PURPOSE: Studies of influenza vaccination during pregnancy and major birth defects generally provide reassuring findings. To maintain public confidence, it is important to continue evaluating the safety of maternal vaccination using well characterized, population-based data. This study extended previous research to examine associations between maternal influenza vaccination and selected birth defects using data from the Birth Defects Study To Evaluate Pregnancy exposureS, a US, multisite case-control study. METHODS: Mothers of case children (diagnosed with a birth defect) and control children (without a birth defect diagnosis) were identified from population-based birth defect surveillance programs and recruited to complete a telephone interview. Data from 2675 case and 1575 control mothers (participants) with deliveries during 2014-2019 were analyzed. Influenza vaccination exposure during the critical exposure period (one month before pregnancy through the first pregnancy month [B1P1] for spina bifida or through the third pregnancy month [B1P3] for other selected birth defects) was assessed controlling for several participant covariates. Logistic regression with propensity score adjustment was used to estimate adjusted odds ratios (aORs) and 95 % confidence intervals (CIs). Several secondary analyses were conducted. A probabilistic bias analysis examined the effect of exposure misclassification. RESULTS: The aOR observed between B1P1 influenza vaccination exposure and spina bifida was 0.9 (95 % CI: 0.4-2.0). The aORs for B1P3 exposure and other selected birth defects examined ranged from 0.4 to 1.3, with 95 % CIs including the null except those for cleft lip ± cleft palate (aOR: 0.6; 95 % CI: 0.4-0.9) and gastroschisis (aOR: 0.4; 95 % CI: 0.2-0.7). Results from secondary analyses were similar to the primary analyses, and those from probabilistic bias analysis were similar to respective primary and secondary analyses. CONCLUSION: Findings showed no statistically significant positive associations between influenza vaccination and the selected birth defects, supporting public health efforts to promote optimal vaccination coverage among pregnant women.

BACKGROUND: We calculated prevalences of birth defects among infants of participants in the Centers for Disease Control and Prevention's (CDC) COVID-19 Vaccine Pregnancy Registry (C19VPR). METHODS: C19VPR enrolled women receiving COVID-19 vaccines ≤ 30 days before the last menstrual period or during pregnancy from December 2020 through June 2021. We included 19,931 participants with singleton pregnancies ending ≥ 20 weeks' gestation who did not report COVID-19 illness during pregnancy. Clinicians identified birth defects from participant-reported infant health information up to 4 months after birth. We compared C19VPR birth defect prevalences to published pre-pandemic estimates. For seven defects originating during embryogenesis (cleft lip with/without cleft palate, atrial septal defect, coarctation of the aorta, ventricular septal defect, esophageal atresia or stenosis, hypospadias, kidney agenesis/hypoplasia/dysplasia), we estimated prevalence ratios comparing those vaccinated < 14 weeks' to those vaccinated ≥ 14 weeks' gestation. RESULTS: Participants reported receiving Pfizer-BioNTech vaccines (59.0%), Moderna (38.2%), and Janssen (2.8%) vaccines. Most (65.2%) participants received their first COVID-19 vaccine after the first trimester. The prevalence of major birth defects was 3.8%. Among defects with comparator estimates available (n = 50), 35 were below or within expected ranges. C19VPR prevalences were higher than the comparator confidence interval for 15 defects; however, C19VPR confidence intervals included comparator estimates. Prevalences did not differ by the timing of vaccination for seven defects examined. CONCLUSIONS: Birth defects prevalence estimates among infants born to women receiving COVID-19 vaccines during or just prior to pregnancy were generally similar to pre-pandemic estimates. While there was no strong evidence of associations between vaccination and specific defects, statistical power was low.

BACKGROUND: Reports from China describe an increase in the frequency of fetal situs inversus in 2023 after the country's "zero-Covid" policy was lifted, suggesting an association with maternal SARS-CoV-2 infection. However, a report of birth defects surveillance data from Scandinavia observed no sustained increase during the SARS-CoV-2 pandemic (2020-2022 vs. 2018-2019). We examined birth defects surveillance data to assess any increase in situs inversus in the U.S. during the SARS-CoV-2 pandemic. METHODS: We combined data from four population-based birth defects programs in Massachusetts, Minnesota, North Carolina, and Atlanta, Georgia, to compare the prevalence of situs inversus among infants and fetuses delivered before (2017-2019) and during (2021-2022) the SARS-CoV-2 pandemic. We defined situs inversus as mirror-image transposition of the heart and/or other organs, or primary ciliary dyskinesis with situs inversus, excluding isolated dextrocardia. The programs varied in the pregnancy outcomes included (live births ± non-live births); all included both prenatal and postnatal diagnoses. RESULTS: We identified 294 infants and fetuses with situs inversus (6.8% non-live births). We estimated the combined prevalence per 10,000 live births as 1.72 during the pandemic versus 1.71 before the pandemic (OR = 1.005; 95% CI: 0.778-1.297). The estimated annual prevalence ranged from 1.41 in 2017 to 2.21 in 2019 with no significant trend across the study period (p = 0.39). CONCLUSIONS: We did not observe an increase in situs inversus during the SARS-CoV-2 pandemic. Because information about SARS-CoV-2 infection among individual pregnancies was not available from all programs, we could not assess a specific association with maternal infection.

