Search

Previous research on risk factors for obstructive heart defects (OHDs) focused on maternal and infant genetic variants, prenatal environmental exposures, and their potential interaction effects. Less is known about the role of paternal genetic variants or environmental exposures and risk of OHDs. We examined parent-of-origin effects in transmission of alleles in the folate, homocysteine, or transsulfuration pathway genes on OHD occurrence in offspring. We used data on 569 families of liveborn infants with OHDs born between October 1997 and August 2008 from the National Birth Defects Prevention Study to conduct a family-based case-only study. Maternal, paternal, and infant DNA were genotyped using an Illumina Golden Gate custom single nucleotide polymorphism (SNP) panel. Relative risks (RR), 95% confidence interval (CI), and likelihood ratio tests from log-linear models were used to estimate the parent-of-origin effect of 877 SNPs in 60 candidate genes in the folate, homocysteine, and transsulfuration pathways on the risk of OHDs. Bonferroni correction was applied for multiple testing. We identified 3 SNPs in the transsulfuration pathway and 1 SNP in the folate pathway that were statistically significant after Bonferroni correction. Among infants who inherited paternally-derived copies of the G allele for rs6812588 in the RFC1 gene, the G allele for rs1762430 in the MGMT gene, and the A allele for rs9296695 and rs4712023 in the GSTA3 gene, RRs for OHD were 0.11 (95% CI: 0.04, 0.29, P = 9.16x10-7), 0.30 (95% CI: 0.17, 0.53, P = 9.80x10-6), 0.34 (95% CI: 0.20, 0.57, P = 2.28x10-5), and 0.34 (95% CI: 0.20, 0.58, P = 3.77x10-5), respectively, compared to infants who inherited maternally-derived copies of the same alleles. We observed statistically significant decreased risk of OHDs among infants who inherited paternal gene variants involved in folate and transsulfuration pathways. Author summary: Obstructive heart defects are birth defects that cause obstruction to the blood flow of the developing heart. Common OHDs include coarctation of the aorta, aortic stenosis and pulmonary stenosis. While there is a fair amount of literature indicating an association between maternal genetic variants and OHDs, less is known about the role of paternal genetic variants in the etiology of OHDs. We used a genotype clustering algorithm, SNPMClust, that was developed in-house at the Arkansas Center for Birth Defects Research and Prevention to study the role of paternal genetic variants in the folate, homocysteine and transsulfuration pathways. Maternal, paternal, and infant DNA specimens were collected from participants of the National Birth Defects Prevention Study, a large population-based case-control study in the United States, and were genotyped using an Illumina Golden Gate custom single nucleotide polymorphism (SNP) panel. We identified 4 SNPs in the folate and transsulfuration pathways, rs6812588, rs1762430, rs9296695, and rs4712023, that were associated with a statistically significant decreased risk of OHDs for infants who inherited a paternally-derived copy of the variant allele compared to infants who inherited a maternal copy of the variant allele. In conclusion, we observed a significantly decreased risk and less epigenetic influence of paternal genetic variants on OHDs compared to maternally-derived variants. [ABSTRACT FROM AUTHOR]

Background: Birth defects are established risk factors for childhood cancer. Nonetheless, cancer epidemiology in children with birth defects is not well characterized.Methods: Using data from population-based registries in 4 US states, this study compared children with cancer but no birth defects (n = 13,111) with children with cancer and 1 or more nonsyndromic birth defects (n = 1616). The objective was to evaluate cancer diagnostic characteristics, including tumor type, age at diagnosis, and stage at diagnosis.Results: Compared with the general population of children with cancer, children with birth defects were diagnosed with more embryonal tumors (26.6% vs 18.7%; q < 0.001), including neuroblastoma (12.5% vs 8.2%; q < 0.001) and hepatoblastoma (5.0% vs 1.3%; q < 0.001), but fewer hematologic malignancies, including acute lymphoblastic leukemia (12.4% vs 24.4%; q < 0.001). In age-stratified analyses, differences in tumor type were evident among children younger than 1 year and children 1 to 4 years old, but they were attenuated among children 5 years of age or older. The age at diagnosis was younger in children with birth defects for most cancers, including leukemia, lymphoma, astrocytoma, medulloblastoma, ependymoma, embryonal tumors, and germ cell tumors (all q < 0.05).Conclusions: The results indicate possible etiologic heterogeneity in children with birth defects, have implications for future surveillance efforts, and raise the possibility of differential cancer ascertainment in children with birth defects.Lay Summary: Scientific studies suggest that children with birth defects are at increased risk for cancer. However, these studies have not been able to determine whether important tumor characteristics, such as the type of tumor diagnosed, the age at which the tumor is diagnosed, and the degree to which the tumor has spread at the time of diagnosis, are different for children with birth defects and children without birth defects. This study attempts to answer these important questions. By doing so, it may help scientists and physicians to understand the causes of cancer in children with birth defects and diagnose cancer at earlier stages when it is more treatable. [ABSTRACT FROM AUTHOR]

