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. Author manuscript; available in PMC: 2026 Apr 21.
Published in final edited form as: Birth Defects Res. 2022 Aug 14;115(2):133–144. doi: 10.1002/bdr2.2074

Maternal exposure to heparin products and risk of birth defects in the National Birth Defects Prevention Study

Meredith M Howley 1, Sarah C Fisher 1, Alissa R Van Zutphen 1,2, Eleni A Papadopoulos 1, Jenil Patel 3,4, Angela E Lin 5, Marilyn L Browne 1,2; the National Birth Defects Prevention Study
PMCID: PMC13093229  NIHMSID: NIHMS2161180  PMID: 36458698

Abstract

Background:

Heparin and low-molecular-weight heparin are the preferred anticoagulants during pregnancy as they do not cross the placenta. Although research on the safety of heparin products has been reassuring, previous studies have considered birth defects as a single outcome or by larger organ system and have not examined associations with specific birth defects.

Methods:

We analyzed data from the National Birth Defects Prevention Study, a multisite, population-based case-control study from 1997-2011. We used unconditional logistic regression with Firth’s penalized likelihood to calculate adjusted odds ratios (OR) and profile likelihood 95% confidence intervals (CI) for defects with at least five exposed cases. For defects with 3-4 exposed cases, we estimated crude ORs and exact 95% CIs.

Results:

Of the 42,743 women in our analysis, 117 (0.4%) case and 44 (0.4%) control mothers reported using a heparin product in early pregnancy. The adjusted ORs ranged from 0.9-3.9 and were elevated for anorectal atresia (OR=2.0, 95% CI=0.8-4.3), longitudinal limb deficiency (3.5, 1.3-7.8), transverse limb deficiency (1.8, 0.6-4.3), atrioventricular septal defect (3.9, 1.4-9.0), and secundum atrial septal defect (2.2, 1.2-3.8).

Conclusions:

We observed elevated associations for some birth defects, although heparin is a rare exposure, which limited our ability to evaluate many associations. Future studies that can explore specific birth defects and adequately control for confounding by indication are needed. Given that women with an indication for heparin products during pregnancy often need to take medication, one must remain mindful of the underlying risk of a birth defect that exists regardless of medication use.

Keywords: birth defects, heparin, enoxaparin, early pregnancy, NBDPS

Introduction

Pregnancy is a prothrombotic state, characterized by pathophysiological changes that may lead to an increase of procoagulant factors, physical changes leading to increased stasis, and acquired thrombophilias (Battinelli, Marshall, & Connors, 2013). Women with a history of thrombosis and women with thrombophilia have nearly a 5-fold increase in the risk of venous thromboembolism during pregnancy (Alshawabkeh, Economy, & Valente, 2016; Heit et al., 2005). Thromboembolism during pregnancy has been associated with obesity, hypertension, smoking, hemoglobinopathies, and several autoimmune disorders (James, 2011; Ramagopalan, Wotton, Handel, Yeates, & Goldacre, 2011; Zoller, Li, Sundquist, & Sundquist, 2012a, 2012b). Most women who take an anticoagulant prior to pregnancy will need to continue to do so during pregnancy and postpartum (Alshawabkeh et al., 2016). Anticoagulants, specifically heparin and low molecular weight heparin (LMWH) products (including enoxaparin and dalteparin), have been used to decrease risk of recurrent miscarriage among those with antiphospholipid syndrome (Kaandorp et al., 2010; Kutteh & Ermel, 1996).

Warfarin is a widely used anticoagulant outside of pregnancy. Given that it crosses the placenta and has been associated with fetal loss and other adverse pregnancy outcomes, it is avoided during pregnancy (Alshawabkeh et al., 2016; Cotrufo et al., 2002; James, 2011; Nassar et al., 2004; Sadler et al., 2000; Soma-Pillay, Nene, Mathivha, & Macdonald, 2011; Vitale et al., 1999). Direct thrombin and direct Xa inhibitors (including rivaroxaban, dabigatran, and apixaban) are known to cross the placenta, so while their effects on the fetus have not yet been studied, their use in pregnancy is not recommended (Alshawabkeh et al., 2016). Thus, heparin and LMWH products are the preferred anticoagulant for use during pregnancy (James, 2011). These do not cross the placenta, so are thought to be safer for the fetus (Ginsberg, Kowalchuk, Hirsh, Brill-Edwards, & Burrows, 1989; Greer & Nelson-Piercy, 2005; James, 2011). While existing studies have not reported associations between maternal use of heparin or LMWH and birth defects, these studies analyzed a combined birth defect outcome which may mask risks among specific birth defects (Bar et al., 2000; Schneider, von Tempelhoff, & Heilmann, 1997; Shlomo et al., 2017; Sorensen et al., 2000).

