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Effect of early-onset preeclampsia on cardiovascular risk in the fifth decade of life

Published:February 13, 2017DOI:https://doi.org/10.1016/j.ajog.2017.02.015

      Background

      Women with hypertensive disorders in pregnancy, in particular early-onset preeclampsia, are at increased risk of developing cardiovascular disease later in life. These women have a more than 2-fold increased risk of dying from cardiovascular diseases. Most studies have focused on identification of risk factors shortly after pregnancy. Less is known on the prevalence of risk factors or actual signs of cardiovascular disease 5–20 years later. The presence of hypertension or metabolic syndrome can be seen as an opportunity for preventive interventions to reduce the development of severe cardiovascular diseases like myocardial infarction and stroke.

      Objective

      To assess cardiovascular risk factors and established cardiovascular disease in women after early-onset preeclampsia, in the fifth decade of life. As a consequence, we can assess whether there is still a window of opportunity for preventive measures and to establish in what proportion of women cardiovascular disease already has developed.

      Study Design

      In a prospective observational study, cardiovascular risk assessment was performed in women with early-onset preeclampsia (<34 weeks’ gestation) and normotensive controls (≥37 weeks’ gestation) 9−16 years after their index pregnancy. Medical records of 2 tertiary hospitals in Amsterdam, The Netherlands, were screened consecutively, and all eligible women were invited. Cardiovascular risk assessment consisted of a questionnaire, blood pressure measurement, anthropometrics, and blood and urine for fasting lipids, lipoproteins, glucose levels, glycated hemoglobin, renal function, N-terminal brain natriuretic peptide, and albuminuria. History of cardiovascular diseases (ie, myocardial infarction and stroke) was determined. Prevalence of women presenting in an optimal window of opportunity for preventive measures was defined by the presence of cardiovascular risk factors (ie, hypertension and metabolic syndrome) but in the absence of established cardiovascular diseases (ie, myocardial infarction and stroke).

      Results

      Women with a history of early-onset preeclampsia (n = 131) had significantly greater systolic and diastolic blood pressure, greater body mass index, more often had an abnormal lipid profile (lower high-density lipoprotein levels, higher triglycerides), greater glycated hemoglobin, and greater levels of albuminuria compared to controls (n = 56). None of the women with a history of early-onset preeclampsia was diagnosed with cardiovascular disease; 38.2% were diagnosed with hypertension; and 18.2% were diagnosed with metabolic syndrome. A total of 42% met the criteria for the window of opportunity for preventive measures. In women with a history of an uncomplicated pregnancy, no women were diagnosed with cardiovascular disease; 14.3% were diagnosed with hypertension; 1.8% with metabolic syndrome. In this cohort, 14.3% met the criteria for the window of opportunity for preventive measures.

      Conclusion

      A large proportion of women who experienced early-onset preeclampsia had major cardiovascular risk factors in the fifth decade of life, compared with healthy controls. These women are currently outside the scope of most preventive programs due to their relatively young age, but have important modifiable risk factors for cardiovascular diseases.

