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Congenital anomalies of the external ear can have a significant impact on a child's development and quality of life. While genetic factors play a crucial role in the etiology of these anomalies, environmental factors such as drug exposure during pregnancy may also contribute to their occurrence. This study aims to investigate the association between drug exposure and congenital anomalies of the external ear using data from an adverse drug reaction report database. Using OpenVigil 2.1, we queried the FAERS database to retrieve adverse event reports from the first quarter of 2004 to the first quarter of 2024. To identify relevant cases, we used Medical Dictionary for Regulatory Activities terms focusing on congenital anomalies of the external ear. Drug generic names were sourced from the DrugBank database. To assess safety signals and rank drugs by their signal strength, we conducted a disproportionality analysis, generating reporting odds ratios (ROR) and proportional reporting ratios (PRR). A total of 20,754,281 AE reports were identified in the FAERS database from Q1 2004 to Q1 2024, of which 1763 were related to congenital anomalies of the external ear. Valproic acid (122 cases) was associated with the most cases, followed by mycophenolate mofetil (105 cases) and lamotrigine (65 cases). According to the disproportionality analysis, the top five drugs with the highest ROR and PRR were primidone (ROR: 397.05, 95% CI 147.21, 1070.9; PRR: 388.71, 95% CI 145.89, 1035.7), valproic acid (ROR: 239.46, 95% CI 123.75, 463.37; PRR: 236.42, 95% CI 123.82, 451.43), tapazole (ROR: 198.35, 95% CI 63.49, 619.67; PRR: 196.25, 95% CI 62.97, 611.67), nevirapine (ROR: 138.24, 95% CI 82.9, 230.51; PRR: 137.23, 95% CI 82.44, 228.44), and sebivo (ROR: 117.1, 95% CI 48.51, 282.67; PRR: 116.37, 95% CI 48.17, 281.12). This study identified several drugs significantly associated with congenital anomalies of the external ear in the FAERS database using disproportionality analysis. The findings can help healthcare professionals better recognize and manage drug-induced congenital anomalies of the external ear, particularly when prescribing high-risk medications. Further research is needed to elucidate the mechanisms underlying these associations and develop strategies for preventing and mitigating drug-induced congenital anomalies of the external ear., (© 2024. The Author(s).)

Importance: Buprenorphine combined with naloxone is commonly used to treat opioid use disorders outside of pregnancy. In pregnancy, buprenorphine alone is generally recommended because of limited perinatal safety data on the combination product., Objective: To compare perinatal outcomes following prenatal exposure to buprenorphine with naloxone vs buprenorphine alone., Design, Settings, and Participants: Population-based cohort study using health care utilization data from Medicaid-insured beneficiaries in the US from 2000 to 2018. The cohort was restricted to pregnant individuals linked to their liveborn infants, with maternal Medicaid enrollment from 3 months before pregnancy to 1 month after delivery and infant enrollment for the first 3 months after birth, unless they died sooner., Exposure: Use of buprenorphine with naloxone vs buprenorphine alone during the first trimester based on outpatient dispensings., Main Outcomes and Measures: Outcomes included major congenital malformations, low birth weight, neonatal abstinence syndrome, neonatal intensive care unit admission, preterm birth, respiratory symptoms, small for gestational age, cesarean delivery, and maternal morbidity. Confounder-adjusted risk ratios were calculated using propensity score overlap weights., Results: This study identified 3369 pregnant individuals exposed to buprenorphine with naloxone during the first trimester (mean [SD] age, 28.8 [4.6] years) and 5326 exposed to buprenorphine alone or who switched from the combination to buprenorphine alone by the end of the first trimester (mean [SD] age, 28.3 [4.5] years). When comparing buprenorphine combined with naloxone with buprenorphine alone, a lower risk for neonatal abstinence syndrome (absolute risk, 37.4% vs 55.8%; weighted relative risk, 0.77 [95% CI, 0.70-0.84]) and a modestly lower risk for neonatal intensive care unit admission (absolute risk, 30.6% vs 34.9%; weighted relative risk, 0.91 [95% CI, 0.85-0.98]) and small for gestational age (absolute risk, 10.0% vs 12.4%; weighted relative risk, 0.86 [95% CI, 0.75-0.98]) was observed. For maternal morbidity, the comparative rates were 2.6% vs 2.9%, respectively, and the weighted relative risk was 0.90 (95% CI, 0.68-1.19). No differences were observed with respect to major congenital malformations overall, low birth weight, preterm birth, respiratory symptoms, or cesarean delivery. Results were consistent across sensitivity analyses., Conclusions and Relevance: There were similar and, in some instances, more favorable neonatal and maternal outcomes for pregnancies exposed to buprenorphine combined with naloxone compared with buprenorphine alone. For the outcomes assessed, compared with buprenorphine alone, buprenorphine with naloxone during pregnancy appears to be a safe treatment option. This supports the view that both formulations are reasonable options for the treatment of opioid use disorder in pregnancy, affirming flexibility in collaborative treatment decision-making.

Objective: To characterize associations of exposure to newer antiretroviral medications in the first trimester with congenital anomalies among infants born to persons with HIV in the United States., Design: Longitudinal cohort of infants born 2012-2022 to pregnant persons with HIV enrolled in the Surveillance Monitoring for ART Toxicities (SMARTT) study., Methods: First-trimester exposures to newer antiretrovirals (ARVs) were abstracted from maternal medical records. Trained site staff conducted physical exams and abstracted congenital anomalies from infant medical records. Investigators classified anomalies using the Metropolitan Atlanta Congenital Defects Program classification system. The prevalence of major congenital anomalies identified by age one year was estimated for infants exposed and unexposed to each ARV. Generalized estimating equation models were used to estimate the odds ratio (OR) of major congenital anomalies for each ARV exposure, adjusting for potential confounders., Results: Of 2034 infants, major congenital anomalies were identified in 135 [6.6%; 95% confidence interval (CI): 5.6-7.8%]. Cardiovascular ( n  = 43) and musculoskeletal ( n  = 37) anomalies were the most common. Adjusted ORs (95% CI) of congenital anomalies were 1.03 (0.62-1.72) for darunavir, 0.91 (0.46-1.81) for raltegravir, 1.04 (0.58-1.85) for rilpivirine, 1.31 (0.71-2.41) for elvitegravir, 0.76 (0.37-1.57) for dolutegravir, and 0.34 (0.05-2.51) for bictegravir, compared to those unexposed to each specific ARV. Findings were similar after adjustment for nucleoside/nucleotide backbones., Conclusions: The odds of congenital anomalies among infants with first-trimester exposure to newer ARVs did not differ substantially from those unexposed to these specific ARVs, which is reassuring. Continued evaluation of these ARVs with larger studies will be needed to confirm these findings., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Metformin is a first-line pharmacotherapy for type 2 diabetes, but there is limited evidence about its safety in early pregnancy., Objective: To evaluate the teratogenicity of metformin use in the first trimester of pregnancy., Design: In an observational cohort of pregnant women with pregestational type 2 diabetes receiving metformin monotherapy before the last menstrual period (LMP), a target trial with 2 treatment strategies was emulated: insulin monotherapy (discontinue metformin treatment and initiate insulin within 90 days of LMP) or insulin plus metformin (continue metformin and initiate insulin within 90 days of LMP)., Setting: U.S. Medicaid health care administration database (2000 to 2018)., Participants: 12 489 pregnant women who met the eligibility criteria., Measurements: The risk and risk ratio of nonlive births, live births with congenital malformations, and congenital malformations among live births were estimated using standardization to adjust for covariates., Results: A total of 850 women were in the insulin monotherapy group and 1557 in the insulin plus metformin group. The estimated risk for nonlive birth was 32.7% under insulin monotherapy (reference) and 34.3% under insulin plus metformin (risk ratio, 1.02 [95% CI, 1.01 to 1.04]). The estimated risk for live birth with congenital malformations was 8.0% (CI, 5.7% to 10.2%) under insulin monotherapy and 5.7% (CI, 4.5% to 7.3%) under insulin plus metformin (risk ratio, 0.72 [CI, 0.51 to 1.09])., Limitation: Possible residual confounding by glycemic control and body mass index., Conclusion: Compared with switching to insulin monotherapy, continuing metformin and adding insulin in early pregnancy resulted in little to no increased risk for nonlive birth among women receiving metformin before pregnancy. Under conventional statistical criteria, anything between a 49% decrease and a 9% increase in risk for congenital malformations was highly compatible with our data., Primary Funding Source: National Institutes of Health., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-2038.

