Clinical features of preeclampsia and hypertensive disorders in pregnancies after different frozen embryo transfer regimens.

OBJECTIVES: To compare whether the clinical features of preeclampsia (PE) or gestational hypertension (GH) were different in pregnancies after a frozen embryo transfer (FET), depending on the FET regimen used. STUDY DESIGN: A retrospective study including 58 pregnancies with PE and 64 pregnancies with GH, all with singleton live births. Pregnancies were stratified according to the presence or absence of a corpus luteum (CL). MAIN OUTCOME MEASURES: Clinical characteristics of PE and GH, maternal background factors, postpartum hemorrhage (PPH), key perinatal outcomes. RESULTS: Among PE patients, no difference was found in the clinical characteristics and in the maternal background factors, when comparing women with a CL to women without a CL. PE patients in the group without a CL had a hemorrhage of > 500 mL or > 1000 mL significantly more often than patients with a CL. Multivariable analyses confirmed this risk. Perinatal outcomes were similar. Among GH patients, there was no difference in the clinical features and maternal background factors, when comparing CL cycles to cycles without a CL. The amount of PPH was higher among the patients without a CL, but the frequency of a > 500 mL or > 1000 mL hemorrhage was similar between groups. No risk increase was seen in multivariable analyses. CONCLUSIONS: Among FET patients with PE, the risk of PPH wasincreased in pregnancies after cycles without a CL, compared to cycles with a CL. The presence or absence of a CL did noteffectthe severity of PE and GH, the duration of pregnancy or blood pressure levels.

Genetic risk of type 2 diabetes modifies the association between lifestyle and glycemic health at 5 years postpartum among high-risk women.

INTRODUCTION: Lifestyle interventions are effective in preventing type 2 diabetes, but genetic background may influence the individual response. In the Finnish gestational diabetes prevention study, RADIEL, lifestyle intervention during pregnancy and first postpartum year was effective in preventing gestational diabetes (GDM) and postpartum glycemic abnormalities only among women at highest genetic risk of type 2 diabetes. This study aimed to assess whether still 5 years postpartum the genetic risk modifies the association between lifestyle and glycemic health. RESEARCH DESIGN AND METHODS: The RADIEL study (randomized controlled trial) aimed to prevent GDM with a lifestyle intervention among high-risk women (body mass index ≥30 kg/m2 and/or prior GDM). The follow-up study 5 years postpartum included anthropometric measurements, laboratory assessments, device-measured physical activity (PA), and questionnaires. A Healthy Lifestyle Score (HLS) indicated adherence to lifestyle goals (PA, diet, smoking) and a polygenic risk score (PRS) based on 50 type 2 diabetes risk alleles depicted the genetic risk. RESULTS: Altogether 314 women provided genetic and glycemic data 5 years postpartum. The PRS for type 2 diabetes was not associated with glycemic abnormalities, nor was HLS in the total study sample. There was, however, an interaction between HLS and type 2 diabetes PRS on glycemic abnormalities (p=0.03). When assessing the association between HLS and glycemic abnormalities in PRS tertiles, HLS was associated with reduced risk of glycemic abnormalities only among women at the highest genetic risk (p=0.008). CONCLUSIONS: These results extend our previous findings from pregnancy and first postpartum year demonstrating that still at 5 years postpartum, healthy lifestyle is associated with a lower risk of prediabetes/diabetes only among women at the highest genetic risk of type 2 diabetes.

Maternal gestational hypertension, smoking and pre-eclampsia are associated with metabolic dysfunction-associated fatty liver disease in overweight offspring.

INTRODUCTION: Due to a steep increase in obesity, metabolic dysfunction-associated fatty liver disease (MAFLD) has also become the most common chronic hepatic condition among children and adolescents. Various maternal and pregnancy-related factors have also been implicated in the development of MAFLD, but human studies remain scarce. MATERIAL AND METHODS: Comprehensive data of 460 overweight or obese children aged 2-16 years were collected and combined with data on selected maternal and pregnancy-related factors for a case-control study. MALFD was defined as alanine aminotransferase >2× upper limit of normal. Children with and without MAFLD were compared regarding to the study variables and multivariable regression analysis was utilized. RESULTS: Median age of the study children was 11.8 (quartiles 9.1-14.2) years; 44% were girls and 17.8% had MAFLD. Children with MAFLD were older (12.7 vs. 11.6 years, p = 0.002), while the groups did not differ age-standardized body mass index (BMI-SDS) or gender. Factors associated with MAFLD in a multivariable model considering also the offspring's present BMI-SDS, sex, and maternal prepregnancy overweight, were child's older age (odds ratio [OR] 1.16, 95% confidence interval [CI]: 1.06-1.28), maternal gestational smoking (OR 2.01, 95% CI: 1.16-3.47), gestational hypertension (OR 3.44, 95% CI: 1.08-11.0) and pre-eclampsia (OR 2.93, 95% CI: 1.15-7.45). There was no significant association between MAFLD and maternal BMI, birth anthropometrics or perinatal complications. CONCLUSIONS: Maternal smoking, gestational hypertension and pre-eclampsia were associated with MAFLD among overweight or obese children. Further prospective studies are needed to verify causal relationships.

