Newborn screening analytes and structural birth defects among 27,000 newborns.

BACKGROUND: Emerging evidence suggests newborn screening analytes may yield insights into the etiologies of birth defects, yet no effort has evaluated associations between a range of newborn screening analytes and birth defects. METHODS: This population-based study pooled statewide data on birth defects, birth certificates, and newborn screening analytes from Texas occurring between January 1, 2007 and December 31, 2009. Associations between a panel of thirty-six newborn screening analytes, collected by the statewide Texas Newborn Screening Program, and the presence of a birth defect, defined as at least one of 39 birth defects diagnoses recorded by the Texas Birth Defects Registry, were assessed using regression analysis. FINDINGS: Of the 27,643 births identified, 20,205 had at least one of the 39 birth defects of interest (cases) as identified by the Texas Birth Defects Registry, while 7,438 did not have a birth defect (controls). Among 1,404 analyte-birth defect associations evaluated, 377 were significant in replication analysis. Analytes most consistently associated with birth defects included the phenylalanine/tyrosine ratio (N = 29 birth defects), tyrosine (N = 28 birth defects), and thyroxine (N = 25 birth defects). Birth defects most frequently associated with a range of analytes included gastroschisis (N = 29 analytes), several cardiovascular defects (N = 26 analytes), and spina bifida (N = 23 analytes). CONCLUSIONS: Several significant and novel associations were observed between newborn screening analytes and birth defects. While some findings could be consequences of the defects themselves or to the care provided to infants with these defects, these findings could help to elucidate mechanisms underlying the etiology of some birth defects.

Classification of isolated versus multiple birth defects: An automated process for population-based registries.

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.

Gastroschisis prevalence patterns in 27 surveillance programs from 24 countries, International Clearinghouse for Birth Defects Surveillance and Research, 1980-2017.

BACKGROUND: Gastroschisis is a serious birth defect with midgut prolapse into the amniotic cavity. The objectives of this study were to evaluate the prevalence and time trends of gastroschisis among programs in the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR), focusing on regional variations and maternal age changes in the population. METHODS: We analyzed data on births from 1980 to 2017 from 27 ICBDSR member programs, representing 24 countries and three regions (Europe+ (includes Iran) , Latin America, North America). Cases were identified using diagnostic codes (i.e., 756.7, 756.71, or Q79.3). We excluded cases of amniotic band syndrome, limb-body wall defect, and ruptured omphalocele. Programs provided annual counts for gastroschisis cases (live births, stillbirths, and legally permitted pregnancy terminations for fetal anomalies) and source population (live births, stillbirths), by maternal age. RESULTS: Overall, gastroschisis occurred in 1 of every 3268 births (3.06 per 10,000 births; 95% confidence intervals [CI]: 3.01, 3.11), with marked regional variation. European+ prevalence was 1.49 (95%CI: 1.44, 1.55), Latin American 3.80 (95%CI: 3.69, 3.92) and North American 4.32 (95%CI: 4.22, 4.42). A statistically significant increasing time trend was observed among six European+ , four Latin American, and four North American programs. Women <20 years of age had the highest prevalence in all programs except the Slovak Republic. CONCLUSIONS: Gastroschisis prevalence increased over time in 61% of participating programs, and the highest increase in prevalence was observed among the youngest women. Additional inquiry will help to assess the impact of the changing maternal age proportions in the birth population on gastroschisis prevalence.

Scientific impact of the National Birth Defects Prevention Network multistate collaborative publications.

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.

An epidemiologic study of penoscrotal transposition by maternal characteristics using data from the Texas birth defects registry.