Investigators with the National Birth Defects Prevention Study (NBDPS), a large, population-based case-control study of risk factors for birth defects, periodically conduct screens of the study database to detect signals for increased risks between medication components and specific birth defects (Louik, Werler, Anderka, & Mitchell, 2015). These screen-based exploratory analyses offer a useful method for generating new hypotheses. This is especially important as pre-marketing clinical trials do not include pregnant women so fetal safety is limited to animal studies and post-marketing surveillance of teratogenicity of medications takes a long time to assess (Lisi et al., 2010). In a recent screen, elevated crude associations were observed between early pregnancy heparin use (defined as one month before conception through the end of the third month of pregnancy) and two birth defects: diaphragmatic hernia and atrioventricular septal defects (AVSD). Additionally, early pregnancy enoxaparin was associated with both craniosynostosis and transverse limb deficiency. This finding prompted our formal analysis of self-reported heparin and LMWH use in early pregnancy with the wide range of birth defects collected within the NBDPS.

Methods

The NBDPS was a large, multisite, population-based, case-control study of birth defects including pregnancies ending on or after October 1, 1997 and estimated delivery dates (EDD) on or before December 31, 2011 (Reefhuis et al., 2015). Pregnancies affected by one or more of 30 categories of major structural birth defects (cases), excluding those attributed to a known chromosomal or single-gene abnormality, were ascertained through birth defects surveillance programs in ten states (Arkansas, California, Georgia, Iowa, Massachusetts, New Jersey, New York, North Carolina, Texas, and Utah). Control infants were live births without major birth defects randomly selected from hospital records or birth certificates in the same time period and geographic area as the cases; the monthly number of controls selected was proportionate to the number of births in the same month in the previous year. Each site obtained Institutional Review Board approval and participants provided informed consent. Overall, 67% of eligible case and 64% of eligible control women participated.

Case inclusion criteria were described previously (Reefhuis et al., 2015). Briefly, case information was obtained from birth defects surveillance programs. Clinical geneticists reviewed clinical information of case infants to determine eligibility according to a standardized case definition and to classify infants as isolated (one major defect or organ system involved), multiple (major defects in more than one organ system), or complex (a group of defects believed to be pathogenetically-related, but the primary defect was not apparent) (Rasmussen, Olney, Holmes, Lin, Keppler-Noreuil, & Moore, 2003). Infants with congenital heart defects (CHD) were further classified according to cardiac phenotype, complexity, and presence of noncardiac defects (Botto, Lin, Riehle-Colarusso, Malik, & Correa, 2007). CHD cases classified as atrial septal defects (ASD) not otherwise specified were likely ASD secundum type and were counted as such in the analysis (Botto, Lin, Riehle-Colarusso, Malik, & Correa, 2007). Oral clefts, glaucoma, cataracts, ventricular septal defects (VSDs), and pulmonary valve stenosis were not ascertained by all sites for all years; when analyzing these, we excluded control infants for the sites and years with incomplete data (Reefhuis et al., 2015). For hypospadias, we restricted the analysis to males.

Trained interviewers conducted telephone interviews in English or Spanish with women between 6 weeks and 24 months post-EDD. Women reported demographics, health conditions, and other exposures before and during pregnancy. Women could report anticoagulant use when asked about any medications taken or diseases occurring before or during pregnancy; the interview did not ask specifically about anticoagulant use. Women were asked start and stop dates, duration, and frequency of medication use in the three months before conception and during pregnancy, using calendar dates or pregnancy months. The Slone Epidemiology Center Drug Dictionary was used to code reported medications and link products to their active ingredient components. We considered women who reported at least one heparin product (heparin or a LMWH medication) during early pregnancy to be exposed. The first three months of pregnancy include the critical period in embryonic development associated with most structural birth defects. We included the month prior to conception as it is often difficult to pinpoint the date of conception. We excluded women who did not report taking heparin or LMWH but reported taking other anticoagulants in the three months before conception through the end of pregnancy (12 women reported a coumarin derivative, 5 reported an unspecified anticoagulant, and 1 woman reported both types). Thus, the unexposed group included women who did not report anticoagulant medication use in the 3 months before pregnancy to birth. We excluded cases classified as complex, except for birth defects that are complex in nature (amniotic band sequence, heterotaxia with CHD, and single ventricle). We restricted our analysis to birth defects with >50 cases.