Nutrients that regulate methylation processes may modify susceptibility to the effects of air pollutants. Data from the National Birth Defects Prevention Study, 1997-2006, were used to estimate associations between maternal exposure to nitrogen dioxide (NO2), dietary intake of methyl nutrients and the odds of congenital heart defects in offspring. NO2 concentrations, a marker of traffic-related air pollution, averaged across post-conception weeks 2-8, were assigned to 6160 non-diabetic mothers of cases and controls using inverse distance-squared weighting of air monitors within 50 km of maternal residence. Intake of choline, folate, methionine, and vitamins B6 and B12 were assessed using a food frequency questionnaire. Hierarchical regression models, which accounted for similarities across defects, were constructed and relative excess risks due to interaction were calculated. Relative to women with the lowest NO2 exposure and high methionine intake, women with the highest NO2 exposure and lowest methionine intake had the greatest odds of offspring with a perimembranous ventricular septal defect (Odds Ratio: 3.23, 95% Confidence Interval, 1.74, 6.01; Relative Excess Risk due to Interaction: 2.15, 95% Confidence Interval, 0.39, 3.92). Considerable departure from additivity was not observed for other defects. These results provide modest evidence of interaction between nutrition and NO2 exposure during pregnancy. [ABSTRACT FROM AUTHOR]

Congenital heart defects (CHDs) are the most prevalent and serious of all birth defects in the United States. However, little is known about the impact of CHD-affected pregnancies on subsequent maternal health. Thus, there is a need to characterize the metabolic alterations associated with CHD-affected pregnancies. Fifty-six plasma samples were identified from post-partum women who participated in the National Birth Defects Prevention Study between 1997 and 2011 and had (1) unaffected control offspring (n = 18), (2) offspring with tetralogy of Fallot (ToF, n = 22), or (3) hypoplastic left heart syndrome (HLHS, n = 16) in this pilot study. Absolute concentrations of 408 metabolites using the AbsoluteIDQ® p400 HR Kit (Biocrates) were evaluated among case and control mothers. Twenty-six samples were randomly selected from above as technical repeats. Analysis of covariance (ANCOVA) and logistic regression models were used to identify significant metabolites after controlling for the maternal age at delivery and body mass index. The receiver operating characteristic (ROC) curve and area-under-the-curve (AUC) are reported to evaluate the performance of significant metabolites. Overall, there were nine significant metabolites (p < 0.05) identified in HLHS case mothers and 30 significant metabolites in ToF case mothers. Statistically significant metabolites were further evaluated using ROC curve analyses with PC (34:1), two sphingolipids SM (31:1), SM (42:2), and PC-O (40:4) elevated in HLHS cases; while LPC (18:2), two triglycerides: TG (44:1), TG (46:2), and LPC (20:3) decreased in ToF; and cholesterol esters CE (22:6) were elevated among ToF case mothers. The metabolites identified in the study may have profound structural and functional implications involved in cellular signaling and suggest the need for postpartum dietary supplementation among women who gave birth to CHD offspring. [ABSTRACT FROM AUTHOR]

Background: Congenital heart defects (CHD) are the most common birth defect and are a major cause of childhood illness and death. Recent progress in management of persons with CHD may have decreased CHD-related mortality. Methods: Year 2000 US death records were used to determine CHD-related mortality by age, sex, and race/ethnicity in children and adults. CHD-related mortality was defined as all deaths with any mention of CHD on the death certificate. Age-, sex-, and racial/ethnic-specific population counts were obtained from the 2000 US Census and used as denominators in mortality rates. Results: In 2000 there were 5441 (.23%) CHD-related deaths and CHDs were mentioned 6121 times as the underlying or contributing cause of death. In 68.4% of CHD-related deaths, CHD was the underlying cause of death. Non-Hispanic Black males had greater risk of CHD-related death than did non-Hispanic White males (RR 1.25, 95% Cl 1.08-1.45). Both Hispanic males and females had lower rates of CHD-related deaths than did non-Hispanic Whites (RR .72, 95% CI .60-.85; RR .52, 95% Cl .42-.65, respectively). "Unspecified congenital malformation of the heart" was the most common cause of death overall; however, "malformation of the coronary vessels" was most often a cause of death for non-Hispanic Blacks and children aged 10-19 years. Conclusions: Racial/ethnic differences in CHD-related mortality exist in the United States. Management of CHD, access to adequate care, and misclassification in cause of death reporting on death records may explain the observed differences. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to measure racial and ethnic differences in the proportion of Medicaid patients who receive epidural analgesia during labor and delivery. Study design: Using 1998 Georgia Medicaid claims data in a standard State Medicaid Research File format, we identified claims for epidural analgesia among all women who had a normal vaginal delivery during1998. Results: There were 29,833 women who met our inclusion criteria, of whom 15,936 (53.4%) had epidural analgesia. Epidural analgesia rates were lower for black women (49.5%), Hispanic women (35.3%), and Asian women (48.1%) than for white, non-Hispanic women (59.6%; P<.001). Rural women had lower epidural rates (39.2%) than urban women (62.1%). Conclusion: The study subjects all had identical Medicaid insurance and met the same low-income Medicaid eligibility criteria, yet race/ethnicity was still a significant predictor of epidural analgesia after we had controlled for age, rural-urban residence, and availability of anesthesiologists. Further studies are needed to assess perceived benefits, risks, costs, and obstacles to epidural analgesia that are perceived by patients, physicians, nurses, and midwives. [ABSTRACT FROM AUTHOR]