Body mass index stratified meta-analysis of genome-wide association studies of polycystic ovary syndrome in women of European ancestry.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a complex multifactorial disorder with a substantial genetic component. However, the clinical manifestations of PCOS are heterogeneous with notable differences between lean and obese women, implying a different pathophysiology manifesting in differential body mass index (BMI). We performed a meta-analysis of genome-wide association study (GWAS) data from six well-characterised cohorts, using a case-control study design stratified by BMI, aiming to identify genetic variants associated with lean and overweight/obese PCOS subtypes. RESULTS: The study comprised 254,588 women (5,937 cases and 248,651 controls) from individual studies performed in Australia, Estonia, Finland, the Netherlands and United States of America, and separated according to three BMI stratifications (lean, overweight and obese). Genome-wide association analyses were performed for each stratification within each cohort, with the data for each BMI group meta-analysed using METAL software. Almost half of the total study population (47%, n = 119,584) were of lean BMI (≤ 25 kg/m2). Two genome-wide significant loci were identified for lean PCOS, led by rs12000707 within DENND1A (P = 1.55 × 10-12) and rs2228260 within XBP1 (P = 3.68 × 10-8). One additional locus, LINC02905, was highlighted as significantly associated with lean PCOS through gene-based analyses (P = 1.76 × 10-6). There were no significant loci observed for the overweight or obese sub-strata when analysed separately, however, when these strata were combined, an association signal led by rs569675099 within DENND1A reached genome-wide significance (P = 3.22 × 10-9) and a gene-based association was identified with ERBB4 (P = 1.59 × 10-6). Nineteen of 28 signals identified in previous GWAS, were replicated with consistent allelic effect in the lean stratum. There were less replicated signals in the overweight and obese groups, and only 4 SNPs were replicated in each of the three BMI strata. CONCLUSIONS: Genetic variation at the XBP1, LINC02905 and ERBB4 loci were associated with PCOS within unique BMI strata, while DENND1A demonstrated associations across multiple strata, providing evidence of both distinct and shared genetic features between lean and overweight/obese PCOS-affected women. This study demonstrated that PCOS-affected women with contrasting body weight are not only phenotypically distinct but also show variation in genetic architecture; lean PCOS women typically display elevated gonadotrophin ratios, lower insulin resistance, higher androgen levels, including adrenal androgens, and more favourable lipid profiles. Overall, these findings add to the growing body of evidence supporting a genetic basis for PCOS as well as differences in genetic patterns relevant to PCOS BMI-subtype.

Costs of abduction treatment in developmental dysplasia of the hip. Analysis of 900 patients.

BACKGROUND: Developmental dysplasia of the hip (DDH) is a disorder of hip development that leads to dysplasia, subluxation, or total hip dislocation. Early detection of DDH is important, and early initiation of abduction treatment is key to successful correction of the hip joint. However, mild forms of DDH, including hip instability without complete dislocation, have good spontaneous healing potential, and a watchful waiting strategy in mild DDH has been found to be safe. In this study, we aimed to evaluate the cost differences between different treatment strategies for DDH. MATERIAL AND METHODS: Data were collected retrospectively from the medical records of all children diagnosed with diagnosis and treatment of DDH in Tampere University hospital between 1998 and 2018. In total, 948 patients were included in the study. Patients who underwent casting or operative treatment (n = 48) were excluded from the analysis. All Ortolani positive children were subjected to early abduction treatment. Children with Ortolani negative DDH were subjected to either watchful waiting or early abduction treatment, based on the clinicians' decision. The regression model estimates for the number of clinical visits with and without ultrasound examination were assessed together with cost reports from Tampere University Hospital for the calculation of savings per patient in spontaneous recovery. RESULTS: Alpha angles at one month of age (p < 0.001) and treatment method (p < 0.001) affected the number of clinical visits and ultrasound examinations during the treatment follow-up. A low alpha angle predicted closer follow-up, and children with spontaneous recovery had lower numbers of clinical visits and ultrasound examinations than children in abduction treatment. Spontaneous recovery was found to result in approximately 375€/patient savings compared to successful abduction treatment. CONCLUSION: With correct patient selection, a watchful waiting strategy is cost-effective in treating mild developmental dysplasia of the hip, considering the high percentage of spontaneous recovery.

