Persistent pulmonary hypertension of the newborn (PPHN) is a serious syndrome in which newborn infants do not undergo the normal fetal-to-neonatal circulatory transition and, as a result, experience severe respiratory failure.  Previous studies have suggested that a mother’s use of nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and aspirin, during pregnancy could increase the risk of having an infant born with PPHN.  We examined this association, with emphasis on maternal use of NSAIDs in the third trimester of pregnancy. We looked at interview data from 377 mothers whose infants had PPHN and 836 mothers whose infants were born without major defects from 1998 to 2003. During the interviews, mothers were asked about prescription and over-the-counter medications used in pregnancy as well as a variety of other factors. Overall, we found that maternal use of NSAIDs during pregnancy was not associated with having an infant born with PPHN.

Pediatrics 2013;131:79-87.

Studies have shown that catechin, an antioxidant found in tea, can interfere with the absorption of folic acid in the body. It is known that folic acid protects against having an infant born with neural tube defects. We examined whether drinking tea during early pregnancy puts women at risk of having an infant born with spina bifida. We looked at data from mothers of 518 spina bifida infants and 6424 infants without defects during three periods (1976-1988, 1998-2005, and 2009-2010). Overall, we did not find that tea consumption during early pregnancy increased the risk of spina bifida. Among women who had daily folic acid intake of 400 µg or more, our data showed that daily consumption of 3 or more cups of tea may increase the risk of spina bifida. This increased risk may be due to the catechins in tea disrupting absorption of folic acid, but more studies need to be done to better understand these findings.

Birth Defects Res A Clin Mol Teratol 2012;94(10):756-61.

Amoxicillin has been the preferred drug for the treatment of common infections during pregnancy. Prior studies had suggested an increased risk of oral clefts after exposure to amoxicillin in early pregnancy, but findings have been inconsistent. We used data from our study to test this hypothesis. We found that maternal use of amoxicillin in the first trimester was associated with a two-fold increased risk of cleft lip. The risk was not elevated for exposures to other antibiotics. Of note, given the baseline risk for oral clefts of about 1 per 1,000 live births, if our findings were correct, the absolute risk would increase among women who use amoxicillin in the first trimester to about 2 per 1,000; that is, the risk that could be due to amoxicillin is quite modest.

Epidemiology 2012;23(5):699-705.

Previous studies have linked high sugar intake with an increased risk of birth defects. Using the dietary data collected in our study, we examined whether foods that raise blood sugar more than others (called “high glycemic index” foods) increased the risk of specific birth defects. Using interviews from 1988 through 1998, we had information on a total of 704 mothers of nonmalformed infants and 1921 mothers of infants with birth defects. The birth defects we looked at included amniotic bands, craniosynostosis, gastroschisis, hypospadias, small intestinal defects, anorectal defects, limb reductions, omphalocele, cleft lip and/or palate, renal agenesis, and tracheoesophageal fistula. For most groups we did not find an increased risk with high sugar intake, though the dietary glycemic intake was linked to an increase in the risk for anorectal defects and for the amniotic band case group. This is the first paper to explore glycemic intake in relation to a large group of birth defects, so more studies are needed.

Paediatr Perinat Epidemiol 2011;25:340-6.

Taking folic acid vitamins during early pregnancy has been shown to reduce the occurrence of neural tube defects such as spina bifida. In order to increase the folic acid available in food, the US Food and Drug Administration mandated that enriched grain products be fortified with folic acid beginning in 1998. We studied whether intake of folic acid from vitamins still reduced the risk of spina bifida now that women are consuming higher levels of folic acid in their diet. Using Slone’s Pregnancy Health Interview Study interviews from 1998-2007, we looked at pre-pregnancy diet and folic acid vitamin use during early pregnancy among 205 mothers of babies with spina bifida and 6357 mothers of babies without any birth defects. We found that use of folic acid-containing vitamins in early pregnancy did not reduce the risk of spina bifida; but increasing amounts of folic acid in the mother’s diet did. Our study findings raise the possibility that in the current era, where foods are fortified with folic acid, folic acid-containing vitamin supplements during early pregnancy may not further reduce the risk for spina bifida. Increasing amounts of dietary folic acid did appear to reduce the risk of spina bifida.

