Search

Many examples of the use of real-world data in the area of pharmacoepidemiology include "big data," such as insurance claims, medical records, or hospital discharge databases. However, "big" is not always better, particularly when studying outcomes with narrow windows of etiologic relevance. Birth defects are such an outcome, for which specificity of exposure timing is critical. Studies with primary data collection can be designed to query details about the timing of medication use, as well as type, dose, frequency, duration, and indication, that can better characterize the "real world." Because birth defects are rare, etiologic studies are typically case‑control in design, like the National Birth Defects Prevention Study, Birth Defects Study to Evaluate Pregnancy Exposures, and Slone Birth Defects Study. Recall bias can be a concern, but the ability to collect detailed information about both prescription and over-the-counter medication use and other exposures such as diet, family history, and sociodemographic factors is a distinct advantage over claims and medical record data sources. Case‑control studies with primary data collection are essential to advancing the pharmacoepidemiology of birth defects. This article is part of a Special Collection on Pharmacoepidemiology., (Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2024.)

Background: Critical congenital heart defects (CCHDs) are associated with considerable morbidity and mortality. This study estimated survival of children with nonsyndromic CCHDs and evaluated relationships between exposures of interest and survival by CCHD severity (univentricular or biventricular function)., Methods: This analysis included 4380 infants with CCHDs (cases) born during 1999-2011 and enrolled in the National Birth Defects Prevention Study, a multisite, population-based case-control study of major birth defects. Cases were linked to state death files. Nonparametric Kaplan-Meier survival functions were used to estimate 1- and 5-year survival probabilities overall and by severity group (univentricular/biventricular) stratified by demographic and clinical exposure variables of interest. The log-rank test was used to determine whether stratified survival curves were equivalent. Survival and 95% confidence intervals (CIs) were also estimated using Cox proportional hazards modeling adjusted for maternal age, education, race/ethnicity, study site, and birth year., Results: One- and five-year survival rates were 85.8% (CI 84.7-86.8) and 83.7% (CI 82.5-84.9), respectively. Univentricular 5-year survival was lower than biventricular case survival [65.3% (CI 61.7-68.5) vs. 89.0% (CI 87.8-90.1; p < 0.001)]. Clinical factors (e.g. preterm birth, low birthweight, and complex/multiple defects) were associated with lower survival in each severity group. Sociodemographic factors (non-Hispanic Black race/ethnicity,

Background: Certain associations observed in the National Birth Defects Prevention Study (NBDPS) contrasted with other research or were from areas with mixed findings, including no decrease in odds of spina bifida with periconceptional folic acid supplementation, moderately increased cleft palate odds with ondansetron use and reduced hypospadias odds with maternal smoking., Objectives: To investigate the plausibility and extent of differential participation to produce effect estimates observed in NBDPS., Methods: We searched the literature for factors related to these exposures and participation and conducted deterministic quantitative bias analyses. We estimated case-control participation and expected exposure prevalence based on internal and external reports, respectively. For the folic acid-spina bifida and ondansetron-cleft palate analyses, we hypothesized the true odds ratio (OR) based on prior studies and quantified the degree of exposure over- (or under-) representation to produce the crude OR (cOR) in NBDPS. For the smoking-hypospadias analysis, we estimated the extent of selection bias needed to nullify the association as well as the maximum potential harmful OR., Results: Under our assumptions (participation, exposure prevalence, true OR), there was overrepresentation of folic acid use and underrepresentation of ondansetron use and smoking among participants. Folic acid-exposed spina bifida cases would need to have been ≥1.2× more likely to participate than exposed controls to yield the observed null cOR. Ondansetron-exposed cleft palate cases would need to have been 1.6× more likely to participate than exposed controls if the true OR is null. Smoking-exposed hypospadias cases would need to have been ≥1.2 times less likely to participate than exposed controls for the association to falsely appear protective (upper bound of selection bias adjusted smoking-hypospadias OR = 2.02)., Conclusions: Differential participation could partly explain certain associations observed in NBDPS, but questions remain about why. Potential impacts of other systematic errors (e.g. exposure misclassification) could be informed by additional research., (© 2023 John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Zika virus (ZIKV) infection in pregnancy is associated with severe abnormalities of the brain and eye and other adverse outcomes. Zika en Embarazadas y Niños was a prospective cohort study conducted in multiple Colombian cities that enrolled pregnant women in their first trimester. Specimens collected from pregnant women (n = 1,519) during February 2017-September 2018 and their infants (n = 1,080) during June 2017-March 2019 were tested for prenatal ZIKV infection by nucleic acid amplification tests or IgM antibody testing. Zika virus infection in pregnancy was present in 3.2% of pregnant women (incidence rate [IR] per 1,000 person-months = 5.9, 95% CI: 4.3-7.8). Presumptive ZIKV infection was present in 0.8% of infants (IR = 1.6, 95% CI: 0.7-2.9). Five percent of infants with prenatal ZIKV exposure or infection presented with Zika-associated abnormalities; 4.7% were small for gestational age. Understanding the risk of ZIKV infection during pregnancy and associated adverse outcomes can help inform counseling efforts.

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., (© 2023 European Sleep Research Society.)

Background: The relationship between maternal physical activity (PA)/sitting and birth defects is largely unexplored. We examined whether pre-pregnancy PA/sitting were associated with having a pregnancy affected by a birth defect., Methods: We used data from two United States population-based case-control studies: 2008-2011 deliveries from the National Birth Defects Prevention Study (NBDPS; 9 states) and 2014-2018 deliveries from the Birth Defects Study To Evaluate Pregnancy exposureS (BD-STEPS; 7 states). Cases with one of 12 non-cardiac birth defects (n = 3798) were identified through population-based registries. Controls (n = 2682) were live-born infants without major birth defects randomly sampled using vital/hospital records. Mothers self-reported pre-pregnancy PA/sitting. Unconditional logistic regression models estimated associations between PA/sitting categories and the 12 birth defects., Results: Mothers engaging in pre-pregnancy PA was associated with a reduced odds of five (spina bifida, cleft palate, anorectal atresia, hypospadias, transverse limb deficiency) and a higher odds of two (anencephaly, gastroschisis) birth defects. Mothers spending less time sitting in pre-pregnancy was associated with a reduced odds of two (anorectal atresia, hypospadias) and a higher odds of one (cleft lip with or without cleft palate) birth defect., Conclusions: Reasonable next steps include replication of these findings, improved exposure assessment, and elucidation of biologic mechanisms., Impact: Using data from two population-based case-control studies, we found that mothers engaging in different types of physical activity in the 3 months before pregnancy had an infant with a reduced odds of five and a higher odds of two birth defects. Mothers spending less time sitting in the 3 months before pregnancy had an infant with a reduced odds of two and a higher odds of one birth defect. Clarification and confirmation from additional studies are needed using more precise exposure measures, distinguishing occupational from leisure-time physical activity, and elucidation of mechanisms supporting these associations., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Background: Previous studies report an association between prenatal maternal urinary tract infections (UTI) and specific congenital heart defects (CHDs); however, the role of fever and antibiotic use on this association is poorly understood. Using data from the National Birth Defects Prevention Study, we examined whether the relationship between maternal UTIs during the periconceptional period and occurrence of CHDs is modified by the presence of fever due to UTI and corresponding antibiotic use among 11,704 CHD case infants and 11,636 live-born control infants., Methods: Information on UTIs, fever associated with UTI and antibiotic use (sulfonamides, nitrofurantoin, cephalosporins, penicillin, macrolides, and quinolones) during pregnancy were obtained using a computer-assisted telephone interview. Using unconditional multivariable logistic regression, we calculated adjusted odds ratios (ORs) to determine the association between maternal UTIs and subtypes of CHDs. Analyses were stratified by the presence of fever and medication use associated with UTI., Results: The prevalence of UTIs during the periconceptional period was 7.6% in control mothers, and 8.7% in case mothers. In the absence of fever, UTI was associated with secundum atrial septal defects (ASD) (OR 1.3; 95% confidence interval [CI] 1.1-1.5) and in the absence of antibiotics, UTI was associated with conotruncal defects as a group and for four specific CHDs. When fever and UTI occurred concomitantly, no significantly elevated odds ratios were noticed for any subtypes of CHD. Among women with UTIs who used antibiotics, an elevated but statistically non-significant estimate was observed for secundum ASD (OR 1.4; 95% CI 1.0-2.0)., Conclusion: Findings in the present study suggest that fever due to UTI and corresponding maternal antibiotic use do not substantially modify the association between maternal UTIs and specific CHDs in offspring. Further studies with larger sample sizes are warranted to guide clinical management of UTIs during the periconceptional period., (© 2023 Wiley Periodicals LLC.)