We compared characteristics among control infants whose mothers reported early pregnancy heparin or LMWH use and those who did not using chi squared tests. We calculated crude odds ratios (OR) with exact 95% confidence intervals (CI) for specific defects. If five or more cases were exposed, we calculated adjusted ORs and profile likelihood 95% CIs using unconditional logistic regression with Firth’s penalized likelihood. Firth’s penalized likelihood estimates of model coefficients and 95% CIs do not assume symmetry of the CI around the coefficient estimate and are more appropriate for small samples (Firth, 1993). We considered the variables listed in Table 1 (and NBDPS study site) potential confounders and selected these a priori based on the literature and hypothesized causal pathways in a directed acyclic graph. To narrow down the list of potential covariates given the small number of exposed, the final multivariable model included only the subset of the a priori selected variables associated with exposure among the controls: maternal age at delivery (continuous), more than high school education level (yes/no), maternal non-Hispanic White race/ethnicity (yes/no), previous miscarriage (yes/no), autoimmune disease (yes/no), and NBDPS site. Self-reported chronic health conditions were manually reviewed to determine if they were autoimmune in nature, as reported previously (Howley et al., 2016). We did not calculate estimates for birth defects with <3 exposed cases.

Table 1. Selected characteristics of women with control offspring, by early pregnancy use of heparin products, National Birth Defects Prevention Study 1997-2011. a.

Unexposed
(n=11,560)		 Heparin or LMWH
in early pregnancy
(n=44)		 p-valueb
Age, mean (SD) 27.7 (6.1) 31.3 (5.0) <0.0001
Race/ethnicity 0.0040
  Non-Hispanic white 6,710 (58.0) 35 (79.6)
  Other 4,844 (41.9) 9 (20.4)
Education <0.0001
  High School or less 4,621 (40.0) 3 (6.8)
  More than high school 6,808 (58.9) 39 (88.6)
Pre-pregnancy body mass index (kg/m2) >0.05
  <25.0 6,531 (56.5) 27 (61.4)
  25-<30 2,516 (21.8) 7 (15.9)
  ≥ 30 2,030 (17.6) 10 (22.7)
Early pregnancy smoking 2,066 (17.9) 3 (6.8) >0.05
Early pregnancy alcohol use 4,257 (36.8) 17 (38.6) >0.05
Folic acid-containing supplement use c 6,106 (52.8) 27 (61.4) >0.05
Autoimmune disease 118 (1.0) 4 (9.1) 0.0011
Chronic or gestational hypertension 1,564 (13.5) 8 (18.2) >0.05
Pre-existing diabetes 71 (0.6) 0
Gestational diabetes in index pregnancy 530 (4.6) 1 (2.3) >0.05
Parity ≥ 1 7,020 (60.7) 27 (61.4) >0.05
Fertility Treatment 507 (4.4) 4 (9.1) >0.05
Previous Miscarriage 2,600 (22.5) 25 (56.8) <0.0001
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LMWH=low molecular weight heparin; SD=standard deviation; CHD=congenital heart defect.

a

Unless otherwise noted, values are n (%). Totals vary because of missing values of covariates.

b

For continuous age, the p-value is from the t-test. For categorical covariates, we presented the chi-square p-value (when cell sizes were 5 or more) or the Fisher's exact test p-value.

c

From one month before pregnancy through the first month of pregnancy.

We performed a number of sub-analyses. First, we restricted to those noncardiac birth defects classified as isolated and the CHDs classified as “simple isolated” (cases with one CHD or a combination considered a single CHD). This analysis was conducted because the etiology of a birth defect that occurs in isolation may differ from that of the same birth defect that occurs in the presence of other defects (Rasmussen, Olney, Holmes, Lin, Keppler-Noreuil, & Moore, 2003). Second, we estimated associations by specific medication component (heparin and LMWH) separately where data permitted. Third, while the critical period for exposure is likely in early pregnancy, we widened the exposure window to include one month before conception through the end of pregnancy for craniosynostosis cases, because suture closure is not completed until after birth (Centers for Disease Control and Prevention, 2020). Fourth, we calculated E-values to evaluate robustness of the results to potential unmeasured confounding (Mathur, Ding, Riddell, & VanderWeele, 2018; VanderWeele & Ding, 2017).

