Maternal polycystic ovary syndrome and risk of neuropsychiatric disorders in offspring: prenatal androgen exposure or genetic confounding?

BACKGROUND: Maternal polycystic ovary syndrome (PCOS) has been proposed as a model for investigating the role of prenatal androgen exposure in the development of neuropsychiatric disorders. However, women with PCOS are at higher risk of developing psychiatric conditions and previous studies are likely confounded by genetic influences. METHODS: A Swedish nationwide register-based cohort study was conducted to disentangle the influence of prenatal androgen exposure from familial confounding in the association between maternal PCOS and offspring attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), and Tourette's disorder and chronic tic disorders (TD/CTD). PCOS-exposed offspring (n = 21 280) were compared with unrelated PCOS-unexposed offspring (n = 200 816) and PCOS-unexposed cousins (n = 17 295). Associations were estimated with stratified Cox regression models. RESULTS: PCOS-exposed offspring had increased risk of being diagnosed with ADHD, ASD, and TD/CTD compared with unrelated PCOS-unexposed offspring. Associations were stronger in girls for ADHD and ASD but not TD/CTD [ADHD: adjusted hazard ratio (aHR) = 1.61 (95% confidence interval (CI) 1.31-1.99), ASD: aHR = 2.02 (95% CI 1.45-2.82)] than boys [ADHD: aHR = 1.37 (95% CI 1.19-1.57), ASD: aHR = 1.46 (95% CI 1.21-1.76)]. For ADHD and ASD, aHRs for girls were stronger when compared with PCOS-unexposed cousins, but slightly attenuated for boys. CONCLUSIONS: Estimates were similar when accounting for familial confounding (i.e. genetics and environmental factors shared by cousins) and stronger in girls for ADHD and ASD, potentially indicating a differential influence of prenatal androgen exposure v. genetic factors. These results strengthen evidence for a potential causal influence of prenatal androgen exposure on the development of male-predominant neuropsychiatric disorders in female offspring of women with PCOS.

Chronic hypertension in pregnancy and the risk of congenital malformations: a cohort study.

OBJECTIVE: Chronic hypertension is a common medical condition in pregnancy. The purpose of the study was to examine the association between maternal chronic hypertension and the risk of congenital malformations in the offspring. STUDY DESIGN: We defined a cohort of 878,126 completed pregnancies linked to infant medical records using the Medicaid Analytic Extract. The risk of congenital malformations was compared between normotensive controls and those with treated and untreated chronic hypertension. Confounding was addressed using propensity score matching. RESULTS: After matching, compared with normotensive controls, pregnancies complicated by treated chronic hypertension were at increased risk of congenital malformations (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.2-1.5), as were pregnancies with untreated chronic hypertension (OR 1.2; 95% CI, 1.1-1.3). In our analysis of organ-specific malformations, both treated and untreated chronic hypertension was associated with a significant increase in the risk of cardiac malformations (OR, 1.6; 95% CI, 1.4-1.9 and OR, 1.5; 95% CI, 1.3-1.7, respectively). These associations persisted across a range of sensitivity analyses. CONCLUSION: There is a similar increase in the risk of congenital malformations (particularly cardiac malformations) associated with treated and untreated chronic hypertension that is independent of measured confounders. Studies evaluating the teratogenic potential of antihypertensive medications must control for confounding by indication. Fetuses and neonates of mothers with chronic hypertension should be carefully evaluated for potential malformations, particularly cardiac defects.

Imprinting disorders in children conceived with assisted reproductive technology in Sweden.

