Association of maternal polycystic ovary syndrome or anovulatory infertility with obesity and diabetes in offspring: a population-based cohort study.

Are children of mothers with polycystic ovary syndrome (PCOS) or anovulatory infertility at increased risks of obesity or diabetes? Maternal PCOS/anovulatory infertility is associated with an increased risk of offspring obesity from early age and diabetes in female offspring from late adolescence. Women with PCOS often have comorbid metabolic disorders such as obesity and diabetes, and children of mothers with PCOS have an increased risk of subtle signs of cardiometabolic alterations. This was a nationwide cohort study of all live births (n = 1 105 997) during 1996-2014 in Finland, excluding those with maternal diagnoses sharing signs and symptoms with PCOS (n = 8244). A total of 1 097 753 births were included and followed up until 31 December 2018. National registries were linked to identify births with maternal PCOS or anovulatory infertility (n = 24 682). The primary outcomes were diagnoses of obesity (ICD-10: E65, E66) and diabetes (ICD-10: E10-E14) in offspring recorded in the Finnish Care Register for Health Care. Cox proportional hazards regression was modeled to analyze the risk of offspring obesity and diabetes in relation to prenatal exposure to maternal PCOS/anovulatory infertility. Differently adjusted models and stratified analyses were used to assess whether the risk was modified by maternal obesity or diabetes diagnoses, pre-pregnancy BMI, fertility treatment or perinatal problems. Exposure to maternal PCOS/anovulatory infertility was associated with a higher cumulative incidence of obesity in the children (exposed: 1.83%; 95% CI 1.66-2.00% vs unexposed: 1.24%; 95% CI 1.22-1.26%). Accounting for birth factors and maternal characteristics such as obesity and diabetes diagnoses, the hazard ratio (HR) for obesity was increased in offspring below 9 years of age (HR 1.58; 95% CI 1.30-1.81), and in those 10-16 years of age (HR 1.37; 95% CI 1.19-1.57), but not in those aged 17-22 years (HR 1.24; 95% CI 0.73-2.11). Sex-stratified analyses revealed similar risk estimates for boys (HR 1.48; 95% CI 1.31-1.68) and girls (HR 1.45; 95% CI 1.26-1.68). Notably, the joint effect of PCOS/anovulatory infertility and BMI-based pre-pregnancy obesity on offspring obesity (HR 8.89; 95% CI 7.06-11.20) was larger than that of either PCOS/anovulatory infertility or obesity alone. Furthermore, PCOS/anovulatory infertility was associated with offspring obesity in children without perinatal problems (HR 1.27; 95% CI 1.17-1.39), with larger effect size for maternal PCOS/anovulatory infertility and joint perinatal problems (HR 1.61; 95% CI 1.35-1.91). However, the risk estimates were comparable between maternal PCOS/anovulatory infertility with (HR 1.54; 95% CI 1.17-2.03) and without fertility treatment (HR 1.46; 95% CI 1.32-1.61). For offspring diabetes, the HR was increased only between 17 and 22 years of age (HR 2.06; 95% CI 1.23-3.46), and specifically for Type 1 diabetes in females (HR 3.23; 95% CI 1.41-7.40). The prevalence of PCOS/anovulatory infertility in this study was 2.2%, lower than that reported in previous studies. In addition, the incidence of obesity in offspring was lower than that reported in studies based on measured or self-reported weight and height and may include mainly moderate and severe obesity cases who needed and/or actively sought medical care. Moreover, mothers with PCOS/anovulatory infertility were identified based on ICD codes, with no information on PCOS phenotypes. Furthermore, maternal pre-pregnancy BMI was available only from 2004. The PCOS/anovulatory infertility association with female offspring diabetes was based on only a few cases. Mothers' weight gain during pregnancy, use of fertility treatment other than fresh or frozen IVF/ICSI, offspring lifestyle, as well as fathers' age, medical disorders or medication prescriptions were not available for this study. These findings support that prenatal PCOS/anovulatory infertility exposure influences metabolic health in the offspring from early age. This study was supported by Shandong Provincial Natural Science Foundation, China [ZR2020MH064 to X.C.], Shandong Province Medical and Health Technology Development Plan [2018WS338 to X.C.], the joint research funding of Shandong University and Karolinska Institute [SDU-KI-2019-08 to X.C. and C.L.], the Finnish Institute for Health and Welfare: Drug and Pregnancy Project [M.G.], the Swedish Research Council [2014-10171 to C.L.], the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institute Stockholm County Council [SLL20170292 and SLL20190589 to C.L.], the Swedish Brain Foundation [FO2018-0141 and FO2019-0201 to C.L.]. X.C. received grants from the China Scholarship Council at the beginning of the study. The authors have no competing interests to disclose. N/A.