      Key words

      Preeclampsia is a pregnancy-specific disorder that affects 3−5% of all pregnancies and is a leading cause of maternal and neonatal morbidity and mortality.
      • Mol B.W.
      • Roberts C.T.
      • Thangaratinam S.
      • Magee L.A.
      • de Groot C.J.
      • Hofmeyr G.J.
      Pre-eclampsia.
      The disorder is characterized by hypertension with 1 or more of the following new-onset conditions: new-onset proteinuria, thrombocytopenia, impaired liver function, new-onset renal insufficiency, pulmonary edema, or new-onset cerebral or visual disturbances.
      American College of Obstetricians and Gynecologists
      Task Force on Hypertension in Pregnancy. Hypertension in pregnancy.
      The association between preeclampsia and cardiovascular disease later in life is well established.
      • Ahmed R.
      • Dunford J.
      • Mehran R.
      • Robson S.
      • Kunadian V.
      Pre-eclampsia and future cardiovascular risk among women: a review.
      • McDonald S.D.
      • Malinowski A.
      • Zhou Q.
      • Yusuf S.
      • Devereaux P.J.
      Cardiovascular sequelae of preeclampsia/eclampsia: a systematic review and meta-analyses.
      Cardiovascular disease is the leading cause of death in women in the Western world.
      • Nichols M.
      • Townsend N.
      • Scarborough P.
      • Rayner M.
      Cardiovascular disease in Europe 2014: epidemiological update.
      Women with a history of preeclampsia even have a more than 2-fold increased risk of dying from cardiovascular diseases.
      • McDonald S.D.
      • Malinowski A.
      • Zhou Q.
      • Yusuf S.
      • Devereaux P.J.
      Cardiovascular sequelae of preeclampsia/eclampsia: a systematic review and meta-analyses.
      It is not clear whether the relationship between preeclampsia and cardiovascular disease is causative or that preeclampsia is an early manifestation (ie, a stress test) of cardiovascular disease, because the pathophysiological link has not been elucidated fully. Nonetheless, the occurrence in relatively young women creates an opportunity for early identification of women at risk and, if necessary, preventive measures and interventions can be undertaken early in life.
      • Sattar N.
      • Greer I.A.
      Pregnancy complications and maternal cardiovascular risk: opportunities for intervention and screening?.
      The influence of cardiovascular risk factors over time, from pregnancy to manifestation of cardiovascular disease, needs more evaluation. Most studies have focused on cardiovascular risk factors short-term postpartum or more than 20 years after pregnancy.
      • Zoet G.A.
      • Koster M.P.
      • Velthuis B.K.
      • et al.
      Determinants of future cardiovascular health in women with a history of preeclampsia.
      More research is needed in the fourth and fifth decade of life, when premature cardiovascular diseases are expected to develop.
      • Zoet G.A.
      • Koster M.P.
      • Velthuis B.K.
      • et al.
      Determinants of future cardiovascular health in women with a history of preeclampsia.
      It could be suggested that women with a history of preeclampsia could benefit highly from screening for cardiovascular disease in these decades of life. Screening would be best, however, if cardiovascular disease has not already developed. Studies focusing on risk factor screening in this time window after pregnancy are lacking, and as a consequence, it is not clear what the most optimal timing for screening and preventive measures is.
      The question this study addresses is: is there still a window of opportunity for preventive measures in the fifth decade of life, or has cardiovascular disease already developed? To clarify this fragile balance, this study investigated cardiovascular risk factors in women with a history of early-onset preeclampsia compared to women with a history of an uncomplicated pregnancy in the fifth decade of life.

      Materials and Methods

      Study population

      All women were recruited from obstetrical databases of 2 tertiary medical centers in the Netherlands, all giving birth between 1998 and 2005. Medical records of women with a history of early-onset preeclampsia were screened consecutively, and all eligible women were invited. Participating women with a history of early-onset preeclampsia were matched with women with an uncomplicated pregnancy, for maternal age (range ± 5 years) and date of delivery (range ± 1 year). Early-onset preeclampsia was diagnosed as delivery before 34 weeks’ gestation, blood pressure ≥140/90 mm Hg, and proteinuria ≥300 mg/24 h by use of the International Society for the Study of Hypertension in Pregnancy ISSHP 2001 criteria, the criteria used at the time of diagnosis of the study population.
      • Brown M.A.
      • Lindheimer M.D.
      • de S.M.
      • Van A.A.
      • Moutquin J.M.
      The classification and diagnosis of the hypertensive disorders of pregnancy: statement from the International Society for the Study of Hypertension in Pregnancy (ISSHP).
      Preeclampsia was defined as severe in the presence of 1 or more of the following conditions: proteinuria ≥5 g/24 h, HELLP (ie, Hemolysis, Elevated Liver enzymes, and Low Platelet count) syndrome, occurrence of eclamptic seizure, or pulmonary edema.
      An uncomplicated pregnancy history was defined as giving birth between 37 and 42 weeks’ gestation after a normotensive pregnancy and with absence of intrauterine growth restriction. For women with both a history of early-onset preeclampsia and uncomplicated pregnancy, exclusion criteria were established chronic hypertension, use of antihypertensive medication or blood pressure at booking, the first blood pressure measured in first trimester, ≥140/90 mm Hg; diabetes mellitus or gestational diabetes; cardiovascular diseases, including renal diseases, Raynaud disease as a possible reflection of impaired vascular function, or the use of cardiovascular related medication before index pregnancy; multiple pregnancies; congenital abnormalities; pregnant at, or the last 6 months before, assessment; and breastfeeding at time of assessment.
      Consenting participants were invited between 2014 and 2016 for a cardiovascular risk assessment at the VU University Medical Center. Approval for the study was obtained from the medical ethics committee of the VU University Medical Center in Amsterdam and locally by the hospital board of the Academic Medical Centre Amsterdam (protocol approval: NL38972.029.12; Dutch trial registration: NTR5297).

