Risk Of Specific Birth Defects Research Articles

Risk of birth defects in pregnant persons with sleep-disordered breathing during pregnancy.

As many as one in four pregnant women may experience sleep-disordered breathing (SDB) during pregnancy. The same sequelae of SDB, such as insulin resistance and inflammation, have been implicated in the development of certain birth defects. This is a secondary analysis of the SDB substudy of the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be study, which included 2106 participants who had a sufficiency sleep study at two visits at different time points in pregnancy. SDB was based on a self-administered home sleep apnea test with data scored by trained, blinded research polysomnologists. SDB was defined as an apnea-hypopnea index (AHI) ≥5. The primary outcome of this analysis was any of the 45 non-chromosomal birth defects included in the National Birth Defects Prevention Network Annual Report. In this cohort, the overall rate of birth defects was 3.1%. The prevalence was similar between those without SDB (3.0%) and those with only mid-pregnancy SDB (3.4%), but was higher in those with early-pregnancy SDB (6.7%). After adjusting for maternal age, chronic hypertension, pregestational diabetes, and body mass index (BMI), there were no statistically significant differences in the risk of birth defects by subject SDB status. Further studies to evaluate the effect of prepregnancy and early-pregnancy SDB on the fetus, as well as the risk of specific birth defects and neonatal outcomes in those with an objectively measured diagnosis of SDB, are still needed.

Maternal exposure to zolpidem and risk of specific birth defects.

Zolpidem is a non-benzodiazepine agent indicated for treatment of insomnia. While zolpidem crosses the placenta, little is known about its safety in pregnancy. We assessed associations between self-reported zolpidem use 1 month before pregnancy through to the end of the third month ("early pregnancy") and specific birth defects using data from two multi-site case-control studies: National Birth Defects Prevention Study and Slone Epidemiology Center Birth Defects Study. Analysis included 39,711 birth defect cases and 23,035 controls without a birth defect. For defects with ≥ 5 exposed cases, we used logistic regression with Firth's penalised likelihood to estimate adjusted odds ratios and 95% confidence intervals, considering age at delivery, race/ethnicity, education, body mass index, parity, early-pregnancy antipsychotic, anxiolytic, antidepressant use, early-pregnancy opioid use, early-pregnancy smoking, and study as potential covariates. For defects with three-four exposed cases, we estimated crude odds ratios and 95% confidence intervals. Additionally, we explored differences in odds ratios using propensity score-adjustment and conducted a probabilistic bias analysis of exposure misclassification. Overall, 84 (0.2%) cases and 46 (0.2%) controls reported early-pregnancy zolpidem use. Seven defects had sufficient sample size to calculate adjusted odds ratios, which ranged from 0.76 for cleft lip to 2.18 for gastroschisis. Four defects had odds ratios > 1.8. All confidence intervals included the null. Zolpidem use was rare. We could not calculate adjusted odds ratios for most defects and estimates are imprecise. Results do not support a large increase in risk, but smaller increases in risk for certain defects cannot be ruled out.

The association of nausea and vomiting of pregnancy, its treatments, and select birth defects: Findings from the National Birth Defect Prevention Study.

Nausea and vomiting of pregnancy (NVP) occurs in approximately 70% of pregnant people. Treatments include pharmacologic and herbal/natural products. Research on the associations between NVP and its treatments and birth defects is limited. We used data from the case-control National Birth Defects Prevention Study (1997-2011) to examine whether first-trimester NVP or its specific treatments were associated with 37 major birth defects. Odds ratios (aOR) and 95% confidence intervals (CIs) were adjusted for sociodemographic and reproductive factors. Mothers of 66.6% of 28,628 cases and 69.9% of 11,083 controls reported first-trimester NVP. Compared to no NVP, mothers with NVP had ≥10% reduction in risk of cardiac and noncardiac defects overall, and of 18 specific defects. Over-the-counter antiemetic use, compared to untreated NVP, was associated with ≥10% increase in risk for nine defect groups (heterotaxy, hypoplastic left heart syndrome [HLHS], aortic stenosis, cataracts, anophthalmos/microphthalmos, biliary atresia, transverse limb deficiency, omphalocele, and gastroschisis), whereas use of prescription antiemetics increased risk ≥10% for seven defect groups (tetralogy of Fallot, HLHS, spina bifida, anopthlamos/microphthalmos, cleft palate, craniosynostosis, and diaphragmatic hernia). We observed increased risks for promethazine and tetralogy of Fallot (aOR: 1.49, 95% CI: 1.05-2.10), promethazine and craniosynostosis (1.44, 1.08-1.92), ondansetron and cleft palate (1.66, 1.18-2.31), pyridoxine and heterotaxy (3.91, 1.49-10.27), and pyridoxine and cataracts (2.57, 1.12-5.88). NVP does not increase risks of birth defects. Our findings that some treatments for NVP increase risk of specific birth defects should be investigated further before clinical recommendations are made.

