drugs.

The number of HAART regimens continues to increase, and there may be new reports of problems, so in addition to consulting with HIV specialists, obstetricians should also make use of the Public Health Service's Web site (

www.aidsinfo.nih.gov/guidelines

Prevention of Resistance

Once therapy is underway, viral loads should be checked every month until the viral load is undetectable. At that point, monitoring should be done every 2–3 months. If the viral load is not dropping or does not become undetectable within 6 months, a decision about new therapy will have to be made.

Before therapy is stopped, however, your patient must undergo resistance testing—a practice that has become a standard component of HIV care, mainly for identifying therapies that should not be used in the new regimen.

If you stop therapy first and draw blood just a week later, the wild-type virus (the nonmutant strain) may have overgrown a minority mutant strain, and the resistant virus may not be detected. You must draw blood before discontinuing therapy.

Also remember that second regimens do not work as well as first regimens, so it is important to do everything possible to prevent nonadherence. Patients who are only intermittently adherent—who have intermediate drug levels—are more likely to develop resistance.

Be sure to explain at the start that it is critical for the patient to be committed to therapy and to take drugs in a timely fashion. And if a patient develops nausea and vomiting, have her stop her drug regimen until the symptoms subside.

Mode of Delivery

As a rule, women who have scheduled a cesarean delivery before the onset of labor and before rupture of membranes have a lower rate of perinatal HIV-1 transmission. However, for a patient whose viral load is very low, there really is no evidence that scheduled cesarean delivery can lower the risk of transmission.

In addition, there is some preliminary evidence to support the notion that even some patients whose viral load is not that low—plasma HIV-1 RNA levels higher than 1,000 copies/mL—may not benefit from cesarean delivery if they are being given HAART. Those data remain to be confirmed.

Considering all that is known and unknown, I would advise a cesarean section for women whose viral load is greater than 1,000 copies/mL. When a patient's viral load is low, however, I would tell her that there is no proven benefit to delivering surgically.

Managing HIV in Pregnancy

When the HIV-AIDS epidemic spread across the Western hemisphere and into the United States, we all were petrified. We've made great strides with research and investigation. Today, we have a greater understanding of the biology of the disease, ways to prevent its transmission, and methods of control. Medication development has moved rapidly.

However, in concert with this good news, patients have become less anxious and, to some extent, have let their guards down. The scare factor seems to have decreased among women and their partners. As a consequence, the rapid decline in incidence that we had hoped for has not materialized.

The number of reported HIV cases in the United States now exceeds 1 million, and the Centers for Disease Control and Prevention estimates that about 25% of those living with HIV are unaware that they have the infection. Increasingly, women are at risk; the CDC reports that from 1999 to 2003, the estimate of AIDS cases increased by 15% among females and 1% among males.

Physicians will therefore continue to be confronted with women who are HIV infected. Like other women, these patients want to have children and provide for their families, so a thorough discussion of the management of HIV in pregnancy is most appropriate at this time. It is particularly important for obstetricians in urban areas, where the presentation of HIV-infected women can be higher. But it is also certainly important in suburban areas, which will see their share of pregnancies in HIV-infected women. Nobody is immune and no community is spared.

I am very pleased to have Howard L. Minkoff, M.D., as my Master Class guest professor this month. He is currently a distinguished professor of ob.gyn. at the State University of New York, and is chair of the department of ob.gyn. at Maimonides Medical Center, both in Brooklyn. Dr. Minkoff has done extensive research and has published widely on the topic of HIV in pregnancy.

The hesitance of obstetricians to recommend exercise to pregnant women is rooted in old-fashioned notions of pregnancy as a time of confinement. In the absence of reassuring data regarding the effects of exercise on the mother and fetus, most obstetricians adhered to the principle of doing no harm—advising women to eat for two and not to move.

With ample evidence to show that regular, moderate exercise in women with healthy pregnancies results in no adverse maternal or fetal effects, it could be argued that, in the spirit of “primum non nocere,” obstetricians should make exercise recommendations a top priority.

Indeed, because it is recognized that habits adopted during pregnancy can result in persistent lifestyle improvements, the promotion of exercise during pregnancy is an important public health issue that could significantly reduce the lifetime risks of obesity, chronic hypertension, and diabetes—not only for our patients, but for their families as well.

Recently, exercise has been recognized as an effective alternative to insulin therapy for treating gestational diabetes and as a means of preventing this disorder, which is frequently the first manifestation of what can become a lifelong condition.

Healthy Pregnancy? Few Restrictions

Despite the profound anatomical and physiologic changes of pregnancy, women with healthy pregnancies and no contraindications can exercise just as their nonpregnant counterparts do, combining both aerobic and resistive elements in their workouts. (See box on opposite page.)

A clinical evaluation of each patient is recommended before prescribing exercise, and physicians must consider the type and intensity of exercise—as well as the duration and frequency of exercise sessions—for each patient, based on her level of fitness and familiarity with various activities.

Contact sports and exercises with a high risk of falling or abdominal trauma should be avoided. Scuba diving should be avoided throughout pregnancy because this activity puts the fetus at increased risk for decompression sickness secondary to the inability of the fetal pulmonary circulation to filter bubbles.

Exercise Intensity

Moderate exercise is defined as a level of intensity that still allows normal conversation—equivalent, for example, to brisk walking at 3–4 miles per hour. For women who have been sedentary and are taking up exercise for the first time, a gradual progression to this intensity for up to 30 minutes per day is recommended. Those who are already fit when they become pregnant should be advised that pregnancy is not a time for greatly improving physical fitness and that, in general, overall activity and fitness levels tend to decline during pregnancy.

Pregnant women should exercise caution in increasing the intensity of their workouts, especially when they are extending exercise sessions beyond 45 minutes, because body core temperatures can rise above safe limits after that time. Strenuous exercise has not been proved to increase overall benefit and could actually be harmful, so this level of exercise intensity should be avoided.

Fetal Effects

Maternal cardiovascular, respiratory, and thermoregulatory adaptation occurs as a result of pregnancy and is further challenged by the addition of exercise. There is decreased availability of maternal oxygen during exercise because of increased maternal oxygen requirements at rest and the increased difficulty in breathing caused by the pressure of the enlarged uterus on the diaphragm. In addition, pregnancy raises basal metabolic rate and heat production, which are then further raised by exercise.

The hesitance of many obstetricians to prescribe exercise for pregnant women centers on the hypothetical fetal risks of impaired transplacental blood flow of oxygen, carbon dioxide, and nutrients during maternal exercise, as well as the potentially teratogenic effects of raising fetal temperature.

Most studies show a minimal to moderate increase in fetal heart rate during maternal exercise, and there is also evidence of fetal heart rate decelerations and bradycardia; however, no lasting fetal effects have been reported.

Data on the effects of increased maternal core temperatures are limited. Hyperthermia during embryogenesis (the first 45–60 days following the last menstrual period) has been shown to cause major congenital malformations (JAMA 1992;268:882–5).

The temperature threshold for human teratogenesis is 39.2° C (103° F). Moderate exercise performed in conditions allowing adequate heat dissipation has been shown to raise core temperatures no higher than 1.5° C during 30 minutes of exercise in nonpregnant women—and this temperature plateaus during as much as 1 hour of exercise.

Loss of fluid through sweat may compromise heat dissipation, so maintenance of euhydration—and thus blood volume—is essential to controlling core temperature.

Extra Nutritional Requirements

Although the published data on a link between low birth weight and maternal exercise are conflicting, it appears that adequate energy intake can offset any exercise-induced decreases in birth weight.

By the second trimester of pregnancy, an extra 1.3 MJ (300 kcal) per day are required to meet general metabolic needs in pregnancy, and this energy requirement is increased with exercise. Pregnant women use carbohydrates at a greater rate than do nonpregnant women—both at rest and during exercise—and there is preferential use of this form of energy during non-weight-bearing exercise, making adequate carbohydrate intake of particular importance.

Elite Athletes

Although routine prenatal care is sufficient for monitoring women in average exercise programs, closer obstetric observation is required for women who are elite athletes.

Most elite athletes choose to continue training during pregnancy, but they must be told that they probably will not achieve the same level of performance as they did before pregnancy, and the physiologic changes they experience—such as weight gain and joint or ligament laxity—will also make them more prone to injury. Women engaging in endurance sports can be prone to anemia that results from increased blood volume during pregnancy. High intensity, prolonged, and frequent exercise can put women at greater risk of thermoregulatory complications as well, and will usually result in less maternal and fetal weight gain than occurs in less active women.

Gestational Diabetes

The American Diabetes Association has endorsed exercise as a helpful adjunctive therapy for gestational diabetes mellitus (GDM) when glycemic control cannot be achieved through diet alone. Approximately 39% of patients with GDM require insulin therapy, but in my experience, exercise is a safe and effective alternative for most of these women.

