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Epidemiologic studies of birth defects often conduct separate analyses for cases that have isolated defects (e.g., spina bifida only) and cases that have multiple defects (e.g., spina bifida and a congenital heart defect). However, in some instances, cases with additional defects (e.g., spina bifida and clubfoot) may be more appropriately considered as isolated because the co‐occurring defect (clubfoot) is believed to be developmentally related to the defect of interest. Determining which combinations should be considered isolated can be challenging and potentially resource intensive for registries. Thus, we developed automated classification procedures for differentiating between isolated versus multiple defects, while accounting for developmentally related defects, and applied the approach to data from the Texas Birth Defects Registry (1999–2018 deliveries). Among 235,544 nonsyndromic cases in Texas, 89% of cases were classified as having isolated defects, with proportions ranging from 25% to 92% across 43 specific defects analyzed. A large proportion of isolated cases with spina bifida (44%), lower limb reduction defects (44%), and holoprosencephaly (32%) had developmentally related defects. Overall, our findings strongly support the need to account for isolated versus multiple defects in risk factor association analyses and to account for developmentally related defects when doing so, which has implications for interpreting prior studies. [ABSTRACT FROM AUTHOR]

Introduction: Traditional strategies for grouping congenital heart defects (CHDs) using birth defect registry data do not adequately address differences in expected clinical consequences between different combinations of CHDs. We report a lesion‐specific classification system for birth defect registry–based outcome studies. Methods: For Core Cardiac Lesion Outcome Classifications (C‐CLOC) groups, common CHDs expected to have reasonable clinical homogeneity were defined. Criteria based on combinations of Centers for Disease and Control‐modified British Pediatric Association (BPA) codes were defined for each C‐CLOC group. To demonstrate proof of concept and retention of reasonable case counts within C‐CLOC groups, Texas Birth Defect Registry data (1999–2017 deliveries) were used to compare case counts and neonatal mortality between traditional vs. C‐CLOC classification approaches. Results: C‐CLOC defined 59 CHD groups among 62,262 infants with CHDs. Classifying cases into the single, mutually exclusive C‐CLOC group reflecting the highest complexity CHD present reduced case counts among lower complexity lesions (e.g., 86.5% of cases with a common atrium BPA code were reclassified to a higher complexity group for a co‐occurring CHD). As expected, C‐CLOC groups had retained larger sample sizes (i.e., representing presumably better‐powered analytic groups) compared to cases with only one CHD code and no occurring CHDs. Discussion: This new CHD classification system for investigators using birth defect registry data, C‐CLOC, is expected to balance clinical outcome homogeneity in analytic groups while maintaining sufficiently large case counts within categories, thus improving power for CHD‐specific outcome association comparisons. Future outcome studies utilizing C‐CLOC‐based classifications are planned. [ABSTRACT FROM AUTHOR]

Choanal atresia and stenosis are common causes of congenital nasal obstruction, but their epidemiology is poorly understood. Compared to bilateral choanal atresia/stenosis, unilateral choanal atresia/stenosis is generally diagnosed later and might be under‐ascertained in birth defect registries. Data from the population‐based Texas Birth Defects Registry and Texas vital records, 1999–2018, were used to assess the prevalence of choanal atresia/stenosis. Poisson regression models were used to evaluate associations with infant and maternal characteristics in two analytic groups: isolated choanal atresia/stenosis (n = 286) and isolated, bilateral choanal atresia/stenosis (n = 105). The overall prevalence of choanal atresia/stenosis was 0.92/10,000, and the prevalence of isolated choanal atresia/stenosis was 0.37/10,000 livebirths. Variables associated with choanal atresia/stenosis in one or both analytic groups included infant sex, pregnancy plurality, maternal race/ethnicity, maternal age, and maternal residence on the Texas–Mexico border. In general, adjusted prevalence ratios estimated from the two analytic groups were in the same direction but tended to be stronger in the analyses restricted to isolated, bilateral defects. Epidemiologic studies of isolated choanal atresia/stenosis should consider focusing on cases with bilateral defects, and prioritizing analyses of environmental, social, and structural factors that could account for the association with maternal residence on the Texas–Mexico border. [ABSTRACT FROM AUTHOR]