Maternal exposure to hydroxychloroquine and birth defects

BackgroundHydroxychloroquine is a treatment for rheumatic disease and considered safe during pregnancy. Interest in hydroxychloroquine has increased as it is being examined as a potential treatment and prophylaxis for coronavirus disease 2019. Data on the risks of specific birth defects associated with hydroxychloroquine use are sparse.MethodsUsing data from two case–control studies (National Birth Defects Prevention Study and Slone Epidemiology Center Birth Defects Study), we described women who reported hydroxychloroquine use in pregnancy and the presence of specific major birth defects in their offspring. Cases had at least one major birth defect and controls were live‐born healthy infants. Women self‐reported medication use information in the few months before pregnancy through delivery.ResultsIn total, 0.06% (19/31,468) of case and 0.04% (5/11,614) of control mothers in National Birth Defects Prevention Study, and 0.04% (11/29,838) of case and 0.05% (7/12,868) of control mothers in Birth Defects Study reported hydroxychloroquine use. Hydroxychloroquine users had complicated medical histories and frequent medication use for a variety of conditions. The observed birth defects among women taking hydroxychloroquine were varied and included nine oral cleft cases; the elevated observed:expected ratios for specific oral cleft phenotypes and for oral clefts overall had 95% confidence intervals that included 1.0.ConclusionWhile teratogens typically produce a specific pattern of birth defects, the observed birth defects among the hydroxychloroquine‐exposed women did not present a clear pattern, suggesting no meaningful evidence for the risk of specific birth defects. The number of exposed cases is small; results should be interpreted cautiously.

Oseltamivir exposure in pregnancy and the risk of specific birth defects.

Influenza during pregnancy contributes to maternal morbidity and mortality. Neuraminidase inhibitors, including oseltamivir, are recommended for treating women with influenza during pregnancy. Data from the Slone Birth Defects Study from 2009 to 2015 were used to investigate associations between oseltamivir and specific birth defects. We classified exposures according to timing in pregnancy and examined 52 and 16 defects with early and potential late pregnancy etiology, respectively; we calculated crude odds ratios (ORs) and 95% confidence intervals (CIs) for defects with three or more exposures. Among 8,379 cases and 4,190 nonmalformed controls, we identified 79 and 42 oseltamivir exposures, respectively. The majority of defects had no exposures. ORs were elevated for several defects, but the CI excluded the null only for intestinal malrotation (OR: 10.7 [1.8, 45.2]; three exposures). Largely null findings for specific defects are reassuring. The association with intestinal malrotation, while unstable, warrants further investigation.

Nuclear radiation and prevalence of structural birth defects among infants born to women from the Marshall Islands.

With their unique history of exposure to extensive nuclear testing between 1946 and 1958, descendants of Marshall Island residents may have underappreciated genetic abnormalities, increasing their risk of birth defects. We conducted a retrospective cohort study of resident women with at least one singleton live birth between 1997 and 2013 in northwest Arkansas using state birth certificate data linked to data from the Arkansas Reproductive Health Monitoring System, a statewide birth defects registry. We calculated unadjusted and adjusted prevalence ratios (PR) and 95% confidence intervals (CI) from modified Poisson regression analyses for non-Hispanic (NH) whites, NH-blacks, Hispanics and Marshallese, using NH-whites as the reference group. Of the 91,662 singleton births during the study period, 2,488 were to Marshallese women. Due to the relatively small number of Marshallese births, we could not calculate prevalence estimates for some defects. Marshallese infants had higher rates of congenital cataracts (PR = 9.3; 95% CI: 3.1, 27.9). Although the number of defects was low, Marshallese infants also had higher rates of truncus arteriosus (PR = 44.0; 95% CI: 2.2, 896.1). Marshallese infants may have increased risk of specific birth defects, but estimates are unstable because of small sample size so results are inconclusive. Larger population-based studies would allow for further investigation of this potential risk among Marshallese infants.

Assisted Reproductive Technology and Developmental Outcomes.