Watchful waiting strategy should be implemented to clinical practice when treating mild DDH as it seems safe and cost effective.

Gestational diabetes is associated with the risk of offspring's congenital anomalies: a register-based cohort study.

BACKGROUND: Gestational diabetes mellitus (GDM) is a common pregnancy-related disorder and a well-known risk factor for adverse pregnancy outcomes. There are conflicting findings on the association of GDM with the risk of congenital anomalies (CAs) in offspring. In this study, we aimed to determine study whether maternal GDM is associated with an increased risk of major CAs in offspring. METHODS: This Finnish Gestational Diabetes (FinnGeDi) register-based study included 6,597 women with singleton pregnancies and a diagnosis of GDM and 51,981 singleton controls with no diabetes identified from the Finnish Medical Birth Register (MBR) in 2009. Data from MBR were combined in this study with the Register of Congenital Malformations, which includes the data of CAs. We used logistic regression to calculate odds ratios (OR) for CAs, together with their 95% confidence intervals (CIs), adjusting for maternal age, parity, pre-pregnancy body mass index (BMI), and maternal smoking status. RESULTS: The risk of major CAs was higher in the GDM-exposed (n = 336, 5.09%) than in the non-exposed group (n = 2,255, 4.33%) (OR: 1.18, 95% CI: 1.05-1.33, p = 0.005). The adjusted OR (aOR) was 1.14 (95% CI: 1.00-1.30, p = 0.047). There was a higher overall prevalence of CAs, particularly chromosomal abnormalities (0.52% vs. 0.21%), in the GDM-exposed group (OR: 2.49, 95% Cl: 1.69-3.66, p < 0.001). The aOR was 1.93 (95% Cl: 1.25-2.99, p = 0.003). CONCLUSIONS: Offspring exposed to GDM have a higher prevalence of major CAs. Of note, risk factors other than GDM, such as older maternal age and a higher pre-pregnancy BMI, diminished the between group differences in the prevalence of major CAs. Nevertheless, our findings suggest that offspring exposed to maternal GDM are more likely to be diagnosed with a chromosomal abnormality, independent of maternal age, parity, pre-pregnancy BMI, and smoking.

Pregnancy-Associated Bleeding and Genetics: Five Sequence Variants in the Myometrium and Progesterone Signaling Pathway are associated with postpartum hemorrhage.

Bleeding in early pregnancy and postpartum hemorrhage (PPH) bear substantial risks, with the former closely associated with pregnancy loss and the latter being the foremost cause of maternal death, underscoring the severity of these complications in maternal-fetal health. Here, we investigated the genetic variation underlying aspects of pregnancy-associated bleeding and identified five loci associated with PPH through a meta-analysis of 21,512 cases and 259,500 controls. Functional annotation analysis indicated candidate genes, HAND2, TBX3, and RAP2C/FRMD7, at three loci and showed that at each locus, associated variants were located within binding sites for progesterone receptors (PGR). Furthermore, there were strong genetic correlations with birth weight, gestational duration, and uterine fibroids. Early bleeding during pregnancy (28,898 cases and 302,894 controls) yielded no genome-wide association signals, but showed strong genetic correlation with a variety of human traits, indicative of polygenic and pleiotropic effects. Our results suggest that postpartum bleeding is related to myometrium dysregulation, whereas early bleeding is a complex trait related to underlying health and possibly socioeconomic status.

Known risk factors of the developmental dysplasia of the hip predicting more severe clinical presentation and failure of Pavlik harness treatment.

PURPOSE: Developmental dysplasia of the hip (DDH) varies from mild instability of the hip to subluxation or total dislocation of the joint. Well-known risk factors of DDH include pre-natal breech position, female sex, positive family history, hip side, primiparity and the mode of delivery. Aim of the present study was to further evaluate known risk-factors of DDH, find associations with more severe dysplasia (characterized with Ortolani positivity) and find risk factors of failure of the Pavlik harness treatment. MATERIAL AND METHODS: All children with the diagnosis of DDH treated in Tampere University hospital in the years 1998-2018 were retrospectively identified for the study and the data was collected from the medical records. Teratological dislocations (n = 3) were excluded from the analysis. Total of 945 patients were included. RESULTS: Breech presentation was strongly associated with Ortolani positivity (p < 0.001). Breech presentation was not associated with ending up for spica casting and/or operative treatment (p = 0.291) despite the association with Ortolani positivity. Ortolani positivity (p = 0.002), positive family history (p = 0.013) and girl sex (p = 0.029) were associated with ending up for spica casting and/or operative treatment. CONCLUSION: Breech presentation seems to increase the risk of Ortolani positive DDH. However, these infants are likely to recover with initially started Pavlik harness treatment, as it was not associated with elevated risk for undergoing more robust treatments. Positive family history and girl sex are associated with the most severe cases of developmental dysplasia of the hip, and it may predispose to the failure of the Pavlik harness treatment.