Many infants with anotia or microtia (A/M) have co‐occurring birth defects, although few receive syndromic diagnoses in the perinatal period. Evaluation of co‐occurring birth defects in children with A/M could identify patterns indicative of undiagnosed/unrecognized syndromes. We obtained information on co‐occurring birth defects among infants with A/M for delivery years 1999–2014 from the Texas Birth Defects Registry. We calculated observed‐to‐expected ratios (OER) to identify birth defect combinations that occurred more often than expected by chance. We excluded children diagnosed with genetic or chromosomal syndromes from analyses. Birth defects and syndromes/associations diagnosed ≤1 year of age were considered. We identified 1310 infants with non‐syndromic A/M, of whom 38% (N = 492) were diagnosed with co‐occurring major defects. Top combinations included: hydrocephalus, ventricular septal defect, and spinal anomalies (OER 58.4); microphthalmia and anomalies of the aorta (OER 55.4); and cleft lip with or without cleft palate and rib or sternum anomalies (OER 32.8). Some combinations observed in our study may represent undiagnosed/atypical presentations of known A/M associations or syndromes, or novel syndromes yet to be described in the literature. Careful evaluation of infants with multiple birth defects including A/M is warranted to identify individuals with potential genetic or chromosomal syndromes. [ABSTRACT FROM AUTHOR]

Structural birth defects that occur in infants with syndromes may be etiologically distinct from those that occur in infants in whom there is not a recognized pattern of malformations; however, population‐based registries often lack the resources to classify syndromic status via case reviews. We developed criteria to systematically identify infants with suspected syndromes, grouped by syndrome type and level of effort required for syndrome classification (e.g., text search). We applied this algorithm to the Texas Birth Defects Registry (TBDR) to describe the proportion of infants with syndromes delivered during 1999–2014. We also developed a bias analysis tool to estimate the potential percent bias resulting from including infants with syndromes in studies of risk factors. Among 207,880 cases with birth defects in the TBDR, 15% had suspected syndromes and 85% were assumed to be nonsyndromic, with a range across defect types from 28.5% (atrioventricular septal defects) to 98.9% (pyloric stenosis). Across hypothetical scenarios varying expected parameters (e.g., nonsyndromic proportion), the inclusion of syndromic cases in analyses resulted in up to 50.0% bias in prevalence ratios. In summary, we present a framework for identifying infants with syndromic conditions; implementation might harmonize syndromic classification across registries and reduce bias in association estimates. [ABSTRACT FROM AUTHOR]

Background: Few risk factors have been identified for nonsyndromic anotia/microtia (A/M). Methods: We obtained data on cases and a reference population of all livebirths in Texas for 1999–2014 from the Texas Birth Defects Registry (TBDR) and Texas vital records. We estimated prevalence ratios (PRs) and 95% confidence intervals (CIs) for A/M (any, isolated, nonisolated, unilateral, and bilateral) using Poisson regression. We evaluated trends in prevalence rates using Joinpoint regression. Results: We identified 1,322 cases, of whom 982 (74.3%) had isolated and 1,175 (88.9%) had unilateral A/M. Prevalence was increased among males (PR: 1.3, 95% CI: 1.2–1.4), offspring of women with less than high school education (PR: 1.3, 95% CI: 1.1–1.5), diabetes (PR: 2.0, 95% CI: 1.6–2.4), or age 30–39 versus 20–29 years (PR: 1.2, 95% CI: 1.0–1.3). The prevalence was decreased among offspring of non‐Hispanic Black versus White women (PR: 0.6, 95% CI: 0.4–0.8) but increased among offspring of Hispanic women (PR: 2.9, 95% CI: 2.5–3.4) and non‐Hispanic women of other races (PR: 1.7, 95% CI: 1.3–2.3). We observed similar results among cases with isolated and unilateral A/M. Sex disparities were not evident for nonisolated or bilateral phenotypes, nor did birth prevalence differ between offspring of non‐Hispanic Black and non‐Hispanic White women. Maternal diabetes was more strongly associated with nonisolated (PR: 4.5, 95% CI: 3.2–6.4) and bilateral A/M (PR: 5.0, 95% CI: 3.3–7.7). Crude prevalence rates increased throughout the study period (annual percent change: 1.82). Conclusion: We identified differences in the prevalence of nonsyndromic A/M by maternal race/ethnicity, education, and age, which may be indicators of unidentified social/environmental risk factors. [ABSTRACT FROM AUTHOR]

