The risks of birth defects and childhood cancer with conception by assisted reproductive technology.

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.

The risk of birth defects with conception by ART.

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.

Sixth grade academic achievement among children conceived with IVF: a population-based study in Texas, USA.

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.

Risks of nonchromosomal birth defects, small-for-gestational age birthweight, and prematurity with in vitro fertilization: effect of number of embryos transferred and plurality at conception versus at birth.

PURPOSE: Excess embryos transferred (ET) (> plurality at birth) and fetal heartbeats (FHB) at 6 weeks' gestation are associated with reductions in birthweight and gestation, but prior studies have been limited by small sample sizes and limited IVF data. This analysis evaluated associations between excess ET, excess FHB, and adverse perinatal outcomes, including the risk of nonchromosomal birth defects. METHODS: Live births conceived via IVF from Massachusetts, New York, North Carolina, and Texas included 138,435 children born 2004-2013 (Texas), 2004-2016 (Massachusetts and North Carolina), and 2004-2017 (New York) were classified by ET and FHB. Major birth defects were reported by statewide registries within the first year of life. Logistic regression was used to estimate adjusted odds ratios (AORs) and 95% CIs of the risks of a major nonchromosomal birth defect, small-for-gestational age birthweight (SGA), low birthweight (LBW), and preterm birth (≤36 weeks), by excess ET, and excess ET + excess FHB, by plurality at birth (singletons and twins). RESULTS: In singletons with [2 ET, FHB =1] and [≥3 ET, FHB=1], risks [AOR (95% CI)] were increased, respectively, for major nonchromosomal birth defects [1.13 (1.00-1.27) and 1.18 (1.00-1.38)], SGA [1.10 (1.03-1.17) and 1.15 (1.05-1.26)], LBW [1.09 (1.02-1.13) and 1.17 (1.07-1.27)], and preterm birth [1.06 (1.00-1.12) and 1.14 (1.06-1.23)]. With excess ET + excess FHB, risks of all adverse outcomes except major nonchromosomal birth defects increased further for both singletons and twins. CONCLUSION: Excess embryos transferred are associated with increased risks for nonchromosomal birth defects, reduced birthweight, and prematurity in IVF-conceived births.

Interpregnancy change in body mass index and infant outcomes in Texas: a population-based study.

BACKGROUND: Maternal prepregnancy body mass index (BMI) is associated with several infant outcomes, but it is unclear whether these associations reflect causal relationships. We conducted a study of interpregnancy change in BMI (IPC-BMI) to improve understanding of the associations between BMI and large for gestational age (LGA), small for gestational age (SGA), and preterm birth (PTB). METHODS: Birth certificate data from 2481 linked sibling pairs (Texas, 2005-2012) were used to estimate IPC-BMI and evaluate its association with LGA, SGA, and PTB in the younger sibling of the pair. Multivariable logistic regression was used to estimate adjusted odds ratios (aOR) and 95% confidence intervals (CI) using data from the full sample and within strata defined by prepregnancy BMI for the older sibling. RESULTS: On average, women gained 1.1 BMI units between pregnancies. In the full sample, interpregnancy BMI decreases were associated with reduced odds of LGA and increased odds of SGA and PTB (IPC-BMI < -1 versus 0 to < 1: LGA aOR 0.7, 95% CI 0.4, 1.1; SGA aOR 1.6, 95% CI 1.0, 2.7; PTB aOR 1.9, 95% CI 1.3, 2.8). In stratified analyses, similar associations were observed in some, but not all, strata. Findings for interpregnancy BMI increases were less consistent, with little evidence for associations between these outcomes and the most extreme IPC-BMI increases. CONCLUSIONS: There is growing evidence that interpregnancy BMI decreases are associated with LGA, SGA, and PTB. However, taken as a whole, the literature provides insufficient evidence to establish causal links between maternal BMI and these outcomes.

Survival of children with trisomy 13 and trisomy 18: A multi-state population-based study.

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.

Prenatal diagnosis, hospital characteristics, and mortality in transposition of the great arteries.

BACKGROUND: The role of prenatal diagnosis in reducing neonatal mortality from transposition of the great arteries (TGA) is controversial. Factors affected by prenatal diagnosis such as proximity at birth to a cardiac surgical center (CSC) and CSC volume are associated with mortality in congenital heart disease. The purpose of the study was to determine the associations between prenatal diagnosis, distance from birthplace to a CSC, CSC TGA volume, and neonatal mortality in patients with TGA. METHODS: The Texas Birth Defects Registry was queried for all live born infants with TGA from 1999 to 2007. Four hundred sixty-eight cases of TGA were included. RESULTS: Forty-eight patients (10.3%) were prenatally diagnosed, and 20 patients died before age 28 days (4.3%). Neither prenatal diagnosis nor close proximity to a CSC at birth (p > 0.05) were associated with decreased mortality. Low CSC TGA volume was associated with increased mortality (p < 0.0002). Mortality at the CSCs with <5 patients per year was 9.6%; CSCs with 5 to 10 patients per year had 0% mortality, and those with >10 patients per year had 2.3% mortality. In multivariable logistic regression, only preterm birth (odds ratio, 7.05; 95% confidence interval, 4.13-12.05) and lower CSC volume (p < 0.001) were associated with neonatal mortality, although prenatal diagnosis attenuated the detrimental association of lower volume CSCs with higher mortality (p for interaction = 0.047). CONCLUSION: Lower CSC TGA patient volume was associated with higher neonatal mortality. Prenatal diagnosis may improve survival in lower volume CSCs. Birth Defects Research (Part A) 106:739-748, 2016. © 2016 Wiley Periodicals, Inc.

