We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10−11 to 5.0 × 10−21). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10−6). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.

Adults who were born preterm with a very low birth weight have higher blood pressure and impaired glucose regulation later in life compared with those born at term. We investigated cardiometabolic risk factors in young adults who were born at any degree of prematurity in the Preterm Birth and Early Life Programming of Adult Health and Disease (ESTER) Study, a population-based cohort study of individuals born in 1985–1989 in Northern Finland. In 2009–2011, 3 groups underwent clinical examination: 134 participants born at less than 34 gestational weeks (early preterm), 242 born at 34–36 weeks (late preterm), and 344 born at 37 weeks or later (controls). Compared with controls, adults who were born preterm had higher body fat percentages (after adjustment for sex, age, and cohort (1985–1986 or 1987–1989), for those born early preterm, difference = 6.2%, 95% confidence interval (CI): 0.4, 13.2; for those born late preterm, difference = 8.0%, 95% CI: 2.4, 13.8), waist circumferences, blood pressure (for those born early preterm, difference = 3.0 mm Hg, 95% CI: 0.9, 5.1; for those born late preterm, difference = 1.7, 95% CI: −0.1, 3.4), plasma uric acid levels (for those born early preterm, difference = 20.1%, 95% CI: 7.9, 32.3; for those born late preterm, difference = 20.2%, 95% CI: 10.7, 30.5), alanine aminotransferase levels, and aspartate transaminase levels. They were also more likely to have metabolic syndrome (for those born early preterm, odds ratio = 3.7, 95% CI: 1.6, 8.2; for those born late preterm, odds ratio = 2.5, 95% CI: 1.2, 5.3). Elevated levels of conventional and emerging risk factors suggest a higher risk of cardiometabolic disease later in life. These risk factors are also present in the large group of adults born late preterm.

Background Preeclampsia, a new-onset hypertensive disorder of pregnancy, is associated with lifetime cardiovascular disease risk, but less is known about risk after other pregnancy-related hypertension. Methods and Results The Northern Finland Birth Cohort 1966 included all expected births from 1 year (N=12 055 women). Blood pressure measurements and other prospective data were determined from prenatal care records and questionnaires for 10 314 women. Subsequent diagnoses were ascertained from Finnish registries (average follow-up, 39.4 years). Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) estimate risks in hypertensive women compared with normotensive women. Hypertension during pregnancy was associated with increased risk of subsequent cardiovascular disease and arterial hypertension. Women with chronic hypertension and superimposed preeclampsia/eclampsia had high risk for future diseases. Gestational hypertension was associated with increased risk of ischemic heart disease (HR, 1.44 [95% CI, 1.24–1.68]), myocardial infarcts (HR, 1.75 [95% CI, 1.40–2.19]), myocardial infarct death (HR, 3.00 [95% CI, 1.98–4.55]), heart failure (HR, 1.78 [95% CI, 1.43–2.21]), ischemic stroke (HR, 1.59 [95% CI, 1.24–2.04]), kidney disease (HR, 1.91 [95% CI, 1.18–3.09]), and diabetes mellitus (HR, 1.52 [95% CI, 1.21–1.89]). Isolated systolic hypertension was associated with increased risk of myocardial infarct death (HR, 2.15 [95% CI, 1.35–3.41]), heart failure (HR, 1.43 [95% CI, 1.13–1.82]), and diabetes mellitus (HR, 1.42 [95% CI, 1.13–1.78]), whereas isolated diastolic hypertension was associated with increased risk of ischemic heart disease (HR, 1.26 [95% CI, 1.05–1.50]). Results were similar in nonsmoking women aged <35 years with normal weight and no diabetes mellitus during pregnancy. Conclusions Elevated blood pressure during pregnancy, regardless of type and even without known risk factors, signals high risk of later cardiovascular disease, chronic kidney disease, and diabetes mellitus. Clinical monitoring, risk factor evaluation, and early intervention could benefit women with hypertension in pregnancy.

Objective To examine if oral metformin is as effective as insulin in the prevention of fetal macrosomy in pregnancies complicated with gestational diabetes mellitus (GDM).Design Open-label prospective randomised controlled study.Setting Maternity outpatient clinics in a secondary and tertiary level hospital in Finland.Sample One hundred women with GDM who did not attain euglycaemia with diet.Methods Women were randomised to therapy with insulin (n = 50) or oral metformin (n = 50).Main outcome measures Incidence of large-for-gestational-age (LGA) infants and neonatal morbidity.Results There were no statistically significant differences in the incidence of LGA (8.5 versus 10.0%, P = 0.97), mean birthweight, mean cord artery pH or neonatal morbidity between the insulin and metformin groups. Fifteen (31.9%) of the 47 women randomised to metformin needed supplemental insulin. They were more obese (with a body mass index of 36 versus 30 kg/m 2 , P = 0.002), had higher fasting blood glucose levels in an oral glucose tolerance test (6.1 versus 5.0 mmol/l, P = 0.001) and needed medical treatment for GDM earlier (26 versus 31 gestational weeks, P = 0.002) than women who were normoglycemic with metformin. There was a tendency to a higher rate of caesarean sections in the metformin group than in the insulin group (RR 1.9; 95% CI 0.99-3.71).Conclusions Metformin seems to be suitable for the prevention of fetal macrosomy, especially in lean or moderately overweight women developing GDM in late gestation. Women with considerable obesity, high fasting blood glucose and an early need for pharmacological treatment may be more suitable for insulin therapy.

