OBJECTIVE: The objective of the present study was to evaluate the cardiovascular risk profile and the prevalence of metabolic syndrome among women with a history of pregnancy-induced hypertension (PIH).
METHODS: From a cohort of 3,799 nulliparous women prospectively recruited between 1989 and 1997, we performed an observational study on 168 case-control pairs 7.8 years after delivery. Participants were scheduled for a visit with a research nurse to evaluate their cardiovascular risk profile using a questionnaire, anthropometric measurements and blood specimen analysis.
RESULTS: One hundred sixty-eight women with prior PIH (105 with gestational hypertension and 63 with preeclampsia) and 168 controls matched for age and year of index delivery were evaluated. The women with PIH (34.6 ± 4.4 years) were more obese and had higher systolic (115 mm Hg versus 108 mm Hg) and diastolic (75 mm Hg versus 70 mm Hg) blood pressures (P < .001) than the 168 controls (35.1 ± 4.5 years). They had lower high-density lipoprotein cholesterol level (1.30 mmol/L versus 1.42 mmol/L; P < .001), increased fasting blood glucose concentration (5.2 mmol/L versus 5.0 mmol/L; P = .002), and higher insulin levels (119 versus 91 pmol/L; P < .001). The prevalence of the metabolic syndrome was higher in the PIH group (unadjusted odds ratio = 4.9; 95% confidence interval 2.1–10.9) compared with controls, even after adjustment for confounders (adjusted odds ratio = 3.6; 95% confidence interval 1.4 –9.0).
CONCLUSION: In white women in their mid-30s, the prevalence of the metabolic syndrome is 3- to 5-fold increased in those with a history of PIH in their first pregnancy. This emphasizes the importance of long-term follow-up assessment for cardiovascular risk factors in these women.
LEVEL OF EVIDENCE: II-2
Women with prior pregnancy-induced hypertension are at increased risk of metabolic syndrome later in life.
From the *Center for the Development, Evaluation and Rational Implementation of New Medical Diagnostic Tools (CEDERINDT)/CETDeQ, Hôpital St-François d'Assise du Centre Hospitalier Universitaire de Québec, Université Laval, Québec, Canada; †Centre Hospitalier, Universitaire de Sherbrooke (CHUS), Pavillon Fleurimont, Sherbrooke, Canada; ‡Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania; and §Magee-Women's Research Institute, Pittsburgh, Pennsylvania.
This work was supported by a grant to Forest et al from the Canadian Institutes of Health Research (MPO-37903) and Valorisation Recherche Québec. Dr. Girouard is a fellow of the Fond de la Recherche en Santé du Québec, and Dr. Giguère is a clinical investigator funded by the Fond de la Recherche en Santé du Québec.
Address reprint requests to: Yves Giguère, MD, PhD, FRCPC, CHUQ, Centre de Recherche de l'Hôpital St-François d'Assise, Unité de Périnatalogie, 10 Rue de l'Espinay, Quebec City, Quebec, Canada, G1 L 3L5; e-mail: firstname.lastname@example.org.
Received December 22, 2004. Received in revised form February 13, 2005. Accepted February 16, 2005.
Pregnancy-induced hypertension (PIH), defined as the occurrence of hypertension after 20 weeks of gestation in a woman without prior hypertension, occurs in about 8% of pregnancies in North America. When accompanied by proteinuria, the disorder is termed preeclampsia, and when occurring without proteinuria it is termed gestational hypertension or transient hypertension.1 Until recently, gestational hypertension and preeclampsia were thought to be limited to pregnancy with recommended follow-up confined to screening of essential hypertension.1
Recent epidemiologic studies have shown an increased risk of cardiovascular disease among women with a history of PIH. In a review of 7,543 hospital records from Iceland, Jonsdottir et al2 found an increased rate of death from ischemic heart disease among women with a history of PIH compared with the general population (relative risk = 1.47; 95% confidence interval [CI] 1.05–2.02). A Scottish retrospective cohort study reported that women with a history of preeclampsia an average of 19 years previously, had a 2-fold elevated risk of being admitted to the hospital for ischemic heart disease or dying from it.3 Irgens et al,4 in a population-based retrospective cohort study from Norway, observed that women with a history of preeclampsia had an increased mortality rate (odds ratio [OR] = 1.65; 95% CI 1.01–2.70) from cardiovascular causes relative to women without preeclampsia 13 years after the index pregnancy. These retrospective studies suggest an association between PIH and long-term risk of cardiovascular disease, but they were limited in their ability to adjust for confounders and they could not suggest the mechanisms underlying the association.
