Prevalence and descriptive epidemiology of choanal atresia and stenosis in Texas, 1999-2018.

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.

Contribution of Preterm Birth to Mortality Among Neonates with Birth Defects.

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.

Trisomy 13 and 18-Prevalence and mortality-A multi-registry population based analysis.

The aim of the study is to determine the prevalence, outcomes, and survival (among live births [LB]), in pregnancies diagnosed with trisomy 13 (T13) and 18 (T18), by congenital anomaly register and region. Twenty-four population- and hospital-based birth defects surveillance registers from 18 countries, contributed data on T13 and T18 between 1974 and 2014 using a common data-reporting protocol. The mean total birth prevalence (i.e., LB, stillbirths, and elective termination of pregnancy for fetal anomalies [ETOPFA]) in the registers with ETOPFA (n = 15) for T13 was 1.68 (95% CI 1.3-2.06), and for T18 was 4.08 (95% CI 3.01-5.15), per 10,000 births. The prevalence varied among the various registers. The mean prevalence among LB in all registers for T13 was 0.55 (95%CI 0.38-0.72), and for T18 was 1.07 (95% CI 0.77-1.38), per 10,000 births. The median mortality in the first week of life was 48% for T13 and 42% for T18, across all registers, half of which occurred on the first day of life. Across 16 registers with complete 1-year follow-up, mortality in first year of life was 87% for T13 and 88% for T18. This study provides an international perspective on prevalence and mortality of T13 and T18. Overall outcomes and survival among LB were poor with about half of live born infants not surviving first week of life; nevertheless about 10% survived the first year of life. Prevalence and outcomes varied by country and termination policies. The study highlights the variation in screening, data collection, and reporting practices for these conditions.

Original Findings and Updated Meta-Analysis for the Association Between Maternal Diabetes and Risk for Congenital Heart Disease Phenotypes.

Maternal diabetes is associated with congenital heart defects (CHDs) as a group, but few studies have assessed risk for specific CHD phenotypes. We analyzed these relationships using data from the Texas Birth Defects Registry and statewide vital records for deliveries taking place in 1999-2009 (n = 48,249 cases). We used Poisson regression to calculate prevalence ratios for the associations between maternal diabetes (pregestational or gestational) and each CHD phenotype, adjusting for potential confounders. Analyses were repeated by type of diabetes. To address the potential for misclassification bias, we performed logistic regression, using malformed controls. We also conducted meta-analyses, combining our estimates of the association between pregestational diabetes and each CHD phenotype with previous estimates. The prevalence of every CHD phenotype was greater among women with pregestational diabetes than among nondiabetic women. Most of these differences were statistically significant (adjusted prevalence ratios = 2.47-13.20). Associations were slightly attenuated for many CHD phenotypes among women with gestational diabetes. The observed associations did not appear to be the result of misclassification bias. In our meta-analysis, pregestational diabetes was significantly associated with each CHD phenotype. These findings contribute to a better understanding of the teratogenic effects of maternal diabetes and improved counseling for risk of specific CHD phenotypes.

Increasing Prevalence of Gastroschisis--14 States, 1995-2012.

Gastroschisis is a serious congenital defect in which the intestines protrude through an opening in the abdominal wall. Gastroschisis requires surgical repair soon after birth and is associated with an increased risk for medical complications and mortality during infancy. Reports from multiple surveillance systems worldwide have documented increasing prevalence of gastroschisis since the 1980s, particularly among younger mothers; however, since publication of a multistate U.S. report that included data through 2005, it is not known whether prevalence has continued to increase. Data on gastroschisis from 14 population-based state surveillance programs were pooled and analyzed to assess the average annual percent change (AAPC) in prevalence and to compare the prevalence during 2006-2012 with that during 1995-2005, stratified by maternal age and race/ethnicity. The pooled data included approximately 29% of U.S. births for the period 1995-2012. During 1995-2012, gastroschisis prevalence increased in every category of maternal age and race/ethnicity, and the AAPC ranged from 3.1% in non-Hispanic white (white) mothers aged <20 years to 7.9% in non-Hispanic black (black) mothers aged <20 years. These corresponded to overall percentage increases during 1995-2012 that ranged from 68% in white mothers aged <20 years to 263% in black mothers aged <20 years. Gastroschisis prevalence increased 30% between the two periods, from 3.6 per 10,000 births during 1995-2005 to 4.9 per 10,000 births during 2006-2012 (prevalence ratio = 1.3, 95% confidence interval [CI]: 1.3-1.4), with the largest increase among black mothers aged <20 years (prevalence ratio = 2.0, 95% CI: 1.6-2.5). Public health research is urgently needed to identify factors contributing to this increase.