Objective: To estimate the risk of stillbirth (fetal death at 20 weeks of gestation or more) associated with specific birth defects.Methods: We identified a population-based retrospective cohort of neonates and fetuses with selected major birth defects and without known or strongly suspected chromosomal or single-gene disorders from active birth defects surveillance programs in nine states. Abstracted medical records were reviewed by clinical geneticists to confirm and classify all birth defects and birth defect patterns. We estimated risks of stillbirth specific to birth defects among pregnancies overall and among those with isolated birth defects; potential bias owing to elective termination was quantified.Results: Of 19,170 eligible neonates and fetuses with birth defects, 17,224 were liveborn, 852 stillborn, and 672 electively terminated. Overall, stillbirth risks ranged from 11 per 1,000 fetuses with bladder exstrophy (95% CI 0-57) to 490 per 1,000 fetuses with limb-body-wall complex (95% CI 368-623). Among those with isolated birth defects not affecting major vital organs, elevated risks (per 1,000 fetuses) were observed for cleft lip with cleft palate (10; 95% CI 7-15), transverse limb deficiencies (26; 95% CI 16-39), longitudinal limb deficiencies (11; 95% CI 3-28), and limb defects due to amniotic bands (110; 95% CI 68-171). Quantified bias analysis suggests that failure to account for terminations may lead to up to fourfold underestimation of the observed risks of stillbirth for sacral agenesis (13/1,000; 95% CI 2-47), isolated spina bifida (24/1,000; 95% CI 17-34), and holoprosencephaly (30/1,000; 95% CI 10-68).Conclusion: Birth defect-specific stillbirth risk was high compared with the U.S. stillbirth risk (6/1,000 fetuses), even for isolated cases of oral clefts and limb defects; elective termination may appreciably bias some estimates. These data can inform clinical care and counseling after prenatal diagnosis. [ABSTRACT FROM AUTHOR]

Background: Because of advancements in care, there has been a decline in mortality from congenital heart defects (CHDs) over the past several decades. However, there are no current empirical data documenting the number of people living with CHDs in the United States. Our aim was to estimate the CHD prevalence across all age groups in the United States in the year 2010.Methods: The age-, sex-, and severity-specific observed prevalence of CHDs in Québec, Canada, in the year 2010 was assumed to equal the CHD prevalence in the non-Hispanic white population in the United States in 2010. A race-ethnicity adjustment factor, reflecting differential survival between racial-ethnic groups through 5 years of age for individuals with a CHD and that in the general US population, was applied to the estimated non-Hispanic white rates to derive CHD prevalence estimates among US non-Hispanic blacks and Hispanics. Confidence intervals for the estimated CHD prevalence rates and case counts were derived from a combination of Taylor series approximations and Monte Carlo simulation.Results: We estimated that ≈2.4 million people (1.4 million adults, 1 million children) were living with CHDs in the United States in 2010. Nearly 300 000 of these individuals had severe CHDs.Conclusions: Our estimates highlight the need for 2 important efforts: planning for health services delivery to meet the needs of the growing population of adults with CHD and the development of surveillance data across the life span to provide empirical estimates of the prevalence of CHD across all age groups in the United States. [ABSTRACT FROM AUTHOR]

Purpose: Studies suggest exposure to ambient particulate matter less than 2.5 μg/m3 in aerodynamic diameter (PM2.5) may be associated with preterm birth (PTB), but few have evaluated how this is modified by ambient temperature. We investigated the relationship between PM2.5 exposure during pregnancy and PTB in infants without birth defects (1999-2006) and enrolled in the National Birth Defects Prevention Study and how it is modified by concurrent temperature.Methods: PTB was defined as spontaneous or iatrogenic delivery before 37 weeks. Exposure was assigned using inverse distance weighting with up to four monitors within 50 kilometers of maternal residence. To account for state-level variations, a Bayesian two-level hierarchal model was developed.Results: PTB was associated with PM2.5 during the third and fourth months of pregnancy (range: (odds ratio (95% confidence interval) = 1.00 (0.35, 2.15) to 1.49 (0.82, 2.68) and 1.31 (0.56, 2.91) to 1.62 (0.7, 3.32), respectively); no week of exposure conveyed greater risk. Temperature may modify this relationship; higher local average temperatures during pregnancy yielded stronger positive relationships between PM2.5 and PTB compared to nonstratified results.Conclusions: Results add to literature on associations between PM2.5 and PTB, underscoring the importance of considering co-exposures when estimating effects of PM2.5 exposure during pregnancy. [ABSTRACT FROM AUTHOR]

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,

Having health insurance is associated with better access to healthcare and lower rates of comorbidity in the general population, but data are limited on insurance's impact on adults with congenital heart disease (ACHD). The Congenital Heart Survey To Recognize Outcomes, Needs and well-beinG (CH STRONG) was conducted among ACHD in three locations from 2016 to 2019. We performed multivariable logistic regression to determine the associations between health insurance and both access to healthcare and presence of comorbidities. We also compared health insurance and comorbidities among ACHD to similarly-aged individuals in the Behavioral Risk Factor Surveillance System (BRFSS) as a proxy for the general population. Of 1354 CH STRONG respondents, the majority were ≤ 30 years old (83.5%), and 8.8% were uninsured versus 17.7% in the BRFSS (p < 0.01). Compared to insured ACHD, uninsured were less likely to report regular medical care (adjusted odds ratio [aOR] 0.2, 95% confidence interval [CI] 0.1-0.3) and visited an emergency room more often (aOR 1.6, CI 1.0-2.3). Among all ACHD reporting disability, uninsured individuals less frequently received benefits (aOR 0.1, CI 0.0-0.3). Depression was common among uninsured ACHD (22.5%), but insured ACHD had lower rates of depression than insured in the BRFSS (13.3% vs. 22.5%, p < 0.01). In conclusion, rates of insurance were higher among ACHD compared to the general population. Nonetheless, uninsured ACHD inconsistently accessed healthcare and benefits. Further studies are needed to determine if insurance ameliorates the risk of morbidity as ACHD age., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Primary congenital glaucoma (PCG) affects approximately 1 in 10,000 live born infants in the United States (U.S.). PCG has a autosomal recessive inheritance pattern, and variable expressivity and reduced penetrance have been reported. Likely causal variants in the most commonly mutated gene, CYP1B1, are less prevalent in the U.S., suggesting that alternative genes may contribute to the condition. This study utilized exome sequencing to investigate the genetic architecture of PCG in the U.S. and to identify novel genes and variants., Methods: We studied 37 family trios where infants had PCG and were part of the National Birth Defects Prevention Study (births 1997-2011), a U.S. multicenter study of birth defects. Samples underwent exome sequencing and sequence reads were aligned to the human reference sample (NCBI build 37/hg19). Variant filtration was conducted under de novo and Mendelian inheritance models using GEMINI., Results: Among candidate variants, CYP1B1 was most represented (five trios, 13.5%). Twelve probands (32%) had potentially pathogenic variants in other genes not previously linked to PCG but important in eye development and/or to underlie Mendelian conditions with potential phenotypic overlap (e.g., CRYBB2, RXRA, GLI2)., Conclusion: Variation in the genes identified in this population-based study may help to further explain the genetics of PCG., (© 2024 Wiley Periodicals LLC.)