The key to achieving euglycemia through exercise is ensuring the adequate duration and intensity of the activity. Exercise improves the impaired insulin sensitivity of women with GDM, which in turn increases glucose uptake by muscles and splanchnic organs, but this effect is achieved only through the activation of large muscles, such as the quadriceps, at adequate intensity, which explains why some studies in the literature fail to show normalization of glucose levels after exercise. At least half an hour of brisk walking per day is sufficient to upregulate insulin sensitivity in patients with GDM, obviating the need for insulin therapy.

Additionally, epidemiologic data suggest that exercise may act as primary prevention for GDM in morbidly obese women, but not in women of normal weight.

Weight Control

Although exercise should never be used for weight control during pregnancy, excessive weight gain should be avoided.

The current Institute of Medicine (IOM) guidelines on weight gain—which recommend a gain of 25–35 pounds for normal-weight women with a singleton pregnancy—are too high and are based on historical concerns about the effects of famine on fetal growth retardation.

The effect of gestational weight gain on pregnancy outcomes in obese women is not well studied. It is my opinion that the IOM guidelines are outdated, and that weight gain recommendations should be individualized. Compared with IOM recommendations for adequate gestational weight gain in obese women (at least 15 pounds), it is well recognized that a gain of less than 15 pounds in this population significantly reduces the risks of preeclampsia, C-section, and large-for-gestational-age infants.

The risk for small-for-gestational-age infants varies significantly, particularly among morbidly obese women in whom no weight gain—or even weight loss—may not have any adverse effect on birth weight.

Postpartum Exercise

Because failure to lose weight gained in pregnancy is a significant contributor to the obesity epidemic, the promotion of good exercise habits during pregnancy can also sow the seeds for postpartum exercise and weight loss.

One study showed that the amount of postpartum weight retention increases with each subsequent pregnancy (Acta. Obstet. Gynecol. Scand. 1979;58:45–7). Another study found that women who gained excessive weight during pregnancy and failed to lose it within 6 months post partum were 8.3 kg heavier 10 years later (Obstet. Gynecol. 2002;100:245–52).

Our study found that a weekly structured exercise program plus diet in postpartum overweight women were much more effective in achieving weight loss after 12 weeks compared with a single 1-hour education session about diet and exercise (J. Women's Health [Larchmt] 2003;12:991–8).

Therefore, women whose exercise habits have become firmly entrenched during pregnancy stand a much better chance of maintaining them post partum—and perhaps even into their next pregnancy.

Maintenance of euhydration is essential to controlling core temperature while exercising in pregnancy. Lynda Banzi

Exercise in Pregnancy

The extraordinary increase in obesity in the United States is giving rise not only to direct complications, such as hypertension and cardiovascular disease, but also to indirect problems such as diabetes. Hence, we have one problem leading into many others, ultimately resulting in a significant increase in morbidity and mortality.

Unfortunately, exercise—which can counter obesity—is not increasing at a concomitant rate. As a result, an emphasis on healthy lifestyles, with exercise as a central theme, has become the focus of national and international efforts undertaken by such groups as the World Health Organization, many of our medical societies, and even certain governmental agencies.

Just as exercise outside of pregnancy has clear benefits, exercise during pregnancy is also very important. For example, we know that a woman with gestational diabetes can certainly improve glucose control with exercise. However, there are clearly guidelines that must be followed when engaging in exercise during pregnancy.

In this month's Master Class, my guest professor is Raul Artal, M.D., who is an internationally recognized expert in the area of exercise physiology and exercise in pregnancy. He will lead us through specific recommendations concerning exercise during pregnancy, with references to gestational diabetes, weight control, and postpartum exercise.

Dr. Artal is professor and chair of the department of ob.gyn. at St. Louis University. He received his medical degree in Israel and his residency and fellowship training in the United States. He served as a faculty member at University of Southern California in Los Angeles and as chairman of ob.gyn. at the State University of New York, Syracuse, before attaining his current position. Dr. Artal is the lead author of the American College of Obstetricians and Gynecologists' Committee Opinion #267, “Exercise During Pregnancy and the Postpartum Period.”

Contraindications To Exercise In Pregnancy

Absolute Contraindications

Hemodynamically significant heart disease

Restrictive lung disease

Incompetent cervix/cerclage

Multiple gestation at risk for premature labor

Persistent second- or third-trimester bleeding

Placenta previa that occurs after 26 weeks' gestation

Premature labor during the current pregnancy

Ruptured membranes

Preeclampsia/pregnancy-induced hypertension

Relative Contraindications

Severe anemia

Unevaluated maternal cardiac arrhythmia

Chronic bronchitis

Poorly controlled type 1 diabetes

Extreme morbid obesity

Extreme underweight

History of extremely sedentary lifestyle

Intrauterine growth restriction in current pregnancy

Poorly controlled hypertension

Orthopedic limitations

Poorly controlled seizure disorder

Poorly controlled hyperthyroidism

Heavy smoker

Source: Obstet. Gynecol. 2002;99:171–3

The hesitance of obstetricians to recommend exercise to pregnant women is rooted in old-fashioned notions of pregnancy as a time of confinement. In the absence of reassuring data regarding the effects of exercise on the mother and fetus, most obstetricians adhered to the principle of doing no harm—advising women to eat for two and not to move.

With ample evidence to show that regular, moderate exercise in women with healthy pregnancies results in no adverse maternal or fetal effects, it could be argued that, in the spirit of “primum non nocere,” obstetricians should make exercise recommendations a top priority.

Indeed, because it is recognized that habits adopted during pregnancy can result in persistent lifestyle improvements, the promotion of exercise during pregnancy is an important public health issue that could significantly reduce the lifetime risks of obesity, chronic hypertension, and diabetes—not only for our patients, but for their families as well.

Recently, exercise has been recognized as an effective alternative to insulin therapy for treating gestational diabetes and as a means of preventing this disorder, which is frequently the first manifestation of what can become a lifelong condition.

Healthy Pregnancy? Few Restrictions

Despite the profound anatomical and physiologic changes of pregnancy, women with healthy pregnancies and no contraindications can exercise just as their nonpregnant counterparts do, combining both aerobic and resistive elements in their workouts. (See box on opposite page.)

A clinical evaluation of each patient is recommended before prescribing exercise, and physicians must consider the type and intensity of exercise—as well as the duration and frequency of exercise sessions—for each patient, based on her level of fitness and familiarity with various activities.

Contact sports and exercises with a high risk of falling or abdominal trauma should be avoided. Scuba diving should be avoided throughout pregnancy because this activity puts the fetus at increased risk for decompression sickness secondary to the inability of the fetal pulmonary circulation to filter bubbles.

Exercise Intensity

Moderate exercise is defined as a level of intensity that still allows normal conversation—equivalent, for example, to brisk walking at 3–4 miles per hour. For women who have been sedentary and are taking up exercise for the first time, a gradual progression to this intensity for up to 30 minutes per day is recommended. Those who are already fit when they become pregnant should be advised that pregnancy is not a time for greatly improving physical fitness and that, in general, overall activity and fitness levels tend to decline during pregnancy.

Pregnant women should exercise caution in increasing the intensity of their workouts, especially when they are extending exercise sessions beyond 45 minutes, because body core temperatures can rise above safe limits after that time. Strenuous exercise has not been proved to increase overall benefit and could actually be harmful, so this level of exercise intensity should be avoided.

Fetal Effects

Maternal cardiovascular, respiratory, and thermoregulatory adaptation occurs as a result of pregnancy and is further challenged by the addition of exercise. There is decreased availability of maternal oxygen during exercise because of increased maternal oxygen requirements at rest and the increased difficulty in breathing caused by the pressure of the enlarged uterus on the diaphragm. In addition, pregnancy raises basal metabolic rate and heat production, which are then further raised by exercise.

The hesitance of many obstetricians to prescribe exercise for pregnant women centers on the hypothetical fetal risks of impaired transplacental blood flow of oxygen, carbon dioxide, and nutrients during maternal exercise, as well as the potentially teratogenic effects of raising fetal temperature.

Most studies show a minimal to moderate increase in fetal heart rate during maternal exercise, and there is also evidence of fetal heart rate decelerations and bradycardia; however, no lasting fetal effects have been reported.

Data on the effects of increased maternal core temperatures are limited. Hyperthermia during embryogenesis (the first 45–60 days following the last menstrual period) has been shown to cause major congenital malformations (JAMA 1992;268:882–5).

The temperature threshold for human teratogenesis is 39.2° C (103° F). Moderate exercise performed in conditions allowing adequate heat dissipation has been shown to raise core temperatures no higher than 1.5° C during 30 minutes of exercise in nonpregnant women—and this temperature plateaus during as much as 1 hour of exercise.

Loss of fluid through sweat may compromise heat dissipation, so maintenance of euhydration—and thus blood volume—is essential to controlling core temperature.

