Hannele Laivuori

Pre-eclampsia affects 2–8% of all pregnancies and remains a leading cause of maternal and perinatal morbidity and mortality. A randomised trial in South Africa suggested metformin used to treat preterm pre-eclampsia (26–32 weeks’ gestation) may prolong pregnancy by 7 days compared with standard care. However, this finding was borderline significant and requires validation in higher-resource settings and in diverse populations. Here, we present a Nordic multicentre trial protocol designed to evaluate whether extended-release metformin can prolong gestation in women with preterm pre-eclampsia. Pre-eclampsia Intervention 4 trial is a phase III, double-blind, multicentre randomised controlled trial conducted in Sweden, Norway and Finland aiming to investigate whether metformin can prolong gestation in preterm pre-eclampsia. A total of 294 women between 22+0 and 33+6 weeks of gestation with pre-eclampsia and planned to undergo expectant management will be enrolled. Participants are randomised to receive one gram of extended-release metformin or matching placebo three times daily. The primary outcome is prolongation of gestation defined as time from randomisation to birth. Secondary outcomes include length of neonatal hospital stay and neonatal birth weight. Adverse events will be reported in line with current clinical trial guidelines. All efficacy analyses will be conducted according to the intention-to-treat principle. The trial is conducted in accordance with Good Clinical Practice, as defined by the International Council for Harmonisation. The protocol, including amendments, was approved by the Swedish Ethical Review Authority and the Swedish Medical Products Agency in accordance with national legislation, and authorised for Finland and Norway through the Clinical Trials Information System in accordance with the EU Clinical Trials Regulation. Results will be disseminated at international conferences and published in peer-reviewed journals and communicated via popular science outlets, media, patient organisations and the trial website: https://www.preeclampsiaresearch.com/pi-trials. NCT06033131.

Background: Preeclampsia (PE) is a hypertensive pregnancy disorder with contributions from both maternal and fetal genetic factors, but how both genomes regulate placental transcription remains incompletely understood. Results: We analyzed placental 5′-end RNA sequencing data from 59 pregnancies in the FINNPEC cohort and performed separate maternal and fetal cis-eQTL analyses using gene-level expression and promoter-level expression defined as Transcript Far 5’ Ends (TFE). Genotype-by-PE interaction models were used to identify genetic effects that differ according to PE status. No gene-level interaction eQTLs remained significant after multiple-testing correction, although suggestive signals included LILRB2 in the maternal and LPCAT3 in the fetal analyses. In contrast, we identified two significant syntenic promoter-level interaction eQTLs: rs12504642–TFE61820 at the FHDC1 locus in the maternal analysis and rs1557150– TFE9032 at the PPIAP31 locus in the fetal analysis. Conclusion: These findings suggest that PE-dependent genetic interaction effects may be detectable at specific transcript promoter regions even when they are not captured at annotated gene levels.

Purpose: The Finnish Genetics of Pre-eclampsia Consortium (FINNPEC) study was originally established between 2008 and 2011 to develop a nationwide clinical and genomic database. By enrolling women with and without pre-eclampsia (PE), alongside their partners and infants, the study aims to identify the genetic and molecular determinants of PE. This update summarises the final dataset, reviews key findings since the 2016 cohort profile, and outlines current research directions. Participants: FINNPEC is a multicentre, cross-sectional case–control cohort collected across five Finnish university hospitals. The final cohort comprises 2810 women (1654 PE cases and 1156 controls), with comprehensive biological samples and clinical data collected from their children and the children’s fathers. A longitudinal subgroup—the FINNCARE study—enrolled 192 families with prior PE and 92 control families between 2019 and 2022. This subgroup underwent cardiovascular risk profiling and participated in a randomised controlled trial evaluating a 12-month lifestyle intervention to mitigate cardiovascular disease (CVD) risk 8–12 years postpartum. Findings to date: Research within FINNPEC has provided novel insights into maternal and fetal genetic susceptibility, revealing a shared genetic architecture between PE, blood pressure regulation and CVD. Studies have also advanced our understanding of the role of angiogenic imbalance, metabolic alterations and non-traditional risk factors in the pathogenesis of PE. Future plans: The current aim is to understand the complex, long-term association of PE and CVD within families. Ongoing studies focus on (1) risk stratification using registry data to classify CVD risk in women with prior PE; (2) assessing how genetic susceptibility to PE and CVD predicts pregnancy outcomes and later-life cardiovascular health; and (3) exploring how paternal and fetal genetics influence maternal PE risk and subsequent CVD morbidity.