Background: The clinical spectrum of infant COVID-19 ranges from asymptomatic infection to life-threatening illness, yet epidemiologic surveillance has been limited for infants., Methods: Using COVID-19 case data (restricted to reporting states) and national mortality data, we calculated incidence, hospitalization, mortality and case fatality rates through March 2022., Results: Reported incidence of COVID-19 was 64.1 new cases per 1000 infant years (95% CI: 63.3-64.9). We estimated that 594,012 infants tested positive for COVID-19 nationwide by March 31, 2022. Viral variant comparisons revealed that incidence was 7× higher during the Omicron (January-March 2022) versus the pre-Delta period (June 2020-May 2021). The cumulative case hospitalization rate was 4.1% (95% CI: 4.0%-4.3%). For every 74 hospitalized infants, one infant death occurred, but overall COVID-19-related infant case fatality was low, with 7.0 deaths per 10,000 cases (95% CI: 5.6-8.7). Nationwide, 333 COVID-19 infant deaths were reported. Only 13 infant deaths (3.9%) were the result of usually lethal congenital anomalies. The majority of infant decedents were non-White (28.2% Black, 26.1% Hispanic, 8.1% Asian, Indigenous or multiracial)., Conclusions: More than half a million US infants contracted COVID-19 by March 2022. Longitudinal assessment of long-term infant SARS-CoV-2 infection sequelae remains a critical research gap. Extremely low infant vaccination rates (<5%), waning adult immunity and continued viral exposure risks suggest that infant COVID-19 will remain a persistent public health problem. Our study underscores the need to increase vaccination rates for mothers and infants, decrease viral exposure risks and improve health equity., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Given the lack of a national, population-based birth defects surveillance program in the United States, the National Birth Defects Prevention Network (NBDPN) has facilitated important studies on surveillance, research, and prevention of major birth defects. We sought to summarize NBDPN peer-reviewed publications and their impact., Methods: We obtained and reviewed a curated list of 49 NBDPN multistate collaborative publications during 2000-2022, as of December 31, 2022. Each publication was reviewed and classified by type (e.g., risk factor association analysis). Key characteristics of study populations and analytic approaches used, along with publication impact (e.g., number of citations), were tabulated., Results: NBDPN publications focused on prevalence estimates (N = 17), surveillance methods (N = 11), risk factor associations (N = 10), mortality and other outcomes among affected individuals (N = 6), and descriptive epidemiology of various birth defects (N = 5). The most cited publications were those that reported on prevalence estimates for a spectrum of defects and those that assessed changes in neural tube defects (NTD) prevalence following mandatory folic acid fortification in the United States., Conclusions: Results from multistate NBDPN publications have provided critical information not available through other sources, including US prevalence estimates of major birth defects, folic acid fortification and NTD prevention, and improved understanding of defect trends and surveillance efforts. Until a national birth defects surveillance program is established in the United States, NBDPN collaborative publications remain an important resource for investigating birth defects and informing decisions related to health services planning of secondary disabilities prevention and care., (© 2023 Wiley Periodicals LLC.)

Background: We provide updated crude and adjusted prevalence estimates of major birth defects in the United States for the period 2016-2020., Methods: Data were collected from 13 US population-based surveillance programs that used active or a combination of active and passive case ascertainment methods to collect all birth outcomes. These data were used to calculate pooled prevalence estimates and national prevalence estimates adjusted for maternal race/ethnicity for all conditions, and maternal age for trisomies and gastroschisis. Prevalence was compared to previously published national estimates from 1999 to 2014., Results: Adjusted national prevalence estimates per 10,000 live births ranged from 0.63 for common truncus to 18.65 for clubfoot. Temporal changes were observed for several birth defects, including increases in the prevalence of atrioventricular septal defect, tetralogy of Fallot, omphalocele, trisomy 18, and trisomy 21 (Down syndrome) and decreases in the prevalence of anencephaly, common truncus, transposition of the great arteries, and cleft lip with and without cleft palate., Conclusion: This study provides updated national estimates of selected major birth defects in the United States. These data can be used for continued temporal monitoring of birth defects prevalence. Increases and decreases in prevalence since 1999 observed in this study warrant further investigation., (© 2024 Wiley Periodicals LLC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Among children with and without heart conditions of different race/ethnicities, upstream social determinants of health, such as socio-economic status, access to care, and healthcare utilisation, may vary. Using caregiver-reported data from the 2016-19 National Survey of Children's Health, we calculated the prevalence of caregiver employment and education, child's health insurance, usual place of medical care in the past 12 months, problems paying for child's care, ≥2 emergency room visits, and unmet healthcare needs by heart condition status and race/ethnicity (Hispanic, non-Hispanic Black, and non-Hispanic White). For each outcome, we used multivariable logistic regression to generate adjusted prevalence ratios controlling for child's age and sex. Of 2632 children with heart conditions and 104,841 without, 65.4% and 58.0% were non-Hispanic White and 52.0% and 51.1% were male, respectively. Children with heart conditions, compared to those without, were 1.7-2.6 times more likely to have problems paying for healthcare, have ≥2 emergency room visits, and have unmet healthcare needs. Hispanic and non-Hispanic Black children with heart conditions, compared to non-Hispanic White, were 1.5-3.2 times as likely to have caregivers employed <50 weeks in the past year and caregivers with ≤ high school education, public or no health insurance, no usual place of care, and ≥2 emergency room visits. Children with heart conditions, compared to those without, may have greater healthcare needs that more commonly go unmet. Among children with heart conditions, Hispanic and non-Hispanic Black children may experience lower socio-economic status and greater barriers to healthcare than non-Hispanic White children.