Racial disparities in heterotaxy syndrome.

BACKGROUND: Heterotaxy syndrome (HTX) is a constellation of defects including abnormal organ lateralization and often including congenital heart defects. HTX has widely divergent population-based estimates of prevalence, racial and ethnic predominance, and mortality in current literature. METHODS: The objective of this study was to use a population-based registry to investigate potential racial and ethnic disparities in HTX. Using the Texas Birth Defects Registry, we described clinical features and mortality of HTX among infants delivered from 1999 to 2006. We calculated birth prevalence and crude prevalence (cPR) ratios for infant sex, maternal diabetes, and sociodemographic factors. RESULTS: A total of 353 HTX cases were identified from 2,993,604 births (prevalence ratio = 1.18 per 10,000 live births. HTX prevalence was approximately 70% higher among infants of Hispanic and non-Hispanic black mothers and 28% higher among female infants (cPR = 1.28; 95% confidence interval,1.04-1.59). There was a twofold higher female preponderance for infants of mothers who were non-Hispanic white or black. Mothers with diabetes were three times more likely to have a child with HTX compared with nondiabetics (cPR = 3.13; 95% confidence interval, 2.12-4.45). Among nondiabetics, HTX cases were 86% more likely to have a Hispanic mother and 72% a non-Hispanic black mother. First-year mortality for live born children with HTX was 30.9%. CONCLUSION: This study represents one of the largest population-based studies of HTX to date, with a novel finding of higher rates of HTX among Hispanic infants of mostly Mexican origin, as well as among female infants of only non-Hispanic white and black mothers. These findings warrant further investigation.

The association between race/ethnicity and major birth defects in the United States, 1999-2007.

OBJECTIVES: We investigated the relationship between race/ethnicity and 27 major birth defects. METHODS: We pooled data from 12 population-based birth defects surveillance systems in the United States that included 13.5 million live births (1 of 3 of US births) from 1999 to 2007. Using Poisson regression, we calculated prevalence estimates for each birth defect and 13 racial/ethnic groupings, along with crude and adjusted prevalence ratios (aPRs). Non-Hispanic Whites served as the referent group. RESULTS: American Indians/Alaska Natives had a significantly higher and 50% or greater prevalence for 7 conditions (aPR = 3.97; 95% confidence interval [CI] = 2.89, 5.44 for anotia or microtia); aPRs of 1.5 to 2.1 for cleft lip, trisomy 18, and encephalocele, and lower, upper, and any limb deficiency). Cubans and Asians, especially Chinese and Asian Indians, had either significantly lower or similar prevalences of these defects compared with non-Hispanic Whites, with the exception of anotia or microtia among Chinese (aPR = 2.08; 95% CI = 1.30, 3.33) and Filipinos (aPR = 1.90; 95% CI = 1.10, 3.30) and tetralogy of Fallot among Vietnamese (aPR = 1.60; 95% CI = 1.11, 2.32). CONCLUSIONS: This is the largest population-based study to our knowledge to systematically examine the prevalence of a range of major birth defects across many racial/ethnic groups, including Asian and Hispanic subgroups. The relatively high prevalence of birth defects in American Indians/Alaska Natives warrants further attention.

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.

Body mass index and birth defects: Texas, 2005-2008.

