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IMPORTANCE An association between maternal preeclampsia and an increased risk of cardiovascular disease in the offspring is plausible, but evidence in this area is limited. OBJECTIVE To investigate (1) the association between maternal preeclampsia and risks of ischemic heart disease (IHD) and stroke in the offspring, (2) whether the association varies by severity or timing of onset of preeclampsia, and (3) the role of preterm birth and small for gestational age (SGA) birth, both of which are related to preeclampsia and cardiovascular diseases, in this association. DESIGN, SETTING, AND PARTICIPANTS This multinational population-based cohort study obtained data from Danish, Finnish, and Swedish national registries. Live singleton births from Denmark (1973-2016), Finland (1987-2014), and Sweden (1973-2014) were followed up until December 31, 2016, in Denmark and December 31, 2014, in Finland and Sweden. Data analyses were performed between September 2020 and September 2022. EXPOSURES Preeclampsia and its subtypes, including early onset (<34 gestational weeks) and late onset (>= 34 gestational weeks), severe and mild or moderate, and with and without SGA birth. MAIN OUTCOMES AND MEASURES Diagnoses of IHD and stroke were extracted from patient and cause-of-death registers. Cox proportional hazards regression models and flexible parametric survival models were used to analyze the associations. Sibling analyses were conducted to control for unmeasured familial factors. RESULTS The cohort included of 8 475 819 births (2 668 697 [31.5%] from Denmark, 1636 116 [19.3%] from Finland, and 4171006 [49.2%] from Sweden, comprising 4350 546 boys [51.3%]). Of these offspring, 188 670 (2.2%) were exposed to maternal preeclampsia, 7446 (0.1%) were diagnosed with IHD, and 10 918 (0.1%) were diagnosed with stroke during the median (IQR) follow-up of 19.3 (9.0-28.1) years. Offspring of individuals with preeclampsia had increased risks of IHD (adjusted hazard ratio [HR], 1.33; 95% CI

Aim This study investigated patent ductus arteriosus (PDA) treatment and neurodevelopmental outcomes when extremely preterm born children reached 6.5 years. Method Our cohort was 435 children with neonatal PDA treatment data and neurodevelopmental follow-up data, born in 2004-2007, who participated in the Extremely Preterm Infants in Sweden Study. Pharmacological or surgical PDA treatment and the age at PDA treatment, were investigated in relation to the risks of moderate to severe neurodevelopmental impairment (NDI) and full-scale intelligence quotient (FSIQ) at 6.5 years. Results The children who received PDA drug treatment, including those who also had surgery, had the same risk of moderate to severe NDI or lower FSIQ as untreated children. However, children who had primary PDA surgery faced increased risks of NDI, with an adjusted incidence rate ratio of 1.62 (95% confidence interval [CI] 1.28-2.06) and a lower adjusted mean difference FSIQ of -7.1 (95% CI -11 to -3.2). Surgery at less than 10 days of life was associated with a significantly increased risk of moderate to severe NDI and lower FSIQ than surgery after 20 days. Conclusion Drug treatment followed by deferred surgery appeared to be a safer option for extremely preterm infants severely affected by PDA.

This Swedish register-based cohort study determined the separate and joint contribution of preeclampsia and multi-fetal pregnancy on a woman's risk of cardiovascular disease (CVD) later in life. The study included 892 425 first deliveries between 1973 and 2010 of women born 1950 until 1971, identified in the Swedish Medical Birth Register. A composite outcome of CVD was retrieved through linkage with the National Patient and Cause of Death Registers. Cox proportional hazard regression was used to assess the risk of CVD in women who had preeclampsia in a singleton or multi-fetal pregnancy, adjusting for potential confounders, and presented as adjusted hazard ratios. Compared with women who had a singleton pregnancy without preeclampsia (the referent group), women with preeclampsia in a singleton pregnancy had an increased risk of CVD (adjusted hazard ratio 1.75 [95% CI, 1.64-1.86]). Women who had a multi-fetal pregnancy without or with preeclampsia did not have an increased risk of future CVD (adjusted hazard ratios 0.94 [95% CI, 0.79-1.10] and 1.25 [95% CI, 0.83-1.86], respectively). As opposed to preeclampsia in a first singleton pregnancy, preeclampsia in a first multi-fetal pregnancy was not associated with increased risk of future CVD. This may support the theory that preeclampsia in multi-fetal pregnancies more often occurs as a result of the larger pregnancy-related burden on the maternal cardiovascular system and excessive placenta-shed inflammatory factors, rather than the woman's underlying cardiovascular phenotype.

