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BACKGROUND Both short and long interpregnancy intervals (IPIs) have been associated with adverse birth outcomes. We undertook a multistate study to describe the prevalence of selected birth defects by IPI. METHODS We obtained data from nine population-based state birth defects registries for singleton live births in 2000-2009 among mothers with a previous live birth identified through birth certificates. IPI was calculated as the difference between prior birthdate and start of the current pregnancy (conception date). We estimated prevalence of selected defects per 10,000 live births and prevalence ratios (PRs) with 95% confidence intervals (CIs) overall and stratified by maternal age at previous birth and race/ethnicity. Primary analyses focused on short IPI

STUDY QUESTION Is there an association between fertility status, method of conception and the risks of birth defects and childhood cancer? SUMMARY ANSWER The risk of childhood cancer had two independent components: (i) method of conception and (ii) presence, type and number of birth defects. WHAT IS KNOWN ALREADY The rarity of the co-occurrence of birth defects, cancer and ART makes studying their association challenging. Prior studies have indicated that infertility and ART are associated with an increased risk of birth defects or cancer but have been limited by small sample size and inadequate statistical power, failure to adjust for or include plurality, differences in definitions and/or methods of ascertainment, lack of information on ART treatment parameters or study periods spanning decades resulting in a substantial historical bias as ART techniques have improved. STUDY DESIGN, SIZE, DURATION This was a population-based cohort study linking ART cycles reported to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) from 1 January 2004 to 31 December 2017 that resulted in live births in 2004–2018 in Massachusetts and North Carolina and live births in 2004–2017 in Texas and New York. A 10:1 sample of non-ART births were chosen within the same time period as the ART birth. Non-ART siblings were identified through the ART mother’s information. Children from non-ART births were classified as being born to women who conceived with ovulation induction or IUI (OI/IUI) when there was an indication of infertility treatment on the birth certificate, and the woman did not link to the SART CORS; all others were classified as being naturally conceived. PARTICIPANTS/MATERIALS, SETTING, METHODS The study population included 165 125 ART children, 31 524 non-ART siblings, 12 451 children born to OI/IUI-treated women and 1 353 440 naturally conceived children. All study children were linked to their respective State birth defect registries to identify major defects diagnosed within the first year of life. We classified children with major defects as either chromosomal (i.e. presence of a chromosomal defect with or without any other major defect) or nonchromosomal (i.e. presence of a major defect but having no chromosomal defect), or all major defects (chromosomal and nonchromosomal), and calculated rates per 1000 children. Logistic regression models were used to generate adjusted odds ratios (AORs) and 95% CIs of the risk of birth defects by conception group (OI/IUI, non-ART sibling and ART by oocyte source and embryo state) with naturally conceived children as the reference, adjusted for paternal and maternal ages; maternal race and ethnicity, education, BMI, parity, diabetes, hypertension; and for plurality, infant sex and State and year of birth. All study children were also linked to their respective State cancer registries. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% CIs of cancer by birth defect status (including presence of a defect, type and number of defects), and conception group. MAIN RESULTS AND THE ROLE OF CHANCE A total of 29 571 singleton children (2.0%) and 3753 twin children (3.5%) had a major birth defect (chromosomal or nonchromosomal). Children conceived with ART from autologous oocytes had increased risks for nonchromosomal defects, including blastogenesis, cardiovascular, gastrointestinal and, for males only, genitourinary defects, with AORs ranging from 1.22 to 1.85; children in the autologous-fresh group also had increased risks for musculoskeletal (AOR 1.28, 95% CI 1.13, 1.45) and orofacial defects (AOR 1.40, 95% CI 1.17, 1.68). Within the donor oocyte group, the children conceived from fresh embryos did not have increased risks in any birth defect category, whereas children conceived from thawed embryos had increased risks for nonchromosomal defects (AOR 1.20, 95% CI 1.03, 1.40) and blastogenesis defects (AOR 1.74, 95% CI 1.14, 2.65). The risk of cancer was increased among ART children in the autologous-fresh group (HR 1.31, 95% CI 1.08, 1.59) and non-ART siblings (1.34, 95% CI 1.02, 1.76). The risk of leukemia was increased among children in the OI/IUI group (HR 2.15, 95% CI 1.04, 4.47) and non-ART siblings (HR 1.63, 95% CI 1.02, 2.61). The risk of central nervous system tumors was increased among ART children in the autologous-fresh group (HR 1.68, 95% CI 1.14, 2.48), donor-fresh group (HR 2.57, 95% CI 1.04, 6.32) and non-ART siblings (HR 1.84, 95% CI 1.12, 3.03). ART children in the autologous-fresh group were also at increased risk for solid tumors (HR 1.39, 95% CI 1.09, 1.77). A total of 127 children had both major birth defects and cancer, of which 53 children (42%) had leukemia. The risk of cancer had two independent components: (i) method of conception (described above) and (ii) presence, type and number of birth defects. The presence of nonchromosomal defects increased the cancer risk, greater for two or more defects versus one defect, for all cancers and each type evaluated. The presence of chromosomal defects was strongly associated with cancer risk (HR 8.70 for all cancers and HR 21.90 for leukemia), further elevated in the presence of both chromosomal and nonchromosomal defects (HR 21.29 for all cancers, HR 64.83 for leukemia and HR 4.71 for embryonal tumors). Among the 83 946 children born from ART in the USA in 2019 compared to their naturally conceived counterparts, these risks translate into an estimated excess of 761 children with major birth defects, 31 children with cancer and 11 children with both major birth defects and cancer. LIMITATIONS, REASONS FOR CAUTION In the SART CORS database, it was not possible to differentiate method of embryo freezing (slow freezing versus vitrification), and data on ICSI were only available in the fresh embryo ART group. In the OI/IUI group, it was not possible to differentiate type of non-ART treatment utilized, and in both the ART and OI/IUI groups, data were unavailable on duration of infertility. Since OI/IUI is underreported on the birth certificate, some OI/IUI children were likely included among the naturally conceived children, which will decrease the difference between all the groups and the naturally conceived children. WIDER IMPLICATIONS OF THE FINDINGS The use of ART is associated with increased risks of major nonchromosomal birth defects. The presence of birth defects is associated with greater risks for cancer, which adds to the baseline risk in the ART group. Although this study does not show causality, these findings indicate that children conceived with ART, non-ART siblings, and all children with birth defects should be monitored more closely for the subsequent development of cancer. STUDY FUNDING/COMPETING INTEREST(S) This project was supported by grant R01 HD084377 from the National Institute of Child Health and Human Development. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Child Health and Human Development, or the National Institutes of Health, nor any of the State Departments of Health which contributed data. M.L.E. reports consultancy for Ro, Hannah, Dadi, Sandstone and Underdog; presidency of SSMR; and SMRU board member. The remaining authors report no conflict of interest. TRIAL REGISTRATION NUMBER N/A.