Epidemiology 2011;22(5):731-7.

The Vaccines and Medications in Pregnancy Surveillance System (VAMPSS) has been designed to assess systematically the safety of vaccines and medications during pregnancy and is suited ideally to evaluate the gestational safety of seasonal and pandemic influenza vaccine and influenza antivirals. VAMPSS is coordinated by the American Academy of Allergy Asthma and Immunology and includes 2 complimentary data collection arms (prospective cohort and case-control surveillance) and a standing independent advisory committee. Both data collection arms obtain information directly from the mother, which facilitates accurate capture of exposures and potential confounders. The full range of perinatal outcomes, which includes specific birth defects, is assessed. Information that is obtained from VAMPSS should allow enhanced prevention and improved treatment of influenza during pregnancy by the identification of any exposures that might be associated with important risks and the provision of reassurance for exposures that are found to be relatively safe.

Am J Obstet Gynecol 2011;204(6 Suppl. 1):S64-8.

Asthma is one of the most common serious medical problems in pregnancy and may be increasing in prevalence. Asthma itself may cause harm to the fetus, but little is known about the risks of medications used to treat asthma. In 2005, the National Asthma Education and Prevention Program (NAEPP) published recommendation for treatment of asthma in pregnancy, suggesting inhaled steroids as first line treatment, but the extent to which the guidelines are being followed is unclear. We used data from mothers of non-malformed infants to assess the prevalence of asthma, levels of asthma symptoms and the use of asthma medications among pregnant women.

We found a high rate of asthma among pregnant women (almost 14%), and about half of these women used at least one medication to treat their asthma during pregnancy. Despite the NAEPP guidelines and the new medications on the market, there were few changes in medications reported over time. We also noted that only about 37% of women whose asthma symptoms were poorly controlled reported use of controller medications. Because some reports have suggested that pregnant women may discontinue use of their asthma medications because of concerns about their safety for their babies, it is important to more clearly understand the risks and safety of these medications in pregnancy.

Ann Allergy Asthma Immunol 2010;105:110-7.

Over the last decade, interest in herbal medications has increased, but we know very little about their safety, efficacy, or rates of use in pregnancy. We looked at our data from mothers of non-malformed infants to determine the prevalence of use and the types of herbal treatments that pregnant women are using.

We found that almost 6% of women reported using some type of herbal or natural treatment during pregnancy, but use of individual, specific products is much lower. The most commonly reported treatments, ginger and Echinacea, were used by only 0.6% of women. Use varied greatly by geographic region, ranging from 4.5% in Massachusetts to 9.2% in Toronto. Use also increased with increasing age.

We also found indirect evidence that women used these products largely for their intended purpose—women who used cough/cold remedies reported having upper respiratory infections and women who used products for nausea and vomiting reported having morning sickness during their pregnancies. They used these products primarily in early pregnancy.

These products need further study to evaluate their safety in pregnancy. Even though rates of use are low, because little is known about their efficacy, even small risks might affect benefit-risk assessments.

Am J Obstet Gynecol 2010;202(5):439.e1-10.

Preterm birth, defined as deliveries at less than 37 weeks’ gestation, is the leading cause of infant morbidity and mortality in developed countries, but its causes remain largely unknown. A previous Swedish study found that women who took a decongestant in pregnancy had a reduced risk of preterm delivery. We examined whether this association was present in our data on 3,271 Massachusetts liveborn births. We also found a reduced risk: women who took decongestants only during the second or third trimester were approximately 58% less likely to experience preterm delivery. Although we controlled for many potential confounding factors such as maternal age, race, income, and reported reason for taking the decongestant, we question whether the observed association implies a cause and effect relationship. It is difficult to identify biologic causes of sinus congestion, particularly in pregnancy when hormone-induced rhinitis sometimes occurs. Thus, the possibility of confounding by underlying condition remains.