BACKGROUND: The Surveillance for Emerging Threats to Pregnant People and Infants Network (SET-NET) collects data abstracted from medical records and birth defects registries on pregnant people and their infants to understand outcomes associated with prenatal exposures. We developed an automated process to categorize possible birth defects for prenatal COVID-19, hepatitis C, and syphilis surveillance. By employing keyword searches, fuzzy matching, natural language processing (NLP), and machine learning (ML), we aimed to decrease the number of cases needing manual clinician review. METHODS: SET-NET captures International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) codes and free text describing birth defects. For unstructured data, we used keyword searches, and then conducted fuzzy matching with a cut-off match score of ≥90%. Finally, we employed NLP and ML by testing three predictive models to categorize birth defect data. RESULTS: As of June 2023, 8326 observations containing data on possible birth defects were submitted to SET-NET. The majority (n = 6758 [81%]) were matched to an ICD-10-CM code and 1568 (19%) were unable to be matched. Through keyword searches and fuzzy matching, we categorized 1387/1568 possible birth defects. Of the remaining 181 unmatched observations, we correctly categorized 144 (80%) using a predictive model. CONCLUSIONS: Using automated approaches allowed for categorization of 99.6% of reported possible birth defects, which helps detect possible patterns requiring further investigation. Without employing these analytic approaches, manual review would have been needed for 1568 observations. These methods can be employed to quickly and accurately sift through data to inform public health responses.

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.

OBJECTIVE: To evaluate the hypothesis that childhood survival for individuals with Down syndrome (DS) and congenital heart defects (CHDs) has improved in recent years, approaching survival of those with DS without CHDs. STUDY DESIGN: Individuals with DS born 1979-2018 were identified through the Metropolitan Atlanta Congenital Defects Program, a population-based birth defects surveillance system administered by the Centers for Disease Control and Prevention. Survival analysis was performed to evaluate predictors of mortality for those with DS. RESULTS: The cohort included 1,671 individuals with DS; 764 had associated CHDs. Five-year survival in those with DS with CHD improved steadily among individuals born in the 1980s through the 2010s (85% to 93%, p=0.01) but remained stable (96% to 95%, p=0.97) in those with DS without CHDs. The presence of a CHD was not associated with mortality through 5 years of age for those born 2010 or later (hazard ratio 2.63 [95% confidence interval 0.95 - 8.37]). In multivariable analyses, atrioventricular septal defects were associated with early (<1 year) and late (>5 year) mortality, while ventricular septal defects were associated with intermediate (1-5 years) mortality and atrial septal defects with late mortality, when adjusting for other risk factors. CONCLUSIONS: The gap in five-year survival between children with DS with and without CHDs has improved over the last four decades. Survival after 5 years remains lower for those with CHDs, although longer follow-up will be needed to determine if this difference lessens for those born in the more recent years.

The lack of United States population-based data on Turner syndrome limits assessments of prevalence and associated characteristics for this sex chromosome abnormality. Therefore, we collated 2000-2017 data from seven birth defects surveillance programs within the National Birth Defects Prevention Network. We estimated the prevalence of karyotype-confirmed Turner syndrome diagnosed within the first year of life. We also calculated the proportion of cases with commonly ascertained birth defects, assessed associations with maternal and infant characteristics using prevalence ratios (PR) with 95% confidence intervals (CI), and estimated survival probability. The prevalence of Turner syndrome of any pregnancy outcome was 3.2 per 10,000 female live births (95% CI = 3.0-3.3, program range: 1.0-10.4), and 1.9 for live birth and stillbirth (≥20 weeks gestation) cases (95% CI = 1.8-2.1, program range: 0.2-3.9). Prevalence was lowest among cases born to non-Hispanic Black women compared to non-Hispanic White women (PR = 0.5, 95% CI = 0.4-0.6). Coarctation of the aorta was the most common defect (11.6% of cases), and across the cohort, individuals without hypoplastic left heart had a five-year survival probability of 94.6%. The findings from this population-based study may inform surveillance practices, prenatal counseling, and diagnosis. We also identified racial and ethnic disparities in prevalence, an observation that warrants further investigation.

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.

During the Centers for Disease Control and Prevention's Zika Virus Response, birth defects surveillance programs adapted to monitor birth defects potentially related to Zika virus (ZIKV) infection during pregnancy. Pregnancy outcomes occurring during January 2016 to June 2017 in 22 U.S. states and territories were used to estimate the prevalence of those brain and eye defects potentially related to ZIKV. Jurisdictions were divided into three groups: areas with widespread ZIKV transmission, areas with limited local ZIKV transmission, and areas without local ZIKV transmission. Prevalence estimates for selected brain and eye defects and microcephaly per 10,000 live births were estimated. Prevalence ratios (PRs) and 95% confidence intervals (CIs) were estimated using Poisson regression for areas with widespread and limited ZIKV transmission compared with areas without local ZIKV transmission. Defects with significantly higher prevalence in areas of widespread transmission were pooled, and PRs were calculated by quarter, comparing subsequent quarters to the first quarter (January-March 2016). Nine defects had significantly higher prevalence in areas of widespread transmission. The highest PRs were seen in intracranial calcifications (PR = 12.6, 95% CI [7.4, 21.3]), chorioretinal abnormalities (12.5 [7.1, 22.3]), brainstem abnormalities (9.3 [4.7, 18.4]), and cerebral/cortical atrophy (6.7 [4.2, 10.8]). The PR of the nine pooled defects was significantly higher in three quarters in areas with widespread transmission. The largest difference in prevalence was observed for defects consistently reported in infants with congenital ZIKV infection. Birth defects surveillance programs could consider monitoring a subset of birth defects potentially related to ZIKV in pregnancy.