PURPOSE: To compare academic achievement in reading and mathematics at the end of sixth grade and progress from third to sixth grade by children conceived with in vitro fertilization (IVF) to those conceived naturally. METHODS: This was a retrospective population-based cohort study of IVF-conceived singleton and twin children who took the 3rd grade and 6th grade public school standardized reading and mathematics testing in Texas. RESULTS: There were 6623 children with reading scores in both the third and sixth grades and 6374 children with mathematics scores in both the third and sixth grades. Mean (± SE) scaled test scores for IVF and control singleton children for reading were 1544.6 ± 3.4 and 1527.7 ± 1.9, respectively, in third grade and 1701.2 ± 3.6 and 1681.0 ± 2.0, respectively, in sixth grade; for mathematics, the scores were 1564.4 ± 3.7 and 1548.9 ± 2.1, respectively, in third grade and 1774.0 ± 4.2 and 1752.0 ± 2.3, respectively, in sixth grade. In multivariate models, singleton IVF children scored significantly higher than control children in reading and mathematics, averaging 17.7 ± 4.0 points and 20.1 ± 4.1 points higher, respectively, in reading in third and sixth grades and 17.8 ± 4.4 points and 25.0 ± 4.8 points higher, respectively, in mathematics in third and sixth grades. CONCLUSIONS: Children conceived with IVF and aged 8–9 years and aged 10–12 years performed as well on third and sixth grade reading and mathematics assessments as their counterparts conceived naturally. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10815-021-02170-9.

Purpose Maternal body mass index (BMI) is inversely associated with gastroschisis, but a causal relationship has not been established. As data demonstrating that a change in exposure status is related to a change in the frequency of the outcome can add to the evidence for causality, we conducted a case-control study of change in maternal BMI, assessed using interpregnancy change in BMI (IPC-BMI), and gastroschisis. Methods Data for 258 gastroschisis cases and 2,561 controls were obtained from the Texas Birth Defects Registry and vital records (2006-2012). Logistic regression was used to estimate the adjusted association between IPC-BMI and gastroschisis. Results The continuous IPC-BMI variable was inversely associated with gastroschisis (adjusted odds ratio [aOR]=0.90, 95% confidence interval [CI]: 0.86-0.95). When assessed as a six-level categorical variable, with weight stable women as the referent, the odds of gastroschisis were higher following a BMI decrease of >1 unit (aOR=1.37, 95% CI: 0.91-2.06) and lower after a BMI increase of > 3 units (aOR=0.62, 95% CI: 0.42-0.94) Conclusions Our findings suggest that maternal change in BMI is associated with gastroschisis and, thus, add to the epidemiological evidence that can be used to inform our understanding of the relationship between BMI and gastroschisis.

Prevalence of gastroschisis, a serious birth defect of the abdominal wall resulting in some of the abdominal contents extending outside the body at birth, has been increasing worldwide (1,2). Gastroschisis requires surgical repair after birth and is associated with digestive and feeding complications during infancy, which can affect development. Recent data from 14 U.S. states indicated an increasing prevalence of gastroschisis from 1995 to 2012 (1). Young maternal age has been strongly associated with gastroschisis, but research suggests that risk factors such as smoking, genitourinary infections, and prescription opioid use also might be associated (3-5). Data from 20 population-based state surveillance programs were pooled and analyzed to assess age-specific gastroschisis prevalence during two 5-year periods, 2006-2010 and 2011-2015, and an ecologic approach was used to compare annual gastroschisis prevalence by annual opioid prescription rate categories. Gastroschisis prevalence increased only slightly (10%) from 2006-2010 to 2011-2015 (prevalence ratio = 1.1, 95% confidence interval [CI] = 1.0-1.1), with the highest prevalence among mothers aged