Birth Defects Res A Clin Mol Teratol 2010;88:715-21.

Preterm delivery and low birth weight can carry significant medical risks. These adverse outcomes occur 2-3 times more frequently in African American births than their White counterparts. This study was to determine whether maternal use of multivitamin supplements might account for the racial disparity. We conducted a retrospective cohort study of 2345 Non-Hispanic White and 135 Non-Hispanic Black mothers and their infants, born in Massachusetts between 1998 and 2007. Preterm delivery and low birth weight were more common, but multivitamin supplementation around the time of conception was less common, in the Non-Hispanic Black group. White mothers who took multivitamin supplements had the same risk of preterm delivery and low birth weight as those who did not take supplements. Black mothers who took multivitamin supplements, on the other hand, had babies born an estimated 493 grams heavier than Black mothers who did not take supplements. A similar pattern was also observed for gestational length, but the longer gestations in Black supplementers compared to Black non-supplementers was not statistically significant. Overall, our findings suggest that periconceptional multivitamin use may improve fetal growth and possibly gestational age in the offspring of African American women.

Ann Epidemiol 2010;20:233-40.

Prevalences of obesity and diabetes have been increasing in the United States in women of all ages. Among the many pregnancy complications associated with obesity and diabetes is the risk of birth defects, particularly neural tube defects. We hypothesized that this increased risk may be a result of high blood sugar levels, also called hyperglycemia. To examine this we looked at high dietary glycemic intakes (i.e., foods that raise blood sugar) and the risk or neural tube defects. We used glycemic index as a measure of the quality of sugar consumed (e.g. fruits versus candy) and the glycemic load as a measure of the quality and quantity consumed. Using interviews from 1988 through 1998, we had a total of 696 mothers of controls and 698 mothers of cases with a neural tube defect. We found that dietary glycemic intake (both glycemic index and load) approximately doubled the risk of neural tube defects. This study adds further evidence that hyperglycemia may be involved with the development of neural tube defects.

Am J Epidemiol 2010;171(4):407-14.

Depression is a common condition in pregnancy, and many women with this condition are treated with antidepressant medications. Antidepressants that belong to the class called “selective serotonin reuptake inhibitors (“SSRIs”) are typically prescribed. To study whether premature (“preterm”) delivery and babies who are small for their gestational age might be related to use of these medications, or possibly the underlying depression among mothers who use these medications, we studied these relationships. We found that there was a modestly increased risk for preterm delivery among women who took SSRIs late in their pregnancies. In addition, the risk of both preterm delivery and having a baby who was small for gestational age were modestly increased for women who took other types of antidepressants. While antidepressant medications may have a role in these outcomes, the fact that different antidepressants seemed to be related to similar effects on the fetus might suggest that the mother’s underlying mood disorder may play a role. Whatever the cause, use of antidepressants in pregnancy may help identify women who are at increased risk for delivering babies who are either preterm or small for their gestational age.

J Clin Psychopharmacol 2009;29(6):555-60.

Persistent pulmonary hypertension of the newborn (PPHN)is a rare but very serious condition affecting roughly 1 in 1000 births. While advances have been made in improving the outcome of babies with PPHN, it would be helpful to be able to predict factors that are linked to it; some of those factors might help us identify which newborns might be most likely to have PPHN, or they may even identify conditions in pregnancy that, if modified, could reduce the risk of an infant being born with PPHN. We conducted a large study involving babies born with PPHN and a comparison group of babies without PPHN.  We found a number of factors that were more common among PPHN babies, including being delivered by Cesarean section, being a late preterm or post-term birth, being large for gestational age, and being born to a mother who was Black or Asian, was overweight, or had diabetes or asthma.  It’s not clear whether these factors are somehow related to causes of PPHN, but the new information can help doctors anticipate that women with these factors may be at higher risk for PPHN. This new knowledge may lead to a better understanding of the true causes of this serious newborn condition.

Pediatrics 2007;120(2);272-82.

The risk of birth defects following exposure to SSRIs (selective serotonin-reuptake inhibitors) in early pregnancy remains controversial.  Some recent studies have reported elevated risks for some birth defects, especially heart defects.