BACKGROUND: Pregnant persons are at increased risk of severe illness from COVID-19 infection, including intensive care unit admission, mechanical ventilation, and death compared with non-pregnant persons of reproductive age. Limited data are available on the safety of COVID-19 vaccines administered during and around the time of pregnancy. OBJECTIVE: To evaluate and summarize reports to the Vaccine Adverse Event Reporting System (VAERS), a national spontaneous reporting system, in pregnant persons who received a COVID-19 vaccine to assess for potential vaccine safety problems. METHODS: We searched VAERS for US reports of adverse events (AEs) in pregnant persons who received a COVID-19 vaccine from 12/14/2020-10/31/2021. Clinicians reviewed reports and available medical records. Crude reporting rates for selected AEs were calculated, and disproportional reporting was assessed using data mining methods. RESULTS: VAERS received 3,462 reports of AEs in pregnant persons who received a COVID-19 vaccine; 1,831 (52.9%) after BNT162b2, 1,350 (38.9%) after mRNA-1273, and 275 (7.9%) after Ad26.COV2.S. Eight maternal deaths and 12 neonatal deaths were reported. Six-hundred twenty-one (17.9%) reports were serious. Pregnancy-specific outcomes included: 878 spontaneous abortions (<20 weeks), 101 episodes of vaginal bleeding, 76 preterm deliveries (<37 weeks), 62 stillbirths (≥20 weeks), and 33 outcomes with birth defects. Crude reporting rates for preterm deliveries and stillbirths, as well as maternal and neonatal mortality rates were below background rates from published sources. No disproportional reporting for any AE was observed. CONCLUSIONS: Review of reports to VAERS following COVID-19 vaccines in pregnant persons did not identify any concerning patterns of maternal or infant-fetal outcomes.

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 one month before through the third pregnancy month as exposed; the exposure window for NTDs was one 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; maternal age; race/ethnicity; plurality; 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 one 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. This article is protected by copyright. All rights reserved.

BACKGROUND: The US Zika Pregnancy and Infant Registry (USZPIR) monitors infants born to mothers with confirmed or possible Zika virus infection during pregnancy. The surveillance case definition for Zika-associated birth defects includes microcephaly based on head circumference (HC). METHODS: We assessed birth and follow-up data from infants with birth HC measurements <3rd percentile and birthweight ≥10th percentile to determine possible misclassification of microcephaly. We developed a schema informed by literature review and expert opinion to identify possible HC measurement inaccuracy using HC growth velocity and longitudinal HC measurements between 2 and 12 months of age. Two or more HC measurements were required for assessment. Inaccuracy in birth HC measurement was suspected if growth velocity was >3 cm/month in the first 3 months or HC was consistently >25th percentile during follow-up. RESULTS: Of 6,799 liveborn infants in USZPIR, 351 (5.2%) had Zika-associated birth defects, of which 111 had birth HC measurements <3rd percentile and birthweight ≥10th percentile. Of 84/111 infants with sufficient follow-up, 38/84 (45%) were classified as having possible inaccuracy of birth HC measurement, 19/84 (23%) had HC ≥3rd percentile on follow-up without meeting criteria for possible inaccuracy, and 27/84 (32%) had continued HC <3rd percentile. After excluding possible inaccuracies, the proportion of infants with Zika-associated birth defects including microcephaly decreased from 5.2% to 4.6%. CONCLUSIONS: About one-third of infants in USZPIR with Zika-associated birth defects had only microcephaly, but indications of possible measurement inaccuracy were common. Implementation of this schema in longitudinal studies can reduce misclassification of microcephaly.

Zika virus infection during pregnancy can cause serious birth defects of the brain and eyes, including intracranial calcifications, cerebral or cortical atrophy, chorioretinal abnormalities, and optic nerve abnormalities (1,2). The frequency of these Zika-associated brain and eye defects, based on data from the U.S. Zika Pregnancy and Infant Registry (USZPIR), has been previously reported in aggregate (3,4). This report describes the frequency of individual Zika-associated brain and eye defects among infants from pregnancies with laboratory evidence of confirmed or possible Zika virus infection. Among 6,799 live-born infants in USZPIR born during December 1, 2015-March 31, 2018, 4.6% had any Zika-associated birth defect; in a subgroup of pregnancies with a positive nucleic acid amplification test (NAAT) for Zika virus infection, the percentage was 6.1% of live-born infants. The brain and eye defects most frequently reported included microcephaly, corpus callosum abnormalities, intracranial calcification, abnormal cortical gyral patterns, ventriculomegaly, cerebral or cortical atrophy, chorioretinal abnormalities, and optic nerve abnormalities. Among infants with any Zika-associated birth defect, one third had more than one defect reported. Certain brain and eye defects in an infant might prompt suspicion of prenatal Zika virus infection. These findings can help target surveillance efforts to the most common brain and eye defects associated with Zika virus infection during pregnancy should a Zika virus outbreak reemerge, and might provide a signal to the reemergence of Zika virus, particularly in geographic regions without ongoing comprehensive Zika virus surveillance.

