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

STUDY QUESTION: Is the presence of polycystic ovary syndrome (PCOS) associated with more adverse infant outcomes in mothers with different types of diabetes? SUMMARY ANSWER: 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. WHAT IS KNOWN ALREADY: 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. STUDY DESIGN, SIZE, DURATION: 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. PARTICIPANTS/MATERIALS, SETTING, METHODS: 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. MAIN RESULTS AND THE ROLE OF CHANCE: 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. LIMITATIONS, REASONS FOR CAUTION: 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. WIDER IMPLICATIONS OF THE FINDINGS: 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. STUDY FUNDING/COMPETING INTEREST(S): 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. TRIAL REGISTRATION NUMBER: N/A.

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

STUDY QUESTION: Are children of mothers with polycystic ovary syndrome (PCOS) or anovulatory infertility at increased risks of obesity or diabetes? SUMMARY ANSWER: Maternal PCOS/anovulatory infertility is associated with an increased risk of offspring obesity from early age and diabetes in female offspring from late adolescence. WHAT IS KNOWN ALREADY: 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. STUDY DESIGN, SIZE, DURATION: 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. PARTICIPANTS/MATERIALS, SETTING, METHODS: 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. MAIN RESULTS AND THE ROLE OF CHANCE: 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). LIMITATIONS, REASONS FOR CAUTION: 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. WIDER IMPLICATIONS OF THE FINDINGS: These findings support that prenatal PCOS/anovulatory infertility exposure influences metabolic health in the offspring from early age. STUDY FUNDING/COMPETING INTEREST(S): 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. TRIAL REGISTRATION NUMBER: N/A.

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

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.

Mutations in KISS1 are not responsible for idiopathic hypogonadotropic hypogonadism in Chinese patients.

PURPOSE: To investigate whether mutations in the KISS1 gene are present in 170 Chinese patients with idiopathic hypogonadotropic hypogonadism (IHH). METHODS: Mutational screening of the KISS1 gene was performed in 170 Chinese patients with IHH (133 male cases and 37 female cases) and 187 matched controls (94 males and 93 females). RESULTS: Two known single-nucleotide polymorphisms (SNP), c. 58G > A in exon 1 and c. 242C > G in exon 2, were identified. However, no difference of genotype and allelic frequencies between cases and controls was observed. CONCLUSIONS: The results suggest that mutations in the coding sequence of KISS1 are not common in patients with IHH in this Chinese population.

The opposing effect of hypoxia-inducible factor-2alpha on expression of telomerase reverse transcriptase.

Hypoxia-inducible factor-1alpha (HIF-1alpha) has been implicated in the transcriptional regulation of the telomerase reverse transcriptase (hTERT) gene expression and telomerase activity, essential elements for cellular immortalization and transformation. However, controversial results were obtained in different studies. Moreover, it is totally unclear whether HIF-2alpha, the paralog of HIF-1alpha, plays a role in regulating hTERT expression. In the present study, we found that hypoxic treatment enhanced hTERT mRNA expression and telomerase activity in three renal cell carcinoma (RCC) cell lines with different genetic backgrounds. Both HIF-1alpha and HIF-2alpha were capable of significantly increasing the hTERT promoter activity in these cells. Moreover, depleting HIF-2alpha led to a down-regulation of hTERT mRNA level in RCC A498 cells expressing constitutive HIF-2alpha. It was found that HIF-2alpha bound to the hTERT proximal promoter and enhanced the recruitment of the histone acetyltransferase p300 and histone H3 acetylation locally in A498 cells treated with hypoxia. Increased levels of hTERT mRNA were observed in two of three hypoxia-treated malignant glioma cell lines. However, HIF-1alpha stimulated whereas HIF-2alpha inhibited the hTERT promoter activity in these glioma cell lines. Ectopic expression of HIF-2alpha resulted in diminished hTERT expression in glioma cells. Collectively, HIF-1alpha activates hTERT and telomerase expression in both RCC and glioma cells, and HIF-2alpha enhances hTERT expression in RCC cells, whereas it represses the hTERT transcription in glioma cells. These findings reveal a complex relationship between HIF-1alpha/2alpha and hTERT/telomerase expression in malignant cells, which may have both biological and clinical implications.