Objective: To investigate 2- to 5-way patterns of defects co-occurring with orofacial clefts using data from a population-based registry. Design: We used data from the Texas Birth Defects Registry for deliveries between 1999 and 2014 to Texas residents, including 1884 cases with cleft palate (CP) and 5289 cases with cleft lip with or without cleft palate (CL±P) without a known syndrome. We identified patterns of defects co-occurring with CP and with CL±P observed more frequently than would be expected if these defects occurred independently. We calculated adjusted observed-to-expected (O / E) ratios to account for the known tendency of birth defects to cluster nonspecifically. Results: Among infants without a syndrome, 23% with CP and 21% with CL±P had at least 1 additional congenital anomaly. Several combinations of defects were observed much more often than expected. For example, the combination of CL±P, congenital hydrocephaly, anophthalmia, and other nose anomalies had an O / E ratio of 605. For both CP and CL±P, co-occurrence patterns with the highest O / E ratios involved craniofacial and brain abnormalities, and many included the skeletal, cardiovascular, and renal systems. Conclusions: The patterns of defects we observed co-occurring with clefts more often than expected may help improve our understanding of the relationships between multiple defects. Further work to better understand some of the top defect combinations could reveal new phenotypic subgroups and increase our knowledge of the developmental mechanisms that underlie the respective defects. [ABSTRACT FROM AUTHOR]

Infants with anophthalmia or microphthalmia frequently have co-occurring birth defects. Nonetheless, there have been few investigations of birth defect patterns among these children. Such studies may identify novel multiple malformation syndromes, which could inform future research into the developmental processes that lead to anophthalmia/microphthalmia and assist physicians in determining whether further testing is appropriate. This study includes cases with anophthalmia/microphthalmia identified by the Texas Birth Defects Registry from 1999 to 2014 without clinical or chromosomal diagnoses of recognized syndromes. We calculated adjusted observed-to-expected ratios for two – through five-way birth defect combinations involving anophthalmia/microphthalmia to estimate whether these combinations co-occur more often than would be expected if they were independent. We report combinations observed in ≥5 cases. We identified 653 eligible cases with anophthalmia/microphthalmia (514 [79%] with co-occurring birth defects), and 111 birth defect combinations, of which 44 were two-way combinations, 61 were three-way combinations, six were four-way combinations and none were five-way combinations. Combinations with the largest observed-to-expected ratios were those involving central nervous system (CNS) defects, head/neck defects, and orofacial clefts. We also observed multiple combinations involving cardiovascular and musculoskeletal defects. Consistent with previous reports, we observed that a large proportion of children diagnosed with anophthalmia/microphthalmia have co-occurring birth defects. While some of these defects may be part of a sequence involving anophthalmia/microphthalmia (e.g., CNS defects), other combinations could point to as yet undescribed susceptibility patterns (e.g., musculoskeletal defects). Data from population-based birth defect registries may be useful for accelerating the discovery of previously uncharacterized malformation syndromes. [ABSTRACT FROM AUTHOR]

BACKGROUND Maternal hypertension has been associated with congenital heart defect occurrence in several studies. We assessed whether maternal genotypes associated with this condition were also associated with congenital heart defect occurrence. METHODS We used data from the National Birth Defects Prevention Study to identify non-Hispanic white (NHW) and Hispanic women with (cases) and without (controls) a pregnancy in which a select simple, isolated heart defect was present between 1999 and 2011. We genotyped 29 hypertension-related single nucleotide polymorphisms (SNPs). We conducted logistic regression analyses separately by race/ethnicity to assess the relationship between the presence of any congenital heart defect and each SNP and an overall blood pressure genetic risk score (GRS). All analyses were then repeated to assess 4 separate congenital heart defect subtypes. RESULTS Four hypertension-related variants were associated with congenital heart defects among NHW women (N = 1,568 with affected pregnancies). For example, 1 intronic variant in ARHGAP2 , rs633185, was associated with conotruncal defects (odds ratio [OR]: 1.3, 95% confidence interval [CI]: 1.1–1.6). Additionally, 2 variants were associated with congenital heart defects among Hispanic women (N = 489 with affected pregnancies). The GRS had a significant association with septal defects (OR: 2.1, 95% CI: 1.2–3.5) among NHW women. CONCLUSIONS We replicated a previously reported association between rs633185 and conotruncal defects. Although additional hypertension-related SNPs were also associated with congenital heart defects, more work is needed to better understand the relationship between genetic risk for maternal hypertension and congenital heart defects occurrence. [ABSTRACT FROM AUTHOR]