OBJECTIVE: To assess whether the use of assisted reproductive technology (ART) therapy for conception is associated with imprinting disorders in children and the impact of parental factors related to infertility. DESIGN: A nationwide register-based cohort study. SETTING: Swedish national registers and nationwide quality IVF register. PATIENT(S): All liveborn singletons in Sweden (N = 2,084,127) between 1997 and 2017 with follow-up to December 31, 2018. INTERVENTION(S): The use of specific methods implemented in ART. MAIN OUTCOME MEASURE(S): The International Classification of Diseases version 10 was used to identify three distinct imprinting disorder groups: Beckwith-Wiedemann syndrome (BWS), Prader-Willi syndrome (PWS), and Silver-Russell syndrome (SRS), as well as central precocious puberty. The Cox model combined with inverse probability treatment weights was used to estimate the weighted hazard ratio (wHR) with a 95% confidence interval (CI), accounting for multiple confounders. RESULT(S): A total of 1,044 children were diagnosed with the disorders of interest, and 52 of them were conceived using ART therapy. The overall risk of being diagnosed with any of the studied imprinting disorders was elevated in children conceived using ART therapy compared with all other children (HR, 1.84; 95% CI, 1.38-2.45). After adjusting for parental background factors, the association was partially attenuated (wHR, 1.50; 95% CI, 0.97-2.32), but remained in the weighted comparison restricted to children of couples with known infertility (wHR, 1.52; 95% CI, 1.05-2.21). For the specific diagnoses of PWS/SRS, and BWS compared with children of couples with known infertility, children conceived with ART therapy showed a small excess risk, which could not be distinguished from the null (wHR, 1.56; 95% CI, 0.93-2.62 and 1.80; 95% CI, 0.99-3.28, respectively). Further subgroup analysis showed that the combined use of intracytoplasmic sperm injection and cryopreserved embryos was associated with a higher risk of both PWS/SRS (wHR, 4.60; 95% CI, 1.72-12.28) and BWS (wHR, 6.69; 95% CI, 2.09-21.45). The number of central precocious puberty cases in children conceived using ART therapy was too small (N = 3) to make any meaningful inference. CONCLUSION(S): The combined use of intracytoplasmic sperm injection and cryopreserved embryos was associated with small elevated risks of PWS/SRS, and BWS in children, independent of parental factors related to infertility.

Prediction of pregnancy-related complications in women undergoing assisted reproduction, using machine learning methods.

OBJECTIVE: To use machine learning methods to develop prediction models of pregnancy complications in women who conceived with assisted reproductive techniques (ART). DESIGN: A nation-wide register-based cohort study with prospectively collected data. SETTING: Swedish national registers and nationwide quality IVF register. PATIENT(S): all nulliparous women who achieved birth within the first 3 ART treatment cycles between 2008 and 2016 in Sweden. INTERVENTION(S): Characteristics before the use of ART, such as demographics and medical history, were considered potential predictors in the development of before treatment prediction models. ART treatment details were further included in after treatment prediction models. MAIN OUTCOME MEASURE(S): Potential diagnoses of preeclampsia, placental complications (previa, accreta, and abruption), and postpartum hemorrhage were identified using the International Classification of Diseases recorded in the Swedish Medical Birth and Patient registers, respectively. Multiple prediction model algorithms were performed and compared for each outcome and treatment cycle, including logistic regression, decision tree model, naïve Bayes classification, support vector machine, random forest, and gradient boosting. The performance of each model was assessed with C statistic, and nested cross-validation was used to aid model selection and hyperparameter tuning. RESULT(S): A total of 14,732 women gave birth after the first (N = 7,302), second (N = 4,688), or third (N = 2,742) ART cycle, representing birth rates of 24.1%, 23.8%, and 22.0%. Overall prediction performance did not vary much across the different methods used. In the first cycle, the before treatment prediction performance was at best 66%, 66%, and 60% for preeclampsia, placental complications, and postpartum hemorrhage, respectively. Inclusion of after treatment characteristics conferred slight improvement (approximately 1%-5%), as did prediction in later cycles (approximately 1%-5%). The top influential and consistent predictors included age, region of residence, infertility diagnosis, and type of embryo transfer (fresh or frozen) in the later (2nd and 3rd) cycles. Body mass index was a top predictor of preeclampsia and was also influential for placental complications but not for postpartum hemorrhage. CONCLUSION(S): The combined use of demographics, medical history, and ART treatment information was not enough to confidently predict serious pregnancy complications in women who conceived with ART. Future studies are needed to assess if additional longitudinal follow-up during pregnancy can improve the prediction to allow clinical protocol development.

