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In recent decades, the use of assisted reproductive technology (ART) has increased rapidly. To assess the relationship between ART and autism diagnosis, we linked California birth records from 2000 through 2016 with contemporaneous records from the National ART Surveillance System (NASS) and autism caseload records from California's Department of Developmental Services from 2000 through November 2019. All 95 149 birth records that were successfully linked to a NASS record, indicating an ART birth, were matched 1:1 using propensity scores to non-ART births. We calculated the hazard risk ratio for autism diagnosis and the proportions of the relationship between ART conception and autism diagnosis mediated by multiple birth pregnancy and related birth complications. The hazard risk ratio for autism diagnosis following ART compared with non-ART conception is 1.26 (95% CI, 1.17-1.35). Multiple birth, preterm birth, and cesarean delivery jointly mediate 77.9% of the relationship between ART conception and autism diagnosis. Thus, increased use of single embryo transfer in the United States to reduce multiple births and related birth complications may be a strategy to address the risk of autism diagnosis among ART-conceived children., (Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2024.)

Autism spectrum disorder (ASD) is a prevalent developmental disorder. Studies indicate that while ASD etiology has a genetic component, the risk is polygenic, with gene-environment interactions being likely. The prenatal period is a critical exposure window for nongenetic risk factors. Previous studies have found positive associations between congenital malformations (all types) and ASD; a few also found specific associations between genitourinary system malformations and ASD; and one study found an association between hypospadias and ASD. In the accompanying article, Rotem et al. (Am J Epidemiol. 2018;187(4):656-663) describe how they conducted a comprehensive analysis focusing on the shared risk of ASD with hypospadias or cryptorchidism, using existing data from a large Israeli health services system, which afforded several advantages because of the large sample size and low attrition of the patient population. The authors conducted a careful analysis, including sensitivity analyses, to account for risk factor and case misclassifications that might have occurred had they relied solely on preexisting diagnostic codes to define exposures and outcome. They observed positive associations between both hypospadias and cryptorchidism and ASD that were independent of numerous sociodemographic and pregnancy health factors. This study advances our understanding of ASD etiology and illustrates how existing data might be used to assess some ASD risk factors.

Participant attrition can limit inferences drawn from study results and inflate research costs. We examined factors associated with completion of the Study to Explore Early Development (2007-2011), a multiple-component, case-control study of risk factors for autism spectrum disorder in preschoolers, conducted in California, Colorado, Georgia, Maryland, North Carolina, and Pennsylvania. Participants (n = 3,769) were asked to complete phone interviews, questionnaires, an in-person evaluation, and biologic sampling. We examined whether participant demographic and administrative factors predicted completion using mixed-effects logistic regression models. Completion of individual key study components was generally 70% or higher. However, 58% of families completed all per-protocol data elements (defined a priori as key study components). Per-protocol completion differed according to mother's age, race, educational level, driving distance to clinic, number of contact attempts to enroll, and number of telephone numbers provided (all P < 0.05). Case status was not associated with completion, despite additional data collection for case-confirmation. Analysis of a subset that completed an early interview revealed no differences in completion by household factors of income, primary language spoken, number of adults, or number of children with chronic conditions. Differences in completion by race and education were notable and need to be carefully considered in developing future recruitment and completion strategies.

Background: Clomiphene citrate (CC) is the first line drug for subfertility treatment. Studies assessing the association between CC and birth defects have been inconclusive., Methods: We used data from the National Birth Defects Prevention Study, a population-based, multi-site case-control study of major birth defects. Women from 10 US regions with deliveries affected by at least one of >30 birth defects (cases) and mothers of live born infants without a major birth defect (controls) who delivered October 1997-December 2005 were interviewed. The exposure of interest was reported CC use in the period from 2 months before conception through the first month of pregnancy. Women who conceived using assisted reproductive technology were excluded. Thirty-six birth defect categories with at least three exposed cases were studied. Multiple logistic regression was used to control for potential confounders., Results: CC use was reported by 1.4% of control mothers (94/6500). Among 36 case-groups assessed, increased adjusted odds ratios (aOR) were found [all: aOR, 95% confidence interval (CI)] for anencephaly (2.3, 1.1-4.7), Dandy-Walker malformation (4.4, 1.7-11.6), septal heart defects (1.6, 1.1-2.2), muscular ventricular septal defect (4.9, 1.4-16.8), coarctation of aorta (1.8, 1.1-3.0), esophageal atresia (2.3, 1.3-4.0), cloacal exstrophy (5.4, 1.6-19.3), craniosynostosis (1.9, 1.2-3.0) and omphalocele (2.2, 1.1-4.5)., Conclusions: Several associations between CC use and birth defects were observed. However, because of the small number of cases, inconsistency of some findings with previous reports, and the fact that we cannot assess the CC effect separately from that of the subfertility, these associations should be interpreted cautiously.