Chen X ，Koivuaho E ，Piltonen TT ，Gissler M ，Lavebratt C ... -  《-》

Association of polycystic ovary syndrome or anovulatory infertility with offspring psychiatric and mild neurodevelopmental disorders: a Finnish population-based cohort study.

Chen X ，Kong L ，Piltonen TT ，Gissler M ，Lavebratt C ... -  《-》

Association of maternal polycystic ovary syndrome and diabetes with preterm birth and offspring birth size: a population-based cohort study.

Is the presence of polycystic ovary syndrome (PCOS) associated with more adverse infant outcomes in mothers with different types of diabetes? The presence of PCOS implies higher risks of total (medically indicated and spontaneously combined) and spontaneous preterm birth in mothers with non-insulin-treated type 2 diabetes and gestational diabetes mellitus (GDM), and lower risk of offspring being large for gestational age (LGA) in mothers with insulin-treated diabetes. PCOS is suggested to be an independent risk factor for adverse infant outcomes, and it is highly prevalent in mothers with diabetes. However, the impact of PCOS on the associations of different types of maternal diabetes with preterm birth and offspring birth sizes has not been reported. This is a population-based cohort study including all live births between 1996 and 2014 in Finland. Children with concurrent maternal diagnoses that could cause signs and symptoms similar to PCOS were excluded. A total of 1 097 753 children were included. National registries were linked to identify births with maternal PCOS (n = 24 682), stratified by diabetes types. Logistic regression was used to examine the association of maternal PCOS and comorbid insulin-treated diabetes, non-insulin-treated type 2 diabetes or GDM with offspring LGA and small for gestational age (SGA). Generalized estimating equation was used to assess the risk of preterm birth in relation to maternal PCOS and diabetes. Potential interaction between PCOS and diabetes was evaluated on both additive and multiplicative scales. Using mothers with no PCOS and no diabetes as the reference and adjusting for maternal and birth factors, there were higher risks of total (odds ratio (OR) 2.84, 95% CI 2.21 - 3.66 vs. OR 1.91, 95% CI 1.77 - 2.07, P = 0.01) and spontaneous (OR 4.02, 95% CI 2.94 - 5.50 vs. OR 2.35, 95% CI 2.13 - 2.59, P = 0.001) preterm birth for those with PCOS in mothers with non-insulin-treated type 2 diabetes and higher risks of total (OR 1.42, 95% CI 1.27-1.58 vs. OR 0.89, 95% CI 0.86-0.91, P = 0.0001) and spontaneous (OR 1.80, 95% CI 1.59-2.05 vs. OR 1.01, 95% CI 0.98-1.05, P = 0.0001) preterm birth for those with PCOS in mothers with GDM. Among mothers with type 2 diabetes, further adjusting for maternal BMI eliminated the difference in preterm birth risks between those with and those without PCOS, and adjustment for infertility treatment and pre-eclampsia also reduced the preterm risks