STUDY QUESTION What is the association between ART conception and treatment parameters and the risk of birth defects? SUMMARY ANSWER Compared to naturally conceived singleton infants, the risk of a major nonchromosomal defect among ART singletons conceived with autologous oocytes and fresh embryos without use of ICSI was increased by 18%, with increases of 42% and 30% for use of ICSI with and without male factor diagnosis, respectively. WHAT IS KNOWN ALREADY Prior studies have indicated that infertility and ART are associated with an increased risk of birth defects but have been limited by small sample size and inadequate statistical power, failure to differentiate results by plurality, differences in birth defect definitions and methods of ascertainment, lack of information on ART treatment parameters or study periods spanning decades resulting in a substantial historical bias as ART techniques have improved. STUDY DESIGN, SIZE, DURATION This was a population-based cohort study linking ART cycles reported to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) from 1 January 2004 to 31 December 2015 that resulted in live births from 1 September 2004 to 31 December 2016 in Massachusetts and North Carolina and from 1 September 2004 to 31 December 2015 for Texas and New York: these were large and ethnically diverse States, with birth defect registries utilizing the same case definitions and data collected, and with high numbers of ART births annually. A 10:1 sample of non-ART births were chosen within the same time period as the ART birth. Naturally conceived ART siblings were identified through the mother’s information. Non-ART children were classified as being born to women who conceived with ovulation induction (OI)/IUI when there was an indication of infertility treatment on the birth certificate, but the woman did not link to the SART CORS; all others were classified as being naturally conceived. PARTICIPANTS/MATERIALS, SETTING, METHODS The study population included 135 051 ART children (78 362 singletons and 56 689 twins), 23 647 naturally conceived ART siblings (22 301 singletons and 1346 twins) and 9396 children born to women treated with OI/IUI (6597 singletons and 2799 twins) and 1 067 922 naturally conceived children (1 037 757 singletons and 30 165 twins). All study children were linked to their respective State birth defect registries to identify major defects diagnosed within the first year of life. We classified children with major defects as either chromosomal (i.e. presence of a chromosomal defect with or without any other major defect) or nonchromosomal (i.e. presence of a major defect but having no chromosomal defect), or all major defects (chromosomal and nonchromosomal). Logistic regression models were used to generate adjusted odds ratios (AORs) and 95% CI to evaluate the risk of birth defects due to conception with ART (using autologous oocytes and fresh embryos), and with and without the use of ICSI in the absence or presence of male factor infertility, with naturally conceived children as the reference. Analyses within the ART group were stratified by combinations of oocyte source (autologous, donor) and embryo state (fresh, thawed), with births from autologous oocytes and fresh embryos as the reference. Analyses limited to fresh embryos were stratified by oocyte source (autologous, donor) and the use of ICSI. Triplets and higher-order multiples were excluded. MAIN RESULTS AND THE ROLE OF CHANCE A total of 21 998 singleton children (1.9%) and 3037 twin children (3.3%) had a major birth defect. Compared to naturally conceived children, ART singletons (conceived from autologous oocytes, fresh embryos without the use of ICSI) had increased risks of a major nonchromosomal birth defect (AOR 1.18, 95% 1.05, 1.32), cardiovascular defects (AOR 1.20, 95% CI 1.03, 1.40), and any birth defect (AOR 1.18, 95% CI 1.09, 1.27). Compared to naturally conceived children, ART singletons conceived (from autologous oocytes, fresh embryos) with the use of ICSI, the risks were increased for a major nonchromosomal birth defect (AOR 1.30, 95% CI 1.16, 1.45 without male factor diagnosis; AOR 1.42, 95% CI 1.28, 1.57 with male factor diagnosis); blastogenesis defects (AOR 1.49, 95% CI 1.08, 2.05 without male factor; AOR 1.56, 95% CI 1.17, 2.08 with male factor); cardiovascular defects (AOR 1.28, 95% CI 1.10,1.48 without male factor; AOR 1.45, 95% CI 1.27, 1.66 with male factor); in addition, the risk for musculoskeletal defects was increased (AOR 1.34, 95% CI 1.01, 1.78 without male factor) and the risk for genitourinary defects in male infants was increased (AOR 1.33, 95% CI 1.08, 1.65 with male factor). Comparisons within ART singleton births conceived from autologous oocytes and fresh embryos indicated that the use of ICSI was associated with increased risks of a major nonchromosomal birth defect (AOR 1.18, 95% CI 1.03, 1.35), blastogenesis defects (AOR 1.65, 95% CI 1.08, 2.51), gastrointestinal defects (AOR 2.21, 95% CI 1.28, 3.82) and any defect (AOR 1.11, 95% CI 1.01, 1.22). Compared to naturally conceived children, ART singleton siblings had increased risks of musculoskeletal defects (AOR 1.32, 95% CI 1.04, 1.67) and any defect (AOR 1.15, 95% CI 1.08, 1.23). ART twins (conceived with autologous oocytes, fresh embryos, without ICSI) were at increased risk of chromosomal defects (AOR 1.89, 95% CI 1.10, 3.24) and ART twin siblings were at increased risk of any defect (AOR 1.26, 95% CI 1.01, 1.57). The 18% increased risk of a major nonchromosomal birth defect in singleton infants conceived with ART without ICSI (∼36% of ART births), the 30% increased risk with ICSI without male factor (∼33% of ART births), and the 42% increased risk with ICSI and male factor (∼31% of ART births) translates into an estimated excess of 386 major birth defects among the 68 908 singleton children born by ART in 2017. LIMITATIONS, REASONS FOR CAUTION In the SART CORS database, it was not possible to differentiate method of embryo freezing (slow freezing vs vitrification), and data on ICSI was only available in the fresh embryo ART group. In the OI/IUI group, it was not possible to differentiate type of non-ART treatment utilized, and in both the ART and OI/IUI groups, data were unavailable on duration of infertility. WIDER IMPLICATIONS OF THE FINDINGS The use of ART is associated with increased risks of a major nonchromosomal birth defect, cardiovascular defect and any defect in singleton children, and chromosomal defects in twins; the use of ICSI further increases this risk, the most with male factor infertility. These findings support the judicious use of ICSI only when medically indicated. The relative contribution of ART treatment parameters versus the biology of the subfertile couple to this increased risk remains unclear and warrants further study. STUDY FUNDING/COMPETING INTEREST(S) This project was supported by grant R01 HD084377 from the National Institute of Child Health and Human Development. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Child Health and Human Development, or the National Institutes of Health, nor any of the State Departments of Health which contributed data. E.W. is a contract vendor for SART; all other authors report no conflicts. TRIAL REGISTRATION NUMBER N/A.

Objective To evaluate if there are differences in standardized testing results at the end of third grade between children conceived with the use of in vitro fertilization (IVF) and those conceived spontaneously. Design Retrospective population-based cohort. Setting Texas public school system. Patient(s) Singleton and twin children 8–9 years of age who took the third-grade public school standardized testing in Texas from 2012 to 2018. Intervention(s) None. Main Outcome Measure(s) Standardized testing in reading and mathematics. Result(s) After exclusions, there were 6,970 IVF and 12,690 non-IVF children with reading scores and 6,973 IVF and 12,729 non-IVF children with mathematics scores. IVF children scored significantly higher in reading (singletons: 1,543 ± 2 vs. 1,525 ± 1; twins: 1,534 ± 2 vs. 1,504 ± 5 [mean ± SE]), and mathematics (singletons: 1,566 ± 2 vs. 1,550 ± 1; twins: 1,557 ± 2 vs. 1,529 ± 5). Children of mothers ≥30 years of age scored consistently higher than children of mothers 18–29 years of age. The differences were of similar magnitude between IVF and control children for older ages, but not significant for IVF. Within the IVF group, there were no significant differences between children born from fresh versus froze-thawed embryos. Conclusion(s) Children of ages 8–9 years who were conceived with the use of IVF performed as well on third-grade reading and math assessments as their counterparts who were conceived spontaneously. We also found consistent racial and ethnic differences, gender differences, and beneficial effects of older maternal age. Because we were not able to adjust adequately for socioeconomic status and other confounding factors, which may explain some of the observed differences, we conclude that there is no negative effect of IVF conception on academic achievement in third grade.