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.)

Many of the estimated 1.4 million adults with congenital heart defects (CHDs) in the United States are lost to follow-up (LTF) despite recommendations for ongoing cardiology care. Using 2016 to 2019 CH STRONG (Congenital Heart Survey To Recognize Outcomes, Needs, and well-beinG) data, we describe cardiac care among community-based adults with CHD, born in 1980 to 1997, identified through state birth defects registries. Our estimates of LTF were standardized to the CH STRONG eligible population and likely more generalizable to adults with CHD than clinic-based data. Half of our sample were LTF and more than 45% had not received cardiology care in over 5 years. Of those who received care, only 1 in 3 saw an adult CHD physician at their last encounter. Not knowing they needed to see a cardiologist, being told they no longer needed cardiology care, and feeling "well" were the top reasons for LTF, and only half of respondents report doctors discussing the need for cardiac follow-up., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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., (© 2023 Wiley Periodicals LLC.)

Background: Residential proximity to greenspace is associated with various health outcomes., Objectives: We estimated associations between maternal residential proximity to greenspace (based on an index of vegetation) and selected structural birth defects, including effect modification by neighborhood-level factors., Methods: Data were from the National Birth Defects Prevention Study (1997-2011) and included 19,065 infants with at least one eligible birth defect (cases) and 8925 without birth defects (controls) from eight Centers throughout the United States. Maternal participants reported their addresses throughout pregnancy. Each address was systematically geocoded and residences around conception were linked to greenspace, US Census, and US Department of Agriculture data. Greenspace was estimated using the normalized difference vegetation index (NDVI); average maximum NDVI was estimated within 100 m and 500 m concentric buffers surrounding geocoded addresses to estimate residential NDVI. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals comparing those in the highest and lowest quartiles of residential NDVI and stratifying by rural/urban residence and neighborhood median income., Results: After multivariable adjustment, for the 500 m buffer, inverse associations were observed for tetralogy of Fallot, secundum atrial septal defects, anencephaly, anotia/microtia, cleft lip ± cleft palate, transverse limb deficiency, and omphalocele, (aORs: 0.54-0.86). Results were similar for 100 m buffer analyses and similar patterns were observed for other defects, though results were not significant. Significant heterogeneity was observed after stratification by rural/urban for hypoplastic left heart, coarctation of the aorta, and cleft palate, with inverse associations only among participants residing in rural areas. Stratification by median income showed heterogeneity for atrioventricular and secundum atrial septal defects, anencephaly, and anorectal atresia, with inverse associations only among participants residing in a high-income neighborhood (aORs: 0.45-0.81)., Discussion: Our results suggest that perinatal residential proximity to more greenspace may contribute to a reduced risk of certain birth defects, especially among those living in rural or high-income neighborhoods., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Fatty acids are crucial in embryologic development, including cardiogenesis. The impact of maternal periconceptional dietary fat intake on the risk of congenital heart defects (CHDs) has not been clearly elucidated. We hypothesized that maternal dietary fat intake during pregnancy is associated with risk of CHDs in offspring., Methods: We analyzed CHD cases and nonmalformed controls from the National Birth Defects Prevention Study, a case-control, multicenter population-based study of birth defects. We used multivariable logistic regression to analyze the association between maternal periconceptional dietary fat intake and occurrence of CHDs., Results: We examined 11,393 infants with CHDs (cases) and 11,029 infants without birth defects (controls). Multivariable analysis of maternal dietary fat intake adjusted for maternal energy intake demonstrated modest change in risk for 2 of the 25 CHDs analyzed; otherwise there was no association. Maternal dietary fat intake unadjusted for total energy was associated with increased risk for several CHDs., Conclusions: After adjusting for total energy intake, maternal periconceptional dietary fat intake has a modest association with risk of a few specific CHDs. If maternal dietary fat intake does impact CHD risk, the effect is minimal., Impact: In this large, case-control study, after adjusting for total caloric intake, maternal periconceptional dietary fat intake was not associated with increased odds of congenital heart defects. This study investigates the hypothesis that women's periconceptional fat intake alters the risk of congenital heart defects in offspring. Our results raise questions about the role maternal fat intake may play in cardiogenesis and risk of congenital heart defects. Additionally, they raise the question about whether maternal lipid metabolism, as opposed to fat intake, may influence cardiac development.