Texas ranks 12th nationally in the proportion of adult residents who are obese; approximately 67 % of Texans are overweight or obese. Studies indicate that obesity is related to an increased risk for birth defects; however, small sample sizes have limited the scope of birth defects investigated, and only four levels of body mass index (BMI) are typically explored. Using six BMI levels, we evaluated the association between maternal BMI and birth defects in a population-based registry covering ~1.6 million births. Texas birth defect cases were linked to 2005-2008 vital records. Maternal BMI was calculated using self-reported prepregnancy weight and height from the vital record and categorized as follows: underweight (BMI <18.5), normal weight (BMI 18.5-24.9), overweight (BMI 25-29.9), class I obese (BMI 30-34.9), class II obese (BMI 35-39.9) and class III obese (BMI ≥40). Prevalence ratios for specific birth defects for maternal BMI categories were estimated by using normal weight as the referent, adjusted for maternal age and race/ethnicity, and stratified by maternal diabetes status. Risk for certain birth defects increased with increasing BMI (i.e., atrial and ventricular septal defects, pulmonary valve atresia, patent ductus arteriosus, and clubfoot). Risk for birth defects was substantially increased among some obese mothers (BMI ≥30) (e.g., spina bifida, tetralogy of Fallot, cleft lip with or without cleft palate, hypospadias, and epispadias). Conversely, mothers with higher BMI had a lower risk for having an infant or fetus with gastroschisis (aPR = 0.35; 95 % CI = 0.12, 0.80). Given the increased risk for birth defects associated with obesity, preconception counseling should emphasize the importance of maintaining normal weight.

Survival of infants and children born with severe microcephaly, Texas, 1999-2015.

BACKGROUND: Severe microcephaly is a brain reduction defect where the delivery head circumference is <3rd percentile for gestational age and sex with subsequent lifelong morbidities. Our objective was to evaluate survival among 2,704 Texas infants with severe microcephaly delivered 1999-2015. METHODS: Infants with severe microcephaly from the Texas Birth Defects Registry were linked to death certificates and the national death index. Survival estimates, hazard ratios (HR) and confidence intervals (CI) were calculated using the Kaplan-Meier method and Cox proportional hazards models stratified by presence versus absence of co-occurring defects. RESULTS: We identified 496 deaths by age 4 years; most (42.9%) occurred in the neonatal period, and another 39.9% died by 1 year of age. Overall infant survival was 84.8%. Lowest infant survival subgroups included those with chromosomal/syndromic conditions (66.1%), very preterm deliveries (63.9%), or co-occurring critical congenital heart defects (44.0%). Among infants with severe microcephaly and a chromosomal/syndromic co-occurring defect, the risk of death was nearly three-fold higher among those with: proportionate microcephaly (i.e., small baby overall), relative to non-proportionate (HR = 2.84, 95% CI = 2.17-3.71); low-birthweight relative to normal (HR = 2.72, 95% CI = 1.92-3.85); critical congenital heart defects (CCHD) relative to no CCHD (HR = 2.90, 95% CI = 2.20-3.80). Trisomies were a leading underlying cause of death (27.5%). CONCLUSIONS: Overall, infants with severe microcephaly had high 4-year survival rates which varied by the presence of co-occurring defects. Infants with co-occurring chromosomal/syndromic anomalies have a higher risk of death by age one than those without any co-occurring birth defects.

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.

Predictors of trisomy 21 in the offspring of older and younger women.

BACKGROUND: Advanced maternal age is the only well-established risk factor for trisomy 21, yet the majority of affected individuals are born to younger women. To identify factors associated with the risk of trisomy 21 in the offspring of younger and older women, we analyzed data for cases with trisomy 21 from the Texas Birth Defects Registry for 1999 to 2007. METHODS: Data were analyzed separately for younger (i.e., <35 years of age at delivery; n = 2306) and older (i.e., ≥ 35 years of age at delivery; n = 1811) women using Poisson regression. RESULTS: After adjustment for maternal age and several other covariates, the prevalence of trisomy 21 in the offspring of women in both maternal age groups was higher in male than in female infants and in offspring of women who were Hispanic (compared with non-Hispanic white women) or who had at least one previous liveborn child compared to those with none. In the offspring of older women only, the prevalence of trisomy 21 was also significantly higher when the father was 20 to 24 years old (compared with 25 to 29 years old; adjusted prevalence ratio [aPR], 2.27; 95% confidence interval [CI], 1.47-3.49) and Hispanic (compared with non-Hispanic white; aPR, 1.34; 95% CI, 1.13-1.58) and among women with less than a high school education (compared with greater than high school). CONCLUSIONS: This study identified several factors, in addition to maternal age, that were associated with trisomy 21 risk. In general, these factors were similar for both maternal age groups, although paternal characteristics were significantly associated with risk of trisomy 21 only in offspring of older women.