Background Epidemiologic studies have consistently identified an association between spina bifida and maternal body mass index (BMI). Whether this reflects a causal relationship is unknown. If this association does reflect a causal relationship, the risk of spina bifida should change with changes in maternal BMI. We evaluated the association between spina bifida and maternal change in BMI, assessed using interpregnancy change in BMI (IPC-BMI). Methods We used data from the Texas Birth Defects Registry and statewide vital records for 248 spina bifida cases and 2,562 controls (2006-2012) to conduct a case-control study. We used logistic regression to estimate the association between IPC-BMI and spina bifida, with adjustment for potential confounders. Results When assessed as a continuous variable, IPC-BMI was associated with spina bifida, with a 5% increase in the odds of spina bifida per unit (approximately 6 pounds) increase in BMI (adjusted odds ratios [aOR] = 1.05, 95% CI: 1.02, 1.09). When assessed as a categorical variable, with weight stable women as the referent, the odds of spina bifida were lower in women with any BMI decrease (aOR = 0.73, 95% CI: 0.50, 1.08) and higher in women with an increase of ≥1 BMI units (aOR = 1.17, 95% CI: 0.85, 1.62). Conclusions Our findings provide suggestive, although not conclusive, evidence that maternal prepregnancy change in BMI, assessed using IPC-BMI, is associated with spina bifida in the later pregnancy. Additional studies aimed at confirming this association and further strengthening the evidence for a causal relationship between spina bifida and maternal BMI are needed.

Background Congenital microcephaly has been linked to maternal Zika virus infection. However, ascertaining infants diagnosed with microcephaly can be challenging. Methods Thirty birth defects surveillance programs provided data on infants diagnosed with microcephaly born 2009 to 2013. The pooled prevalence of microcephaly per 10,000 live births was estimated overall and by maternal/infant characteristics. Variation in prevalence was examined across case finding methods. Nine programs provided data on head circumference and conditions potentially contributing to microcephaly. Results The pooled prevalence of microcephaly was 8.7 per 10,000 live births. Median prevalence (per 10,000 live births) was similar among programs using active (6.7) and passive (6.6) methods; the interdecile range of prevalence estimates was wider among programs using passive methods for all race/ethnicity categories except Hispanic. Prevalence (per 10,000 live births) was lowest among non-Hispanic Whites (6.5) and highest among non-Hispanic Blacks and Hispanics (11.2 and 11.9, respectively); estimates followed a U-shaped distribution by maternal age with the highest prevalence among mothers

Background Hypoplastic left heart syndrome (HLHS) is strongly associated with Turner syndrome (TS); outcome data when these conditions coexist is sparse. We aimed to investigate long-term survival and causes of death in this population. Methods The Texas Birth Defects Registry was queried for all live born infants with HLHS during 1999–2007. We used Kaplan–Meier and Cox regression analyses to compare survival among patients with HLHS with TS (HLHS/TS+) to patients who had HLHS without genetic disorders or extracardiac birth defects (HLHS/TS−). Results Of the 542 patients with HLHS, 11 had TS (2.0%), 71 had other extracardiac birth defects or genetic disorders, and 463 had neither. The median follow-up time was 4.2 y (interquartile range [IQR] 2.1–6.5). Comparing those with HLHS/TS+ to HLHS/TS−, 100% versus 35% were female (P

Importance Children with birth defects have a greater risk of developing cancer, but this association has not yet been evaluated in children conceived with in vitro fertilization (IVF). Objective To assess whether the association between birth defects and cancer is greater in children conceived via IVF compared with children conceived naturally. Design, setting, and participants This cohort study of live births, birth defects, and cancer from Massachusetts, New York, North Carolina, and Texas included 1 000 639 children born to fertile women and 52 776 children conceived via IVF (using autologous oocytes and fresh embryos) during 2004-2016 in Massachusetts and North Carolina, 2004-2015 in New York, and 2004-2013 in Texas. Children were followed up for an average of 5.7 years (6 008 985 total person-years of exposure). Data analysis was conducted from April 1 to August 31, 2020. Exposures Conception by IVF for state residents who gave birth to liveborn singletons during the study period. Birth defect diagnoses recorded by statewide registries. Main outcomes and measures Cancer diagnosis as recorded by state cancer registries. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% CIs for birth defect-cancer associations separately in fertile and IVF groups. Results A total of 1 000 639 children (51.3% boys; 69.7% White; and 38.3% born between 2009-2012) were in the fertile group and 52 776 were in the IVF group (51.3% boys; 81.3% White; and 39.6% born between 2009-2012). Compared with children without birth defects, cancer risks were higher among children with a major birth defect in the fertile group (hazard ratio [HR], 3.15; 95% CI, 2.40-4.14) and IVF group (HR, 6.90; 95% CI, 3.73-12.74). The HR of cancer among children with a major nonchromosomal defect was 2.07 (95% CI, 1.47-2.91) among children in the fertile group and 4.04 (95% CI, 1.86-8.77) among children in the IVF group. The HR of cancer among children with a chromosomal defect was 15.45 (95% CI, 10.00-23.86) in the fertile group and 38.91 (95% CI, 15.56-97.33) in the IVF group. Conclusions and relevance This study found that among children with birth defects, those conceived via IVF were at greater risk of developing cancer compared with children conceived naturally.