Background: We sought to investigate associations between maternal/infant characteristics and isolated craniosynostosis as well as its subtypes sagittal, metopic, and coronal synostosis, and assess trends in the prevalence of these conditions. Methods: We identified cases in the Texas Birth Defects Registry from 1999 to 2014. We used Poisson regression to identify associations between maternal/infant characteristics and craniosynostosis. We used joinpoint regression and unadjusted Poisson regression to evaluate temporal trends. Finally, we computed adjusted Poisson models to evaluate whether temporal trends were evident after accounting for changes in the population distributions of maternal/infant characteristics over time. Results: Relative to all live births in the general population, cases were more frequently male or preterm. Mothers of cases were more frequently non‐Hispanic white and more frequently obese. Non‐Hispanic black or Hispanic maternal race/ethnicity was associated with a lower prevalence of all craniosynostosis subtypes. Previous live births were associated with sagittal synostosis; residence on the U.S.‐Mexico border was associated with sagittal and coronal synostosis. The prevalence of any isolated craniosynostosis increased (average annual percent change estimated from joinpoint regression [AAPC]: 2.9%), as did the prevalences of sagittal (AAPC: 3.3%) and metopic synostosis (AAPC: 5.4%). In crude Poisson models, the same temporal trends were observed, however these were attenuated after adjusting for maternal/infant characteristics. Conclusions: Prevalence of isolated craniosynostosis increased from 1999 to 2014. The largest AAPC was observed for metopic synostosis. Changes in the population distribution of associated maternal/infant characteristics may explain these trends. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the relationships between maternal fish consumption and pregnancy outcomes in a large, population-based sample of women in the USA.Design: We collected average fish consumption prior to pregnancy using a modified version of the semi-quantitative Willett FFQ. We estimated adjusted OR (aOR) and 95 % CI for associations between different levels of fish consumption and preterm birth (<37 weeks), early preterm birth (<32 and <35 weeks) and small-for-gestational-age infants (SGA; <10th percentile).Setting: The National Birth Defects Prevention Study (NBDPS).Subjects: Control mother-infant pairs with estimated delivery dates between 1997 and 2011 (n 10 919).Results: No significant associations were observed between fish consumption and preterm birth or early preterm birth (aOR = 0·7-1·0 and 0·7-0·9, respectively). The odds of having an SGA infant were elevated (aOR = 2·1; 95 % CI 1·2, 3·4) among women with daily fish consumption compared with women consuming fish less than once per month. No associations were observed between other levels of fish consumption and SGA (aOR = 0·8-1·0).Conclusions: High intake of fish was associated with twofold higher odds of having an SGA infant, while moderate fish consumption prior to pregnancy was not associated with preterm or SGA. Our study, like many other studies in this area, lacked information regarding preparation methods and the specific types of fish consumed. Future studies should incorporate information on nutrient and contaminant contents, preparation methods and biomarkers to assess these relationships. [ABSTRACT FROM AUTHOR]

Objective: To estimate the proportion of neonatal mortality risk attributable to preterm delivery among neonates with birth defects.Study Design: Using a statewide cohort of live born infants from the Texas Birth Defects Registry (1999-2014 deliveries), we estimated the population attributable fraction and 95% CI of neonatal mortality (death <28 days) attributable to prematurity (birth at <37 weeks vs ≥37 weeks) for 31 specific birth defects. To better understand the overall population burden, analyses were repeated for all birth defects combined.Results: Our analyses included 169 148 neonates with birth defects, of which 40 872 (24.2%) were delivered preterm. The estimated proportion of neonatal mortality attributable to prematurity varied by birth defect, ranging from 12.5% (95% CI: 8.7-16.1) for hypoplastic left heart syndrome to 71.9% (95% CI: 41.1-86.6) for anotia or microtia. Overall, the proportion was 51.7% (95% CI: 49.4-54.0) for all birth defects combined.Conclusions: A large proportion of deaths among neonates with birth defects are attributable to preterm delivery. Our results highlight differences in this burden across common birth defects. Our findings may be helpful for prioritizing future work focused on better understanding the etiology of prematurity among neonates with birth defects and the mechanisms by which prematurity contributes to neonatal mortality in this population. [ABSTRACT FROM AUTHOR]

Background: We examined the association between the maternal genotype for celiac disease‐associated variants and risk of neural tube defects (NTDs). Methods: We conducted a case–control study, using data from the National Birth Defects Prevention Study. We evaluated 667 cases (women with an offspring with NTD) and 743 controls (women with an offspring without a birth defect). We classified women as having low, intermediate, or high risk of celiac disease based on human leukocyte antigen (HLA) variants. We used logistic regression to assess the relationship between HLA celiac risk group (low, intermediate, high) and risk of NTDs. Fifteen non‐HLA variants (identified from genome‐wide association studies of celiac disease) were individually evaluated and modeled additively. Results: There was no association between HLA celiac risk group and NTDs (intermediate vs. low risk: aOR, 1.0; 95% CI, 0.8–1.3; high vs. low risk: aOR, 0.8; 95% CI, 0.5–1.3). Of the fifteen non‐HLA variants, we observed five significant associations after accounting for multiple comparisons. Three negative associations were observed with rs10903122, rs13314993, rs13151961 (aOR range: 0.69–0.81), and two positive associations were observed with rs13003464 and rs11221332 (aOR range: 1.27–1.73). Conclusion: If confirmed, our results suggest that the maternal variants related to celiac disease may be involved in the risk of NTDs. [ABSTRACT FROM AUTHOR]