Background: This paper assesses the risk of cerebral palsy (CP) in children born after assisted conception compared with children born after natural conception (NC)., Methods: This population based follow-up study included all 588,967 children born in Denmark from 1995 to 2003. Assisted conception was defined as IVF, with or without ICSI, and ovulation induction (OI), with or without subsequent insemination., Results: There were 33 139 (5.6%) children born in Denmark from 1995 to 2003 as a result of assisted conception and through to June 2009, 1146 (0.19%) children received a CP diagnosis. Children born after assisted conception had an increased risk of a CP diagnosis, crude hazard rate ratio (HRR) 1.90 (95% CI: 1.57-2.31) compared with NC children. Divided into IVF and OI children compared with NC children, the risk was HRR 2.34 (95% CI: 1.81-3.01) and HRR 1.55 (95% CI: 1.17-2.06), respectively. When we included the intermediate factors multiplicity and gestational age in multivariate models, the risk of CP in assisted conception disappeared. In general, children with CP born after assisted conception had similar CP subtypes and co-morbidities as children with CP born after NC., Conclusion: The risk of CP is increased after both IVF and OI. The increased risk of CP in children born after assisted conception, and in particular IVF, is strongly associated with the high proportion of multiplicity and preterm delivery in these pregnancies. A more widespread use of single embryo transfer warrants consideration to enhance the long-term health of children born after IVF.

Infertility treatments that include ovulation stimulation, both assisted reproductive technologies (ARTs) and non-ART ovulation stimulation, are associated with increased risks of multiple birth and concomitant sequelae and adverse outcomes, even among singletons. While a US surveillance system for ART-induced births is ongoing, no population-based tracking system exists for births resulting from non-ART treatments. The authors developed a multistage model to estimate the uncertain proportion of US infants born in 2005 who were conceived by using non-ART ovulation treatments. Using published surveillance data, they estimated proportions of US multiple births conceived naturally and by ART and assumed that the remainder were conceived with non-ART treatments. They used Bayesian meta-analyses to summarize published clinical studies on the multiple-gestation risk associated with non-ART ovulation treatments, applied a fetal survival factor, and used this multiple-birth risk estimate and their own estimate of the proportion of US multiple births attributable to non-ART ovulation stimulation to estimate the total (and, through subtraction, singleton) proportion of infants conceived with such treatments. On the basis of the model, the authors estimate that 4.6% of US infants born in 2005 (95% uncertainty range: 2.8%-7.1%) resulted from non-ART ovulation treatments. Notably, this figure is 4 times greater than the ART contribution.

Background: An increasing number of children are born after assisted conception and in surveillance programmes information on mode of conception is often achieved via maternal self-report. We assessed the validity of self-reported assisted conception in The Danish National Birth Cohort (DNBC), a prospective pregnancy cohort. Here, the term assisted conception refers to IVF, ICSI, ovulation induction and insemination., Methods: We compared self-reported assisted conception in the DNBC to corresponding data from Danish national registers; the IVF Register and Danish Drug Prescription Register, providing method of conception in the entire population. In the DNBC, 101,042 women accepted the invitation in early pregnancy from 1996 to 2002. Our final study population comprised 88,151 DNBC women aged 20 years and older who participated in the first DNBC interview with a pregnancy resulting in a live born child., Results: In the DNBC, assisted conception was reported with a sensitivity of 83% and positive predictive value of 88%. Misclassification was largely explained by ambiguous phrasing of the DNBC interview question and interview skip patterns. Women with false negative reporting were more often multipara (P < 0.001) and older (P = 0.027 for IVF/ICSI and P = 0.002 for ovulation induction). The risk ratio (RR) for being born preterm in IVF/ICSI children was lower for children identified via the DNBC, RR 3.61 (95% confidence interval (CI) 3.31-3.94), than the IVF Register, RR 4.36 (95% CI 4.02-4.74)., Conclusions: There was a high positive predictive value of self-reported assisted conception in the DNBC, but the structure of the DNBC interview represented a problem and misclassification could introduce bias.