BACKGROUND: Penoscrotal transposition (PST) is an uncommon urogenital malformation in which the penis is mal-positioned to be inferior to the scrotum. The purpose of this study was to explore PST risk by maternal characteristics and to describe co-occurring congenital abnormalities in the Texas Birth Defects Registry (TBDR). METHODS: We conducted a population-based descriptive study examining occurrence of PST in the TBDR between 1999 and 2019. The primary outcome variable was PST diagnosis during infancy. Descriptive variables included maternal age, education, and race/ethnicity. Prevalence ratios (PRs) were calculated within each maternal variable category using Poisson regression. Counts and percentages of cases with select co-occurring congenital abnormalities were also calculated. RESULTS: Overall, 251 infants had PST, providing a prevalence of 0.61/10,000 live male births (95% CI: 0.53-0.68). PST prevalence was significantly lower among infants of mothers who had lower educational attainment (high school), who were younger (<25 vs. 25-34), and who were Hispanic (vs. non-Hispanic White) and was significantly higher among older mothers (35+ vs. 25-39). Hypospadias was the most common co-occurring genitourinary anomaly, affecting close to 70% of cases. CONCLUSIONS: To our knowledge, this is the first investigation exploring the prevalence of PST in a population-based birth defects registry. Our findings help to understand the risk for PST among select maternal demographic characteristics and may assist in generating hypotheses about the underlying etiology of this condition for future work.

Pediatric cancer incidence among individuals with overgrowth syndromes and overgrowth features: A population-based assessment in seven million children.

BACKGROUND: Overgrowth syndromes (e.g., Beckwith-Wiedemann) are associated with an increased risk of pediatric cancer, although there are few population-based estimates of risk. There are also limited studies describing associations between other overgrowth features (e.g., hepatosplenomegaly) and pediatric cancer. Therefore, cancer risk among children with these conditions was evaluated with data from a large, diverse population-based registry linkage study. METHODS: This study includes all live births in Texas during the years 1999-2017. Children with overgrowth features and syndromes were identified from the Texas Birth Defects Registry; children with cancer were identified by linkage to the Texas Cancer Registry. Cox regression models were used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for the association between each overgrowth syndrome/feature and cancer, which were adjusted for infant sex and maternal age. RESULTS: In the total birth cohort (n = 6,997,422), 21,207 children were identified as having an overgrowth syndrome or feature. Children with Beckwith-Wiedemann syndrome were 42 times more likely to develop pediatric cancer (95% CI, 24.20-71.83), with hepatoblastoma being the most common, followed by Wilms tumor. The presence of any isolated overgrowth feature was associated with increased cancer risk (HR, 4.70; 95% CI, 3.83-5.77); associations were strongest for hepatosplenomegaly (HR, 23.04; 95% CI, 13.37-39.69) and macroglossia (HR, 11.18; 95% CI, 6.35-19.70). CONCLUSIONS: This population-based assessment confirmed prior findings that children with either overgrowth syndromes or features were significantly more likely to develop cancer. Overall, this study supports recommendations for cancer surveillance in children with these conditions and may also inform future research into cancer etiology.

Prevalence of congenital anomalies according to maternal race and ethnicity, Texas, 1999-2018.

BACKGROUND: Few studies of congenital anomalies provide prevalence estimates stratified by maternal race/ethnicity. We sought to determine whether the prevalence of a broad spectrum of anomalies varies among offspring of women from different race/ethnic groups. METHODS: We obtained information on cases with anomalies from the population-based Texas Birth Defects Registry, and denominator data on livebirths among Texas residents during 1999-2018 from the Texas Center for Health Statistics. We estimated the prevalence ratio (PR) and 95% confidence interval (CI) of N = 145 anomalies among offspring of Hispanic and non-Hispanic Black relative to non-Hispanic White women using Poisson regression, adjusting for maternal age, education, body mass index, and previous livebirths. We performed a two-stage analysis with a Bonferroni-adjusted p < 1.7 × 10-4 in the initial screening phase to identify anomalies with statistically significant variation. RESULTS: There were 7,698,768 livebirths and 1,187,385 anomalies diagnosed in 368,393 cases. The prevalence of any monitored congenital anomaly was similar among offspring of non-Hispanic White (referent), non-Hispanic Black (PR 0.98, CI 0.96-1.00), and Hispanic (PR 0.95, CI 0.93-0.96) women. We observed statistically significant racial/ethnic variation for 42 anomalies. Marked differences were observed when comparing offspring of non-Hispanic Black to non-Hispanic White women with respect to polydactyly (PR 4.38, CI 4.07-4.72), pyloric stenosis (PR 0.34, CI 0.29-0.40), and aortic valve atresia/stenosis (PR 0.51, CI 0.36-0.72). CONCLUSIONS: Birth prevalence of many major congenital anomalies varies by maternal race and ethnicity. While the reasons for these differences are likely multifactorial, a thorough understanding of racial and ethnic disparities is useful to stimulate etiologic research.