The association between neonatal thyroxine and craniosynostosis, Texas, 2004-2007.

BACKGROUND: Craniosynostosis (CS), a structural anomaly characterized by premature fusion of cranial sutures, occurs in 1 in 2000 live births. Associations of CS with the thyroid have been reported. Neonatal thyroid hormone (T4) is evaluated nationally at birth by the Newborn Screening Program (NBS). This study evaluated the relationship between NBS T4 levels and craniosynostosis. METHODS: Live-born singleton babies born in 2004 through 2007 were identified through the Texas Birth Defects Registry (499 cases) and Texas Bureau of Vital Statistics (3570 controls) and successfully linked to analyte data available in the Texas NBS Database. Cases were classified based on the absence of other major defects (isolated cases, n = 382) and suture(s) involved. Mean T4 levels were compared between controls and cases (overall and stratified by classification). T4 levels were stratified by quintiles to evaluate differences between cases and controls within quintiles. The diagnostic utility of NBS T4 was evaluated using receiver operator characteristic (ROC) curves. RESULTS: Mean T4 levels were lower in isolated cases (16.89 µg/dl) than in controls (17.77 µg/dl; p = 0.0004). This trend persisted for sagittal (16.69 µg/dl; p = 0.002) and metopic (16.83 µg/dl; p = 0.042) CS. When stratified by quintiles, 54% of isolated lambdoid CS were in the first quintile compared to controls (p = 0.012). ROC area under the curve (AUC) was approximately 0.55 for all classifications except lambdoid (AUC = 0.73). CONCLUSION: NBS T4 levels were slightly lower among cases with nearly half of all lambdoid CS having T4 levels in the lowest quintile. However, overall NBS T4 levels are not suitable for potential screening or diagnostic application.

Association between thyroxine levels at birth and choanal atresia or stenosis among infants in Texas, 2004-2007.

BACKGROUND: The causes of choanal atresia or stenosis (CA) are largely unknown. Infant thyroxine (T(4) ) levels collected during newborn screening may be proxy measures for a risk factor present during the critical period of development. Therefore, we conducted a case-control study to examine the association between newborn T(4) levels and CA. METHODS: Data for cases with CA and controls were obtained from the Texas Birth Defects Registry for the period of 2004 to 2007. Information on infant T(4) levels at birth was obtained from the Texas Newborn Screening Program. Controls (n = 3570) were drawn from unaffected births in Texas for the same period and frequency matched to cases (n = 69) on year of birth, then linked to the newborn screening database. Logistic regression was used to evaluate the association between continuous and categorical infant T(4) levels and nonsyndromic CA. RESULTS: After adjustment for gestational age and year of birth, infant T(4) levels were inversely associated with CA (adjusted odds ratio [AOR], 0.85; 95% confidence interval [CI], 0.80-0.90). We observed a linear trend (p < 0.001) across quartiles of T(4) ; compared to infants with low levels, AORs for CA were 0.50 (95% CI, 0.28-0.91), 0.39 (95% CI, 0.20-0.75), and 0.15 (95% CI, 0.06-0.40) for infants with medium-to-low, medium, and high levels, respectively. CONCLUSIONS: Our findings suggest a role of low thyroid hormone levels in the development of CA, or that low newborn T(4) levels are potential proxy measures of a risk factor present during the critical period. Birth Defects Research (Part A), 2012.

Descriptive epidemiology of non-syndromic complete atrioventricular canal defects.

BACKGROUND: Complete atrioventricular canal defects (CAVC) are a common heart defect, but few epidemiologic studies have evaluated non-syndromic CAVC. Risk factors for non-syndromic CAVC have not been well established. METHODS: To assess the relationship between risk for non-syndromic CAVC in offspring and several sociodemographic and reproductive parental factors, including maternal diabetes and obesity, we conducted Poisson regression analyses, using data ascertained through the Texas Birth Defects Registry, a large, population-based birth defects registry. Data were evaluated for 563 non-syndromic cases with CAVC. RESULTS: Significant associations were observed between non-syndromic CAVC in offspring and maternal pregestational diabetes (adjusted prevalence ratio (aPR) 6.74; 95% confidence interval (CI) 3.67, 12.37), gestational diabetes (aPR 1.69; 95% CI 1.03, 2.79) and obesity (aPR 1.69; 95% CI 1.24, 2.30). CONCLUSIONS: Our findings add non-syndromic CAVC to the growing list of birth defects that appear to be associated with maternal diabetes and obesity.

