Preeclampsia and other vascular disorders in pregnancy, such as gestational hypertension; hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome; eclampsia; placental abruption; fetal growth restriction; and stillbirth as a result of placental insufficiency, complicate up to 10% of all pregnancies, accounting for considerable maternal and neonatal morbidity and mortality.1,2 To date, vascular-complicated pregnancies are thought to be superimposed on a wide range of maternal constitutional conditions including the metabolic syndrome. The metabolic syndrome, firstly defined in 1998 by the World Health Organization (WHO), is characterized by the concomitant presence of insulin resistance, dyslipidemia, hypertension, and obesity, and it is known to be an independent risk factor for non–insulin-dependent diabetes mellitus and cardiovascular disease.3–5 Circulating lipid levels and insulin resistance rise in the course of normal pregnancy.6 Preeclampsia differs from normal pregnancy by the development of a more pronounced dyslipidemia and insulin resistance, suggesting that preeclampsia develops in concert with enhanced metabolic syndrome.7–9 Early-and late-onset vascular complications in pregnancy appear to be different disorders with overlapping clinical signs.10,11 It is generally known that early-onset vascular disorder in pregnancy has a larger impact on the fetus and neonate than late-onset disease due to more severe prematurity and dysmaturity.12 The unfavorable long-term maternal consequences for women with a history of early-onset hypertensive disorder in pregnancy are increasingly known.13,14 These observations raise the question of whether the metabolic syndrome predisposes equally to both types of vascular disorder–complicated pregnancy. This study was designed to test the hypothesis that the metabolic syndrome is associated with early-onset rather than with late-onset vascular-complicated pregnancy.
MATERIALS AND METHODS
To test our hypothesis we conducted a retrospective cohort study in women after pregnancy complicated by preeclampsia or another vascular-related disorder in pregnancy. Between September 1996 and August 2006, we evaluated a cohort of 849 women. They were recruited at the 6 weeks postpartum outpatient follow-up in three tertiary referral hospitals in the Netherlands. Women diagnosed with at least one of the following disorders during former pregnancy were included: preeclampsia, gestational hypertension, the HELLP syndrome, eclampsia, placental abruption, fetal growth restriction, and stillbirth as a result of placental insufficiency.
Preeclampsia, gestational hypertension, and HELLP syndrome were defined according to the criteria of the Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy.1 Briefly, the presence of blood pressure of 140/90 mm Hg or above on two occasions 6 hours apart before labor was considered to represent gestational hypertension. Additionally, women who had proteinuria in excess of 0.3 g/24 hours or a positive qualitative result (dipstick 2+ or greater) were diagnosed as having preeclampsia. Eclampsia was defined as the occurrence of epileptic seizures in preeclamptic women who were not diagnosed with epilepsy in the past. In this study, placental abruption was diagnosed on a clinical basis: vaginal bleeding, uterine tenderness, fetal distress, maternal shock, and/or maternal coagulopathy. We defined fetal growth restriction as a neonatal birth weight below the tenth centile of our general population. Stillbirth was supposed to be the result of placental insufficiency in case of fetal death after 24 weeks of gestation and signs of placental insufficiency at pathological examination. For this study, we excluded women with multiple pregnancy, delivery before 24 weeks of gestation, and fetal growth restriction based on congenital malformation, chromosomal abnormalities, or drug/alcohol abuse during pregnancy. The study was approved by the hospital’s medical ethical committee (CMO 2007/252).
Participants were scheduled for a visit with a nurse who performed measurements. At the time of evaluation, participants were at least 6 months postpartum. Women taking antihypertensive drugs discontinued their medication at least 2 weeks before measurement for the purpose of the study, and none of the participants used hormonal contraceptives. After an overnight fast, blood specimens were collected to determine the following variables by standard hospital laboratory procedures: glucose, insulin, hemoglobin A1c, high-density lipoprotein, and triglycerides. The ratio of fasting glucose and insulin (homeostasis model assessment index) was calculated (insulin [milliunits/L] × glucose [mmol/L]/22.5) to estimate insulin resistance as detailed elsewhere.15,16 In a 24-hour urine collection, we measured the concentrations of albumin, protein, and creatinine to define (micro)albuminuria corrected for creatinine output and the 24-hour protein excretion. Arterial blood pressure was measured after 5 minutes rest in supine position by using the mean values of ten blood pressure recordings assessed during 30 minutes of monitoring at the right upper arm using a semiautomatic oscillometric device (Dinamap Vital Signs Monitor 1846; Critikon, Tampa, FL). Height and weight were measured to calculate body mass index (BMI). Clinical data concerning the index pregnancy and delivery were retrospectively extracted from medical files, including type of obstetric disorder and fetal birth weight, sex, and gestational age at time of delivery. Neonatal birth weight centile was determined using Dutch reference values for birth weight, which are standardized for parity and the infant’s sex. Data on the participant’s general medical and obstetric history, medication use, lifestyle habits including alcohol consumption, coffee use, and smoking, were obtained from chart-revision and interview-based self-report.