      Measures

      All participants were asked to fill in a questionnaire that included smoking status, obstetric history, family history regarding cardiovascular diseases, current medical conditions, and use of medication. The part of the questionnaire regarding medical conditions contained questions about treatment by a medical specialist, type of specialist, for what diagnosis; and presence and/or treatment of cardiovascular risk factors or cardiovascular diseases including diabetes, increased cholesterol, stroke, high blood pressure, heart attack, coronary artery disease, and heart failure. The cardiovascular risk assessment consisted of blood pressure measurement, anthropometrics, blood sampling, and urine collection. Blood pressure was measured twice manually with the patient in a sitting position. The first and fifth phase Korotkoff sounds were used for systolic and diastolic blood pressure. The mean value of 2 measurements was used.
      Body height was measured with a wall-mounted stadiometer at 0.5 cm precision with the subject not wearing shoes. Body weight was measured with a mechanical scale at 0.5 kg precision in light indoors with the subject clothed without shoes. Body mass index was calculated as body weight divided by the square of the body height (kg/m2). Waist and hip circumference was measured on uncovered skin with an inelastic tape measure at the narrowest point of the waist and the widest part of the hips to the nearest 0.5 cm. Waist-hip-ratio was calculated as waist circumference divided by hip circumference (cm/cm). The venous blood samples were taken after an overnight fast for analysis of lipids, lipoproteins, glucose, glycated hemoglobin, renal function, and N-terminal brain natriuretic peptide. Immediately after the patient woke up, urine was collected at home for microalbuminuria assessment.
      The window of opportunity for preventive measures was defined as presence of the cardiovascular risk factors hypertension and/or metabolic syndrome but in absence of the established cardiovascular diseases myocardial infarction and stroke. These cardiovascular diseases were chosen to be reliable in self-report.
      • Okura Y.
      • Urban L.H.
      • Mahoney D.W.
      • Jacobsen S.J.
      • Rodeheffer R.J.
      Agreement between self-report questionnaires and medical record data was substantial for diabetes, hypertension, myocardial infarction and stroke but not for heart failure.
      Hypertension was defined as either current use of antihypertensive medication and/or blood pressure ≥140/90 mm Hg measured at risk assessment.
      • Chobanian A.V.
      • Bakris G.L.
      • Black H.R.
      • et al.
      The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report.
      Metabolic syndrome was diagnosed according to the Adult Treatment Panel III criteria. Metabolic syndrome was defined as the presence of 3 or more of the following characteristics: waist circumference >88 cm, triglyceride levels ≥1.7 mmol/L, high-density lipoprotein cholesterol <1.29 mmol/L, blood pressure ≥130/85 mm Hg, and fasting glucose levels ≥5.7 mmol/L.
      Expert Panel on Detection Evaluation, and Treatment of High Blood Cholesterol in Adults
      Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III).