Women in whom PIH eventually develops are more likely to enter pregnancy overweight and to demonstrate, during pregnancy, some of the risk factors characterizing atherosclerosis, such as dyslipidemia (hypertriglyceridemia, low levels of high-density lipoprotein [HDL] cholesterol and small dense low-density lipoprotein [LDL] cholesterol),5,6 insulin resistance,7,8 and endothelial dysfunction.9 Indeed, these metabolic aberrations (increased adiposity, hyperlipidemia, hyperglycemia, and elevated blood pressure) are reminiscent of the metabolic syndrome. This syndrome is considered an independent risk factor for cardiovascular disease,10,11 and organizations such as The National Cholesterol Education Program, Adult Treatment Panel III (NCEP III),12 and the World Health Organization (WHO)13 have proposed criteria to better define people at risk for the metabolic syndrome. Obesity, hypertension, blood lipid profile, fasting blood glucose concentration, and, for the WHO criteria, assessment of insulin resistance are the main criteria.
Based on the observation that women who suffer from PIH present a syndrome similar to the metabolic syndrome and that these women seem at increased risk of cardiovascular disease later in life, we hypothesized that women with prior PIH could be at risk for the metabolic syndrome a few years after giving birth. If so, this could suggest a mechanism by which women with prior PIH experience increased cardiovascular morbidity and mortality later in life. The objective of the current study was to assess the prevalence of the metabolic syndrome using defined criteria and the cardiovascular risk profile among women who had been prospectively diagnosed with de novo hypertensive disorder in their first pregnancy compared with women who had uneventful pregnancy.
MATERIALS AND METHODS
Between 1989 and 1997, we performed 3 prospective studies examining biochemical and sonographic markers for the early detection of preeclampsia in nulliparous women.14,15 Women with known renal diseases, diabetes mellitus, or cardiovascular disease as well as multiparous women were excluded from these studies. The diagnosis of hypertensive complications during pregnancy was assessed by a single senior obstetrician using the diagnostic criteria of the National High Blood Pressure Education Program Working Group.16 Briefly, the presence of blood pressure of 140/90 mm Hg or above on 2 occasions 6 hours apart before labor was considered as gestational hypertension. Additionally, women who had proteinuria level of more than 0.3 g/24 hours or a positive qualitative results (“dipstick 2+”) were considered as preeclampsia. To fully ascertain the diagnosis among women who suffered from gestational hypertension or preeclampsia, blood pressure was measured 6 weeks postpartum and values below 120/80 mm Hg were considered normal.
From the initial studies described above, there were 3,799 women for whom the pregnancy outcome could be ascertained. We excluded 223 women who had hypertension before the 20th week of gestation of the index pregnancy. From the remaining 3,576 women, 341 with prior gestational hypertension or preeclampsia were eligible for the present study (Fig. 1). We were able to contact by phone 244 (71.5%) of the 341 eligible women, of whom 169 (69.3%) agreed to participate in the present study and 71 (29.1%) refused (not interested, lack of time). Pregnant women and women who had delivered within 6 months of the scheduled visit were excluded. Each woman with prior PIH recruited in the current study was matched to 1 control from the same cohort for maternal age and year of delivery of the index pregnancy (within 1 year). For each participant, a questionnaire regarding sociodemographic data, family history (diabetes, chronic hypertension, early cardiovascular disease, and PIH), personal history (diabetes, hypertension, cardiovascular disease), and life habits was mailed to their homes. All participants gave written and informed consent and the study protocol was accepted by the Ethics Committee of the Centre Hospitalier Universitaire de Québec.
