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BACKGROUND:The strong inverse association between maternal age and risk of gastroschisis in offspring has spurred many investigators to hypothesize that behaviors among younger females are the cause. Examples include cigarette smoking, illicit drugs, genitourinary infections, and sexually transmitted diseases, each of which has been reported to be associated with gastroschisis. Although these exposures are more common in young women, recent studies have shown that cigarette smoking, genitourinary infections, and sexually transmitted diseases are most strongly associated with gastroschisis in older women. There is both anecdotal and published evidence showing that gastroschisis sometimes but not always occurs in clusters, raising the possibility that an infectious agent might be involved in its pathogenesis.RESULTS:One such agent whose epidemiologic characteristics parallel those of gastroschisis is EpsteinBarr virus EBV. Primary EBV infection in early childhood has been decreasing over time, leaving a greater proportion of adolescents at risk, as reflected by increased rates of infectious mononucleosis over time. During the childbearing years, risk of primary EBV infection decreases dramatically, as does risk of gastroschisis. The stronger risks of gastroschisis associated with cigarette smoking, genitourinary infections, and sexually transmitted diseases in older women might be explained by EBV reactivation resulting from multiple challenges to immune response such as pregnancy, age, toxic exposures, and genitourinary and sexually transmitted infections.CONCLUSION:EBV and other herpes viruses should be added to the research agenda for gastroschisis. Birth Defects Research Part A 2010. © 2009 WileyLiss, Inc.

BACKGROUND:Antihistamines are commonly used during pregnancy. There is little evidence that they have teratogenic effects, but there are knowledge gaps with respect to newer products, as well as the relationship between specific antihistamines and specific birth defects.METHODS:Using the National Birth Defects Prevention Study 1997–2003, the authors examined associations between maternal use of 14 antihistamines during early pregnancy and 26 isolated major birth defects. A Bayesian analysis incorporating prior knowledge about the relationships between antihistamines, birth defects, and measured covariates was conducted.RESULTS:Of the 364 associations investigated, 24 had 95 posterior intervals excluding 1.0. All 24 associations were positive; 23 associations were of weak to moderate magnitude posterior OR < 3.0 and one was strong OR > 6.0 but very imprecise. Of the 24 associations, 20 were with noncardiac defects. Eight associations involved the antihistamine diphenhydramine.CONCLUSIONS:The results of this study generally were consistent with no association between birth defects and antihistamine use during early pregnancy. Several of the findings might warrant further investigation, although the observed elevated associations should be interpreted in the context of the number of associations investigated and the analysis of retrospective, selfreported data. Birth Defects Research Part A 2009. © 2009 WileyLiss, Inc.

BACKGROUND:Limb reduction deficiencies that are accompanied by amniotic bands ABLs and terminal transverse limb deficiencies TLDs have each been attributed to vascular disruption; for the former, however, it is not clear if amniotic bands are the primary cause of or are secondary to vascular disruption. If amniotic bands are secondary to vascular disruption, then a shared pathogenesis for each case group might be exhibited by similar risk factors. METHODS:We evaluated maternal age, education, raceethnicity, parity, pregnancy wantedness, and vasoactive exposures among 139 ABL and 373 TLD cases, using interview data collected from mothers in 10 states by the National Birth Defects Prevention Study. Vasoactive exposures included maternal cigarette smoking and use of decongestants, nonsteroid antiinflammatory drugs, and antihypertensive drugs in the periconceptional period. RESULTS:Increased risk estimates were observed for Black mothers OR 2.5; 95 CI: 1.5–4.1 and nulliparous mothers 2.1; 1.4–3.0 in relation to ABL, while neither was associated with TLD. Hispanic women 1.4; 1.0–1.9 and those not wanting the pregnancy 1.5; 1.1–2.1 had increased risks of TLD, but not ABL. Maternal cigarette smoking and aspirin use each increased the risk of ABL, but not TLD; while decongestants and possibly antihypertensive medications increased the risk of TLD, but not ABL. CONCLUSIONS:The lack of consistent findings for the two case groups suggests that ABL and TLD may be distinct entities. The inconsistencies also suggest that these vasoactive exposures may not be markers for vascular disruption or that vascular disruption may not play a major role in the pathogenesis of these two types of limb deficiencies. Birth Defects Research Part A, 2009. © 2008 WileyLiss, Inc.