Background: The North American AED Pregnancy Registry (NAAPR) provides crucial data for understanding the risks of antiepileptic drug (AED) exposure in pregnancy. This study aims to quantify the Canadian contribution to NAAPR and compare AED usage in pregnancy in Canada and the USA., Methods: Enrollment rate ratios (ERR) to NAAPR, adjusted for the populations of women of childbearing age, were calculated for the USA, Canada, and for the different Canadian provinces. Methods of enrollment to NAAPR and AED usage were compared between the two countries using chi-squared tests., Results: Between 1997 and 2019, 10,215 pregnant women enrolled into NAAPR: 4.1% were Canadian (n = 432, ERR = 0.39, CI 95% = 0.35-0.43). Within Canada, no patients were enrolled from the three northern territories or from Prince Edward Island. While fewer patients than expected enrolled from Quebec (ERR = 0.35, CI 95% = 0.19-0.58), Nova Scotia had the highest enrollment rate (ERR = 1.55; CI 95% = 0.66-3.11). Compared with their American peers, Canadians were less likely to have been enrolled by their healthcare provider and more likely to have been enrolled via social media ( p < 0.01). Canadian women were more likely to be taking carbamazepine (24% vs. 15%; p < 0.01) or valproic acid (8% vs. 4%; p < 0.01)., Conclusion: The proportion of Canadian enrollees into NAAPR was less than expected based on the relative population size of Canadian women of reproductive age. Greater Canadian enrollment to NAAPR would contribute to ongoing worldwide efforts in assessing the risks of AEDs use in pregnant women and help quantify rates of AED usage, major congenital malformations, and access to subspecialized epilepsy care within Canada.

The scientific community relies on postmarketing approaches to define the risk of using medications in pregnancy because information available at the time of drug approval is limited. Most studies carried out in pregnancy focus on a single outcome or selected outcomes. However, women must balance the benefit of treatment against all possible adverse effects. We aimed to apply and evaluate a tree-based scan statistic data-mining method (TreeScan; Martin Kulldorff, Harvard Medical School, Boston, Massachusetts) as a safety surveillance approach that allows for simultaneous evaluation of a comprehensive range of adverse pregnancy outcomes, while preserving the overall rate of false-positive alerts. We evaluated TreeScan with a cohort design and adjustment via propensity score techniques, using 2 test cases: 1) opioids and neonatal opioid withdrawal syndrome and 2) valproate and congenital malformations, implemented in pregnancy cohorts nested within the Medicaid Analytic eXtract (January 1, 2000-December 31, 2014) and the IBM MarketScan Research Database (IBM, Armonk, New York) (January 1, 2003-September 30, 2015). In both cases, we identified known safety concerns, with only 1 previously unreported alert at the preset statistical alerting threshold. This evaluation shows the promise of TreeScan-based approaches for systematic drug safety monitoring in pregnancy. A targeted screening approach followed by deeper investigation to refine understanding of potential signals will ensure that pregnant women and their physicians have access to the best available evidence to inform treatment decisions., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: To examine the prevalence of, and factors associated with, atypical antipsychotic use among U.S. pregnant women, and potential associations between early pregnancy atypical antipsychotic use and risk for 14 birth defects., Methods: We analyzed data from the National Birth Defects Prevention Study (1997-2011), a U.S. population-based case-control study examining risk factors for major structural birth defects., Results: Atypical antipsychotic use during pregnancy was more common among women with pre-pregnancy obesity, and women who reported illicit drug use before and during pregnancy, smoking during pregnancy, alcohol use during pregnancy, or use of other psychiatric medications during pregnancy. We observed elevated associations (defined as a crude odds ratio [cOR] ≥2.0) between early pregnancy atypical antipsychotic use and conotruncal heart defects (6 exposed cases; cOR: 2.3, 95% confidence interval [CI]: 0.9-6.1), and more specifically Tetralogy of Fallot (3 exposed cases; cOR: 2.5, 95% CI: 0.7-8.8), cleft palate (4 exposed cases, cOR: 2.5, 95% CI: 0.8-7.6), anorectal atresia/stenosis (3 exposed cases, cOR: 2.8, 95% CI: 0.8-9.9), and gastroschisis (3 exposed cases, cOR: 2.1, 95% CI: 0.6-7.3)., Conclusions: Our findings support the close clinical monitoring of pregnant women using atypical antipsychotics. Women treated with atypical antipsychotics generally access healthcare services before pregnancy; efforts to reduce correlates of atypical antipsychotic use might improve maternal and infant health in this population., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to report., (Published by Elsevier B.V.)

Purpose: The purpose of the study is to develop an algorithm to identify pregnancies in administrative databases and apply it to assess pregnancy rates and outcomes in women prescribed isotretinoin or tretinoin., Methods: Using the 2011 to 2015 Truven Health MarketScan Database, we identified pregnancies, including losses and terminations. In a cohort design, nonpregnant women filling a prescription for isotretinoin or tretinoin were matched to five women without either prescription. Women were followed for 365 days or until conception, medication discontinuation, or enrollment discontinuation ("prescription episode"). Rates of pregnancy, risks of pregnancy losses, and prevalence of infant malformations at birth were assessed by exposure., Results: We identified 2 179 192 livebirths, 8434 stillbirths, 2521 mixed births, 415 110 spontaneous abortions, 124 556 elective terminations, and 8974 unspecified abortions. There were 86 834 isotretinoin and 973 587 tretinoin episodes, matched to 5 302 105 unexposed women. Pregnancy rates were 3 (isotretinoin), 19 (tretinoin), and 34 (unexposed) per 1000 person-years. Risk of spontaneous pregnancy losses were similar; however, terminations were more common in the isotretinoin-exposed (28% [95% CI: 21%-36%]) than the tretinoin-exposed (10% [95% CI: 9%-11%]) or unexposed pregnancies (6%). Malformations occurred in 4.5% (95% CI: 3.5%-5.6%) of the tretinoin-exposed pregnancies and 4.2% of the unexposed pregnancies (adjusted odds ratio: 1.16 [95% CI: 0.85-1.58]); isotretinoin-exposed births were too few to assess malformations., Conclusions: Administrative databases can complement risk evaluation and mitigation strategies (REMS) for known teratogens and contribute to safety surveillance for other medications. Here, isotretinoin-exposed pregnancy rates were low, but existent, and many pregnancies were terminated. Tretinoin exposure was not associated with a meaningfully elevated risk of losses or malformations as compared with unexposed pregnancies., (© 2019 John Wiley & Sons, Ltd.)

Background: Birth outcome data with dolutegravir exposure during pregnancy, particularly in the first trimester, are needed., Setting: Data were prospectively collected from the Antiretroviral Pregnancy Registry and European Pregnancy and Paediatric HIV Cohort Collaboration., Methods: We reviewed 2 large, independent antiretroviral pregnancy registries to assess birth outcomes associated with maternal dolutegravir treatment during pregnancy., Results: Of 265 pregnancies reported to the Antiretroviral Pregnancy Registry, initial exposure to dolutegravir occurred at conception or first trimester in 173 pregnancies and during the second or third trimester in 92 pregnancies. There were 246 (92.8%) live births resulting in 255 neonates (9 twins), 6 (2.3%) induced abortions, 11 (4.2%) spontaneous abortions, and 2 (0.8%) stillbirths. Birth defects occurred in 7 (2.7%) of 255 live-born neonates, 5 (3.1%) of 162 (includes 6 twins) with conception/first-trimester exposure. Of 101 pregnancies reported to the European Pregnancy and Paediatric HIV Cohort Collaboration, outcomes were available for 84 pregnancies (16 continuing to term and 1 lost to follow-up). There were 81 live births (80 with known initial dolutegravir exposure at conception or first, second, and third trimesters in 42, 21, and 17 live births, respectively), 1 stillbirth (second-trimester exposure), 1 induced abortion (first-trimester exposure), and 1 spontaneous abortion (first-trimester exposure), respectively. Birth defects occurred in 4 live births (4.9%; 95% confidence interval: 1.4 to 12.2), 3 of 42 (7.1%) with exposure at conception or first trimester., Conclusions: Our findings are reassuring regarding dolutegravir treatment of HIV infection during pregnancy but remain inconclusive because of small sample sizes.