* Abbreviation: ART — : assisted reproductive technology Assisted reproductive technologies (ARTs), including in vitro fertilization with fresh or frozen embryos as well as intracytoplasmic sperm injection, have come into increasing use in Western nations since the late 1970s. Pregnancies resulting from ART are more likely to result in stillbirth, multiple gestation, preterm delivery, and low birth weight, with higher rates of adverse outcomes after procedures that involve the placing of either a single embryo or multiple embryos.1 Infant mortality rates are higher as well, whereas evidence for an increased risk of specific birth defects is equivocal.2–4 Research on child health and developmental outcomes is more limited, and for this reason, the study by Hansen et al5 is a welcome addition to our literature. Hansen et al5 use population-based data from Western Australia garnered through probabilistic record linkage based … Address correspondence to Russell S. Kirby, PhD, MS, FACE, College of Public Health, University of South Florida, 13201 Bruce B. Downs Blvd, MDC 56, Tampa, FL 33612. E-mail: rkirby{at}health.usf.edu

Ondansetron for Treatment of Nausea and Vomiting of Pregnancy and the Risk of Specific Birth Defects.

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. 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. 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. 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.

The association between maternal parity and birth defects

Previous studies observed that first birth is associated with an increased risk of some categories of birth defects. However, multiple statistical tests were conducted and it was unclear which of these associations would be replicated in a larger study. We used a large database to assess the association between maternal parity and 65 birth defects including birth defects that have not been previously studied. Using data from the Texas Birth Defects Registry for years 1999-2009, the risk of a birth defect occurring in a first, third, or fourth or higher birth was compared to the risk of a birth defect occurring in a second birth. Women having their first birth had significantly increased odds of having an infant with 24 of 65 categories of birth defects when compared to women having their second birth. We also observed associations between first birth and an increased risk of five birth defects not previously reported (small penis, preaxial polydactyly, anomalies of the thoracic vertebrae, anomalies of the lumbar vertebrae, and sacroccygeal anomalies). Women having their third or fourth or higher birth had significantly increased odds of giving birth to infants with five of 65 birth defects when compared to second births. Our observations regarding the categories of birth defects that were associated with first births were highly consistent with observations from two previous studies. Research into biological, behavioral, and environmental factors that may increase the risk of specific birth defects among first births is needed to further explore these associations.

Use of Oral Fluconazole During Pregnancy and the Risk of Birth Defects

Whether common doses of oral fluconazole used in treating fungal infections of the skin or mucous membranes increase the risk of specific birth defects remains a concern. The teratogenic potential of oral azole antifungal agents is important because pregnant women are at increased risk for vaginal candidiasis, the most common clinical indication for these drugs. This registry-based, nationwide cohort study evaluated the association between first-trimester oral fluconazole exposure and the risk of major birth defects. Using a nationwide cohort of all live-born infants born between 1996 and 2011, data were obtained on prescriptions for oral fluconazole, itraconazole, and ketoconazole that were filled by the cohort women during their pregnancies. Unexposed women were those who did not fill prescriptions for oral azole antifungal agents during the first trimester. The 15 specific birth defects previously associated with azole antifungal agents were craniosynostosis, cleft palate, cleft lip with or without cleft palate, other craniofacial defects, middle ear defects, limb defects, limb reduction defects, polydactyly, syndactyly, diaphragmatic hernia, heart defects, tetralogy of Fallot (TOF), pulmonary artery hypoplasia, ventricular septal defects, and hypoplastic left heart. Chromosomal aberrations, genetic syndromes, birth defect syndromes with known causes, congenital viral infections associated with malformations, and minor defects were excluded. Prevalence odds ratios (ORs) with 95% confidence intervals (CIs) were estimated by logistic regression for each exposure category and each birth defect outcome. Primary analyses included any exposure to fluconazole or exposure to different fluconazole doses and the outcome of either birth defects overall or birth defects linked with azole antifungal agents. Categories of cumulative doses during the first trimester were 150, 300, and 350 to 6000 mg, based on the standard treatment of vaginal candidiasis. Secondary analyses included exposure to itraconazole and ketoconazole and the outcome of birth defects overall. A total of 976,300 live-born infants were included in the study. No significantly increased risk of birth defects overall was observed among 7352 pregnancies exposed to any fluconazole, as compared with 968,236 unexposed pregnancies (adjusted prevalence OR, 1.06; 95% CI, 0.92–1.21); evaluation of exposure using the cumulative doses did not change this result. No significantly increased risk was found for 14 of the defects, with the only exception being TOF. Based on 7 exposed pregnancies, the risk of TOF was 3 times higher (prevalence 0.10%) than that among 287 unexposed pregnancies (prevalence, 0.03%; adjusted prevalence OR, 3.16; 95% CI, 1.49–6.71). Similar results were observed when the 15 birth defects were evaluated according to cumulative fluconazole dose. No significantly increased risk of birth defects overall was observed among the 687 and 72 pregnancies exposed to itraconazole and ketoconazole, respectively, and no clustering of malformations was observed. Exposure to any oral fluconazole or to the described cumulative doses during the first trimester of pregnancy was not associated with significantly increased risks of birth defects overall, nor was exposure to oral itraconazole or ketoconazole. The only birth defect at higher risk was TOF, but the absolute risk was small. However, this association should be confirmed in future studies.