Background: Individual measures of socioeconomic status (SES) have been associated with an increased risk of neural tube defects (NTDs); however, the association between neighborhood SES and NTD risk is unknown. Using data from the National Birth Defects Prevention Study (NBDPS) from 1997 to 2011, we investigated the association between measures of census tract SES and NTD risk., Methods: The study population included 10,028 controls and 1829 NTD cases. We linked maternal addresses to census tract SES measures and used these measures to calculate the neighborhood deprivation index. We used generalized estimating equations to calculate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) estimating the impact of quartiles of census tract deprivation on NTDs adjusting for maternal race-ethnicity, maternal education, and maternal age at delivery., Results: Quartiles of higher neighborhood deprivation were associated with NTDs when compared with the least deprived quartile (Q2: aOR = 1.2; 95% CI = 1.0, 1.4; Q3: aOR = 1.3, 95% CI = 1.1, 1.5; Q4 (highest): aOR = 1.2; 95% CI = 1.0, 1.4). Results for spina bifida were similar; however, estimates for anencephaly and encephalocele were attenuated. Associations differed by maternal race-ethnicity., Conclusions: Our findings suggest that residing in a census tract with more socioeconomic deprivation is associated with an increased risk for NTDs, specifically spina bifida., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Potential reproductive effects of organic solvent exposure during pregnancy remain unclear. We investigated the association between maternal occupational exposure during pregnancy to six chlorinated solvents, three aromatic solvents, and Stoddard solvent, and delivery of preterm infants or those born small-for-gestational age (SGA)., Methods: In this case-control study of SGA and preterm birth (PTB) nested within the National Birth Defects Prevention Study (NBDPS) from 1997 to 2011, we analyzed data from 7504 singleton live births without major birth defects and their mothers. Self-reported information on jobs held in the periconceptional period was assessed for solvent exposure. Unconditional logistic regression was used to estimate the association between maternal occupational exposure (any, none) during early pregnancy to organic solvents and PTB and SGA. Linear regression was used to examine changes in mean birthweight potentially associated with maternal occupational solvent exposure., Results: Maternal occupational exposure to any organic solvents overall was not associated with an increased odds of PTB (adjusted odds ratio [aOR] = 0.94; 95% confidence interval [CI] 0.67-1.33) or SGA (aOR = 0.93; 95% CI 0.65-1.34). Point estimates increased modestly for higher estimated exposure versus lower, but confidence intervals were wide and not statistically significant. Maternal exposure to solvents was not associated with a statistically significant change in term birthweight among infants., Conclusions: Occupational exposure to organic solvents at the frequency and intensity levels found in a population-based sample of pregnant workers was not associated with PTB or SGA; however, we cannot rule out any effects among pregnant workers with uncommonly high exposure to organic solvents., (© 2023 Wiley Periodicals LLC.)

The objective of this analysis was to describe patterns of prescription medication use during pregnancy, including secular trends, with consideration of indication, and distributions of use within demographic subgroups. We conducted a descriptive secondary analysis using data from 9,755 women whose infants served as controls in two large United States case-control studies from 1997-2011 and 2014-2018. After excluding vitamin, herbal, mineral, vaccine, i.v. fluid, and topical products and over-the-counter medications, the proportion of women that reported taking at least one prescription medication in the first trimester increased over the study years, from 37% to 50% of women. The corresponding proportions increased with increasing maternal age and years of education, were highest for non-Hispanic White women (47%) and lowest for Hispanic women (24%). The most common indication for first trimester use of a medication was infection (12-15%). Increases were observed across the years for medications used for indications related to nausea/vomiting, depression/anxiety, infertility, thyroid disease, diabetes, and epilepsy. The largest relative increase in use among women was observed for medications to treat nausea/vomiting, which increased from 3.8% in the earliest years of the study (1997-2001) to 14.8% in 2014-2018, driven in large part by ondansetron use. Prescription medication use in the first trimester of pregnancy is common and increasing. Many medical conditions require treatments among pregnant women, often involving pharmacotherapy, which necessitates consideration of the risk and safety profiles for both mother and fetus., (© 2023 The Authors. Clinical Pharmacology & Therapeutics © 2023 American Society for Clinical Pharmacology and Therapeutics.)

Purpose: Cyclobenzaprine is a muscle relaxant indicated for acute pain. Little is known about cyclobenzaprine's safety during pregnancy. We explored the association between maternal cyclobenzaprine exposure and risk of birth defects among offspring., Methods: We combined data from two large, multi-site, population-based case-control studies in the United States. Cases were identified from birth defects registries across 10 states; controls were liveborn infants without birth defects randomly selected from the same catchment areas. Participants reported cyclobenzaprine use during the month before conception through the third month of pregnancy ("periconception") via computer-assisted telephone interview. We used logistic regression to assess associations between periconceptional cyclobenzaprine exposure and selected structural birth defects. We calculated crude odds ratios (OR) with corresponding 95% confidence intervals (CI)., Results: Our study included 33 615 cases and 13 110 controls. Overall, 51 case (0.15%) and 9 control (0.07%) participants reported periconceptional cyclobenzaprine use. We observed increased risk for all seven defects with ≥3 exposed cases: cleft palate (OR = 4.79, 95% CI 1.71-13.44), cleft lip (OR = 2.50, 95% CI 0.89-7.02), anorectal atresia/stenosis (OR = 6.91, 95% CI 1.67, 28.65), d-transposition of the great arteries (OR = 6.97, 95% CI 2.17-22.36), coarctation of the aorta (OR = 5.58, 95% CI 1.88-16.58), pulmonary valve stenosis (OR = 4.55, 95% CI 1.10-18.87), and secundum atrial septal defect (OR = 3.08, 95% CI 0.83-11.45)., Conclusions: Even in our large sample, cyclobenzaprine use was rare. Our estimates are unadjusted and imprecise so should be interpreted cautiously. These hypothesis-generating results warrant confirmation and further research to explore possible mechanisms., (© 2023 John Wiley & Sons Ltd.)

Changing treatments and medical costs necessitate updates to hospitalization cost estimates for birth defects. The 2019 National Inpatient Sample was used to estimate the service delivery costs of hospitalizations among patients aged <65 years for whom one or more birth defects were documented as discharge diagnoses. In 2019, the estimated cost of these birth defect-associated hospitalizations in the United States was $22.2 billion. Birth defect-associated hospitalizations bore disproportionately high costs, constituting 4.1% of all hospitalizations among persons aged <65 years and 7.7% of related inpatient medical costs. Updating estimates of hospitalization costs provides information about health care resource use associated with birth defects and the financial impact of birth defects across the life span and illustrates the need to determine the continued health care needs of persons born with birth defects to ensure optimal health for all., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Russell S. Kirby holds the Marrell endowed chair at the University of South Florida, College of Public Health and serves on the board of directors for the National Birth Defects Prevention Network. Jason L. Salemi and Jean Paul Tanner report grant support to the Florida Department of Health, subcontracted to the University of South Florida, for Advancing Population-based Surveillance of Birth Defects. No other potential conflicts of interest were disclosed.