BACKGROUND: Preterm birth increases risk for adult cardiovascular disease. We hypothesized that arteries in 6-y-old children born preterm are narrower, with thicker intima-media and stiffer than in peers born at term. METHODS: Children born extremely preterm (EXP, n = 176, birthweights: 348-1,161 g) and at term (CTRL, n = 174, birth weights: 2,430-4,315 g) were included. Using ultrasonography, we determined diameters of the coronaries (CA), common carotid arteries (CCA) and aorta, the carotid intima media thickness (CIMT), and the stiffness index of the CCA and aorta. RESULTS: Arteries were 5-10% narrower in EXP than in CTRL (P < 0.005) but after adjustment for body surface area, diameter differences diminished or disappeared. EXP-children born small for gestational age exhibited similar arterial dimensions as those born appropriate for date. The cIMT was 0.38 (SD = 0.04) mm and did not differ between groups. Carotid but not aortic stiffness was lower in EXP than in CTRL. CONCLUSION: In 6-y-old children born extremely preterm, conduit arteries are of similar or smaller size than in controls born at term, and they have no signs of accelerated intima media thickening or arterial stiffening. While these findings are reassuring for these children and their families, the causal pathways from preterm birth to adult cardiovascular disease remain unknown.

Pregnancy characteristics are associated with risk of cardiovascular diseases, but their independent associations with hypertension or blood pressure (BP) levels remain uncertain. We linked the Swedish Medical Birth Register with Vesterbotten Intervention Program data (Northern Sweden). Using linear and logistic regression, we related pregnancy factors in any prior pregnancy with BP and hypertension at 40 years of age in 15 896 parous women free of prepregnancy hypertension. Pregnancy factors included parity, age at first delivery, preeclampsia, gestational diabetes mellitus, placental abruption, shortest gestational age small for gestational age baby (= 140 mm Hg and diastolic BP >= 90 mm Hg or antihypertensive use. Multivariable models were adjusted for all pregnancy factors and potential lifestyle and sociodemographic confounders. At 40 years of age, 1535 women (9.6%) had hypertension. In multivariable models, lower parity, younger age at first birth, preeclampsia, small for gestational age, and placental abruption were independently associated with higher systolic and diastolic BP levels at 40 years of age. Younger age at first birth, preeclampsia, gestational age <32 versus >= 37 weeks, and small for gestational age were independently associated with hypertension. Our findings raise the possibility that earlier and more frequent BP screening may be desirable in women with these pregnancy characteristics.

Importance: Administration-to-birth intervals of antenatal corticosteroids (ANS) vary. The significance of this variation is unclear. Specifically, to our knowledge, the shortest effective administration-to-birth interval is unknown.Objective: To explore the associations between ANS administration-to-birth interval and survival and morbidity among very preterm infants.Design, Setting, and Participants: The Effective Perinatal Intensive Care in Europe (EPICE) study, a population-based prospective cohort study, gathered data from 19 regions in 11 European countries in 2011 and 2012 on 4594 singleton infants with gestational ages between 24 and 31 weeks, without severe anomalies and unexposed to repeated courses of ANS. Data were analyzed November 2016.Exposure: Time from first injection of ANS to delivery in hours and days.Main Outcomes and Measures: Three outcomes were studied: in-hospital mortality; a composite of mortality or severe neonatal morbidity, defined as an intraventricular hemorrhage grade of 3 or greater, cystic periventricular leukomalacia, surgical necrotizing enterocolitis, or stage 3 or greater retinopathy of prematurity; and severe neonatal brain injury, defined as an intraventricular hemorrhage grade of 3 or greater or cystic periventricular leukomalacia.Results: Of the 4594 infants included in the cohort, 2496 infants (54.3%) were boys, and the mean (SD) gestational age was 28.5 (2.2) weeks and mean (SD) birth weight was 1213 (400) g. Mortality for the 662 infants (14.4%) unexposed to ANS was 20.6% (136 of 661). Administration of ANS was associated with an immediate and rapid decline in mortality, reaching a plateau with more than 50% risk reduction after an administration-to-birth interval of 18 to 36 hours. A similar pattern for timing was seen for the composite mortality or morbidity outcome, whereas a significant risk reduction of severe neonatal brain injury was associated with longer administration-to-bi