PURPOSE: This study determined the prevalence, mortality and time trends of children with congenital diaphragmatic hernia (CDH). METHODS: Twenty-five hospital- and population-based surveillance programs in 19 International Clearinghouse for Birth Defects Surveillance and Research member countries provided birth defects mortality data between 1974 and 2015. CDH cases included live births, stillbirths, or elective termination of pregnancy for fetal anomalies. Prevalence, cumulative mortality rates, and 95% confidence intervals (CI) were calculated using Poisson regression and Kaplan-Meier product-limit method. Joinpoint regression analyses were conducted to assess time trends. RESULTS: The prevalence of CDH was 2.6 per 10,000 total births (95% CI: 2.5-2.7), slightly increasing between 2001 and 2012 (average annual percent change [AAPC] = 0.5%; 95% CI:-0.6-1.6). The total percent mortality of CDH was 37.7%, with hospital-based registries having more deaths among live births than population-based registries (45.1% vs. 33.8%). Mortality rates decreased over time (AAPC = -2.4%; 95% CI: -3.8--1.1). Most deaths due to CDH occurred among 2- to 6-day-old infants for both registry types (36.3%, hospital-based; 12.1%, population-based). CONCLUSION: The mortality of CDH has decreased over time. Mortality remains high during the first week and varied by registry type.

BACKGROUND: Omphalocele is the second most common abdominal birth defect and often occurs with other structural and genetic defects. The objective of this study was to determine omphalocele prevalence, time trends, and mortality during early childhood, by geographical region, and the presence of associated anomalies. METHODS: We conducted a retrospective study with 23 birth defect surveillance systems in 18 countries who are members of the International Clearinghouse for Birth Defects Surveillance and Research that submitted data on cases ascertained from 2000 through 2012, approximately 16 million pregnancies were surveyed that resulted in live births, stillbirths, or elective terminations of pregnancy for fetal anomalies (ETOPFA) and cases with omphalocele were included. Overall prevalence and mortality rates for specific ages were calculated (day of birth, neonatal, infant, and early childhood). We used Kaplan-Meier estimates with 95% confidence intervals (CI) to calculate cumulative mortality and joinpoint regression for time trend analyses. RESULTS: The prevalence of omphalocele was 2.6 per 10,000 births (95% CI: 2.5, 2.7) and showed no temporal change from 2000-2012 (average annual percent change = -0.19%, p = .52). The overall mortality rate was 32.1% (95% CI: 30.2, 34.0). Most deaths occurred during the neonatal period and among children with multiple anomalies or syndromic omphalocele. Prevalence and mortality varied by registry type (e.g., hospital- vs. population-based) and inclusion or exclusion of ETOPFA. CONCLUSIONS: The prevalence of omphalocele showed no temporal change from 2000-2012. Approximately one-third of children with omphalocele did not survive early childhood with most deaths occurring in the neonatal period.

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.

OBJECTIVE: Despite recommendations by professional organizations that all pregnant women receive inactivated influenza vaccine, safety concerns remain a barrier. Our objective was to assess the effect of trivalent influenza vaccines (IIV3) during pregnancy on parent report 6-month infant development. METHODS: We conducted a multi-site prospective birth cohort study during the 2010-2011 influenza season and followed pregnant women and their newborns through 6 months of age. Information on IIV3 during pregnancy was ascertained from the EHR and self-report. The Ages and Stages Questionnaire-3 (ASQ-3) was completed by the mother to assess 6-month infant neurodevelopment in five domains (communication, gross motor, fine motor, problem-solving, and personal adaptive skills). Scores for each domain above the cut-off point indicating typical development were categorized as "on schedule" while scores in the zones indicating the need for either monitoring or further assessment were categorized as "not on schedule". Multivariable logistic regression was conducted. RESULTS: Of the 1225 infant-mother pairs, 65% received IIV3 during pregnancy. In bivariate analysis, infants of women who received IIV3 during pregnancy were moderately-less likely to need monitoring or further assessment in the personal social domain compared with infants of unvaccinated women (10.0% vs. 14.1%, p = 0.033; crude OR (cOR): 0.68(95%CI:0.48,0.97)). However, after controlling for potential confounders, the findings were no longer statistically significant (aOR:0.72,95%CI: 0.49,1.06,p = 0.46). No significant unadjusted or adjusted associations emerged in any other ASQ-3 domain. CONCLUSION: There was no significant association between IIV3 exposure during pregnancy and 6-month infant development. Studies of IIV3 during pregnancy to assess longer-term developmental outcomes are indicated.