Extra Nutritional Requirements

Although the published data on a link between low birth weight and maternal exercise are conflicting, it appears that adequate energy intake can offset any exercise-induced decreases in birth weight.

By the second trimester of pregnancy, an extra 1.3 MJ (300 kcal) per day are required to meet general metabolic needs in pregnancy, and this energy requirement is increased with exercise. Pregnant women use carbohydrates at a greater rate than do nonpregnant women—both at rest and during exercise—and there is preferential use of this form of energy during non-weight-bearing exercise, making adequate carbohydrate intake of particular importance.

Elite Athletes

Although routine prenatal care is sufficient for monitoring women in average exercise programs, closer obstetric observation is required for women who are elite athletes.

Most elite athletes choose to continue training during pregnancy, but they must be told that they probably will not achieve the same level of performance as they did before pregnancy, and the physiologic changes they experience—such as weight gain and joint or ligament laxity—will also make them more prone to injury. Women engaging in endurance sports can be prone to anemia that results from increased blood volume during pregnancy. High intensity, prolonged, and frequent exercise can put women at greater risk of thermoregulatory complications as well, and will usually result in less maternal and fetal weight gain than occurs in less active women.

Gestational Diabetes

The American Diabetes Association has endorsed exercise as a helpful adjunctive therapy for gestational diabetes mellitus (GDM) when glycemic control cannot be achieved through diet alone. Approximately 39% of patients with GDM require insulin therapy, but in my experience, exercise is a safe and effective alternative for most of these women.

The key to achieving euglycemia through exercise is ensuring the adequate duration and intensity of the activity. Exercise improves the impaired insulin sensitivity of women with GDM, which in turn increases glucose uptake by muscles and splanchnic organs, but this effect is achieved only through the activation of large muscles, such as the quadriceps, at adequate intensity, which explains why some studies in the literature fail to show normalization of glucose levels after exercise. At least half an hour of brisk walking per day is sufficient to upregulate insulin sensitivity in patients with GDM, obviating the need for insulin therapy.

Additionally, epidemiologic data suggest that exercise may act as primary prevention for GDM in morbidly obese women, but not in women of normal weight.

Weight Control

Although exercise should never be used for weight control during pregnancy, excessive weight gain should be avoided.

The current Institute of Medicine (IOM) guidelines on weight gain—which recommend a gain of 25–35 pounds for normal-weight women with a singleton pregnancy—are too high and are based on historical concerns about the effects of famine on fetal growth retardation.

The effect of gestational weight gain on pregnancy outcomes in obese women is not well studied. It is my opinion that the IOM guidelines are outdated, and that weight gain recommendations should be individualized. Compared with IOM recommendations for adequate gestational weight gain in obese women (at least 15 pounds), it is well recognized that a gain of less than 15 pounds in this population significantly reduces the risks of preeclampsia, C-section, and large-for-gestational-age infants.

The risk for small-for-gestational-age infants varies significantly, particularly among morbidly obese women in whom no weight gain—or even weight loss—may not have any adverse effect on birth weight.

Postpartum Exercise

Because failure to lose weight gained in pregnancy is a significant contributor to the obesity epidemic, the promotion of good exercise habits during pregnancy can also sow the seeds for postpartum exercise and weight loss.

One study showed that the amount of postpartum weight retention increases with each subsequent pregnancy (Acta. Obstet. Gynecol. Scand. 1979;58:45–7). Another study found that women who gained excessive weight during pregnancy and failed to lose it within 6 months post partum were 8.3 kg heavier 10 years later (Obstet. Gynecol. 2002;100:245–52).

Our study found that a weekly structured exercise program plus diet in postpartum overweight women were much more effective in achieving weight loss after 12 weeks compared with a single 1-hour education session about diet and exercise (J. Women's Health [Larchmt] 2003;12:991–8).

Therefore, women whose exercise habits have become firmly entrenched during pregnancy stand a much better chance of maintaining them post partum—and perhaps even into their next pregnancy.

Maintenance of euhydration is essential to controlling core temperature while exercising in pregnancy. Lynda Banzi

Exercise in Pregnancy

The extraordinary increase in obesity in the United States is giving rise not only to direct complications, such as hypertension and cardiovascular disease, but also to indirect problems such as diabetes. Hence, we have one problem leading into many others, ultimately resulting in a significant increase in morbidity and mortality.

Unfortunately, exercise—which can counter obesity—is not increasing at a concomitant rate. As a result, an emphasis on healthy lifestyles, with exercise as a central theme, has become the focus of national and international efforts undertaken by such groups as the World Health Organization, many of our medical societies, and even certain governmental agencies.

Just as exercise outside of pregnancy has clear benefits, exercise during pregnancy is also very important. For example, we know that a woman with gestational diabetes can certainly improve glucose control with exercise. However, there are clearly guidelines that must be followed when engaging in exercise during pregnancy.

In this month's Master Class, my guest professor is Raul Artal, M.D., who is an internationally recognized expert in the area of exercise physiology and exercise in pregnancy. He will lead us through specific recommendations concerning exercise during pregnancy, with references to gestational diabetes, weight control, and postpartum exercise.

Dr. Artal is professor and chair of the department of ob.gyn. at St. Louis University. He received his medical degree in Israel and his residency and fellowship training in the United States. He served as a faculty member at University of Southern California in Los Angeles and as chairman of ob.gyn. at the State University of New York, Syracuse, before attaining his current position. Dr. Artal is the lead author of the American College of Obstetricians and Gynecologists' Committee Opinion #267, “Exercise During Pregnancy and the Postpartum Period.”

Contraindications To Exercise In Pregnancy

Absolute Contraindications

Hemodynamically significant heart disease

Restrictive lung disease

Incompetent cervix/cerclage

Multiple gestation at risk for premature labor

Persistent second- or third-trimester bleeding

Placenta previa that occurs after 26 weeks' gestation

Premature labor during the current pregnancy

Ruptured membranes

Preeclampsia/pregnancy-induced hypertension

Relative Contraindications

Severe anemia

Unevaluated maternal cardiac arrhythmia

Chronic bronchitis

Poorly controlled type 1 diabetes

Extreme morbid obesity

Extreme underweight

History of extremely sedentary lifestyle

Intrauterine growth restriction in current pregnancy

Poorly controlled hypertension

Orthopedic limitations

Poorly controlled seizure disorder

Poorly controlled hyperthyroidism

Heavy smoker

Source: Obstet. Gynecol. 2002;99:171–3

The hesitance of obstetricians to recommend exercise to pregnant women is rooted in old-fashioned notions of pregnancy as a time of confinement. In the absence of reassuring data regarding the effects of exercise on the mother and fetus, most obstetricians adhered to the principle of doing no harm—advising women to eat for two and not to move.

With ample evidence to show that regular, moderate exercise in women with healthy pregnancies results in no adverse maternal or fetal effects, it could be argued that, in the spirit of “primum non nocere,” obstetricians should make exercise recommendations a top priority.

Indeed, because it is recognized that habits adopted during pregnancy can result in persistent lifestyle improvements, the promotion of exercise during pregnancy is an important public health issue that could significantly reduce the lifetime risks of obesity, chronic hypertension, and diabetes—not only for our patients, but for their families as well.

Recently, exercise has been recognized as an effective alternative to insulin therapy for treating gestational diabetes and as a means of preventing this disorder, which is frequently the first manifestation of what can become a lifelong condition.

Healthy Pregnancy? Few Restrictions

Despite the profound anatomical and physiologic changes of pregnancy, women with healthy pregnancies and no contraindications can exercise just as their nonpregnant counterparts do, combining both aerobic and resistive elements in their workouts. (See box on opposite page.)

A clinical evaluation of each patient is recommended before prescribing exercise, and physicians must consider the type and intensity of exercise—as well as the duration and frequency of exercise sessions—for each patient, based on her level of fitness and familiarity with various activities.

Contact sports and exercises with a high risk of falling or abdominal trauma should be avoided. Scuba diving should be avoided throughout pregnancy because this activity puts the fetus at increased risk for decompression sickness secondary to the inability of the fetal pulmonary circulation to filter bubbles.

Exercise Intensity

Moderate exercise is defined as a level of intensity that still allows normal conversation—equivalent, for example, to brisk walking at 3–4 miles per hour. For women who have been sedentary and are taking up exercise for the first time, a gradual progression to this intensity for up to 30 minutes per day is recommended. Those who are already fit when they become pregnant should be advised that pregnancy is not a time for greatly improving physical fitness and that, in general, overall activity and fitness levels tend to decline during pregnancy.

Pregnant women should exercise caution in increasing the intensity of their workouts, especially when they are extending exercise sessions beyond 45 minutes, because body core temperatures can rise above safe limits after that time. Strenuous exercise has not been proved to increase overall benefit and could actually be harmful, so this level of exercise intensity should be avoided.

