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Nausea and vomiting of pregnancy (NVP) occurs in up to 80% of pregnant women, yet its association with birth outcomes is not clear. Several medications are used for the treatment of NVP; however, data are limited on their possible associations with birth defects.
Using data from the National Birth Defects Prevention Study (NBDPS), a multi-site population-based case-control study, we examined whether NVP or its treatment was associated with the most common non-cardiac defects in the NBDPS (non-syndromic cleft lip with or without cleft palate (CL/P), cleft palate alone (CP), neural tube defects (NTDs), and hypospadias) compared to randomly-selected non-malformed live births.
Among the 4524 cases and 5859 controls included in this study, 67.1% reported first trimester NVP, and 15.4% of them reported using at least one agent for NVP. Nausea and vomiting of pregnancy was not associated with CP or NTDs, but modest risk reductions were observed for CL/P (aOR=0.87, 0.77–0.98), and hypospadias (OR=0.84, 0.72–0.98). In regards to treatments for NVP in the first trimester, the following adjusted associations were observed with an increased risk: proton pump inhibitors and hypospadias (aOR=4.36, 1.21–15.81), steroids and hypospadias (aOR=2.87, 1.03–7.97), and ondansetron and CP (aOR=2.37, 1.18–4.76), while antacids were associated with a reduced risk for CL/P (aOR=0.58, 0.38–0.89).
Nausea and vomiting of pregnancy was not observed to be associated with an increased risk of birth defects, but possible risks related to three treatments (i.e. proton pump inhibitors, steroids and ondansetron), which could be chance findings, warrant further investigation.
Nausea and vomiting of pregnancy (NVP) occurs in up to 80 percent of pregnant women (Gill and Einarson, 2007). While there is consistency in reports about the association of NVP with reduction in risk of miscarriage, reports of the association of NVP with other pregnancy outcomes such as low birth weight and birth defects are conflicting (Weigel, 2000; Furneaux et al., 2001). It is most prevalent early in pregnancy, usually starting at about 4–9 weeks, peaking at about 7–12 weeks, and ceasing at by 16 weeks (Ebrahimi et al., 2010). Nausea and vomiting of pregnancy itself or its medication treatments, therefore, occur at a point in gestation when many embryologic systems are developing and thus are potentially susceptible to teratogenic effects of various exposures (Dilts, 1992).
For many years the mainstay of NVP treatment was Bendectin (Merrell Dow Pharmaceuticals, Kansas City, MO) (originally a combination of doxylamine succinate, dicyclomine and pyridoxine; a later formulation excluded the dicyclomine), the one medication in the United States approved for treatment of NVP. Following Bendectin’s removal from the market in 1982 after allegations that it caused fetal damage (Brent, 1995), there has been limited information on what women in the US are using to treat NVP. While there is existing literature on the optimal management of NVP and the risk of some of these medications (Ebrahimi et al., 2010; ACOG, 2004; Arsenault et al., 2002; Asker et al., 2005; Borrelli et al., 2005; Einarson et al., 2007; Gill and Einarson, 2007; Koren et al., 2010; Portnoi et al., 2003), a number of them have not been adequately tested for safety in pregnancy.
We examined NVP experienced by women in the National Birth Defects Prevention Study (NBDPS), delineated medications used to treat NVP among these women, and investigated whether NVP itself or use of NVP medications in the first trimester of pregnancy was associated with selected birth defects.
We used data from the NBDPS, a multi-site population-based case-control study, which seeks to identify risk factors associated with birth defects. Annually, each NBDPS site contributes maternal interviews of approximately 300 case subjects with any of over 30 selected birth defects and 100 control subjects without birth defects. All ten sites use a standardized protocol that was developed by the NBDPS collaborative. Case infants are identified from birth defects surveillance systems in the participating states. All infants with study-eligible birth defects who reside in the study areas are invited to participate. Controls are either randomly selected from birth certificates or selected from birth hospitals using a stratified random sampling design. Sites in the NBDPS during some or all of the study period were located in Arkansas, California, Georgia, Iowa, Massachusetts, New Jersey, New York, North Carolina, Texas and Utah. The NBDPS has been described in detail elsewhere (Yoon et al, 2001; Rasmussen et al, 2003). All study sites obtained IRB approval and study participants provided informed consent.
