Cardiac Structure and Function in 8- to 12-Year-Old Children Following In-Utero Exposure to Preeclampsia (FINNCARE Study).

BACKGROUND: We evaluated how elevated blood pressure in children exposed to preeclampsia (PE) impacted on their cardiac structure and function, as well as relations with maternal, gestational, and perinatal factors and child body size and composition. METHODS AND RESULTS: A total of 182 PE (46 early-onset preeclampsia) and 85 unexposed (non-PE) children were examined in the FINNCARE study 8 to 12 years after the index pregnancy with echocardiography; office, central, and 24-hour ambulatory blood pressures; and body anthropometrics and composition. PE children had lower right ventricular basal sphericity index (mean difference, -0.26 95% CI, -0.39 to -0.12) and lower mitral lateral E'-wave peak velocity (-1.4 cm/s [95% CI, -2.1 to -0.6]), as well as higher E to E' ratio (0.40 [95% CI, 0.15-0.65]) and indexed tricuspid annular plane systolic excursion (0.03 [95% CI, 0.01-0.05]) compared with non-PE children. These differences were accentuated in early-onset PE children. Left ventricular mass (LVM) or left atrial volume were not different between PE and non-PE children. Lean body mass, body fat percentage, and 24-hour systolic blood pressure were independent predictors of LVM. Lean body mass and body fat percentage were independent predictors of left atrial volume. No significant associations between LVM or left atrial volume and maternal, gestational, or perinatal parameters were found. CONCLUSIONS: Preadolescent PE children display a more globular-shaped right ventricle with higher longitudinal systolic displacement as well as mildly altered diastolic indices, with the alterations being pronounced in early-onset preeclampsia. Lean body mass and adiposity are independently related with LVM and left atrial volume, and systolic blood pressure with LVM in both PE and non-PE children. These unfavorable associations indicate remodeling of cardiac structure in young children also reflected in mild functional changes in PE children. REGISTRATION: URL: https://www.clinicaltrials.gov; unique identifier: NCT04676295.

Long-Term Mortality, Recovery, and Vocational Status After a Maternal Stroke: Register-Based Observational Case-Control Study.

BACKGROUND AND OBJECTIVES: Maternal stroke is a rare event with an increasing incidence. Data on the long-term prognosis after a maternal stroke are limited. We aimed to examine long-term mortality, recovery, vocational status and morbidity after a maternal stroke in a population-based setting including a comparison with matched, stroke-free controls. METHODS: In this register-based study with hospital chart validation, we included all women with a maternal stroke in Finland in 1987-2016 who survived the first year after the event. The recovery of the cases was assessed from the hospital charts by modified Rankin scale (mRS). Three controls matched by delivery year, age, and parity were selected for each case. All deaths until 2022 were identified from the Register for Causes of Death. Data on vocational status were obtained from Statistics Finland and morbidity from the Hospital Discharge Register and patient charts until year 2016. RESULTS: The study included 235 women with a maternal stroke and 694 matched controls. The median follow-up time was 17.5 years (interquartile range [IQR] 9.6-25.4) for mortality and 11.8 years (IQR 3.8-19.8) for vocational status and subsequent morbidity. Mortality among cases was 5.5% and among controls, 2.4% (age-adjusted odds ratio [OR] 2.3, 95% [CI] 1.1-4.9). At the end of the follow-up, 90.3% of the cases were independent in daily activities (mRS ≤2). In 2016, fewer women with a maternal stroke were working compared with controls (65.9% vs 79.1%, OR 0.5, 95% CI 0.4-0.7) and were more often receiving a pension (18.2% vs 4.9%, OR 4.4, 95% CI 2.7-7.3). Cerebrovascular events (age-adjusted OR 8.6 95% CI 4.4-17.1), cardiac diseases (age-adjusted OR 3.3, 95% CI 1.4-7.7), and major cardiovascular events were more common among cases during the follow-up (age-adjusted OR 7.6 95% CI 3.1-18.7). DISCUSSION: Despite having higher overall mortality and higher cardiovascular morbidity, the majority of the maternal stroke survivors recovered well. As expected, the vocational status of cases was inferior to that of controls, but most women were working at the end of the follow-up. Our study provides important information on the prognosis and sequalae after a maternal stroke to help in patient counseling and to improve secondary prevention.