Background Higher prevalence of selected birth defects has been reported among American Indian/Alaska Native (AI/AN) newborns. We examine whether known risk factors for birth defects explain the higher prevalence observed for selected birth defects among this population. Methods Data from 12 population-based birth defects surveillance systems, covering a birth population of 11 million from 1999 to 2007, were used to examine prevalence of birth defects that have previously been reported to have elevated prevalence among AI/ANs. Prevalence ratios (PRs) were calculated for non-Hispanic AI/ANs and any AI/ANs (regardless of Hispanic ethnicity), adjusting for maternal age, education, diabetes, and smoking, as well as type of case-finding ascertainment surveillance system. Results After adjustment, the birth prevalence of two of seven birth defects remained significantly elevated among AI/ANs compared to non-Hispanic whites (NHWs): anotia/microtia was almost threefold higher, and cleft lip +/- cleft palate was almost 70% higher compared to NHWs. Excluding AI/AN subjects who were also Hispanic had only a negligible impact on adjusted PRs. Conclusions Additional covariates accounted for some of the elevated birth defect prevalences among AI/ANs compared to NHWs. Exclusion of Hispanic ethnicity from the AI/AN category had little impact on birth defects prevalences in AI/ANs. NHWs serve as a viable comparison group for analysis. Birth defects among AI/ANs require additional scrutiny to identify modifiable risk and protective factors.

BACKGROUND There are limited population-based studies on microcephaly. We characterized the epidemiology of microcephaly in Texas during a 5-year period (2008-2012), prior to the Zika epidemic in the Western hemisphere (2015). The associations of suspected risk factors were compared across four clearly defined case groups. METHODS Data from the Texas Birth Defects Registry were used to calculate the prevalence of congenital microcephaly and crude and adjusted prevalence ratios using Poisson regression. Twelve maternal and infant factors were assessed across case groups, which included total (explained + unexplained), explained (e.g., syndromic), unexplained, and severe unexplained microcephaly (head circumference

Background— Most studies have not demonstrated improved survival after prenatal diagnosis of critical congenital heart disease, including hypoplastic left heart syndrome (HLHS). However, the effect of delivery near a cardiac surgical center (CSC), the recommended action after prenatal diagnosis, on HLHS mortality has been poorly investigated. Methods and Results— Using Texas Birth Defects Registry data, 1999 through 2007, which monitored >3.4 million births, we investigated the association between distance (calculated driving time) from birth center to CSC and neonatal mortality in 463 infants with HLHS. Infants with extracardiac birth defects or genetic disorders were excluded. The associations between prenatal diagnosis, CSC HLHS volume, and mortality were also examined. Neonatal mortality in infants born 90 minutes 39.6% ( P for trend P =0.14). In multivariable analysis, birth >90 minutes from a CSC remained associated with increased mortality (odds ratio, 2.03; 95% confidence interval, 1.19–3.45), compared with 90 minutes from a CSC was associated with higher pretransport mortality (odds ratio, 6.69; 95% confidence interval, 2.52–17.74) and birth 10 to 90 minutes with higher presurgical mortality (odds ratio, 4.45; 95% confidence interval, 1.17–17.00). Higher surgical mortality was associated with lower CSC HLHS volume (odds ratio per 10 patients, 0.88; 95% confidence interval, 0.84–0.91). Conclusions— Infants with HLHS born far from a CSC have increased neonatal mortality, and most of this mortality is presurgical. Efforts to improve prenatal diagnosis of HLHS and subsequent delivery near a large volume CSC may significantly improve neonatal HLHS survival.

BACKGROUND Infants with congenital heart defects (CHD) have increased risk of morbidity and mortality. Little is known about racial/ethnic differences in timing of death during childhood. Our intent was to investigate racial/ethnic differences in mortality for CHDs during specific time periods in childhood. METHODS Texas Birth Defect Registry data were used for a retrospective cohort study with 30,015 singleton infants with a CHD, born January 1, 1999, to December 31, 2007, to non-Hispanic (NH) white, NH-black, or Hispanic women. Texas Birth Defect Registry data were linked to Texas death records to ascertain death. Kaplan–Meier survival probabilities and multivariable Cox-proportional hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. RESULTS NH-blacks and Hispanics with specific CHDs had increased mortality during the postneonatal period and early childhood. NH-blacks had increased postneonatal mortality compared with NH-whites for transposition of the great arteries (HR = 2.4; 95% CI, 1.5–4.0), pulmonary valve atresia without ventricular septal defect (HR = 4.1; 95% CI, 1.7–9.7), Ebstein's anomaly (HR = 8.6; 95 CI, 1.2–61.1), hypoplastic left heart syndrome (HR = 2.1; 95% CI, 1.2–3.7), coarctation of the aorta (HR = 2.1; 95% CI, 1.2–3.5), ventricular septal defect (HR = 2.1; 95% CI, 1.6−2.8), and atrial septal defect (HR = 1.4; 95% CI, 1.1−1.8). Hispanics had increased postneonatal mortality risk for tetralogy of Fallot (HR = 2.0; 95% CI, 1.1–3.5). Racial/ethnic increases in mortality risk were also observed during infancy and childhood. CONCLUSION Racial/ethnic differences in mortality were most notably observed during the postneonatal period and early childhood. Future studies should assess factors associated with this disparity in mortality risk for infants with CHDs. Birth Defects Research (Part A) 97:628–640, 2013. © 2013 Wiley Periodicals, Inc.

Trisomy 13 (T13) and trisomy 18 (T18) are among the most prevalent autosomal trisomies. Both are associated with a very high risk of mortality. Numerous instances, however, of long-term survival of children with T13 or T18 have prompted some clinicians to pursue aggressive treatment instead of the traditional approach of palliative care. The purpose of this study is to assess current mortality data for these conditions. This multi-state, population-based study examined data obtained from birth defect surveillance programs in nine states on live-born infants delivered during 1999-2007 with T13 or T18. Information on children's vital status and selected maternal and infant risk factors were obtained using matched birth and death certificates and other data sources. The Kaplan-Meier method and Cox proportional hazards models were used to estimate age-specific survival probabilities and predictors of survival up to age five. There were 693 children with T13 and 1,113 children with T18 identified from the participating states. Among children with T13, 5-year survival was 9.7%; among children with T18, it was 12.3%. For both trisomies, gestational age was the strongest predictor of mortality. Females and children of non-Hispanic black mothers had the lowest mortality. Omphalocele and congenital heart defects were associated with an increased risk of death for children with T18 but not T13. This study found survival among children with T13 and T18 to be somewhat higher than those previously reported in the literature, consistent with recent studies reporting improved survival following more aggressive medical intervention for these children. © 2015 Wiley Periodicals, Inc.