The NBDPS collects information on cases with over 30 different birth defects diagnosed prenatally, at birth or during the first year of life. During at least some of the study period, 9 of the 10 participating sites also collected information on affected fetal deaths at 20 weeks gestation or greater and eight of the ten sites included pregnancies that were prenatally diagnosed and electively terminated. The NBDPS excludes cases with recognized or strongly suspected chromosome abnormalities or single-gene conditions.
This analysis was limited to the most common non-cardiac NBDPS-eligible birth defect categories: orofacial clefts, neural tube defects (NTDs) and hypospadias. Cardiac defects will be the topic of a separate analysis. For analyses of clefts, we analyzed data on infants with cleft lip with or without cleft palate (CL/P) and cleft palate alone (CP) separately, given that these diagnoses are presumed to be pathogenetically and etiologically distinct (Genisca et al., 2009). Infants with clefts secondary to another defect (e.g., holoprosencephaly or amniotic band sequence) were excluded. For NTDs, we included infants with anencephaly, craniorachischisis, spina bifida, or encephalocele. Because of concern for incomplete ascertainment of first-degree hypospadias (urethral opening on the glans or corona), only infants with severe hypospadias (urethral opening at the penile shaft, scrotum or perineum) were included in the NBDPS. Orofacial clefts that were diagnosed prenatally, but not confirmed postnatally, were excluded from the NBDPS. Neural tube defects, diagnosed prenatally that did not have a postnatal examination to confirm the defect because a pregnancy termination was performed, were included if sufficient information was available to ensure that an NTD was the most likely diagnosis.
Clinical geneticists in each site reviewed information abstracted from medical records to ensure that case infants met the eligibility criteria and each infant was classified by clinical geneticists as having an isolated defect (if there was no other major anomaly or only minor anomalies) or multiple defects (one or more major, unrelated accompanying anomalies). More information on case eligibility criteria has been described in detail elsewhere (Rasmussen et al, 2003).
This study included subjects from the NBDPS with expected dates of delivery between September 24, 1997 and December 31, 2004. The interview participation rates during this period were 76% for case mothers with CL/P, 75% for CP, 71% for NTDs, 69% for hypospadias and 69% percent for control mothers. Of subjects for whom complete interview data were available, 1546 had CL/P, 821 had CP, 1038 had an NTD, 1144 had 2nd or 3rd degree hypospadias and 5859 were control infants without birth defects. Hypospadias case infants were compared to the 2946 male control infants. The mean interval between birth and interview was 8.9 months for controls, and for cases, 10.4 months for CL/P, 10.9 months for CP, 11.7 months for NTDs and 13.1 months for hypospadias.
We obtained histories of NVP and treatments from a standardized computer- assisted telephone interview with the mother, which asked if, when and how often women experienced NVP. The series of questions used to assess NVP in the NBDPS was developed by the collaborative based on a previous CDC questionnaire used for the Atlanta Birth Defects Case-Control Study (Boneva et al., 1999). These data were collected by month for the first trimester and by trimester for the second and third trimesters. Women who reported NVP were also asked about frequency, duration, timing and indication for any prescription or nonprescription medication use (including herbal products) to treat NVP. Medications were classified and coded according to the Slone Drug Dictionary of the Slone Epidemiology Center at Boston University. This analysis focused on medications used to treat NVP in the first trimester because that is considered the vulnerable time for development of the birth defects under study.