Background: With >1% of US births occurring following use of assisted reproductive technology (ART), it is critical to examine whether ART is associated with birth defects., Methods: We analyzed data from the National Birth Defects Prevention Study, a population-based, multicenter, case-control study of birth defects. We included mothers of fetuses or live-born infants with a major birth defect (case infants) and mothers who had live-born infants who did not have a major birth defect (control infants), delivered during the period October 1997-December 2003. We compared mothers who reported ART use (IVF or ICSI) with those who had unassisted conceptions. Multiple logistic regression was used to adjust for the following confounders: maternal race/ethnicity, maternal age, smoking and parity; we stratified by plurality., Results: ART was reported by 1.1% of all control mothers, and by 4.5% of control mothers 35 years or older. Among singleton births, ART was associated with septal heart defects (adjusted odds ratio [aOR] = 2.1, 95% confidence intervals [CI] 1.1-4.0), cleft lip with or without cleft palate (aOR = 2.4, 95% CI 1.2-5.1), esophageal atresia (aOR = 4.5, 95% CI 1.9-10.5) and anorectal atresia (aOR = 3.7, 95% CI 1.5-9.1). Among multiple births, ART was not significantly associated with any of the birth defects studied., Conclusions: These findings suggest that some birth defects occur more often among infants conceived with ART. Although the mechanism is not clear, couples considering ART should be informed of all potential risks and benefits.

This study evaluated independent effects of maternal and paternal age on risk of autism spectrum disorder. A case-cohort design was implemented using data from 10 US study sites participating in the Centers for Disease Control and Prevention's Autism and Developmental Disabilities Monitoring Network. The 1994 birth cohort included 253,347 study-site births with complete parental age information. Cases included 1,251 children aged 8 years with complete parental age information from the same birth cohort and identified as having an autism spectrum disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria. After adjustment for the other parent's age, birth order, maternal education, and other covariates, both maternal and paternal age were independently associated with autism (adjusted odds ratio for maternal age > or =35 vs. 25-29 years = 1.3, 95% confidence interval: 1.1, 1.6; adjusted odds ratio for paternal age > or =40 years vs. 25-29 years = 1.4, 95% confidence interval: 1.1, 1.8). Firstborn offspring of 2 older parents were 3 times more likely to develop autism than were third- or later-born offspring of mothers aged 20-34 years and fathers aged <40 years (odds ratio = 3.1, 95% confidence interval: 2.0, 4.7). The increase in autism risk with both maternal and paternal age has potential implications for public health planning and investigations of autism etiology.

Background: Approximately 18% of multiple births in the USA result from assisted reproduction technology (ART). Although many studies comparing ART and naturally conceived twins report no difference in risks for perinatal outcomes, others report slight to moderate positive or protective associations., Methods: We selected twin deliveries with and without indication of ART from Massachusetts live birth-infant death records from 1997 to 2000 linked to the US ART surveillance system. The sample was restricted to deliveries by mothers with increased socioeconomic status, private health insurance and intermediate/plus prenatal care use. Our final sample included 1446 and 2729 ART and non-ART twin deliveries, respectively. Odds ratios (OR) for associations between ART and perinatal outcomes were adjusted for maternal demographic factors, smoking, prenatal care and hospital care level., Results: ART twin deliveries were less likely than non-ART to be very preterm (adjusted OR 0.75; 95% confidence interval 0.58-0.97) or include a very low birthweight (<1500 g) infant (0.75; 0.58-0.95) or infant death (0.55; 0.35-0.88). In stratified analyses, these findings were observed among primiparous deliveries, but there were no risk differences among multiparous ART and non-ART twin deliveries., Conclusions: ART treatment was not a risk factor for adverse perinatal outcome, and risks for several outcomes were somewhat lower among ART twin deliveries. Nonetheless, ART is strongly associated with twinning and twins remain a high-risk group, relative to singletons. Promoting singleton gestation in assisted conception is an important strategy for reducing adverse outcomes.

Approximately 30% of pregnancies in the United States may end in miscarriage or stillbirth. Whether pregnancies conceived through assisted reproductive technology (ART) are at an increased risk of loss is inconclusive, and data on maternal age-, ART type-, and gestational age-specific risk of loss are limited. Data on 148,494 ART pregnancies conceived from 1999 through 2002 were analyzed by use of the Kaplan-Meier method to estimate risks of pregnancy loss after specified gestational ages (conditional risk) for 14 groups stratified by maternal age and ART procedure. Births, maternal deaths, and induced abortions were censored. The Kaplan-Meier estimate of total risk of pregnancy loss was 29% but ranged from 22% to 63% depending on patient age and ART procedure. By 6 weeks' gestation, 58% of all pregnancy losses occurred. Conditional risk of pregnancy loss ranged from 10% to 45% at 6 weeks' gestation and from 2% to 7% at the first trimester; it was less than 2% after 20 weeks' gestation. Results can be used to counsel ART patients and inform future research on the etiology of pregnancy loss.