Fetal Effects

Maternal cardiovascular, respiratory, and thermoregulatory adaptation occurs as a result of pregnancy and is further challenged by the addition of exercise. There is decreased availability of maternal oxygen during exercise because of increased maternal oxygen requirements at rest and the increased difficulty in breathing caused by the pressure of the enlarged uterus on the diaphragm. In addition, pregnancy raises basal metabolic rate and heat production, which are then further raised by exercise.

The hesitance of many obstetricians to prescribe exercise for pregnant women centers on the hypothetical fetal risks of impaired transplacental blood flow of oxygen, carbon dioxide, and nutrients during maternal exercise, as well as the potentially teratogenic effects of raising fetal temperature.

Most studies show a minimal to moderate increase in fetal heart rate during maternal exercise, and there is also evidence of fetal heart rate decelerations and bradycardia; however, no lasting fetal effects have been reported.

Data on the effects of increased maternal core temperatures are limited. Hyperthermia during embryogenesis (the first 45–60 days following the last menstrual period) has been shown to cause major congenital malformations (JAMA 1992;268:882–5).

The temperature threshold for human teratogenesis is 39.2° C (103° F). Moderate exercise performed in conditions allowing adequate heat dissipation has been shown to raise core temperatures no higher than 1.5° C during 30 minutes of exercise in nonpregnant women—and this temperature plateaus during as much as 1 hour of exercise.

Loss of fluid through sweat may compromise heat dissipation, so maintenance of euhydration—and thus blood volume—is essential to controlling core temperature.

Extra Nutritional Requirements

Although the published data on a link between low birth weight and maternal exercise are conflicting, it appears that adequate energy intake can offset any exercise-induced decreases in birth weight.

By the second trimester of pregnancy, an extra 1.3 MJ (300 kcal) per day are required to meet general metabolic needs in pregnancy, and this energy requirement is increased with exercise. Pregnant women use carbohydrates at a greater rate than do nonpregnant women—both at rest and during exercise—and there is preferential use of this form of energy during non-weight-bearing exercise, making adequate carbohydrate intake of particular importance.

Elite Athletes

Although routine prenatal care is sufficient for monitoring women in average exercise programs, closer obstetric observation is required for women who are elite athletes.

Most elite athletes choose to continue training during pregnancy, but they must be told that they probably will not achieve the same level of performance as they did before pregnancy, and the physiologic changes they experience—such as weight gain and joint or ligament laxity—will also make them more prone to injury. Women engaging in endurance sports can be prone to anemia that results from increased blood volume during pregnancy. High intensity, prolonged, and frequent exercise can put women at greater risk of thermoregulatory complications as well, and will usually result in less maternal and fetal weight gain than occurs in less active women.

Gestational Diabetes

The American Diabetes Association has endorsed exercise as a helpful adjunctive therapy for gestational diabetes mellitus (GDM) when glycemic control cannot be achieved through diet alone. Approximately 39% of patients with GDM require insulin therapy, but in my experience, exercise is a safe and effective alternative for most of these women.

The key to achieving euglycemia through exercise is ensuring the adequate duration and intensity of the activity. Exercise improves the impaired insulin sensitivity of women with GDM, which in turn increases glucose uptake by muscles and splanchnic organs, but this effect is achieved only through the activation of large muscles, such as the quadriceps, at adequate intensity, which explains why some studies in the literature fail to show normalization of glucose levels after exercise. At least half an hour of brisk walking per day is sufficient to upregulate insulin sensitivity in patients with GDM, obviating the need for insulin therapy.

Additionally, epidemiologic data suggest that exercise may act as primary prevention for GDM in morbidly obese women, but not in women of normal weight.

Weight Control

Although exercise should never be used for weight control during pregnancy, excessive weight gain should be avoided.

The current Institute of Medicine (IOM) guidelines on weight gain—which recommend a gain of 25–35 pounds for normal-weight women with a singleton pregnancy—are too high and are based on historical concerns about the effects of famine on fetal growth retardation.

The effect of gestational weight gain on pregnancy outcomes in obese women is not well studied. It is my opinion that the IOM guidelines are outdated, and that weight gain recommendations should be individualized. Compared with IOM recommendations for adequate gestational weight gain in obese women (at least 15 pounds), it is well recognized that a gain of less than 15 pounds in this population significantly reduces the risks of preeclampsia, C-section, and large-for-gestational-age infants.

The risk for small-for-gestational-age infants varies significantly, particularly among morbidly obese women in whom no weight gain—or even weight loss—may not have any adverse effect on birth weight.

Postpartum Exercise

Because failure to lose weight gained in pregnancy is a significant contributor to the obesity epidemic, the promotion of good exercise habits during pregnancy can also sow the seeds for postpartum exercise and weight loss.

One study showed that the amount of postpartum weight retention increases with each subsequent pregnancy (Acta. Obstet. Gynecol. Scand. 1979;58:45–7). Another study found that women who gained excessive weight during pregnancy and failed to lose it within 6 months post partum were 8.3 kg heavier 10 years later (Obstet. Gynecol. 2002;100:245–52).

Our study found that a weekly structured exercise program plus diet in postpartum overweight women were much more effective in achieving weight loss after 12 weeks compared with a single 1-hour education session about diet and exercise (J. Women's Health [Larchmt] 2003;12:991–8).

Therefore, women whose exercise habits have become firmly entrenched during pregnancy stand a much better chance of maintaining them post partum—and perhaps even into their next pregnancy.

Maintenance of euhydration is essential to controlling core temperature while exercising in pregnancy. Lynda Banzi

Exercise in Pregnancy

The extraordinary increase in obesity in the United States is giving rise not only to direct complications, such as hypertension and cardiovascular disease, but also to indirect problems such as diabetes. Hence, we have one problem leading into many others, ultimately resulting in a significant increase in morbidity and mortality.

Unfortunately, exercise—which can counter obesity—is not increasing at a concomitant rate. As a result, an emphasis on healthy lifestyles, with exercise as a central theme, has become the focus of national and international efforts undertaken by such groups as the World Health Organization, many of our medical societies, and even certain governmental agencies.

Just as exercise outside of pregnancy has clear benefits, exercise during pregnancy is also very important. For example, we know that a woman with gestational diabetes can certainly improve glucose control with exercise. However, there are clearly guidelines that must be followed when engaging in exercise during pregnancy.

In this month's Master Class, my guest professor is Raul Artal, M.D., who is an internationally recognized expert in the area of exercise physiology and exercise in pregnancy. He will lead us through specific recommendations concerning exercise during pregnancy, with references to gestational diabetes, weight control, and postpartum exercise.

Dr. Artal is professor and chair of the department of ob.gyn. at St. Louis University. He received his medical degree in Israel and his residency and fellowship training in the United States. He served as a faculty member at University of Southern California in Los Angeles and as chairman of ob.gyn. at the State University of New York, Syracuse, before attaining his current position. Dr. Artal is the lead author of the American College of Obstetricians and Gynecologists' Committee Opinion #267, “Exercise During Pregnancy and the Postpartum Period.”

Contraindications To Exercise In Pregnancy

Absolute Contraindications

Hemodynamically significant heart disease

Restrictive lung disease

Incompetent cervix/cerclage

Multiple gestation at risk for premature labor

Persistent second- or third-trimester bleeding

Placenta previa that occurs after 26 weeks' gestation

Premature labor during the current pregnancy

Ruptured membranes

Preeclampsia/pregnancy-induced hypertension

Relative Contraindications

Severe anemia

Unevaluated maternal cardiac arrhythmia

Chronic bronchitis

Poorly controlled type 1 diabetes

Extreme morbid obesity

Extreme underweight

History of extremely sedentary lifestyle

Intrauterine growth restriction in current pregnancy

Poorly controlled hypertension

Orthopedic limitations

Poorly controlled seizure disorder

Poorly controlled hyperthyroidism

Heavy smoker

Source: Obstet. Gynecol. 2002;99:171–3

Infant mortality is one of the dominant measures by which a nation's health is judged. Many factors contribute to the number of babies who survive in a given country, making infant mortality a rather unrefined gauge of overall health. Yet it has been accepted worldwide as a generally fair and realistic reflection of national health.

Leaders in the medical community and government have long recognized that the United States has unacceptably high infant mortality in comparison with other nations. I served, in fact, on the Department of Health and Human Services' Secretary's Committee on Infant Mortality under President George H.W. Bush, as part of a major effort to reduce by half our infant mortality. We still have not succeeded, despite concerted efforts.

Because this is a complex issue that will be solved only by using multiple strategies, we may do well to learn from other countries' successes. The Scandinavian countries, which boast very low infant mortality, have homogeneous populations that are difficult to compare with our own. But right next door is Canada, a country with an increasingly diverse population that may serve as a more analogous example of how programs can work to reduce infant mortality.