BACKGROUND: In small clinical studies, preterm birth was associated with altered cardiac structure and increased cardiovascular mortality in the young. OBJECTIVES: The goal of this study was to determine the association between preterm birth and risk of incident heart failure (HF) in children and young adults. METHODS: This register-based cohort study included 2,665,542 individuals born in Sweden from 1987 to 2012 who were followed up from 1 year of age to December 31, 2013. The main study outcome was diagnosis of HF in the National Patient Register or the Cause of Death Register. The association between preterm birth and risk of incident HF was analyzed by using a Poisson regression model. Estimates were adjusted for maternal and pregnancy characteristics, socioeconomic status, and maternal and paternal cardiovascular disease. RESULTS: During 34.8 million person-years of follow-up (median 13.1 years), there were 501 cases of HF. After exclusion of 52,512 individuals with malformations (n = 196 cases), 305 cases of HF remained (0.88 per 100,000 person-years). Gestational age was inversely associated with the risk of HF. Compared with individuals born at term (>= 37 weeks' gestation), adjusted incidence relative risks for HF were 17.0 (95% confidence interval [CI]: 7.96 to 36.3) after extremely preterm birth (<28 weeks) and 3.58 (95% CI: 1.57 to 8.14) after very preterm birth (28 to 31 weeks). There was no risk increase after moderately preterm birth (32 to 36 weeks) (relative risk: 1.36; 95% CI: 0.87 to 2.13). CONCLUSIONS: There was a strong association between preterm birth before 32 weeks of gestation and HF in childhood and young adulthood. Although the absolute risk of HF is low in young age, our findings indicate that preterm birth may be a previously unknown risk factor for HF. (J Am Coll Cardiol 2017;69:2634-42) (C) 2017 by the American College of Cardiology Foundation., Funding Agencies:Swedish Research Council for Health, Working Life and Welfare 2010-0643Stockholm County CouncilKarolinska Institutet Distinguished Professor Award

Objective: To determine if maternal use of snuff (containing high levels of nicotine, low levels of nitrosamines and no combustion products) is associated with an increased risk of oral cleft malformations in the infant and whether cessation of snuff use or smoking before the antenatal booking influences the risk. Method: A population-based cohort study was conducted on all live born infants, recorded in the Swedish Medical Birth Register from 1999 through 2009 (n = 1 086 213). Risks of oral clefts were evaluated by multivariate logistic regression analyses (using adjusted odds ratios, with 95% confidence intervals [CI]). Results: Among 975 866 infants that had information on maternal tobacco use, 1761 cases of oral clefts were diagnosed. More than 50% of the mothers who used snuff or smoked three months prior pregnancy stopped using before the antenatal booking. Almost 8% of the mothers were smoking at the antenatal booking and 1,1% of the mothers used snuff. Compared with infants of non-tobacco users, the adjusted odds ratios (95% CI) of any oral cleft for infants of mothers who continued to use snuff or to smoke were 1.48 [1.00-2.21] and 1.19 [1.01-1.41], respectively. In contrast, in infants of mothers who stopped using snuff or stopped smoking before the antenatal booking, the corresponding risks were not increased (adjusted odds ratios [95% CI] were 0.71 [0.44-1.14] and 0.88 [0.73-1.05], respectively). Conclusion: Maternal snuff use or smoking in early pregnancy is associated with an increased risk of oral clefts. Infants of mothers who stopped using snuff or stopped smoking before the antenatal booking had no increased risk of oral cleft malformations. Oral snuff or other sources of nicotine should not be recommended as an alternative for smoke-cessation during pregnancy.