We looked at data from mothers of 9,849 infants with birth defects and 5,860 infants without defects and analyzed defects previously linked to SSRI use.  Overall, we found that SSRI use was not associated with significantly increased risks of craniosynostosis (where connections between skull bones close prematurely), omphalocele (intestines or other  abdominal organs protrude from the navel) or heart defects overall.  Analysis of individual SSRIs and specific defects showed significant associations between setraline (e.g. Zoloft) and omphalocele and septal defects (defects in the walls that separate the chambers of the heart) and between paroxetine (e.g. Paxil) and certain heart defects that interfere with blood flow to the lungs.  It is important to keep in mind that even if a specific SSRI increased rates four-fold, as was observed for some of these associations, the risk of having an affected child would still be less than one percent. Depression in pregnancy can be a serious problem for both the mother and her baby and women who have depression and are pregnant or who are planning a pregnancy should consult their health care providers regarding both the risks and benefits of using these drugs in pregnancy.

N Engl J Med 2007;356(26):2675-83.

About 1 in 1000 babies is born with a birth defect involving high blood pressure in its lungs (“persistent pulmonary hypertension of the newborn”, or PPHN). This condition can be fatal, and even babies who survive it can have lifelong problems. About 10 years ago, a study had suggested that women who took “SSRI” antidepressants in the last half of pregnancy might have an increased risk of having a baby with PPHN, but that study was far too small to be convincing. The SSRIs include many widely-used antidepressants (such as Prozac, Paxil, and Zoloft), and it was important to see if this risk might be real. The Birth Defects Study developed the largest-ever study of PPHN, and looked at whether use of SSRIs was indeed associated with higher rates of this condition. We found that women who took the drugs during the second half of pregnancy had a 6-fold increase in the risk of having a baby with PPHN. In contrast, women who stopped their SSRI medication during the first half of pregnancy didn’t have any increase in risk, nor was there an increased risk among women who took antidepressants that weren’t SSRIs. The increased risk that was identified needs to be kept in perspective, however– even if the increased risk is true, it would still mean that, among mothers who took SSRIs in late pregnancy, over 99% of babies would NOT have PPHN. Depression in pregnancy can be a serious problem for both the mother and her baby, and the risk of PPHN may not be, in itself, a reason to avoid these medications. Rather, these findings contribute to our understanding about the risks of SSRI medications, and they should be considered when women and their health care providers consider both the risks and benefits of using these drugs in pregnancy.

N Engl J Med 2006;354(6):579-87.

Medicines that can be bought without a prescription, so-called over-the-counter medications (or OTCs), are among the most common exposures during pregnancy. Over 75% of women in our study reported that they took at least one OTC medication during pregnancy. Acetaminophen, the active ingredient in Tylenol and many other pain, fever, cough, and cold products, was used by the highest proportion of women, with two-thirds taking it sometime during pregnancy. Ibuprofen, taken for pain, fever, and inflammation in popular products like Advil and Motrin, was used by one in five women. Pseudoephedrine, found in Sudafed and other decongestant products, was used by one in seven women. It is not surprising that medicines taken for headaches, pain, colds and flu would be most commonly used during pregnancy, as pregnant women are not spared these conditions. It was surprising to us, however, that some OTC medicines were taken more often during pregnancy than before pregnancy. For example, acetaminophen, pseudoephedrine, diphenhydramine (in Benadryl and other products) and guaifenesin (in Robitussin and other products) were taken by more women in each of the three trimesters of pregnancy than in the three month period before pregnancy began.

Am J Obstet Gynecol 2005;193:771-7.