GWAS meta-analyses clarify the genetics of cervical phenotypes and inform risk stratification for cervical cancer.

Genome-wide association studies (GWAS) have successfully identified associations for cervical cancer, but the underlying mechanisms of cervical biology and pathology remain uncharacterised. Our GWAS meta-analyses fill this gap, as we characterise the genetic architecture of cervical phenotypes, including cervical ectropion, cervicitis, cervical dysplasia, as well as up to 9229 cases and 490 304 controls for cervical cancer from diverse ancestries. Leveraging the latest computational methods and gene expression data, we refine the association signals for cervical cancer and propose potential causal variants and genes at each locus. We prioritise PAX8/PAX8-AS1, LINC00339, CDC42, CLPTM1L, HLA-DRB1 and GSDMB as the most likely candidate genes for cervical cancer signals, providing insights into cervical cancer pathogenesis and supporting the involvement of reproductive tract development, immune response and cellular proliferation/apoptosis. We construct a genetic risk score (GRS) that is associated with cervical cancer [hazard ratios (HR) = 3.1 (1.7-5.6) for the top 15% vs lowest 15% of individuals], and with other HPV- and immune-system-related diagnoses in a phenome-wide association study analysis. Our results propose valuable leads for further functional studies and present a GRS for cervical cancer that allows additional risk stratification and could potentially be used to personalise the conventional screening strategies for groups more susceptible to cervical cancer.

Associations of low sex hormone-binding globulin and androgen excess in early pregnancy with fasting and post-prandial hyperglycaemia, gestational diabetes, and its severity.

AIMS: We studied whether androgen excess and low sex hormone-binding globulin (SHBG) measured in early pregnancy are independently associated with fasting and post-prandial hyperglycaemia, gestational diabetes (GDM), and its severity. MATERIALS AND METHODS: This nationwide case-control study included 1045 women with GDM and 963 non-diabetic pregnant controls. We measured testosterone (T) and SHBG from biobanked serum samples (mean 10.7 gestational weeks) and calculated the free androgen index (FAI). We first studied their associations with GDM and secondly with the type of hyperglycaemia (fasting, 1 and 2 h glucose concentrations during the oral glucose tolerance test), early-onset GDM (<20 gestational weeks) and the need for anti-diabetic medication. RESULTS: After adjustments for gestational weeks at sampling, pre-pregnancy BMI, and age, women with GDM had 3.7% (95% CI 0.1%-7.3%) lower SHBG levels, 3.1% (95% CI 0.1%-6.2%) higher T levels, and 4.6% (95% CI 1.9%-7.3%) higher FAI levels than controls. SHBG was inversely associated with fasting glucose, whereas higher FAI and T were associated with higher post-prandial glucose concentrations. Women with early-onset GDM had 6.7% (95% CI 0.7%-12.7%) lower SHBG levels and women who needed insulin for fasting hyperglycaemia 8.7% (95% CI 1.8%-14.8%) lower SHBG levels than other women with GDM. CONCLUSIONS: Lower SHBG levels were associated especially with early-onset GDM, higher fasting glucose and insulin treatment, whereas androgen excess was associated with higher post-prandial glucose values. Thus, a low SHBG level may reflect the degree of existing insulin resistance, while androgen excess might impair post-prandial insulin secretion.

Subarachnoid Hemorrhage During Pregnancy and Puerperium: A Population-Based Study.