PRM21 - Studying drug safety in pregnancy: Different approaches, same conclusions?

Various methods are used to monitor safety of drug exposures in pregnancy, including prospective pregnancy registries, longitudinal database studies, and case-control studies. This abstract seeks to evaluate these approaches and examine impact on interpretation of results. Study designs for the three types of pregnancy monitoring studies were examined to determine strengths and limitations in effectively monitoring drug safety in pregnancy and the types of conclusions that can meaningfully be drawn from each. Pregnancy registries are prospective studies with active data collection from reliable sources providing detailed, quality data on exposure and outcome. Their voluntary nature can lead to selection bias and a lengthy enrollment period may be needed to reach sufficient sample size/power. Longitudinal database studies are population based and offer timely and cost-efficient results, but often require complex linkage of multiple databases. Misclassification bias can occur because critical variables (exposure and outcome) may lack precision/detail. Case-control studies begin with the outcome of interest and retrospectively assess drug exposure offering substantial statistical power to identify teratogens among relatively rare exposures, but are subject to recall bias. Only registries are useful in monitoring safety early in the drug lifecycle. Pregnancy registries can detect major teratogenic effects, but have limited power to detect risk of specific birth defects. Database studies can detect major teratogenic effects and due to their large size/power may also detect risk of specific defects. Both approaches can assess other outcomes. Case-control studies provide insights into the strength of association between exposure and a specific defect, but cannot be used to estimate birth defect prevalence or other outcomes. All three approaches are viable for studying drug safety in pregnancy, but differ in the types of conclusions that may be drawn. In choosing a design, it is important to consider study objectives and outcomes of interest.

Water disinfection by-products and the risk of specific birth defects: a population-based cross-sectional study in Taiwan

BackgroundRecent findings suggest that exposure to disinfection by-products may increase the risk of birth defects. Previous studies have focused mainly on birth defects in general or groups of defects. The objective of the present study was to assess the effect of water disinfection by-products on the risk of most common specific birth defects.MethodsWe conducted a population-based cross-sectional study of 396,049 Taiwanese births in 2001–2003 using information from the Birth Registry and Waterworks Registry. We compared the risk of eleven most common specific defects in four disinfection by-product exposure categories based on the levels of total trihalomethanes (TTHMs) representing high (TTHMs 20+ μg/L), medium (TTHMs 10–19 μg/L), low exposure (TTHMs 5–9 μg/L), and 0–4 μg/L as the reference category. In addition, we conducted a meta-analysis of the results from the present and previous studies focusing on the same birth defects.ResultsIn multivariate logistic regression analysis the risk of ventricular septal defects (adjusted odds ratio 1.81, 95% confidence interval: 0.98 3.35), cleft palate (1.56. 95% CI: 1.00, 2.41), and anencephalus (1.96, 95% CI: 0.94, 4.07) were elevated in the high exposure compared to the reference category. In the meta-analysis, the summary odds ratio for ventricular septal defects (1.59, 95% CI: 1.21, 2.07) was consistently elevated.ConclusionThe present study suggests that prenatal exposure to disinfection by-products increases the risk of ventricular septal defects, cleft palate, and anencephalus. The evidence on ventricular septal defects is consistent in the three available studies.

Maternal occupational exposure and risk of specific birth defects

Gregg identified the teratogenic effect of maternal rubella infection in 1941 and since then there has been a focus on risk factors for birth defects. In nearly 70% of all birth defects, there is still no known risk factor and close to 30% of all pregnancies end in a foetal loss or spontaneous abortion, often because of a defect in the foetus. A large percentage of the workforce consists of women of reproductive age. A search in MEDLINE for original literature and examination of the association between exposure during pregnancy and the risk of birth defects. Five specific birth defects were identified: neural tube defects, cleft lip and cleft palate, congenital heart defects, urinary tract defects and limb defects. The next step was to include studies with information on occupational exposure during pregnancy. There seems to be growing concern as to whether organic solvents, including glycol ethers, pesticides and heavy metals may play a teratogenic role. There is no convincing evidence linking occupational exposure during pregnancy and birth defects.

Risk of specific birth defects in relation to chlorination and the amount of natural organic matter in the water supply.