Background: Coloboma is a rare congenital malformation in which part of the tissue that makes up the eye is missing and may cause visual impairment or blindness. Little is known about the epidemiology of this condition. Therefore, we obtained data from the Texas Birth Defects Registry on children identified with coloboma for the period 1999-2014., Methods: Using information on all live births from the same period, prevalence ratios (PRs) for selected demographic and clinical factors were used to estimate associations using Poisson regression among cases with coloboma. Coloboma cases were divided into subgroups to explore patterns of co-occurring defects and syndromes. All variables significant in unadjusted models (p < 0.05) were included in multivariable models to evaluate adjusted PRs (aPRs)., Results: We identified 1587 cases with coloboma, of whom 934 (58.8%) were nonsyndromic, and 474 (29.9%) were isolated. When considering all identified cases, factors associated with significant differences in prevalence included plurality (multiple vs. singleton aPR = 1.4, 95% CI: 1.1-1.8); maternal education (college or greater vs. less than high school aPR = 0.7, 95% CI: 0.6-0.9); maternal race/ethnicity (Hispanic vs. non-Hispanic White aPR = 0.9, 95% CI: 0.8-1.0); and maternal diabetes (yes vs. no aPR = 1.3, 95% CI: 1.0-1.6). There was a notable increase in the birth prevalence of coloboma during the study period (p-for-trend < 0.001). Effect estimates were similar across the different subgroups., Conclusion: In our large population, we identified several factors associated with the prevalence of coloboma. These findings may help define subgroups of women more likely to have children affected by coloboma, which could inform improved screening efforts., (© 2024 Wiley Periodicals LLC.)

Objective: To develop risk prediction models for preterm birth among infants with orofacial clefts., Design: Data from the Texas Birth Defects Registry for infants with orofacial clefts born between 1999-2014 were used to develop preterm birth predictive models. Logistic regression was used to consider maternal and infant characteristics, and internal validation of the final model was performed using bootstrapping methods. The area under the curve (AUC) statistic was generated to assess model performance, and separate predictive models were built and validated for infants with cleft lip and cleft palate alone. Several secondary analyses were conducted among subgroups of interest., Setting: State-wide, population-based Registry data., Patients/participants: 6774 infants with orofacial clefts born in Texas between 1999-2014., Main Outcome Measure(s): Preterm birth among infants with orofacial clefts., Results: The final predictive model performed modestly, with an optimism-corrected AUC of 0.67 among all infants with orofacial clefts. The optimism-corrected models for cleft lip (with or without cleft palate) and cleft palate alone had similar predictive capability, with AUCs of 0.66 and 0.67, respectively. Secondary analyses had similar results, but the model among infants with delivery prior to 32 weeks demonstrated higher optimism-corrected predictive capability (AUC = 0.74)., Conclusions: This study provides a first step towards predicting preterm birth risk among infants with orofacial clefts. Identifying pregnancies affected by orofacial clefts at the highest risk for preterm birth may lead to new avenues for improving outcomes among these infants.

Objective: To investigate 2- to 5-way patterns of defects co-occurring with orofacial clefts using data from a population-based registry., Design: We used data from the Texas Birth Defects Registry for deliveries between 1999 and 2014 to Texas residents, including 1884 cases with cleft palate (CP) and 5289 cases with cleft lip with or without cleft palate (CL±P) without a known syndrome. We identified patterns of defects co-occurring with CP and with CL±P observed more frequently than would be expected if these defects occurred independently. We calculated adjusted observed-to-expected ( O / E ) ratios to account for the known tendency of birth defects to cluster nonspecifically., Results: Among infants without a syndrome, 23% with CP and 21% with CL±P had at least 1 additional congenital anomaly. Several combinations of defects were observed much more often than expected. For example, the combination of CL±P, congenital hydrocephaly, anophthalmia, and other nose anomalies had an O / E ratio of 605. For both CP and CL±P, co-occurrence patterns with the highest O / E ratios involved craniofacial and brain abnormalities, and many included the skeletal, cardiovascular, and renal systems., Conclusions: The patterns of defects we observed co-occurring with clefts more often than expected may help improve our understanding of the relationships between multiple defects. Further work to better understand some of the top defect combinations could reveal new phenotypic subgroups and increase our knowledge of the developmental mechanisms that underlie the respective defects.