Pregnancy is a condition of broad interest across many medical and health services research domains, but one not easily identified in healthcare claims data. Our objective was to establish an algorithm to identify pregnant women and their pregnancies in claims data. We identified pregnancy-related diagnosis, procedure, and diagnosis-related group codes, accounting for the transition to International Statistical Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) diagnosis and procedure codes, in health encounter reporting on 10/1/2015. We selected women in Merative MarketScan commercial databases aged 15-49 years with pregnancy-related claims, and their infants, during 2008-2019. Pregnancies, pregnancy outcomes, and gestational ages were assigned using the constellation of service dates, code types, pregnancy outcomes, and linkage to infant records. We describe pregnancy outcomes and gestational ages, as well as maternal age, census region, and health plan type. In a sensitivity analysis, we compared our algorithm-assigned date of last menstrual period (LMP) to fertility procedure-based LMP (date of procedure + 14 days) among women with embryo transfer or insemination procedures. Among 5,812,699 identified pregnancies, most (77.9%) were livebirths, followed by spontaneous abortions (16.2%); 3,274,353 (72.2%) livebirths could be linked to infants. Most pregnancies were among women 25-34 years (59.1%), living in the South (39.1%) and Midwest (22.4%), with large employer-sponsored insurance (52.0%). Outcome distributions were similar across ICD-9 and ICD-10 eras, with some variation in gestational age distribution observed. Sensitivity analyses supported our algorithm's framework; algorithm- and fertility procedure-derived LMP estimates were within a week of each other (mean difference: -4 days [IQR: -13 to 6 days]; n = 107,870). We have developed an algorithm to identify pregnancies, their gestational age, and outcomes, across ICD-9 and ICD-10 eras using administrative data. This algorithm may be useful to reproductive health researchers investigating a broad range of pregnancy and infant outcomes., Competing Interests: The authors have declared that no competing interests exist, (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Background: Although results from studies of first-trimester influenza vaccination and congenital heart defects (CHDs) have been reassuring, data are limited for specific CHDs., Methods: We assessed associations between reported maternal influenza vaccination, 1 month before pregnancy (B1) through end of third pregnancy month (P3), and specific CHDs using data from a multisite, population-based case-control study. Analysis included 2,982 case children diagnosed with a simple CHD (no other cardiac involvement with or without extracardiac defects) and 4,937 control children without a birth defect with estimated delivery dates during 2006-2011. For defects with ≥5 exposed case children, we used logistic regression to estimate propensity score-adjusted odds ratios (aORs) and 95% confidence intervals (CIs), adjusting for estimated delivery year and season; plurality; and maternal age at delivery, race/ethnicity, low folate intake, and smoking and alcohol use during B1P3., Results: Overall, 124 (4.2%) simple CHD case mothers and 197 (4.0%) control mothers reported influenza vaccination from 1 month before through the third pregnancy month. The aOR for any simple CHD was 0.97 (95% CI: 0.76-1.23). Adjusted ORs for specific simple CHDs ranged from 0.62 for hypoplastic left heart syndrome to 2.34 for total anomalous pulmonary venous return (TAPVR). All adjusted CIs included the null except for TAPVR., Conclusions: Although we cannot fully exclude that exposure misclassification may have masked risks for some CHDs, findings add to existing evidence supporting the safety of inactivated influenza vaccination during pregnancy. The TAPVR result may be due to chance, but it may help inform future studies., (© 2022 The Authors. Birth Defects Research published by Wiley Periodicals LLC.)

Purpose: To assess associations between influenza vaccination during etiologically-relevant windows and selected major structural non-cardiac birth defects., Study Design: We analyzed data from the National Birth Defects Prevention Study, a multisite, population-based case-control study, for 8233 case children diagnosed with a birth defect and 4937 control children without a birth defect with delivery dates during 2006-2011. For all analyses except for neural tube defects (NTDs), we classified mothers who reported influenza vaccination 1 month before through the third pregnancy month as exposed; the exposure window for NTDs was 1 month before through the first pregnancy month. For defects with five or more exposed case children, we used logistic regression to estimate propensity score-adjusted odds ratios (aORs) and 95% confidence intervals (CIs), adjusting for estimated delivery year and season; plurality; maternal age, race/ethnicity, smoking and alcohol use, low folate intake; and, for NTDs, folate antagonist medications., Results: There were 334 (4.1%) case and 197 (4.0%) control mothers who reported influenza vaccination from 1 month before through the third pregnancy month. Adjusted ORs ranged from 0.53 for omphalocele to 1.74 for duodenal atresia/stenosis. Most aORs (11 of 19) were ≤1 and all adjusted CIs included the null. The unadjusted CIs for two defects, hypospadias and craniosynostosis, excluded the null. These estimates were attenuated upon covariate adjustment (hypospadias aOR: 1.25 (95% CI 0.89, 1.76); craniosynostosis aOR: 1.23 (95% CI: 0.88, 1.74))., Conclusions: Results for several non-cardiac major birth defects add to the existing evidence supporting the safety of inactivated influenza vaccination during pregnancy. Under-reporting of vaccination may have biased estimates downward., (© 2022 John Wiley & Sons Ltd.)

Objective: Fetal death certificates (FDCs) are the main source of stillbirth surveillance data in the United States, yet previous studies suggest FDCs have incomplete ascertainment. The objectives of this analysis were (1) to evaluate whether the use of an existing birth defects surveillance program (the Metropolitan Atlanta Congenital Defects Program [MACDP]) to conduct surveillance on stillbirths enhances case ascertainment, and (2) to compare stillbirth prevalence estimates in metropolitan Atlanta using data from MACDP and FDCs, independently and combined, from 2009-2015., Methods: Stillbirths were ascertained by MACDP and FDCs from 2009-2015. Capture-recapture methods were used to estimate the relative contributions of each data source. Prevalence estimates generated from each data source independently and combined were compared., Results: There were 3,031 stillbirths ascertained by FDCs and MACDP in metropolitan Atlanta from 2009-2015. It was assumed that 35% of FDCs unlinked to MACDP were misclassified as stillbirth. Under this assumption, an estimated 2,610 total stillbirths occurred. Accounting for potential misclassification in the FDC, the prevalence rate for stillbirth was 6.9 per 1,000 live births plus stillbirths for stillbirths captured only in FDC, and 6.2 per 1,000 live births plus stillbirths for stillbirths caught only in MACDP. Using both sources combined for casefinding, the prevalence rate was 10.0 per 1,000 live births plus stillbirths for all years combined., Conclusions: Expanding certain birth defects surveillance programs to conduct surveillance on stillbirths could potentially enhance existing surveillance data on stillbirths when linked to FDCs., (© 2022 National Cancer Registrars Association.)

We assessed maternal and infant cytomegalovirus (CMV) infection in Colombia. Maternal serum was tested for CMV immunoglobulin G antibodies at a median of 10 (interquartile range: 8-12) weeks gestation (n = 1501). CMV DNA polymerase chain reaction was performed on infant urine to diagnose congenital (≤21 days of life) and postnatal (>21 days) infection. Maternal CMV seroprevalence was 98.1% (95% confidence interval [CI]: 97.5%-98.8%). Congenital CMV prevalence was 8.4 (95% CI: 3.9%-18.3%; 6/711) per 1000 live births. Among 472 infants without confirmed congenital CMV infection subsequently tested at age 6 months, 258 (54.7%, 95% CI: 50.2%-59.1%) had postnatal infection., (© 2021 Wiley Periodicals LLC.)

Background: Urinary tract infection (UTI) is the most common bacterial infection in pregnancy. Known risk factors for UTI in pregnancy include diabetes and certain urologic conditions. Other maternal characteristics might also be associated with risk and could provide clues to the etiology of UTI in pregnancy. Our objective was to identify maternal characteristics associated with UTI in pregnancy. Materials and Methods: We used data from pregnant women participating in the National Birth Defects Prevention Study, a population-based study of risk factors for major structural birth defects in 10 U.S. sites, from 1997 to 2011. In cross-sectional analyses, we used multivariable log-binomial regression to estimate prevalence ratios (PRs) and 95% confidence intervals (CIs) for associations between self-reported maternal characteristics and UTI in pregnancy. Results: In our sample of 41,869 women, the overall prevalence of reported UTI in pregnancy was 18%, but ranged from 11% to 26% between study sites. In adjusted models, diabetes was moderately associated with higher UTI prevalence (PR 1.39, 95% CI: 1.24-1.57). Higher UTI prevalence was associated even more strongly with low educational attainment (PR 2.06, 95% CI: 1.77-2.40 for some high school vs. graduate school), low household income (PR 1.64, 95% CI: 1.46-1.84 for <$10,000 vs. ≥$50,000), and race/ethnicity (PR 1.45, 95% CI: 1.13-1.80 for American Indian or Alaska Native vs. White women). Conclusions: About one in six women reported UTI in pregnancy but the prevalence varied markedly by geography and maternal characteristics. This variability could provide clues to the causes of UTI in pregnancy.

Background: Hydroxychloroquine 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., Methods: Using 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., Results: In 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., Conclusion: While 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., (© 2021 Wiley Periodicals LLC.)

Background: Some studies have reported associations between prenatal use of venlafaxine, a serotonin-norepinephrine reuptake inhibitor used for depressive and anxiety disorders, and some birth defects. We described the prevalence of venlafaxine prescription claims among privately insured women of reproductive age and pregnant women., Methods: Venlafaxine prescription claims were examined using the IBM MarketScan Commercial Databases. We included women of reproductive age (15-44 years) who had ≤45 days of lapsed enrollment during the calendar year of interest (2011-2016) in a non-capitated healthcare plan sponsored by a large, self-insured employer with prescription drug coverage and no mental health service carve-out. Annual cohorts of pregnant women were identified among eligible women of reproductive age via pregnancy diagnosis and procedure codes. Venlafaxine prescriptions were identified via National Drug Codes in outpatient pharmacy claims and we estimated the annual proportion of women with venlafaxine claims by pregnancy trimester (pregnant women only), age, and Census division., Results: Each year during 2011-2016, approximately 1.2% of eligible reproductive-aged and 0.3% of eligible pregnant women filled a venlafaxine prescription. Among pregnant women, the proportion with venlafaxine claims was highest during the first trimester and decreased during the second and third trimesters. Small temporal increases in venlafaxine claims were observed for reproductive-aged and pregnant women, with the largest among women aged 15-19 years., Conclusions: Venlafaxine prescription claims were low among women of reproductive age and pregnant women during 2011-2016, with some increasing use over time among women aged 15-19 years., (Published 2021. This article is a U.S. Government work and is in the public domain in the USA.)