Background: To evaluate pregnancy outcomes among women participating in the antiepileptic drug (AED) Levetiracetam Registry (LEV-Registry), and to review the impact of using two other registries' outcome definitions on the number of major congenital malformations (MCMs)., Methods: This US-based prospective study (ClinicalTrials.gov NCT00345475) was overseen by an independent Expert Panel. Women exposed to levetiracetam at any time during pregnancy enrolled, directly, or via their healthcare provider. The primary outcome was prevalence of MCMs, defined according to a modified version of the Metropolitan Atlanta Congenital Defects Program criteria., Results: Of 491 women enrolled, 465 (94.7%) had a documented outcome. Most (92.3%) received levetiracetam for epilepsy; 323 (69.4%) as monotherapy and 142 (30.5%) as polytherapy. With three twin pregnancies, there were 468 outcomes-444 livebirths, 3 stillbirths, 19 miscarriages, and 2 terminations. Based on the MCM definition used by LEV-Registry, 46 infants among 444 livebirths had MCMs resulting in 10.4% (95% CI 7.7, 13.6) for overall prevalence, 9.4% (95% CI 6.4, 13.2) with monotherapy, and 12.6% (95% CI 7.5, 19.4) with polytherapy. When MCM reports were reviewed independently by staff at EURAP (International Registry of AEDs) and North American AED Pregnancy Registry according to their respective criteria, only 22 and 7 infants of the 46, respectively, were classified as having MCMs., Conclusion: The LEV-Registry Expert Panel did not find evidence suggestive of teratogenic association with prenatal exposure to levetiracetam. The substantial differences in which physical findings were considered MCMs highlight the major impact of pregnancy registry methodology on MCM prevalence estimates., (© 2019 Wiley Periodicals, Inc.)

Purpose: The purpose of this study is to describe dispensing patterns and comparative safety of disease-modifying therapies (DMTs) during pregnancy in women with multiple sclerosis (MS)., Methods: We identified pregnancies from the Truven Health Marketscan® Commercial Claims and Encounters Database (2011-2015) and ascertained MS before delivery from inpatient and outpatient claims. We computed the proportion of women with DMT dispensing claims around pregnancy and estimated risk ratios of spontaneous abortion, infections, cesarean section, preterm delivery, poor fetal growth, preeclampsia, and major structural malformations by DMT exposure., Results: Of 984 058 pregnancies, 1649 were to women with MS. Thirty-five percent of women with MS filled a prescription for a DMT in the 90 days before pregnancy. DMT use declined during pregnancy but increased again after delivery. Glatiramer acetate and interferon beta were most commonly dispensed. Pregnancies with and without early DMT exposure had similar risks of outcomes to one another and to pregnancies in women without MS. Small numbers did not allow evaluation of specific DMTs., Conclusions: Approximately one third of commercially insured women with MS in the United States uses DMTs before conception. Neither MS itself nor early pregnancy use of DMTs overall seems to be associated with a substantial risk of adverse pregnancy outcomes., (© 2019 John Wiley & Sons, Ltd.)

The need to maximize agricultural productivity has made pesticides an indispensable part of current times. Farmers are unaware of the lurking consequences of the pesticide exposure, which endanger their health. It also puts the unsuspecting consumers in peril. The pesticides (from organophosphates, organochlorine, and carbamate class) disrupt the immune and hormonal signaling, causing recurrent inflammation, which leads to a wide array pathologies, including teratogenicity. Numerous farmers have fallen victim to neural disorders-driven suicides and lungs, prostate/breast cancer-caused untimely deaths. Green revolution which significantly escalated agricultural productivity is backfiring now. It is high time that environmental and agricultural authorities act to restrain the excessive usage of the detrimental chemicals and educate farmers regarding the crisis. This review discusses the biological mechanisms of pesticide-driven pathogenesis (such as the activation or inhibition of caspase, serine protease, acetylcholinesterase) and presents the pesticide-exposure-caused health deterioration in USA, India, and Africa. This holistic and critical review should be an eye-opener for general public, and a guide for researchers.

Purpose: The recent expansion of electronic health and medical record systems may present an opportunity to generate robust post-approval safety data and obviate the limitations of prospective pregnancy exposure registries. We examined and compared, over the same time frame, the outcomes of triptan exposure in pregnancy using (1) a retrospective claims database and (2) a previously completed pregnancy registry., Methods: Using the Marketscan database, the risk of major birth defects was ascertained in live-born infants whose birth mothers were exposed to sumatriptan, naratriptan, or sumatriptan/naproxen during pregnancy. The frequencies of outcomes observed were compared with the findings of the 16-year sumatriptan, naratripan, and sumatriptan/naproxen prospective pregnancy registry., Results: About 5120 pregnancies were identified in the retrospective claims cohort in contrast to 617 included in the prospective registry during the same time frame. The proportion of major birth defects among first-semester sumatriptan exposures was 4.0%, which is exactly the same as the proportion of major birth defects reported for first-semester sumatriptan exposures in the registry. There were very few non-livebirth outcomes in both the claims analyses and registry., Conclusions: These results confirm broad agreement between the database analysis and the registry regarding the safety of triptans during pregnancy. Of note, the number of triptan-exposed pregnancies identified in this large US database was about 7-fold that included in the prospective registry over the same time frame. The findings of this study support an approach of using existing health care database (s) in the post-approval assessment of medication exposure in pregnancy., (© 2018 Amgen Inc. Pharmacoepidemiology & Drug Safety Published by John Wiley & Sons Ltd.)

Objective: To use data from two large studies of birth defects to describe time trends in ondansetron use for the treatment of first-trimester nausea and vomiting of pregnancy and to investigate associations, either previously reported or undescribed, between first-trimester ondansetron use and major birth defects., Methods: We used data from two case-control studies, the National Birth Defects Prevention Study (1997-2011) and the Slone Birth Defects Study (1997-2014). The prevalence of ondansetron use for the treatment of first-trimester nausea and vomiting of pregnancy among control patients was calculated in 2-year intervals. Using women with untreated first-trimester nausea and vomiting of pregnancy as the reference, we calculated adjusted odds ratios (ORs) and 95% CIs for associations between first-trimester ondansetron use for treatment of nausea and vomiting of pregnancy and specific birth defects. A secondary exposure group of other prescription antiemetics was used to address confounding by indication., Results: In the National Birth Defects Prevention Study and Slone Birth Defects Study, respectively, 6,751 and 5,873 control mothers and 14,667 and 8,533 case mothers who reported first-trimester nausea and vomiting of pregnancy were included in the analysis. Among women in the control group, ondansetron exposure increased from less than 1% before 2000 to 13% in 2013-2014. Ondansetron use was not associated with an increased risk for most of the 51 defect groups analyzed. Modest increases in risk were observed for cleft palate (adjusted OR 1.6, 95% CI 1.1-2.3) in the National Birth Defects Prevention Study and renal agenesis-dysgenesis (adjusted OR 1.8, 95% CI 1.1-3.0) in the Birth Defects Study, although these findings may be the result of chance., Conclusion: Off-label use of ondansetron for the treatment of nausea and vomiting of pregnancy increased to 13% by the end of the study period. For the majority of specific birth defects investigated, there was no increased risk associated with first-trimester use of ondansetron for treatment of nausea and vomiting of pregnancy compared with no treatment, although modest associations with cleft palate and renal agenesis-dysgenesis warrant further study.