BACKGROUND: Previous studies suggested associations between maternal smoking, a source of exposure to polycyclic aromatic hydrocarbons (PAHs) and other chemicals, and central nervous system and face birth defects; however, no previous studies have evaluated maternal occupational PAH exposure itself. METHODS: Jobs held in the periconceptional period were retrospectively assigned for occupational PAH exposures. Associations between maternal occupational PAH exposure and selected rare defects of the face (cataracts, microphthalmia, glaucoma, microtia, and choanal atresia) and central nervous system (holoprosencephaly, hydrocephaly, cerebellar hypoplasia, and Dandy-Walker malformation) were evaluated using data from the National Birth Defects Prevention Study, a population-based case-control study in the United States. Crude and adjusted odds ratios (ORs) with 95% confidence intervals were calculated to estimate associations between each evaluated defect and PAH exposure using multivariable logistic regression. RESULTS: Food and beverage serving, as well as cooks and food preparation occupations, were among the most frequent jobs held by exposed mothers. Cataracts, microtia, microphthalmia, and holoprosencephaly were significantly associated with PAH exposure with evidence of dose-response (P-values for trend </=.05). Hydrocephaly was associated with any PAH exposure, but not significant for trend. Sensitivity analyses that reduced possible sources of exposure misclassification tended to strengthen associations. CONCLUSIONS: This is the first population-based case-control study to evaluate associations between maternal occupational PAH exposures and these rare birth defects of the central nervous system and face.

Zika virus infection during pregnancy can cause congenital brain and eye abnormalities and is associated with neurodevelopmental abnormalities (1-3). In areas of the United States that experienced local Zika virus transmission, the prevalence of birth defects potentially related to Zika virus infection during pregnancy increased in the second half of 2016 compared with the first half (4). To update the previous report, CDC analyzed population-based surveillance data from 22 states and territories to estimate the prevalence of birth defects potentially related to Zika virus infection, regardless of laboratory evidence of or exposure to Zika virus, among pregnancies completed during January 1, 2016-June 30, 2017. Jurisdictions were categorized as those 1) with widespread local transmission of Zika virus; 2) with limited local transmission of Zika virus; and 3) without local transmission of Zika virus. Among 2,004,630 live births, 3,359 infants and fetuses with birth defects potentially related to Zika virus infection during pregnancy were identified (1.7 per 1,000 live births, 95% confidence interval [CI] = 1.6-1.7). In areas with widespread local Zika virus transmission, the prevalence of birth defects potentially related to Zika virus infection during pregnancy was significantly higher during the quarters comprising July 2016-March 2017 (July-September 2016 = 3.0; October-December 2016 = 4.0; and January-March 2017 = 5.6 per 1,000 live births) compared with the reference period (January-March 2016) (1.3 per 1,000). These findings suggest a fourfold increase (prevalence ratio [PR] = 4.1, 95% CI = 2.1-8.4) in birth defects potentially related to Zika virus in widespread local transmission areas during January-March 2017 compared with that during January-March 2016, with the highest prevalence (7.0 per 1,000 live births) in February 2017. Population-based birth defects surveillance is critical for identifying infants and fetuses with birth defects potentially related to Zika virus regardless of whether Zika virus testing was conducted, especially given the high prevalence of asymptomatic disease. These data can be used to inform follow-up care and services as well as strengthen surveillance.

In May 2018, a study of birth defects in infants born to women with diagnosed human immunodeficiency virus (HIV) infection in Botswana reported an eightfold increased risk for neural tube defects (NTDs) among births with periconceptional exposure to antiretroviral therapy (ART) that included the integrase inhibitor dolutegravir (DTG) compared with other ART regimens (1). The World Health Organization* (WHO) and the U.S. Department of Health and Human Services(dagger) (HHS) promptly issued interim guidance limiting the initiation of DTG during early pregnancy and in women of childbearing age with HIV who desire pregnancy or are sexually active and not using effective contraception. On the basis of additional data, WHO now recommends DTG as a preferred treatment option for all populations, including women of childbearing age and pregnant women. Similarly, the U.S. recommendations currently state that DTG is a preferred antiretroviral drug throughout pregnancy (with provider-patient counseling) and as an alternative antiretroviral drug in women who are trying to conceive.( section sign) Since 1981 and 1994, CDC has supported separate surveillance programs for HIV/acquired immunodeficiency syndrome (AIDS) (2) and birth defects (3) in state health departments. These two surveillance programs can inform public health programs and policy, linkage to care, and research activities. Because birth defects surveillance programs do not collect HIV status, and HIV surveillance programs do not routinely collect data on occurrence of birth defects, the related data have not been used by CDC to characterize birth defects in births to women with HIV. Data from these two programs were linked to estimate overall prevalence of NTDs and prevalence of NTDs in HIV-exposed pregnancies during 2013-2017 for 15 participating jurisdictions. Prevalence of NTDs in pregnancies among women with diagnosed HIV infection was 7.0 per 10,000 live births, similar to that among the general population in these 15 jurisdictions, and the U.S. estimate based on data from 24 states. Successful linking of data from birth defects and HIV/AIDS surveillance programs for pregnancies among women with diagnosed HIV infection suggests that similar data linkages might be used to characterize possible associations between maternal diseases or maternal use of medications, such as integrase strand transfer inhibitors used to manage HIV, and pregnancy outcomes. Although no difference in NTD prevalence in HIV-exposed pregnancies was found, data on the use of integrase strand transfer inhibitors in pregnancy are needed to understand the safety and risks of these drugs during pregnancy.