To assess the effect of water chlorination by-products on specific birth defects, the authors conducted a nationwide cross-sectional study of 285,631 Norwegian births in 1993-1998. Risks of birth defects according to four chlorination by-product exposure categories were compared on the basis of chlorination (yes/no) and level of water color (mg Pt/liter), representing the amount of natural organic matter: high (chlorination, < or =20), medium (chlorination, 10-19.9), and low (chlorination, <10) exposure, with no chlorination and low color (<10) as the reference category. In logistic regression analysis, the risks of any birth defect (adjusted odds ratio (OR) = 1.13, 95% confidence interval (CI): 1.01, 1.25) and of cardiac (adjusted OR = 1.37, 95% CI: 1.00, 1.89), respiratory system (adjusted OR = 1.89, 95% CI: 1.00, 3.58), and urinary tract (adjusted OR = 1.46, 95% CI: 1.00, 2.13) defects were significantly associated with exposure (medium and high combined). Regarding risk of specific birth defects, only that for ventricular septal defects was significantly elevated, with an exposure-response pattern, yielding adjusted odds ratios of 1.63 (95% CI: 1.02, 2.58) for the medium and 1.81 (95% CI: 1.05, 3.09) for the high exposure categories. Furthermore, risk of neural tube defects was related to high color (adjusted OR = 2.60, 95% CI: 1.30, 5.26).

What's in the Water: The Disinfectant Dilemma

Research ArticleOpen AccessWhat's in the water: the disinfectant dilemma.is corrected byErrata: What's in the water: the disinfectant dilemma J Tibbetts J Tibbetts Search for more papers by this author Published:1 January 1995https://doi.org/10.1289/ehp.9510330Cited by:6AboutSectionsPDF ToolsDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InReddit FiguresReferencesRelatedDetailsCited by Liu P, Farré M, Keller J and Gernjak W (2016) Reducing natural organic matter and disinfection by-product precursors by alternating oxic and anoxic conditions during engineered short residence time riverbank filtration: A laboratory-scale column study, Science of The Total Environment, 10.1016/j.scitotenv.2016.05.061, 565, (616-625), Online publication date: 1-Sep-2016. Hwang B, Jaakkola J and Guo H (2008) Water disinfection by-products and the risk of specific birth defects: a population-based cross-sectional study in Taiwan, Environmental Health, 10.1186/1476-069X-7-23, 7:1, Online publication date: 1-Dec-2008. Hanson M, Sibley P, Mabury S, Solomon K and Muir D (2002) Trichloroacetic acid (TCA) and trifluoroacetic acid (TFA) mixture toxicity to the macrophytes Myriophyllum spicatum and Myriophyllum sibiricum in aquatic microcosms, Science of The Total Environment, 10.1016/S0048-9697(01)00955-X, 285:1-3, (247-259), Online publication date: 1-Feb-2002. Hanson M, Sibley P, Ellis D, Fineberg N, Mabury S, Solomon K and Muir D (2002) Trichloroacetic acid fate and toxicity to the macrophytes Myriophyllum spicatum and Myriophyllum sibiricum under field conditions, Aquatic Toxicology, 10.1016/S0166-445X(01)00211-9, 56:4, (241-255), Online publication date: 1-Mar-2002. Pandhal J, Siswanto A, Kuvshinov D, Zimmerman W, Lawton L and Edwards C (2018) Cell Lysis and Detoxification of Cyanotoxins Using a Novel Combination of Microbubble Generation and Plasma Microreactor Technology for Ozonation, Frontiers in Microbiology, 10.3389/fmicb.2018.00678, 9 Hwang B, Jaakkola J and Zenclussen A (2012) Risk of Stillbirth in the Relation to Water Disinfection By-Products: A Population-Based Case-Control Study in Taiwan, PLoS ONE, 10.1371/journal.pone.0033949, 7:3, (e33949) Related articlesErrata: What's in the water: the disinfectant dilemma1 March 1995Environmental Health Perspectives Vol. 103, No. 1 January 1995Metrics About Article Metrics Publication History Originally published1 January 1995Published in print1 January 1995 Financial disclosuresPDF download License information EHP is an open-access journal published with support from the National Institute of Environmental Health Sciences, National Institutes of Health. All content is public domain unless otherwise noted. Note to readers with disabilities EHP strives to ensure that all journal content is accessible to all readers. However, some figures and Supplemental Material published in EHP articles may not conform to 508 standards due to the complexity of the information being presented. If you need assistance accessing journal content, please contact [email protected]. Our staff will work with you to assess and meet your accessibility needs within 3 working days.