associated with PCOS significantly. For mothers with GDM, however, the risks of total and spontaneous preterm birth remained higher for those with PCOS following these aforementioned adjustments or stratified analysis. The risk of offspring being LGA was lower for those with PCOS than those without PCOS among mothers with insulin-treated diabetes (OR 18.90, 95% CI 14.21-25.14 vs. OR 32.04, 95% CI 29.79-34.46, P = 0.0001), showing departure from additivity (relative excess risk due to interaction -11.74, 95% CI -16.17 to -7.31, P < 0.001) and multiplicativity (P < 0.001). PCOS did not alter the risk estimate of preterm birth in mothers with insulin-treated diabetes or offspring LGA and SGA in mothers with type 2 diabetes or GDM. The register-based diagnoses used in this study captured only women with PCOS seeking medical care and having live births. Including female infertility associated with anovulation as PCOS exposure was a risk for misclassification. Sample sizes for pregestational diabetes were small. Insulin purchase during pregnancy in those without a diabetes diagnosis was not accounted for in the analysis. For patients treated with insulin or other medications, we were unable to assess how they complied with such prescriptions. Also, maternal BMI was recorded only once in early pregnancy, thus the potential influence of gestational weight gain on birth outcomes could not be examined. Data on the causes for preterm birth were not available from the registers. The presence of PCOS implied higher risks of total and spontaneous preterm birth in mothers with type 2 diabetes or GDM, and lower risk of offspring being LGA in mothers with insulin-treated diabetes. The higher risks of preterm birth added by PCOS could be explained by prepregnancy BMI or in part by infertility treatment and pre-eclampsia in maternal non-insulin-treated type 2 diabetes, but not in maternal GDM. The differential effects of PCOS on the associations of different types of maternal diabetes with infant outcomes have implications for preventative strategies and clinical counseling for affected pregnancies. This study was supported by Shandong Provincial Natural Science Foundation, China (ZR2020MH064 to X.C.), Shandong Province Medical and Health Technology Development Plan (2018WS338 to X.C.), the joint research funding of Shandong University and Karolinska Institute (SDU-KI-2019-08 to X.C. and C.L.), the Finnish National Institute for Health and Welfare: Drug and pregnancy project (M.G.), the Swedish Research Council (2014-10171 to C.L.), the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institute Stockholm County Council (SLL20170292 and SLL20190589 to C.L.), the Swedish Brain Foundation (FO2019-0201 and FO2020-0305 to C.L.). X.C. received grants from the China Scholarship Council at the beginning of the study. The authors have no competing interests to disclose. N/A.