Background: Malaria chemoprophylaxis options in pregnancy are limited, and atovaquone-proguanil (AP) is not recommended because of insufficient safety evidence. An anonymous, internet-based survey was disseminated to describe outcomes of pregnancies accidentally exposed to AP. Outcomes of interest included miscarriage (defined as pregnancy loss before 20 weeks), stillbirth (defined as pregnancy loss at or after 20 weeks), preterm birth or live birth prior to 37 weeks, and the presence of congenital anomalies., Results: A total of 487 women responded and reported on 822 pregnancies. Of the 807 pregnancies with information available on exposure and outcomes, 10 (1.2%) had atovaquone-proguanil exposure, all in the first trimester, and all resulted in term births with no birth defects., Conclusions: Use of an anti-malarial not recommended in pregnancy is likely to occur before the woman knows of her pregnancy. This study adds to the limited evidence of the safety of AP in pregnancy. Further study on use of AP in pregnancy should be a high priority, as an alternative option for the prevention of malaria in pregnancy in non-immune travellers is urgently needed.

Objective: To assess the relative risk of oral clefts associated with maternal use of high and low doses of topiramate during the first trimester for epilepsy and nonepilepsy indications., Methods: This population-based study nested in the US 2000-2010 Medicaid Analytic eXtract included a cohort of 1,360,101 pregnant women with a live-born infant enrolled in Medicaid from 3 months before conception through 1 month after delivery. Oral clefts were defined as the presence of a recorded diagnosis in claims during the first 90 days after birth. Women with a topiramate dispensing during the first trimester were compared with those without any dispensing and with an active reference group of women with a lamotrigine dispensing during the first trimester. Risk ratios (RRs) were estimated with generalized linear models with fine stratification on the propensity score of treatment to control for potential confounders. Stratified analyses by indication of use and dose were conducted., Results: The risk of oral clefts at birth was 4.1 per 1,000 in the 2,425 infants born to women exposed to topiramate compared with 1.1 per 1,000 in the unexposed group (RR 2.90, 95% confidence interval [CI] 1.56-5.40). The RR among women with epilepsy was 8.30 (95% CI 2.65-26.07); among women with other indications such as bipolar disorder, it was 1.45 (95% CI 0.54-3.86). The median daily dose for the first prescription filled during the first trimester was 200 mg for women with epilepsy and 100 mg for women without epilepsy. For topiramate monotherapy, the RR for oral clefts associated with doses ≤100 mg was 1.64 (95% CI 0.53-5.07) and for doses >100 mg it was 5.16 (95% CI 1.94-13.73). Results were similar when lamotrigine was used as a reference group., Conclusion: The increased risk of oral clefts associated with use of topiramate early in pregnancy was more pronounced in women with epilepsy, who used higher doses., (Copyright © 2017 American Academy of Neurology.)

In 23 states and Washington D.C., alcohol retailers are required by law to post alcohol warning signs (AWS) that warn against the risks of drinking during pregnancy. Using the variation in the adoption of these laws across states and within states over time, I find a statistically significant reduction in prenatal alcohol use associated with AWS. I then use this plausibly exogenous change in drinking behavior to establish a causal link between prenatal alcohol exposure and birth outcomes. I find that AWS laws are associated with decreases in the odds of very low birth weight and very pre-term birth., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Birth defects are the leading cause of infant death. While causes of most are unknown, those that might be due to medication use are among the most preventable. This study describes an approach to identifying those medications that most warrant attention by using a "screen" program that calculates odds ratios for pairs of exposures and specific birth defects., Methods: We discuss the development of this tool and illustrate its application to two large risk factor studies, the Slone Epidemiology Center's Birth Defects Study and the Centers for Disease Control and Prevention's National Birth Defects Prevention Study, ideal settings for the systematic study of risks and relative safety of drugs in relation to birth defects while recognizing the inherent limitations of such an approach., Results: Suggestions for establishing criteria for exposures and outcomes that balance the need for specific details with the practical considerations of sample size and volume of output are presented. Selection of appropriate exposure reference categories and control groups is also discussed, as well as the need to address potential confounding. An example that motivated a detailed investigation of possible associations between a medication (butalbital) and selected specific birth defects is provided., Conclusion: While screening programs such as the one described can be a valuable tool for exploring potential associations in large data bases, they must be applied with caution. The issue of multiple testing and chance findings is a major concern. While statistics are a necessary component, human judgment must be an integral part of the process., (© 2015 Wiley Periodicals, Inc.)

Background: Obtaining human pregnancy data to inform product labeling is important for drug and biological products., Methods: Collection and analyses of safety data on their use during pregnancy is usually performed after approval., Results: The Centers for Disease Control National Birth Defects Prevention Study has provided important data on the relationship between drug use in pregnancy and birth defects., Conclusion: The Pregnancy and Lactation Labeling Rule will set new and improved standards for the inclusion of information about the use of prescription drugs and biological products during pregnancy; the National Birth Defects Prevention Study, along with other data sources, will be critical for providing safety data to inform product labeling., (© 2015 Wiley Periodicals, Inc.)

Objective: To follow up on previously reported associations between periconceptional use of selective serotonin reuptake inhibitors (SSRIs) and specific birth defects using an expanded dataset from the National Birth Defects Prevention Study., Design: Bayesian analysis combining results from independent published analyses with data from a multicenter population based case-control study of birth defects., Setting: 10 centers in the United States., Participants: 17,952 mothers of infants with birth defects and 9857 mothers of infants without birth defects, identified through birth certificates or birth hospitals, with estimated dates of delivery between 1997 and 2009., Exposures: Citalopram, escitalopram, fluoxetine, paroxetine, or sertraline use in the month before through the third month of pregnancy. Posterior odds ratio estimates were adjusted to account for maternal race/ethnicity, education, smoking, and prepregnancy obesity., Main Outcome Measure: 14 birth defects categories that had associations with SSRIs reported in the literature., Results: Sertraline was the most commonly reported SSRI, but none of the five previously reported birth defects associations with sertraline was confirmed. For nine previously reported associations between maternal SSRI use and birth defect in infants, findings were consistent with no association. High posterior odds ratios excluding the null value were observed for five birth defects with paroxetine (anencephaly 3.2, 95% credible interval 1.6 to 6.2; atrial septal defects 1.8, 1.1 to 3.0; right ventricular outflow tract obstruction defects 2.4, 1.4 to 3.9; gastroschisis 2.5, 1.2 to 4.8; and omphalocele 3.5, 1.3 to 8.0) and for two defects with fluoxetine (right ventricular outflow tract obstruction defects 2.0, 1.4 to 3.1 and craniosynostosis 1.9, 1.1 to 3.0)., Conclusions: These data provide reassuring evidence for some SSRIs but suggest that some birth defects occur 2-3.5 times more frequently among the infants of women treated with paroxetine or fluoxetine early in pregnancy., (© Reefhuis et al 2015.)

Objective: Atypical antipsychotics are widely used by reproductive-age women to treat a spectrum of psychiatric illnesses. Despite widespread use of this class of agents in women of childbearing potential, reproductive safety data across these medicines remain limited. The National Pregnancy Registry for Atypical Antipsychotics (NPRAA) at Massachusetts General Hospital was established in 2008 to address this knowledge gap., Method: Data are prospectively collected from pregnant women, ages 18-45 years, using 3 phone interviews conducted at the following times: (1) proximate to the time of enrollment, (2) 7 months' gestation, and (3) 2-3 months postpartum. Subjects include pregnant women with histories of fetal exposure to second-generation antipsychotics and a comparison group of nonexposed pregnant women. Medical record release authorization is obtained for obstetric, labor and delivery, and newborn pediatric (up to 6 months of age) records. Information regarding the presence of major malformations is abstracted from the medical records along with other data regarding neonatal and maternal health outcomes. Identified cases of congenital malformations are sent to a dysmorphologist blinded to drug exposure for final adjudication., Results: As of May 2014, 428 subjects have enrolled in the NPRAA. Efforts continue to increase enrollment for the purpose of enhancing the capacity to define risk estimates of in utero exposure to atypical antipsychotics., Conclusions: The NPRAA gathers prospective data regarding risk for critical outcomes following use of atypical antipsychotics during pregnancy. The NPRAA offers a systematic way to collect reproductive safety information that informs the care of women who use these agents to sustain psychiatric well-being., Trial Registration: ClinicalTrials.gov identifier: NCT01246765., (© Copyright 2015 Physicians Postgraduate Press, Inc.)