Results

After excluding 1,286 women our final sample size comprised 42,743 women and their offspring (31,139 cases and 11,604 controls; Figure 1). Exposure to a heparin product during early pregnancy was rare, reported by 117 (0.4%) women with case infants and 44 (0.4%) women with control infants. Of the exposed, heparin use was reported by 62 (53%) case women and 22 (50%) control women, whereas 56 (48%) case women and 24 (55%) control women reported using LMWH. The majority of women who reported LMWH used enoxaparin; one case woman and one control woman reported dalteparin use in early pregnancy. One case and two control women reported using both heparin and enoxaparin during early pregnancy. The vast majority of exposed women [82% (95/117) cases and 70% (31/44) controls] reported starting their anticoagulant during early pregnancy and continued to take it until the end of their pregnancy. Of those who took a heparin product in early pregnancy, only 8 (7%) case women and 5 (11%) control women reported also taking the medication before conception.

Figure 1.

Figure 1.

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Study population, exclusions, and use of heparin prodcuts in the month before pregnancy through the third month of pregnancy (early pregnancy) among women in the NBDPS (1997-2011).

Table 1 contains the distributions of selected characteristics by early pregnancy heparin or LMWH use among controls. Compared to unexposed control women, control women who reported using a heparin product were older and more frequently reported being non-Hispanic White. Additionally, among controls heparin use was more frequently reported among women with more than a high school education, women with an existing autoimmune disease, and women experiencing at least one previous miscarriage.

Table 2 lists the number of exposed and unexposed infants with each birth defect evaluated in this study. The main analysis included 51 specific birth defects (33 noncardiac birth defects and 18 cardiac birth defects), of which 10 defects had five or more exposed cases. The adjusted ORs for early pregnancy exposure to heparin products range from 0.9 for hypospadias to 3.9 for AVSD. Compared to mothers who reported no use in pregnancy, reported use of a heparin product during early pregnancy was associated with an elevated risk for anorectal atresia (OR=2.0, 95% CI=0.8-4.3), longitudinal limb deficiency (3.5, 1.3-7.8), transverse limb deficiency (1.8, 0.6-4.3), AVSD (3.9, 1.4-9.0), and secundum ASD (2.2, 1.2-3.8) after adjusting for model covariates.

Table 2. Association of early pregnancy heparin product use and select birth defects for all cases and subgroup of isolated cases in the National Birth Defects Prevention Study, 1997-2011.