Among 22,381 women participating in the NBDPS during the study period, 75 different medications and a number of herbal products were reported as treatment for NVP. This count excludes intravenous fluids and replacement solutions, non-B6 vitamins and minerals, and a few medications that were reported as being used for this condition but seemed implausible (e.g. narcotics, antiinfectives, cough/cold medications (mainly pseudoephedrine)). In producing the count of different medications reported for NVP, combination products (pharmaceuticals with two or more active ingredients) were counted only once.
A research pharmacist grouped medication exposures reported for NVP by women participating in the NBDPS into categories based on their therapeutic and pharmacologic class. Medication groups reported by more than 15 of the selected birth defect case and control women and for which at least 20 percent of use was reported by women with first trimester NVP treatment were included in the analysis. The medication groups meeting these criteria were antihistamine antiemetics, other antihistamines, antihistamine antiemetics plus B6 combinations, phenothiazines (other than promethazine), prokinetics, 5HT3 antagonists, emetrol/coke syrup, bismuth subsalicylate, antacids, histamine H2-receptor antagonists (H2 blockers), proton pump inhibitors (PPIs) (e.g. lansoprazole, omeprazole, esomeprazole), pyroxidine (vitamin B6), steroids and herbal/natural products. Categories not meeting the criteria, and which were therefore excluded from the analysis of relative risk were cannabinoids, antispasmodics, antidiarrheals, laxatives, analgesics and muscle relaxants.
The main comparison was between women with NVP who used NVP medications in the first trimester versus those who did not. We included women who used these NVP medications regardless of indication for use. The women with no NVP permitted comparison of the effect of the condition itself regardless of medication use.. Measures of association were calculated for medication categories and individual medications or herbal products with at least four exposed cases.
Potential confounders for the adjusted analyses were selected a priori and included maternal age, race-ethnicity, education, parity, smoking in the month before conception through the first trimester, plurality, previous miscarriage, infant sex, use of multivitamin with folic acid anytime between the month before conception through the first trimester, body mass index (BMI), study site, and year of expected date of delivery. Adjusted odds ratios and their corresponding 95 percent confidence intervals were estimated using unconditional logistic regression. Subjects with a parent, sibling or half sibling with the same birth defect were excluded because their birth defects may be etiologically different from subjects without such a family history.
Where an association was observed between first trimester medication use and a birth defect, medication exposure was further examined according to month of pregnancy and the intensity of nausea and vomiting (average frequency of NVP in months 1, 2 and 3 of pregnancy). These analyses were repeated excluding women with pre-existing diabetes and excluding infants with more than one major birth defect.
The prevalence of NVP was 68.6% among controls, and among them, the prevalence of treatment was 15.4%. The percent of controls treated for NVP according to maternal characteristics is shown in Table 1. Treatment was less likely for Hispanic compared to white, non-Hispanic women and was more likely for women with the highest BMIs and for women with unknown folic acid use compared with women reporting any use of folic acid in the month before conception through the first trimester. The percent of mothers reporting treatment also varied by study site, ranging from 8.9 to 23.5 percent.
As shown in Table 2, adjusted analyses revealed that cases were less likely than controls to experience NVP for CL/P and hypospadias, but not for CP and NTDs. Adjusted effect measures ranged from 0.84 to 1.00.
As reflected in Table 3, antacid use, primarily calcium carbonate, was associated with a lower relative odds for CL/P (aOR=0.58; CI, 0.38–0.89).
Table 4 presents measures of effect between CP and medication use in the first trimester. We observed a higher odds ratio among women exposed to ondansetron (aOR=2.37; CI, 1.18–4.76). There was also higher odds among women exposed to PPIs, in the crude analysis, but the confidence interval of the adjusted association included 1.0 (aOR=2.59; CI, 0.88–7.63).
Table 5 presents measures of effect between NTDs and medication use in the first trimester. Women exposed to bismuth subsalicylate were at higher odds for developing NTDs in the crude analysis, but the confidence interval of the adjusted association included 1.0 (aOR=2.37; CI, 0.90–6.21), based on 7 and 15 exposed case and control mothers, respectively. Results were similar when the exposure period was defined as one month before and after conception (aOR=2.27; CI, 0.79–6.48), based on 6 and 13 exposed case and control mothers, respectively.