A research nurse met every participant at the research clinic. Anthropometric data (height, weight, waist and hip circumference) were measured and 2 series of 3 measures of blood pressure in a seated position were recorded. Fasting blood specimens were collected for measurement of biochemical variables and were stored at −20°C until analysis. Data for the index pregnancy (self-reported prepregnancy weight, height, age, gestational age and baby weight) were extracted from the databases of the initial studies performed between 1989 and 1997. For the present study, data from the questionnaire, anthropometric measurements, and biochemical results were compiled in an Access Database (Microsoft Corporation, Mississauga, Canada). Subjects were classified as having the metabolic syndrome if they fulfilled the criteria recently published by the NCEP III12 or the criteria of the WHO13 with the modifications suggested by the European Group for the Study of Insulin Resistance.17
Continuous variables are expressed as their mean and standard deviation. Comparisons of the women with prior PIH (gestational hypertension and preeclampsia separately and combined) against the control group were performed using unpaired t tests, χ2 tests, or Fisher exact tests where appropriate. Odds ratio and their 95% confidence intervals were used to quantify the risk of women with prior PIH in comparison with controls. Logistic regression was performed to evaluate the potential confounding effect of different variables on the relation between groups and the metabolic syndrome (actual age as a continuous variable; tobacco use, alcohol consumption, exercise, and oral contraceptive use as yes/no; first-degree family history of hypertension, PIH, diabetes, or cardiovascular disease < 55 years as yes/no). We also controlled for the body mass index (BMI) at the index pregnancy to estimate the BMI-independent association between a history of prior PIH and the risk of developing metabolic syndrome. We used dummy variables to categorized women (BMI < 25; BMI ≥ 25 and < 30; BMI ≥ 30) because these intervals are widely used and accepted in clinical settings to identify healthy weight, overweight, and obesity. To correct for multiple comparisons between the 3 study groups (gestational hypertension, preeclampsia, and the combined case group versus the control group), we used the Bonferroni correction, and P values less than .017 were considered statistically significant.
Between January 2001 and January 2003, we evaluated 169 women with prior PIH (106 with gestational hypertension and 63 with preeclampsia) and 169 matched controls. One pair of matched subjects was excluded because the woman with prior PIH was pregnant at the time of the scheduled visit, leaving 168 pairs for statistical analysis. All but 3 women were of Caucasian origin. The average period from the index pregnancy to the scheduled visit was 7.8 years (range 5.1–13.0 years). General characteristics and clinical variables for the study subjects are shown in Table 1. At the index pregnancy, all groups were of similar age, but women in whom PIH developed tended to have a higher prepregnancy BMI than controls. Women who suffered from preeclampsia had smaller babies and delivered earlier, as expected.
For the current study, women with prior PIH still had a higher BMI than controls as well as higher waist circumference and waist-to-hip ratio. Systolic (115.5 mm Hg for gestational hypertension, 114.8 mm Hg for preeclampsia, and 107.9 mm Hg for controls) and diastolic (74.6 mm Hg for gestational hypertension, 75.0 mm Hg for preeclampsia, and 70.0 mm Hg for controls) blood pressures were significantly higher in women with prior PIH compared with women who had had a normal pregnancy (P < .001). Of note, the prevalence of hypertension was 13% in women with prior PIH (11% for gestational hypertension and 16% for preeclampsia) compared with only 1% in controls. As shown in Table 1, we found similar total cholesterol and LDL-cholesterol concentrations between groups but lower HDL-cholesterol values (1.28 mmol/L for gestational hypertension, 1.33 mmol/L for preeclampsia, and 1.42 mmol/L for controls; P < .001) and higher levels of triglycerides (1.21 mmol/L for gestational hypertension, 1.18 mmol/L for preeclampsia, and 1.02 mmol/L for controls; P = .02) in women with prior PIH. Apolipoprotein B levels were significantly higher in these women (+12.5%) compared with controls (P < .001). Fasting blood glucose was slightly higher in women with prior PIH (especially in the gestational hypertension group) compared with controls. Also, fasting insulin levels were higher in women with a history of PIH (124 pmol/liter for gestational hypertension, 108 pmol/L for preeclampsia, and 91 pmol/L for controls), but this difference was significant only for the gestational hypertension and the combined groups (P < .001). Tobacco use, alcohol consumption, exercise, and oral contraceptive use were similar among all study groups. We observed more commonly first-degree family histories of hypertension (53% for gestational hypertension, 65% for preeclampsia, and 32% for controls) and pregnancy hypertensive complications (16% for gestational hypertension, 22% for preeclampsia, and 9% for controls) among women with prior PIH compared with controls.