Background The majority of U.S. birth defects surveillance programs do not include elective terminations before 20 weeks gestation among the pregnancy outcomes covered. To assess the impact of defects among elective terminations before 20 weeks gestation, data from a birth defects registry that does include terminations before 20 weeks gestation were analyzed. Methods Using information from the Texas Birth Defects Registry, the number of cases and rate of 49 conditions were analyzed in two ways: excluding defects detected among elective pregnancy terminations before 20 weeks gestation, and including defects among terminations before 20 weeks. Results By including defects detected among elective terminations before 20 weeks, the number of cases increased by five percent or greater for nine conditions: anencephaly (29%); spina bifida without anencephaly (13%); encephalocele (21%); Patau syndrome (19%); Edwards syndrome (11%); Down syndrome (6%); omphalocele (15%); gastroschisis (5%); and anophthalmia (7%). There was no impact for 27 conditions, for which there were no cases detected among elective terminations before 20 weeks. The greatest impact was observed for anencephaly; the rate of anencephaly increased from 2.76 to 3.56 per 10,000 live births when defects among elective terminations before 20 weeks were included. Conclusions Excluding defects among elective terminations before 20 weeks results in counts and rates that are somewhat incomplete, especially for conditions that are more commonly detected and electively terminated before 20 weeks. The impact varies by condition. Teratology 66:S32–S35, 2002. © 2002 Wiley-Liss, Inc.

BACKGROUND AND OBJECTIVE: Newborn pulse oximetry screening is recommended to promote early referral of neonates with critical congenital heart disease (CCHD) and reduce mortality; however, the impact of late referral on mortality is not well defined. The purpose of this population-based study was to describe the association between timing of referral to a cardiac center and mortality in 2360 liveborn neonates with CCHD. METHODS: Neonates with CCHD born before pulse oximetry screening (1996–2007) were selected from the Texas Birth Defects Registry and linked to state birth and death records. Age at referral was ascertained from date of first cardiac procedure at a cardiac center. Logistic and Cox proportional hazards regression models were used to estimate factors associated with late referral and mortality; the Kaplan-Meier method was used to estimate 3-month survival. RESULTS: Median age at referral was 1 day (25th–75th percentile: 0–6 days). Overall, 27.5% (649 of 2360) were referred after age 4 days and 7.5% (178 of 2360) had no record of referral. Neonatal mortality was 18.1% (277 of 1533) for those referred at 0 to 4 days of age, 9.0% (34 of 379) for those referred at 5 to 27 days of age, and 38.8% (69 of 178) for those with no referral. No improvement in age at referral was found across the 2 eras within 1996–2007. CONCLUSIONS: A significant proportion of neonates with CCHD experienced late or no referral to cardiac specialty centers, accounting for a significant number of the deaths. Future population-based studies are needed to determine the benefit of pulse oximetry screening on mortality and morbidity.

Since 1997, the National Birth Defects Prevention Network (NBDPN), in collaboration with the Centers for Disease Control and Prevention (CDC), has published data on major birth defects affecting the central nervous, eye, ear, cardiovascular, orofacial, gastrointestinal, genitourinary, and musculoskeletal systems, as well as trisomies, amniotic bands, and fetal alcohol syndrome, from population-based birth defects surveillance programs in the United States. Annually, the NBDPN Data Committee issues a data request to population-based birth defects programs for data on 47 major birth defects; the specific defects with accompanying diagnostic codes are detailed in Appendix 1 on page 10. This year’s report containing data from 41 population-based birth defects surveillance programs for births occurring from January 1, 2005, through December 31, 2009, is available as a supplement on pages. The data are presented by racial/ethnic groups for all defects and additionally by maternal age for triso-mies 13, 18, and 21. To calculate prevalence, programs were also asked to provide the number of total live births and male live births for each calendar year submitted. The standard method for calculating birth defects prevalence is to divide the number of cases (birth defect for any pregnancy outcome) by total live births for the catchment area and then multiply by 10,000 to obtain the prevalence per 10,000 live births; Mason et al. (2005) provide further detail and rationale for this approach. This methodology is used for all defects except hypospadias, which is calculated using a denominator of total male live births. An attempt was made to standardize both the submitted data and presentation of state surveillance data, however, differences in the way programs collect and report birth defects data are listed in the footnotes of the accompanying tables and may be referenced in the program directories on pages S121-S169 (online). Some programs were able to only provide data for selected years, were unable to report counts and prevalence by race/ethnicity, or were unable to provide data for each specific defect requested due to differences in the coding systems (i.e., International Classification of Diseases, 9th Revision, Clinical Modification [ICD-9-CM] vs CDC/British Pediat-ric Association [BPA]) Classification of Diseases used to classify birth defects. Critical Congenital Heart Defects Targeted for Pulse Oximetry Screening This year’s data report includes several enhancements to address the interest in pulse oximetry screening of new-borns for critical congenital heart defects (CCHDs). Congenital heart defects (CHDs) occur in an estimated 1 in 110 births in the United States (Reller et al., 2008) and approximately 25% of CHDs are considered CCHDs, defined as requiring surgery or catheter intervention within the first year of life (Mahle et al., 2009). Children with CCHDs are at risk for death or disability if the defect is not detected shortly after birth (Mahle et al., 2009). Thus, in 2011, the Secretary of Health and Human Services recommended that CCHDs be added to the U.S. Recommended Uniform Screening Panel for newborns (Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children, 2011). When implemented, newborns would undergo pulse oximetry screening for CCHDs after 24 hours of life, which detects low blood oxygen levels (hypoxemia). The Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children (2011) named seven CCHDs as primary targets for screening: common truncus, d-transposition of the great arteries, tetralogy of Fallot, pulmonary valve atresia, tricuspid valve atresia, hypoplastic left heart syndrome, and total anomalous pulmonary venous return (Mahle et al., 2009; Kemper et al., 2011). Other CCHDs may also be detected using pulse oximetry screening, but because they may not consistently have hypoxemia at or soon after birth, their identification would be variable and incomplete. The following CCHDs are considered secondary targets of pulse oximetry screening: coarctation of the aorta, double outlet right ventricle, Ebstein anomaly, interrupted aortic arch, single ventricle, severe aortic stenosis and severe pulmonary stenosis (Mahle et al., 2009). The implementation of pulse oximetry screening for CCHDs is currently underway in a few states, with more considering legislation and implementation (Olney and Botto, 2012). Surveillance case definitions, including both ICD-9-CM and CDC/BPA diagnostic codes, for each of the seven primary CCHD targets of pulse oximetry screening are presented in Appendix 2. In using these case definitions, it is important to consider as a potential limitation the coding system’s ability to capture cases of CCHDs. Three of the seven conditions (‘pulmonary valve atresia and stenosis’, ‘tricuspid valve atresia and stenosis’, and ‘transposition of the great arteries’) include both broad codes to capture all possible cases that are generally collected for surveillance purpose and more refined codes that are targeted for newborn screening of CCHDs using pulse oximetry. For example, the surveillance category of ‘tricuspid valve atresia and stenosis’ encompasses both tricuspid valve atresia (one of the seven targeted CCHDs) as well as milder cases of tricuspid stenosis. Programs that are able to use more refined codes provided data separately for pulmonary valve atresia, tricuspid valve atresia, and d-transposition of the great arteries.