Background: Increasing use of IVF in the USA has been a major contributor to the rising national multiple birth rate. Many have advocated that reducing the number of embryos transferred is essential for addressing the IVF-associated multiple birth problem., Methods: A population-based sample of 506 072 IVF transfers performed in the USA in 1996-2002 was used to investigate trends in embryo transfer practices and to determine whether any changes in practice patterns have impacted the multiple gestation risk associated with IVF., Results: The proportion of procedures in which >or=3 embryos were transferred declined significantly for most patient groups between 1996 and 2002. However, declines for some groups were not sizeable (from 79 to 73% and from 76 to 71% for fresh, non-donor procedures among women aged 38-40 and 41-42 years respectively) and transferring >or=3 embryos remained the norm for all groups. As of 2002, single embryo transfer had not increased for most groups and remained uncommon. Some declines in overall multiple gestation rates were observed, although multiple gestation risk associated with 2 embryos transferred increased significantly for all groups., Conclusions: Despite changes in embryo transfer practices, multiple gestation risk remains high, in part due to increased multiple gestation rates associated with the transfer of two embryos.

Background: Multiple births are associated with serious adverse infant and maternal outcomes. The objective of this study was to assess the multiple-birth risk (MBR) associated with IVF and determine whether the risk is impacted by stage of embryo development at transfer., Methods: A population-based sample of 50 819 IVF transfers utilizing day 3 or day 5 embryos performed in the USA in 2001 on women aged 20-40 years was used to assess MBR and live-birth rate (LBR), stratified by patient age, supernumerary embryo availability, and number of embryos transferred., Results: Although significantly more day 5 than day 3 transfers used < or =2 embryos (69.2 versus 27.7%), the former were not associated with decreased MBR. MBR was high when >1 embryo was transferred, irrespective of embryo development stage. LBR were generally maximized with 2 embryos transferred, and for some (day 5 transfers, patients aged 35-37 years) with one embryo. Electing to transfer a single day 5 embryo appeared efficacious for some patients: women aged 20-37 years with supernumerary embryos cryopreserved had LBR of 31.6-39.5%., Conclusions: MBR is high when > or =2 embryos are transferred. Single embryo transfer is the only way to prevent many multiple births and associated adverse health outcomes.

Research aimed at the empirical evaluation of infertility treatment including assisted reproductive technologies (ART) on child health and development is hampered by investigators' inability to methodologically separate possible treatment effects from underlying fecundity impairments. While the literature continues to identify ART as a risk factor for many child health outcomes, less attention has been paid to the methodologic rigor needed to answer this question. We identify aspects of fecundity and the nuances of medical practice that need to be considered and captured when designing epidemiologic investigations aimed at assessing ART and child health. These include: (i) the use of prospective study designs in which the unit of analysis (cycle versus individual versus couple) is defined; (ii) data collection on relevant time-varying covariates at, before and during treatment; and (iii) the use of statistical techniques appropriate for hierarchical data and correlated exposures. While none of these issues in and by itself is unique to ART research, attention to these issues has been lacking in much of the published research limiting our ability to evaluate health consequences for children. Longitudinal studies of children conceived with ART will benefit from attention to these issues and, hopefully, produce answers to lingering questions about safety.

Background: This study examines the association between day of embryo transfer and monozygotic (MZ) twinning., Methods: We used a population-based sample of 108,36 IVF/embryo transfer procedures in which the patients oocytes' were freshly fertilized (non-frozen; non-donor) and 39,98 resultant pregnancies from US clinics in 1999 and 2000. Cases were pregnancies for which the number of fetal hearts observed on ultrasound exceeded the number of embryos transferred. These pregnancies were considered to contain at least one set of MZ twins. A total of 226 MZ pregnancies were compared with two control groups: 23,880 singleton pregnancies (one fetal heart) and 15,092 other multiple-gestation pregnancies (> or = 2 fetal hearts but the number of fetal hearts on ultrasound was less than or equal to the number of embryos transferred)., Results: Cases of presumed MZ multiple-gestation pregnancies were more likely to have had a day 5 embryo transfer compared with day 3 embryo transfers than singleton pregnancies [adjusted odds ratio (AOR) = 3.92, 95% confidence interval (CI) = 2.97-5.17] or other multiple-gestation pregnancies (AOR = 3.91, 95% CI = 2.96-5.17) conceived with IVF/embryo transfer., Conclusions: Day 5 embryo transfer may be associated with increased MZ twinning., (Copyright 2004 European Society of Human Reproduction and Embryology)