Gestational diabetes mellitus (GDM) affects ~14% of pregnancies and increases maternal type 2 diabetes mellitus (T2DM) risk. The GenDiP Consortium presents trans-generational, multi-ancestry genome-wide association study meta-analyses of GDM and pregnancy glycemic traits in up to 38,305 GDM cases and 776,145 controls. We identify 37 GDM-associated loci (7 novel) and five novel loci for pregnancy glycemic traits, all operating through the maternal genome. We classify 12 GDM variants with stronger effects in GDM than T2DM into five biologically informed categories, revealing pleiotropy patterns, pregnancy-dependent effect modification, and diagnostic heterogeneity. While all these loci overlap with T2DM and/or non-pregnant glycaemic traits, four (G6PC2, CAST-PCSK1, HKDC1, FOXA2) lack genome-wide-significant T2DM associations; GCK shows distinct causal variants for GDM, and MTNR1B exhibits pregnancy-amplified effects. Our findings provide new genetic insights into GDM and highlight the need for larger, ancestrally diverse studies of GDM and glycaemic traits during pregnancy to understand potential pregnancy-specific effects.

Intrahepatic cholestasis of pregnancy, which affects 0.2-2% of pregnancies, is characterized by pruritus, increased aminotransferase activity and elevated serum bile acids. Previous studies have implicated liver-enriched genes in intrahepatic cholestasis of pregnancy. We conducted a meta-analysis of intrahepatic cholestasis of pregnancy genome-wide association studies in the FinnGen study, deCODE, Estonian Biobank, the Danish Blood Donor Study and Copenhagen Hospital Biobank with 4,738 women with prior ICP and 436,834 female controls. The analysis found 26 genome-wide significant associations of which 10 were novel. Genes in the associated loci were prioritized using lead SNP expression quantitative trait loci associations and colocalization analysis to assess potential causality. The associated loci implicate bile acid synthesis, LDL cholesterol, and lipid metabolism. Additionally, comorbidity, genetic correlation and polygenic risk score analyses further indicated a link between intrahepatic cholestasis of pregnancy and pancreatitis, suggesting shared genetic underpinnings.

Background: Posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS) are related neurovascular conditions, with pregnancy as a shared risk factor. In this study, we aimed to describe shared and distinctive risk factors and outcomes in patients with pregnancy‐associated PRES and/or RCVS. Methods: In this retrospective, nationwide, population‐based cohort study, the national healthcare registers were utilized to identify women with PRES and/or RCVS during pregnancy or puerperium during 1987–2016. Subsequent pregnancies, vascular events, and deaths until 2022 were identified. Medical records were reviewed to classify cerebrovascular events and collect clinical details. Results: In total, 27 patients had pregnancy‐associated PRES and/or RCVS (18 PRES; 5 PRES + RCVS; 4 RCVS) during 1987–2016, resulting in an incidence of 1.52 per 100,000 (95% Cl 1.02–2.18) deliveries. All patients with PRES ± RCVS had preeclampsia with severe features during late pregnancy or early puerperium. In contrast, isolated RCVS showed a weaker association to preeclampsia and occurred in late puerperium, with a median puerperal day of 26 (IQR 11–45). Altogether, 40.7% of all patients had a stroke, 90.9% of which were hemorrhagic. Preeclampsia was diagnosed in 90.9% of stroke patients. Maternal mortality was 3.7%, whereas perinatal mortality was 7.4%. At 3 months, 92.3% had a good recovery (mRS 0–2). During follow‐up, stroke recurrence was 3.7% and 33.3% had subsequent uneventful, full‐term pregnancies. Conclusions: Pregnancy‐associated PRES and RCVS are potentially life‐threatening, rare conditions that can result in hemorrhagic stroke. PRES ± RCVS is strongly associated with preeclampsia with severe features, whereas puerperal RCVS seems to be a separate, later‐occurring condition.