For a commentary on this important issue, we turn to C. Robin Walker, M.D., Ch.B., president of the Canadian Paediatric Society and professor of pediatrics at the University of Ottawa. He has studied infant mortality as an international issue, publishing on such topics as population-based approaches to prevention of preterm birth, an important contributor to infant mortality.

We hope his thoughts will provide fresh insight into a very important health measure that we continue to try to improve.

Infant mortality is one of the dominant measures by which a nation's health is judged. Many factors contribute to the number of babies who survive in a given country, making infant mortality a rather unrefined gauge of overall health. Yet it has been accepted worldwide as a generally fair and realistic reflection of national health.

Leaders in the medical community and government have long recognized that the United States has unacceptably high infant mortality in comparison with other nations. I served, in fact, on the Department of Health and Human Services' Secretary's Committee on Infant Mortality under President George H.W. Bush, as part of a major effort to reduce by half our infant mortality. We still have not succeeded, despite concerted efforts.

Because this is a complex issue that will be solved only by using multiple strategies, we may do well to learn from other countries' successes. The Scandinavian countries, which boast very low infant mortality, have homogeneous populations that are difficult to compare with our own. But right next door is Canada, a country with an increasingly diverse population that may serve as a more analogous example of how programs can work to reduce infant mortality.

For a commentary on this important issue, we turn to C. Robin Walker, M.D., Ch.B., president of the Canadian Paediatric Society and professor of pediatrics at the University of Ottawa. He has studied infant mortality as an international issue, publishing on such topics as population-based approaches to prevention of preterm birth, an important contributor to infant mortality.

We hope his thoughts will provide fresh insight into a very important health measure that we continue to try to improve.

Infant mortality is one of the dominant measures by which a nation's health is judged. Many factors contribute to the number of babies who survive in a given country, making infant mortality a rather unrefined gauge of overall health. Yet it has been accepted worldwide as a generally fair and realistic reflection of national health.

Leaders in the medical community and government have long recognized that the United States has unacceptably high infant mortality in comparison with other nations. I served, in fact, on the Department of Health and Human Services' Secretary's Committee on Infant Mortality under President George H.W. Bush, as part of a major effort to reduce by half our infant mortality. We still have not succeeded, despite concerted efforts.

Because this is a complex issue that will be solved only by using multiple strategies, we may do well to learn from other countries' successes. The Scandinavian countries, which boast very low infant mortality, have homogeneous populations that are difficult to compare with our own. But right next door is Canada, a country with an increasingly diverse population that may serve as a more analogous example of how programs can work to reduce infant mortality.

For a commentary on this important issue, we turn to C. Robin Walker, M.D., Ch.B., president of the Canadian Paediatric Society and professor of pediatrics at the University of Ottawa. He has studied infant mortality as an international issue, publishing on such topics as population-based approaches to prevention of preterm birth, an important contributor to infant mortality.

We hope his thoughts will provide fresh insight into a very important health measure that we continue to try to improve.

Preterm labor is one of the most important and vexing challenges complicating pregnancy. Premature babies account for an estimated 6%–10% of births, yet they account for 70%–85% of neonatal morbidity and mortality.

In multiple gestations, which are increasingly common as a result of delayed childbearing and the use of assisted reproductive technologies, preterm labor is an even greater risk. The literature points to an incidence of preterm labor of 20%–75% in multiple gestations. Although these figures may be somewhat high, I think it is safe to say that at least 1 in 10 multiple gestations seen at my institution are complicated by preterm labor. Not all of these patients will be admitted or will deliver early, but the very common nature of this problem and the potentially lethal consequences of premature multiple deliveries make this an issue that every physician and institution should approach carefully.

First, it is important to consider the delivery goal of a multiple gestation pregnancy. Overall, most twins are delivered at 37–38 weeks. For triplets, the gestational age is closer to 34 weeks, and quadruplets are born at around 30 weeks. These are reasonable numbers applicable to community practice.

If a patient arrives in preterm labor, you have to decide what to do, considering her situation and the capabilities of your local hospital and medical staff. It is clear that premature babies fare best when they are cared for in the institution where they are born. If someone needs to be transferred, it should be the mother, not the baby.

Obviously, if a patient carrying twins presents in labor at 35 or 36 weeks, most obstetricians would be inclined to do very little to cut short the labor, because—in the absence of other complications—these babies are likely to do well. However, if she presents at 29 weeks, it would make sense to be more aggressive.

Can the patient be safely and aggressively managed for preterm labor in her local community? The answer hinges on the plan for delivery if the treatment fails. Each hospital and service has to pick a gestational age at which neonatal survival is acceptably high. Then, options for the mother should be discussed with her and with the neonatal intensive care unit at your hospital or the institution to which she will be transferred.

Depending on the circumstances, the treatment of preterm labor may be undertaken for several reasons:

▸ To delay delivery until the patient can be transferred to a tertiary medical center with a high-level neonatal intensive care unit.

▸ To delay delivery 24–48 hours for the administration of corticosteroid therapy.

▸ To reduce the strength and frequency of uterine contractions, enabling the fetus to further develop in the uterus.

▸ To minimize hospital stays for the mother and the neonate.

▸ To reduce the risk of neonatal morbidity and mortality by preventing preterm delivery, the most dangerous complication of multiple gestation pregnancies.

When I consult with a woman in preterm labor, I go through a list of available options. Unfortunately, a careful review of the literature reveals few really good, effective treatments.

Although new ideas emerge every few years, not many interventional strategies have withstood attempts to corroborate results from single institutions. It may be tempting to “just do something,” but we owe it to our patients to stick to scientifically valid and efficacious treatments.

Bed Rest

Bed rest or activity restriction will not prevent preterm labor. Rest neither lengthens gestation nor reduces neonatal morbidity in multiple gestation pregnancies. In some studies these patients did worse.

If a patient carrying multiples has a short cervix and threatened preterm labor, there is some evidence to support getting her off her feet rather than having her continue working at a very active job.

Once a multiple pregnancy is complicated by preterm labor, hospitalization may be necessary for observation and implementation of a treatment course.

Hydration

There is no evidence that hydration is an effective treatment for preterm labor. In fact, the initial administration of bolus intravenous fluids may pose some risk to patients with multiple gestations. These patients already have an increased blood volume and could develop pulmonary edema from fluid overload if tocolytic therapy is initiated after unnecessary fluids are administered.

Progesterone

A study by Paul J. Meis, M.D., and colleagues (N. Engl. J. Med. 2003;348:2379–85) suggests recurrent preterm birth in singleton pregnancies can be prevented by 17 δ-hydroxyprogesterone caproate. The jury is still out on whether progesterone can be useful in managing active or threatened preterm labor in a multiple gestation pregnancy.

Studies are underway that may provide us with more guidance in the use of this agent. However, no evidence exists that it is safe and efficacious in multiple gestation pregnancies, so I suggest its use be reserved for patients in clinical trials.

Antibiotics

It is tantalizing to believe antibiotics would be helpful in preventing or treating preterm labor. Many researchers theorize that intrauterine infection or fetal infection may be responsible for preterm labor, particularly in pregnancies that are not complicated by multiple fetuses. However, the data do not show that antibiotic treatment is any more efficacious than placebo in prolonging pregnancy or preventing preterm delivery.

Tocolytics

The use of tocolytics to decrease or halt preterm labor is controversial in multiple gestations as well as in singleton pregnancies because the drugs pose risks to the mother and, in some cases, to the fetus. However, the available data support the position that tocolytic agents work for a short period—about 48 hours, although Roger B. Newman, M.D., and colleagues have shown that some multiple gestations can be prolonged for more than 7 days (Am. J. Obstet. Gynecol. 1989;161:547–55; “Multifetal Pregnancy: A Handbook for Care of the Pregnant Patient” [Philadelphia: Lippincott Williams & Wilkins, 2000]).

Each tocolytic agent carries its own benefits, risks, contraindications, and adverse effects profile. Numerous sources are available for this information; for quick reference; I recently published a summary in chart form (Clin. Obstet. Gynecol. 2004;47:216–26). Keep in mind that women with multiple gestations have an elevated risk of cardiovascular complications, such as pulmonary edema resulting from anemia, lower colloid oncotic pressure, and higher blood volume.

I would take a middle-of-the-road approach in choosing an agent or agents for tocolysis. For example, oral terbutaline, oral calcium channel blockers, and oral Indocin have been well-studied and widely used, with varying levels of success.

John P. Elliott, M.D., and Tari Radin, Ph.D., studied a small number of high-order multiple gestations and found similar levels of serum magnesium in triplets and quadruplets and in singleton pregnancies after the administration of magnesium sulfate for tocolysis (J. Reprod. Med. 1995;40:450–2). However, they concluded that higher levels of magnesium sulfate are needed in multiple gestations to inhibit labor. They suggested administration at infusion rates of 4–5 g/h in triplet and quadruplet pregnancies.