Racial and ethnic differences in infant survival for hydrocephaly-Texas, 1999-2017.

BACKGROUND: Congenital hydrocephaly, an abnormal accumulation of fluid within the ventricular spaces at birth, can cause disability or death if untreated. Limited information is available about survival of infants born with hydrocephaly in Texas. Therefore, the purpose of the study was to calculate survival estimates among infants born with hydrocephaly without spina bifida in Texas. METHODS: A cohort of live-born infants delivered during 1999-2017 with congenital hydrocephaly without spina bifida was identified from the Texas Birth Defects Registry. Deaths within 1 year of delivery were identified using vital and medical records. One-year infant survival estimates were generated for multiple descriptive characteristics using the Kaplan-Meier method. Crude hazard ratios (HRs) for one-year survival among infants with congenital hydrocephaly by maternal and infant characteristics and adjusted HRs for maternal race and ethnicity were estimated using Cox proportional hazard models. RESULTS: Among 5709 infants born with congenital hydrocephaly without spina bifida, 4681 (82%) survived the first year. The following characteristics were associated with infant survival: maternal race and ethnicity, clinical classification (e.g., chromosomal or syndromic), preterm birth, birth weight, birth year, and maternal education. In the multivariable Cox proportional hazards model, differences in survival were observed by maternal race and ethnicity after adjustment for other maternal and infant characteristics. Infants of non-Hispanic Black (HR: 1.28, 95% CI: 1.04-1.58) and Hispanic (HR: 1.31, 95% CI: 1.12-1.54) women had increased risk for mortality, compared with infants of non-Hispanic White women. CONCLUSIONS: This study showed infant survival among a Texas cohort differed by maternal race and ethnicity, clinical classification, gestational age, birth weight, birth year, and maternal education in infants with congenital hydrocephaly without spina bifida. Findings confirm that mortality continues to be common among infants with hydrocephaly without spina bifida. Additional research is needed to identify other risk factors of mortality risk.

Survival of neonates, infants, and children with birth defects: a population-based study in Texas, 1999-2018.

Background: Birth defects are a leading cause of neonatal, infant, and childhood mortality, but recent population-based survival estimates for a spectrum in the U.S. are lacking. Methods: Using the statewide Texas Birth Defects Registry (1999-2017 births) and vital records linkage to ascertain deaths, we conducted Kaplan-Meier analyses to estimate survival probabilities at 1, 7, and 28 days, and 1, 5, and 10 years. We evaluated survival in the full cohort of infants with any major defect and for 30 specific conditions. One-year survival analyses were stratified by gestational age, birth year, and case classification. Findings: Among 246,394 live-born infants with any major defect, the estimated survival probabilities were 98.9% at 1 day, 95.0% at 1 year, and 93.9% at 10 years. Ten-year survival varied by condition, ranging from 36.9% for holoprosencephaly to 99.3% for pyloric stenosis. One-year survival was associated with increasing gestational age (e.g., increasing from 46.9% at <28 weeks to 95.8% at ≥37 weeks for spina bifida). One-year survival increased in more recent birth years for several defect categories (e.g., increasing from 86.0% among 1999-2004 births to 93.1% among 2014-2017 births for unilateral renal agenesis/dysgenesis) and was higher among infants with an isolated defect versus those with multiple defects. Interpretation: This study describes short- and long-term survival outcomes from one of the largest population-based birth defect registries in the world and highlights improved survival over time for several conditions. Our results may lend insight into future healthcare initiatives aimed at reducing mortality in this population. Funding: This study was funded in part by a Centers for Disease Control and Prevention (CDC) birth defects surveillance cooperative agreement with the Texas Department of State Health Services and Health Resources and Services Administration (HRSA) Block Grant funds.