      Sample size calculation

      In addition the cardiovascular risk assessment, an evaluation of diastolic function by ultrasound was carried out in the study population. The sample size calculation was based on data of the prevalence of diastolic dysfunction in a randomly recruited European population.
      • Kloch-Badelek M.
      • Kuznetsova T.
      • Sakiewicz W.
      • et al.
      Prevalence of left ventricular diastolic dysfunction in European populations based on cross-validated diagnostic thresholds.
      To detect the expected difference in prevalence of 10%, with a power of 80% and a 2-sided α of 0.05, we needed 137 women in both groups. Because diastolic dysfunction, and its associated signs measured by ultrasound, was never reported long term after preeclampsia, an interim analysis was performed when all women with a history of early-onset preeclampsia were included, at a 2:1 ratio (early-onset preeclampsia vs healthy pregnancy). At interim analysis, a significant difference on diastolic function was observed between both groups (P < .0001); therefore, the study population was completed. A total number of 131 women with a history of early-onset preeclampsia and 56 women with a history of an uncomplicated pregnancy participated in the cardiovascular risk assessment study (Figure 1).
      Figure thumbnail gr1
      Figure 1Recruitment study population
      Bokslag et al. Long-term cardiovascular risk after preeclampsia. Am J Obstet Gynecol 2017.

      Statistical analyses

      Characteristics were reported as means with standard deviations for normal distributed numerical data, medians with interquartile ranges for not normal distributed numerical data, and as percentages for categorical data. Differences were analyzed by unpaired t test, Mann-Whitney U test, and the Fisher exact test when appropriate. In all analyses, a P < .05 was considered statistically significant. Data were analyzed with SPSS 22 software (IBM Corp, Armonk, NY).

      Results

      The baseline characteristics at index pregnancy are described in Table 1. Women with a history of early-onset preeclampsia were younger at delivery (P = .046), more often were primiparous (P = .001), and more often delivered via caesarean delivery (P < .0001) compared with women with an uncomplicated pregnancy history. As expected, the women with former early-onset preeclampsia had greater blood pressures during pregnancy (P < .0001). In addition, they had a shorter gestational age (P < .0001), children with lower birth weight (P < .0001), and lower placental weight (P < .0001). Of the women with a history of early-onset preeclampsia, 86 (66%) had a severe disease.
      Table 1Baseline characteristics at index pregnancy
      CharacteristicsEarly-onset preeclampsia