BACKGROUND: Medical advancements have resulted in better survival and life expectancy among those with spina bifida, but a significantly increased risk of perinatal and postnatal mortality for individuals with spina bifida remains. OBJECTIVES: To examine stillbirth and infant and child mortality among those affected by spina bifida using data from multiple countries. METHODS: We conducted an observational study, using data from 24 population- and hospital-based surveillance registries in 18 countries contributing as members of the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR). Cases of spina bifida that resulted in livebirths or stillbirths from 20 weeks' gestation or elective termination of pregnancy for fetal anomaly (ETOPFA) were included. Among liveborn spina bifida cases, we calculated mortality at different ages as number of deaths among liveborn cases divided by total number of liveborn cases with spina bifida. As a secondary outcome measure, we estimated the prevalence of spina bifida per 10 000 total births. The 95% confidence interval for the prevalence estimate was estimated using the Poisson approximation of binomial distribution. RESULTS: Between years 2001 and 2012, the overall first-week mortality proportion was 6.9% (95% CI 6.3, 7.7) and was lower in programmes operating in countries with policies that allowed ETOPFA compared with their counterparts (5.9% vs. 8.4%). The majority of first-week mortality occurred on the first day of life. In programmes where information on long-term mortality was available through linkage to administrative databases, survival at 5 years of age was 90%-96% in Europe, and 86%-96% in North America. CONCLUSIONS: Our multi-country study showed a high proportion of stillbirth and infant and child deaths among those with spina bifida. Effective folic acid interventions could prevent many cases of spina bifida, thereby preventing associated childhood morbidity and mortality.

BACKGROUND: Many public health surveillance programs utilize hospital discharge data in their estimation of disease prevalence. These databases commonly use the International Classification of Diseases (ICD) coding scheme, which transitioned from the ICD-9 clinical modification (ICD-9-CM) to ICD-10-CM on October 1, 2015. This study examined this transition's impact on the prevalence of major birth defects among infant hospitalizations. METHODS: Using data from the Agency for Health Care Research and Quality-sponsored National Inpatient Sample, hospitalizations during the first year of life with a discharge date between January 1, 2012 and December 31, 2016 were used to estimate the monthly national hospital prevalence of 46 birth defects for the ICD-9-CM and ICD-10-CM timeframes separately. Survey-weighted Poisson regression was used to estimate 95% confidence intervals for each hospital prevalence. Interrupted time series framework and corresponding segmented regression was used to estimate the immediate change in monthly hospital prevalence following the ICD-9-CM to ICD-10-CM transition. RESULTS: Between 2012 and 2016, over 21 million inpatient hospitalizations occurred during the first year of life. Among the 46 defects studied, statistically significant decreases in the immediate hospital prevalence of five defects and significant increases in the immediate hospital prevalence of eight defects were observed after the ICD-10-CM transition. CONCLUSIONS: Changes in prevalence were expected based on changes to ICD-10-CM. Observed changes for some conditions may result from variation in monthly hospital prevalence or initial unfamiliarity of coders with ICD-10-CM. These findings may help birth defects surveillance programs evaluate and interpret changes in their data related to the ICD-10-CM transition.

OBJECTIVES: To assess international trends and patterns of prenatal diagnosis of critical congenital heart defects (CCHDs) and their relation to total and live birth CCHD prevalence and mortality. SETTING: Fifteen birth defect surveillance programmes that participate in the International Clearinghouse for Birth Defects Surveillance and Research from 12 countries in Europe, North and South America and Asia. PARTICIPANTS: Live births, stillbirths and elective terminations of pregnancy for fetal anomaly diagnosed with 1 of 12 selected CCHD, ascertained by the 15 programmes for delivery years 2000 to 2014. RESULTS: 18 243 CCHD cases were reported among 8 847 081 births. The median total prevalence was 19.1 per 10 000 births but varied threefold between programmes from 10.1 to 31.0 per 10 000. CCHD were prenatally detected for at least 50% of the cases in one-third of the programmes. However, prenatal detection varied from 13% in Slovak Republic to 87% in some areas in France. Prenatal detection was consistently high for hypoplastic left heart syndrome (64% overall) and was lowest for total anomalous pulmonary venous return (28% overall). Surveillance programmes in countries that do not legally permit terminations of pregnancy tended to have higher live birth prevalence of CCHD. Most programmes showed an increasing trend in prenatally diagnosed CCHD cases. DISCUSSION AND CONCLUSIONS: Prenatal detection already accounts for 50% or more of CCHD detected in many programmes and is increasing. Local policies and access likely account for the wide variability of reported occurrence and prenatal diagnosis. Detection rates are high especially for CCHD that are more easily diagnosed on a standard obstetric four-chamber ultrasound or for fetuses that have extracardiac anomalies. These ongoing trends in prenatal diagnosis, potentially in combination with newborn pulse oximetry, are likely to modify the epidemiology and clinical outcomes of CCHD in the near future.