The NCEP III12 and the modified WHO criteria17 were used to estimate the prevalence of the metabolic syndrome at the scheduled visit among the different groups (Table 2). The prevalence of abdominal obesity, increased blood pressure (≥ 135/85 mm Hg), and increased level of fasting insulin (> 75th percentile) was higher in women with prior PIH compared with controls. As a consequence, the metabolic syndrome was more prevalent among affected women using either the NCEP III (OR = 3.4, 95% CI 1.6–6.9) or the modified WHO (OR = 4.9, 95% CI 2.1–10.9) criteria. Using the WHO criteria, women with prior preeclampsia and women with prior gestational hypertension were both significantly more likely to have metabolic syndrome, whereas using NCEP III criteria, the prevalence of the metabolic syndrome was significantly higher only in the gestational hypertension group. Odds ratios after adjustments for potentially confounding variables are shown in Table 3. Odds ratios for the risk of metabolic syndrome were modestly affected when controlling for all variables except BMI, but when the index BMI was included, the risks decreased and remained significant after Bonferroni correction for the preeclampsia and the combined groups using the WHO criteria.
In former studies, we recruited prospectively primiparous women for the evaluation of early markers of preeclampsia. After an average of 7.8 years from the index pregnancy, we recalled women with prior PIH and women with a normotensive pregnancy from the same cohort to evaluate their cardiovascular risk profile and the prevalence of the metabolic syndrome. Recent reviews have emphasized the importance of prospective studies to elucidate the link between PIH and future risk of cardiovascular disease.18,19 However, it is difficult to perform a “state of the art” prospective study mainly because of the long delay between reproductive age and the age at which cardiovascular disease events occur. In this study, the diagnosis was established prospectively minimizing the risk of misclassification, especially with regard to chronic hypertension before pregnancy.
Few studies have investigated cardiovascular disease risk factors later in life among women who have had PIH. Two small studies have observed insulin resistance in women a few weeks after delivery20 and up to 17 years after a first preeclamptic pregnancy.21 Atherogenic blood lipid profiles (high triglycerides, low HDL-cholesterol, high LDL-cholesterol, and high atherogenic index) are less consistent among women with prior preeclampsia,21,22 although one study showed higher apolipoprotein B levels, smaller LDL-cholesterol particles, and a higher atherogenic index in postmenopausal women with prior eclampsia.23 A recent study evaluated the presence of metabolic aberrations in women 6 years after an episode of PIH and found higher blood pressure, increased obesity, and increased insulin levels in these women. Unfortunately, the authors did not assess the prevalence of the metabolic syndrome based on the available criteria and the diagnosis was established in routine clinical settings and revised retrospectively, which could have led to misclassification bias.24
In the present study, we found an unfavorable cardiovascular disease risk profile in women with a history of PIH despite their relatively young age (mean age 34.8 years). These aberrations included greater adiposity (measured by BMI, waist circumference, and waist/hip ratio), higher blood pressure, dyslipidemia (characterized by lower HDL-cholesterol, higher triglyceride levels, and higher apolipoprotein B levels) and higher fasting blood glucose and insulin levels. Interestingly, major retrospective studies have found an increased risk of cardiovascular disease mainly in women who delivered before term.3,4 In our study, the majority of women delivered after 36 weeks of gestation (92.3% for women with PIH and 97.0% for controls), suggesting that women with a milder form of PIH are also at increased risk of cardiovascular disease later in life. Moreover, we observed that women from both gestational hypertension and preeclampsia groups were similar with respect to their cardiovascular disease risk profiles when compared with controls, suggesting that they may have similar long-term risks. These findings contrast with the fact that during pregnancy women with preeclampsia have more severe outcomes compared with women with gestational hypertension, a condition generally considered a benign form of the disease.19
