Factors associated with infant sex and preterm birth status for selected birth defects from the National Birth Defects Prevention Study, 1997-2011.

BACKGROUND: Birth defects and preterm birth co-occur, with some overlapping risk factors. Many birth defects and preterm births tend to have a male preponderance. We explored potential risk factors impacting sex and preterm (<37 weeks of gestation) birth differences among infants with selected birth defects delivered from 1997 to 2011 using data from the National Birth Defects Prevention Study (NBDPS). METHODS: The NBDPS was a large multisite, population-based case-control study. Using random forests, we identified important predictors of male preterm, female preterm, and male term, each compared with female term births for each birth defect. Using logistic regression, we estimated odds ratios for associations between important predictors and sex-preterm birth status by birth defect. RESULTS: We examined 11,379 infants with nine specific birth defects. The top 10 most important predictors of sex-preterm birth status from the random forests varied greatly across the birth defects and sex-preterm comparisons within a given defect group, with several being novel factors. However, one consistency was that short interpregnancy interval was associated with sex-preterm birth status for many of the studied birth defects. Although obesity has been identified as a risk factor for preterm birth and birth defects in other research, it was not associated with sex-preterm birth status for any of the examined defects. CONCLUSIONS: We confirmed expected associations for sex-preterm birth status differences and found new potential risk factors for further exploration among the studied birth defects.

Trends in Delayed Diagnosis of Critical Congenital Heart Defects in an Era of Enhanced Screening, 2004-2018.

OBJECTIVE: To describe trends in delayed diagnosis of critical congenital heart defects (CCHDs) with prenatal and postnatal screening advances. STUDY DESIGN: We evaluated a retrospective cohort of live births with CCHD delivered between 2004 and 2018 from a statewide, population-based birth defects surveillance system in Massachusetts. Demographic information were obtained from vital records. We estimated timely (prenatal or birth/transfer hospital) and delayed diagnosis (after discharge) proportions by year and time periods coinciding with the transition to mandatory pulse oximetry in 2015. RESULTS: We identified 1524 eligible CCHD cases among 1 087 027 live births. By 2018, 92% of cases received a timely diagnosis, most prenatally. From 2004 to 2018, prenatal diagnosis increased from 46% to 76% of cases, while hospital diagnosis decreased from 38% to 17%, and delayed diagnosis declined from 16% to 7%. These trends were consistent across all characteristics evaluated. Among cases without a prenatal diagnosis, the proportion with delayed diagnosis did not change over time, even after implementation of mandatory pulse oximetry screening. Prenatal detection increased the most among severe cases (treated or died in first month of life). Well-appearing newborns without prenatal diagnosis made up 79% of delayed diagnosis cases by 2015-2018. Delayed diagnosis was most common for coarctation. CONCLUSIONS: While prenatal diagnosis of CCHD increased dramatically, there was no reduction in delayed diagnosis among postnatally diagnosed infants, even after pulse oximetry screening became mandatory. Pulse oximetry may not reduce delayed diagnosis in settings with high prenatal detection, and other strategies are needed to ensure timely diagnosis of well-appearing newborns.

Use of vasoactive medications in pregnancy and the risk of stillbirth among birth defect cases.

BACKGROUND: Many previous studies have identified risk factors for stillbirth, but few examine stillbirth among pregnancies affected with birth defects. Because many hypothesized etiologies of stillbirth work through vascular pathologies of the placenta, we examined maternal use of vasoactive medications in relation to stillbirth among pregnancies affected with birth defects. METHODS: Data were analyzed from the National Birth Defects Prevention Study (1997-2011). We examined use of nonsteroidal anti-inflammatory drugs (NSAIDs), decongestants, short- or long-acting beta-agonists (SABA/LABA), and antihypertensive medications in relation to pregnancies affected by birth defects ending in stillbirth compared to live birth. Associations were measured with odds ratios (ORs) for early pregnancy use and hazard ratios (HRs) for time-varying late pregnancy use. RESULTS: Among all birth defects (n = 12,394), the risk of stillbirth was associated with use of antihypertensive medications in early (odds ratio [OR]: 1.8; 95% confidence interval [CI]: 1.0, 3.1) and late pregnancy (HR: 2.0; 95% CI: 1.1, 3.6). Other vasoactive medications were not associated with increased risk of stillbirth. Of 27 specific defect groups, increased risks were observed for only one medication/defect pair: early decongestant use was more common among mothers of stillbirth versus live birth cases with spina bifida (OR: 2.4; 95% CI: 0.9, 6.5). CONCLUSION: This exploratory analysis of vasoactive medication use suggests that use of NSAIDs, decongestants, and SABA/LABA is not associated with increased risk of stillbirth among pregnancies affected with birth defects. Our finding of increased risks associated with antihypertensive medication use raises questions of confounding by indication, which we were not able to fully address.