BACKGROUND: Pregnancy-related subarachnoid hemorrhage (pSAH) is rare, but it causes high mortality and morbidity. Nevertheless, data on pSAH are limited. The objectives here were to examine the incidence trends, causes, risk factors, and outcomes of pSAH in a nationwide population-based cohort study in Finland covering 30 years. METHODS: We performed a retrospective population-based cohort study and nested case-control study in Finland for the period 1987-2016 (Stroke in Pregnancy and Puerperium in Finland). The Medical Birth Register was linked to the Hospital Discharge Register to identify women with incident stroke during pregnancy or puerperium. A subcohort of women with SAH is included in this analysis. The temporal connection of SAH to pregnancy and clinical details were verified from patient records. RESULTS: The unadjusted incidence of pSAH was 3.21 (95% CI, 2.46-4.13) per 100 000 deliveries. No significant increase occurred in the incidence throughout the study period. However, the age of the mother had a significant increasing effect on the incidence. In total, 77% of patients suffered an aneurysmal pSAH, resulting in death in 16.3% of women and with only 68.2% achieving good recovery (modified Rankin Scale score 0-2) at 3 months. Patients with nonaneurysmal pSAH recovered well. The significant risk factors for pSAH were smoking (odds ratio, 3.27 [1.56-6.86]), prepregnancy hypertension (odds ratio, 12.72 [1.39-116.46]), and pre-eclampsia/eclampsia (odds ratio, 3.88 [1.00-15.05]). CONCLUSIONS: The incidence of pSAH has not changed substantially over time in Finland. The majority of pSAH cases were aneurysmal and women with aneurysm had considerable mortality and morbidity. Counseling of pregnant women about smoking cessation and monitoring of blood pressure and symptoms of pre-eclampsia are important interventions to prevent pSAH.

Clinical and sonographic improvement of developmental dysplasia of the hip: analysis of 948 patients.

BACKGROUND: Developmental dysplasia of the hip is a common condition, which varies in severity. Abduction treatment is widely used to correct the development of the hips, but mild forms of DDH can also recover spontaneously. The purpose of this study was to evaluate factors affecting the rate of improvement of developmental dysplasia of the hip, and evaluate any risk factors slowing the process. MATERIAL AND METHODS: The study population consisted of patients diagnosed with DDH in Tampere University hospital in the years 1998-2018. Data were retrospectively collected, and associations between clinical variables and rate of improvement were analyzed. Alpha angles were assessed monthly, and associations between risk factors and improvement of alpha angles were studied. A total of 948 patients were included in the analysis. RESULTS: More severe first status of the hips was associated with faster improvement in dynamic ultrasound compared to milder DDH in univariate design in first 3 months of age; in the multivariable design, Ortolani positivity was conversely associated with lower alpha angles in 1-month follow-up. Immediate abduction treatment was associated with faster recovery rate compared to delayed abduction or watchful waiting. Female sex and positive family history were associated with slower rate of improvement and lower alpha angles. In multivariable design, female sex, positive family history and treatment strategy remained statistically significant as initiation time of the treatment explained the first found association of clinical hip status and the recovery rate after 2 months of age. CONCLUSION: Female sex and positive family history might be independent risk factors for slower recovery in DDH before 6 months of age. These children might need special attention in their follow-up plans and abduction treatment.

Optimized detection of homologous recombination deficiency improves the prediction of clinical outcomes in cancer.

Homologous recombination DNA-repair deficiency (HRD) is a common driver of genomic instability and confers a therapeutic vulnerability in cancer. The accurate detection of somatic allelic imbalances (AIs) has been limited by methods focused on BRCA1/2 mutations and using mixtures of cancer types. Using pan-cancer data, we revealed distinct patterns of AIs in high-grade serous ovarian cancer (HGSC). We used machine learning and statistics to generate improved criteria to identify HRD in HGSC (ovaHRDscar). ovaHRDscar significantly predicted clinical outcomes in three independent patient cohorts with higher precision than previous methods. Characterization of 98 spatiotemporally distinct metastatic samples revealed low intra-patient variation and indicated the primary tumor as the preferred site for clinical sampling in HGSC. Further, our approach improved the prediction of clinical outcomes in triple-negative breast cancer (tnbcHRDscar), validated in two independent patient cohorts. In conclusion, our tumor-specific, systematic approach has the potential to improve patient selection for HR-targeted therapies.

Increased Oral Care Needs and Third Molar Symptoms in Women with Gestational Diabetes Mellitus: A Finnish Gestational Diabetes Case-Control Study.

(1) Hyperglycemia and oral pathology accelerate each other in diabetes. We evaluated whether gestational diabetes mellitus (GDM) is associated with self-reported increased oral health care needs and oral symptoms, including third molar symptoms, during pregnancy. (2) Pregnant women with (n = 1030) and without GDM (n = 935) were recruited in this multicenter Finnish Gestational Diabetes study in 2009-2012. Of the women with GDM, 196 (19.0%) receiving pharmacological treatment, 797 (77.0%) receiving diet treatment and 233 (23.0%) with recurrent GDM were analyzed separately. Oral health was assessed using structured questionnaires and analyzed by multivariable logistic regression adjusted for background risk factors. (3) Women with GDM were more likely to report a higher need for oral care than controls (31.1% vs. 24.5%; odds ratio (OR) 1.39; 95% confidence interval (CI) 1.14-1.69), particularly women with recurrent GDM (38.1% vs. 24.5%; OR 1.90; 95% CI 1.40-2.58). Women with pharmacologically treated GDM (46.9%) more often had third molar symptoms than controls (36.1%; OR 1.57; 95% CI 1.15-2.15) than women with diet-treated GDM (38.0%; OR 1.47; 95% CI 1.07-2.02). (4) GDM is associated with perceived oral care needs. Third molar symptoms were associated with pharmacologically treated GDM.