Research on combination tocolytic therapy has produced conflicting results. Most of the studies on this topic are dated, limited in scope, and not specifically focused on multiple gestations. Some concerns, however, have been raised. For example, magnesium sulfate administered in conjunction with nifedipine can result in significant neuromuscular blockage and a subsequent marked hypotensive effect.

My recommendation is to administer combination tocolytic therapy only with great caution, using agents such as intravenous magnesium sulfate with oral terbutaline or indomethacin. The mother and fetus also should be monitored closely by professionals well-versed in side effects linked to this form of therapy.

Should tocolytic therapy be maintained after successful cessation of labor? A careful reading of the available evidence suggests the answer is no. In well-designed studies, maintenance tocolytic therapy has reduced neither preterm deliveries nor perinatal morbidity or mortality.

Corticosteroids

Corticosteroids are among the few noncontroversial agents for use during preterm labor. These agents—which clearly reduce the incidence and severity of neonatal respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, and neonatal mortality—should be administered to any patient in preterm labor at 24–34 weeks, using the same regimen as in singleton gestations.

The accepted corticosteroid treatment consists of two intramuscular doses of betamethasone or four intramuscular doses of dexamethasone.

In higher-order gestations, Dr. Elliott and Dr. Radin have observed that beta-methasone can increase uterine contractions and advance labor in patients with frequent contractions. They therefore recommend that corticosteroids be reserved in these pregnancies for patients having fewer than three contractions per hour (Obstet. Gynecol. 1995;85:250–54). Uterine activity in higher-order gestations should be closely monitored following the administration of corticosteroids.

It once was suggested that multiple courses of prenatal corticosteroids might be of benefit. This recommendation is no longer made, because there is no good evidence for enhanced efficacy and because repeated doses are associated with clear risks, including decreased fetal growth and reduced birth weight.

Adjunctive Treatments

Isolated studies have suggested a role in preterm labor for such interventions as vaginal lever pessaries, blood transfusions, and cerclage. None of these have been put to rigorous scientific scrutiny. Cerclage obviously has no role in patients who do not have an incompetent cervix, or in such specific cases as the previable delivery of one dichorionic twin when a delayed-interval delivery of the second twin is desired.

Treating the Whole Patient

Not infrequently, preterm labor in a multiple gestation pregnancy requires the prolonged hospitalization of the mother, who may be a busy professional woman or the parent of other small children. Spending 5–10 weeks in a hospital is a long, frustrating time, replete with boredom and anxiety.

At my institution, a clinical nurse specialist who was concerned with the psychosocial effect of hospitalization on the women in our unit proposed what has become a highly successful multidimensional program: Mom Matters. The program offers support, diversion, and empathy in the form of wheelchair outings, Internet access, flexible visitation for family members (including children), manicures, pedicures, movies, and get-togethers.

The success of our program and the gratitude expressed by the mothers on our service have convinced me that this is a kind and therapeutic approach worth considering and implementing elsewhere.

The Future

The road to safe and effective therapy for preterm labor has been a long and frustrating one. I am hopeful that researchers are now on the right track, focusing on subtle indications of infection and other potential causes of preterm labor.

In multiple gestations, of course, preterm labor is often caused simply because there are too many fetuses in the womb. Uterine overdistension will not be an easy problem to overcome, except by reducing multiple gestations. Many of our colleagues in reproductive endocrinology have gotten the message that implanting too many embryos is unwise and unethical.

I believe that in the coming years, we will gain a better understanding of organic causes of preterm labor, permitting us to customize therapy according to individual circumstances of each pregnancy.

A twin pregnancy at 25 weeks' gestation shows discordancy for fetal size. The patient presented in preterm labor and will be followed closely. Courtesy Dr. Washington Hill

A Practical Perspective on a Complicated Problem

The health of any country is judged by the survival of its infants. The United States spends 15% of its gross national product on health care, yet it ranks 21st in the world in its infant mortality rate of 8 deaths per 1,000 live births, according to the World Health Organization. The two main contributors to this death rate are prematurity and birth defects.

Aggressive research programs are aimed at trying to understand the pathophysiology of preterm birth, and clinical interventions have been introduced in an attempt to reduce this unacceptably high rate of preterm birth.

Washington Clark Hill, M.D., the guest expert for the Master Class this month, has long studied preterm labor in the context of both singleton and multiple gestations. He has published comprehensive overviews of research on the complications of tocolysis and the prevention and treatment of preterm labor.

A graduate of Temple University School of Medicine in Philadelphia, Dr. Hill did his residency training at William Beaumont Army Medical Center in El Paso, Tex., before completing a fellowship in maternal-fetal medicine at the University of California, San Francisco.

He is director of the perinatal center and the division of maternal-fetal medicine at the Sarasota (Fla.) Memorial Hospital. Dr. Hill brings a clinical and practical perspective to this complicated problem. His insights will allow us to disentangle fact from fiction and what works from what doesn't.

Preterm labor is one of the most important and vexing challenges complicating pregnancy. Premature babies account for an estimated 6%–10% of births, yet they account for 70%–85% of neonatal morbidity and mortality.

In multiple gestations, which are increasingly common as a result of delayed childbearing and the use of assisted reproductive technologies, preterm labor is an even greater risk. The literature points to an incidence of preterm labor of 20%–75% in multiple gestations. Although these figures may be somewhat high, I think it is safe to say that at least 1 in 10 multiple gestations seen at my institution are complicated by preterm labor. Not all of these patients will be admitted or will deliver early, but the very common nature of this problem and the potentially lethal consequences of premature multiple deliveries make this an issue that every physician and institution should approach carefully.

First, it is important to consider the delivery goal of a multiple gestation pregnancy. Overall, most twins are delivered at 37–38 weeks. For triplets, the gestational age is closer to 34 weeks, and quadruplets are born at around 30 weeks. These are reasonable numbers applicable to community practice.

If a patient arrives in preterm labor, you have to decide what to do, considering her situation and the capabilities of your local hospital and medical staff. It is clear that premature babies fare best when they are cared for in the institution where they are born. If someone needs to be transferred, it should be the mother, not the baby.

Obviously, if a patient carrying twins presents in labor at 35 or 36 weeks, most obstetricians would be inclined to do very little to cut short the labor, because—in the absence of other complications—these babies are likely to do well. However, if she presents at 29 weeks, it would make sense to be more aggressive.

Can the patient be safely and aggressively managed for preterm labor in her local community? The answer hinges on the plan for delivery if the treatment fails. Each hospital and service has to pick a gestational age at which neonatal survival is acceptably high. Then, options for the mother should be discussed with her and with the neonatal intensive care unit at your hospital or the institution to which she will be transferred.

Depending on the circumstances, the treatment of preterm labor may be undertaken for several reasons:

▸ To delay delivery until the patient can be transferred to a tertiary medical center with a high-level neonatal intensive care unit.

▸ To delay delivery 24–48 hours for the administration of corticosteroid therapy.

▸ To reduce the strength and frequency of uterine contractions, enabling the fetus to further develop in the uterus.

▸ To minimize hospital stays for the mother and the neonate.

▸ To reduce the risk of neonatal morbidity and mortality by preventing preterm delivery, the most dangerous complication of multiple gestation pregnancies.

When I consult with a woman in preterm labor, I go through a list of available options. Unfortunately, a careful review of the literature reveals few really good, effective treatments.

Although new ideas emerge every few years, not many interventional strategies have withstood attempts to corroborate results from single institutions. It may be tempting to “just do something,” but we owe it to our patients to stick to scientifically valid and efficacious treatments.

Bed Rest

Bed rest or activity restriction will not prevent preterm labor. Rest neither lengthens gestation nor reduces neonatal morbidity in multiple gestation pregnancies. In some studies these patients did worse.

If a patient carrying multiples has a short cervix and threatened preterm labor, there is some evidence to support getting her off her feet rather than having her continue working at a very active job.

Once a multiple pregnancy is complicated by preterm labor, hospitalization may be necessary for observation and implementation of a treatment course.

Hydration

There is no evidence that hydration is an effective treatment for preterm labor. In fact, the initial administration of bolus intravenous fluids may pose some risk to patients with multiple gestations. These patients already have an increased blood volume and could develop pulmonary edema from fluid overload if tocolytic therapy is initiated after unnecessary fluids are administered.

Progesterone

A study by Paul J. Meis, M.D., and colleagues (N. Engl. J. Med. 2003;348:2379–85) suggests recurrent preterm birth in singleton pregnancies can be prevented by 17 δ-hydroxyprogesterone caproate. The jury is still out on whether progesterone can be useful in managing active or threatened preterm labor in a multiple gestation pregnancy.

Studies are underway that may provide us with more guidance in the use of this agent. However, no evidence exists that it is safe and efficacious in multiple gestation pregnancies, so I suggest its use be reserved for patients in clinical trials.