Birth Defect All Cases a Isolated Cases
Exp/Unexp Crude OR
(95% CI) b 		Adjusted OR
(95% CI) c 		Exp/Unexp Crude OR
(95% CI) b 		Adjusted OR
(95% CI) c
Amniotic band sequence 0/333 - - 0/281 - -
Central nervous system
  Anencephaly 1/646 - - 1/578 - -
  Spina bifida 4/1,268 0.8 (0.2, 2.3) - 2/1,119 - -
  Encephalocele 2/224 - - 2/168 - -
  Holoprosencephaly 1/171 - - 1/123 - -
  Dandy-Walker malformation 1/184 - - 1/112 - -
  Hydrocephaly 1/509 - - 0/352 - -
  Cerebellar hypoplasia 1/61 - - 0/36 - -
Eye
  Anophthalmos/microphthalmos 1/230 - - 1/138 - -
  Congenital cataracts 1/351 - - 1/310 - -
  Glaucoma 1/181 - - 1/148 - -
Anotia/microtia 1/689 - - 0/475 - -
Orofacial
  Choanal atresia 1/163 - - 0/87 - -
  Cleft palate only 8/1,593 1.3 (0.5, 2.8) 1.2 (0.5, 2.6) 5/1,278 1.0 (0.3, 2.6) 0.9 (0.3, 2.1)
  Cleft lip only 2/1,095 - - 2/1,019 - -
  Cleft lip with cleft palate 2/2,020 - - 0/1,721 - -
Gastrointestinal
  Esophageal atresia 4/748 1.4 (0.4, 3.9) - 2/315 - -
  Duodenal atresia 0/237 - - 0/148 - -
  Small intestinal atresia 0/477 - - 0/407 - -
  Colonic atresia 0/56 - - 0/50 - -
  Anorectal atresia 6/1,042 1.5 (0.5, 3.6) 2.0 (0.8, 4.3) 2/462 - -
  Biliary atresia 0/199 - - 0/170 - -
Genitourinary
  Hypospadias 12/2,542 1.1 (0.5, 2.3) 0.9 (0.4, 1.9) 11/2,274 1.1 (0.5, 2.4) 1.0 (0.4, 1.9)
  Renal agenesis 0/184 - - 0/134 - -
  Bladder exstrophy 0/72 - - 0/55 - -
  Cloacal exstrophy 1/97 - - 0/57 - -
Musculoskeletal
  Longitudinal limb deficiency 5/527 2.5 (0.8, 6.3) 3.5 (1.3, 7.9) 3/302 2.6 (0.5, 8.2)
  Transverse limb deficiency 6/710 2.2 (0.8, 5.3) 1.8 (0.6, 4.3) 5/596 2.2 (0.7, 5.6) 2.0 (0.7, 5.0)
  Craniosynostosis 11/1,586 1.8 (0.8, 3.6) 1.4 (0.6, 2.7) 11/1,436 2.0 (0.9, 4.0) 1.4 (0.6, 2.7)
  Diaphragmatic hernia 4/858 1.2 (0.3, 3.4) - 4/661 1.6 (0.4, 4.4) -
  Omphalocele 0/420 - - 0/258 - -
  Gastroschisis 2/1,409 - - 1/1280 - -
  Sacral agenesis 1/103 - - 0/12 - -
Congenital heart defects
  Truncus arteriosus 0/138 - - 0/92 - -
  Tetralogy of Fallot 4/1,204 0.9 (0.2, 2.4) - 4/949 1.1 (0.3, 3.1) -
  D-transposition of the great arteries 0/770 - - 0/573 - -
  DORV-TGA 2/189 - - 0/51 - -
  Conoventricular VSD 0/117 - - 0/53 - -
  Atrioventricular septal defect 6/361 4.4 (1.5, 10.4) 3.9 (1.4, 9.0) 4/169 6.2 (1.6, 17.4) -
  Total anomalous pulmonary venous return 0/302 - - 0/255 - -
  Hypoplastic heart syndrome 1/659 - - 1/585 - -
  Coarctation of the aorta 5/1,165 1.1 (0.3, 2.8) 1.1 (0.4, 2.4) 5/556 2.4 (0.7, 6.0) 2.1 (0.8, 4.9)
  Aortic valve stenosis 1/512 - - 1/338 - -
  Pulmonary atresia 0/264 - - 0/165 - -
  Pulmonary valve stenosis 4/1,553 0.6 (0.2, 1.8) - 1/1,046 - -
  Tricuspid atresia 2/177 - - 1/70 - -
  Ebstein anomaly 1/179 - - 1/109 - -
  Perimembranous VSD 7/1,378 1.5 (0.5, 3.6) 1.4 (0.5, 3.3) 3/840 1.0 (0.2, 3.5) -
  Secundum atrial septal defect 21/3,049 1.8 (1.0, 3.1) 2.2 (1.2, 3.8) 10/1,540 1.7 (0.8, 3.4) 1.9 (0.9, 3.6)
  Single ventricle defects d 0/174 - - - - -
  Heterotaxy d 0/343 -
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OR=odds ratio, CI=confidence interval, DORV-TGA=double-outlet right ventricle-transposition of the great arteries, VSD=ventricular septal defect

a

Includes cases with isolated defects and those with additional defects.

b

Crude estimates and exact 95% confidence intervals.

c

Adjusted estimates and profile likelihood 95% confidence intervals (CIs) using unconditional logistic regression with Firth’s penalized likelihood are presented for birth defects with 5 or more exposed cases, adjusting for maternal age at delivery, race/ethnicity, education, previous miscarriage, autoimmune disease, and study site. Analyses included 44 exposed and 11,560 unexposed controls, with four exceptions: cleft palate (44 exposed/11,426 unexposed), hypospadias (25 exposed/5,882 unexposed), pulmonary valve stenosis (44 exposed/11,091 unexposed), and perimembranous VSD (23 exposed/6,694 unexposed).

d

All cases in the birth defect group were considered complex.

When we restricted to isolated cases, we calculated adjusted estimates for six defects (Table 2). The adjusted estimates for early pregnancy use of a heparin product and isolated cases did not differ materially from those presented above, with one exception. The adjusted OR for isolated coarctation of the aorta was markedly further from the null than the estimate for all cases (2.1 for isolated cases vs. 1.1 for all cases), but the confidence interval was wide and still included the null value of 1.0. Additionally, crude estimates were elevated for isolated longitudinal limb deficiency and isolated AVSD, but these were based on 3 or 4 exposed cases and have correspondingly wide confidence intervals.

Heparin use appeared to drive the association with secundum ASD, whereas LMWH (enoxaparin more specifically) appeared to drive the association with transverse limb deficiency (Table 3), although the number of exposed cases were small for analyses involving specific heparin products. There were not enough AVSD cases exposed to either only heparin or only LMWH to calculate adjusted estimates; while the crude OR for heparin only use remained elevated (4.8), the corresponding exact CI was exceptionally wide (0.9-16.3). Additionally, we observed an elevated adjusted association between heparin use and cleft palate and between LMWH and craniosynostosis.

Table 3. Association of early pregnancy heparin product use and select birth defects by medication component in the National Birth Defects Prevention Study, 1997-2011.