Over the last decade, the link between the metabolic syndrome and cardiovascular disease has become well established.10,25 It has been shown that clustering of the risk factors associated with this syndrome acts synergistically resulting in a higher risk of cardiovascular disease than the addition of each factors in risk scoring algorithms.11 In our study, we used 2 definitions of the metabolic syndrome suggested by the NCEP III12 and the WHO13,17 because they may be variably predictive for cardiovascular disease and diabetes, in that 15–20% of people are classified differently.26 We found that the prevalence of the metabolic syndrome was 3.4-fold (NCEP III) and 4.9-fold (WHO modified) higher in women who had PIH in their first pregnancy compared with those with normotensive pregnancy. However, after adjustment for confounding variables (including prepregnancy BMI), the risk of developing the metabolic syndrome was lower but remained significant for the preeclampsia subgroup and the combined group when using the WHO criteria. These findings suggest that the metabolic syndrome appears early in a subset of women after an episode of PIH. Thus, we believe that the metabolic syndrome may play a role in the pathophysiology linking PIH to long-term cardiovascular disease. Of note, 2 recent reviews18,27 proposed the hypothesis that the metabolic syndrome could be unmasked during pregnancy in predisposed women and become clinically apparent a few years postpartum, to eventually increase the risk of cardiovascular disease events. Our results support the second part of this hypothesis.
In this study, we could not evaluate the prevalence of the metabolic syndrome before the index pregnancy, which could lessen our findings. However, the mean prepregnancy BMI was below 25 kg/m2 in the 3 subgroups (gestational hypertension, preeclampsia, and controls), suggesting that the prevalence of metabolic syndrome was low before the index pregnancy. Also, we controlled for age and BMI (obesity) at the beginning of the index pregnancy to attenuate differences among groups. Another potential pitfall of this study is the moderate recruitment rate which could result in a selection bias. However, after comparing BMI and age at the index pregnancy of women enrolled in this study (n = 336) to those in the original cohort (n = 3,240), we did not find any significance differences. We also performed analyses on the 172 women with prior PIH who did not participate in this study. These women were similar to the 168 women with prior PIH in terms of BMI, gestational age, and preterm delivery at the index pregnancy, but were slightly younger (25.8 years versus 27.0 years; P = .02). We believe that a 1-year difference would not have changed our result significantly. Finally, because the studied population is largely of Caucasian origin, the study findings apply only to this population and may not be transferable to other ethnic groups without additional studies because of differences in the prevalence of the metabolic syndrome.
In conclusion, this study shows that many cardiovascular disease risk factors are more prevalent in white women in their mid-30s with a history of PIH than in controls. Also, it shows that the prevalence of metabolic syndrome is 3–5-fold increased in these women compared with those with uneventful pregnancy. Our results suggest that the metabolic syndrome could represent the biologic link explaining the increased morbidity and mortality from later cardiovascular disease observed among women who have had PIH, although this hypothesis needs to be confirmed in a prospective study. These findings emphasize the importance of introducing measures to prevent, screen for, and treat the metabolic syndrome shortly after the index pregnancy among women who have had PIH.
1. Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Am J Obstet Gynecol 2000;183:S1–22.
2. Jonsdottir LS, Arngrimsson R, Geirsson RT, Sigvaldason H, Sigfusson N. Death rates from ischemic heart disease in women with a history of hypertension in pregnancy. Acta Obstet Gynecol Scand 1995;74:772–6.
3. Smith GC, Pell JP, Walsh D. Pregnancy complications and maternal risk of ischaemic heart disease: a retrospective cohort study of 129,290 births. Lancet 2001;357:2002–6.
4. Irgens HU, Reisaeter L, Irgens LM, Lie RT. Long term mortality of mothers and fathers after pre-eclampsia: population based cohort study. BMJ 2001;323:1213–7.