Objective: To estimate the annual percentage of women of reproductive age with private insurance or Medicaid who had opioid prescription claims during 2013-2017 and describe trends over time., Design: A secondary analysis of insurance claims data from IBM MarketScan® Commercial and Multi-State Medicaid Databases to assess outpatient pharmacy claims for prescription opioids among women aged 15-44 years during 2013-2017., Participants: Annual cohorts of 3.5-3.8 million women aged 15-44 years with private insurance and 0.9-2.1 million women enrolled in Medicaid., Main Outcome Measure: The percentage of women aged 15-44 years with outpatient pharmacy claims for opioid prescriptions., Results: During 2013-2017, the proportion of women aged 15-44 years with private insurance who had claims for opioid prescriptions decreased by 22.1 percent, and among women enrolled in Medicaid, the proportion decreased by 31.5 -percent., Conclusions: Opioid prescription claims decreased from 2013 to 2017 among insured women of reproductive age. However, opioid prescription claims remained common and were more common among women enrolled in Medicaid than those with private insurance; additional strategies to improve awareness of the risks associated with opioid prescribing may be needed.

Objective: To estimate the excess maternal health services utilization and direct maternal medical expenditures associated with hypertensive disorders during pregnancy and one year postpartum among women with private insurance in the United States., Study Design: We used 2008-2014 IBM MarketScan® Commercial Databases to identify women aged 15-44 who had a pregnancy resulting in live birth during 1/1/09-12/31/13 and were continuously enrolled with non-capitated or partially capitated coverage from 12 months before pregnancy through 12 months after delivery. Hypertensive disorders identified by diagnosis codes were categorized into three mutually exclusive types: preeclampsia and eclampsia, chronic hypertension, and gestational hypertension. Multivariate negative binomial and generalized linear models were used to estimate service utilization and expenditures, respectively., Main Outcome Measures: Per person excess health services utilization and medical expenditures during pregnancy and one year postpartum associated with hypertensive disorders (in 2014 US dollars)., Results: Women with preeclampsia and eclampsia, chronic hypertension, and gestational hypertension had $9,389, $6,041, and $2,237 higher mean medical expenditures compared to women without hypertensive disorders ($20,252), respectively (ps < 0.001). One-third (36%) of excess expenditure associated with hypertensive disorders during pregnancy was attributable to outpatient services., Conclusions: Hypertensive disorders during pregnancy were associated with significantly higher health services utilization and medical expenditures among privately insured women with hypertensive disorders. Medical expenditures varied by types of hypertensive disorders. Stakeholders can use this information to assess the potential economic benefits of interventions that prevent these conditions or their complications., (Copyright © 2020. Published by Elsevier B.V.)

The incidence of neonatal abstinence syndrome (NAS), a withdrawal syndrome associated with prenatal opioid or other substance exposure (1), has increased as part of the U.S. opioid crisis (2). No national NAS surveillance system exists (3), and data about the accuracy of state-based surveillance are limited (4,5). In February 2018, the Pennsylvania Department of Health began surveillance for opioid-related NAS in birthing facilities and pediatric hospitals* (6). In March 2019, CDC helped the Pennsylvania Department of Health assess the accuracy of this reporting system at five Pennsylvania hospitals. Medical records of 445 infants who possibly had NAS were abstracted; these infants had either been reported by hospital providers as having NAS or assigned an International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) hospital discharge code potentially related to NAS. † Among these 445 infants, 241 were confirmed as having NAS. Pennsylvania's NAS surveillance identified 191 (sensitivity = 79%) of the confirmed cases. The proportion of infants with confirmed NAS who were assigned the ICD-10-CM code for neonatal withdrawal symptoms from maternal use of drugs of addiction (P96.1) was similar among infants reported to surveillance (71%) and those who were not (78%; p = 0.30). Infants with confirmed NAS who were not assigned code P96.1 typically had less severe signs and symptoms. Accurate NAS surveillance, which is necessary to monitor changes and regional differences in incidence and assist with planning for needed services, includes and is strengthened by a combination of diagnosis code assessment and focused medical record review., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Introduction: Women and healthcare providers lack adequate information on medication safety during pregnancy. While resources describing fetal risk are available, information is provided in multiple locations, often with subjective assessments of available data. We developed a list of medications of greatest concern during pregnancy to help healthcare providers counsel reproductive-aged and pregnant women., Methods: Prescription drug labels submitted to the U.S. Food and Drug Administration with information in the Teratogen Information System (TERIS) and/or Drugs in Pregnancy and Lactation by Briggs & Freeman were included (N = 1,186 medications; 766 from three data sources, 420 from two). We used two supervised learning methods ('support vector machine' and 'sentiment analysis') to create prediction models based on narrative descriptions of fetal risk. Two models were created per data source. Our final list included medications categorized as 'high' risk in at least four of six models (if three data sources) or three of four models (if two data sources)., Results: We classified 80 prescription medications as being of greatest concern during pregnancy; over half were antineoplastic agents (n = 24), angiotensin converting enzyme inhibitors (n = 10), angiotensin II receptor antagonists (n = 8), and anticonvulsants (n = 7)., Discussion: This evidence-based list could be a useful tool for healthcare providers counseling reproductive-aged and pregnant women about medication use during pregnancy. However, providers and patients may find it helpful to weigh the risks and benefits of any pharmacologic treatment for both pregnant women and the fetus when managing medical conditions before and during pregnancy.

Background In women with congenital heart defects (CHD), changes in blood volume, heart rate, respiration, and edema during pregnancy may lead to increased risk of adverse outcomes and conditions. The American Heart Association recommends providers of pregnant women with CHD assess cardiac health and discuss risks and benefits of cardiac-related medications. We described receipt of American Heart Association-recommended cardiac evaluations, filled potentially teratogenic or fetotoxic (Food and Drug Administration pregnancy category D/X) cardiac-related prescriptions, and adverse conditions among pregnant women with CHD compared with those without CHD. Methods and Results Using 2007 to 2014 US healthcare claims data, we ascertained a retrospective cohort of women with and without CHD aged 15 to 44 years with private insurance covering prescriptions during pregnancy. CHD was defined as ≥1 inpatient code or ≥2 outpatient CHD diagnosis codes >30 days apart documented outside of pregnancy and categorized as severe or nonsevere. Log-linear regression, accounting for multiple pregnancies per woman, generated adjusted prevalence ratios (aPRs) for associations between the presence/severity of CHD and stillbirth, preterm birth, and adverse conditions from the last menstrual period to 90 days postpartum. We identified 2056 women with CHD (2334 pregnancies) and 1 374 982 women without (1 524 077 pregnancies). During the last menstrual period to 90 days postpartum, 56% of women with CHD had comprehensive echocardiograms and, during pregnancy, 4% filled potentially teratogenic or fetotoxic cardiac-related prescriptions. Women with CHD, compared with those without, experienced more adverse conditions overall (aPR, 1.9 [95% CI, 1.7-2.1]) and, specifically, obstetric (aPR, 1.3 [95% CI, 1.2-1.4]) and cardiac conditions (aPR, 10.2 [95% CI, 9.1-11.4]), stillbirth (aPR, 1.6 [95% CI, 1.1-2.4]), and preterm delivery (aPR, 1.6 [95% CI, 1.4-1.8]). More women with severe CHD, compared with nonsevere, experienced adverse conditions overall (aPR, 1.5 [95% CI, 1.2-1.9]). Conclusions Women with CHD have elevated prevalence of adverse cardiac and obstetric conditions during pregnancy; 4 in 100 used potentially teratogenic or fetotoxic medications, and only half received an American Heart Association-recommended comprehensive echocardiogram.