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.

Associations between birth defects with neural crest cell origins and pediatric embryonal tumors.

BACKGROUND: There are few assessments evaluating associations between birth defects with neural crest cell developmental origins (BDNCOs) and embryonal tumors, which are characterized by undifferentiated cells having a molecular profile similar to neural crest cells. The effect of BDNCOs on embryonal tumors was estimated to explore potential shared etiologic pathways and genetic origins. METHODS: With the use of a multistate, registry-linkage cohort study, BDNCO-embryonal tumor associations were evaluated by generating hazard ratios (HRs) and 95% confidence intervals (CIs) with Cox regression models. BDNCOs consisted of ear, face, and neck defects, Hirschsprung disease, and a selection of congenital heart defects. Embryonal tumors included neuroblastoma, nephroblastoma, and hepatoblastoma. Potential HR modification (HRM) was investigated by infant sex, maternal race/ethnicity, maternal age, and maternal education. RESULTS: The risk of embryonal tumors among those with BDNCOs was 0.09% (co-occurring n = 105) compared to 0.03% (95% CI, 0.03%-0.04%) among those without a birth defect. Children with BDNCOs were 4.2 times (95% CI, 3.5-5.1 times) as likely to be diagnosed with an embryonal tumor compared to children born without a birth defect. BDNCOs were strongly associated with hepatoblastoma (HR, 16.1; 95% CI, 11.3-22.9), and the HRs for neuroblastoma (3.1; 95% CI, 2.3-4.2) and nephroblastoma (2.9; 95% CI, 1.9-4.4) were elevated. There was no notable HRM by the aforementioned factors. CONCLUSIONS: Children with BDNCOs are more likely to develop embryonal tumors compared to children without a birth defect. Disruptions of shared developmental pathways may contribute to both phenotypes, which could inform future genomic assessments and cancer surveillance strategies of these conditions.

Associations between birth defects and childhood and adolescent germ cell tumors according to sex, histologic subtype, and site.

BACKGROUND: Studies have reported increased rates of birth defects among children with germ cell tumors (GCTs). However, few studies have evaluated associations by sex, type of defect, or tumor characteristics. METHODS: Birth defect-GCT associations were evaluated among pediatric patients (N = 552) with GCTs enrolled in the Germ Cell Tumor Epidemiology Study and population-based controls (N = 6380) without cancer from the Genetic Overlap Between Anomalies and Cancer in Kids Study. The odds ratio (OR) and 95% confidence interval (CI) of GCTs according to birth defects status were estimated by using unconditional logistic regression. All defects were considered collectively and by genetic and chromosomal syndromes and nonsyndromic defects. Stratification was by sex, tumor histology (yolk sac tumor, teratoma, germinoma, and mixed/other), and location (gonadal, extragonadal, and intracranial). RESULTS: Birth defects and syndromic defects were more common among GCT cases than controls (6.9% vs. 4.0% and 2.7% vs. 0.2%, respectively; both p < .001). In multivariable models, GCT risk was increased among children with birth defects (OR, 1.7; 95% CI, 1.3-2.4) and syndromic defects (OR, 10.4; 95% CI, 4.9-22.1). When stratified by tumor characteristics, birth defects were associated with yolk sac tumors (OR, 2.7; 95% CI, 1.3-5.0) and mixed/other histologies (OR, 2.1; 95% CI, 1.2-3.5) and both gonadal tumors (OR, 1.7; 95% CI, 1.0-2.7) and extragonadal tumors (OR, 3.8; 95% CI, 2.1-6.5). Nonsyndromic defects specifically were not associated with GCTs. In sex-stratified analyses, associations were observed among males but not females. CONCLUSIONS: These data suggest that males with syndromic birth defects are at an increased risk of pediatric GCTs, whereas males with nonsyndromic defects and females are not at an increased risk. PLAIN LANGUAGE SUMMARY: We investigated whether birth defects (such as congenital heart disease or Down syndrome) are linked to childhood germ cell tumors (GCTs), cancers that mainly develop in the ovaries or testes. We studied different types of birth defects (defects that were caused by chromosome changes such as Down syndrome or Klinefelter syndrome and defects that were not) and different types of GCTs. Only chromosome changes such as Down syndrome or Klinefelter syndrome were linked to GCTs. Our study suggests that most children with birth defects are not at an increased risk of GCTs because most birth defects are not caused by chromosome changes.