BACKGROUND: Hypospadias is a common male birth defect that has shown widespread variation in reported prevalence estimates. Many countries have reported increasing trends over recent decades. OBJECTIVE: To analyze the prevalence and trends of hypospadias for 27 international programs over a 31-yr period. DESIGN, SETTING, AND PARTICIPANTS: The study population included live births, stillbirths, and elective terminations of pregnancy diagnosed with hypospadias during 1980-2010 from 27 surveillance programs around the world. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We used joinpoint regression to analyze changes over time in international total prevalence of hypospadias across programs, prevalence for each specific program, and prevalence across different degrees of severity of hypospadias. RESULTS AND LIMITATIONS: The international total prevalence of hypospadias for all years was 20.9 (95% confidence interval: 19.2-22.6) per 10000 births. The prevalence for each program ranged from 2.1 to 39.1 per 10000 births. The international total prevalence increased 1.6 times during the study period, by 0.25 cases per 10000 births per year (p<0.05). When analyzed separately, there were increasing trends for first-, second-, and third-degree hypospadias during the early 1990s to mid-2000s. The majority of programs (61.9%) had a significantly increasing trend during many of the years evaluated. Limitations include known differences in data collection methods across programs. CONCLUSIONS: Although there have been changes in clinical practice and registry ascertainment over time in some countries, the consistency in the observed increasing trends across many programs and by degrees of severity suggests that the total prevalence of hypospadias may be increasing in many countries. This observation is contrary to some previous reports that suggested that the total prevalence of hypospadias was no longer increasing in recent decades. PATIENT SUMMARY: We report on the prevalence and trends of hypospadias among 27 birth defect surveillance systems, which indicate that the prevalence of hypospadias continues to increase internationally.

Zika virus (ZIKV) was first recognized as a human teratogen in 2016 (Rasmussen, Jamieson, Honein, & Petersen, 2016). During the ZIKV outbreak in the Americas, we launched rapid surveillance of pregnancies with laboratory evidence of ZIKV infection and targeted surveillance of birth defects. Because little was known about the birth defects associated with congenital ZIKV infection, a broad case definition was used for surveillance of birth defects potentially related to ZIKV based on early reports of congenital ZIKV infection in the literature and expert opinion. The initial case definition included microcephaly and/or brain abnormalities, neural tube defects (NTDs) and other early brain malformations (e.g., holoprosencephaly), eye abnormalities, and consequences of central nervous system (CNS) dysfunction such as arthrogryposis and hearing loss (Honein et al., 2017). The baseline prevalence of these defects in the United States prior to the ZIKV outbreak was estimated as 2.86 per 1,000 live births (95% CI: 2.65–3.07) using data from statewide birth defects surveillance programs in Massachusetts and North Carolina in 2013 and from three counties in metropolitan Atlanta, Georgia, during 2013–2014 (Cragan et al., 2017).

BACKGROUND: This report describes the results of recruitment efforts and the subsequent participation of pregnant women in study activities in a 2010-2012 observational study focused on influenza illness and vaccination in California and Oregon, USA. METHODS: Socio-demographic and health characteristics extracted from electronic medical records were compared among pregnant women who enrolled in the study, refused to participate, or were never reached for study invitation. These characteristics plus additional self-reported information were compared between women who enrolled in two study tracks: a prospective cohort vs. women enrolled following an acute respiratory illness (ARI) medical encounter. The characteristics of women who participated in weekly ARI surveillance (cohort enrollees, year one) and a 6-month follow-up interview (all enrollees) were also examined. RESULTS: In year one, we reached 51% (6938/13,655) of the potential participants we tried to contact by telephone, and 20% (1374/6938) of the women we invited agreed to join the prospective cohort. Women with chronic medical conditions, pregnancy complications, and medical encounters for ARI (prior to pregnancy or during the study period) were more likely to be reached for recruitment and more likely to enroll in the cohort. Twenty percent of cohort enrollees never started weekly surveillance reports; among those who did, reports were completed for 55% of the surveillance weeks. Receipt of the influenza vaccine was higher among women who joined the cohort (76%) than those who refused (56%) or were never reached (54%). In contrast, vaccine uptake among medical enrollees in year one (54%; 53/98) and two (52%; 79/151) was similar to other pregnant women in those years. Study site, white race, non-Hispanic ethnicity, and not having a child aged < 13 years at home were most consistently associated with joining as a cohort or medical enrollee and completing study activities after joining. CONCLUSIONS: We observed systematic differences in socio-demographic and health characteristics across different levels of participant engagement and between cohort and medical enrollees. More methodological research and innovation in conducting prospective observational studies in this population are needed, especially when extended participant engagement and ongoing surveillance are required.