Background: Zika virus infection during pregnancy can cause serious birth defects, which include brain and eye abnormalities. The clinical importance of detection of Zika virus RNA in amniotic fluid is unknown., Objective: The purpose of this study was to describe patterns of Zika virus RNA testing of amniotic fluid relative to other clinical specimens and to examine the association between Zika virus detection in amniotic fluid and Zika-associated birth defects. Our null hypothesis was that Zika virus detection in amniotic fluid was not associated with Zika-associated birth defects., Study Design: We conducted a retrospective cohort analysis of women with amniotic fluid specimens submitted to Colombia's National Institute of Health as part of national Zika virus surveillance from January 2016 to January 2017. Specimens (maternal serum, amniotic fluid, cord blood, umbilical cord tissue, and placental tissue) were tested for the presence of Zika virus RNA with the use of a singleplex or multiplex real-time reverse transcriptase-polymerase chain reaction assay. Birth defect information was abstracted from maternal prenatal and infant birth records and reviewed by expert clinicians. Chi-square and Fisher's exact tests were used to compare the frequency of Zika-associated birth defects (defined as brain abnormalities [with or without microcephaly, but excluding neural tube defects and their associated findings] or eye abnormalities) by frequency of detection of Zika virus RNA in amniotic fluid., Results: Our analysis included 128 women with amniotic fluid specimens. Seventy-five women (58%) had prenatally collected amniotic fluid; 42 women (33%) had amniotic fluid collected at delivery, and 11 women (9%) had missing collection dates. Ninety-one women had both amniotic fluid and other clinical specimens submitted for testing, which allowed for comparison across specimen types. Of those 91 women, 68 had evidence of Zika virus infection based on detection of Zika virus RNA in ≥1 specimen. Testing of amniotic fluid that was collected prenatally or at delivery identified 39 of these Zika virus infections (57%; 15 [22%] infections were identified only in amniotic fluid), and 29 infections (43%) were identified in other specimen types and not amniotic fluid. Among women who were included in the analysis, 89 had pregnancy outcome information available, which allowed for the assessment of the presence of Zika-associated birth defects. Zika-associated birth defects were significantly (P<.05) more common among pregnancies with Zika virus RNA detected in amniotic fluid specimens collected prenatally (19/32 specimens; 59%) than for those with no laboratory evidence of Zika virus infection in any specimen (6/23 specimens; 26%), but the proportion was similar in pregnancies with only Zika virus RNA detected in specimens other than amniotic fluid (10/23 specimens; 43%). Although Zika-associated birth defects were more common among women with any Zika virus RNA detected in amniotic fluid specimens (ie, collected prenatally or at delivery; 21/43 specimens; 49%) than those with no laboratory evidence of Zika virus infection (6/23 specimens; 26%), this comparison did not reach statistical significance (P=.07)., Conclusion: Testing of amniotic fluid provided additional evidence for maternal diagnosis of Zika virus infection. Zika-associated birth defects were more common among women with Zika virus RNA that was detected in prenatal amniotic fluid specimens than women with no laboratory evidence of Zika virus infection, but similar to women with Zika virus RNA detected in other, nonamniotic fluid specimen types., (Published by Elsevier Inc.)

Background: The American Heart Association recommends women with congenital heart defects (CHD) receive contraceptive counseling early in their reproductive years, but little is known about contraceptive method use among women with CHD. We describe recent female sterilization and reversible prescription contraceptive method use by presence of CHD and CHD severity in 2014., Methods: Using IBM MarketScan Commercial Databases, we included women aged 15 to 44 years with prescription drug coverage in 2014 who were enrolled ≥11 months annually in employer-sponsored health plans between 2011 and 2014. CHD, CHD severity, contraceptive methods, and obstetrics-gynecology and cardiology provider encounters were identified using billing codes. We used log-binomial regression to calculate adjusted prevalence ratios (aPRs) and 95% confidence intervals (CIs) to compare contraceptive method use overall and by effectiveness tier by CHD presence and, for women with CHD, severity., Results: Recent sterilization or current reversible prescription contraceptive method use varied slightly among women with (39.2%) and without (37.3%) CHD, aPR = 1.04, 95% CI [1.01-1.07]. Women with CHD were more likely to use any Tier I method (12.9%) than women without CHD (9.3%), aPR = 1.41, 95% CI [1.33-1.50]. Women with severe, compared to non-severe, CHD were less likely to use any method, aPR = 0.85, 95% CI [0.78-0.92], or Tier I method, aPR = 0.84, 95% CI [0.70-0.99]. Approximately 60% of women with obstetrics-gynecology and <40% with cardiology encounters used any included method., Conclusions: There may be missed opportunities for providers to improve uptake of safe, effective contraceptive methods for women with CHD who wish to avoid pregnancy., (Published by Elsevier Inc.)

Objective: The objective of this study was to examine the prevalence of, and maternal characteristics associated with, ADHD medication use before and during pregnancy, and associations between early pregnancy ADHD medication use and risk for 12 selected birth defects. Method: We used data from the National Birth Defects Prevention Study (1998-2011), a U.S. population-based case-control study examining risk factors for major structural birth defects. Results: There was an increase in ADHD medication use from 1998-1999 (0.2%) to 2010-2011 (0.5%; p < .001). Early pregnancy ADHD medication use was more commonly reported by mothers of infants/fetuses with gastroschisis (crude odds ratio [cOR]: 2.9, 95% confidence interval [CI] = [1.2, 6.9]), omphalocele (cOR: 4.0, 95% CI = [1.2, 13.6]), and transverse limb deficiency (cOR: 3.3, 95% CI = [1.1, 9.6]). Conclusion: ADHD medication use before and during pregnancy was rare, but the prevalence of use has increased over time. In this analysis, early pregnancy ADHD medication use was associated with three of 12 selected birth defects.

Birth defects are a leading cause of infant mortality in the United States, accounting for 20.6% of infant deaths in 2017 (1). Rates of infant mortality attributable to birth defects (IMBD) have generally declined since the 1970s (1-3). U.S. linked birth/infant death data from 2003-2017 were used to assess trends in IMBD. Overall, rates declined 10% during 2003-2017, but decreases varied by maternal and infant characteristics. During 2003-2017, IMBD rates decreased 4% for infants of Hispanic mothers, 11% for infants of non-Hispanic black (black) mothers, and 12% for infants of non-Hispanic white (white) mothers. In 2017, these rates were highest among infants of black mothers (13.3 per 10,000 live births) and were lowest among infants of white mothers (9.9). During 2003-2017, IMBD rates for infants who were born extremely preterm (20-27 completed gestational weeks), full term (39-40 weeks), and late term/postterm (41-44 weeks) declined 20%-29%; rates for moderate (32-33 weeks) and late preterm (34-36 weeks) infants increased 17%. Continued tracking of IMBD rates can help identify areas where efforts to reduce IMBD are needed, such as among infants born to black and Hispanic mothers and those born moderate and late preterm (32-36 weeks)., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

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.)

Background Our objective was to estimate receipt of preconception health care among women with congenital heart defects (CHD), according to 2017 American Heart Association recommendations, as a baseline for evaluating recommendation implementation. Methods and Results Using 2007 to 2013 IBM MarketScan Commercial Databases, we identified women with CHD diagnosis codes ages 15 to 44 years who became pregnant and were enrolled in health insurance for ≥11 months in the year before estimated conception. We assessed documentation of complete blood count, electrolytes, thyroid-stimulating hormone, liver function, ECG, comprehensive echocardiogram, and exercise stress test, using procedural codes, and outpatient prescription claims for US Food and Drug Administration category D and X cardiac-related medications. Differences were examined according to CHD severity, age, region of residence, year of conception, and documented encounters at obstetric and cardiology practices. We found 2524 pregnancies among 2003 women with CHD (14.4% severe CHD). In the 98.3% of women with a healthcare encounter in the year before conception, <1% received all and 22.6% received no American Heart Association-recommended tests or assessments (range: 54.4% for complete blood count to 3.1% for exercise stress test). Women with the highest prevalence of receipt of recommended care were 35 to 44 years old, pregnant in 2012 to 2013, or had a documented obstetric or cardiology encounter in the year before conception ( P <0.05 for all). In 9.0% of pregnancies, ≥1 prescriptions for US Food and Drug Administration category D or X cardiac-related medications were filled in the year before conception. Conclusions A low percentage of women with CHD received American Heart Association-recommended preconception health care in the year before conception.

