Children born to women with polycystic ovary syndrome—short- and long-term impacts on health and development

Vanky, Eszter; Hanem, Liv Guro Engen; Abbott, David H.

doi:10.1016/j.fertnstert.2019.03.015

Cited by 26 publications

(13 citation statements)

References 116 publications

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“…In addition to body weight and ovary phenotype, we observed a significant increase in testosterone and LH levels in both genders of F1 and F2 offspring. Additional metabolic changes are also presented, such as increased serum TG, insulin and impaired glucose tolerance, which are consistent with clinical reports of abnormal glucose tolerance, serum insulin and lipid levels, and prepubertal ovarian enlargement in female offspring of PCOS women (34). Prenatal androgen exposure may impair the function of islet, and decrease the ability of secreting insulin in islet β cells (35).…”

Section: Discussionsupporting

confidence: 82%

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Transgenerational Inheritance of Reproductive and Metabolic Phenotypes in PCOS Rats

Zhang

Dong

et al. 2020

Front. Endocrinol.

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Androgen exposure of female fetuses could be an important factor in the development of polycystic ovary syndrome (PCOS) in subsequent generations. The present study aimed to investigate the transgenerational effects of PCOS on the growth, reproduction, and metabolism of the first-and second-generation offspring in rats. Female F0 rats received excessive dehydroepiandrosterone (DHEA) exposure to establish PCOS or the same amount of vehicle as controls. These F0 females were crossed with normal males to obtain control (C) and DHEA (D) F1 offspring, whereas F2 offspring were obtained by inter-crossing between F1 rats for 4 groups: (1) C♂-C♀; (2) D♂-C♀; (3) C♂-D♀ and (4) D♂-D♀. Compared with control groups, F1 and F2 offspring with ancestral DHEA exposure showed higher body weight with increasing age. In addition, female F1 and F2 offspring with ancestral DHEA exposure exhibited PCOS-like reproductive and metabolic phenotypes, including disrupted estrous cycles and polycystic ovaries, as well as increased serum levels of testosterone, impaired glucose tolerance and widespread metabolic abnormalities. Male offspring with ancestral DHEA exposure exhibited lower quality of sperms. These findings confirm the negative effects of excessive androgen exposure of female fetuses on subsequent generations.

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Section: Discussionsupporting

confidence: 82%

“…In addition to female offspring, several studies have reported the presence of hyperandrogenism in male offspring (34,36). Brothers of PCOS women show elevated levels of total cholesterol, LDL, TG and insulin as well as insulin resistance (40).…”

Section: Discussionmentioning

confidence: 99%

Transgenerational Inheritance of Reproductive and Metabolic Phenotypes in PCOS Rats

Zhang

Dong

et al. 2020

Front. Endocrinol.

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“…On the other hand, birth weight and thinness at birth independently predict symptoms of PCOS in adulthood (83). Many coexisting elements, such as maternal obesity, pregnancy complications, and other comorbidity make it difficult to identify the real contribution of PCOS mothers to health and development of offspring (84).…”

Section: Resolution 2: the Symptoms And Signs Of Pcos Appear Early Inmentioning

confidence: 99%

Fundamental Concepts and Novel Aspects of Polycystic Ovarian Syndrome: Expert Consensus Resolutions

et al. 2020

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Polycystic ovary syndrome (PCOS) is a very common endocrine and metabolic disorder with the involvement of both genetic and environmental factors. Although much has been clarified on its pathogenesis, diagnosis, clinical manifestations, and therapy, there are still areas of uncertainty. To address fundamental concepts, novel aspects and hypotheses, and future perspectives, including the possible additional benefits of treatment with nutraceuticals, an expert consensus panel formed by endocrinologists and gynecologists was established. After an independent review of the literature, the panel convened electronically on February 3, 2020, and six resolutions were created, debated, and agreed upon discussion, and finally approved in their final form in a consensus livestream meeting held on April 15. The summary of the resolutions are: (1) PCOS is a well-established medical condition that negatively affects reproduction, general health, sexual health, and quality of life; (2) the symptoms and signs of PCOS appear early in life especially in female newborns from PCOS carriers; (3) women with PCOS have significantly increased risk of pregnancy-related complications including gestational diabetes mellitus; (4) a male PCOS equivalent exists, and it may impact on metabolic health and probably on reproduction; (5) the evidence supports that medical therapy for PCOS is effective, rational, and evidence-based; (6) the evidence supports a major research initiative to explore possible benefits of nutraceutical therapy for PCOS. The proposed resolutions may be regarded as points of agreement based on the current scientific evidence available.