For assisted reproductive technology (ART) treatments, measures of success that move beyond traditional measures of pregnancy and live birth and narrow the numerator to infant outcomes with an optimal short- and long-term prognosis are needed. Hence, presentation of singleton live birth delivery rates is warranted. Twins have greatly increased risks for morbidity and mortality in comparison with singletons. Success rates based on singleton live births will more completely inform patients evaluating which ART treatment options will maximize their chance for a healthy infant. Additionally, providers who limit embryos transferred can feel they are on an even playing field in reporting their success rates. Measures of success that narrow the numerator further to exclude preterm or low birth weight singleton births might also be informative. However, the utility of such measures is less clear because the aetiologies of preterm birth and low birth weight among singletons are probably multifactorial. While it may be desirable to consider adverse outcomes such as congenital anomalies in defining treatment success, it is unfeasible to collect complete and accurate data on anomalies in current ART registries. As ART use increases, continual re-examination and critique of the manner in which success is defined and presented to the public is critical.

Background: Increasing use of assisted reproductive technology treatments has been associated with the current rise in multiple births in the USA. Embryo cryopreservation and subsequent thawed embryo transfer may favourably impact the multiple-birth risk by relieving some pressure that patients and providers may feel to transfer several embryos in a single cycle. The study objective was to examine both live-birth rates and multiple-birth risk in thawed cycles., Methods: The authors used a population-based sample of 21 555 assisted reproductive technology procedures performed in US clinics in 1999 and 2000 that used thawed embryos derived from the patient's oocytes., Results: Both patient age and the number of embryos transferred were independent predictors of live birth. Even among women aged 20-29 years, the transfer of three embryos resulted in an increase in the live-birth rate compared with cycles in which one or two embryos were transferred. This increase in success was accompanied by an increased multiple-birth risk. In all age groups up to 40 years, the transfer of just two embryos resulted in a multiple-birth risk of 16-17%. The multiple-birth risk increased with the number of embryos transferred., Conclusions: Patient age and the number of embryos transferred significantly affect live-birth and multiple-birth rates among women who use thawed embryos.

Multiple birth, which is associated with adverse fetal, infant, and maternal outcomes, is increasingly related to the use of in vitro fertilization (IVF). Among women undergoing IVF who use their own eggs, greater maternal age is associated with decreased risk of multiple birth; using donor eggs from younger women may negate this age effect. Data from 6,936 IVF procedures performed in the United States in 1996-1997 on women aged 35-54 years who used donor eggs were analyzed to assess the effect of maternal age, number of embryos transferred, and cryopreservation of extra, nontransferred embryos (an indicator of higher embryo quality) on risk of multiple birth. Greater maternal age did not decrease multiple-birth risk. Rates of multiple birth were related to number of embryos transferred and whether extra embryos had been cryopreserved, and they were high compared with those of IVF patients the same age who had used their own eggs. Among women who had extra embryos cryopreserved, transferring more than two embryos increased multiple-birth risk, with no corresponding increase in the chance for a livebirth. These results highlight the need to consider the age of the donor and embryo quality when making embryo transfer decisions involving use of donor eggs.

This study examined the validity of self-reported delivery weight among 3,518 respondents to the 1988 National Maternal and Infant Health Survey. Self-reported delivery weight was ascertained from a mail survey administered during the postpartum period. Measured delivery weight was obtained by abstraction of medical records from the hospital of delivery. On average, a woman's reported delivery weight was 2.82 pounds (1 pound = 0.45 kg) less than her measured delivery weight (p < 0.001). The level of underreporting increased significantly with increases in prepregnancy body mass index, current body mass index, pregnancy weight gain, and weight change from delivery to recall. Reporting error also increased among women who were non-White, less educated, and unmarried; whose pregnancy was unintended; and who initiated prenatal care late, responded late to the survey questionnaire, became pregnant again before responding, and reported a delivery weight ending in zero. When reported delivery weight was used to calculate weight gain and was categorized into typical weight gain categories, 30-40% of women were classified incorrectly. An empirical evaluation of how this misclassification might impact epidemiologic analyses indicated that associations between weight gain and birth weight were attenuated when weight gain was based on reported delivery weight rather than on measured delivery weight.