Neonatal abstinence syndrome (NAS) is a drug withdrawal syndrome that can occur following prenatal exposure to opioids (1). NAS surveillance in the United States is based largely on diagnosis codes in hospital discharge data, without validation of these codes or case confirmation. During 2004-2014, reported NAS incidence increased from 1.5 to 8.0 per 1,000 U.S. hospital births (2), based on International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes identified in hospital discharge data, without case confirmation. However, little is known about how well these codes identify NAS or how the October 1, 2015, transition from ICD-9-CM to the tenth revision of ICD-CM (ICD-10-CM) codes affected estimated NAS incidence. This report describes a pilot project in Illinois, New Mexico, and Vermont to use birth defects surveillance infrastructure to obtain state-level, population-based estimates of NAS incidence among births in 2015 (all three states) and 2016 (Illinois) using hospital discharge records and other sources (varied by state) with case confirmation, and to evaluate the validity of NAS diagnosis codes used by each state. Wide variation in NAS incidence was observed across the three states. In 2015, NAS incidence for Illinois, New Mexico, and Vermont was 3.0, 7.5, and 30.8 per 1,000 births, respectively. Among evaluated diagnosis codes, those with the highest positive predictive values (PPVs) for identifying confirmed cases of NAS, based on a uniform case definition, were drug withdrawal syndrome in a newborn (ICD-9-CM code 779.5; state range = 58.6%-80.2%) and drug withdrawal, infant of dependent mother (ICD-10-CM code P96.1; state range = 58.5%-80.2%). The methods used to assess NAS incidence in this pilot project might help inform other states' NAS surveillance efforts., Competing Interests: All authors have completed and submitted the ICMJE form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

From 2004 to 2014, the incidence of neonatal abstinence syndrome (NAS) in the United States increased 433%, from 1.5 to 8.0 per 1,000 hospital births. The latest national data from 2014 indicate that one baby was born with signs of NAS every 15 minutes in the United States (1). NAS is a drug withdrawal syndrome that most commonly occurs among infants after in utero exposure to opioids, although other substances have also been associated with NAS. Prenatal opioid exposure has also been associated with poor fetal growth, preterm birth, stillbirth, and possible specific birth defects (2-5). NAS surveillance has often depended on hospital discharge data, which historically underestimate the incidence of NAS and are not available in real time, thus limiting states' ability to quickly direct public health resources (6,7). This evaluation focused on six states with state laws implementing required NAS case reporting for public health surveillance during 2013-2017 and reviews implementation of the laws, state officials' reports of data quality before and after laws were passed, and advantages and challenges of legally mandating NAS reporting for public health surveillance in the absence of a national case definition. Using standardized search terms in an online legal research database, laws in six states mandating reporting of NAS from medical facilities to state health departments (SHDs) or from SHDs to a state legislative body were identified. SHD officials in these six states completed a questionnaire followed by a semistructured telephone interview to clarify open-text responses from the questionnaire. Variability was found in the type and number of surveillance data elements reported and in how states used NAS surveillance data. Following implementation, five states with identified laws reported receiving NAS case reports within 30 days of diagnosis. Mandated NAS case reporting allowed SHDs to quantify the incidence of NAS in their states and to inform programs and services. This information might be useful to states considering implementing mandatory NAS surveillance., Competing Interests: All authors have completed and submitted the ICMJE form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that affects individuals across the lifespan. ADHD medication use among pregnant women is increasing (1), but consensus about the safety of ADHD medication use during pregnancy is lacking. Given that nearly half of U.S. pregnancies are unintended (2), and early pregnancy is a critical period for fetal development, examining trends in ADHD medication prescriptions among reproductive-aged women is important to quantify the population at risk for potential exposure. CDC used the Truven Health MarketScan Commercial Database* for the period 2003-2015 to estimate the percentage of women aged 15-44 years with private employer-sponsored insurance who filled prescriptions for ADHD medications each year. The percentage of reproductive-aged women who filled at least one ADHD medication prescription increased 344% from 2003 (0.9% of women) to 2015 (4.0% of women). In 2015, the most frequently filled medications were mixed amphetamine salts, lisdexamfetamine, and methylphenidate. Prescribing ADHD medications to reproductive-aged women is increasingly common; additional research on ADHD medication safety during pregnancy is warranted to inform women and their health care providers about any potential risks associated with ADHD medication exposure before and during pregnancy., Competing Interests: No conflicts of interest were reported.

Urinary tract infections (UTIs) occur in about 8% of pregnant women, and untreated UTIs can have serious consequences, including pyelonephritis, preterm labor, low birth weight, and sepsis (1). Pregnant women are typically screened for UTIs during early pregnancy, and those with bacteriuria are treated with antibiotics (1,2). Antibiotic stewardship is critical to improving patient safety and to combating antibiotic resistance. Because of the potential risk for birth defects, including anencephaly, heart defects, and orofacial clefts, associated with use of sulfonamides and nitrofurantoin during pregnancy (3), a 2011 committee opinion from the American College of Obstetricians and Gynecologists (ACOG) recommended that sulfonamides and nitrofurantoin may be prescribed in the first trimester of pregnancy only when other antimicrobial therapies are deemed clinically inappropriate (4). To assess the effects of these recommendations, CDC analyzed the Truven Health MarketScan Commercial Database* to examine antibiotic prescriptions filled by pregnant women with UTIs. Among 482,917 pregnancies in 2014, 7.2% of women had an outpatient UTI diagnosis during the 90 days before the date of last menstrual period (LMP) or during pregnancy. Among pregnant women with UTIs, the most frequently prescribed antibiotics during the first trimester were nitrofurantoin, ciprofloxacin, cephalexin, and trimethoprim-sulfamethoxazole. Given the potential risks associated with use of some of these antibiotics in early pregnancy and the potential for unrecognized pregnancy, women's health care providers should be familiar with the ACOG recommendations and consider the possibility of early pregnancy when treating women of reproductive age., Competing Interests: No conflicts of interest were reported.

Importance: In 2011, critical congenital heart disease was added to the US Recommended Uniform Screening Panel for newborns, but whether state implementation of screening policies has been associated with infant death rates is unknown., Objective: To assess whether there was an association between implementation of state newborn screening policies for critical congenital heart disease and infant death rates., Design, Setting, and Participants: Observational study with group-level analyses. A difference-in-differences analysis was conducted using the National Center for Health Statistics' period linked birth/infant death data set files for 2007-2013 for 26 546 503 US births through June 30, 2013, aggregated by month and state of birth., Exposures: State policies were classified as mandatory or nonmandatory (including voluntary policies and mandates that were not yet implemented). As of June 1, 2013, 8 states had implemented mandatory screening policies, 5 states had voluntary screening policies, and 9 states had adopted but not yet implemented mandates., Main Outcomes and Measures: Numbers of early infant deaths (between 24 hours and 6 months of age) coded for critical congenital heart disease or other/unspecified congenital cardiac causes for each state-month birth cohort., Results: Between 2007 and 2013, there were 2734 deaths due to critical congenital heart disease and 3967 deaths due to other/unspecified causes. Critical congenital heart disease death rates in states with mandatory screening policies were 8.0 (95% CI, 5.4-10.6) per 100 000 births (n = 37) in 2007 and 6.4 (95% CI, 2.9-9.9) per 100 000 births (n = 13) in 2013 (for births by the end of July); for other/unspecified cardiac causes, death rates were 11.7 (95% CI, 8.6-14.8) per 100 000 births in 2007 (n = 54) and 10.3 (95% CI, 5.9-14.8) per 100 000 births (n = 21) in 2013. Early infant deaths from critical congenital heart disease through December 31, 2013, decreased by 33.4% (95% CI, 10.6%-50.3%), with an absolute decline of 3.9 (95% CI, 3.6-4.1) deaths per 100 000 births after states implemented mandatory screening compared with prior periods and states without screening policies. Early infant deaths from other/unspecified cardiac causes declined by 21.4% (95% CI, 6.9%-33.7%), with an absolute decline of 3.5 (95% CI, 3.2-3.8) deaths per 100 000 births. No significant decrease was associated with nonmandatory screening policies., Conclusions and Relevance: Statewide implementation of mandatory policies for newborn screening for critical congenital heart disease was associated with a significant decrease in infant cardiac deaths between 2007 and 2013 compared with states without these policies.

Purpose: To compare the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and/or opioids to the use of acetaminophen without NSAIDs or opioids with respect to associations with birth defects., Methods: We used data from the National Birth Defects Prevention Study (1997-2011). Exposure was self-reported maternal analgesic use from the month before through the third month of pregnancy (periconceptional). Adjusted odds ratios (aORs) were calculated to examine associations with 16 birth defects., Results: Compared to acetaminophen, mothers reporting NSAIDs were significantly more likely to have offspring with gastroschisis, hypospadias, cleft palate, cleft lip with cleft palate, cleft lip without cleft palate, anencephaly, spina bifida, hypoplastic left heart syndrome, pulmonary valve stenosis, and tetralogy of Fallot (aOR range, 1.2-1.6). Opioids were associated with tetralogy of Fallot, perimembranous ventricular septal defect, and ventricular septal defect with atrial septal defect (aOR range, 1.8-2.3), whereas use of both opioids and NSAIDs was associated with gastroschisis, cleft palate, spina bifida, hypoplastic left heart syndrome, and pulmonary valve stenosis (aOR range, 2.0-2.9)., Conclusions: Compared to periconceptional use of acetaminophen, selected birth defects occurred more frequently among infants of women using NSAIDs and/or opioids. However, we could not definitely determine whether these risks relate to the drugs or to indications for treatment., (Published by Elsevier Inc.)