BACKGROUND AND OBJECTIVE: Despite improvements in congenital heart disease (CHD) survival over the past 4 decades, ethnic disparities persist. Several studies have shown higher postoperative CHD adjusted mortality in black and Hispanic children. Others noted that non–English-speaking language at home was associated with appointment noncompliance, which the parents attributed to misunderstanding and living too far from a health center. The purpose of this study was to determine the effect of home distance to a cardiac center, or having a Latin American–born parent, on first-year mortality in infants with severe CHD. METHODS: Infants with severe CHD, having an estimated first-year mortality >25%, born 1996–2003, were identified from the Texas Birth Defects Registry and linked to state and national vital records. We examined the effects of defect type; birth weight; gestational age; extracardiac anomalies; infant gender; maternal race/ethnicity, marital status, and education; residence in a Texas county bordering Mexico; home distance to cardiac center; and parental birth country on first-year survival. RESULTS: Overall first-year survival was 59.9%, and no race/ethnic differences were noted; however, survival was significantly (P < .05) lower for Hispanic infants with hypoplastic left heart syndrome. Neither home distance to a cardiac center nor parental birth country was related to first-year survival; however, survival was noted to be lower in Texas counties bordering Mexico, counties that have high rates of poverty. CONCLUSIONS: Further studies are needed to determine if these disparities in survival of infants with severe CHD are attributable to delays in referral to a cardiac center.

We concur with several of the issues addressed in the letter by Dr Hill and his colleagues. The low 5-year survival of 38% for hypoplastic left heart syndrome in our population-based study, in contrast to recent surgical survival reports for the Norwood procedure, may be explained by several factors. First, from 1996 to 2003, surgical outcomes were …

BACKGROUND We examined the separate and joint effects of gestational age, size at birth and maternal race/ethnicity on early childhood survival among 48,391 singleton infants with major birth defects. METHODS Texas Birth Defects Registry data were linked to death records and the National Death Index to ascertain deaths. Gestational age categories were preterm or term birth; size at birth included small for gestational age (SGA), appropriate for gestational age (AGA), and large for gestational age (LGA). Kaplan-Meier survival estimates were calculated, and Cox-proportional hazards models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) to determine risk of death after adjusting for covariates. RESULTS Overall, relative to non-Hispanic (NH) -whites, NH-blacks, and Hispanics had a 51 and 10% greater risk of death during early childhood, respectively. Compared to NH-whites born term and AGA (survival = 97%), Hispanic children born SGA and preterm had the greatest risk of death (HRa = 6.1; 95% CI, 5.2, 7.2) and the lowest early childhood survival (76%), followed by SGA preterm NH-blacks (HRa = 4.8; 95% CI, 3.6, 6.5; survival = 81%) and SGA preterm NH-whites (HRa = 4.5; 95% CI, 3.7, 5.6; survival = 83%). Children born LGA at term had no increased risk of mortality regardless of maternal race/ethnicity. CONCLUSIONS The joint effect of gestational age and size at birth had greatest impact on childhood mortality. Additional population based studies are needed to better understand causes of racial/ethnic disparities in mortality among children with birth defects. Birth Defects Research (Part A), 2010. © 2010 Wiley-Liss, Inc.

Background— Infants with functional single ventricle have a high risk of death during the early years of life. Studies have reported improvement in postoperative survival, but they do not include preoperative deaths or those occurring before transfer. The purpose of this population-based study was to estimate 5-year survival in infants with functional single ventricle, to define factors associated with survival, and to estimate improvement in outcome. Methods and Results— Patients with hypoplastic left heart syndrome, pulmonary atresia intact ventricular septum, single ventricle, and tricuspid atresia born in 1996 to 2003 were identified from the Texas Birth Defects Registry and linked to state and national birth and death vital records. We examined the effects of defect type, birth era, birth weight, gestational age, maternal race/ethnicity, extracardiac anomalies, sex, and maternal age and education on survival. Five-year survival varied by defect type: hypoplastic left heart syndrome, 38.0% (95% confidence interval, 32.6 to 43.5); single ventricle, 56.1% (95% confidence interval, 49.9 to 61.7); pulmonary atresia intact ventricular septum, 55.7% (95% confidence interval, 45.8 to 64.4); and tricuspid atresia, 74.6% (95% confidence interval, 62.4 to 83.4). The presence of extracardiac defects increased the adjusted risk of death by 84%. Non-Hispanic blacks had an adjusted risk of death that was 41% higher than that for non-Hispanic whites, and Hispanics had a 26% higher risk. Patients born in 2001 to 2003 had a 47% lower risk than those born in 1996 to 2000. Conclusions— This population-based study demonstrates significant improvement in overall 5-year survival, particularly in cases of hypoplastic left heart syndrome and single ventricle. Additional studies are needed to determine the factors causing racial/ethnic and regional differences in outcome.