A number of studies have shown that taking the vitamin folic acid around the time of conception reduces the risk of spina bifida and certain other birth defects, and that there’s enough folic acid in a daily multivitamin to provide this benefit. To find out what women know about folic acid and whether they are taking it, we reviewed information from over 16,000 women who participated in our study from 1988 to 2002. We had asked these women whether they had taken multivitamins early in pregnancy and whether they knew that folic acid could reduce the risk of birth defects. No women knew about the benefits of folic acid in 1988, but by 1996, 50% did. At the same time, use of vitamins that contain folic acid increased from 15% of pregnant women in 1988 to 40% in the last few years. While the increases in folic acid awareness and use over the past decades were encouraging, only 40% of women have been using it in recent years and that number is not increasing. Groups who were least likely to know about and use folic acid were women with the least education and income, and those who did not plan their pregnancies. By identifying these groups of women, the study findings could lead to targeted educational campaigns that could result in wider use of folic acid, which in turn would further reduce risks of birth defects.

Am J Obstet Gynecol 2005;192:121-8.

Rarely, a baby can be born with a defect in the diaphragm that allows the abdominal contents to push into the chest, creating a potentially fatal condition called “congenital diaphragmatic hernia”, or CDH. One study has suggested that being underweight before pregnancy could increase the risk of having a baby with CDH, so we examined experience in the BDS to see if this could be true. Overall, we compared mothers’ pre-pregnancy weight and other factors among 85 infants with CDH and 655 who did not have this defect. When infants had CDH combined with another birth defect, the mother’s weight made no difference in risk. On the other hand, when CDH was the only problem the infant had, there was a suggestion that women who were unusually thin or underweight for their height had an almost 2-fold increase in risk of having a baby with CDH; however, the difference was not statistically significant (that is, it could have been due to chance). This finding offers some additional support for the idea that being underweight might somehow increase a woman’s risk for having a baby with CDH.

Birth Defects Res A Clin Mol Teratol 2003;67:73-6.

Nowadays, it is widely accepted that folic acid reduces the risk of having an infant with spina bifida and other neural tube defects (NTDs). We looked at whether taking a medication that interferes with folic acid (a “folic acid antagonist”) around the time a woman becomes pregnant would therefore increase the risk of brain and spinal defects. We compared data on 1,242 infants with brain and spinal defects to a group of 6,660 infants who had malformations that weren’t affected by vitamin supplementation. We found that use of folic acid antagonists (the most common ones were anti-seizure medications and an antibiotic called trimethoprim) during the first or second months after the last menstrual period was linked to an increased risk of NTDs.

N Engl J Med 2000;343:1608-14.

It is well known that taking folic acid around the time a woman becomes pregnant reduces the risk of spina bifida and other neural tube defects (NTDs). However, it has been unclear whether folic acid also reduces the risk of other birth defects as well. Some studies suggest that folic acid taken as part of a multivitamin may reduce the risk of heart defects, cleft lip and palate, and urinary tract defects. The question: Is it the folic acid or the other vitamins that make the difference?

Using a novel approach, we reasoned that if folic acid reduced these birth defects, a medication that interferes with folic acid (a “folic acid antagonist”) might increase the risk of those same defects.

In interviews of over 15,000 new mothers, we asked if the women had taken any of these folic acid antagonists in early pregnancy (the most common ones were anti-seizure medications and trimethoprim, an antibiotic). We compared data on exposure to folic acid antagonists for 3870 infants with heart defects, 1962 with cleft lip or cleft palate, and 1100 with urinary tract defects with data on 8387 infants with malformations that were not affected by vitamin supplementation. We found that taking these anti-folate medications did indeed seem to increase the risks of heart defects, cleft lip and cleft palate, and urinary tract defects, suggesting that folic acid may be the component of multivitamins that reduces the risk of these defects. For certain folic acid antagonists, we found that those risks were minimized if women also took a multivitamin containing folic acid. For other folic acid antagonists, such anti-seizure drugs, the usual amount of folic acid in multivitamins did not seem to prevent these birth defects. These findings add further support to public health recommendations that women of childbearing potential take a daily supplement of folic acid.

Am J Epidemiol 2001;153:961-8.