Context: Opioid use and abuse have increased dramatically in recent years, particularly among women., Objectives: We conducted a systematic review to evaluate the association between prenatal opioid use and congenital malformations., Data Sources: We searched Medline and Embase for studies published from 1946 to 2016 and reviewed reference lists to identify additional relevant studies., Study Selection: We included studies that were full-text journal articles and reported the results of original epidemiologic research on prenatal opioid exposure and congenital malformations. We assessed study eligibility in multiple phases using a standardized, duplicate review process., Data Extraction: Data on study characteristics, opioid exposure, timing of exposure during pregnancy, congenital malformations (collectively or as individual subtypes), length of follow-up, and main findings were extracted from eligible studies., Results: Of the 68 studies that met our inclusion criteria, 46 had an unexposed comparison group; of those, 30 performed statistical tests to measure associations between maternal opioid use during pregnancy and congenital malformations. Seventeen of these (10 of 12 case-control and 7 of 18 cohort studies) documented statistically significant positive associations. Among the case-control studies, associations with oral clefts and ventricular septal defects/atrial septal defects were the most frequently reported specific malformations. Among the cohort studies, clubfoot was the most frequently reported specific malformation., Limitations: Variabilities in study design, poor study quality, and weaknesses with outcome and exposure measurement., Conclusions: Uncertainty remains regarding the teratogenicity of opioids; a careful assessment of risks and benefits is warranted when considering opioid treatment for women of reproductive age., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2017 by the American Academy of Pediatrics.)

In the United States, major structural or genetic birth defects affect approximately 3% of live births (1) and are responsible for 20% of infant deaths (2). Birth defects can affect persons across their lifespan and are the cause of significant lifelong disabilities. CDC used the Healthcare Cost and Utilization Project (HCUP) 2013 National Inpatient Sample (NIS), a 20% stratified sample of discharges from nonfederal community hospitals, to estimate the annual cost of birth defect-associated hospitalizations in the United States, both for persons of all ages and by age group. Birth defect-associated hospitalizations had disproportionately high costs, accounting for 3.0% of all hospitalizations and 5.2% of total hospital costs. The estimated annual cost of birth defect-associated hospitalizations in the United States in 2013 was $22.9 billion. Estimates of the cost of birth defect-associated hospitalizations offer important information about the impact of birth defects among persons of all ages on the overall health care system and can be used to prioritize prevention, early detection, and care.

In Colombia, approximately 105,000 suspected cases of Zika virus disease (diagnosed based on clinical symptoms, regardless of laboratory confirmation) were reported during August 9, 2015-November 12, 2016, including nearly 20,000 in pregnant women (1,2). Zika virus infection during pregnancy is a known cause of microcephaly and serious congenital brain abnormalities and has been associated with other birth defects related to central nervous system damage (3). Colombia's Instituto Nacional de Salud (INS) maintains national surveillance for birth defects, including microcephaly and other central nervous system defects. This report provides preliminary information on cases of congenital microcephaly identified in Colombia during epidemiologic weeks 5-45 (January 31-November 12) in 2016. During this period, 476 cases of microcephaly were reported, compared with 110 cases reported during the same period in 2015. The temporal association between reported Zika virus infections and the occurrence of microcephaly, with the peak number of reported microcephaly cases occurring approximately 24 weeks after the peak of the Zika virus disease outbreak, provides evidence suggesting that the period of highest risk is during the first trimester of pregnancy and early in the second trimester of pregnancy. Microcephaly prevalence increased more than fourfold overall during the study period, from 2.1 per 10,000 live births in 2015 to 9.6 in 2016. Ongoing population-based birth defects surveillance is essential for monitoring the impact of Zika virus infection during pregnancy on birth defects prevalence and measuring the success in preventing Zika virus infection and its consequences, including microcephaly.

Background: Health insurance claims are a rich data source to examine medication use in pregnancy. Our objective was to identify pregnant women, their pregnancy outcomes, and date of their last menstrual period (LMP), and to estimate antidepressant dispensations in pregnancy., Methods: From a literature search, we identified diagnosis and procedure codes indicating the end of a pregnancy. Using Truven Health MarketScan ® Commercial Claims and Encounters Databases, we identified all inpatient admissions and outpatient service claims with these codes. We developed an algorithm to assign: (1) pregnancy outcome (ectopic pregnancy, induced or spontaneous abortion, live birth, or stillbirth), and (2) estimated gestational age, to each inpatient or outpatient visit. For each pregnancy outcome, we estimated the LMP as the admission (for inpatient visits) or service (for outpatient visits) date minus the gestational age. To differentiate visits associated with separate pregnancies, we required ≥ 2 months between one pregnancy outcomes and the LMP of the next pregnancy. We used this algorithm to identify pregnancies in 2013 and to estimate the proportion of women who filled a prescription for an antidepressant from an outpatient pharmacy at various time points in pregnancy., Results: We identified 488,887 pregnancies in 2013; 79% resulted in a live birth. A prescription for an antidepressant was filled in 6.2% of pregnancies. Dispensations varied throughout pregnancy and were lowest (3.1%) during the second trimester., Conclusion: This work will inform future efforts to estimate medication dispensations during critical periods of preconception, interconception, and pregnancy using health insurance claims data. Birth Defects Research (Part A) 106:927-934, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Background: Previous studies noted associations between birth defects and some antibiotics (e.g., nitrofurantoin, sulfonamides) but not others (e.g., penicillins). It is unclear if previous findings were due to antibiotic use, infections, or chance. To control for potential confounding by indication, we examined associations between antibiotic use and birth defects, among women reporting urinary tract infections (UTIs)., Methods: The National Birth Defects Prevention Study is a multi-site, population-based case-control study. Case infants/fetuses have any of over 30 major birth defects and controls are live-born infants without major birth defects. We analyzed pregnancies from 1997 to 2011 to estimate the association between maternally reported periconceptional (month before conception through the third month of pregnancy) use of nitrofurantoin, trimethoprim-sulfamethoxazole, or cephalosporins and specific birth defects, among women with periconceptional UTIs. Women with periconceptional UTIs who reported penicillin use served as the comparator., Results: Periconceptional UTIs were reported by 7.8% (2029/26,068) of case and 6.7% (686/10,198) of control mothers. Most (68.2% of case, 66.6% of control mothers) also reported antibiotic use. Among 608 case and 231 control mothers reporting at least one periconceptional UTI and certain antibiotic use, compared with penicillin, nitrofurantoin use was associated with oral clefts in the offspring (adjusted odds ratio, 1.97 [95% confidence interval, 1.10-3.53]), trimethoprim-sulfamethoxazole use with esophageal atresia (5.31 [1.39-20.24]) and diaphragmatic hernia (5.09 [1.20-21.69]), and cephalosporin use with anorectal atresia/stenosis (5.01 [1.34-18.76])., Conclusion: Periconceptional exposure to some antibiotics might increase the risk for certain birth defects. However, because individual birth defects are rare, absolute risks should drive treatment decisions.Birth Defects Research (Part A) 106:940-949, 2016.© 2016 Wiley Periodicals, Inc., Competing Interests: None of the authors have any conflicts of interest to disclose., (© 2016 Wiley Periodicals, Inc.)