Genetic risk of type 2 diabetes modifies the effects of a lifestyle intervention aimed at the prevention of gestational and postpartum diabetes.

AIMS/HYPOTHESIS: The aim of this study was to assess the interaction between genetic risk and lifestyle intervention on the occurrence of gestational diabetes mellitus (GDM) and postpartum diabetes. METHODS: The RADIEL study is an RCT aimed at prevention of GDM and postpartum diabetes through lifestyle intervention. Participants with a BMI ≥30 kg/m2 and/or prior GDM were allocated to intervention and control groups before pregnancy or in early pregnancy. The study visits took place every 3 months before pregnancy, once in each trimester, and at 6 weeks and 6 and 12 months postpartum. We calculated a polygenic risk score (PRS) based on 50 risk variants for type 2 diabetes. RESULTS: Altogether, 516 participants provided genetic and GDM data. The PRS was associated with higher glycaemic levels (fasting glucose and/or HbA1c) and a lower insulin secretion index in the second and third trimesters and at 12 months postpartum, as well as with a higher occurrence of GDM and glycaemic abnormalities at 12 months postpartum (n = 356). There was an interaction between the PRS and lifestyle intervention (p=0.016 during pregnancy and p=0.024 postpartum) when analysing participants who did not have GDM at the first study visit during pregnancy (n = 386). When analysing women in tertiles according to the PRS, the intervention was effective in reducing the age-adjusted occurrence of GDM only among those with the highest genetic risk (OR 0.37; 95% CI 0.17, 0.82). The risk of glycaemic abnormalities at 12 months postpartum was reduced in the same group after adjusting additionally for BMI, parity, smoking and education (OR 0.35; 95% CI 0.13, 0.97). CONCLUSIONS/INTERPRETATION: Genetic predisposition to diabetes modifies the response to a lifestyle intervention aimed at prevention of GDM and postpartum diabetes. This suggests that lifestyle intervention may benefit from being tailored according to genetic risk. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01698385.

Leveraging Northern European population history: novel low-frequency variants for polycystic ovary syndrome.

