Prediction of Preterm Birth among Infants with Orofacial Cleft Defects.

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.

Association between maternal smoking and survival among infants with trisomy 21.

BACKGROUND: Trisomy 21 (T21) is common, with affected infants having an increased risk of infant mortality (5.9-7.1%). Maternal smoking is associated with infant mortality in the general population, and we evaluated if similar associations were present among infants with T21. METHODS: We identified infants with T21 from the Texas Birth Defects Registry, and maternal smoking and infant vital status were obtained from linked birth and death certificate data, respectively. Cox proportional hazards regression models were used to calculate hazard ratios between maternal smoking and death between 0 to ≤ 364 days, 28-364 days, and 0-27 days. RESULTS: We found a significant association between maternal smoking and death between 0 to ≤ 364 (unadjusted HR 1.72, 95% CI 1.07, 2.77), which was no longer statistically significant after adjustment for covariates (adjusted HR 1.55, 95% CI 0.94, 2.56). A similar pattern was observed for death between 28-364 days (adjusted HR: 1.68, 95% CI 0.93, 3.03), whereas the association for 0-27 days (adjusted HR: 1.30, 95% CI 0.51, 3.29) was not statistically significant before and after adjustment. CONCLUSIONS: The observed magnitudes of associations were similar to previous estimates among the general population. Further work considering the role of other maternal and infant risk factors and social determinants of health is necessary to better understand the observed results.

Patterns of congenital anomalies among individuals with trisomy 13 in Texas.

Few population-based studies have analyzed patterns of co-occurring birth defects among those with trisomy 13. We evaluated the frequency of all possible combinations of any one, two, three, or four additional co-occurring birth defects among 736 individuals with trisomy 13 using data from the Texas Birth Defects Registry for deliveries during 1999-2014. We calculated the observed-to-expected ratio for each combination, adjusting for the known tendency for birth defects to cluster non-specifically. To address potential ascertainment differences among live births and non-live births, we repeated analyses specifically among live births. The combination of defects with the largest observed-to-expected ratio was microcephalus, reduction deformities of brain (e.g., holoprosencephaly), anomalies of nose, and polydactyly. As expected, most of the highest 30 observed-to-expected ratios involved combinations with documented features of trisomy 13, including defects of the scalp (e.g., aplasia cutis) and heart. Results were similar among sensitivity analyses restricted to live births. Our findings may help further delineate the phenotypic spectrum for trisomy 13 and may inform future research related to improving screening and counseling for the condition.

Maternal Hypertension-Related Genotypes and Congenital Heart Defects.

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.

Patterns of co-occurring birth defects among infants with hypospadias.

INTRODUCTION: Hypospadias, one of the most common male genital birth defects, occurs in 1 out of every 200 male births in the United States and is increasing in prevalence globally. OBJECTIVE: This study aimed to characterize the combinations of birth defects that co-occur with hypospadias more often than expected by chance, while accounting for the complex clustering patterns of congenital defects. STUDY DESIGN: We analyzed cases with hypospadias and at least one additional co-occurring defect from the Texas Birth Defect Registry born between 1999 and 2014. For each combination, we calculated adjusted observed-to-expected (O/E) ratios, using Co-Occurring Defect Analysis (CODA). RESULTS: Among 16,442 cases with hypospadias and without known syndromes, 2,084 (12.7%) had at least one additional defect. Many of the birth defect combinations within the highest adjusted O/E ratios included cardiac, musculoskeletal, and additional urogenital defects. For example, a top combination with an adjusted O/E of 139.0 included renal agenesis and dysgenesis, reduction defects of the upper limb, and other anomalies of upper limb (including shoulder girdle). High adjusted O/E ratios were also observed in combinations that included defects outside of the urogenital developmental field. For instance, the combination with the highest O/E ratio included buphthalmos, and congenital cataract and lens anomalies (adjusted O/E ratio: 192.9). Similar results were obtained when we restricted our analyses to cases with second- or third-degree hypospadias. DISCUSSION: Many combinations in the top results were expected (e.g., multiple urogenital defects); however, some combinations with seemingly unrelated patterns of defects may suggest the presence of some etiologic mechanisms yet to be identified. CONCLUSION: In summary, this study described patterns of co-occurring defect combinations with hypospadias that can inform further study and may provide insights for screening and diagnostic practices.

Birth defects that co-occur with non-syndromic gastroschisis and omphalocele.

Gastroschisis and omphalocele are the two most common abdominal wall birth defects, and epidemiologic characteristics and frequency of occurrence as part of a syndromic condition suggest distinct etiologies between the two defects. We assessed complex patterns of defect co-occurrence with these defects separately using the Texas Birth Defects Registry. We used co-occurring defect analysis (CODA) to compute adjusted observed-to-expected (O/E) ratios for all observed birth defect patterns. There were 2,998 non-syndromic (i.e., no documented syndrome diagnosis identified) cases with gastroschisis and 789 (26%) of these had additional co-occurring defects. There were 720 non-syndromic cases with omphalocele, and 404 (56%) had additional co-occurring defects. Among the top 30 adjusted O/E ratios for gastroschisis, most of the co-occurring defects were related to the gastrointestinal system, though cardiovascular and kidney anomalies were also present. Several of the top 30 combinations co-occurring with omphalocele appeared suggestive of OEIS (omphalocele, exstrophy of cloaca, imperforate anus, spinal defects) complex. After the exclusion of additional cases with features suggestive of OEIS in a post-hoc sensitivity analysis, the top combinations involving defects associated with OEIS (e.g., spina bifida) were no longer present. The remaining top combinations involving omphalocele included cardiovascular, gastrointestinal, and urogenital defects. In summary, we identified complex patterns of defects that co-occurred more frequently than expected with gastroschisis and omphalocele using a novel software platform. Better understanding differences in the patterns between gastroschisis and omphalocele could lead to additional etiologic insights.

Perspectives on challenges and opportunities for birth defects surveillance programs during and after the COVID-19 era.

In recent months, various public health measures have been implemented throughout the world in response to the coronavirus disease 2019 (COVID-19) pandemic. This outbreak, and the subsequent containment policies, may have a range of potential short- and long-term impacts on the monitoring and surveillance of other conditions, such as birth defects. In this commentary, we provide a perspective on these potential impacts on birth defects surveillance and analysis. We discuss possible effects on clinical birth defect diagnoses, routine birth defects surveillance system activities, and epidemiologic considerations, as well as opportunities for mitigating the impact of COVID-19. Like many other sectors of public health and medicine, birth defects surveillance programs may be faced with organizational and methodological obstacles in the wake of a changing landscape. A better understanding of these potential challenges faced by birth defects surveillance programs could facilitate better planning and collaboration across programs to overcome barriers to core activities and to prepare for novel opportunities for research and prevention.