Studies of outcomes among adults with congenital heart defects (CHDs) have focused on those receiving cardiac care, limiting generalizability. The Congenital Heart Survey To Recognize Outcomes, Needs, and well-beinG (CH STRONG) will assess comorbidities, health care utilization, quality of life, and social and educational outcomes from a US population-based sample of young adults living with CHD., Methods: Individuals with CHD born between 1980 and 1997 were identified using active, population-based birth defects surveillance systems from 3 US locations (Arkansas [AR]; Arizona [AZ]; and Atlanta, Georgia [GA]) linked to death records. Individuals with current contact information responded to mailed survey materials during 2016 to 2019. Respondents and nonrespondents were compared using χ 2 tests., Results: Sites obtained contact information for 74.6% of the 9,312 eligible individuals alive at recruitment. Of those, 1,656 returned surveys, either online (18.1%) or via paper (81.9%), for a response rate of 23.9% (AR: 18.3%; AZ: 30.7%; Atlanta, GA: 28.0%; P value < .01). For 20.0% of respondents, a proxy completed the survey, with 63.9% reporting that the individual with CHD was mentally unable. Among respondents and nonrespondents, respectively, sex (female: 54.0% and 47.3%), maternal race/ethnicity (non-Hispanic white: 74.3% and 63.0%), CHD severity (severe: 33.8% and 27.9%), and noncardiac congenital anomalies (34.8% and 38.9%) differed significantly (P value < .01); birth year (1991-1997: 56.0% and 57.5%) and presence of Down syndrome (9.2% and 8.9%) did not differ., Conclusions: CH STRONG will provide the first multisite, population-based findings on long-term outcomes among the growing population of US adults with CHD., (Published by Elsevier Inc.)

Background/objectives: In this report, the National Birth Defects Prevention Network (NBDPN) examines and compares gastroschisis and omphalocele for a recent 5-year birth cohort using data from 30 population-based birth defect surveillance programs in the United States., Methods: As a special call for data for the 2019 NBDPN Annual Report, state programs reported expanded data on gastroschisis and omphalocele for birth years 2012-2016. We estimated the overall prevalence (per 10,000 live births) and 95% confidence intervals (CI) for each defect as well as by maternal race/ethnicity, maternal age, infant sex, and case ascertainment methodology utilized by the program (active vs. passive). We also compared distribution of cases by maternal and infant factors and presence/absence of other birth defects., Results: The overall prevalence estimates (per 10,000 live births) were 4.3 (95% CI: 4.1-4.4) for gastroschisis and 2.1 (95% CI: 2.0-2.2) for omphalocele. Gastroschisis was more frequent among young mothers (<25 years) and omphalocele more common among older mothers (>40 years). Mothers of infants with gastroschisis were more likely to be underweight/normal weight prior to pregnancy and mothers of infants with omphalocele more likely to be overweight/obese. Omphalocele was twice as likely as gastroschisis to co-occur with other birth defects., Conclusions: This report highlights important differences between gastroschisis and omphalocele. These differences indicate the importance of distinguishing between these defects in epidemiologic assessments. The report also provides additional data on co-occurrence of gastroschisis and omphalocele with other birth defects. This information can provide a basis for future research to better understand these defects., (Published 2019. This article is a U.S. Government work and is in the public domain in the USA.)

Background/objectives: In this data brief, we examine major eye and ear anomalies (anophthalmia/microphthalmia, anotia/microtia, and congenital cataract) for a recent 5-year birth cohort using data from 30 population-based birth defects surveillance programs in the United States., Methods: As a special call for data for the 2018 NBDPN Annual Report, state programs reported expanded data on eye/ear anomalies for birth years 2011-2015. We calculated the combined overall prevalence (per 10,000 live births) and 95% confidence intervals (CI), for the three anomalies as well as by maternal age, maternal race/ethnicity, infant sex, laterality, presence/absence of other major birth defects, and case ascertainment methodology utilized by the program (active vs. passive)., Results: The overall prevalence estimate (per 10,000 live births) was 1.5 (95% CI: 1.4-1.5) for anophthalmia/microphthalmia, 1.5 (95% CI: 1.4-1.6) for congenital cataract, and 1.8 (95% CI: 1.7-1.8) for anotia/microtia. Congenital cataract prevalence varied little by maternal race/ethnicity, infant sex, or case ascertainment methodology; prevalence differences were more apparent across strata for anophthalmia/microphthalmia and anotia/microtia. Prevalence among active vs. passive ascertainment programs was 50% higher for anophthalmia/microphthalmia (1.9 vs. 1.2) and two-fold higher for anotia/microtia (2.6 vs. 1.2). Anophthalmia/microphthalmia was more likely than other conditions to co-occur with other birth defects. All conditions were more frequent among older mothers (40+ years)., Conclusions: This data brief provides recent prevalence estimates for anophthalmia/microphthalmia, congenital cataract, and anotia/microtia that address a data gap by examining pooled data from 30 population-based surveillance systems, covering a five-year birth cohort of about 12.4 million births., (© 2018 Wiley Periodicals, Inc.)