Chen X ，Gissler M ，Lavebratt C 《-》

Birth outcomes in mothers with hypertensive disorders and polycystic ovary syndrome: a population-based cohort study.

Is polycystic ovary syndrome (PCOS) associated with higher risks of extreme birth size and/or preterm birth in mothers with different hypertension types? PCOS was associated with additional risks of preterm birth in mothers with chronic hypertension and in singleton pregnancies of mothers with pre-eclampsia, and with higher risks of offspring born large for gestational age (LGA) in mothers with gestational hypertension. Women with PCOS are more likely to develop gestational hypertension, pre-eclampsia, and chronic hypertension. Although adverse birth outcomes have been frequently reported in mothers with PCOS, such associations in the setting of a hypertensive disorder remain unknown. This is a population-based cohort study including all live births 2004-2014 in Finland (n = 652 732). To ensure diagnosis specificity, mothers with diagnoses that could cause signs and symptoms resembling PCOS were excluded. Maternal diagnoses of PCOS, gestational hypertension, chronic hypertension, and pre-eclampsia were identified from the Finnish national registries. Generalized estimating equation and multivariable logistic regression were used to assess the adjusted odds ratio (aOR) and 95% CIs of preterm birth, very preterm birth, and offspring being small for gestational age (SGA) or LGA in hypertensive mothers with or without PCOS, using normotensive mothers without PCOS as reference. Of 43 902 (6.7%) mothers with hypertensive disorders, 1709 (3.9%) had PCOS. Significant interactions were detected for PCOS with hypertension on preterm birth, very preterm birth, offspring born SGA and LGA (Fpreterm = 504.1, Pinteraction < 0.001; Fvery preterm = 124.2, Pinteraction < 0.001; FSGA = 99.5, Pinteraction < 0.001; FLGA = 2.7, Pinteraction = 0.012, respectively). Using mothers with no hypertensive disorder and no PCOS as reference, the risks of preterm and very preterm birth were overrepresented in non-PCOS mothers with chronic hypertension or pre-eclampsia. PCOS was associated with higher risks of preterm birth (aORPCOS 4.02, 3.14-5.15 vs aORnon-PCOS 2.51, 2.32-2.71) in mothers with chronic hypertension, with significant interaction between the exposures (F = 32.7, Pinteraction < 0.001). PCOS was also associated with a higher risk of preterm birth in singleton pregnancies of mothers with pre-eclampsia (aORPCOS 7.33, 5.92-9.06 vs aORnon-PCOS 5.72, 5.43-6.03; F = 50.0, Pinteraction < 0.001). Furthermore, the associations of PCOS comorbid with chronic hypertension or pre-eclampsia was detected also for spontaneous births. Moreover, the risk of offspring LGA was higher in mothers with PCOS and gestational hypertension although lower in those with gestational hypertension alone (aORPCOS 2.04, 1.48-2.80 vs aORnon-PCOS 0.80, 0.72-0.89; F = 9.7, Pinteraction = 0.002), whereas for offspring SGA, the risks were comparable between hypertensive mothers with and those without PCOS. Information on medication treatment, gestational weeks of onset for pre-eclampsia and gestational hypertension, weight gain during pregnancy, and PCOS phenotypes were not available. All diagnoses were retrieved from registries, representing only those seeking medical care for their symptoms. The ICD-9 codes used to identify PCOS before year 1996 are known to underestimate the prevalence of PCOS, while the inclusion of anovulatory infertility as PCOS might introduce an overrepresentation bias, although PCOS constitutes 80% of anovulatory infertility. The risk of very preterm birth in relation to maternal PCOS and hypertensive disorders should be interpreted with caution owing to limited sample sizes. Multifetal pregnancies among maternal PCOS were too few for a subgroup analysis. Moreover, ART included IVF/ICSI only. Potential effects of other treatments, such as ovulation induction, were not examined. PCOS was associated with additional risks of preterm birth or offspring being LGA in hypertensive mothers, which varied between hypertension types. The exacerbated risks highlight consideration of PCOS in pregnancy counseling and management for women with hypertensive disorders. This study was supported by Shandong Provincial Natural Science Foundation, China [ZR2020MH064 to X.C.], the joint research funding of Shandong University and Karolinska Institute [SDU-KI-2019-08 to X.C. and C.L.], the Finnish Institute for Health and Welfare: Drug and pregnancy project [M.G.], the Swedish Research Council [2022-01188 to C.L.], the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institute Stockholm County Council [RS2021-0855 to C.L.], the Swedish Brain Foundation [FO2021-0412 to C.L.]. The funders had no role in study design, data collection, analysis, and interpretation, writing of the report or decision to submit for publication. The authors report no conflicts of interest. N/A.

Chen X ，Gissler M ，Lavebratt C 《-》

BMI in childhood and adolescence is associated with impaired reproductive function-a population-based cohort study from birth to age 50 years.