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“…PCOS status, together with associated obesity, insulin resistance, and pregnancy complications, is potentially to provide an altered intrauterine environment, which may negatively influence the offspring ( Vanky et al , 2019 ). Maternal PCOS has been proposed as a model of exposure to excessive androgens in uterus, reporting that the affected children had increased risks of neuropsychiatric disorders including autism spectrum disorder (ASD), attention deficit/hyperactivity disorders (ADHDs) and possibly Tourette syndrome/chronic tic disorders ( Palomba et al , 2012 ; Kosidou et al , 2016 ; Kosidou et al , 2017 ; Cherskov et al , 2018 ; Cesta et al , 2019 ).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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STUDY QUESTION Is maternal polycystic ovary syndrome (PCOS) associated with increased risks for a broad spectrum of psychiatric and mild neurodevelopmental disorders in offspring? SUMMARY ANSWER Maternal PCOS and/or anovulatory infertility is independently, and jointly with maternal obesity, perinatal problems, cesarean delivery and gestational diabetes, associated with increased risks in offspring for almost all groups of psychiatric and mild neurodevelopmental disorders with onset in childhood or adolescence. WHAT IS KNOWN ALREADY Maternal PCOS was previously associated with autism spectrum disorder, attention-deficit/hyperactivity disorders and possibly developmental delay in offspring. Few studies have investigated the association between maternal PCOS and other psychiatric and neurodevelopmental disorders in offspring. STUDY DESIGN, SIZE, DURATION This was a population-based cohort study in Finland including all live births between 1996 and 2014 (n = 1 105 997). After excluding births to mothers with symptoms similar to PCOS, a total of 1 097 753 births by 590 939 mothers remained. Children were followed up until 31 December 2018, i.e. up to the age of 22 years. PARTICIPANTS/MATERIALS, SETTING, METHODS National registries were used to link data of the included births and their mothers. Data from 24 682 (2.2%) children born to mothers with PCOS were compared with 1 073 071 (97.8%) children born to mothers without PCOS. Cox proportional hazards modeling was used to evaluate the hazard ratio (HR) and 95% CI for the risk of neuropsychiatric disorders in relation to maternal PCOS. Stratified analyses were performed to test the independent role of PCOS and the joint effects of PCOS with maternal obesity, perinatal problems, cesarean delivery, gestational diabetes and use of fertility treatment. The analysis was adjusted for maternal age, country of birth, marriage status at birth, smoking, parity, psychiatric disorders, prescription of psychotropic N05/N06 during pregnancy and systemic inflammatory diseases when applicable. MAIN RESULTS AND THE ROLE OF CHANCE A total of 105 409 (9.8%) children were diagnosed with a neurodevelopmental or psychiatric disorder. Firstly, maternal PCOS was associated with any psychiatric diagnosis (HR 1.32; 95% CI 1.27–1.38) in offspring. Particularly, the risk was increased for sleeping disorders (HR 1.46; 95% CI 1.27–1.67), attention-deficit/hyperactivity disorders and conduct disorders (HR 1.42; 95% CI 1.33–1.52), tic disorders (HR 1.42; 95% CI 1.21–1.68), intellectual disabilities (HR 1.41; 95% CI 1.24–1.60), autism spectrum disorder (HR 1.40; 95% CI 1.26–1.57), specific developmental disorders (HR 1.37; 95% CI 1.30–1.43), eating disorders (HR 1.36; 95% CI 1.15–1.61), anxiety disorders (HR 1.33; 95% CI 1.26–1.41), mood disorders (HR 1.27; 95% CI 1.18–1.35) and other behavioral and emotional disorders (ICD-10 F98, HR 1.49; 95% CI 1.39–1.59). In short, there was no significant difference between sexes. The results were robust when restricting the analyses to the first-born children or births to mothers without psychiatric diagnosis or purchase of psychotropic medication. Secondly, stratified analysis according to maternal BMI showed that the risk of any neuropsychiatric disorder was increased in offspring to normal-weight mothers with PCOS (HR 1.20; 95% CI 1.09–1.32), and markedly higher in those to severely obese mothers with PCOS (HR 2.11; 95% CI 1.76–2.53) compared to offspring to normal-weight mothers without PCOS. When excluding perinatal problems, mothers with PCOS were still associated with increased risks of any neuropsychiatric disorders in offspring (HR 1.28; 95% CI 1.22–1.34) compared to mothers without PCOS. However, an additional increase was observed for PCOS in combination with perinatal problems (HR 1.99; 95% CI 1.84–2.16). Likewise, excluding cases with maternal gestational diabetes (HR 1.30; 95% CI 1.25–1.36), cesarean delivery (HR 1.29; 95% CI 1.23–1.35) or fertility treatment (HR 1.31; 95% CI 1.25–1.36) did not eliminate the associations. LIMITATIONS, REASONS FOR CAUTION The register-based prevalence of PCOS was lower than previously reported, suggesting that this study may capture the most severe cases. To combine anovulatory infertility with PCOS diagnosis as PCOS exposure might introduce diagnostic bias. It was not feasible to distinguish between subtypes of PCOS. Furthermore, familial factors might confound the association between maternal PCOS and neuropsychiatric disorders in offspring. Maternal BMI was available for birth cohort 2004–2014 only and there was no information on gestational weight gain. WIDER IMPLICATIONS OF THE FINDINGS This study provides further evidence that maternal PCOS and/or anovulatory infertility, independently and jointly with maternal obesity, perinatal problems, gestational diabetes and cesarean delivery, implies a broad range of adverse effects on offspring neurodevelopment. These findings may potentially help in counseling and managing pregnancies. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by the joint research funding of Shandong University and Karolinska Institute (SDU-KI-2019-08 to X.C and C.L.), THL 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 to C.L.], the Swedish Brain Foundation [FO2018-0141 and FO2019-0201 to C.L.]. X.C. was supported by the China Scholarship Council during her training in Karolinska Institute. L.K. was supported by the China Scholarship Council for his PhD study in Karolinska Institute. The authors have no competing interests to disclose. TRIAL REGISTRATION NUMBER N/A.

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Children born to women with polycystic ovary syndrome—short- and long-term impacts on health and development

Cited by 26 publications

References 116 publications

Transgenerational Inheritance of Reproductive and Metabolic Phenotypes in PCOS Rats

Transgenerational Inheritance of Reproductive and Metabolic Phenotypes in PCOS Rats

Fundamental Concepts and Novel Aspects of Polycystic Ovarian Syndrome: Expert Consensus Resolutions

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

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