Intracranial Arteriovenous Malformations During Pregnancy and Puerperium-A Retrospective Nationwide Population-Based Cohort Study.

BACKGROUND AND OBJECTIVES: The knowledge about the management of patients with brain arteriovenous malformations (AVM) during pregnancy is limited, owing partly to insufficient evidence about the outcomes of newborns. This study aims to explore symptomatic AVMs and their outcomes during pregnancy, delivery, and the postpartum period. METHODS: We conducted a retrospective analysis by combining patients with symptomatic AVM from a nationwide population-based cohort of all women with a pregnancy resulting in delivery during 1987 to 2016 (n = 1 773 728 deliveries) and our AVM database (n = 805, 1942-2014). Cerebrovascular events during pregnancy were identified through International Classification of Diseases-9, International Classification of Diseases-10, or surgical procedure codes from the Hospital Discharge and Medical Birth Registers. Our analysis focused on treatment characteristics and outcomes of patients with AVM hemorrhage or symptomatic AVM during pregnancy, delivery, or puerperium. RESULTS: A total of 28 women with symptomatic AVMs during pregnancy, delivery, or postpartum period were followed for an average of 12.8 years (SD = 15.5) after admission. Among them, 21 (75%) experienced AVM hemorrhages during pregnancy, puerperium, or delivery. The mean age of patients was 28.9 years (SD = 5.5). Hemorrhages occurred predominantly during the second (n = 9, 43% of all ruptures) or the third trimester (n = 5, 24%). Two AVM ruptures occurred during labor. Treatment for AVM took place during pregnancy (n = 7, 25%) or puerperium (n = 3, 14%) in 10 patients (35.7%). Only 5 mothers (17.8%) had not been previously pregnant. There was no significant difference in mean Apgar scores between those with AVM hemorrhage (8.3) and those without (8.4). CONCLUSION: Most mothers in the study had prior pregnancies, suggesting a potentially weaker association between AVM rupture and pregnancy compared to previous reports. Notably, 2 AVM ruptures occurred during spontaneous vaginal deliveries. Outcomes were generally favorable in both mothers and infants. More research is needed to refine our understanding of the optimal timing for invasive treatment during pregnancy.

Fetal cord plasma herpesviruses and preeclampsia: an observational cohort study.

A previous study suggested that fetal inheritance of chromosomally integrated human herpesvirus 6 (ici-HHV6) is associated with the hypertensive pregnancy disorder preeclampsia (PE). We aimed to study this question utilizing cord plasma samples (n = 1276) of the Finnish Genetics of Preeclampsia Consortium (FINNPEC) cohort: 539 from a pregnancy with PE and 737 without. We studied these samples and 30 placentas from PE pregnancies by a multiplex qPCR for the DNAs of all nine human herpesviruses. To assess the population prevalence of iciHHV-6, we studied whole-genome sequencing data from blood-derived DNA of 3421 biobank subjects. Any herpes viral DNA was detected in only two (0.37%) PE and one (0.14%) control sample (OR 2.74, 95% CI 0.25-30.4). One PE sample contained iciHHV-6B and another HHV-7 DNA. The control's DNA was of iciHHV-6B; the fetus having growth restriction and preterm birth without PE diagnosis. Placentas showed no herpesviruses. In the biobank data, 3 of 3421 subjects (0.08%) had low level HHV-6B but no iciHHV-6. While iciHHV-6 proved extremely rare, both fetuses with iciHHV-6B were growth-restricted, preterm, and from a pregnancy with maternal hypertension. Our findings suggest that human herpesviruses are not a significant cause of PE, whereas iciHHV-6 may pose some fetal risk.

Delayed versus early delivery leads to similar outcome in selected cases of preeclampsia in the Finnish Genetics of Pre-eclampsia Consortium (FINNPEC) cohort.