Objective: To examine the teratogenic potential of statins., Design: Cohort study., Setting: United States., Participants: A cohort of 886,996 completed pregnancies linked to liveborn infants of women enrolled in Medicaid from 2000 to 2007., Methods: We examined the risk of major congenital malformations and organ specific malformations in offspring associated with maternal use of a statin in the first trimester. Propensity score based methods were used to control for potential confounders, including maternal demographic characteristics, obstetric and medical conditions, and use of other drugs., Results: 1152 (0.13%) women used a statin during the first trimester. In unadjusted analyses, the prevalence of malformations in the offspring of these women was 6.34% compared with 3.55% in those of women who did not use a statin in the first trimester (relative risk 1.79, 95% confidence interval 1.43 to 2.23). Controlling for confounders, particularly pre-existing diabetes, accounted for this increase in risk (1.07, 0.85 to 1.37). There were also no statistically significant increases in any of the organ specific malformations assessed after accounting for confounders. Results were similar across a range of sensitivity analyses., Conclusions: Our analysis did not find a significant teratogenic effect from maternal use of statins in the first trimester. However, these findings need to be replicated in other large studies, and the long term effects of in utero exposure to statins needs to be assessed, before use of statins in pregnancy can be considered safe., (© Bateman et al 2015.)

Purpose: Bupropion is a drug uniquely used both to treat depression and as an aid to smoking cessation. We investigated previously reported associations between first-trimester exposure to bupropion and cardiac defects., Methods: Using data gathered since 2003 by the Slone Epidemiology Center's Case-control Birth Defects Study, we classified subjects with cardiac defects into subgroups. Exposure categories included first-trimester bupropion alone or in combination with other antidepressants, first-trimester antidepressants other than bupropion, and no exposure to any antidepressant at any time from 2 months prior to pregnancy through delivery. We calculated odds ratios and 95% confidence intervals, controlling for confounding using logistic regression., Results: There were 8611 non-malformed infants and 7913 infants with cardiac defects. Eight cardiac subgroups had sufficient subjects (two or more exposed cases) for analysis. The adjusted odds ratio (aOR) for first-trimester bupropion use in relation to ventricular septal defect (VSD) was slightly elevated (1.6, 95% confidence interval 1.0-2.8); for exposure to bupropion alone, the aOR was 2.5 (95% confidence interval 1.3-5.0). Risks were not materially elevated for bupropion in relation to the other seven cardiac subgroups., Conclusions: We did not confirm previously reported associations for left-sided defects overall but had too few exposed cases to evaluate specific defects in this category. We did observe an elevated risk of VSD following first-trimester bupropion use, particularly when used without other antidepressants. This pattern for bupropion alone was observed in all our risk comparisons and was not explained by higher doses or gestational timing., (Copyright © 2014 John Wiley & Sons, Ltd.)

Fetal alcohol spectrum disorder (FASD) is a term used to describe the spectrum of conditions associated with prenatal alcohol exposure. These are characterized by facial dysmorphia, growth deficits and central nervous system abnormalities. FASDs are the most common preventable cause of intellectual disability in the United States and have high financial costs. Therefore, efforts at prevention are paramount. When an individual with an FASD goes undiagnosed and when appropriate interventions are not instituted, secondary disabilities such as substance abuse, school dropout, and criminal involvement are common with corresponding suffering endured by both the affected individual and the family. The diagnostic process opens up access to existing tools and resources, including the new American Academy of Pediatrics (AAP) FASD algorithm for the evaluation of FASDs, the new AAP FASD toolkit and evidence-based interventions specific to FASDs. Pediatric and adolescent clinicians are challenged to participate in the continuum of care from FASD prevention to identification, diagnosis, and management, including provision of supportive services for families in order for clinicians to make a difference in this 100% preventable disorder., (Copyright © 2014 Mosby, Inc. All rights reserved.)

FASDs are the most common preventable cause of developmental and intellectual disabilities in the United States and yet can easily be overlooked in pediatric and adolescent practices. Early diagnosis, presence of developmental and educational services, and a nurturing home environment have been associated with decreased occurrence of secondary disabilities such as substance use and criminal involvement.23 Therefore, it is important for providers to know how to go about the identification, diagnostic, and evaluation process. Pediatric care clinicians should be knowledgeable about the diagnostic criteria for fetal alcohol syndrome and know common differentiating conditions. Furthermore, they should be able to recognize other disorders on the spectrum, and in doing so, they should facilitate appropriate referral, initial management, and coordination of care.

Background: Previous studies of prenatal exposure to drinking-water nitrate and birth defects in offspring have not accounted for water consumption patterns or potential interaction with nitrosatable drugs., Objectives: We examined the relation between prenatal exposure to drinking-water nitrate and selected birth defects, accounting for maternal water consumption patterns and nitrosatable drug exposure., Methods: With data from the National Birth Defects Prevention Study, we linked addresses of 3,300 case mothers and 1,121 control mothers from the Iowa and Texas sites to public water supplies and respective nitrate measurements. We assigned nitrate levels for bottled water from collection of representative samples and standard laboratory testing. Daily nitrate consumption was estimated from self-reported water consumption at home and work., Results: With the lowest tertile of nitrate intake around conception as the referent group, mothers of babies with spina bifida were 2.0 times more likely (95% CI: 1.3, 3.2) to ingest ≥ 5 mg nitrate daily from drinking water (vs. < 0.91 mg) than control mothers. During 1 month preconception through the first trimester, mothers of limb deficiency, cleft palate, and cleft lip cases were, respectively, 1.8 (95% CI: 1.1, 3.1), 1.9 (95% CI: 1.2, 3.1), and 1.8 (95% CI: 1.1, 3.1) times more likely than control mothers to ingest ≥ 5.42 mg of nitrate daily (vs. < 1.0 mg). Higher water nitrate intake did not increase associations between prenatal nitrosatable drug use and birth defects., Conclusions: Higher water nitrate intake was associated with several birth defects in offspring, but did not strengthen associations between nitrosatable drugs and birth defects.

Background: Few epidemiologic studies have investigated the use of venlafaxine (Effexor XR capsules, Product Monograph, Wyeth, Montreal, Canada), an antidepressant used to treat major depression and anxiety disorders in adults, during pregnancy. Our objective was to determine whether use of venlafaxine during pregnancy is associated with specific birth defects., Methods: We used data from the National Birth Defects Prevention Study (NBDPS), a population-based, case-control study in the United States. Our analysis included mothers with pregnancies affected by one of 30 selected birth defects (cases) and babies without birth defects (controls) with estimated dates of delivery between 1997 and 2007. Exposure was any reported use of venlafaxine from 1 month preconception through the third month of pregnancy. We calculated adjusted odds ratios (aORs) and 95% Fisher Exact confidence intervals (CIs) for 24 birth defect groups for which at least 400 case mothers were interviewed. Our adjusted analyses controlled for maternal age and race/ethnicity., Results: Among the 27,045 NBDPS participants who met inclusion criteria, 0.17% (14/8002) of control mothers and 0.40% (77/19,043) of case mothers reported any use of venlafaxine from 1 month preconception through the third month of pregnancy. Statistically significant associations were found for anencephaly, atrial septal defect (ASD) secundum, or ASD not otherwise specified, coarctation of the aorta, cleft palate, and gastroschisis., Conclusions: Our data suggest associations between periconceptional use of venlafaxine and some birth defects. However, sample sizes were small, CIs were wide, and additional studies are needed to confirm these results., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: Nitrosatable drugs can react with nitrite in the stomach to form N-nitroso compounds, and results from animal studies suggest that N-nitroso compounds are teratogens. With data from the National Birth Defects Prevention Study, the relation between prenatal exposure to nitrosatable drugs and limb deficiencies, oral cleft, and heart malformations in offspring was examined., Methods: Maternal reports of drugs taken during the first trimester of pregnancy were classified with respect to nitrosatability for mothers of 741 babies with limb deficiencies, 2774 with oral cleft malformations, 8091 with congenital heart malformations, and 6807 without major congenital malformations. Nitrite intake was estimated from maternal responses to a food frequency questionnaire., Results: Isolated transverse limb deficiencies and atrioventricular septal defects were associated with secondary amine drug exposures (adjusted odds ratios [aORs], 1.51; 95% confidence limit [CI], 1.11-2.06 and aOR, 1.97; 95% CI, 1.19-3.26, respectively). Tertiary amines were associated with hypoplastic left heart syndrome (aOR, 1.50; 95% CI, 1.10-2.04) and single ventricle (aOR, 1.61; 95% CI, 1.06-2.45). These two malformations were also significantly associated with amide drugs. For several malformations, the strongest associations with nitrosatable drug use occurred among mothers with the highest estimated dietary nitrite intake, especially for secondary amines and atrioventricular septal defects (highest tertile of nitrite, aOR, 3.30; 95% CI, 1.44-7.58)., Conclusion: Prenatal exposure to nitrosatable drugs may be associated with several congenital malformations, especially with higher nitrite intake. The possible interaction between nitrosatable drugs and dietary nitrite on risk of congenital malformations warrants further attention., (Copyright © 2012 Wiley Periodicals, Inc.)