Antibiotics

It is tantalizing to believe antibiotics would be helpful in preventing or treating preterm labor. Many researchers theorize that intrauterine infection or fetal infection may be responsible for preterm labor, particularly in pregnancies that are not complicated by multiple fetuses. However, the data do not show that antibiotic treatment is any more efficacious than placebo in prolonging pregnancy or preventing preterm delivery.

Tocolytics

The use of tocolytics to decrease or halt preterm labor is controversial in multiple gestations as well as in singleton pregnancies because the drugs pose risks to the mother and, in some cases, to the fetus. However, the available data support the position that tocolytic agents work for a short period—about 48 hours, although Roger B. Newman, M.D., and colleagues have shown that some multiple gestations can be prolonged for more than 7 days (Am. J. Obstet. Gynecol. 1989;161:547–55; “Multifetal Pregnancy: A Handbook for Care of the Pregnant Patient” [Philadelphia: Lippincott Williams & Wilkins, 2000]).

Each tocolytic agent carries its own benefits, risks, contraindications, and adverse effects profile. Numerous sources are available for this information; for quick reference; I recently published a summary in chart form (Clin. Obstet. Gynecol. 2004;47:216–26). Keep in mind that women with multiple gestations have an elevated risk of cardiovascular complications, such as pulmonary edema resulting from anemia, lower colloid oncotic pressure, and higher blood volume.

I would take a middle-of-the-road approach in choosing an agent or agents for tocolysis. For example, oral terbutaline, oral calcium channel blockers, and oral Indocin have been well-studied and widely used, with varying levels of success.

John P. Elliott, M.D., and Tari Radin, Ph.D., studied a small number of high-order multiple gestations and found similar levels of serum magnesium in triplets and quadruplets and in singleton pregnancies after the administration of magnesium sulfate for tocolysis (J. Reprod. Med. 1995;40:450–2). However, they concluded that higher levels of magnesium sulfate are needed in multiple gestations to inhibit labor. They suggested administration at infusion rates of 4–5 g/h in triplet and quadruplet pregnancies.

Research on combination tocolytic therapy has produced conflicting results. Most of the studies on this topic are dated, limited in scope, and not specifically focused on multiple gestations. Some concerns, however, have been raised. For example, magnesium sulfate administered in conjunction with nifedipine can result in significant neuromuscular blockage and a subsequent marked hypotensive effect.

My recommendation is to administer combination tocolytic therapy only with great caution, using agents such as intravenous magnesium sulfate with oral terbutaline or indomethacin. The mother and fetus also should be monitored closely by professionals well-versed in side effects linked to this form of therapy.

Should tocolytic therapy be maintained after successful cessation of labor? A careful reading of the available evidence suggests the answer is no. In well-designed studies, maintenance tocolytic therapy has reduced neither preterm deliveries nor perinatal morbidity or mortality.

Corticosteroids

Corticosteroids are among the few noncontroversial agents for use during preterm labor. These agents—which clearly reduce the incidence and severity of neonatal respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, and neonatal mortality—should be administered to any patient in preterm labor at 24–34 weeks, using the same regimen as in singleton gestations.

The accepted corticosteroid treatment consists of two intramuscular doses of betamethasone or four intramuscular doses of dexamethasone.

In higher-order gestations, Dr. Elliott and Dr. Radin have observed that beta-methasone can increase uterine contractions and advance labor in patients with frequent contractions. They therefore recommend that corticosteroids be reserved in these pregnancies for patients having fewer than three contractions per hour (Obstet. Gynecol. 1995;85:250–54). Uterine activity in higher-order gestations should be closely monitored following the administration of corticosteroids.

It once was suggested that multiple courses of prenatal corticosteroids might be of benefit. This recommendation is no longer made, because there is no good evidence for enhanced efficacy and because repeated doses are associated with clear risks, including decreased fetal growth and reduced birth weight.

Adjunctive Treatments

Isolated studies have suggested a role in preterm labor for such interventions as vaginal lever pessaries, blood transfusions, and cerclage. None of these have been put to rigorous scientific scrutiny. Cerclage obviously has no role in patients who do not have an incompetent cervix, or in such specific cases as the previable delivery of one dichorionic twin when a delayed-interval delivery of the second twin is desired.

Treating the Whole Patient

Not infrequently, preterm labor in a multiple gestation pregnancy requires the prolonged hospitalization of the mother, who may be a busy professional woman or the parent of other small children. Spending 5–10 weeks in a hospital is a long, frustrating time, replete with boredom and anxiety.

At my institution, a clinical nurse specialist who was concerned with the psychosocial effect of hospitalization on the women in our unit proposed what has become a highly successful multidimensional program: Mom Matters. The program offers support, diversion, and empathy in the form of wheelchair outings, Internet access, flexible visitation for family members (including children), manicures, pedicures, movies, and get-togethers.

The success of our program and the gratitude expressed by the mothers on our service have convinced me that this is a kind and therapeutic approach worth considering and implementing elsewhere.

The Future

The road to safe and effective therapy for preterm labor has been a long and frustrating one. I am hopeful that researchers are now on the right track, focusing on subtle indications of infection and other potential causes of preterm labor.

In multiple gestations, of course, preterm labor is often caused simply because there are too many fetuses in the womb. Uterine overdistension will not be an easy problem to overcome, except by reducing multiple gestations. Many of our colleagues in reproductive endocrinology have gotten the message that implanting too many embryos is unwise and unethical.

I believe that in the coming years, we will gain a better understanding of organic causes of preterm labor, permitting us to customize therapy according to individual circumstances of each pregnancy.

A twin pregnancy at 25 weeks' gestation shows discordancy for fetal size. The patient presented in preterm labor and will be followed closely. Courtesy Dr. Washington Hill

A Practical Perspective on a Complicated Problem

The health of any country is judged by the survival of its infants. The United States spends 15% of its gross national product on health care, yet it ranks 21st in the world in its infant mortality rate of 8 deaths per 1,000 live births, according to the World Health Organization. The two main contributors to this death rate are prematurity and birth defects.

Aggressive research programs are aimed at trying to understand the pathophysiology of preterm birth, and clinical interventions have been introduced in an attempt to reduce this unacceptably high rate of preterm birth.

Washington Clark Hill, M.D., the guest expert for the Master Class this month, has long studied preterm labor in the context of both singleton and multiple gestations. He has published comprehensive overviews of research on the complications of tocolysis and the prevention and treatment of preterm labor.

A graduate of Temple University School of Medicine in Philadelphia, Dr. Hill did his residency training at William Beaumont Army Medical Center in El Paso, Tex., before completing a fellowship in maternal-fetal medicine at the University of California, San Francisco.

He is director of the perinatal center and the division of maternal-fetal medicine at the Sarasota (Fla.) Memorial Hospital. Dr. Hill brings a clinical and practical perspective to this complicated problem. His insights will allow us to disentangle fact from fiction and what works from what doesn't.

Preterm labor is one of the most important and vexing challenges complicating pregnancy. Premature babies account for an estimated 6%–10% of births, yet they account for 70%–85% of neonatal morbidity and mortality.

In multiple gestations, which are increasingly common as a result of delayed childbearing and the use of assisted reproductive technologies, preterm labor is an even greater risk. The literature points to an incidence of preterm labor of 20%–75% in multiple gestations. Although these figures may be somewhat high, I think it is safe to say that at least 1 in 10 multiple gestations seen at my institution are complicated by preterm labor. Not all of these patients will be admitted or will deliver early, but the very common nature of this problem and the potentially lethal consequences of premature multiple deliveries make this an issue that every physician and institution should approach carefully.

First, it is important to consider the delivery goal of a multiple gestation pregnancy. Overall, most twins are delivered at 37–38 weeks. For triplets, the gestational age is closer to 34 weeks, and quadruplets are born at around 30 weeks. These are reasonable numbers applicable to community practice.

If a patient arrives in preterm labor, you have to decide what to do, considering her situation and the capabilities of your local hospital and medical staff. It is clear that premature babies fare best when they are cared for in the institution where they are born. If someone needs to be transferred, it should be the mother, not the baby.

Obviously, if a patient carrying twins presents in labor at 35 or 36 weeks, most obstetricians would be inclined to do very little to cut short the labor, because—in the absence of other complications—these babies are likely to do well. However, if she presents at 29 weeks, it would make sense to be more aggressive.

Can the patient be safely and aggressively managed for preterm labor in her local community? The answer hinges on the plan for delivery if the treatment fails. Each hospital and service has to pick a gestational age at which neonatal survival is acceptably high. Then, options for the mother should be discussed with her and with the neonatal intensive care unit at your hospital or the institution to which she will be transferred.

Depending on the circumstances, the treatment of preterm labor may be undertaken for several reasons:

▸ To delay delivery until the patient can be transferred to a tertiary medical center with a high-level neonatal intensive care unit.

▸ To delay delivery 24–48 hours for the administration of corticosteroid therapy.