OBJECTIVES: Most guidelines recommend induction of labor after 37 weeks of gestation in preeclampsia. This study assessed the effect of interval between diagnosis of preeclampsia and delivery on maternal and perinatal outcomes. STUDY DESIGN: A cohort of 1637 women with preeclampsia recruited at five university hospitals in Finland was studied. Outcomes were compared in two groups according to the time interval between diagnosis of PE and delivery: delivery in less than 10 days (the early delivery group) and delivery at 10 days or later after the diagnosis (the delayed delivery group). MAIN OUTCOME MEASURES: Maternal outcomes included significantly preterm delivery (delivery before 34 weeks of gestation), placental abruption, eclampsia and maternal intensive care or intensive monitoring for more than 24 h. Neonatal outcomes included small for gestational age, Apgar score of less than seven at the age of five minutes, umbilical artery pH < 7.05 and fetal death. RESULTS: No differences in frequency of preterm deliveries or maternal need for intensive care were observed between groups. Eclampsia and fetal death were rare, and their incidence did not differ between the groups. No maternal deaths were observed. Low Apgar score at five minutes of age was reported more commonly in the early delivery group, but there was no difference in fetal acidemia between groups. CONCLUSION: Early and delayed delivery lead to comparable outcomes in this cohort. Expectant management could be beneficial in women with an unripe cervix or preterm preeclampsia without severe features.

Risk assessment of hypertensive disorders of pregnancy and other adverse pregnancy outcomes after frozen embryo transfers following an artificial cycle: A retrospective cohort study.

OBJECTIVES: The primary aim was to investigate if frozen embryo transfer (FET) without a corpus luteum increases the risk of hypertensive disorders of pregnancy (HDP). The secondary aim was to investigate other adverse maternal and perinatal outcomes. METHODS: This was a retrospective cohort study of 1168 singleton pregnancies and live births following a FET with either an artificial cycle (AC-FET) (n = 631) or a natural/modified natural/stimulated cycle (CL-FET) (n = 537) between 2012 and 2020. The data were collected from patient records. The primary outcome was HDP. Secondary outcomes included cesarean sections, placental retention problems, postpartum hemorrhage (PPH), the duration of pregnancy, birth weight, low birth weight, macrosomia, length of gestation, preterm birth, small for gestational age, and large for gestational age. RESULTS: In the AC-FET group, there was an increased incidence of pre-eclampsia, gestational hypertension, cesarean sections, PPH over 500 and 1000 mL, and retained placental tissue, compared with the CL-FET group. These associations remained significant in logistic regression analyses with clinically relevant adjustments. CONCLUSION: The risk of HDP and several other maternal complications seems to be increased after AC-FET compared with CL-FET. Our findings support most earlier studies regarding HDP and add to the knowledge on other maternal and perinatal risks involved in AC-FET, including an increased risk of milder forms of placental retention. More studies are needed to confirm these findings.

Serum Hydroxysteroid (17beta) dehydrogenase 1 concentration in pregnant women correlates with pregnancy-associated plasma protein a but does not serve as an independent marker for preeclampsia.

Hydroxysteroid (17beta) dehydrogenase 1 (HSD17B1) is a steroid synthetic enzyme expressed in ovarian granulosa cells and placental syncytiotrophoblasts. Here, HSD17B1 serum concentration was measured with a validated immuno assay during pregnancy at three time points (12-14, 18-20 and 26-28 weeks of gestation). The concentration increased 2.5-fold (p < 0.0001) and 1.7-fold (p = 0.0019) during the follow-up period for control women and women who later developed preeclampsia (PE), respectively, and a significant difference was observed at weeks 26-28 (p = 0.0266). HSD17B1 concentration at all the three time points positively correlated with serum PAPPA measured at the first time point (first time point r = 0.38, p = 1.1x10-10; second time point r = 0.27, p = 5.9x10-6 and third timepoint r = 0.26, p = 2.3x10-5). No correlation was observed between HSD17B1 and placental growth factor (PLGF). Serum HSD17B1, furthermore, negatively correlated with the mother's weight and body mass index (BMI), mirroring the pattern observed for PAPPA. The univariable logistic regression identified a weak association between HSD17B1 at 26-28 weeks and later development of PE (P = 0.04). Also, the best multivariable model obtained using penalized logistic regression with stable iterative variable selection at 26-28 weeks included HSD17B1, together with PLGF, PAPPA and the mother's BMI. While the area under the ROC curve of the model was higher than that of the adjusted PLGF, the difference was not statistically significant. In summary, the serum concentration of HSD17B1 correlated with PAPPA, another protein expressed in syncytiotrophoblasts, and with mother's weight and BMI but could not be considered as an independent marker for PE.