Prevalence and Clustering of Congenital Heart Defects Among Boys With Hypospadias.

Importance: Hypospadias is a common birth defect of the male urinary tract that may be isolated or may co-occur with other structural malformations, including congenital heart defects (CHDs). The risk for co-occurring CHDs among boys with hypospadias remains unknown, which limits screening and genetic testing strategies. Objective: To characterize the risk of major CHDs among boys born with hypospadias. Design, Setting, and Participants: This retrospective cohort study used data from population-based birth defect surveillance programs on all male infants born in 11 US states from January 1, 1995, to December 31, 2014. Statistical analysis was performed from September 2, 2020, to March 25, 2022. Exposure: Hypospadias. Main Outcomes and Measures: Demographic and diagnostic data were obtained from 2 active state-based birth defect surveillance programs for primary analyses, the Texas Birth Defects Registry and the Arkansas Reproductive Health Monitoring System, with validation among 9 additional states in the National Birth Defects Prevention Network (NBDPN). Birth defect diagnoses were identified using the British Pediatric Association coding for hypospadias (exposure) and major CHDs (primary outcomes). Maternal covariates and birth year were also abstracted from the vital records. Poisson regression was used to estimate adjusted prevalence ratios and 95% CIs for major CHDs within Texas and Arkansas and combined using inverse variance-weighted meta-analysis. Findings were validated using the NBDPN. Results: Among 3.7 million pregnancies in Texas and Arkansas, 1485 boys had hypospadias and a co-occurring CHD. Boys with hypospadias were 5.8 times (95% CI, 5.5-6.1) more likely to have a co-occurring CHD compared with boys without hypospadias. Associations were observed for every specific CHD analyzed among boys with hypospadias, occurred outside of chromosomal anomalies, and were validated in the NBDPN. An estimated 7.024% (95% CI, 7.020%-7.028%) of boys with hypospadias in Texas and 5.503% (95% CI, 5.495%-5.511%) of boys with hypospadias in Arkansas have a co-occurring CHD. In addition, hypospadias severity and maternal race and ethnicity were independently associated with the likelihood for hypospadias to co-occur with a CHD; boys in Texas with third-degree (ie, more severe) hypospadias were 2.7 times (95% CI, 2.2-3.4) more likely than boys with first-degree hypospadias to have a co-occurring CHD, with consistent estimates in Arkansas (odds ratio, 2.7; 95% CI, 1.4-5.3), and boys with hypospadias born to Hispanic mothers in Texas were 1.5 times (95% CI, 1.3-1.8) more likely to have a co-occurring CHD than boys with hypospadias born to non-Hispanic White mothers. Conclusions and Relevance: In this cohort study, boys with hypospadias had a higher prevalence of CHDs than boys without hypospadias. These findings support the need for consideration of additional CHD screening programs for boys born with hypospadias.

Conjoined twins: a worldwide collaborative epidemiological study of the International Clearinghouse for Birth Defects Surveillance and Research.

Conjoined twins (CT) are a very rare developmental accident of uncertain etiology. Prevalence has been previously estimated to be 1 in 50,000 to 1 in 100,000 births. The process by which monozygotic twins do not fully separate but form CT is not well understood. The purpose of the present study was to analyze diverse epidemiological aspects of CT, including the different variables listed in the Introduction Section of this issue of the Journal. The study was made possible using the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR) structure. This multicenter worldwide research includes the largest sample of CT ever studied. A total of 383 carefully reviewed sets of CT obtained from 26,138,837 births reported by 21 Clearinghouse Surveillance Programs (SP) were included in the analysis. Total prevalence was 1.47 per 100,000 births (95% CI: 1.32-1.62). Salient findings including an evident variation in prevalence among SPs: a marked variation in the type of pregnancy outcome, a similarity in the proportion of CT types among programs: a significant female predominance in CT: particularly of the thoracopagus type and a significant male predominance in parapagus and parasitic types: significant differences in prevalence by ethnicity and an apparent increasing prevalence trend in South American countries. No genetic, environmental or demographic significant associated factors were identified. Further work in epidemiology and molecular research is necessary to understand the etiology and pathogenesis involved in the development of this fascinating phenomenon of nature.