▸ To reduce the strength and frequency of uterine contractions, enabling the fetus to further develop in the uterus.

▸ To minimize hospital stays for the mother and the neonate.

▸ To reduce the risk of neonatal morbidity and mortality by preventing preterm delivery, the most dangerous complication of multiple gestation pregnancies.

When I consult with a woman in preterm labor, I go through a list of available options. Unfortunately, a careful review of the literature reveals few really good, effective treatments.

Although new ideas emerge every few years, not many interventional strategies have withstood attempts to corroborate results from single institutions. It may be tempting to “just do something,” but we owe it to our patients to stick to scientifically valid and efficacious treatments.

Bed Rest

Bed rest or activity restriction will not prevent preterm labor. Rest neither lengthens gestation nor reduces neonatal morbidity in multiple gestation pregnancies. In some studies these patients did worse.

If a patient carrying multiples has a short cervix and threatened preterm labor, there is some evidence to support getting her off her feet rather than having her continue working at a very active job.

Once a multiple pregnancy is complicated by preterm labor, hospitalization may be necessary for observation and implementation of a treatment course.

Hydration

There is no evidence that hydration is an effective treatment for preterm labor. In fact, the initial administration of bolus intravenous fluids may pose some risk to patients with multiple gestations. These patients already have an increased blood volume and could develop pulmonary edema from fluid overload if tocolytic therapy is initiated after unnecessary fluids are administered.

Progesterone

A study by Paul J. Meis, M.D., and colleagues (N. Engl. J. Med. 2003;348:2379–85) suggests recurrent preterm birth in singleton pregnancies can be prevented by 17 δ-hydroxyprogesterone caproate. The jury is still out on whether progesterone can be useful in managing active or threatened preterm labor in a multiple gestation pregnancy.

Studies are underway that may provide us with more guidance in the use of this agent. However, no evidence exists that it is safe and efficacious in multiple gestation pregnancies, so I suggest its use be reserved for patients in clinical trials.

Antibiotics

It is tantalizing to believe antibiotics would be helpful in preventing or treating preterm labor. Many researchers theorize that intrauterine infection or fetal infection may be responsible for preterm labor, particularly in pregnancies that are not complicated by multiple fetuses. However, the data do not show that antibiotic treatment is any more efficacious than placebo in prolonging pregnancy or preventing preterm delivery.

Tocolytics

The use of tocolytics to decrease or halt preterm labor is controversial in multiple gestations as well as in singleton pregnancies because the drugs pose risks to the mother and, in some cases, to the fetus. However, the available data support the position that tocolytic agents work for a short period—about 48 hours, although Roger B. Newman, M.D., and colleagues have shown that some multiple gestations can be prolonged for more than 7 days (Am. J. Obstet. Gynecol. 1989;161:547–55; “Multifetal Pregnancy: A Handbook for Care of the Pregnant Patient” [Philadelphia: Lippincott Williams & Wilkins, 2000]).

Each tocolytic agent carries its own benefits, risks, contraindications, and adverse effects profile. Numerous sources are available for this information; for quick reference; I recently published a summary in chart form (Clin. Obstet. Gynecol. 2004;47:216–26). Keep in mind that women with multiple gestations have an elevated risk of cardiovascular complications, such as pulmonary edema resulting from anemia, lower colloid oncotic pressure, and higher blood volume.

I would take a middle-of-the-road approach in choosing an agent or agents for tocolysis. For example, oral terbutaline, oral calcium channel blockers, and oral Indocin have been well-studied and widely used, with varying levels of success.

John P. Elliott, M.D., and Tari Radin, Ph.D., studied a small number of high-order multiple gestations and found similar levels of serum magnesium in triplets and quadruplets and in singleton pregnancies after the administration of magnesium sulfate for tocolysis (J. Reprod. Med. 1995;40:450–2). However, they concluded that higher levels of magnesium sulfate are needed in multiple gestations to inhibit labor. They suggested administration at infusion rates of 4–5 g/h in triplet and quadruplet pregnancies.

Research on combination tocolytic therapy has produced conflicting results. Most of the studies on this topic are dated, limited in scope, and not specifically focused on multiple gestations. Some concerns, however, have been raised. For example, magnesium sulfate administered in conjunction with nifedipine can result in significant neuromuscular blockage and a subsequent marked hypotensive effect.

My recommendation is to administer combination tocolytic therapy only with great caution, using agents such as intravenous magnesium sulfate with oral terbutaline or indomethacin. The mother and fetus also should be monitored closely by professionals well-versed in side effects linked to this form of therapy.

Should tocolytic therapy be maintained after successful cessation of labor? A careful reading of the available evidence suggests the answer is no. In well-designed studies, maintenance tocolytic therapy has reduced neither preterm deliveries nor perinatal morbidity or mortality.

Corticosteroids

Corticosteroids are among the few noncontroversial agents for use during preterm labor. These agents—which clearly reduce the incidence and severity of neonatal respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, and neonatal mortality—should be administered to any patient in preterm labor at 24–34 weeks, using the same regimen as in singleton gestations.

The accepted corticosteroid treatment consists of two intramuscular doses of betamethasone or four intramuscular doses of dexamethasone.

In higher-order gestations, Dr. Elliott and Dr. Radin have observed that beta-methasone can increase uterine contractions and advance labor in patients with frequent contractions. They therefore recommend that corticosteroids be reserved in these pregnancies for patients having fewer than three contractions per hour (Obstet. Gynecol. 1995;85:250–54). Uterine activity in higher-order gestations should be closely monitored following the administration of corticosteroids.

It once was suggested that multiple courses of prenatal corticosteroids might be of benefit. This recommendation is no longer made, because there is no good evidence for enhanced efficacy and because repeated doses are associated with clear risks, including decreased fetal growth and reduced birth weight.

Adjunctive Treatments

Isolated studies have suggested a role in preterm labor for such interventions as vaginal lever pessaries, blood transfusions, and cerclage. None of these have been put to rigorous scientific scrutiny. Cerclage obviously has no role in patients who do not have an incompetent cervix, or in such specific cases as the previable delivery of one dichorionic twin when a delayed-interval delivery of the second twin is desired.

Treating the Whole Patient

Not infrequently, preterm labor in a multiple gestation pregnancy requires the prolonged hospitalization of the mother, who may be a busy professional woman or the parent of other small children. Spending 5–10 weeks in a hospital is a long, frustrating time, replete with boredom and anxiety.

At my institution, a clinical nurse specialist who was concerned with the psychosocial effect of hospitalization on the women in our unit proposed what has become a highly successful multidimensional program: Mom Matters. The program offers support, diversion, and empathy in the form of wheelchair outings, Internet access, flexible visitation for family members (including children), manicures, pedicures, movies, and get-togethers.

The success of our program and the gratitude expressed by the mothers on our service have convinced me that this is a kind and therapeutic approach worth considering and implementing elsewhere.

The Future

The road to safe and effective therapy for preterm labor has been a long and frustrating one. I am hopeful that researchers are now on the right track, focusing on subtle indications of infection and other potential causes of preterm labor.

In multiple gestations, of course, preterm labor is often caused simply because there are too many fetuses in the womb. Uterine overdistension will not be an easy problem to overcome, except by reducing multiple gestations. Many of our colleagues in reproductive endocrinology have gotten the message that implanting too many embryos is unwise and unethical.

I believe that in the coming years, we will gain a better understanding of organic causes of preterm labor, permitting us to customize therapy according to individual circumstances of each pregnancy.

A twin pregnancy at 25 weeks' gestation shows discordancy for fetal size. The patient presented in preterm labor and will be followed closely. Courtesy Dr. Washington Hill

A Practical Perspective on a Complicated Problem

The health of any country is judged by the survival of its infants. The United States spends 15% of its gross national product on health care, yet it ranks 21st in the world in its infant mortality rate of 8 deaths per 1,000 live births, according to the World Health Organization. The two main contributors to this death rate are prematurity and birth defects.

Aggressive research programs are aimed at trying to understand the pathophysiology of preterm birth, and clinical interventions have been introduced in an attempt to reduce this unacceptably high rate of preterm birth.

Washington Clark Hill, M.D., the guest expert for the Master Class this month, has long studied preterm labor in the context of both singleton and multiple gestations. He has published comprehensive overviews of research on the complications of tocolysis and the prevention and treatment of preterm labor.

A graduate of Temple University School of Medicine in Philadelphia, Dr. Hill did his residency training at William Beaumont Army Medical Center in El Paso, Tex., before completing a fellowship in maternal-fetal medicine at the University of California, San Francisco.

He is director of the perinatal center and the division of maternal-fetal medicine at the Sarasota (Fla.) Memorial Hospital. Dr. Hill brings a clinical and practical perspective to this complicated problem. His insights will allow us to disentangle fact from fiction and what works from what doesn't.