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.

Acute recanalization therapy for ischemic stroke during pregnancy and puerperium.

BACKGROUND: The safety and efficacy of intravenous thrombolysis (IVT) and endovascular thrombectomy for an ischemic stroke (IS) during pregnancy and puerperium are poorly studied. We evaluated the complications and outcome of recanalization therapy in maternal ISs. METHODS: A nationwide cohort of maternal ISs in Finland during 1987-2016 was collected by linking national healthcare registers: Medical Birth Register, Hospital Discharge Register, and Cause-Of-Death Register. The diagnoses were verified retrospectively from patient records. IVT-treated patients were compared to controls, who were young females with non-pregnancy-related IS from the Helsinki Stroke Thrombolysis Registry. RESULTS: Totally, 12 of 97 (12.4%) maternal ISs were treated with recanalization therapy. Compared to controls, IVT-treated maternal IS patients had more frequently early (age-adjusted odds ratio (aOR) = 7.63, 95% CI 1.49-39.04) and major (aOR = 8.59, 95% CI 2.09-35.31) neurological improvements, measured using the National Institute of Health Stroke Scale. Good functional outcomes (modified Rankin Scale 0-2) at three months were equally common in maternal ISs and controls. No other complications were observed in IVT-treated maternal ISs than 1 (9.1%) symptomatic nonfatal intracranial hemorrhage. Among maternal IS patients treated with recanalization or conventional therapy, good functional outcome at the end of the follow-up was less common in recanalization-treated patients (66.7% vs 89.4%, aOR = 0.22, 95% CI 0.052-0.90), but otherwise outcomes were similar. CONCLUSIONS: In this small nationwide cohort of maternal ISs, the complications of recanalization therapy were rare, and the outcomes were similar in IVT-treated maternal IS patients and controls. Maternal ISs should not be excluded from recanalization therapy in otherwise eligible situations.

Rare variants in genes coding for components of the terminal pathway of the complement system in preeclampsia.

Preeclampsia is a common multifactorial disease of pregnancy. Dysregulation of the complement activation is among emerging candidates responsible for disease pathogenesis. In a targeted exomic sequencing study we identified 14 variants within nine genes coding for components of the membrane attack complex (MAC, C5b-9) that are associated with preeclampsia. We found two rare missense variants in the C5 gene that predispose to preeclampsia (rs200674959: I1296V, OR (CI95) = 24.13 (1.25-467.43), p-value = 0.01 and rs147430470: I330T, OR (CI95) = 22.75 (1.17-440.78), p-value = 0.01). In addition, one predisposing rare variant and one protective rare variant were discovered in C6 (rs41271067: D396G, OR (CI95) = 2.93 (1.18-7.10), p-value = 0.01 and rs114609505: T190I, 0.02 OR (CI95) = 0.47 (0.22-0.92), p-value = 0.02). The results suggest that variants in terminal complement pathway predispose to preeclampsia.

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.

Genome-wide analyses identify 21 infertility loci and over 400 reproductive hormone loci across the allele frequency spectrum.