STUDY QUESTION: Can we identify novel variants associated with polycystic ovary syndrome (PCOS) by leveraging the unique population history of Northern Europe? SUMMARY ANSWER: We identified three novel genome-wide significant associations with PCOS, with two putative independent causal variants in the checkpoint kinase 2 (CHEK2) gene and a third in myosin X (MYO10). WHAT IS KNOWN ALREADY: PCOS is a common, complex disorder with unknown aetiology. While previous genome-wide association studies (GWAS) have mapped several loci associated with PCOS, the analysis of populations with unique population history and genetic makeup has the potential to uncover new low-frequency variants with larger effects. STUDY DESIGN, SIZE, DURATION: A population-based case-control GWAS was carried out. PARTICIPANTS/MATERIALS, SETTING, METHODS: We identified PCOS cases from national registers by ICD codes (ICD-10 E28.2, ICD-9 256.4, or ICD-8 256.90), and all remaining women were considered controls. We then conducted a three-stage case-control GWAS: in the discovery phase, we had a total of 797 cases and 140 558 controls from the FinnGen study. For validation, we used an independent dataset from the Estonian Biobank, including 2812 cases and 89 230 controls. Finally, we performed a joint meta-analysis of 3609 cases and 229 788 controls from both cohorts. Additionally, we reran the association analyses including BMI as a covariate, with 2169 cases and 160 321 controls from both cohorts. MAIN RESULTS AND THE ROLE OF CHANCE: Two out of the three novel genome-wide significant variants associating with PCOS, rs145598156 (P = 3.6×10-8, odds ratio (OR) = 3.01 [2.02-4.50] minor allele frequency (MAF) = 0.005) and rs182075939 (P = 1.9×10-16, OR = 1.69 [1.49-1.91], MAF = 0.04), were found to be enriched in the Finnish and Estonian populations and are tightly linked to a deletion c.1100delC (r2 = 0.95) and a missense I157T (r2 = 0.83) in CHEK2. The third novel association is a common variant near MYO10 (rs9312937, P = 1.7 × 10-8, OR = 1.16 [1.10-1.23], MAF = 0.44). We also replicated four previous reported associations near the genes Erb-B2 Receptor Tyrosine Kinase 4 (ERBB4), DENN Domain Containing 1A (DENND1A), FSH Subunit Beta (FSHB) and Zinc Finger And BTB Domain Containing 16 (ZBTB16). When adding BMI as a covariate only one of the novel variants remained genome-wide significant in the meta-analysis (the EstBB lead signal in CHEK2 rs182075939, P = 1.9×10-16, OR = 1.74 [1.5-2.01]) possibly owing to reduced sample size. LARGE SCALE DATA: The age- and BMI-adjusted GWAS meta-analysis summary statistics are available for download from the GWAS Catalog with accession numbers GCST90044902 and GCST90044903. LIMITATIONS, REASONS FOR CAUTION: The main limitation was the low prevalence of PCOS in registers; however, the ones with the diagnosis most likely represent the most severe cases. Also, BMI data were not available for all (63% for FinnGen, 76% for EstBB), and the biobank setting limited the accessibility of PCOS phenotypes and laboratory values. WIDER IMPLICATIONS OF THE FINDINGS: This study encourages the use of isolated populations to perform genetic association studies for the identification of rare variants contributing to the genetic landscape of complex diseases such as PCOS. STUDY FUNDING/COMPETING INTEREST(S): This work has received funding from the European Union's Horizon 2020 research and innovation programme under the MATER Marie Sklodowska-Curie grant agreement No. 813707 (N.P.-G., T.L., T.P.), the Estonian Research Council grant (PRG687, T.L.), the Academy of Finland grants 315921 (T.P.), 321763 (T.P.), 297338 (J.K.), 307247 (J.K.), 344695 (H.L.), Novo Nordisk Foundation grant NNF17OC0026062 (J.K.), the Sigrid Juselius Foundation project grants (T.L., J.K., T.P.), Finska Läkaresällskapet (H.L.) and Jane and Aatos Erkko Foundation (H.L.). The funders had no role in study design, data collection and analysis, publishing or preparation of the manuscript. The authors declare no conflicts of interest.

The Association Between High Birth Weight and Long-Term Outcomes-Implications for Assisted Reproductive Technologies: A Systematic Review and Meta-Analysis.

Background: Studies have shown that the prevalence of children born with high birth weight or large for gestational age (LGA) is increasing. This is true for spontaneous pregnancies; however, children born after frozen embryo transfer (FET) as part of assisted reproductive technology (ART) also have an elevated risk. In recent years, the practice of FET has increased rapidly and while the perinatal and obstetric risks are well-studied, less is known about the long-term health consequences. Objective: The aim of this systematic review was to describe the association between high birth weight and LGA on long-term child outcomes. Data Sources: PubMed, Scopus, and Web of Science were searched up to January 2021. Exposure included high birth weight and LGA. Long-term outcome variables included malignancies, psychiatric disorders, cardiovascular disease, and diabetes. Study Selection: Original studies published in English or Scandinavian languages were included. Studies with a control group were included while studies published as abstracts and case reports were excluded. Data Extraction: The methodological quality, in terms of risk of bias, was assessed by pairs of reviewers. Robins-I (www.methods.cochrane.org) was used for risk of bias assessment in original articles. For systematic reviews, AMSTAR (www.amstar.ca) was used. For certainty of evidence, we used the GRADE system. The systematic review followed PRISMA guidelines. When possible, meta-analyses were performed. Results: The search included 11,767 articles out of which 173 met the inclusion criteria and were included in the qualitative analysis, while 63 were included in quantitative synthesis (meta-analyses). High birth weight and/or LGA was associated with low to moderately elevated risks for certain malignancies in childhood, breast cancer, several psychiatric disorders, hypertension in childhood, and type 1 and 2 diabetes. Conclusions: Although the increased risks for adverse outcome in offspring associated with high birth weight and LGA represent serious health effects in childhood and in adulthood, the size of these effects seems moderate. The identified risk association should, however, be taken into account in decisions concerning fresh and frozen ART cycles and is of general importance in view of the increasing prevalence in high birthweight babies.

Stroke in Pregnancy and Puerperium: Validated Incidence Trends With Risk Factor Analysis in Finland 1987-2016.