Prevalence of critical congenital heart defects and selected co-occurring congenital anomalies, 2014-2018: A U.S. population-based study.

BACKGROUND: Critical congenital heart defects (CCHDs) are one of the most common types of birth defects and can lead to significant morbidity and mortality along with surgical or catheter interventions within the first year of life. This report updates previously published estimates of CCHD prevalence with the latest population-based surveillance data from 19 birth defect surveillance programs. METHODS: The U.S. population-based surveillance programs submitted data on identified cases of 12 CCHDs and co-occurring cardiovascular and chromosomal birth defects from 2014 to 2018. We estimated prevalence by program type and maternal and infant characteristics. Among nine programs with active case ascertainment that collect more than live births, we estimated the percentage of co-occurring cardiovascular and chromosomal birth defects for the 12 CCHDs. RESULTS: We identified 18,587 cases of CCHD among all participating programs. Overall CCHD prevalence was 19.6 per 10,000 live births among all 19 programs and 20.2 per 10,000 live births among active programs. Among maternal racial/ethnic groups, infants/fetuses born to American Indian/Alaska Native mothers showed the highest overall prevalence for all CCHDs (28.3 per 10,000) along with eight of the 12 individual CCHDs. Among 7,726 infants/fetuses with CCHD from active case ascertainment programs, 15.8% had at least one co-occurring chromosomal birth defect. CONCLUSION: Our study provides prevalence estimates for CCHDs by maternal and infant characteristics along with co-occurrence with cardiovascular and chromosomal birth defects among infants/fetuses with CCHD using one of the largest and most recent cohorts since the implementation of widespread CCHD screening. These data can provide a basis for future research to better understand risk factors for these defects.

Interpregnancy interval and prevalence of selected birth defects: A multistate study.

BACKGROUND: Both short and long interpregnancy intervals (IPIs) have been associated with adverse birth outcomes. We undertook a multistate study to describe the prevalence of selected birth defects by IPI. METHODS: We obtained data from nine population-based state birth defects registries for singleton live births in 2000-2009 among mothers with a previous live birth identified through birth certificates. IPI was calculated as the difference between prior birthdate and start of the current pregnancy (conception date). We estimated prevalence of selected defects per 10,000 live births and prevalence ratios (PRs) with 95% confidence intervals (CIs) overall and stratified by maternal age at previous birth and race/ethnicity. Primary analyses focused on short IPI < 6 months and long IPI ≥ 60 months compared to 18-23 months (referent). Sensitivity analyses limited to active-surveillance states and those with<10% missing IPI. RESULTS: Among 5,147,962 eligible births, 6.3% had short IPI while 19.8% had long IPI. Compared to referent, prevalence with short IPI was elevated for gastroschisis (3.7, CI: 3.0-4.5 vs. 2.0, CI: 1.6-2.4) and with both short and long IPI for tetralogy of Fallot (short: 3.4, 2.8-4.2 long: 3.8, 3.4-4.3 vs. 2.7, 2.3-3.2) and cleft lip ± palate (short: 9.9, 8.8-11.2 long: 9.2, 8.5-9.8 vs. 8.4, 7.6-9.2). Stratified analyses identified additional associations, including elevated prevalence of anencephaly with short IPI in younger mothers and limb defects with long IPI in those ages 25-34 at prior birth. Sensitivity analyses showed similar results. CONCLUSION: In this population-based study, we observed increased prevalence of several birth defects with short and long IPI.

Co-occurrence of congenital anomalies by maternal race/ethnicity among infants and fetuses with Down syndrome, 2013-2017: A U.S. population-based analysis.

BACKGROUND: Individuals with Down syndrome (DS) have a higher prevalence of additional congenital anomalies, especially cardiovascular defects, compared to the general population. Several reports have indicated that the prevalence of DS among live births varies by race and ethnicity within the United States. We aim to examine variations in co-occurring congenital anomalies by maternal race/ethnicity among infants and fetuses diagnosed with DS born during 2013-2017. METHODS: State birth defect surveillance systems (N = 12) submitted data on infants and fetuses diagnosed with DS born during 2013-2017. We calculated the prevalence of co-occurring major and minor congenital anomalies, by organ system, and four selected cardiovascular birth defects, all stratified by maternal race/ethnicity. RESULTS: Among 5,836 cases of DS, 79.7% had one or more co-occurring congenital anomalies. There was a higher percentage of co-occurring congenital anomalies among infants and fetuses born to Hispanic mothers. The lowest percentage of co-occurring congenital anomalies, including three out of the four individual cardiovascular conditions examined, was among infants/fetuses born to non-Hispanic American Indian/Alaska Native mothers. CONCLUSIONS: We describe differences in DS co-occurrence with additional congenital anomalies among maternal racial/ethnic groups. These data may help focus future research on differences among racial/ethnic groups in the diagnosis and reporting of co-occurring congenital anomalies in infants/fetuses diagnosed with DS.