      n = 131
      Uncomplicated pregnancy

      n = 56
      P value
      Maternal age, y30.9 ± 5.032.3 ± 4.1.046
      Primiparous101 (77.1)29 (51.8).001
      Blood pressure
       SBP at booking,
      First blood pressure measured in pregnancy, all in the first trimester
      mm Hg
      117 ± 10.2109 ± 9.9<.0001
       DBP at booking,
      First blood pressure measured in pregnancy, all in the first trimester
      mm Hg
      72 ± 7.965 ± 7.0<.0001
       Highest SBP, mm Hg182 ± 22.0123 ± 9.2<.0001
       Highest DBP, mm Hg115 ± 8.275 ± 5.9<.0001
      Severity
      Multiple conditions possible.
       Proteinuria ≥ 5 g/24h59 (45.0)
       HELLP syndrome43 (32.8)
       Eclampsia10 (7.6)
       Pulmonary edema6 (4.6)
      Outcome
       Gestational age at delivery, wk30.5 ± 2.140.0 ± 1.4<.0001
       Caesarean delivery119 (90.8)9 (16.1)<.0001
       Birth weight, g1136 ± 3623571 ± 440<.0001
       Fetal sex, girls77 (58.8)27 (48.2).201
       Fetal death18 (13.7)0.002
       Placental weight, g226 ± 81644 ± 125<.0001
      Values are mean ± SD or n (%).
      DBP, diastolic blood pressure; HELLP, Hemolysis, Elevated Liver enzymes, and Low Platelet count; SBP, systolic blood pressure.
      Bokslag et al. Long-term cardiovascular risk after preeclampsia. Am J Obstet Gynecol 2017.
      a First blood pressure measured in pregnancy, all in the first trimester
      b Multiple conditions possible.
      Table 2 presents the characteristics of the participants at risk assessment 9−16 years after their index pregnancy. Women with a history of early-onset preeclampsia were younger (mean difference 2.5 years, P = .004) and the time between pregnancy and risk assessment was shorter (mean difference 1.1 year, P = .003). They more often had first-degree relatives with a hypertensive pregnancy disorders (P = .03) and stroke (P = .002). Having a first-degree relative with myocardial infarction was similar in both groups.
      Table 2Characteristics at cardiovascular risk assessment 9−16 years after index pregnancy
      CharacteristicsEarly-onset preeclampsia, n = 131Uncomplicated pregnancy, n = 56P value
      Age, y44.0 ± 5.646.5 ± 4.8.004
      Time postindex pregnancy, years13.1 ± 2.214.2 ± 2.3.003
      White113 (86.3)49 (87.5)1.000
      Current smoking23 (17.6)9 (16.1)1.000
      Obstetric history
      Preeclampsia in other pregnancy25 (19.1)
      Stillbirth in history12 (9.2)1 (1.8).113
      Family history
      Family history: only first-degree relatives mentioned.
      Hypertensive pregnancy disorder27 (20.6)4 (7.1).030
      Myocardial infarction37 (28.2)19 (33.9).459
      Stroke26 (19.8)4 (7.1).002
      Values are mean ± SD or n (%).
      Bokslag et al. Long-term cardiovascular risk after preeclampsia. Am J Obstet Gynecol 2017.
      a Family history: only first-degree relatives mentioned.
      All results from the cardiovascular risk assessment are shown in Table 3. Women with a history of early-onset preeclampsia had significantly greater blood pressures, both systolic and diastolic, and mean arterial blood pressure was increased (all P < .0001). Regarding anthropometrics, they had greater body mass index (P = .006), greater waist circumference (P = .007), and more often had an increased waist-to-hip ratio (P = .041). Biomarker analyses revealed lower levels of high-density lipoprotein (P = .001) and greater levels of triglyceride, glycated hemoglobin, and microalbumin in urine (P values .005, <.0001, and .015, respectively) compared with women with an uncomplicated pregnancy history.
      Table 3Cardiovascular risk assessment 9−16 years after index pregnancy
      CharacteristicsEarly-onset preeclampsia