Exome-wide assessment of isolated biliary atresia: A report from the National Birth Defects Prevention Study using child-parent trios and a case-control design to identify novel rare variants.

The etiology of biliary atresia (BA) is unknown, but recent studies suggest a role for rare protein-altering variants (PAVs). Exome sequencing data from the National Birth Defects Prevention Study on 54 child-parent trios, one child-mother duo, and 1513 parents of children with other birth defects were analyzed. Most (91%) cases were isolated BA. We performed (1) a trio-based analysis to identify rare de novo, homozygous, and compound heterozygous PAVs and (2) a case-control analysis using a sequence kernel-based association test to identify genes enriched with rare PAVs. While we replicated previous findings on PKD1L1, our results do not suggest that recurrent de novo PAVs play important roles in BA susceptibility. In fact, our finding in NOTCH2, a disease gene associated with Alagille syndrome, highlights the difficulty in BA diagnosis. Notably, IFRD2 has been implicated in other gastrointestinal conditions and warrants additional study. Overall, our findings strengthen the hypothesis that the etiology of BA is complex.

Evaluating the proportion of isolated cases among a spectrum of birth defects in a population-based registry.

INTRODUCTION: Because the etiology and outcomes of birth defects may differ by the presence vs. absence of co-occurring anomalies, epidemiologic studies often attempt to classify cases into isolated versus non-isolated groupings. This report describes a computer algorithm for such classification and presents results using data from the Texas Birth Defects Registry (TBDR). METHODS: Each of the 1,041 birth defects coded by the TBDR was classified as chromosomal, syndromic, minor, or "needs review" by a group of three clinical geneticists. A SAS program applied those classifications to each birth defect in a case (child/fetus), and then hierarchically combined them to obtain one summary classification for each case, adding isolated and multiple defect categories. The program was applied to 136,121 cases delivered in 2012-2017. RESULTS: Of total cases, 49% were classified by the platform as isolated (having only one major birth defect). This varied widely by birth defect; of those examined, the highest proportion classified as isolated was found in pyloric stenosis (87.6%), whereas several cardiovascular malformations had low proportions, including tricuspid valve atresia/stenosis (2.3%). DISCUSSION: This is one of the first and largest attempts to identify the proportion of isolated cases across a broad spectrum of birth defects, which can inform future epidemiologic and genomic studies of these phenotypes. Our approach is designed for easy modification for use with any birth defects coding system and category definitions, allowing scalability for different studies or birth defects registries, which often do not have resources for individual clinical review of all case records.

Epidemiology of Nonsyndromic, Orofacial Clefts in Texas: Differences by Cleft Type and Presence of Additional Defects.