CDC has updated its interim guidance for U.S. health care providers caring for pregnant women with possible Zika virus exposure, to include the emerging data indicating that Zika virus RNA can be detected for prolonged periods in some pregnant women. To increase the proportion of pregnant women with Zika virus infection who receive a definitive diagnosis, CDC recommends expanding real-time reverse transcription-polymerase chain reaction (rRT-PCR) testing. Possible exposures to Zika virus include travel to or residence in an area with active Zika virus transmission, or sex* with a partner who has traveled to or resides in an area with active Zika virus transmission without using condoms or other barrier methods to prevent infection.(†) Testing recommendations for pregnant women with possible Zika virus exposure who report clinical illness consistent with Zika virus disease(§) (symptomatic pregnant women) are the same, regardless of their level of exposure (i.e., women with ongoing risk for possible exposure, including residence in or frequent travel to an area with active Zika virus transmission, as well as women living in areas without Zika virus transmission who travel to an area with active Zika virus transmission, or have unprotected sex with a partner who traveled to or resides in an area with active Zika virus transmission). Symptomatic pregnant women who are evaluated <2 weeks after symptom onset should receive serum and urine Zika virus rRT-PCR testing. Symptomatic pregnant women who are evaluated 2-12 weeks after symptom onset should first receive a Zika virus immunoglobulin (IgM) antibody test; if the IgM antibody test result is positive or equivocal, serum and urine rRT-PCR testing should be performed. Testing recommendations for pregnant women with possible Zika virus exposure who do not report clinical illness consistent with Zika virus disease (asymptomatic pregnant women) differ based on the circumstances of possible exposure. For asymptomatic pregnant women who live in areas without active Zika virus transmission and who are evaluated <2 weeks after last possible exposure, rRT-PCR testing should be performed. If the rRT-PCR result is negative, a Zika virus IgM antibody test should be performed 2-12 weeks after the exposure. Asymptomatic pregnant women who do not live in an area with active Zika virus transmission, who are first evaluated 2-12 weeks after their last possible exposure should first receive a Zika virus IgM antibody test; if the IgM antibody test result is positive or equivocal, serum and urine rRT-PCR should be performed. Asymptomatic pregnant women with ongoing risk for exposure to Zika virus should receive Zika virus IgM antibody testing as part of routine obstetric care during the first and second trimesters; immediate rRT-PCR testing should be performed when IgM antibody test results are positive or equivocal. This guidance also provides updated recommendations for the clinical management of pregnant women with confirmed or possible Zika virus infection. These recommendations will be updated when additional data become available.

Antidepressant medication use during pregnancy has been increasing in the United States (1). Many women require antidepressants on an ongoing basis, and a clear consensus on the safest medication options for both the mother and her fetus does not exist (2). Given that half of all U.S. pregnancies are unplanned (3), antidepressant use will occur during the first weeks of pregnancy, a critical period for fetal development. To understand trends among women of reproductive age, CDC used Truven Health's MarketScan Commercial Claims and Encounters data* to estimate the number of antidepressant prescriptions filled by women aged 15-44 years with private employer-sponsored insurance. During 2008-2013, an average of 15.4% of women aged 15-44 years filled at least one prescription for an antidepressant in a single year. The most frequently filled antidepressants included sertraline, bupropion, and citalopram. Prescribing of antidepressants is common, and research on antidepressant safety during pregnancy needs to be accelerated to provide evidence-based information to health care providers and women about the potential risks for antidepressant exposure before and during pregnancy and between pregnancies.

Background: When making decisions about medication use in pregnancy, women consult many information sources, including the Internet. The aim of this study was to assess the content of publicly accessible YouTube videos that discuss medication use in pregnancy., Methods: Using 2023 distinct combinations of search terms related to medications and pregnancy, we extracted metadata from YouTube videos using a YouTube video Application Programming Interface. Relevant videos were defined as those with a medication search term and a pregnancy-related search term in either the video title or description. We viewed relevant videos and abstracted content from each video into a database. We documented whether videos implied each medication to be "safe" or "unsafe" in pregnancy and compared that assessment with the medication's Teratogen Information System (TERIS) rating., Results: After viewing 651 videos, 314 videos with information about medication use in pregnancy were available for the final analyses. The majority of videos were from law firms (67%), television segments (10%), or physicians (8%). Selective serotonin reuptake inhibitors (SSRIs) were the most common medication class named (225 videos, 72%), and 88% of videos about SSRIs indicated that they were unsafe for use in pregnancy. However, the TERIS ratings for medication products in this class range from "unlikely" to "minimal" teratogenic risk., Conclusion: For the majority of medications, current YouTube video content does not adequately reflect what is known about the safety of their use in pregnancy and should be interpreted cautiously. However, YouTube could serve as a platform for communicating evidence-based medication safety information., (Copyright © 2015 John Wiley & Sons, Ltd.)

Background and Objectives: In 2011, the US Secretary of Health and Human Services recommended universal screening of newborns for critical congenital heart defects (CCHDs), yet few estimates of the number of infants with CCHDs likely to be detected through universal screening exist. Our objective was to estimate the number of infants with nonsyndromic CCHDs in the United States likely to be detected (true positives) and missed (false negatives) through universal newborn CCHD screening., Methods: We developed a simulation model based on estimates of birth prevalence, prenatal diagnosis, late detection, and sensitivity of newborn CCHD screening through pulse oximetry to estimate the number of true-positive and false-negative nonsyndromic cases of the 7 primary and 5 secondary CCHD screening targets identified through screening., Results: We estimated that 875 (95% uncertainty interval [UI]: 705-1060) US infants with nonsyndromic CCHDs, including 470 (95% UI: 360-585) infants with primary CCHD screening targets, will be detected annually through newborn CCHD screening. An additional 880 (UI: 700-1080) false-negative screenings, including 280 (95% UI: 195-385) among primary screening targets, are expected. We estimated that similar numbers of CCHDs would be detected under scenarios comparing "lower" (∼19%) and "higher" (∼41%) than current prenatal detection prevalences., Conclusions: A substantial number of nonsyndromic CCHD cases are likely to be detected through universal CCHD screening; however, an equal number of false-negative screenings, primarily among secondary targets of screening, are likely to occur. Future efforts should document the true impact of CCHD screening in practice., (Copyright © 2015 by the American Academy of Pediatrics.)

In 2011, statewide newborn screening programs for critical congenital heart defects began in the United States, and subsequently screening has been implemented widely. In this review, we focus on data reports and collection efforts related to both prenatal diagnosis and newborn screening. Defect-specific, maternal, and geographic factors are associated with variations in prenatal detection, so newborn screening provides a population-wide safety net for early diagnosis. A new web-based repository is collecting information on newborn screening program policies, quality indicators related to screening programs, and specific case-level data on infants with these defects. Birth defects surveillance programs also collect data about critical congenital heart defects, particularly related to diagnostic timing, mortality, and services. Individuals from state programs, federal agencies, and national organizations will be interested in these data to further refine algorithms for screening in normal newborn nurseries, neonatal intensive care settings, and other special populations; and ultimately to evaluate the impact of screening on outcomes., (Published by Elsevier Inc.)

Prescription opioid use in the United States has become widespread, and studies of opioid exposure in pregnancy suggest increased risk for adverse pregnancy outcomes, including neonatal abstinence syndrome and birth defects (e.g., neural tube defects, gastroschisis, and congenital heart defects). The development of birth defects often results from exposures during the first few weeks of pregnancy, which is a critical period for organ formation. Given that many pregnancies are not recognized until well after the first few weeks and half of all U.S. pregnancies are unplanned, all women who might become pregnant are at risk. Therefore, it is important to assess opioid medication use among all women of reproductive age. CDC used Truven Health's MarketScan Commercial Claims and Encounters and Medicaid data to estimate the number of opioid prescriptions dispensed by outpatient pharmacies to women aged 15-44 years. During 2008-2012, opioid prescription claims were consistently higher among Medicaid-enrolled women when compared with privately insured women (39.4% compared with 27.7%, p<0.001). The most frequently prescribed opioids among women in both groups were hydrocodone, codeine, and oxycodone. Efforts are needed to promote interventions to reduce opioid prescriptions among this population when safer alternative treatments are available.

Introduction: Approximately 10 - 15% of women reportedly take an antihistamine during pregnancy for the relief of nausea and vomiting, allergy and asthma symptoms, or indigestion. Antihistamines include histamine H1-receptor and H2-receptor antagonists., Areas Covered: This is a systematic evaluation of the peer-reviewed epidemiologic literature published through February 2014 on the association between prenatal exposure to antihistamines and birth defects. Papers addressing histamine H1- or H2-receptor antagonists are included. Papers addressing pyridoxine plus doxylamine (Bendectin in the United States, Debendox in the United Kingdom, Diclectin in Canada, Lenotan and Merbental in other countries) prior to the year 2001 were excluded post hoc because of several previously published meta-analyses and commentaries on this medication., Expert Opinion: The literature on the safety of antihistamine use during pregnancy with respect to birth defects is generally reassuring though the positive findings from a few large studies warrant corroboration in other populations. The findings in the literature are considered in light of three critical methodological issues: i) selection of appropriate study population; ii) ascertainment of antihistamine exposures; and iii) ascertainment of birth defect outcomes. Selected antihistamines have been very well studied (e.g., loratadine); others, especially H2-receptor antagonists, require additional study before an assessment of safety with respect to birth defect risk could be made.