      n = 131
      Uncomplicated pregnancy

      n = 56
      P value
      Anthropometrics
       SBP, mm Hg126 ± 18.6115 ± 17.0<.0001
       DBP, mm Hg82 ± 9.874 ± 9.4<.0001
       MAP, mm Hg96.7 ± 11.887.4 ± 11.3<.0001
       BMI, kg/m225.6 [22.7−28.9]23.9 [21.2−26.6].006
       BMI > 25 kg/m271 (54.2)24 (42.9).201
       Waist circumference, cm79.0 [75.0−90.0]77.0 [71.0−82.8].007
       Waist-Hip-ratio >0.8038 (29.0)8 (14.3).041
      Biomarkers
       Cholesterol, mmol/L4.9 [4.2−5.6]5.2 [4.5−5.8].150
       HDL, mmol/L1.53 [1.29−1.91]1.78 [1.52−2.18].001
       LDL, mmol/L2.8 [2.3−3.3]2.9 [2.3−3.4].702
       TC/HDL ratio2.95 [2.56−3.85]2.80 [2.34−3.39].054
       Triglycerides, mmol/L1.0 [0.7−1.4]0.8 [0.7−1.1].005
       Glucose, mmol/mL5.1 [4.9−5.4]5.1 [4.8−5.3].173
       HbA1c, mmol/mol36 [33−38]33 [32−36]<.0001
       eGFR, mL/min/1.73 m290 [82−90]90 [82−90].805
       NT-proBNP, ng/L51 [28−78]52 [31−86].573
       Microalbumin in urine, g/mol creatinine4.4 [3.0−7.8]3.0 [3.0−3.9].015
      Cardiovascular implication
       Cardiovascular risk factor
      Presence of hypertension and/or metabolic syndrome
      55 (42.0)8 (14.3)<.0001
      Hypertension
      Current use of antihypertensive medication and/or blood pressure ≥140/90 mm Hg at risk assessment
      50 (38.2)8 (14.3).001
      Use of antihypertensive medication23 (17.6)0<.0001
      SBP ≥140 and/or DBP ≥ 90 mm Hg37 (28.2)8 (14.3).042
      Metabolic syndrome22 (16.8)1 (1.8).003
       Healthy at risk assessment
      Absence of cardiovascular risk factors.
      76 (58.0)48 (85.7)<.0001
      Values are mean ± SD, n (%), or median [IQR].
      BMI, body mass index; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HbA1c, glycated haemoglobin; HDL, high-density lipoprotein; IQR, interquartile range; LDL, low-density lipoprotein; MAP, mean arterial pressure; NT-proBNP, n-terminal prohormone of brain natriuretic peptide; SBP, systolic blood pressure; TC, total cholesterol.
      Bokslag et al. Long-term cardiovascular risk after preeclampsia. Am J Obstet Gynecol 2017.
      a Presence of hypertension and/or metabolic syndrome
      b Current use of antihypertensive medication and/or blood pressure ≥140/90 mm Hg at risk assessment
      c Absence of cardiovascular risk factors.
      In total, 42% of the women with former preeclampsia met the criteria for the window of opportunity for preventive measures by having hypertension or metabolic syndrome in absence of established cardiovascular diseases. This was significantly greater than in women with an uncomplicated pregnancy in history, of whom 14.3% met the criteria (P < .0001).
      Of the women with early-onset preeclampsia in history, 38.2% was diagnosed with hypertension. This was specified by use of antihypertensive medication in 17.6% and increased blood pressure at risk assessment in 28.2%. Hypertension was diagnosed significantly less often in women with an uncomplicated pregnancy in history, 14.3% (P = .001). Of these women, all were diagnosed with increased blood pressure at risk assessment, and none used antihypertensive medication. Metabolic syndrome was present in 16.8% of the women with a history of early-onset preeclampsia and in 1.8% of the women with a history of uncomplicated pregnancy, a significant difference (P = .003).