Birth Defect Unexposed Heparin only use LMWH only use cases
Exposed Crude OR
(95% CI) a 		Adjusted OR
(95% CI) b 		Exposed Crude OR
(95% CI) a 		Adjusted OR
(95% CI) b
Spina bifida 1,268 3 1.4 (0.3, 4.6) - 1 - -
Cleft palate only 1,593 6 2.2 (0.7, 5.6) 2.1 (0.7, 5.2) 2 - -
Esophageal atresia 748 1 - - 3 2.1 (0.4, 7.0) -
Anorectal atresia 1,042 2 - - 4 2.0 (0.5, 6.0) -
Hypospadias 2,542 6 1.3 (0.4, 3.7) 1.0 (0.3, 2.7) 6 1.0 (0.3, 2.8) 0.9 (0.3, 2.4)
Longitudinal limb deficiency 527 3 3.3 (0.6, 11.1) - 2 - -
Transverse limb deficiency 710 1 - - 5 3.7 (1.1, 10.1) 3.0 (0.8, 8.2)
Craniosynostosis 1,586 3 1.1(0.2, 3.7) - 8 2.7 (1.0, 6.2) 2.1 (0.9, 4.8)
Diaphragmatic hernia 858 4 2.7 (0.7, 8.1) - 0 - -
Tetralogy of Fallot 1,204 1 - - 3 1.3 (0.3, 4.4) -
Atrioventricular septal defect 361 3 4.8 (0.9, 16.3) - 2 - -
Coarctation of the aorta 1,165 3 1.5 (0.3, 5.0) - 2 - -
Pulmonary valve stenosis 1,553 1 - - 3 1.0 (0.2, 3.2) -
Perimembranous VSD 1,378 4 1.4 (0.3, 4.4) - 3 2.1 (0.4, 9.1) -
Secundum atrial septal defect 3,049 12 2.3 (1.0, 4.9) 3.0 (1.4, 6.3) 9 1.6 (0.6, 3.5) 1.6 (0.6, 3.7)
Controls c 11,560 20 Reference Reference 22 Reference Reference
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OR=odds ratio, CI=confidence interval, VSD=ventricular septal defect.

a

Crude estimates and exact 95% confidence intervals.

b

Adjusted estimates and profile likelihood 95% confidence intervals (CIs) using unconditional logistic regression with Firth’s penalized likelihood are presented for birth defects with 5 or more exposed cases, adjusting for maternal age at delivery, race/ethnicity, education, previous miscarriage, autoimmune disease, and study site.

c

Heparin only analyses included 20 exposed and 11,560 unexposed control, with four exceptions: cleft palate (20 exposed/11,426 unexposed), hypospadias (11 exposed/5,882 unexposed), pulmonary valve stenosis (20 exposed/11,091 unexposed), and perimembranous VSD (14 exposed/6,694 unexposed). LMWH only analyses included 22 exposed and 11,560 unexposed control, with four exceptions: cleft palate (22 exposed/11,426 unexposed), hypospadias (14 exposed/5,882 unexposed), pulmonary valve stenosis (22 exposed/11,091 unexposed), and perimembranous VSD (7 exposed/6,694 unexposed).

Sensitivity analyses using E-values suggested that the observed association for AVSD was moderately robust to potential unmeasured confounding, including confounding by maternal co-morbidities or history of blood clot (Supplemental Table 1). To explain the OR of 3.9 for AVSD, an unmeasured confounder associated with both heparin product use and AVSD by an OR of 7.3-fold each (above the measured covariates) could suffice, but weaker confounding could not. To shift the lower CI to include the null value for AVSD, an unmeasured confounder associated with both heparin product use and AVSD of 2.2-fold could suffice, but weaker confounding could not. For comparability, the association between a history of autoimmune disease, the strongest measured confounder of heparin use and AVSD in our analysis, was 2.3 (1.1, 4.2). E-value sensitivity analyses for the observed associations for longitudinal limb deficiency and secundum ASD suggested the observed associations for these defects were less robust to potential unmeasured confounding (Supplemental Table 1). Unmeasured confounders of the association between heparin use and longitudinal limb deficiency of 6.4-fold could explain the elevated ORs. To shift the lower CIs for these two birth defects to include the null value, an unmeasured confounder associated with both heparin product use and longitudinal limb deficiency of 1.8-fold could suffice. For heparin use and secundum ASD, unmeasured confounders of 3.8-fold could explain the elevated ORs. To shift the lower CIs for these two birth defects to include the null value, an unmeasured confounder associated with both heparin product use and secundum ASD of 1.7-fold could suffice. Lastly, increasing the exposure window for craniosynostosis cases, did not alter the estimates (data not shown).