The Unrecognized Mortality Burden of Genetic Disorders in Infancy.

Objectives. To determine how deaths of infants with genetic diagnoses are described in national mortality statistics. Methods. We present a retrospective cohort study of mortality data, obtained from the National Death Index (NDI), and clinical data for 517 infants born from 2011 to 2017 who died before 1 year of age in the United States. Results. Although 115 of 517 deceased infants (22%) had a confirmed diagnosis of a genetic disorder, only 61 of 115 deaths (53%) were attributed to International Classification of Diseases, 10th Revision codes representing congenital anomalies or genetic disorders (Q00-Q99) as the underlying cause of death because of inconsistencies in death reporting. Infants with genetic diagnoses whose underlying causes of death were coded as Q00-Q99 were more likely to have chromosomal disorders than monogenic conditions (43/61 [70%] vs 18/61 [30%]; P < .001), which reflects the need for improved accounting for monogenic disorders in mortality statistics. Conclusions. Genetic disorders, although a leading cause of infant mortality, are not accurately captured by vital statistics. Public Health Implications. Expanded access to genetic testing and further clarity in death reporting are needed to describe properly the contribution of genetic disorders to infant mortality.

Maternal exposure to hydroxychloroquine and birth defects.

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.

Prevalence of structural birth defects among infants with Down syndrome, 2013-2017: A US population-based study.

BACKGROUND: Down syndrome is the most common chromosomal disorder at birth and is often accompanied by structural birth defects. Current data on major structural defects in this population are limited. METHODS: States and territorial population-based surveillance programs submitted data on identified cases of Down syndrome and identified structural birth defects during 2013-2017. We estimated prevalence by program type and maternal and infant characteristics. Among programs with active case ascertainment, we estimated the prevalence of birth defects by organ system and for specific defects by maternal age (<35, ≥35) and infant sex. RESULTS: We identified 13,376 cases of Down syndrome. Prevalence among all programs was 12.7 per 10,000 live births. Among these children, 75% had at least one reported co-occurring birth defect diagnosis code. Among 6,210 cases identified by active programs, 66% had a cardiovascular defect with septal defects being the most common: atrial (32.5%), ventricular (20.6%), and atrioventricular (17.4%). Defect prevalence differed by infant sex more frequently than by maternal age. For example, atrioventricular septal defects were more common in female children (20.1% vs. 15.1%) while limb deficiencies were more prevalent in male children (0.4% vs. 0.1%). CONCLUSIONS: Our study provides updated prevalence estimates for structural defects, including rare defects, among children with Down syndrome using one of the largest and most recent cohorts to date. These data may aid clinical care and surveillance.

Quantification of selection bias in studies of risk factors for birth defects among livebirths.

BACKGROUND: Risk factors for birth defects are frequently investigated using data limited to liveborn infants. By conditioning on survival, results of such studies may be distorted by selection bias, also described as "livebirth bias." However, the implications of livebirth bias on risk estimation remain poorly understood. OBJECTIVES: We sought to quantify livebirth bias and to investigate the conditions under which it arose. METHODS: We used data on 3994 birth defects cases and 11 829 controls enrolled in the National Birth Defects Prevention Study to compare odds ratio (OR) estimates of the relationship between three established risk factors (antiepileptic drug use, smoking, and multifetal pregnancy) and four birth defects (anencephaly, spina bifida, omphalocele, and cleft palate) when restricted to livebirths as compared to among livebirths, stillbirths, and elective terminations. Exposures and birth defects represented varying strengths of association with livebirth; all controls were liveborn. We performed a quantitative bias analysis to evaluate the sensitivity of our results to excluding terminated and stillborn controls. RESULTS: Cases ranged from 33% liveborn (anencephaly) to 99% (cleft palate). Smoking and multifetal pregnancy were associated with livebirth among anencephaly (crude OR [cOR] 0.61 and cOR 3.15, respectively) and omphalocele cases (cOR 2.22 and cOR 5.22, respectively). For analyses of the association between exposures and birth defects, restricting to livebirths produced negligible differences in estimates except for anencephaly and multifetal pregnancy, which was twofold higher among livebirths (adjusted OR [aOR] 4.93) as among all pregnancy outcomes (aOR 2.44). Within tested scenarios, bias analyses suggested that results were not sensitive to the restriction to liveborn controls. CONCLUSIONS: Selection bias was generally limited except for high mortality defects in the context of exposures strongly associated with livebirth. Findings indicate that substantial livebirth bias is unlikely to affect studies of risk factors for most birth defects.