Objectives: Approximately 4% to 12% of pregnant women have asthma; few studies have examined the effects of maternal asthma medication use on birth defects. We examined whether maternal asthma medication use during early pregnancy increased the risk of selected birth defects., Methods: National Birth Defects Prevention Study data for 2853 infants with 1 or more selected birth defects (diaphragmatic hernia, esophageal atresia, small intestinal atresia, anorectal atresia, neural tube defects, omphalocele, or limb deficiencies) and 6726 unaffected control infants delivered from October 1997 through December 2005 were analyzed. Mothers of cases and controls provided telephone interviews of medication use and additional potential risk factors. Exposure was defined as maternal periconceptional (1 month prior through the third month of pregnancy) asthma medication use (bronchodilator or anti-inflammatory). Associations between maternal periconceptional asthma medication use and individual major birth defects were estimated by using adjusted odds ratios (aOR) and 95% confidence intervals (95%CI)., Results: No statistically significant associations were observed for maternal periconceptional asthma medication use and most defects studied; however, positive associations were observed between maternal asthma medication use and isolated esophageal atresia (bronchodilator use: aOR = 2.39, 95%CI = 1.23, 4.66), isolated anorectal atresia (anti-inflammatory use: aOR = 2.12, 95%CI = 1.09, 4.12), and omphalocele (bronchodilator and anti-inflammatory use: aOR = 4.13, 95%CI = 1.43, 11.95)., Conclusions: Positive associations were observed for anorectal atresia, esophageal atresia, and omphalocele and maternal periconceptional asthma medication use, but not for other defects studied. It is possible that observed associations may be chance findings or may be a result of maternal asthma severity and related hypoxia rather than medication use.

Background: Well-executed knowledge transfer and translation (KT) has become a vital part of effective health management. Following the thalidomide disaster, women and their health care providers became fearful of medications and environmental exposures that could affect the health of the unborn child. Therefore, it is important to disseminate evidenced-based information to pregnant women and their health care providers, enabling them to make empowered decisions regarding exposures during pregnancy., Objectives: The objectives were twofold: (1) to explore the knowledge transfer process of teratology information from the research community to health care providers, pregnant women, and the general public; and (2) to examine how this impacts pregnant women and their health care providers who require this information., Methods: We searched the peer reviewed literature (PUBMED, MEDLINE, and EMBASE), retrieved and examined original studies and review articles, and identified relevant data to evaluate how KT is conducted in this field., Results: We found that KT and teratology information is very complex, with confusing information, over-estimated fears of teratogenicity, as well as unhelpful, often negatively biased information from the media. Of all the methods we identified, Teratogen Information Services (TIS) appears to conduct the most effective KT approaches in this field., Conclusion: It is evident that KT in this area needs improvement. Women and their health care providers are highly impacted by the type of teratology information they receive, affecting for example, deciding to terminate a wanted pregnancy or discontinue a needed pharmacotherapy. When disseminating information in this very sensitive and complex field, it is imperative that good KT strategies are used, encompassing the availability and appropriate interpretation of information. It is most important that an evidence-based decision is made to ensure the optimal outcome for both the mother and her unborn child., (Copyright © 2011 Wiley-Liss, Inc.)

Purpose: To evaluate use of specific antiepileptic drugs (AEDs) in pregnancy in relation to specific birth defects., Methods: Using data from the National Birth Defects Prevention Study, we assessed use of AEDs and the risk of neural tube defects (NTDs), oral clefts (OCs), heart defects (HDs), hypospadias, and other major birth defects, taking specific agent, timing, and indication into consideration., Results: Drug-specific increased risks were observed for valproic acid in relation to NTDs [adjusted odds ratio (aOR), 9.7;, 95% confidence interval (CI), 3.4-27.5], OCs (aOR, 4.4; 95% CI, 1.6-12.2), HDs (aOR, 2.0; 95% CI, 0.78-5.3), and hypospadias (aOR. 2.4; 95% CI, 0.62-9.0), and for carbamazapine in relation to NTDs (aOR, 5.0; 95% CI, 1.9-12.7). Epilepsy history without AED use did not seem to increase risk., Conclusions: Valproic acid, which current guidelines suggest should be avoided in pregnancy, was most notable in terms of strength and breadth of its associations. Carbamazapine was associated with NTDs, even after controlling for folic acid use. Sample sizes were still too small to adequately assess risks of less commonly used AEDs, but our findings support further study to identify lower risk options for pregnant women., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: To estimate the risk of major congenital anomalies after exposure to selective serotonin reuptake inhibitors during pregnancy., Methods: A retrospective cohort study based on national population-based registers (years 1996-2006) of births, congenital anomalies, and terminations of pregnancy because of severe fetal anomalies (maintained by National Institute for Health and Welfare, source offspring population n=635,583) and drug reimbursements (Social Insurance Institution) linked by a personal identification number. Offspring exposed to selective serotonin reuptake inhibitors during the first trimester (n=6,976) were compared with unexposed referent offspring., Results: Overall major congenital anomalies were not more common in selective serotonin reuptake inhibitor-exposed offspring compared with unexposed referent offspring (adjusted odds ratio [OR] 1.08, 95% confidence interval [CI] 0.96-1.22). Fluoxetine was associated with an increased risk of isolated ventricular septal defects (adjusted OR 2.03, 95% CI 1.28-3.21) and paroxetine was associated with an increased risk of right ventricular outflow tract defects (adjusted OR 4.68, 95% CI 1.48-14.74). Citalopram use was associated with neural tube defects (adjusted OR 2.46, 95% CI 1.20-5.07). Fetal alcohol spectrum disorders were 10-times more common in the selective serotonin reuptake inhibitor-exposed offspring than in unexposed referent offspring., Conclusion: Fluoxetine use is associated with an increased risk of isolated ventricular septal defects and paroxetine is associated with right ventricular outflow tract defects. The absolute risk for these specific cardiac anomalies is small but should guide clinicians not to consider fluoxetine or paroxetine the first option when prescribing selective serotonin reuptake inhibitors to women planning pregnancy. Special attention should be given to alcohol use in pregnant women using selective serotonin reuptake inhibitors.