Discussion

Early pregnancy use of heparin products was rare in NBDPS, reported by less than 1% of mothers of control infants. For the vast majority of the specific 51 birth defects examined, we did not have enough exposed cases to calculate estimates. We calculated estimates for 15 defects (five crude and ten adjusted estimates) and observed elevated adjusted associations for five specific defects with ORs ranging from 1.8 to 3.9. Three of these (longitudinal limb deficiency, AVSD, and secundum ASD) had corresponding 95% CI that excluded the null value of 1.0. In both sub-analyses that restricted to isolated birth defects and that examined specific medication use, several birth defects had less than five exposed cases. We found some elevated crude odds ratios, but their confidence intervals were wide. These unstable estimates, particularly in the context of multiple comparisons, should be interpreted cautiously.

We performed this analysis of heparin products and the risk of birth defects because a recent NBDPS medication screen flagged some statistical associations for four specific birth defects. Post-marketing surveillance does not exist, and such screens can yield important information that can generate new hypotheses about medication use in pregnancy that were not assessed in pre-marketing clinical trials. Thus, we leveraged available data from NBDPS to explore this association (Lisi et al., 2010; Louik et al., 2015). An association between heparin and AVSD was noted in the NBDPS screen of medications, and this was the strongest adjusted association observed in our analysis. When restricted to isolated cases, the crude association was further from the null (crude OR, 6.2; 95% CI, 1.6-17.4). Nonetheless, given the small number of exposed cases, the 95% confidence intervals for these associations, particularly the crude associations, were wide. Among the six exposed AVSD cases, three reported heparin only use, two reported LMWH only, and 1 reported both, inhibiting our ability to further explore associations by medication component.

Warfarin, a vitamin K antagonist, is commonly used in non-pregnant women, but is contraindicated in pregnancy and known to cause a specific pattern of birth defects, including nasal hypoplasia, skeletal defects, central nervous system abnormalities or ocular abnormalities (Genetic and Rare Diseases Information Center, 2017). We excluded 13 women (11 case women and 2 control women) who reported using warfarin in the three months before pregnancy through conception. Unlike vitamin K antagonists, heparin and LMWH are both thought to be safe for the fetus, as they do not cross the placenta (Bates et al., 2016; James, 2011). One study in sheep suggested maternal exposure might still alter fetal coagulation system (Andrew et al., 1986). Other authors have suggested that it may affect fetal development through placental vasculature and bleeding at the placental level, although a convincing biological mechanism has not been identified (Shlomo et al., 2017). Existing research on heparin products has been reassuring (Bar et al., 2000; Nelson-Piercy, Letsky, & de Swiet, 1997; Schneider et al., 1997; Shlomo et al., 2017; Sorensen et al., 2000; Wahlberg & Kher, 1994), although existing studies have grouped birth defects as a single outcome and did not evaluate risks of specific types of birth defects which may obscure association with specific birth defects. While not shown in the tables, the association between heparin product use and the risk for all birth defects in aggregate within our data is 1.0 (0.7-1.4); this is similar to the previous findings.

Strengths of our study include the multi-site, population-based design with strict inclusion criteria and case classification by clinical geneticists (Botto, Lin, Riehle-Colarusso, Malik, & Correa, 2007; Rasmussen, Olney, Holmes, Lin, Keppler-Noreuil, & Moore, 2003). Additionally, our relatively large sample size allows us to consider risk for some specific birth defects, even for this rare exposure. Our results should be interpreted cautiously given certain limitations. The specific defects included in the NBDPS are rare, as is use of a heparin product in early pregnancy. We therefore had limited statistical power to assess many of the associations with specific defects, resulting in an inability to estimate ORs for most of the NBDPS defects and unstable OR estimates with wide CIs for some of the associations we were able to examine. We assessed many possible associations, some of those we observed may be due to chance. We calculated 15 OR estimates in our main analysis, of which 3 had CIs that excluded the null. Since we required a minimum number of exposed cases, we were more likely to observe associations above the null. Additionally, the NBDPS relied on maternal self-reported exposure information, so there is potential for recall error and possibly biased reporting of maternal use of heparin products. The NBDPS lacked specific questions about use of anticoagulants during pregnancy or specific conditions for which anticoagulants are used. We were not able to assess potential impact of different doses or, more importantly, control for indication of use. Underlying maternal disease or the success of anticoagulant medications could play a role in the development of birth defects and explain some of our observations. Women with a history of thrombosis and women with thrombophilia have an increased risk of venous thromboembolism during pregnancy and thus may take a heparin product during pregnancy (James, 2011; Ghaji, Boulet, Tepper, & Hooper, 2013). Studies of the associations between these specific indications and birth defects are lacking. Additionally, heparin products have been used to decrease the risk of recurrent miscarriage among women with antiphospholipid antibody syndrome, an autoimmune disorder. While antiphospholipid antibody syndrome has been associated with a range of adverse obstetric complications (recurrent miscarriage, stillbirth, pre-term delivery, intrauterine growth restriction, pre-eclampsia, HELLP syndrome, and placental insufficiency), there have not been studies specifically exploring the association with birth defects specifically, likely due to the combination of rare exposure and rare outcomes (Schreiber & Hunt, 2019; Ruiz-Irastorza, Crowther, Branch & Khamashta, 2010). Although some women within our analysis reported an indication for heparin (antiphospholipid syndrome or a blood clotting disorder), this information was not routinely collected, most often not available or not reported with enough detail (for example, reported use for a “blood clot”). In reviewing text responses, we did not identify any woman who reported heart valve replacements. Two of the exposed women with pregnancies affected by AVSD reported a specific indication: one reported a “blood clotting disorder” and mentioned taking heparin products to “prevent pregnancy complications”, the other reported antiphospholipid antibody syndrome.