What is the association between childhood and adolescent BMI and reproductive capacity in women? Adolescent girls with obesity had an increased risk of infertility and childlessness in adulthood independently of their marital status or the presence of polycystic ovary syndrome (PCOS). Girls with obesity (BMI (kg/m2)>95th percentile) more often exhibit menstrual irregularities and infertility problems as compared to those with normal weight, and premenarcheal girls with obesity have an increased risk of childlessness and infertility in adulthood. Follow-up studies on the relation between childhood and adolescence growth patterns and fertility or parity throughout the reproductive life span are limited. A prospective, population-based cohort study (the Northern Finland birth cohort 1966) was performed with 5889 women born in 1966 and followed from birth to age 50 years. Postal questionnaires at ages 31 and 46 years addressed questions on reproductive capacity evaluated by decreased fecundability, need for infertility assessment and treatment by 46 years of age. Childlessness and number of children by age 50 years were recovered from registers. Women who did not report ever having attempted to achieve pregnancy (n = 1507) were excluded. The final study population included 4382 women who attempted to achieve pregnancy before age 46 years. Data on BMI were collected by trained personnel at all stages. We assessed association with both prospectively measured BMI at various time points and with early adiposity phenotypes derived from linear mixed models including the timing and the BMI at adiposity peak (AP) and adiposity rebound (AR). Self-reported infertility assessments and treatments were assessed at ages 31 and 46 years. Data on deliveries were collected from the national birth register. Decreased fecundability was defined at age 31 years as time to achieve pregnancy over 12 months. Logistic regression analyses were conducted with adjustments for marital status, education level and smoking at age 31 years. Women with PCOS were excluded from stratification-based sensitivity analyses. Obesity at a specific age group was defined by having at least one BMI value above the 95th percentile during the related period. BMI at the age of AR (5-7 years) was not associated with fertility outcomes after adjustments, but girls with AR <5.1 years had a higher risk of remaining childless compared to girls with AR over 5.1 years (adjusted odds ratio (OR): 1.45 (1.10-1.92)). At ages 7-10 and 11-15 years, obesity was associated with decreased fecundability (adjusted OR 2.05 (1.26-3.35) and 2.04 (1.21-3.44), respectively) and a lower number of children. At age 11-15 years, both overweight and obesity were associated with a higher risk of childlessness (adjusted OR 1.56 (1.06-2.27), 1.77 (1.02-3.07), respectively), even after excluding women with PCOS. Underweight at age 11-15 years was associated with an increased risk for infertility treatment (adjusted OR 1.55 (1.02-2.36)) and a tendency for an increased risk for infertility assessment (adjusted OR 1.43 (0.97-2.10)) after excluding women with PCOS. Despite a high participation rate throughout the follow-up, some growth data for children over the different age groups were missing. Infertility outcomes were self-reported. A potential over-diagnosis of obesity may have reduced the significance of the association between childhood obesity and fertility outcomes, and the diagnosis of PCOS was self-reported. This study supports previous results showing that girls with obesity in late childhood and in adolescence displayed reduced fertility and an increased risk of remaining childless in adulthood, independently of marital history and PCOS in adulthood. These findings corroborate the body of evidence for a causal relation between early adiposity and the reproductive functions in women. We recommend reinforcing the prevention of obesity in school-age girls to reduce the risk of impaired reproductive functions. NFBC1966 received financial support from University of Oulu Grant no. 65354, Oulu University Hospital Grant no. 2/97, 8/97, Ministry of Health and Social Affairs Grant no. 23/251/97, 160/97, 190/97, National Institute for Health and Welfare, Helsinki Grant no. 54121, Regional Institute of Occupational Health, Oulu, Finland Grant no. 50621, 54231. The Finnish Medical Foundation, the North Ostrobothnia Regional Fund, the Academy of Finland (project grants 315921, 104781, 120315, 129269, 1114194, 24300796), Center of Excellence in Complex Disease Genetics and SALVE, the Sigrid Juselius Foundation, Biocenter Oulu, University Hospital Oulu and University of Oulu (75617), Jalmari ja Rauha Ahokkaan säätiö, The Finnish Medical Foundation, Medical Research Center Oulu, National Institute for Health Research (UK). M. R. J., S. S. and R. N. received funding by the Academy of Finland (#268336) and the European Union's Horizon 2020 research and innovation program (under Grant agreement no. 633595 for the DynaHEALTH action and GA 733206 for LifeCycle). The funders had no role in study design, in the collection, analysis and interpretation of the data, in the writing of the article and in the decision to submit it for publication. The authors have no conflict of interest to disclose. N/A.

Laru J ，Nedelec R ，Koivuaho E ，Ojaniemi M ，Järvelin MR ，Tapanainen JS ，Franks S ，Tolvanen M ，Piltonen TT ，Sebert S ，Morin-Papunen L ... -  《-》