OBJECTIVE: To investigate whether previously reported increasing incidence of pregnancy-associated stroke (PAS) is observed in chart-validated register data in Finland. In an exploratory analysis, we studied risk factors for PAS. METHODS: We performed a retrospective population-based cohort study and nested case-control study in Finland from 1987 to 2016. The Medical Birth Register (MBR) was linked to the Hospital Discharge Register to identify women with incident stroke (ischemic stroke, cerebral venous thrombosis, intracerebral or subarachnoid hemorrhage) during pregnancy or puerperium. Cases were verified from patient records. Incidence of PAS over the study period in 5-year age groups and pregnancy/postpartum period was calculated per number of deliveries. Three matched controls were selected for each case from MBR to compare risk factors. RESULTS: After chart review, 29.6% (257 of 868) of cases were PAS. The incidence of PAS was 14.5 (95% confidence interval [CI] 12.8-16.3) per 100,000 deliveries. Incidence increased from 11.1 to 25.2 per 100,000 deliveries from 1987 to 1991 to 2012 to 2016 (p < 0.0001). Incidence increased by age from 9.8 to 29.9 per 100,000 deliveries from 20 to 24 years to >40 years of age (p < 0.0001). During the early postpartum period, incidence was 5-fold greater compared to the first trimester. Maternal mortality was 6.6%. In the multivariable-adjusted model, smoking beyond 12 gestational weeks (odds ratio [OR] 1.8, 95% CI 1.2-2.7), migraine (OR 16.3, 95% CI 5.3-49.8), and hypertensive disorders of pregnancy (OR 4.0, 95% CI 2.5-6.3) were the most important risk factors for PAS. CONCLUSION: PAS incidence is increasing, stressing the importance of careful pregnancy surveillance and risk factor management, particularly in older expectant mothers and extending to puerperium. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that smoking beyond 12 gestational weeks, migraine, and hypertensive disorders of pregnancy are associated with an increased risk of PAS.

Characteristics of epigenetic aging across gestational and perinatal tissues.

BACKGROUND: Epigenetic clocks have been used to indicate differences in biological states between individuals of same chronological age. However, so far, only few studies have examined epigenetic aging in newborns-especially regarding different gestational or perinatal tissues. In this study, we investigated which birth- and pregnancy-related variables are most important in predicting gestational epigenetic age acceleration or deceleration (i.e., the deviation between gestational epigenetic age estimated from the DNA methylome and chronological gestational age) in chorionic villus, placenta and cord blood tissues from two independent study cohorts (ITU, n = 639 and PREDO, n = 966). We further characterized the correspondence of epigenetic age deviations between these tissues. RESULTS: Among the most predictive factors of epigenetic age deviations in single tissues were child sex, birth length, maternal smoking during pregnancy, maternal mental disorders until childbirth, delivery mode and parity. However, the specific factors related to epigenetic age deviation and the direction of association differed across tissues. In individuals with samples available from more than one tissue, relative epigenetic age deviations were not correlated across tissues. CONCLUSION: Gestational epigenetic age acceleration or deceleration was not related to more favorable or unfavorable factors in one direction in the investigated tissues, and the relative epigenetic age differed between tissues of the same person. This indicates that epigenetic age deviations associate with distinct, tissue specific, factors during the gestational and perinatal period. Our findings suggest that the epigenetic age of the newborn should be seen as a characteristic of a specific tissue, and less as a general characteristic of the child itself.

Angiogenic Effect of Pravastatin Alone and with Sera from Healthy and Complicated Pregnancies Studied by in vitro Vasculogenesis/Angiogenesis Assay.

OBJECTIVE: To determine the direct effect of pravastatin on angiogenesis and to study the interaction between pravastatin and maternal sera from women with early- or late-onset pre-eclampsia (PE), intrauterine growth restriction, or healthy pregnancy. METHODS: We collected 5 maternal serum samples from each group. The effect of pravastatin on angiogenesis was assessed with and without maternal sera by quantifying tubule formation in a human-based in vitro assay. Pravastatin was added at 20, 1,000, and 8,000 ng/mL concentrations. Concentrations of angiogenic and inflammatory biomarkers in serum and in test medium after supplementation of serum alone and with pravastatin (1,000 ng/mL) were measured. RESULTS: Therapeutic concentration of pravastatin (20 ng/mL) did not have significant direct effect on angiogenesis, but the highest concentrations inhibited angiogenesis. Pravastatin did not change the levels of biomarkers in the test media. There were no changes in angiogenesis when therapeutic dose of pravastatin was added with maternal sera, but there was a trend to wide individual variation towards enhanced angiogenesis, particularly in the early-onset PE group. CONCLUSIONS: At therapeutic concentration, pravastatin alone or with maternal sera has no significant effect on angiogenesis, but at high concentrations the effect seems to be anti-angiogenic estimated by in vitro assay.