Background: We evaluated selected birth defects over a 9-year period to assess prevalence trends by selected maternal and infant factors., Methods: Data were pooled from 11 population-based birth defects surveillance programs in the United States for children born between 1999 and 2007. Overall prevalence, as well as 3-year interval prevalence, was calculated for 26 specific birth defects, stratified by maternal age, maternal race/ethnicity, and infant sex. Average annual percent change (AAPC) was calculated for each birth defect. Poisson regression was used to determine change in AAPC, and joinpoint regression to identify breakpoints and changes in slope for prevalence of each defect over time., Results: Between 1999 and 2001 and 2005 and 2007, four birth defects increased by 10% or more: coarctation of the aorta (17%), gastroschisis (83%), omphalocele (11%), and Down syndrome (10%). Among mothers <20 years of age, the gastroschisis AAPC increased 10.1% overall and, cross-classified by maternal race/ethnicity, the AAPC for mothers <20 years increased 9.2%, 25.7%, and 7.7% among non-Hispanic white (NHW), non-Hispanic black (NHB), and Hispanic mothers, respectively. A small increase in Down syndrome (AAPC 4.4%) was found for NHB mothers ≥35 years., Conclusion: No significant trends in prevalence were identified for most birth defects. Gastroschisis prevalence increased significantly among NHW and NHB mothers <20 years of age, with the greatest increases in NHB mothers. Prevalence of Down syndrome among NHB mothers ≥35 years also increased slightly. Stratified results may suggest avenues of research in birth defect etiology and in evaluating prevention efforts. Birth Defects Research 109:1442-1450, 2017.© 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Background: The Birth Defects Study To Evaluate Pregnancy exposureS (BD-STEPS) is a population-based, multi-Center case-control study of modifiable risk factors for selected birth defects in the United States. BD-STEPS is the second major research effort of the Centers for Birth Defects Research and Prevention, which extends and expands the initial research effort, the National Birth Defects Prevention Study (NBDPS)., Methods: BD-STEPS focuses on 17 categories of structural birth defects selected based on severity, prevalence, consistent ascertainment, and previous findings that warrant additional research. Cases are identified through existing birth defects surveillance programs; controls are from vital records or birth hospital logs from the same catchment area. BD-STEPS uses a standardized computer-assisted telephone interview to collect information from case and control mothers on topics including demographics, health conditions, and medication use. Following the maternal interview, selected Centers request permission to sample residual newborn screening blood spots from state repositories for genetic analyses. New components planned for BD-STEPS include linkages with external datasets and use of online questionnaires to collect in-depth information on selected exposures., Results: BD-STEPS extends NBDPS by continuing to collect data on many exposures that were assessed in NBDPS, allowing data from both studies to be combined and providing an unprecedented sample size to analyze rare exposures. BD-STEPS expands upon NBDPS by collecting more detailed information on existing exposures as well as new exposures., Conclusion: The goal of BD-STEPS is to provide women and healthcare providers with information they need to make decisions to promote the healthiest pregnancy possible., (© 2015 Wiley Periodicals, Inc.)

Objectives: To examine racial/ethnic-specific survival of children with major birth defects in the US., Study Design: We pooled data on live births delivered during 1999-2007 with any of 21 birth defects from 12 population-based birth defects surveillance programs. We used the Kaplan-Meier method to calculate cumulative survival probabilities and Cox proportional hazards models to estimate mortality risk., Results: For most birth defects, there were small-to-moderate differences in neonatal (<28 days) survival among racial/ethnic groups. However, compared with children born to non-Hispanic white mothers, postneonatal infant (28 days to <1 year) mortality risk was significantly greater among children born to non-Hispanic black mothers for 13 of 21 defects (hazard ratios [HRs] 1.3-2.8) and among children born to Hispanic mothers for 10 of 21 defects (HRs 1.3-1.7). Compared with children born to non-Hispanic white mothers, a significantly increased childhood (≤ 8 years) mortality risk was found among children born to Asian/Pacific Islander mothers for encephalocele (HR 2.6), tetralogy of Fallot, and atrioventricular septal defect (HRs 1.6-1.8) and among children born to American Indian/Alaska Native mothers for encephalocele (HR 2.8), whereas a significantly decreased childhood mortality risk was found among children born to Asian/Pacific Islander mothers for cleft lip with or without cleft palate (HR 0.6)., Conclusion: Children with birth defects born to non-Hispanic black and Hispanic mothers carry a greater risk of mortality well into childhood, especially children with congenital heart defect. Understanding survival differences among racial/ethnic groups provides important information for policy development and service planning., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: We examined the association between survival of infants with severe congenital heart defects (CHDs) and community-level indicators of socioeconomic status., Methods: We identified infants born to residents of Arizona, New Jersey, New York, and Texas between 1999 and 2007 with selected CHDs from 4 population-based, statewide birth defect surveillance programs. We linked data to the 2000 US Census to obtain 11 census tract-level socioeconomic indicators. We estimated survival probabilities and hazard ratios adjusted for individual characteristics., Results: We observed differences in infant survival for 8 community socioeconomic indicators (P < .05). The greatest mortality risk was associated with residing in communities in the most disadvantaged deciles for poverty (adjusted hazard ratio [AHR] = 1.49; 95% confidence interval [CI]  = 1.11, 1.99), education (AHR = 1.51; 95% CI = 1.16, 1.96), and operator or laborer occupations (AHR = 1.54; 95% CI = 1.16, 1.96). Survival decreased with increasing numbers of indicators that were in the most disadvantaged decile. Community-level mortality risk persisted when we adjusted for individual-level characteristics., Conclusions: The increased mortality risk among infants with CHDs living in socioeconomically deprived communities might indicate barriers to quality and timely care at which public health interventions might be targeted.