Genome-wide association studies (GWASs) may help inform treatments for infertility, whose causes remain unknown in many cases. Here we present GWAS meta-analyses across six cohorts for male and female infertility in up to 41,200 cases and 687,005 controls. We identified 21 genetic risk loci for infertility (P≤5E-08), of which 12 have not been reported for any reproductive condition. We found positive genetic correlations between endometriosis and all-cause female infertility (rg=0.585, P=8.98E-14), and between polycystic ovary syndrome and anovulatory infertility (rg=0.403, P=2.16E-03). The evolutionary persistence of female infertility-risk alleles in EBAG9 may be explained by recent directional selection. We additionally identified up to 269 genetic loci associated with follicle-stimulating hormone (FSH), luteinising hormone, oestradiol, and testosterone through sex-specific GWAS meta-analyses (N=6,095-246,862). While hormone-associated variants near FSHB and ARL14EP colocalised with signals for anovulatory infertility, we found no rg between female infertility and reproductive hormones (P>0.05). Exome sequencing analyses in the UK Biobank (N=197,340) revealed that women carrying testosterone-lowering rare variants in GPC2 were at higher risk of infertility (OR=2.63, P=1.25E-03). Taken together, our results suggest that while individual genes associated with hormone regulation may be relevant for fertility, there is limited genetic evidence for correlation between reproductive hormones and infertility at the population level. We provide the first comprehensive view of the genetic architecture of infertility across multiple diagnostic criteria in men and women, and characterise its relationship to other health conditions.

Patterns of reproductive health in inflammatory rheumatic diseases and other immune-mediated diseases: a nationwide registry study.

OBJECTIVES: Rheumatic diseases may impair reproductive success and pregnancy outcomes, but systematic evaluations across diseases are lacking. We conducted a nationwide cohort study to examine the impact of rheumatic diseases on reproductive health measures, comparing the impacts with those of other immune-mediated diseases (IMDs). METHODS: Out of all of the 5 339 804 Finnish citizens, individuals born 1964-1984 and diagnosed with any of the 19 IMDs before age 30 (women) or 35 (men) were matched with 20 controls by birth year, sex, and education. We used data from nationwide health registers to study the impact of IMDs on reproductive health measures, such as reproductive success and, for women, ever having experienced adverse maternal and perinatal outcomes. RESULTS: Several of the rheumatic diseases, particularly SLE, JIA, and seropositive RA, were associated with higher rates of childlessness and fewer children. The risks for pre-eclampsia, newborns being small for gestational age, preterm delivery, non-elective Caesarean sections, and need of neonatal intensive care were increased in many IMDs. Particularly, SLE, SS, type 1 diabetes, and Addison's disease showed >2-fold risks for some of these outcomes. In most rheumatic diseases, moderate (1.1-1.5-fold) risk increases were observed for diverse adverse pregnancy outcomes, with similar effects in IBD, celiac disease, asthma, ITP, and psoriasis. CONCLUSION: Rheumatic diseases have a broad impact on reproductive health, with effects comparable with that of several other IMDs. Of the rheumatic diseases, SLE and SS conferred the largest risk increases on perinatal adverse event outcomes.

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.

Associations of polymetabolic risk of high maternal pre-pregnancy body mass index with pregnancy complications, birth outcomes, and early childhood neurodevelopment: findings from two pregnancy cohorts.