Table 6 presents measures of association between hypospadias and medication use in the first trimester. An association was observed between hypospadias and maternal use of PPIs (aOR=4.36; CI, 1.21–15.81), based on 7 exposed cases and 5 exposed controls. Steroids were also associated with hypospadias (aOR=2.87; CI, 1.03–7.97), based on 10 exposed cases and 8 exposed controls.
Excluding women with pre-existing diabetes and cases with other than an isolated defect did not meaningfully change the associations, nor did controlling for intensity of NVP.
This study found that after controlling for covariates, mothers of infants with CL/P and hypospadias had a reduced odds of experiencing NVP relative to controls. Treatment of NVP with a wide variety of different agents was relatively frequent - over 15% among women who reported NVP and about 10% of all women. The majority of medication groups and specific medications were not associated with the four birth defects studied, but numbers of exposed subjects were sometimes small. We did find, however, some positive associations with first trimester use of these medications: PPIs and hypospadias, steroids and hypospadias, ondansetron and CP. We also saw positive associations between PPIs and CP, and bismuth subsalicylate and NTDs; although the confidence intervals in the adjusted analyses included 1. The one inverse association was antacids and CL/P.
Our results show that pregnant women are currently taking a wide range of agents for treatment of NVP. While there is existing literature on the optimal management of NVP, much of the literature on the safety of the wide range of medications used by pregnant women is based on samples that are too small to assess risks for specific birth defects, and the large majority of teratogenic effects in humans have been shown to affect specific defects rather than increase the risk of birth defects overall. Thus, a major strength of the NBDPS case-control approach is our ability to evaluate the risks and safety of various exposures with respect to specific birth defects that have been clinically validated. The wide variety of medications reported resulted in relatively small cell sizes, limiting our ability to investigate the risk or safety of individual medications.
We observed an elevated risk for hypospadias and CP among women exposed to PPIs in the first trimester. PPI medications to which women were exposed included lansoprazole, omeprazole and esomerprazole magnesium. The number of subjects exposed to specific PPI medications was small, which made it difficult to consider relationships with the specific PPIs. While cohort studies (Lalkin et al., 1998; Ruigomez et al., 1999; Kallen 2001; Kallen 1998) and two meta-analyses (Nikfar et al., 2002; Gill et al., 2009) did not suggest an increased risk of birth defects overall among women who ingested PPIs in the first trimester, none had the power to rule out even modest increases in risk of specific defects. A recent study found no risk of major birth defects overall with use of PPIs in the first trimester, but did not have sufficient power to consider the risk of specific birth defects (Pasternak and Hviid, 2010; Mitchell, 2010).
Ondansetron is an anti-nausea medication primarily used to treat nausea and vomiting in patients receiving chemotherapy. However, women are also using this medication for treatment of NVP. Two previous studies (Asker et al, 2005; Einarson et al, 2004) found no association with use of this medication in pregnancy and major birth defects overall, but the sample sizes were quite small and insufficient to consider risks of specific defects. Our data were compatible with their findings except for CP, for which we observed a doubling in odds.
Bismuth subsalicylate, a combination of bismuth salts and sodium salicylate, can be a source of a large amount of salicylate (262 mg for original strength and 525 mg for maximum strength per tablespoon) and thus is not recommended for use in pregnancy (Black and Hill, 2003). In previous human studies, salicylates have been associated with gastroschisis (Martinez-Frias et al., 1997) and holoprosencephaly (Croen et al, 2000), but our finding of an association of borderline significance with neural tube defects has not been seen before. In this analysis, steroids were associated with increased risk of hypospadias A previous analysis, which used NBDPS data to assess the odds of hypospadias after use of any corticosteroid through the 18th week of pregnancy, found a weak association which decreased in magnitude (and had a lower 95% CI below 1.0) after adjustment for confounders (Carmichael et al, 2009). Two previous case control studies reported a moderately increased risk for CL/P with use of steroids in the first trimester (Carmichael et al., 2007; Pradat et al, 2003) and a meta-analysis showed a greater than threefold risk of oral clefts with such exposure (Park-Wylllie et al., 2000). We did not find an increased risk of CL/P based on 6 exposed cases and 15 exposed controls; there were not enough exposed cases with CP to calculate a measure of association.