Background: Trichlorophenols (TCPs) are organochlorine compounds which are ubiquitous in the environment and well known for their carcinogenic effects. However, little is known about their neurotoxicity in humans., Objectives: Our goal was to examine the association between body burden of TCPs (ie, 2,4,5-TCP and 2,4,6-TCP) and attention deficit hyperactivity disorder (ADHD)., Methods: We calculated ORs and 95% CIs from logistic regression analyses using data from the 1999-2004 National Health and Nutrition Examination Survey (NHANES) to evaluate the association between urinary TCPs and parent-reported ADHD among 2546 children aged 6-15 years., Results: Children with low levels (<3.58 μg/g) and high levels (≥3.58 μg/g) of urinary 2,4,6-TCP had a higher risk of parent-reported ADHD compared to children with levels below the limit of detection (OR 1.54, 95% CI 0.97 to 2.43 and OR 1.77, 95% CI 1.18 to 2.66, respectively; p for trend=0.006) after adjusting for covariates. No association was found between urinary 2,4,5-TCP and parent-reported ADHD., Conclusion: Exposure to TCP may increase the risk of behavioural impairment in children. The potential neurotoxicity of these chemicals should be considered in public health efforts to reduce environmental exposures/contamination, especially in countries where organochlorine pesticides are still commonly used.

Background: Infants with congenital heart defects (CHDs) have increased risk of childhood morbidity and mortality. However, little is known about racial/ethnic differences in early childhood mortality., Patients and Methods: We conducted a retrospective cohort study with data from the Texas Birth Defect Registry on 19 530 singleton, live-born infants with a CHD and born January 1, 1996, to December 31, 2003, to non-Hispanic (NH) white, NH black, and Hispanic women. Texas Birth Defect Registry data were linked to Texas death records and the National Death Index to ascertain deaths between January 1, 1996, and December 31, 2005. Kaplan-Meier survival estimates were computed, and hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated from multivariable Cox-proportional hazard regression models to determine the effect of maternal race/ethnicity on mortality for selected CHD phenotypes., Results: After adjusting for covariates, compared with NH white children, NH black children had increased early childhood mortality risk for transposition of the great arteries (HR: 2.04 [95% CI: 1.40-2.97]), tetralogy of Fallot (HR: 1.85 [95% CI: 1.09-3.12]), pulmonary valve atresia without ventricular septal defect (VSD) (HR: 2.60 [95% CI: 1.32-5.12]), VSD (HR: 1.56 [95% CI: 1.19-2.03]), and atrial septal defect (HR: 1.34 [95% CI: 1.08-1.66]). Hispanic children had higher mortality risk for pulmonary valve atresia without VSD (HR: 1.76 [95% CI: 1.06-2.91]) and hypoplastic left heart syndrome (HR: 1.51 [95% CI: 1.13-2.02])., Conclusions: We provide evidence that supports racial/ethnic disparities in early childhood mortality among infants with CHDs. Identifying infants with the greatest risk of early childhood mortality will facilitate development of interventions and policies to mitigate these risks.

Background: Previous reports suggest that mortality resulting from congenital heart disease (CHD) among infants and young children has been decreasing. There is little population-based information on CHD mortality trends and patterns among older children and adults., Methods and Results: We used data from death certificates filed in the United States from 1999 to 2006 to calculate annual CHD mortality by age at death, race-ethnicity, and sex. To calculate mortality rates for individuals ≥1 year of age, population counts from the US Census were used in the denominator; for infant mortality, live birth counts were used. From 1999 to 2006, there were 41,494 CHD-related deaths and 27,960 deaths resulting from CHD (age-standardized mortality rates, 1.78 and 1.20 per 100,000, respectively). During this period, mortality resulting from CHD declined 24.1% overall. Mortality resulting from CHD significantly declined among all race-ethnicities studied. However, disparities persisted; overall and among infants, mortality resulting from CHD was consistently higher among non-Hispanic blacks compared with non-Hispanic whites. Infant mortality accounted for 48.1% of all mortality resulting from CHD; among those who survived the first year of life, 76.1% of deaths occurred during adulthood (≥18 years of age)., Conclusions: CHD mortality continued to decline among both children and adults; however, differences between race-ethnicities persisted. A large proportion of CHD-related mortality occurred during infancy, although significant CHD mortality occurred during adulthood, indicating the need for adult CHD specialty management.

Congenital heart defects (CHDs) are a leading cause of infant morbidity and mortality. Infants with CHDs have increased risk of preterm birth (PTB) compared to infants without birth defects. Although non-Hispanic (NH) Blacks are more likely to be born preterm and Hispanics have rates similar to those of PTB to NH-Whites, it is unknown if this pattern is present for infants with specific types of CHDs. Our intent was to determine if defect-specific risk of PTB varies by maternal race/ethnicity among infants with CHDs. We conducted a retrospective cohort study with 14,888 singleton infants from the Florida Birth Defects Registry, born in 1998-2003 to resident NH-White, NH-Black, and Hispanic women aged 15-49, diagnosed with 11 CHDs. Covariates were taken from Florida live birth certificates. PTB was defined as 20-36 weeks of gestation. Odds ratios (OR) and P-values were calculated from defect-specific multivariable logistic regression models; statistical significance was set at P < 0.002. The greatest risk of PTB was for NH-Black infants with conotruncal CHDs. NH-Blacks with common truncus, transposition of the great vessels, and tetralogy of Fallot had increased risk of PTB compared to NH-Whites (OR = 4.8, P = 0.015; OR = 3.1, P = 0.004; and OR = 2.0, P = 0.005, respectively). Hispanics with conotruncal CHDs had almost a twofold risk of PTB compared to NH-Whites (P > 0.002). NH-Blacks with tricuspid valve atresia/stenosis had 4.1 times (P = 0.034) and Hispanics had 2.1 times (P = 0.314) the risk for PTB compared to NH-Whites. NH-Blacks with hypoplastic left heart syndrome had 2.0 times (P = 0.047) the risk for PTB as NH-Whites. Both NH-Black and Hispanic infants with CHDs may be at increased risk of PTB, depending on the type of CHD, but the etiology is unknown. Future research is needed to further examine this complex relationship.