Maternal and fetal genetic contributions to postterm birth: familial clustering in a population-based sample of 475,429 Swedish births.

This study examines the familial clustering and relative influence of genetic and environmental effects on postterm birth in the Swedish population by considering all full- and half-siblings born in Sweden between 1992 and 2004. Of the eligible 475,429 births, 21% occurred after 41 completed weeks and 5.5% occurred after 42 completed weeks of gestation. Odds of postterm birth increased if mothers were older, heavier, more educated, primiparous, or carrying a male fetus. The highest odds increase was seen in women with a previous postterm birth, both with the same partner (odds ratio = 4.4, 95% confidence interval: 4.0, 4.6) and after a partner change (odds ratio = 3.4, 95% confidence interval: 2.9, 3.9). Sisters of women with a postterm birth were also at increased odds of postterm birth (odds ratio = 1.8, 95% confidence interval: 1.6, 2.0) while brothers' partners were not. Half of the variation in postterm birth could not be explained by factors shared in families, and the remaining half was explained by genetic factors, namely fetal (26%) and maternal (21%) genetic factors. Familial clustering of postterm birth is attributed to genetic effects, and fetal genetic effects have a considerable influence on the liability of postterm birth.

Low digit ratio predicts early age at menarche in Colombian schoolgirls.

BACKGROUND: The ratio between the lengths of the second and fourth fingers (digit ratio: 2D : 4D), a purported negative correlate of prenatal androgen exposure, has been inversely related to age at menarche. However, a recent study found high digit ratios in carriers of a single variant in the LIN28B gene, which has been linked to delayed menarche. METHODS: We investigated the association of digit ratio and age at menarche in 299 pre-menarcheal girls aged 5-12 years who participated in a longitudinal cohort study in Bogotá, Colombia. Finger lengths were measured at baseline and the occurrence of menarche was periodically ascertained over a median 32 months of follow-up. We used time-to-event analysis to estimate median ages at menarche as well as hazard ratios for menarche according to tertiles of the digit ratio for each hand. RESULTS: Estimated median age at menarche was lower for girls in the lowest digit ratio tertile of the right hand compared with those in the highest (12.0 vs. 12.3 years; P-value = 0.04). After adjustment for baseline age, height- and body mass index-for-age z-scores, the hazard of menarche was 86% higher in girls of the lowest digit ratio tertile (hazard ratio 1.9 [95% confidence interval 1.2, 2.9]) compared with those in the highest digit ratio tertile of the right hand. No significant associations were found with the left hand. CONCLUSIONS: Digit ratio was positively associated with age at menarche in this longitudinal investigation, consistent with results from a recent gene-linkage study.

Long-term Follow-up of Psychiatric Disorders in Children and Adolescents Conceived by Assisted Reproductive Techniques in Sweden.