We found an odds ratio of 2.36 for metoclopramide for CP, based on 5 exposed cases and 18 exposed controls, with a lower confidence bound that did not exclude 1.0. While a recent study of over 3000 exposed pregnancies found no increase in risk of major birth defects overall, the study had insufficient power to consider risks associated with specific birth defects (Matok et al., 2009).
A previous paper used NBDPS data to study the association between use of antihistamines in early pregnancy and risk of a spectrum of birth defects (Gilboa et al., 2009). That study found associations between certain antihistamines and birth defects that we did not observe in this study. Specifically, they saw and increased risk for NTDs with use of diphenhydramine, doxylamine and promethazine; for CL/P with use of diphenhydramine; and, for CP with use of meclizine. Four of these five associations were weak to moderate (OR < 2.5) and one was stronger (OR > 6) but was imprecise. The present study differed from that study in that we used an additional year of NBDPS data and our study population was limited to women with NVP in the first trimester, a subset of women in the NBDPS.
Our study has a number of limitations including the potential for exposure misclassification due to incomplete recall or recall/reporting bias and selection bias as well as sparse data for some analyses. We obtained both NVP and NVP treatment information via a maternal interview conducted between six weeks and 24 months after the estimated date of delivery. Since on average, control mothers were interviewed three months sooner than cases, NVP and/or medication use could have been differentially recalled. If cases more often underreported their use of medication, the observed risk might be underestimated. We used as controls infants with no major birth defects. Studies have shown that recall of exposure information can depend on disease status (Khoury et al., 1994). If mothers of cases recalled NVP and its treatment differently from controls, recall bias could result. To improve recall, we provided NBDPS subjects with a pregnancy calendar in advance of the interview to help them more accurately respond to questions about the exposure timing.
Interpretation is limited due to the small number of women exposed to specific medications or medication groups. Further, residual confounding could exist due to uncontrolled factors that differed between women who used and did not use NVP treatment (e.g. genetic factors). Of course, those factors would have to be associated with risk of the defects under study.
Since the analyses of the relationship between NVP medications and birth defects were limited to subjects with NVP who were either exposed or not exposed to treatments, confounding by NVP was unlikely to play a role; however, confounding by severity of NVP could have influenced the observed results. Though key analyses were repeated controlling for frequency of nausea and vomiting, this process is unlikely to control fully for confounding by indication.
Perhaps of most importance is the possibility of chance as an explanation for the statistically significant associations that we observed. There were 70 comparisons made which would suggest that three to four such associations would be expected by chance alone. Nevertheless, this is the first study with extensive medication and defect-specific data and the observed associations deserve further research.
The authors thank the other NBDPS collaborators and staff as well as the families who participated in this research. The authors also acknowledge Kathy Kelley, research pharmacist from the Slone Epidemiology Center, who categorized the reported NVP medications. We also thank Chia-ling Liu, data analyst contractor to the MA Department of Public Health, for computer programming support.
The NBDPS is funded by a grant from the Centers for Disease Control and Prevention (U50/CCU 113247). This work was also supported by a New Investigator in MCH Research Dissertation Award from MCHB, HHS (1 R03 MC 00004) and by a Grant (RO1 HD 046595) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
Preliminary results were presented at the annual meeting of the Centers for Birth Defects Research and Prevention (San Antonio, TX 11/17/2004) and at the annual Maternal and Child Health Epidemiology Conference (Atlanta, GA, 12/7/2006).
The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention or the Massachusetts Department of Public Health.