Sirenomelia: an epidemiologic study in a large dataset from the International Clearinghouse of Birth Defects Surveillance and Research, and literature review.

Sirenomelia is a very rare limb anomaly in which the normally paired lower limbs are replaced by a single midline limb. This study describes the prevalence, associated malformations, and maternal characteristics among cases with sirenomelia. Data originated from 19 birth defect surveillance system members of the International Clearinghouse for Birth Defects Surveillance and Research, and were reported according to a single pre-established protocol. Cases were clinically evaluated locally and reviewed centrally. A total of 249 cases with sirenomelia were identified among 25,290,172 births, for a prevalence of 0.98 per 100,000, with higher prevalence in the Mexican registry. An increase of sirenomelia prevalence with maternal age less than 20 years was statistically significant. The proportion of twinning was 9%, higher than the 1% expected. Sex was ambiguous in 47% of cases, and no different from expectation in the rest. The proportion of cases born alive, premature, and weighting less than 2,500 g were 47%, 71.2%, and 88.2%, respectively. Half of the cases with sirenomelia also presented with genital, large bowel, and urinary defects. About 10-15% of the cases had lower spinal column defects, single or anomalous umbilical artery, upper limb, cardiac, and central nervous system defects. There was a greater than expected association of sirenomelia with other very rare defects such as bladder exstrophy, cyclopia/holoprosencephaly, and acardia-acephalus. The application of the new biological network analysis approach, including molecular results, to these associated very rare diseases is suggested for future studies.

Bladder exstrophy: an epidemiologic study from the International Clearinghouse for Birth Defects Surveillance and Research, and an overview of the literature.

Bladder exstrophy (BE) is a complex congenital anomaly characterized by a defect in the closure of the lower abdominal wall and bladder. We aimed to provide an overview of the literature and conduct an epidemiologic study to describe the prevalence, and maternal and case characteristics of BE. We used data from 22 participating member programs of the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR). All cases were reviewed and classified as isolated, syndrome, and multiple congenital anomalies. We estimated the total prevalence of BE and calculated the frequency and odds ratios for various maternal and case characteristics. A total of 546 cases with BE were identified among 26,355,094 births. The total prevalence of BE was 2.07 per 100,000 births (95% CI: 1.90-2.25) and varied between 0.52 and 4.63 among surveillance programs participating in the study. BE was nearly twice as common among male as among female cases. The proportion of isolated cases was 71%. Prevalence appeared to increase with increasing categories of maternal age, particularly among isolated cases. The total prevalence of BE showed some variations by geographical region, which is most likely attributable to differences in registration of cases. The higher total prevalence among male cases and older mothers, especially among isolated cases, warrants further attention.

Acardia: epidemiologic findings and literature review from the International Clearinghouse for Birth Defects Surveillance and Research.

Acardia is a severe, complex malformation of monozygotic twinning, but beyond clinical case series, very few epidemiologic data are available. The goals of this study were to assess the epidemiologic characteristics of acardia from birth defect registries in the International Clearinghouse for Birth Defects Surveillance and Research (Clearinghouse), and compare these findings to current literature. The study included 17 surveillance programs of the Clearinghouse representing 23 countries from North and South America, Europe, China, and Australia. Anonymized individual records with clinical and demographic data were reviewed centrally by clinical geneticists. A literature search was performed. A total of 164 cases of acardia were reported from an underlying cohort of 21.2 million births. Of these, 23% were elective pregnancy terminations. Rates did not vary significantly by maternal age. For many cases, information on pregnancy exposures and genetic testing was missing. However, these limited data did not suggest high rates of chronic illnesses (diabetes, seizure disorders) or lifestyle factors such as smoking. One case had trisomy 13. Major malformations were reported in 2.4% of co-twins. With some basic assumptions, the total prevalence of acardia was estimated at 1 in 50,000-70,000 births, and 1 in 200-280 monozygotic twins. In summary, acardia is a dramatic, probably underreported, and incompletely understood malformation. Studies on its epidemiology and etiology are challenging and still rare. An international collaboration of epidemiologists, clinicians, and geneticists is necessary to understand the etiology, pathogenesis, and occurrence of this severe malformation complex.