The higher odds of longitudinal limb deficiency, AVSD, or secundum ASD associated with heparin product use may be accounted for by the frequent use of these medications by women with conditions that are independently associated with these specific birth defects. Our adjusted estimates, however, controlled for maternal conditions that may be associated with both heparin use and the risk of specific birth defects by including variables for history of an autoimmune disease and previous miscarriages (Howley et al., 2016; Khoury & Erickson, 1993; Mehta, Smythe, & Mattson, 2011). In a previous NBDPS analysis, autoimmune disease (including autoimmune thrombophilias like antiphospholipid syndrome) was found to be associated with an increased risk for secundum ASD although the 95% confidence intervals included 1.0 (Howley et al., 2016). There was some evidence via the E-value that the observed association for AVSD was at least moderately robust to potential unmeasured confounding, whereas the observed associations for longitudinal limb deficiency and secundum atrial septal defect were less robust to unmeasured confounding. Lastly, teratogens typically produce a specific pattern of birth defects, often including multiple minor anomalies, during embryogenesis (Khoury, Moore, James, & Cordero, 1992; Tinker et al., 2015). In our analysis, we explored a range of structural birth defects, but did not explore occurrence of birth defect patterns associated with exposure.

The vast majority of birth defects in NBDPS did not have enough exposed cases to calculate estimates, but we observed evidence of increased risk for some specific defects that need to be replicated in other studies. These results should not be interpreted to suggest that medications used to treat blood clotting disorders are teratogens, as the associations observed may reflect effects of the underlying disease. More studies that adequately control for confounding by indication are needed. Additionally, even if the observed estimate represents a true increase in risk attributable to the use of heparin products, the absolute risk for each individual defect is still very low. Given that women with blood clotting disorders and those with an indication for heparin products during pregnancy often need to take an anticoagulant, when interpreting the risk associated with these medications one must remain mindful of the underlying risk of a birth defect that exists regardless of medication use.

Supplementary Material

Table S1

Acknowledgements

We thank the participating families, scientists, and staff from all of the NBDPS sites. Additional thank to Eva Williford for replicating the analysis. This project was supported through Centers for Disease Control and Prevention (CDC) cooperative agreements under PA #96043, PA #02081, FOA #DD09-001, FOA #DD13-003, and NOFO #DD18-001 to the Centers for Birth Defects Research and Prevention participating in the National Birth Defects Prevention Study (NBDPS) and/or the Birth Defects Study To Evaluate Pregnancy exposureS (BD-STEPS). Coding of drug information in the NBDPS used the Slone Epidemiology Center Drug Dictionary, under license from the Slone Epidemiology Center at Boston University.

FUNDING STATEMENT:

This project was supported through Centers for Disease Control and Prevention (CDC) cooperative agreements under PA #96043, PA #02081, FOA #DD09-001, FOA #DD13-003, and NOFO #DD18-001 to the Centers for Birth Defects Research and Prevention participating in the National Birth Defects Prevention Study and/or the Birth Defects Study To Evaluate Pregnancy exposureS.

Footnotes

CONFLICT OF INTEREST STATEMENT: The authors report no conflicts of interest.

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Supplementary Materials

Table S1
NIHMS2161180-supplement-Table_S1.docx (13.9KB, docx)

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