Polycystic ovary syndrome (PCOS) and its underlying features remain poorly understood. In this genetic study ( n = 544,513), we expand the number of genetic loci from 16 to 29, and additionally identify 31 associated plasma proteins. Many risk-increasing loci were associated with later age at menopause, underscoring the reproductive longevity related to an increased oocyte number and/or availability across the lifespan. Hormonal regulation in the etiology of this condition, through metabolic and reproductive features, was emphasized. The proteomic analysis highlighted metabolic biology known to be related to PCOS. A polygenic risk score (PRS) was associated with adverse cardiometabolic outcomes, with differing relevance of testosterone and body mass index in women and men. Finally, while oligo-anovulation and anovulatory infertility are features of PCOS, we observed no impact of PCOS susceptibility on childlessness. We suggest that PCOS susceptibility confers balanced pleiotropic influences on fertility in women, and life-long adverse metabolic consequences in both sexes.

Context: Prepregnancy body mass index (pBMI) is associated with the maternal metabolome during pregnancy. However, evidence remains inconclusive whether pBMI is also associated with alterations in the fetal cord blood metabolome, and whether pBMI modifies the associations between maternal and fetal metabolomes. Objective: This work aimed to examine whether pBMI is associated with the fetal cord blood metabolome and whether maternal and fetal metabolomes are associated and vary according to the degree of maternal pBMI. Methods: We derived pBMI from medical records and tested it in relation to 95 cord blood metabolic measures of 1702 newborns in the PREDO, RADIEL, and ITU studies. We tested the associations between maternal and fetal metabolomes and moderation by pBMI in 556 mother-child dyads of the PREDO and RADIEL studies contributing maternal blood samples at 3 time points during pregnancy. Results: In the meta-analysis of the 3 studies, higher pBMI was associated with 12 of the 95 cord blood metabolic measures, including lower levels of high-density lipoprotein–associated measures and higher levels of branched-chain and aromatic amino acids, as well as ketone bodies. Associations between maternal and fetal metabolomes were significant for 61 of the 95 measures; 26 of the 95 associations were modified by maternal pBMI, being stronger among mothers with obesity than those without. Conclusion: Maternal pBMI is associated with alterations in fetal cord blood metabolome. Maternal and fetal metabolomes are associated, and associations vary according to maternal pBMI.

The long-term prognosis after maternal ischemic stroke (IS) remains understudied. The objectives were to examine if mortality and long-term morbidity are more frequent in women with prior maternal IS compared with women without a pregnancy-related stroke and to assess recovery in maternal IS patients based on functional outcomes and vocational status. In this retrospective nationwide cohort study, maternal IS patients in Finland during years 1987-2016 were identified from national healthcare registers and verified from patient records. Three pregnant controls without a pregnancy-related stroke were selected for each case and matched by delivery year, age, parity, and geographical area. Deaths were acquired from the Causes-Of-Death Register until 2022. Morbidities (cardiovascular diseases and depression) were collected from Hospital Discharge Register and vocational status from Statistics Finland until 2016 for those who survived ≥1 year after stroke. Functional outcomes by modified Rankin scale (mRS) were estimated from patient records. There were 97 women with maternal IS, of whom 92 survived ≥1 year after stroke, and 265 matched controls (median age 30.6 years at index delivery in both groups). The median follow-up time was 17.4 years for mortality and 11.6 years for morbidity and vocational status. The overall mortality was higher in maternal IS patients than controls (8.3% vs 1.8%, age-adjusted odds ratio [aOR] 4.96, 95% CI 1.58-15.60) but did not differ significantly after the first year. There were 5 (5.6%) recurrent strokes in maternal IS patients. Patients had more frequently major cardiovascular events (6.7% vs 0%, p < 0.001), cardiac diseases (aOR 8.57, 95% CI 2.22-33.08), and depression (aOR 3.92, 95% CI 1.86-8.24) than controls. Of the patients who survived until the end of follow-up, 92.1% had good functional outcomes (mRS 0-2). Still, employment was rarer (aOR 0.55, 95% CI 0.32-0.94) and retirement (aOR 4.55, 95% CI 2.03-10.17) more common in maternal IS patients than controls. Maternal IS patients had a significant cardiovascular burden and were retired more often than controls at the end of follow-up, although most patients had good functional outcomes. Optimizing long-term prognosis in these young patients necessitates comprehensive management of vascular risk factors and targeted rehabilitation strategies to address residual neurologic deficits.