      Comment

      Women with a history of early-onset preeclampsia who were in the fifth decade of life had high rates of cardiovascular risk factors, although cardiovascular diseases had not developed yet. As a result, the women could still benefit from measures preventing cardiovascular disease. We conclude that there is a window of opportunity for preventive measures in women in their forties, for those who have a history of early-onset preeclampsia (42%).
      We have found that 38.2% of women with early-onset preeclampsia in history had hypertension 9−16 years after pregnancy, at an average age of 44 years (SD ± 5.6). Lower rates of hypertension were found in studies investigating women with early-onset preeclampsia in the first year after pregnancy, 22−25%.
      • van Rijn B.B.
      • Nijdam M.E.
      • Bruinse H.W.
      • et al.
      Cardiovascular disease risk factors in women with a history of early-onset preeclampsia.
      • Manten G.T.
      • Sikkema M.J.
      • Voorbij H.A.
      • Visser G.H.
      • Bruinse H.W.
      • Franx A.
      Risk factors for cardiovascular disease in women with a history of pregnancy complicated by preeclampsia or intrauterine growth restriction.
      Nine years after pregnancy, at a mean age of 39 years (SD ± 4.9), Drost et al
      • Drost J.T.
      • Arpaci G.
      • Ottervanger J.P.
      • et al.
      Cardiovascular risk factors in women 10 years post early preeclampsia: the Preeclampsia Risk EValuation in FEMales study (PREVFEM).
      found a prevalence of hypertension of 43.1%, which was comparable with our study. The prevalence of hypertension in the general Dutch female population between 40 and 49 years old is 15%, similar to the observed prevalence in our participants with a history of an uncomplicated pregnancy.
      • Blokstra A.
      • Vissink P.
      • Venmans L.M.A.J.
      • et al.
      Nederland de Maat Genomen, 2009-2010. Monitoring van risicofactoren in de algemene bevolking.
      The rate of hypertension in our participants with a history of early-onset preeclampsia was comparable with that of Dutch women between 50 and 59 years old (32%).
      • Blokstra A.
      • Vissink P.
      • Venmans L.M.A.J.
      • et al.
      Nederland de Maat Genomen, 2009-2010. Monitoring van risicofactoren in de algemene bevolking.
      Therefore, women with early-onset preeclampsia seemed to have a cardiovascular state of women 10 years older. This finding is in line with the study of Heida et al,
      • Heida K.Y.
      • Franx A.
      • van Rijn B.B.
      • et al.
      Earlier age of onset of chronic hypertension and type 2 diabetes mellitus after a hypertensive disorder of pregnancy or gestational diabetes mellitus.
      who found that the mean age of onset of chronic hypertension after a hypertensive pregnancy disorder was 43.5 years compared with 51.2 years after a normotensive pregnancy.
      Guidelines concerning cardiovascular health in women mention the increased cardiovascular risk after hypertensive pregnancy disorders, but well-founded recommendations for when to start screening, interval and prevention are lacking.
      • Heida K.Y.
      • Bots M.L.
      • de Groot C.J.
      • et al.
      Cardiovascular risk management after reproductive and pregnancy-related disorders: a Dutch multidisciplinary evidence-based guideline.
      • Perk J.
      • De Backer G.
      • Gohlke H.
      • et al.
      European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts).
      • Mosca L.
      • Benjamin E.J.
      • Berra K.
      • et al.
      Effectiveness-based guidelines for the prevention of cardiovascular disease in women—2011 update: a guideline from the American Heart Association.
      Our results suggest that a cardiovascular risk assessment as preventive measure might be opportune in the fifth decade of life.
      Van Rijn et al
      • van Rijn B.B.
      • Nijdam M.E.
      • Bruinse H.W.
      • et al.
      Cardiovascular disease risk factors in women with a history of early-onset preeclampsia.
      and Drost et al
      • Drost J.T.
      • Arpaci G.
      • Ottervanger J.P.
      • et al.
      Cardiovascular risk factors in women 10 years post early preeclampsia: the Preeclampsia Risk EValuation in FEMales study (PREVFEM).
      investigated women 9 months and 10 years after early-onset preeclampsia. In both studies, in different phases of life, the observed prevalence of metabolic syndrome was similar to our observation (15.2%, 18%, and 16.8% respectively). In contrast to our study, Hermes et al
      • Hermes W.
      • Franx A.
      • van Pampus M.G.
      • et al.
      Cardiovascular risk factors in women who had hypertensive disorders late in pregnancy: a cohort study.
      investigated women with term preeclampsia (>36 weeks of gestation) along with term gestational hypertension and compared with healthy pregnancies, 2.5 years postpartum. They found a prevalence of 25%, which was greater than in our population. These findings might suggest that metabolic syndrome is increased in women with a history of hypertensive pregnancy disorder, irrespective of the severity of the condition. This also is stated by Veerbeek et al,
      • Veerbeek J.H.
      • Hermes W.
      • Breimer A.Y.
      • et al.
      Cardiovascular disease risk factors after early-onset preeclampsia, late-onset preeclampsia, and pregnancy-induced hypertension.
      who found similar prevalence rates of metabolic syndrome in early-onset preeclampsia, late-onset preeclampsia, and pregnancy-induced hypertension, 0.5 to 2.5 years postpartum.