Population-based microcephaly surveillance in the United States, 2009 to 2013: An analysis of potential sources of variation.

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 <20 years (11.5) and ≥40 years (13.2). For gestational age and birth weight, the highest prevalence was among infants <32 weeks gestation and infants <1500 gm. Case definitions varied; 41.8% of cases had an HC ≥ the 10th percentile for sex and gestational age. CONCLUSION: Differences in methods, population distribution of maternal/infant characteristics, and case definitions for microcephaly can contribute to the wide range of observed prevalence estimates across individual birth defects surveillance programs. Addressing these factors in the setting of Zika virus infection can improve the quality of prevalence estimates. Birth Defects Research (Part A) 106:972-982, 2016. © 2016 Wiley Periodicals, Inc.

Prenatal diagnosis, birth location, surgical center, and neonatal mortality in infants with hypoplastic left heart syndrome.

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 <10 minutes from a CSC was 21.0%, 10 to 90 minutes 25.2%, and >90 minutes 39.6% (P for trend <0.001). Prenatal diagnosis alone was not associated with improved survival (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 <10 minutes. In subanalysis, birth >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.

Racial/ethnic disparities in timing of death during childhood among children with congenital heart defects.

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.

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

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

Interpregnancy interval and prevalence of selected birth defects: A multistate study.

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 < 6 months and long IPI ≥ 60 months compared to 18-23 months (referent). Sensitivity analyses limited to active-surveillance states and those with<10% missing IPI. RESULTS: Among 5,147,962 eligible births, 6.3% had short IPI while 19.8% had long IPI. Compared to referent, prevalence with short IPI was elevated for gastroschisis (3.7, CI: 3.0-4.5 vs. 2.0, CI: 1.6-2.4) and with both short and long IPI for tetralogy of Fallot (short: 3.4, 2.8-4.2 long: 3.8, 3.4-4.3 vs. 2.7, 2.3-3.2) and cleft lip ± palate (short: 9.9, 8.8-11.2 long: 9.2, 8.5-9.8 vs. 8.4, 7.6-9.2). Stratified analyses identified additional associations, including elevated prevalence of anencephaly with short IPI in younger mothers and limb defects with long IPI in those ages 25-34 at prior birth. Sensitivity analyses showed similar results. CONCLUSION: In this population-based study, we observed increased prevalence of several birth defects with short and long IPI.

Mortality in first 5 years in infants with functional single ventricle born in Texas, 1996 to 2003.

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.

Mortality among infants with birth defects: Joint effects of size at birth, gestational age, and maternal race/ethnicity.

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 (HR(a) = 6.1; 95% CI, 5.2, 7.2) and the lowest early childhood survival (76%), followed by SGA preterm NH-blacks (HR(a) = 4.8; 95% CI, 3.6, 6.5; survival = 81%) and SGA preterm NH-whites (HR(a) = 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.

Gastroschisis prevalence in Texas 1999-2003.

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 <0.02). Infants of young and nulliparous mothers were at greatest risk in crude analyses. Other characteristics associated with increased risk were 12 or fewer years of education, border residence, and Hispanic ethnicity. Black mothers were at lower risk. When adjusted for maternal age, race/ethnicity, education, parity, and residence, we found that border residence, educational level, and Hispanic race/ethnicity were no longer significant, but young mothers and nulliparous mothers remained at higher risk, and blacks at reduced risk. Differences in prevalence observed between regions and counties largely disappeared when adjusted for maternal factors. No significant difference between urban and rural residence was found. CONCLUSION: The prevalence of gastroschisis increased in Texas during 1999-2003. Black mothers were at lower risk, and Hispanic mothers were at no greater risk than whites. No differences were found between urban/rural or border/nonborder residents.

Change in prepregnancy body mass index and gastroschisis.

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 2561 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 greater than 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.

Third grade academic achievement among children conceived with the use of in vitro fertilization: a population-based study in Texas.

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.

Assessment of Birth Defects and Cancer Risk in Children Conceived via In Vitro Fertilization in the US.

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.

Association of interpregnancy change in body mass index and spina bifida.

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.

Pre-Zika descriptive epidemiology of microcephaly in Texas, 2008-2012.

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 <3rd percentile). RESULTS: The birth prevalence for total and total severe microcephaly were 14.7 and 4.8 per 10,000 livebirths, respectively. For explained and unexplained cases, significantly elevated risks were noted for mothers who were older (35+), less educated (≤12 years), diabetic (pre-pregnancy or gestational), or had a preterm delivery. Unlike explained cases, however, mothers who were non-White or smoked had an increased risk for unexplained microcephaly. Furthermore, young maternal age (<20), multiparity, and higher BMI reduced the risk for unexplained microcephaly. For severe unexplained cases, the risk profile was similar to that for all unexplained cases-with the exception of null associations noted for diabetes and birth year. CONCLUSIONS: We found that risk patterns for microcephaly varied across case groupings. Risk factors included maternal race/ethnicity, age, and smoking during pregnancy. Among severe unexplained cases, notable positive associations were seen among mothers who were non-Hispanic Black or less educated, while inverse associations were noted for obesity.