Women were divided into two groups according to gestational age at delivery: an early-onset group with delivery before 32 weeks and a late-onset group with delivery at or beyond 32 weeks of pregnancy.
The primary outcome measure of the study was the presence of metabolic syndrome. Participants were classified as having metabolic syndrome if they fulfilled internationally accepted criteria specified by the WHO,3 International Diabetes Federation,17 Third Adult Treatment Panel,18 or the Third Adult Treatment Panel updated version.19 Adjustments were made concerning the WHO criteria: in this study, no oral glucose tolerance test was performed, and hyperinsulinemia was defined using cutoff values for insulin and/or homeostasis model assessment of higher than the mean plus two times the standard deviation for a healthy population at a comparable time elapsed after uneventful pregnancy.16 As most women experience changes in waist circumference due to a larger gap between both abdominal rectus muscles in the first year after giving birth, Third Adult Treatment Panel updated criteria were modified by using BMI 30 kg/m2 or greater instead of female waist greater than 88 cm as a cutoff value to determine obesity. Modified International Diabetes Federation criteria uses BMI 25 kg/m2 or greater instead of female waist greater than 80 cm. In accordance with the official criteria of metabolic syndrome mentioned above, women taking antihypertensive drugs were considered to have hypertension, and women taking insulin were considered to have insulin resistance.
Secondary outcome measures included the single features of metabolic syndrome, including blood pressure, BMI, (micro)albuminuria, proteinuria, glucose, insulin, homeostasis model assessment, triglycerides, and high-density lipoprotein.
Sample size was calculated for the primary outcome, metabolic syndrome, using a power formula with an alpha level of 0.05 and a power of 90%. The expected incidence of metabolic syndrome after late-onset vascular-complicated pregnancy was approximately 12.5%. Allowing detection of a change in the primary outcome from 12.5% in the late-onset group to 20% in the early-onset group, the total number of women needed using this calculation was 822.
Statistical analysis was performed using SPSS 16.0 (SPSS Inc, Chicago, IL). Outcome measures are presented as odds ratios and 95% confidence intervals (CIs) to quantify the risk of women in the early-onset group in comparison with the risk of women in the late-onset group. We performed multivariable logistic regression to calculate adjusted odds ratios. Adjustments were made for maternal age, smoking, alcohol intake, coffee use, birth weight centile, stillbirth, and interval between delivery and measurements. The multivariable model was constructed starting with all potential confounders included, followed by sequentially removing all variables with insignificant probability. Data distribution was evaluated using histograms and quantile-quantile plots. Continuous data were tested for normality using the Kolmogorov-Smirnov method and reported as either mean or standard deviation for normally distributed data or as median and interquartile range for skewed data. Comparisons between groups were performed using Student t test or Wilcoxon rank sum test, whichever appropriate. Proportions are presented as percentages and compared with the χ2 test. P<.05 was considered statistically significant.
A total of 876 eligible women was included in our study population. Awaiting evaluation, eight women conceived again, and one refrained from further participation. Information about the index pregnancy was incomplete in 18 cases. The remaining 849 women were included in the analysis and categorized into two groups: the early-onset group (delivery before 32 weeks, n=376) and the late-onset group (delivery at or beyond 32 weeks, n=473). Baseline characteristics and clinical variables are listed in Table 1. Mean gestational age at delivery was 28.6±2.8 weeks in the early-onset group and 35.8±2.5 weeks in the late-onset group. The median interval between delivery and measurements was 36 weeks in the early-onset group and 52 weeks in the late-onset group. As compared with the late-onset group, the early-onset group was younger, smoked more often, consumed more coffee but used fewer alcohol-containing beverages, had a four-times-higher rate of stillbirth, and had a lower mean birth weight centile. All participants had at least one vascular complication in the preceding pregnancy, with preeclampsia being the most common. The distribution of participants among the three participating hospitals was similar in the groups. The mean gestational age at delivery was 32.9±5.0, 32.5±4.3, and 32.9±4.2 weeks in the three participating hospitals.
Table 2 lists the intergroup comparison of each of the individual factors contributing to the metabolic syndrome. Data showed differences for almost all variables. Women in the early-onset group differed from the late-onset group by a higher BMI, fasting blood glucose, insulin, hemoglobin A1c, homeostasis model assessment, triglycerides, (micro)albuminuria, and blood pressure and by lower high-density lipoprotein levels. The 24-hour urinary protein output was comparable in the two groups.
Table 3 lists the prevalence of the metabolic syndrome in both groups, presented as percentages, (un)adjusted odds ratios, and 95% CIs. In this study, the overall prevalence of metabolic syndrome in the total study population was 17%, 19%, 10% and 13%, according to the criteria of the WHO, International Diabetes Federation, Third Adult Treatment Panel and Third Adult Treatment Panel updated, respectively. The prevalence of metabolic syndrome in the early-onset group was significantly higher than in the late-onset group. The odds ratio differed for each definition used, but was consistently higher in the early-onset group irrespective the definitions used, also after adjustment for maternal age, smoking, alcohol, coffee use, birth weight centile, stillbirth, and interval between delivery and measurements.