Objectives: The aim of the study was to quantify the benefits (life expectancy gains) and risks (efavirenz-related teratogenicity) associated with using efavirenz in HIV-infected women of childbearing age in the USA., Methods: We used data from the Women's Interagency HIV Study in an HIV disease simulation model to estimate life expectancy in women who receive an efavirenz-based initial antiretroviral regimen compared with those who delay efavirenz use and receive a boosted protease inhibitor-based initial regimen. To estimate excess risk of teratogenic events with and without efavirenz exposure per 100,000 women, we incorporated literature-based rates of pregnancy, live births, and teratogenic events into a decision analytic model. We assumed a teratogenicity risk of 2.90 events/100 live births in women exposed to efavirenz during pregnancy and 2.68/100 live births in unexposed women., Results: Survival for HIV-infected women who received an efavirenz-based initial antiretroviral therapy (ART) regimen was 0.89 years greater than for women receiving non-efavirenz-based initial therapy (28.91 vs. 28.02 years). The rate of teratogenic events was 77.26/100,000 exposed women, compared with 72.46/100,000 unexposed women. Survival estimates were sensitive to variations in treatment efficacy and AIDS-related mortality. Estimates of excess teratogenic events were most sensitive to pregnancy rates and number of teratogenic events/100 live births in efavirenz-exposed women., Conclusions: Use of non-efavirenz-based initial ART in HIV-infected women of childbearing age may reduce life expectancy gains from antiretroviral treatment, but may also prevent teratogenic events. Decision-making regarding efavirenz use presents a trade-off between these two risks; this study can inform discussions between patients and health care providers.

Prenatal exposure to diethylstilbestrol (DES) is associated with adverse health outcomes, including anatomic anomalies of the reproductive tract in women and of the genitourinary tract in men. The mouse model, which replicates many DES-related effects seen in humans, suggests that prenatal DES exposure causes alterations that may affect the next generation of offspring. We asked women participating in a large, multi-centre study of prenatal DES exposure to report birth defects occurring among 4029 sons and 3808 daughters (i.e., the third generation). A subcohort of 793 third generation daughters was also queried for birth defects. We used logistic regression models to generate odds ratio and 95% confidence intervals for the association between prenatal DES exposure in the mother and birth defects in the offspring. Based on the mothers' reports, overall birth defects were elevated in the sons (OR = 1.53; 95% CI = 1.04, 2.23) and in the daughters (OR = 2.35; 95% CI = 1.44, 3.82). Most estimates of association were imprecise, but daughters appeared to have an excess of heart conditions (OR = 4.56; 95% CI = 1.27, 16.34). Our data suggest a possible association between the mother's prenatal DES exposure and birth defects in their offspring, particularly in daughters. We cannot, however, rule-out the possible influence of reporting bias. In particular, the exposed daughters' elevated risk of cardiac defects may be as a result of the underreporting of these conditions by unexposed mothers.

Background: Oral contraceptives (OCs) are the most commonly used reversible contraceptive method among US women. Although the majority of previous studies have reported no association between OC use during pregnancy and birth defects, some studies have reported increased occurrence of neural tube defects, limb reduction defects, and urinary tract anomalies., Methods: We assessed OC use among mothers who participated in the multisite, case-control, National Birth Defects Prevention Study. Mothers of 9986 infants with 32 types of birth defects and 4000 infants without birth defects were included., Results: Maternal OC use during the first 3 months of pregnancy was associated with an increased odds ratio for 2 of 32 birth defects: hypoplastic left heart syndrome (adjusted odds ratio = 2.3 [95% confidence interval = 1.3-4.3) and gastroschisis (1.8 [1.3-2.7])., Conclusion: Previous reports of associations between OC use and specific types of anomalies were not corroborated. Given that associations were assessed for 32 types of birth defects, our findings of 2 increased associations between OC use and gastroschisis and hypoplastic left heart syndrome should be interpreted as hypotheses until they can be evaluated further. Overall, our findings are consistent with the majority of previous studies that found women who use OCs during early pregnancy have no increased risk for most types of major congenital malformations.

Objective: To investigate whether exposure during the first trimester of pregnancy to single-ingredient acetaminophen increases the risk of major birth defects., Methods: Data from the National Birth Defects Prevention Study, a population-based, case-control study, were used. Women who delivered between January 1, 1997, and December 31, 2004, and participated in the telephone interview were included. Type and timing of acetaminophen use were assigned based on maternal report. Women reporting first-trimester acetaminophen use in a combination product were excluded, resulting in a total of 11,610 children in the case group and 4,500 children in the control group for analysis., Results: The prevalence of first-trimester single-ingredient-acetaminophen use was common: 46.9% (n=5,440) among women in the case group and 45.8% (n=2,059) among women in the control group (P=.21). Overall, acetaminophen was not associated with an increased risk of any birth defect. Among women reporting a first-trimester infection and fever, use of acetaminophen was associated with a statistically significantly decreased odds ratio (OR) for anencephaly or craniorachischisis (adjusted OR 0.35, 95% confidence interval [CI] 0.08-0.80), encephalocele (adjusted OR 0.17, 95% CI 0.03-0.87), anotia or microtia (adjusted OR 0.25, 95% CI 0.07-0.86), cleft lip with or without cleft palate (adjusted OR 0.44, 95% CI 0.26-0.75), and gastroschisis (adjusted OR 0.41, 95% CI 0.18-0.94)., Conclusion: Single-ingredient-acetaminophen use during the first trimester does not appear to increase the risk of major birth defects. It may decrease the risk of selected malformations when used for a febrile illness., Level of Evidence: II.

Objective: To better describe the safety profile of pregnancy exposures to the human papillomavirus (HPV) type 6/11/16/18 vaccine by acquiring and analyzing postmarketing data on pregnancy outcomes (ie, live births, abortions, fetal deaths, and congenital anomalies)., Methods: Enrollment criteria included an identifiable patient and health care provider from the United States, France, or Canada and exposure within 1 month before the date of onset of the last menstrual period or at any time during pregnancy. Outcomes of interest were pregnancy outcomes and birth defects. Prospectively reported cases (reported before the outcome of the pregnancy was known) were used for rate calculations., Results: For the 517 prospective reports with known outcome, 451 (87.2%) were live births, including three sets of twins. Of 454 neonates, 439 (96.7%) were normal. The overall rate of spontaneous abortion was 6.9 per 100 outcomes (95% confidence interval [CI] 4.8-9.6). The prevalence of major birth defects was 2.2 per 100 liveborn neonates (95% CI 1.05-4.05). There were seven fetal deaths (1.5 per 100 outcomes, 95% CI 0.60-3.09)., Conclusion: Rates of spontaneous abortions and major birth defects were not greater than the unexposed population rates. Although no adverse signals have been identified to date, the HPV6/11/16/18 vaccine is not recommended for use in pregnant women., Level of Evidence: III.

Objective: To estimate the association between antibacterial medications and selected birth defects., Design, Setting, and Participants: Population-based, multisite, case-control study of women who had pregnancies affected by 1 of more than 30 eligible major birth defects identified via birth defect surveillance programs in 10 states (n = 13 155) and control women randomly selected from the same geographical regions (n = 4941)., Main Exposure: Reported maternal use of antibacterials (1 month before pregnancy through the end of the first trimester)., Main Outcome Measure: Odds ratios (ORs) measuring the association between antibacterial use and selected birth defects adjusted for potential confounders., Results: The reported use of antibacterials increased during pregnancy, peaking during the third month. Sulfonamides were associated with anencephaly (adjusted OR [AOR] = 3.4; 95% confidence interval [CI], 1.3-8.8), hypoplastic left heart syndrome (AOR = 3.2; 95% CI, 1.3-7.6), coarctation of the aorta (AOR = 2.7; 95% CI, 1.3-5.6), choanal atresia (AOR = 8.0; 95% CI, 2.7-23.5), transverse limb deficiency (AOR = 2.5; 95% CI, 1.0-5.9), and diaphragmatic hernia (AOR = 2.4; 95% CI, 1.1-5.4). Nitrofurantoins were associated with anophthalmia or microphthalmos (AOR = 3.7; 95% CI, 1.1-12.2), hypoplastic left heart syndrome (AOR = 4.2; 95% CI, 1.9-9.1), atrial septal defects (AOR = 1.9; 95% CI, 1.1-3.4), and cleft lip with cleft palate (AOR = 2.1; 95% CI, 1.2-3.9). Other antibacterial agents that showed associations included erythromycins (2 defects), penicillins (1 defect), cephalosporins (1 defect), and quinolones (1 defect)., Conclusions: Reassuringly, penicillins, erythromycins, and cephalosporins, although used commonly by pregnant women, were not associated with many birth defects. Sulfonamides and nitrofurantoins were associated with several birth defects, indicating a need for additional scrutiny.