OBJECTIVEThe associations of prenatal exposures to maternal prepregnancy overweight and gestational diabetes mellitus (GDM) with offspring overweight are controversial. Research estimating risk for offspring overweight due to these exposures, separately and concomitantly, is limited.RESEARCH DESIGN AND METHODSPrevalence of overweight and abdominal obesity at age 16 years and odds ratios (ORs) for prenatal exposures to maternal prepregnancy overweight and GDM were estimated in participants of the prospective longitudinal Northern Finland Birth Cohort of 1986 (N = 4,168).RESULTSThe prevalence and estimates of risk for overweight and abdominal obesity were highest in those exposed to both maternal prepregnancy overweight and GDM (overweight prevalence 40% [OR 4.05], abdominal obesity prevalence 25.7% [3.82]). Even in offspring of mothers with a normal oral glucose tolerance test during pregnancy, maternal prepregnancy overweight is associated with increased risk for these outcomes (overweight prevalence 27.9% [2.56], abdominal obesity prevalence 19.5% [2.60]). In offspring of women with prepregnancy normal weight, the prevalence or risks of the outcomes were not increased by prenatal exposure to GDM. These estimates of risk were adjusted for parental prepregnancy smoking, paternal overweight, and offspring sex and size at birth.CONCLUSIONSMaternal prepregnancy overweight is an independent risk factor for offspring overweight and abdominal obesity at age 16 years. The risks are highest in offspring with concomitant prenatal exposure to maternal prepregnancy overweight and GDM, whereas the risks associated with GDM are only small.

First-trimester antibody positivity is a risk factor for perinatal death but not thyroid hormone status as such. Thyroid dysfunction early in pregnancy seems to affect fetal and placental growth.

Objective To examine whether intrapartum monitoring by means of automatic ST analysis (STAN) of fetal electrocardiography could reduce the rate of neonatal acidemia and the rate of operative intervention during labour, compared with monitoring by means of cardiotocography (CTG).Design Randomised controlled trial.Setting Labour ward in tertiary-level university hospital.Sample A total of 1483 women in active labour with singleton term fetus in cephalic presentation.Methods Women were randomly assigned to be monitored either by STAN or by CTG. Fetal blood sampling (FBS) was optional in both groups.Main outcome measures Neonatal acidemia (umbilical artery pH <7.10), neonatal metabolic acidosis (umbilical artery pH <7.05 and base excess <-12 mmol/l) and operative interventions: caesarean section rate, vacuum outlet (VO) rate and FBS rate.Results There were no statistically significant differences between the STAN group and CTG group in the incidence of neonatal acidemia (5.8 versus 4.7%) or metabolic acidosis (1.7 versus 0.7%). The caesarean section rate (6.4 versus 4.7%) and the VO rate (9.5 versus 10.7%) were also similar in the STAN and CTG groups. The incidence of FBS was lower (P < 0.001) in the STAN group (7.0%) than in the CTG group (15.6%).Conclusions Intrapartum fetal monitoring by means of automatic STAN did not improve the neonatal outcome or decrease the caesarean section rate. However, the need for FBS during labour was lower in the STAN group.

The intrauterine environment is a major contributor to increased rates of metabolic disease in adults. Intrahepatic cholestasis of pregnancy (ICP) is a liver disease of pregnancy that affects 0.5%-2% of pregnant women and is characterized by increased bile acid levels in the maternal serum. The influence of ICP on the metabolic health of offspring is unknown. We analyzed the Northern Finland birth cohort 1985-1986 database and found that 16-year-old children of mothers with ICP had altered lipid profiles. Males had increased BMI, and females exhibited increased waist and hip girth compared with the offspring of uncomplicated pregnancies. We further investigated the effect of maternal cholestasis on the metabolism of adult offspring in the mouse. Females from cholestatic mothers developed a severe obese, diabetic phenotype with hepatosteatosis following a Western diet, whereas matched mice not exposed to cholestasis in utero did not. Female littermates were susceptible to metabolic disease before dietary challenge. Human and mouse studies showed an accumulation of lipids in the fetoplacental unit and increased transplacental cholesterol transport in cholestatic pregnancy. We believe this is the first report showing that cholestatic pregnancy in the absence of altered maternal BMI or diabetes can program metabolic disease in the offspring.