      We performed an extensive risk assessment in a large cohort of women, for all of whom we had obstetrical data. The major strength of our study was that we examined women with a history of early-onset preeclampsia in their forties, so in the fifth decade of life. Our study has some limitations, however. It should be noted that measuring blood pressure twice in 1 visit might have overstate the rate of hypertension, compared with measuring blood pressure at 2 or more visits.
      • James P.A.
      • Oparil S.
      • Carter B.L.
      • et al.
      2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8).
      Although the procedure was similar for participants with preeclampsia and uncomplicated pregnancy in history, this procedure also was similar to the one used in studies to which we compared our data.
      • van Rijn B.B.
      • Nijdam M.E.
      • Bruinse H.W.
      • et al.
      Cardiovascular disease risk factors in women with a history of early-onset preeclampsia.
      • Manten G.T.
      • Sikkema M.J.
      • Voorbij H.A.
      • Visser G.H.
      • Bruinse H.W.
      • Franx A.
      Risk factors for cardiovascular disease in women with a history of pregnancy complicated by preeclampsia or intrauterine growth restriction.
      • Drost J.T.
      • Arpaci G.
      • Ottervanger J.P.
      • et al.
      Cardiovascular risk factors in women 10 years post early preeclampsia: the Preeclampsia Risk EValuation in FEMales study (PREVFEM).
      For that reason, we believe that the pragmatically chosen procedure 2 measures in 1 visit did not affect the results considerably. The response rates in both groups were low, 53% in the early-onset preeclampsia group and 26% in the uncomplicated pregnancy group. This was mainly the result of that we could not locate the potential participants; many addresses were outdated 9−16 years after pregnancy. In total, 43 women in the early-onset preeclampsia group and 26 women in the uncomplicated pregnancy group actually declined participation. It might be conceivable that from all women with a history of early-onset preeclampsia, the women with most severe disease in pregnancy were more willing to participate. Because earlier onset of preeclampsia is associated with greater cardiovascular risk, this might induce some selection bias, which can overstate the difference we have found.
      Furthermore, women who had a reason to be examined or reassured on their cardiovascular state, for example, positive family history of myocardial infarction, high body mass index, or smoking, would be more willing to participate in a cardiovascular risk assessment study. Because this applied to all participants, the difference found between both groups would not have been remarkably affected. In addition, age differed significantly between both groups. Women with an uncomplicated pregnancy history were on average 2.5 years older. We could not explain why relatively older women were more willing to participate. Because advanced age is associated with increased risk of cardiovascular disease, this could result in an underestimation of the difference of risk factors between both groups. It should be noted, however, that the absolute difference in age might not be clinically relevant.
      Several prediction models exist to calculate the long-term risk of developing cardiovascular disease, but none of these models were validated for women with a history of preeclampsia. The use of the standard prediction models in these women might not be appropriate. Therefore, future research should focus on moderation and validation of these models before use in women with a history of preeclampsia.
      To determine whether preventive measures can indeed reduce the development of cardiovascular disease in this specific patient group, more research is necessary. For example, reduction of blood pressure is proven to be beneficial to reduce cardiovascular events in all ages in the general population, but these interventions are not examined specifically in women with a history of preeclampsia.
      • Turnbull F.
      • Neal B.
      • Ninomiva T.
      • et al.
      Blood Pressure Lowering Treatment Trialists Collaboration
      Effects of different regimens to lower blood pressure on major cardiovascular events in older and younger adults: meta-analysis of randomised trials.
      Lifestyle interventions (diet, exercise, smoking cessation, alcohol intake reduction) have been studied in the general population and in postpartum women, but not in women with a history of preeclampsia. The current focus of lifestyle intervention studies in postpartum women is on the first year postpartum
      • Berks D.
      • Hoedjes M.
      • Raat H.
      • Duvekot J.J.
      • Steegers E.A.
      • Habbema J.D.
      Risk of cardiovascular disease after pre-eclampsia and the effect of lifestyle interventions: a literature-based study.
      ; however, long-term effects studies also should focus on women in the fourth and fifth decade of life, when first signs of cardiovascular disease are expected to occur.
      In conclusion, women who experienced early-onset preeclampsia are still in the window of opportunity for preventive measures in the fifth decade of their life. These women have important modifiable risk factors for cardiovascular diseases but are currently outside the scope of most preventive programs because of their relatively young age.

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