5. Belo L, Caslake M, Gaffney D, Santos-Silva A, Pereira-Leite L, Quintanilha A, et al. Changes in LDL size and HDL concentration in normal and preeclamptic pregnancies. Atherosclerosis 2002;162:425–32.
6. Sattar N, Bendomir A, Berry C, Shepherd J, Greer IA, Packard CJ. Lipoprotein subfraction concentrations in preeclampsia: pathogenic parallels to atherosclerosis. Obstet Gynecol 1997;89:403–8.
7. Kaaja R, Laivuori H, Laakso M, Tikkanen MJ, Ylikorkala O. Evidence of a state of increased insulin resistance in preeclampsia. Metabolism 1999;48:892–6.
8. Seely EW, Solomon CG. Insulin resistance and its potential role in pregnancy-induced hypertension. J Clin Endocrinol Metab 2003;88:2393–8.
9. Roberts JM. Endothelial dysfunction in preeclampsia. Semin Reprod Endocrinol 1998;16:5–15.
10. Isomaa B, Almgren P, Tuomi T, Forsen B, Lahti K, Nissen M, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 2001;24:683–9.
11. Girman CJ, Rhodes T, Mercuri M, Pyorala K, Kjekshus J, Pedersen TR, et al. The metabolic syndrome and risk of major coronary events in the Scandinavian Simvastatin Survival Study (4S) and the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). Am J Cardiol 2004;93:136–41.
12. 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). JAMA 2001;285:2486–97.
13. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998;15:539–53.
14. Masse J, Forest JC, Moutquin JM, Marcoux S, Brideau NA, Belanger M. A prospective study of several potential biologic markers for early prediction of the development of preeclampsia. Am J Obstet Gynecol 1993;169:501–8.
15. Irion O, Masse J, Forest JC, Moutquin JM. Prediction of pre-eclampsia, low birthweight for gestation and prematurity by uterine artery blood flow velocity waveforms analysis in low risk nulliparous women. Br J Obstet Gynaecol 1998;105:422–9.
16. National High Blood Pressure Education Program Working Group Report on High Blood Pressure in Pregnancy. Am J Obstet Gynecol 1990;163:1691–712.
17. Balkau B, Charles MA. Comment on the provisional report from the WHO consultation. European Group for the Study of Insulin Resistance (EGIR). Diabet Med 1999;16:442–3.
18. Sattar N, Greer IA. Pregnancy complications and maternal cardiovascular risk: opportunities for intervention and screening? BMJ 2002;325:157–60.
19. Roberts JM, Pearson G, Cutler J, Lindheimer M. Summary of the NHLBI Working Group on Research on Hypertension During Pregnancy. Hypertension 2003;41:437–45.
20. Fuh MM, Yin CS, Pei D, Sheu WH, Jeng CY, Chen YI, et al. Resistance to insulin-mediated glucose uptake and hyperinsulinemia in women who had preeclampsia during pregnancy. Am J Hypertens 1995;8:768–71.
21. Laivuori H, Tikkanen MJ, Ylikorkala O. Hyperinsulinemia 17 years after preeclamptic first pregnancy. J Clin Endocrinol Metab 1996;81:2908–11.
22. Sattar N, Ramsay J, Crawford L, Cheyne H, Greer IA. Classic and novel risk factor parameters in women with a history of preeclampsia. Hypertension 2003;42:39–42.
23. Hubel CA, Snaedal S, Ness RB, Weissfeld LA, Geirsson RT, Roberts JM, et al. Dyslipoproteinaemia in postmenopausal women with a history of eclampsia. BJOG 2000;107:776–84.
24. Pouta A, Hartikainen AL, Sovio U, Gissler M, Laitinen J, McCarthy MI, et al. Manifestations of metabolic syndrome after hypertensive pregnancy. Hypertension 2004;43:825–31.
25. Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 2002;288:2709–16.
26. Ford ES, Giles WH. A comparison of the prevalence of the metabolic syndrome using two proposed definitions. Diabetes Care 2003;26:575–81.
© 2005 The American College of Obstetricians and Gynecologists
27. Williams D. Pregnancy: a stress test for life. Curr Opin Obstet Gynecol 2003;15:465–71.