Importance: Individuals conceived with assisted reproductive techniques (ARTs) could be at elevated risk of psychiatric disorders owing to potential adverse effects of the procedures themselves, or because such traits or their risk factors may be more common in couples with infertility. Objective: To investigate the risk of psychiatric disorders in adolescents and young adults conceived with ARTs and to evaluate the role of treatment-related parental characteristics. Design, Setting, and Participants: This prospective follow-up of a nationwide birth cohort used linkage of Swedish population registers with coverage through 2018. All children born in Sweden from January 1, 1994, to December 31, 2006, were included in the analysis. Follow-up was completed on December 31, 2018, when participants were 12 to 25 years of age, and data was analyzed from March 17, 2020, to September 10, 2021. Exposures: In vitro fertilization with or without intracytoplasmic sperm injection and transfer of fresh or frozen-thawed embryos. Main Outcomes and Measures: Clinical diagnoses of mood disorder, including major depression, anxiety, obsessive-compulsive disorder (OCD), or suicidal behavior, were identified from hospital records and outpatient specialist care. Suicide was additionally identified from death certificates. Antidepressant use was identified from dispensations of prescribed medications. Results: A total of 1 221 812 children (48.6% female, 51.4% male) born between 1994 and 2006 were followed up to a median age of 18 (IQR, 15-21) years. Among these participants, 31 565 (2.6%) were conceived with ART. Compared with all others, adolescents conceived with ART had an elevated risk of OCD (hazard ratio [HR], 1.35 [95% CI, 1.20-1.51]), but the association was attenuated and no longer statistically significant after adjustment for parental characteristics (adjusted HR [aHR], 1.10 [95% CI, 0.98-1.24]) and was no longer present when restricted to individuals born to couples with known infertility (aHR, 1.02 [95% CI, 0.89-1.17]). Adolescents conceived with ARTs were not at elevated risk of depression or suicidal behavior compared with other adolescents (irrespective of parental infertility). Type of fertilization (standard in vitro fertilization or intracytoplasmic sperm injection) had no association with outcomes. Compared with non-ART-conceived children of couples with infertility, fresh, but not frozen, embryo transfer was associated with a lower risk of mood disorders (aHR, 0.90 [95% CI, 0.83-0.97]), making frozen embryo transfer appear less advantageous when directly contrasted with fresh embryo transfer. Conclusions and Relevance: These findings suggest that adolescents conceived with ARTs around the millennium are not at risk of poor psychiatric health compared with the general population, except for an elevated risk of OCD that may be explained by differences in parental characteristics.

Within-Family Analysis of Interpregnancy Interval and Adverse Birth Outcomes.

OBJECTIVE: To examine associations among interpregnancy interval, the duration from the preceding birth to the conception of the next-born index child, and adverse birth outcomes using designs that adjust for measured and unmeasured factors. METHODS: In this prospective cohort study, we used population-based Swedish registries from 1973 to 2009 to estimate the associations between interpregnancy interval (referent 18-23 months) and adverse birth outcomes (ie, preterm birth [less than 37 weeks of gestation], low birth weight [LBW; less than 2,500 g], small for gestational age [SGA; greater than 2 SDs below average weight for gestational age]). Analyses included cousin and sibling comparisons and postbirth intervals (ie, the interval between secondborn and thirdborn offspring predicting secondborn outcomes) to address unmeasured familial confounding. RESULTS: Traditional cohort-wide analyses showed higher odds of preterm birth (adjusted odds ratio [OR] 1.51, 99% CI 1.39-1.63, 5.99% preterm births]) and LBW (adjusted OR 1.25, 99% CI 1.13-1.39, 3.32% LBW) after a short interpregnancy interval (0-5 months) compared with offspring born after an interpregnancy interval of 18-23 months (3.21% preterm births, 1.92% LBW). Except for preterm birth (adjusted OR 1.72, 99% CI 1.26-2.35), associations were attenuated in cousin comparisons. A small association between a short interpregnancy interval and preterm birth remained in sibling comparisons (adjusted OR 1.22, 99% CI 1.11-1.35), but associations with LBW (adjusted OR 0.83, 99% CI 0.74-0.94) and SGA (adjusted OR 0.74, 99% CI 0.64-0.85) reversed direction. For pregnancy intervals of 60 months or more, odds of preterm birth (adjusted OR 1.51, 99% CI 1.43-1.60, 5.07% preterm births), LBW (adjusted OR 1.61, 99% CI 1.50-1.73, 3.43% low-birth-weight births), and SGA (adjusted OR 1.54, 99% CI 1.42-1.66, 2.49% SGA births) were also higher when compared with the reference interval (1.53% SGA). Associations between long interpregnancy interval and adverse birth outcomes remained through cousin and sibling comparisons. Postbirth interval analyses showed familial confounding is present for short interpregnancy intervals, but supported independent associations for long interpregnancy intervals. CONCLUSION: Familial confounding explains most of the association between a short interpregnancy interval and adverse birth outcomes, whereas associations with long interpregnancy intervals were independent of measured and unmeasured factors.