Background: Maternal smoking is associated with disturbed cardiorespiratory control in the infant. Despite lacking knowledge of whether the harmful effects of smoking are caused by combustion products in tobacco smoke or by nicotine, it has been argued that nicotine-replacement therapy during pregnancy is safer than smoking. Objective: The goal of this study was to investigate if the disturbances in cardiorespiratory control associated with maternal smoking are also seen in infants prenatally exposed to snuff. We hypothesized that prenatal nicotine exposure (via moist snuff) causes disturbances in autonomic control and thereby increases the risk of apnea in the newborn. Methods: In a nationwide Swedish cohort study, we studied associations between maternal tobacco use during pregnancy and neonatal apnea. Of 609 551 live-born singleton infants, 7599 were born to snuff-using mothers, 41 391 and 16 928 were born to light (1-9 cigarettes per day) and heavy (≥10 cigarettes per day) smokers, respectively. Logistic regression was used to calculate odds ratios, using 95% confidence intervals. Results: Compared with infants of nontobacco users, infants with prenatal exposure to snuff were at an increased risk of apnea even after adjustment for differences in gestational age (odds ratio: 1.96 [95% confidence interval: [1.30-2.96]) Smoking was associated with increased risk of apnea before, but not after, adjusting for gestational age. Conclusions: Snuff use during pregnancy is associated with a higher risk of neonatal apnea than smoking. Maternal use of snuff or nicotine-replacement therapy cannot be regarded as an alternative to smoking during pregnancy.

BACKGROUND: Prior studies showing an inverse relationship between low birth weight in offspring and maternal risks of cardiovascular diseases (CVD) are limited by lack of information on gestational age and/or insufficient adjustment for confounders. METHODS AND RESULTS: In a nationwide Swedish study, we included information on 923 686 women and their first singleton births between 1983 and 2005. Cox proportional hazards models were used to study associations between gestational length, fetal growth, and maternal incident hospitalization or death from CVD (coronary heart disease, cerebrovascular events, and heart failure). Multivariable adjusted models accounted for birth year, income, education, country of birth, smoking, diabetes mellitus, hypertension, and preeclampsia. The risk of maternal CVD increased with decreasing gestational age whereas the risk increase related to fetal growth appeared to be restricted to very small-for-gestational-age (SGA) infants. Compared with mothers of non-SGA infants born at term, the hazard ratio of CVD ranged from 1.39 (95% confidence interval 1.22-1.58) to 2.57 (95% confidence interval 1.97-3.34) among mothers to moderately and very preterm infants, respectively. There was a significant interaction between preterm birth and fetal growth with respect to mothers' risk of CVD (P<0.001). Among mothers to very SGA infants, the hazard ratio of CVD ranged from 1.38 (95% confidence interval 1.15-1.65) to 3.40 (95% confidence interval 2.26-5.11) in mothers to term and very preterm infants, respectively. CONCLUSIONS: Delivery of a preterm or SGA infant is associated with later life maternal hospitalization or death from CVD even after accounting for socioeconomic factors, smoking, and pregnancy-related complications.

Cardiovascular disease is a leading cause of morbidity and mortality worldwide. A large number of studies show that the risk of cardiovascular disease is increased in people born with low birth weight. The aim of this thesis is to study the contribution of preterm birth, the most common cause of low birth weight, to later cardiovascular function and disease risk. Clinical follow-up studies of children and adolescents born very preterm (total n=118) in the 1980’s and 1990’s were performed. Vascular endothelial function was assessed using Laser-Doppler measurements of skin perfusion responses to acetylcholine, an endothelium-dependent vasodilator (paper I-II). Dermal capillary density was studied using intra-vital video microscopy (paper II). Arterial stiffness was measured using pulse wave analysis, pulse wave velocity and ultrasound techniques (paper I and III). Arterial dimensions were studied using ultrasound and magnetic resonance imaging (paper I, III and IV). Paper I shows that adolescent girls, born at a mean gestational age of 29 w, had narrower abdominal aorta and lower skin perfusion, as compared to controls born at term. No signs of arterial stiffening were found and the endothelial function was unaffected after preterm birth. Paper II demonstrates that in 9-year old children born very preterm, the skin capillary density was reduced, but not the endothelial function, as compared to controls. Paper III shows that the 9-year old children born very preterm had the same carotid dimensions and stiffness as controls. Paper IV reports results from magnetic resonance imaging of the aorta in 86 healthy adolescents, of whom half were born very preterm. This study confirms the findings from paper I, showing lasting aortic narrowing after preterm birth. In addition, the aortic size was also strongly and independently associated with maternal smoking in pregnancy. Papers I, II and IV also show that children and adolescents born preterm have increased blood pressure. In