BACKGROUND The worldwide prevalence of gastroschisis is increasing. Maternal age, race/ethnicity, and place of residence have been associated with increased risk. METHODS We obtained descriptive characteristics of mothers of infants with gastroschisis and mothers of all live births from the Texas Birth Defects Registry and Texas vital records for 1999–2003. We calculated prevalence, crude prevalence ratios, and prevalence ratios adjusted for maternal age, parity, education, race/ethnicity, and geographic entity (Mexican border proximity, urban/rural residence, health service region, and county). RESULTS We observed 764 cases of gastroschisis among 1,827,317 live births, for a prevalence of 4.18 per 10,000 births (95% confidence interval 3.88–4.48). Prevalence increased during 1999–2003 (p for trend

BACKGROUND: The Texas Birth Defects Registry (TBDR) does not access prenatal diagnostic facilities to ascertain cases. Objectives of the study were to determine how many cases may be missing from the registry as a result, and to assess the feasibility and utility of prenatal surveillance for birth defects, through a pilot test in one region of Texas. METHODS: A trained abstractor reviewed medical records of all patients with abnormal ultrasound findings during 2004 in all prenatal diagnostic facilities in Texas Health Region 11 (n = 6 facilities). When birth defects were prenatally detected, demographic and diagnostic data were abstracted. Prenatal abstractions were matched to cases in the TBDR. Those that did not match to registry cases were matched to vital records to determine where and when the pregnancy ended; delivery hospital medical records were reviewed for these cases. RESULTS: Approximately 760 patient charts were reviewed at prenatal diagnostic facilities and 365 were abstracted. Of these, 165 (45%) matched to cases in the TBDR. Delivery medical records were located and reviewed for 177 prenatal abstractions, with 170 (47%) indicating at delivery no defects monitored by the registry. Delivery records for one (0.3%) prenatal abstraction were not found by the hospital. Date and place of delivery were unknown for 22 (6%) prenatal abstractions. Only eight additional infants and fetuses (one twin pair) eligible for the registry were identified. CONCLUSIONS: For Texas Health Service Region 11, it is not necessary to conduct surveillance in prenatal diagnostic facilities, and to do so would be very labor-intensive. Birth Defects Research (Part A) 79:788–791, 2007. © 2007 Wiley-Liss, Inc.

Encephaloceles are congenital malformations characterized by a sac-like protrusion of the brain and/or its' covering membranes through an opening in the skull. The etiology of encephalocele is considered to be complex, and in most cases the causes of this condition remain elusive. The present study was undertaken to determine the prevalence of encephalocele among deliveries to Texas residents during 1999-2002, and to identify maternal and demographic factors associated with encephalocele. Data were examined from 125 infants and fetuses with encephalocele and no identified chromosome abnormality; identified in Texas and delivered in 1999-2002. During the same period there were 1,449,943 live births. The birth prevalence of encephalocele and both crude and adjusted prevalence ratios were estimated from these data. Compared with the offspring of White women, encephaloceles were significantly more common among the offspring of Hispanic women (adjusted prevalence ratio: 1.91, 95% confidence interval (CI) 1.34-2.70). In addition, compared to the offspring of women 25-29 years of age, encephaloceles were more common among the offspring of women 20-24 years of age (adjusted prevalence ratio: 1.52, 95% CI 1.01-2.27) and those less than 20 years of age (adjusted prevalence ratio: 1.55, 95% CI 0.98-2.45). These findings add to the existing literature on the descriptive epidemiology of encephalocele.

Objectives To determine the prevalence, patterns, and predictors of alcohol consumption prior to and during various intervals of pregnancy in the U.S. Methods Alcohol-related, pregnancy-related, and demographic data were derived from computer-assisted telephone interviews with 4,088 randomly selected control mothers from the National Birth Defects Prevention Study who delivered live born infants without birth defects during 1997–2002. Alcohol consumption rates and crude and adjusted odds ratios (OR) were calculated. Results 30.3% of all women reported drinking alcohol at some time during pregnancy, of which 8.3% reported binge drinking (4+ drinks on one occasion). Drinking rates declined considerably after the first month of pregnancy, during which 22.5% of women reported drinking, although 2.7% of women reported drinking during all trimesters of pregnancy and 7.9% reported drinking during the 3rd trimester. Pre-pregnancy binge drinking was a strong predictor of both drinking during pregnancy (adjusted OR = 8.52, 95% CI = 6.67–10.88) and binge drinking during pregnancy (adjusted OR = 36.02, 95% CI = 24.63–52.69). Other characteristics associated with both any drinking and binge drinking during pregnancy were non-Hispanic white race/ethnicity, cigarette smoking during pregnancy, and having an unintended pregnancy. Conclusions Our study revealed that drinking during pregnancy is fairly common, three times the levels reported in surveys that ask only about drinking during the month before the survey. Women who binge drink before pregnancy are at particular risk for drinking after becoming pregnant. Sexually active women of childbearing ages who drink alcohol should be advised to use reliable methods to prevent pregnancy, plan their pregnancies, and stop drinking before becoming pregnant.

Objective To examine factors that may explain a 9-fold increase in plagiocephaly in Texas from 1999 to 2007. Design Descriptive epidemiologic study of time trends and a nested case-control study. Setting Texas. Participants Cases in the Texas Birth Defects Registry. Outcome Measures Time trends in the birth prevalence of plagiocephaly overall and by region, demographic group, and clinical subgroup. Trends in percentage of cases using specific facilities or procedures. Results From 1999 to 2007, the prevalence of plagiocephaly in Texas increased from 3.0 cases per 10 000 live births to 28.8, an average increase of 21.2% per year. This was highly statistically significant. The time trend was most pronounced in the Dallas/Fort Worth region and in certain health care facilities. It was observed in all demographic and clinical subgroups. Cases born in 2004 and 2005 were not more likely to be postnatally acquired when compared with cases born in 1999 and 2000. There was no commensurate decrease in other birth defects of the face or skull. Conclusions A small part of the trend might have been due to delayed compliance with the infant supine sleeping recommendation and a slight increase in preterm births. It was not due to changes in birth defect coding practice or trends in multiple births, torticollis, or oligohydramnios. Because the plagiocephaly trend was observed mainly in patients visiting certain health care facilities, among mild cases, and among cases with minimally invasive procedures, we suspect it may be due mainly to changes in available therapies and insurance reimbursement practices.