BACKGROUND: A substantial proportion of maternal pregnancy complications, adverse birth outcomes and neurodevelopmental delay in children may be attributable to high maternal pre-pregnancy Body Mass Index (BMI). However, BMI alone is insufficient for the identification of all at-risk mothers and children as many women with non-obesity(< 30 kg/m2) or normal weight(18.5-24.99 kg/m2) and their children may suffer from adversities. Evidence suggests that BMI-related metabolic changes during pregnancy may predict adverse mother-child outcomes better than maternal anthropometric BMI. METHODS: In a cohort of 425 mother-child dyads, we identified maternal BMI-defined metabolome based on associations of 95 metabolic measures measured three times during pregnancy with maternal pre-pregnancy BMI. We then examined whether maternal BMI-defined metabolome performed better than anthropometric BMI in predicting gestational diabetes, hypertensive disorders, gestational weight gain (GWG), Caesarian section delivery, child gestational age and weight at birth, preterm birth, admission to neonatal intensive care unit (NICU), and childhood neurodevelopment. Based on metabolic measures with the highest contributions to BMI-defined metabolome, including inflammatory and glycolysis-related measures, fatty acids, fluid balance, ketone bodies, lipids and amino acids, we created a set of maternal high BMI-related polymetabolic risk scores (PMRSs), and in an independent replication cohort of 489 mother-child dyads tested their performance in predicting the same set of mother-child outcomes in comparison to anthropometric BMI. RESULTS: BMI-defined metabolome predicted all of the studied mother-child outcomes and improved their prediction over anthropometric BMI, except for gestational hypertension and GWG. BMI-related PMRSs predicted gestational diabetes, preeclampsia, Caesarian section delivery, admission to NICU, lower gestational age at birth, lower cognitive development score of the child, and improved their prediction over anthropometric BMI. BMI-related PMRSs predicted gestational diabetes, preeclampsia, Caesarean section delivery, NICU admission and child's lower gestational age at birth even at the levels of maternal non-obesity and normal weight. CONCLUSIONS: Maternal BMI-defined metabolome improves the prediction of pregnancy complications, birth outcomes, and neurodevelopment in children over anthropometric BMI. The novel, BMI-related PMRSs generated based on the BMI-defined metabolome have the potential to become biomarkers identifying at-risk mothers and their children for timely targeted interventions even at the level of maternal non-obesity and normal weight.

Etiology of intracerebral hemorrhage during pregnancy or puerperium: A nationwide study.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage during pregnancy or puerperium (pICH) is one of the leading causes of maternal death worldwide. However, limited epidemiological data exist on the etiology and outcomes of pICH, which is required to guide prevention and treatment. METHODS: A retrospective nationwide cohort study and a nested case-control study was performed in Finland 1987-2016. We identified women with incident pICH by linking the Medical Birth Register (MBR) and the Hospital Discharge Register (HDR). The clinical details were collected from patient records. Three matched controls with a pregnancy without ICH were selected for each case from the MBR. RESULTS: In total, 49 pICH cases were identified. Half of these cases occurred during pregnancy, and the other half during peripartum and puerperium. Based on the SMASH-U (structural vascular lesion, medication, amyloid angiopathy, systemic disease, hypertension, undetermined) classification, 35.4% of the patients had a systemic disease, most commonly preeclampsia, eclampsia, or HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome; 31.3% had a structural vascular lesion; 31.3% had an undetermined etiology; and one patient (2.1%) had hypertension. The most important risk factor was hypertensive disorders of pregnancy (HDP; odds ratio = 3.83, 95% confidence interval = 1.60-9.15), occurring in 31% of the cases. Maternal mortality was 12.5%, and 20.9% of the surviving women had significant disability (modified Rankin Scale = 3-5) 3 months after the pICH. Women with systemic disease had the worst outcomes. CONCLUSIONS: Even in a country with a comprehensive pregnancy surveillance system, the maternal mortality rate for pICH is high, and the sequelae are severe. Early recognition and treatment of the key risk factor, HDP, is crucial to help prevent this serious pregnancy complication.

Validation of the Finnish Care register for Health Care diagnoses for preeclampsia, gestational diabetes and preterm delivery.