The rates of the individual characteristics contributing to the metabolic syndrome are presented in Table 4, including the (un)adjusted odds ratios with 95% CIs. All single features were different between the two groups, except for fasting blood glucose greater than 6.1 mmol/L.
The odds ratios of metabolic syndrome as a function of gestational age at delivery are presented in Figure 1, with the risk at term defined as reference value. In this comparison, consistently higher odds of having metabolic syndrome were shown in all gestational age groups before 32 weeks compared with the groups of women who delivered at or beyond 32 weeks.
In this study, we observed a twofold higher prevalence of the metabolic syndrome in women after vascular-complicated pregnancy when they delivered before 32 weeks of gestation as compared with at or beyond 32 weeks. This difference was independent of criteria used to define the metabolic syndrome and persisted after correction for confounders.
Several studies provided evidence for preeclampsia to develop in concert with an enhanced form of the metabolic syndrome.20,21 Others reported postpartum persistence, not only of preeclampsia-related abnormalities, such as endothelial dysfunction, but also of metabolic syndrome–related abnormalities, such as insulin resistance and dyslipidemia.22,23
There is increasing evidence for a different pathogenesis of early-onset and late-onset preeclampsia.10,11 Particularly, women with a history of early-onset preeclampsia have an elevated risk of developing cardiovascular morbidity at middle age.14,24–26 A large follow-up study provided evidence of an increased risk of dying because of cardiovascular disease after early-onset and a lower risk after late-onset preeclampsia (hazard ratio 8.12 [95% CI 4.31–15.33] and 1.65 [95% CI 1.01–2.07], respectively).14 This raises the question whether this effect is secondary to the “acquired” metabolic syndrome during pregnancy in these women or to an “inherited” accelerated aging of the cardiovascular system. In addition, Clausen et al27 found that dyslipidemia before 20 weeks of pregnancy is related to early-onset preeclampsia. Furthermore, Lampinen et al28 reported that severity and gestational age at onset of the preeclampsia were related to later insulin sensitivity. The authors reported that, in formerly preeclamptic women, increased central obesity with unfavorable lipid profile only predisposed to lower insulin sensitivity at middle age after severe early-onset preeclampsia. These data not only support the view of a preexistent metabolic syndrome in pregnancy expediting onset of a vascular related complication in pregnancy, but they also suggest that the early-onset form of the disease in a woman with the metabolic syndrome might be related to increased risk of developing cardiovascular morbidity in middle age.
In this study, we obtained the information on the metabolic syndrome at least 6 months postpartum. Therefore, the metabolic syndrome could have been preexistent or could have developed during the complicated pregnancy. Because obesity, dyslipidemia, insulin resistance, and hypertension before or early in pregnancy all predispose to hypertensive disorders in pregnancy,29,30 it is likely that in most cases the metabolic syndrome was preexistent with possible enhancement by the pregnancy.
In our study, we used four different internationally accepted definitions of the metabolic syndrome.3,17–19 The odds of finding the metabolic syndrome was highest using the WHO definition, which is the only one requiring insulin resistance for the diagnosis. In earlier studies, increased insulin resistance was found to be an important component of the metabolic changes in former preeclamptic women.7,31,32
Although this study enabled the analysis of a large dataset allowing correction for confounders without significant loss of statistical power, some limitations need to be addressed. First, overrepresentation of women with a more severe vascular complicated disorder in the postpartum screening might have introduced selection bias. Second, the observational nature of this study increases the risk for confounding. To overcome this problem, we tried to identify potential confounders and calculated adjusted odds ratios in a multivariable model. Nonetheless, for some associated factors, such as family predisposition to preeclampsia, personal nutritional habits, and socioeconomic status, we could not correct as this information was lacking in our data set. Third, and most important, our measurements were performed only postpartum, which implies that we do not have information about whether or not the metabolic syndrome was preexistent. Therefore, our findings do not provide direct evidence for a causal relationship between the metabolic syndrome and early-onset vascular disorder–complicated pregnancy.
Treatment and prevention of cardiovascular disease is a major health goal. One of the problems in the prevention of cardiovascular diseases has been the difficulty of identifying individuals at risk at an early-enough stage for them to benefit from intervention, such as modification of their lifestyle. In our study, we concluded that young women with a recent history of early-onset gestational vascular disorder are at increased risk for metabolic syndrome postpartum. Therefore, this particular cohort of young women could be included in early prevention and treatment programs, such as lifestyle modifications, additional medical check-ups, and antihypertensive and cholesterol-lowering therapy, to prevent cardiovascular complications at middle age.
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