To describe the current epidemiology of nonsyndromic cleft palate alone (CP) and cleft lip with or without cleft palate (CL ± P) in Texas and examine differences in the characteristics of infants with CP and CL ± P based on the presence/absence of additional defects.We used data from the Texas Birth Defects Registry, a statewide active birth defect surveillance system, from 1815 cases with CP and 5066 with CL ± P, without a syndrome diagnosis (1999-2014 deliveries). All live births in Texas were used for comparison. Poisson regression was used to calculate crude and adjusted prevalence ratios (aPR) for each characteristic, separately for each cleft subphenotype.The prevalence of CL ± P and CP in our study was estimated as 8.3 and 3.0 per 10 000 live births, respectively. After adjusting for several characteristics, several factors were associated with CL ± P, CP, or both, including infant sex and maternal race/ethnicity, age, smoking, and diabetes. There were several differences between infants with isolated versus nonisolated clefts. For example, maternal prepregnancy diabetes was associated with an increased prevalence of CL ± P (aPR 7.91, 95% confidence interval [CI]: 5.53, 11.30) and CP (aPR 3.24, 95% CI: 1.43, 7.36), but only when additional defects were present.Findings from this study provide a contemporary description of the distribution of orofacial clefts in Texas accounting for differences between isolated and nonisolated clefts. They may contribute to increasing our understanding of the etiology of CP and CL ± P.

Prevalence and mortality among children with anorectal malformation: A multi-country analysis.

PURPOSE: We examined the total prevalence, trends in prevalence, and age-specific mortality among individuals with anorectal malformation (ARM) METHODS: We conducted a retrospective cohort study using data from 24 population- and hospital-based birth defects surveillance programs affiliated with the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR) from 18 countries and for births from 1974 to 2014. We estimated pooled and program-specific total prevalence per 10,000 total births. Poisson regression was used to assess time trends in prevalence from 2001 to 2012 when most programs contributed data. We calculated selected age-specific proportions of deaths, stratified by case status RESULTS: The pooled total prevalence of ARM was 3.26 per 10,000 total births (95% Confidence Interval = 3.19, 3.32) for birth years 1974-2014. About 60% of cases were multiple or syndromic. Prevalence of multiple, syndromic, and stillborn cases decreased from 2001 to 2012. The first week mortality proportion was 12.5%, 3.2%, 28.3%, and 18.2% among all, isolated, multiple, and syndromic cases, respectively CONCLUSIONS: ARM is relatively rare, with multiple and syndromic cases showing decreasing prevalence during the study period. Mortality is a concern during the first week of life, and especially among multiple and syndromic cases. Our descriptive epidemiological findings increase our understanding of geographic variation in the prevalence of ARM and can be used to plan needed clinical services. Exploring factors influencing prevalence and mortality among individuals with ARM could inform future studies.

Patterns of co-occurring birth defects in children with anotia and microtia.

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.

Factors associated with nonsyndromic anotia and microtia, Texas, 1999-2014.

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.

Connecting children with birth defects to health and social service programs: A collaboration between the Texas Birth Defects Registry and agency social workers.

BACKGROUND: Timely referral to services for children born with birth defects can improve health outcomes. Birth defects surveillance registries may be a valuable data source for connecting children to health and social service programs. METHODS: Population-based, state-wide data from the Texas Birth Defects Registry (TBDR) at the Texas Department of State Health Services (DSHS) were used to connect children 9-18 months old, born with select birth defects with DSHS social workers. The social workers reviewed developmental milestones and referred children and their families to various health and social service programs. We tabulated the proportions of children meeting milestones and referral characteristics by referral program type and type of birth defect. RESULTS: Social workers reached 67% (909/1,362) of identified families. Over half of children (54%, 488/909) were not meeting the developmental milestones for their age. Social workers provided over 3,000 program referrals, including referring 21% (194/909) of children to Early Childhood Intervention (ECI) and 28% (257/909) to case management. CONCLUSION: Our results illustrate a method of leveraging a birth defects surveillance system for referral services. Given the large number of referrals made, our findings suggest that birth defects registries can be a valuable source of data for referring children to programs.

Identifying syndromes in studies of structural birth defects: Guidance on classification and evaluation of potential impact.

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.