BACKGROUND: Centrally collected Finnish national health register data on adverse pregnancy outcomes are available for research, but the validity of the data is largely unknown. Our aim was to compare the diagnoses of preeclampsia (PE), gestational diabetes (GDM), and preterm delivery from hospital records with the registry based diagnoses from the Finnish Care Register for Health Care (FCR). Data on gestational age at delivery from the Medical Birth Registry (MBR) was also studied. METHODS: The Finnish Genetics of Pre-eclampsia Consortium (FINNPEC) Study cohort was used as a data source. Each diagnosis was ascertained from electronic hospital records. The validity of diagnoses obtained by record linkage of FCR and MBR was assessed against the classification previously confirmed independently by a research nurse and a study physician. RESULTS: Sensitivity of PE diagnoses in FCR was 80.3 % (95 % CI 78.3 % to 82.2 %) andspecificity 95.3 % (95 % CI 93.9 % to 96.4 %). Sensitivity for GDM was 64.1 % (95 % CI: 58.7 % - 69.3 %) and specificity 98.5 % (95 % CI: 97.9 % - 98.9 %), whereas sensitivity and specificity for preterm delivery were 32.4 % (95 % CI: 29.0 % - 36.0 %) and 99.7 % (95 % CI: 99.3 % - 99.9 %). Sensitivity of preterm delivery in the MBR was 99.1 % and specificity 99.9 %. CONCLUSIONS: FCR registry diagnoses for PE have satisfactory sensitivity and high specificity. Diagnoses for GDM and preterm delivery have lower sensitivity limiting their use in studies, and data from MBR should be preferred when studying preterm deliveries.

Endometrial preparation protocols prior to frozen embryo transfer - convenience or safety?

The number of frozen embryo transfer (FET) cycles is increasing rapidly worldwide. Different endometrial preparations for FET result in comparable live birth rates. However, several recent publications have reported higher maternal risks for hypertensive disorders of pregnancy (HDP), pre-eclampsia and postpartum haemorrhage (PPH) in programmed cycles (PC-FET) compared with natural cycles and modified natural cycles with an intact corpus luteum. Nevertheless, PC-FET is frequently used in ovulatory women despite the increased risks for HDP, pre-eclampsia and PPH. Although randomized controlled studies have been suggested, PC-FET raises several methodological problems. Large study populations would be required to investigate the outcomes in question, and the inclusion of ovulatory women, where the intervention may increase the risk of a negative outcome, is ethically troublesome. In the authors' opinion, the existing evidence from large observational studies and systematic reviews is sufficiently strong to recommend an endometrial preparation strategy that aims to maintain or stimulate the corpus luteum to minimize the risk of HDP and pre-eclampsia after FET cycles.

Preeclampsia-exposed children's heart rate variability 8-12 yr after index pregnancy: FINNCARE study.

Preeclampsia is related with elevated systolic blood pressure (SBP) in children. We studied if preeclampsia-exposed (PE) children develop alterations in heart rate variability (HRV) and if this is reflected in their blood pressure (BP), as well as overall associations with body size and composition, gestational and perinatal factors. We examined 182 PE (46 early-onset PE) and 85 unexposed (non-PE) children 8-12 yr after preeclampsia exposure. HRV monitoring was performed 5 min in supine followed by 5 min in standing position and compared with office, 24-h ambulatory, and central BPs in relation to body anthropometrics and composition, gestational, and perinatal data. There were no major differences in HRV between PE and non-PE children. HRV in supine position was strongly associated with office and ambulatory heart rates (HRs), and HR was independently associated with office BPs. However, HRV was not related with office or 24-h SBP and PP, nor with elevated SBP in PE compared with non-PE children [adjusted mean differences for office and 24-h SBP 4.8 (P < 0.001) and 2.5 mmHg (P = 0.049), respectively]. In supine position, high-frequency (HF) power [ß, -0.04 (95% CI -0.06 to -0.01)], root mean square of successive differences in R-R intervals (rMSSD) [-0.015 (-0.028 to -0.002)], and the ratio of low-frequency (LF) to HF power [0.03 (0.01-0.04)] were independently associated with child fat mass. LF and HF power and rMSSD displayed independent inverse associations with child age. There were no significant associations between child HRV and gestational and perinatal factors. During prepuberty, the HRV in children with PE is similar to that in non-PE children. Elevated SBP following preeclampsia exposure is not related with HRV. Child adiposity could be related to decreased cardiac vagal tone.NEW & NOTEWORTHY Heart rate variability in preadolescent children exposed to preeclampsia in utero is no different from age-matched controls. Preeclampsia-exposed children's elevated SBP is not related to alterations in heart rate variability, which is a noninvasive measure of the modulation of heart rate by autonomic tone. However, childhood adiposity might be coupled with diminished cardiac vagal tone.