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Prediction of women at high risk of preeclampsia is important for prevention and increased surveillance of the disease. Current prediction models need improvement, particularly with regard to late-onset preeclampsia. Preeclampsia shares pathophysiological entities with cardiovascular disease; thus, cardiovascular biomarkers may contribute to improving prediction models. In this nested case-control study, we explored the predictive importance of mid-pregnancy cardiovascular biomarkers for subsequent preeclampsia. We included healthy women with singleton pregnancies who had donated blood in mid-pregnancy (~ 18 weeks' gestation). Cases were women with subsequent preeclampsia (n = 296, 10% of whom had early-onset preeclampsia [< 34 weeks]). Controls were women who had healthy pregnancies (n = 333). We collected data on maternal, pregnancy, and infant characteristics from medical records. We used the Olink cardiovascular II panel immunoassay to measure 92 biomarkers in the mid-pregnancy plasma samples. The Boruta algorithm was used to determine the predictive importance of the investigated biomarkers and first-trimester pregnancy characteristics for the development of preeclampsia. The following biomarkers had confirmed associations with early-onset preeclampsia (in descending order of importance): placental growth factor (PlGF), matrix metalloproteinase (MMP-12), lectin-like oxidized LDL receptor 1, carcinoembryonic antigen-related cell adhesion molecule 8, serine protease 27, pro-interleukin-16, and poly (ADP-ribose) polymerase 1. The biomarkers that were associated with late-onset preeclampsia were BNP, MMP-12, alpha-L-iduronidase (IDUA), PlGF, low-affinity immunoglobulin gamma Fc region receptor II-b, and T cell surface glycoprotein. Our results suggest that MMP-12 is a promising novel preeclampsia biomarker. Moreover, BNP and IDUA may be of value in enhancing prediction of late-onset preeclampsia.

Background: Preeclampsia and small-for-gestational-age (SGA) birth share several pathophysiologic features involving the cardiovascular system, inflammation, and placenta. To gain increased knowledge of pathophysiological differences and similarities, we performed a comparative study on alterations in circulating mid-pregnancy proteins in pregnancies with subsequent preeclampsia, SGA birth, or combined preeclampsia and SGA birth.

Methods: Using the Olink cardiovascular panel II, mid-pregnancy plasma values of 92 different proteins were measured in healthy women with subsequent normal pregnancies (n=480), preeclampsia (n=273), SGA birth (n=106), or combined preeclampsia and SGA birth (n=31). False discovery rate adjusted Kruskal-Wallis test and Dunn's post-hoc test with Bonferroni correction identified differences in protein levels between groups.

Results: In comparison with normal pregnancy, 16 mid-pregnancy proteins differed in subsequent preeclampsia, but not in SGA birth. Out of these proteins, angiotensin-converting enzyme 2 and B-type natriuretic peptide were amongst those proteins with the highest fold change. Using the same comparison group, lower values of adrenomedullin and P-selectin glycoprotein ligand were only found in women with subsequent SGA birth. Matrix metalloproteinase-12 and placental growth factor were lower in all groups of cases, compared with normal pregnancy. The highest fold changes for these proteins were seen in women with combined preeclampsia and SGA birth.

Conclusions: Alternations in cardiovascular and inflammatory proteins were found in women with subsequent preeclampsia, but not women with SGA birth. Dysregulation of key proteins for placentation were shared in women with subsequent preeclampsia, SGA birth and combined disorder, supporting that mal-placentation is the main shared pathophysiological pathway.

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: The female prevalence of myocardial infarction (MI) is increasing. Prior pregnancy-induced hypertension (PIH) is associated with doubled MI-risk. We investigated the mechanisms behind this increased risk, studying cardiovascular risk factors at first MI in relation to prior PIH status. 

Method: This nationwide register-based cohort study identified 17 814 women with a singleton pregnancy giving birth 1973-2019 with a first MI 2006-2020. Exclusion criteria were pre-gestational disorders associated with increased risk of MI. Exposure was PIH (gestational hypertension, N=661; preeclampsia, N=1 092), with normotensive pregnancies as reference group (N=16 061). Outcomes were the cardiovascular risk factors age, body mass index (BMI), smoking, chronic hypertension, diabetes mellitus, hyperlipidemia, blood pressure, plasma glucose level and serum levels for lipids and creatinine collected at MI. Binary logistic regression assessed the associations between prior PIH and each outcome, including all outcomes simultaneously to account for their mutual influence. PIH was further divided into gestational hypertension and preeclampsia; preterm and term delivery; and single and recurrent PIH.

Results:  At MI, chronic hypertension was more common in women with prior PIH than normotensive pregnancies (59.3% vs 40.9%, p<0.001). Compared with normotensive pregnancies, women with PIH had more than doubled odds of having chronic hypertension at MI, after adjusting for mutual influence of the other risk factors (adjusted odds ratio 95% confidence interval 2.34; 2.02–2.71). This association was even higher in women with recurrent preeclampsia. High systolic blood pressure and BMI were also more prevalent in women with prior PIH, but smoking was less prevalent.  

Conclusion: In women with prior PIH, chronic hypertension post-pregnancy is the single strongest cardiovascular risk factor for MI. As a modifiable risk factor occurring early post birth, it is imperative to target and treat these women to reduce their excess MI-risk. Optimizing prevention and management of chronic hypertension, as well as achieving a normal BMI in women with prior PIH is necessary to improve their long-term cardiovascular health.