Hypertensive disorders occur in an estimated 5–10% of pregnancies, but few studies have examined birth defects in relation to high blood pressure and antihypertensive medication use. The objective of this study was to investigate the relationship between high blood pressure, antihypertensive medication use, and severe hypospadias.We used data from the National Birth Defects Prevention Study, a population‐based, multicenter, case‐control study of birth defects to assess risks for severe hypospadias in relation to self‐reported high blood pressure and prenatal exposures to antihypertensive drugs in 758 male infants with severe hypospadias and 2,058 male controls born between 1997 and 2002. Logistic regression analyses estimated ORs and 95% CIs, adjusted for potential confounders.We observed slight to moderate elevations in the risk of severe hypospadias for maternal untreated hypertension (adjusted OR 2.1; 95% CI: 1.6–2.9) and antihypertensive medication use during 1 month preconception through pregnancy month 4 (adjusted OR 1.4; 95% CI: 0.7–2.9). The association was strongest for subjects initiating medications after the fourth month (adjusted OR 5.0; 95% CI: 1.9–12.9).We observed an association between hypertension, antihypertensive medication use, and the risk of severe hypospadias, particularly when medication use began late in pregnancy. Because hypospadias occurs in early pregnancy, the data suggest that hypertension and its morphologic/physiologic precursors play an etiologic role, perhaps via compromised uteroplacental perfusion. Birth Defects Research (Part A) 2008. © 2007 Wiley‐Liss, Inc.

Pseudoephedrine is contained in decongestants such as the Sudafed line of products. It is an alpha‐adrenergic receptor agonist, which causes blood vessel constriction, including the therapeutic effect of reducing airflow resistance in the nasal cavity. Pseudoephedrine is one of the most commonly used medications in pregnancy, with an estimated 25% of women exposed. It has been demonstrated that alpha‐adrenergic receptor agonists slow uterine blood flow, but their effects have not been studied in relation to most reproductive outcomes in animals or humans. Two analyses of health maintenance organization pharmacy data identified 9 malformed infants among 902 first‐trimester pseudoephedrine exposures, suggesting no association with birth defects overall; however, studies of such data sets often lack sufficient power to identify risks for specific birth defects. The related compounds, epinephrine, ephedrine, and phenylephrine, have been associated with hemorrhages and cardiovascular and limb malformations in animal models. Risk of ventricular septal defects was associated with decongestant use in pregnant women in 1 recent study. The vasoconstrictive effects of these drugs raise the hypothesis that their use in early pregnancy might increase the risk of vascular disruption defects. Case‐control studies, which often do have power to identify risks related to specific birth defects, have explored this hypothesis. Decongestant use in the first trimester has been associated with small increases in risks of 3 defects thought to arise, at least in some instances, from vascular disruption–gastroschisis, small intestinal atresia, and hemifacial microsomia. These findings are somewhat consistent in terms of magnitude of effect and suggest that risks are even greater among women also exposed to the vasoconstrictive effects of cigarette smoking. There are, however, limitations to these studies, including the possibilities of inaccurate recall of exposures and confounding by indication. In addition, the majority of decongestant use is in oral form and the question of whether intranasal formulations carry risk has not been adequately addressed. Birth Defects Research (Part A) 76:445–452, 2006. © 2006 Wiley‐Liss, Inc.

Muscular ventricular septal defects (mVSDs) are the most common congenital heart defects. Previous studies have suggested maternal use of acetaminophen or nonsteroidal anti‐inflammatory drugs (NSAIDs), and/or fever as risk factors. We evaluated the association between mVSDs and maternal use of acetaminophen or NSAIDs adjusting for fever.Infants with nonsyndromic mVSDs (cases) and without birth defects (controls), with gestational age ≥37 weeks and their mothers were enrolled in the National Birth Defects Prevention Study. Two exposure periods were defined: the first trimester of pregnancy, and one month before pregnancy through delivery. Mothers reporting fever or medication use at least once during either period were considered exposed. Adjusted odds ratios and 95% confidence intervals were estimated independently for each exposure period.The analysis included 168 cases and 692 controls. Two case groups were evaluated: all mVSD infants (n = 168) (including those with associated minor cardiac defects or noncardiac defects), and infants with isolated mVSDs (n = 133). Mothers of cases were less likely to be African‐American than Caucasian (OR, 0.36; 95% CI, 0.18, 0.73). Approximately equal numbers of case mothers and control mothers (10.4 versus 9.7%, respectively) reported at least one febrile episode during the first trimester. Neither acetaminophen nor NSAID exposure was significantly associated with mVSDs. This was true for both case groups and both exposure periods.Significant associations were not detected between the occurrence of mVSDs and maternal use of NSAIDs or acetaminophen adjusting for maternal fever, nor were they detected between maternal fever and mVSDs. Birth Defects Research (Part A), 2004. Published 2004 Wiley‐Liss, Inc.