Zika virus infection during pregnancy can cause serious birth defects, including microcephaly and brain abnormalities (1). Population-based birth defects surveillance systems are critical to monitor all infants and fetuses with birth defects potentially related to Zika virus infection, regardless of known exposure or laboratory evidence of Zika virus infection during pregnancy. CDC analyzed data from 15 U.S. jurisdictions conducting population-based surveillance for birth defects potentially related to Zika virus infection.* Jurisdictions were stratified into the following three groups: those with 1) documented local transmission of Zika virus during 2016; 2) one or more cases of confirmed, symptomatic, travel-associated Zika virus disease reported to CDC per 100,000 residents; and 3) less than one case of confirmed, symptomatic, travel-associated Zika virus disease reported to CDC per 100,000 residents. A total of 2,962 infants and fetuses (3.0 per 1,000 live births; 95% confidence interval [CI] = 2.9-3.2) (2) met the case definition.(dagger) In areas with local transmission there was a non-statistically significant increase in total birth defects potentially related to Zika virus infection from 2.8 cases per 1,000 live births in the first half of 2016 to 3.0 cases in the second half (p = 0.10). However, when neural tube defects and other early brain malformations (NTDs)( section sign) were excluded, the prevalence of birth defects strongly linked to congenital Zika virus infection increased significantly, from 2.0 cases per 1,000 live births in the first half of 2016 to 2.4 cases in the second half, an increase of 29 more cases than expected (p = 0.009). These findings underscore the importance of surveillance for birth defects potentially related to Zika virus infection and the need for continued monitoring in areas at risk for Zika.

Pregnant women living in or traveling to areas with local mosquito-borne Zika virus transmission are at risk for Zika virus infection, which can lead to severe fetal and infant brain abnormalities and microcephaly (1). In February 2016, CDC recommended 1) routine testing for Zika virus infection of asymptomatic pregnant women living in areas with ongoing local Zika virus transmission at the first prenatal care visit, 2) retesting during the second trimester for women who initially test negative, and 3) testing of pregnant women with signs or symptoms consistent with Zika virus disease (e.g., fever, rash, arthralgia, or conjunctivitis) at any time during pregnancy (2). To collect information about pregnant women with laboratory evidence of recent possible Zika virus infection* and outcomes in their fetuses and infants, CDC established pregnancy and infant registries (3). During January 1, 2016-April 25, 2017, U.S. territoriesdagger with local transmission of Zika virus reported 2,549 completed pregnancies section sign (live births and pregnancy losses at any gestational age) with laboratory evidence of recent possible Zika virus infection; 5% of fetuses or infants resulting from these pregnancies had birth defects potentially associated with Zika virus infection paragraph sign (4,5). Among completed pregnancies with positive nucleic acid tests confirming Zika infection identified in the first, second, and third trimesters, the percentage of fetuses or infants with possible Zika-associated birth defects was 8%, 5%, and 4%, respectively. Among liveborn infants, 59% had Zika laboratory testing results reported to the pregnancy and infant registries. Identification and follow-up of infants born to women with laboratory evidence of recent possible Zika virus infection during pregnancy permits timely and appropriate clinical intervention services (6).

BACKGROUND: Major birth defects are important infant outcomes that have not been well studied in the postmarketing surveillance of vaccines given to pregnant women. We assessed the presence of major birth defects following vaccination in the Vaccine Adverse Event Reporting System (VAERS), a national spontaneous reporting system used to monitor the safety of vaccines in the United States. METHODS: We searched VAERS for reports of major birth defects during January 1, 1990, through December 31, 2014. We excluded birth defects from vaccines that had been studied in pregnancy registries or other epidemiological studies (e.g., human papilloma virus, varicella, measles/mumps/rubella, and anthrax vaccines). Birth defects were categorized into trimester of vaccination and classified based on the organs and/or systems affected. If several birth defects affecting different systems were described, we classified those as multiple body systems. Empirical Bayesian data mining was used to assess for disproportionate reporting. RESULTS: We identified 50 reports of major birth defects; in 28 reports, the vaccine was given during the first trimester; 25 were reports with single vaccines administered. Birth defects accounted for 0.03% of all reports received by VAERS during the study period and 3.2% of pregnancy reports; reported defects affected predominately the musculoskeletal (N = 10) or nervous (N = 10) systems. No unusual clusters or specific birth defects were identified. CONCLUSION: This review of the VAERS database found that major birth defects were infrequently reported, with no particular condition reported disproportionally. Birth defects after routine maternal vaccination will continue to be monitored in VAERS for signals to prompt future studies.

Background: Zika virus is a newly recognized human teratogen; monitoring its impact on the birth prevalence of microcephaly and other adverse pregnancy outcomes will continue to be an urgent need in the United States and worldwide. Methods: When the Centers for Disease Control and Prevention (CDC) activated the Emergency Operations Center for the Zika virus outbreak response in January of 2016, public health leadership recognized that a joint, coordinated effort was required between activities focused on the effects of the infection among pregnant women and those focused on birth defects in fetuses and infants. Before the introduction of Zika virus in the Americas, population-based birth defects surveillance occurred independently of pregnancy surveillance activities. Results: The coordination of pregnancy surveillance and birth defects surveillance implemented through the CDC Zika virus response represents a paradigm shift. Conclusion: Coordination of these surveillance systems provides an opportunity to capture information from both a prospective and retrospective approach. This relatively modest investment in the public health infrastructure can continue to protect pregnant women and their infants during the ongoing response to Zika virus and in the next emergent threat to maternal and child health. Birth Defects Research 109:372–378, 2017.