High blood pressure occurring after 20 weeks of pregnancy (gestational hypertension) and its complications (preeclampsia or toxemia) are major complications of pregnancy. Although their precise causes are unknown, recent studies have suggested that high blood levels of a substance called homocysteine increases the risk of gestational hypertension. We all have homocysteine in our blood; it is a breakdown product of an amino acid found in protein-containing foods. In healthy people, homocysteine levels are kept in check by vitamins such as folate. But when folate is in short supply in the body, the amount of homocysteine builds up. Although it has been shown that folic acid supplementation decreases plasma homocysteine concentrations, it’s not known whether folic acid supplements can prevent or improve gestational hypertension and preeclampsia.

We studied whether women who took folic acid supplements had lower risk of gestational hypertension and preeclampsia. Between 1993 and 2000, women in the United States and Canada who delivered healthy infants were interviewed within six months after delivery about social, economic and medical factors, the occurrence of high blood pressure during pregnancy, and about multivitamin use in pregnancy. Of 2100 women, 204 (9.7%) had had gestational hypertension. The risk of developing this condition was lower among women taking folic acid supplementation. This finding suggests that folic acid-containing multivitamins may reduce the risk of gestational hypertension.

Am J Epidemiol 2002;156:806-12.

This study is a good example of how we use the cheek swabs that we collect from subjects. As noted in the summary above, homocysteine levels are affected by folic acid intake.

We investigated whether a known genetic variation in the homocysteine conversion process (5, 10 methylentetrahydrofolate reductase C677T polymorphism) results in a higher risk of gestational hypertension, and whether supplementation with folic acid could overcome the effects of such genetic factors. The study population included US and Canadian women with healthy infants participating in the study between 1993 and 2000. Genetic material from mothers and their offspring was extracted from cheek cells. Our findings suggested that maternal and fetal genetic variations (MTHFR C677T polymorphism) may increase the risk of gestational hypertension, but only among women who do not take folic acid supplements during pregnancy.

Epidemiology 2005;16(5):628-34.

Folic acid is a B-vitamin that protects against spina bifida and other serious brain defects in the developing fetus. Folic acid is found in green, leafy vegetables and citrus fruits, but in only small to moderate amounts. To make sure that pregnant women get more folic acid in their diets, extra amounts of this nutrient are now added to most flour, corn meal, pasta, and breakfast cereals. In our study, we ask women to report how much they ate of different foods before they became pregnant. We were able to combine this information with the amount of folic acid that is added to grain-based foods, to see if pregnant women would be getting enough folic acid to protect against spinal or brain defects. We estimated that only one in five women would get enough from natural sources (like fruits and vegetables) and fortified grain products. Fortunately, most multivitamins contain enough folic acid, so the easiest way to protect against these birth defects is for women to take a daily multivitamin that includes folic acid. This is important to do even if women aren’t planning on getting pregnant, because once a woman finds out she is pregnant, the spinal column and brain are already developing and it is too late for the folic acid benefits.

Am J Epidemiol 1999;89:1637-40.

Women are advised to not drink any alcohol during pregnancy because of possible problems with growth and brain development in their unborn baby. We explored the question of whether cleft lip or palate is linked to mother’s alcohol drinking in pregnancy. We found that among women who do drink in pregnancy, most reported having less than three drinks in one sitting and they did not have an increased risk of having a baby with a cleft lip or palate. But women who had 3 or more drinks on the days that they did drink had a higher risk of having a baby with a cleft palate in combination with a small chin (also known as Pierre Robin sequence). We also found that women who drink 5 or more drinks in a day had an increased risk of having a baby with cleft lip in combination with a cleft palate.

Birth Defects Res A Clin Mol Teratol 2003;67:509-14.

Women are told to not smoke cigarettes during pregnancy because the baby’s growth can be slowed. Other problems in the baby might result too. We looked at whether smoking during pregnancy is linked to cleft lip or palate. We found that smoking was slightly more common in mothers of babies with clefts. Even though most smokers don’t have babies with clefts and most mothers of babies with clefts don’t smoke, this slight association has now been observed in many studies, suggesting that smoking may somehow be involved in development of cleft lip or palate. Because the link is small, other factors (such as genes or other exposures) may play a role too.

Am J Epidemiol 1999;150(7):683-94.