Background: Diethylstilbestrol (DES), a synthetic estrogen widely prescribed to pregnant women during the 1940s70s, has been shown to cause reproductive problems in the daughters. Studies of prenatally-exposed males have yielded conflicting results., Methods: In data from a collaborative follow-up of three U.S. cohorts of DES-exposed sons, we examined the relation of prenatal DES exposure to occurrence of male urogenital abnormalities. Exposure status was determined through review of prenatal records. Mailed questionnaires (1994, 1997, 2001) asked about specified abnormalities of the urogenital tract. Risk ratios (RR) were estimated by Cox regression with constant time at risk and control for year of birth., Results: Prenatal DES exposure was not associated with varicocele, structural abnormalities of the penis, urethral stenosis, benign prostatic hypertrophy, or inflammation/infection of the prostate, urethra, or epididymus. However, RRs were 1.9 (95% confidence interval 1.13.4) for cryptorchidism, 2.5 (1.54.3) for epididymal cyst, and 2.4 (1.54.4) for testicular inflammation/infection. Stronger associations were observed for DES exposure that began before the 11th week of pregnancy: RRs were 2.9 (1.65.2) for cryptorchidism, 3.5 (2.06.0) for epididymal cyst, and 3.0 (1.75.4) for inflammation/infection of testes., Conclusion: These results indicate that prenatal exposure to DES increases risk of male urogenital abnormalities and that the association is strongest for exposure that occurs early in gestation. The findings support the hypothesis that endocrine disrupting chemicals may be a cause of the increased prevalence of cryptorchidism that has been seen in recent years.

Objectives: To investigate if live births conceived in months when surface water agrichemicals are highest are at greater risk for birth defects., Methods: Monthly concentrations during 1996-2002 of nitrates, atrazine and other pesticides were calculated using United States Geological Survey's National Water Quality Assessment data. Monthly United States birth defect rates were calculated for live births from 1996 to 2002 using United States Centers for Disease Control and Prevention natality data sets. Birth defect rates by month of last menstrual period (LMP) were then compared to pesticide/nitrate means using logistical regression models., Results: Mean concentrations of agrichemicals were highest in April-July. Total birth defects, and eleven of 22 birth defect subcategories, were more likely to occur in live births with LMPs between April and July. A significant association was found between the season of elevated agrichemicals and birth defects., Conclusion: Elevated concentrations of agrichemicals in surface water in April-July coincided with higher risk of birth defects in live births with LMPs April-July. While a causal link between agrichemicals and birth defects cannot be proven from this study an association might provide clues to common factors shared by both variables.

Objective: To present any congenital anomalies with respect to tumor necrosis factor (TNF) antagonists reported to the US Food and Drug Administration (FDA) to determine if there are common findings., Methods: A review of the FDA database of reported adverse events with etanercept, infliximab, and adalimumab from 1999 through December of 2005 was performed. Key words for congenital anomalies were employed as search tools. Duplicate reports were eliminated. Any concomitant medicines were recorded., Results: Our review of > 120,000 adverse events revealed a total of 61 congenital anomalies in 41 children born to mothers taking a TNF antagonist. Of these mothers, 22 took etanercept and 19 took infliximab. There were no reports in women taking adalimumab. The most common reported congenital anomaly was some form of heart defect. Twenty-four of the 41 (59%) children had one or more congenital anomalies that are part of vertebral abnormalities, anal atresia, cardiac defect, tracheoesophageal, renal, and limp abnormalities (VACTERL) association. There were 34 specific types of congenital anomalies in total, and 19 (56%) of those are part of the VACTERL spectrum. Nine of these 19 (47%) types of VACTERL anomalies were observed statistically significantly more than historical controls (p < 0.01); in 4 of these 9 the p value was < or = 0.0001. Thirteen (32%) of the children had more than one congenital anomaly; 7 of these 13 children had 2 defects that are part of the VACTERL spectrum. However, only 1 child was diagnosed with VACTERL. In 24/41 cases (59%) the mother was taking no other concomitant medications., Conclusion: A seemingly high number of congenital anomalies that are part of the VACTERL spectrum have been reported. These congenital anomalies are occurring at a rate higher than historical controls. This commonality raises concerns of a possible causative effect of the TNF antagonists.

Background: In 2004, the Survey on Drug Use and Health showed that 5% of American women reported use of an illicit drug during pregnancy. The results of studies determining the association between periconceptional illicit drug use and birth defects have been inconsistent., Methods: We analyzed data from the National Birth Defects Prevention Study, a case-control study of major birth defects, and assessed all birth defects categories in which there were at least 250 interviewed case mothers. We included 10,241 infants with major congenital malformations (case infants) and 4,967 infants without major congenital malformations (control infants) born between 1997 and 2003 for whom there was a completed maternal interview with detailed information on prenatal illicit drug use and potential confounders. We used multivariable logistic regression to estimate the associations between cannabis, cocaine, and stimulant use in the month before pregnancy or during the first trimester (periconceptional period) and the occurrence of selected birth defects., Results: In the periconceptional period, 5% of the 15,208 mothers reported any use of illicit drugs. We did not find associations between illicit drug use and most of the 20 eligible categories of congenital malformations. Periconceptional cannabis use seemed to be associated with an increased risk of anencephaly (adjusted odds ratio = 1.7; 95% confidence interval = 0.9-3.4), whereas cocaine use in the periconceptional period was associated with the risk of cleft palate (2.5; 1.1-5.4)., Conclusions: There were very few suggestions of positive associations between periconceptional illicit drug use and the 20 birth defects categories.

Most pregnant women with epilepsy require antiepileptic drug (AED) therapy. Present guidelines recommend optimizing treatment prior to conception, choosing the most effective AED for seizure type and syndrome, using monotherapy and lowest effective dose, and supplementing with folate. The Epilepsy Therapy Project established the international Health Outcomes in Pregnancy and Epilepsy (HOPE) forum to learn more about the impact of AEDs on the developing fetus, particularly the role of pregnancy registries in studying AED teratogenicity. The primary outcome of interest in these registries is the occurrence of major congenital malformations, with some data collected on minor malformations. Cognitive and behavioral outcomes are often beyond the timeframe for follow-up of these registries and require independent study. The HOPE consensus report describes the current state of knowledge and the limitations to interpretations of information from the various sources. Data regarding specific risks for both older and newer AEDs need to be analyzed carefully, considering study designs and confounding factors. There is a critical need for investigations to delineate the underlying mechanisms and explain the variance seen in outcomes across AEDs and within a single AED.

Objective: This study examined whether first-trimester antifungal drug use was associated with the risk of selected birth defects., Study Design: Subjects were participants in a case-control study, the National Birth Defects Prevention Study, with singleton deliveries from 1997 to 2003. Based on maternal interviews, first-trimester antifungal drug use was compared between 7047 cases with isolated defects and 4774 nonmalformed controls using unconditional logistic regression., Results: Risk was elevated for hypoplastic left heart syndrome (odds ratio, 2.30; 95% confidence interval, 1.04, 5.06) but not for other cardiovascular defects. An increased risk of 1.88 was observed for diaphragmatic hernia but was not statistically significant. Estimates approximated unity for neural tube defects, oral clefts, anorectal atresia, hypospadias, and craniosynostosis., Conclusion: First-trimester antifungal drug exposure was not strongly associated with the risk of most birth defects, but further studies should examine the preliminary results of an association with hypoplastic left heart syndrome.

We estimate the effect of illicit drug use during pregnancy on two measures of poor infant health: low birth weight and abnormal infant health conditions. We use data from a national longitudinal study of urban parents that includes postpartum interviews with mothers, hospital medical record data on the mothers and their newborns, and information about the neighborhood in which the mother resides. We address the potential endogeneity of prenatal drug use. Depending on how prenatal drug use is measured, we find that it increases low birth weight by 4-6 percentage points and that it increases the likelihood of an abnormal infant health condition by 7-12 percentage points., (Copyright (c) 2006 John Wiley & Sons, Ltd.)