Objective
The purpose of this study was to determine cardiovascular risk factors in women with a history of hypertensive pregnancy disorders at term (HTP) 2.5 years after pregnancy.
Study Design
In a multicenter cohort study in The Netherlands from June 2008 through November 2010, cardiovascular risk factors were compared between women with a history of HTP (HTP cohort, n = 306) and women with a history of normotensive pregnancies at term (NTP cohort, n = 99). HTP women had participated in a randomized, longitudinal trial assessing the effectiveness of induction of labor in women with hypertensive pregnancy disorders at term. All women were assessed 2.5 years after pregnancy for blood pressure, anthropometrics, glucose, glycosylated hemoglobin, insulin, homeostatic model assessment score, total cholesterol, high-density lipoprotein cholesterol, triglycerides, high-sensitivity C-reactive protein, and microalbumin and metabolic syndrome.
Results
After a mean follow-up period of 2.5 years, hypertension (HTP, 34%; NTP, 1%; P < .001) and metabolic syndrome (HTP, 25%; NTP, 5%; P < .001) were more prevalent in HTP women compared with NTP women. HTP women had significantly higher systolic and diastolic blood pressure, higher body mass index, and higher waist circumference. Glucose, glycosylated hemoglobin, insulin, homeostatic model assessment score, total cholesterol, triglycerides, and high-sensitivity C-reactive protein levels were significantly higher and high-density lipoprotein cholesterol was significantly lower in HTP women.
Conclusion
In women with a history of HTP, hypertension and metabolic syndrome are more common, and they have higher levels of biochemical cardiovascular risk factors 2.5 years after pregnancy.
Cardiovascular disease (CVD) is the leading cause of death in women in the Western world. Heart disease symptoms in women are different from symptoms in men and diagnostic tools in women seem to be less sensitive and specific than for men.
Hypertensive disorders are common complications of pregnancy. Observational studies have shown a relation between hypertensive disorders in pregnancy and CVD morbidity and mortality later in life. This suggests that hypertensive disorders in pregnancy share common risk factors and pathophysiological pathways. The exact underlying link between hypertensive pregnancy disorders and future CVD remains unclear. It has been suggested that pregnancy can potentially be looked upon as a “stress test,” unmasking underlying defects, thus identifying women at a young age at increased risk for cardiovascular events. Determining cardiovascular risk factors in women who respond to this stress test with transient hypertension could be an opportunity for identifying high-risk women for early prevention of modifiable cardiovascular risk factors. Until now, most studies have focused on severe preterm preeclampsia, which is a rare disease. Most hypertensive disorders develop > 36 weeks’ gestation. Therefore, we conducted a follow-up study of a randomized controlled trial in The Netherlands to assess cardiovascular risk factors in women with a history of hypertensive pregnancy disorders at term (HTP) 2.5 years after their complicated pregnancy.
Materials and Methods
Ethics statement
The follow-up study was approved by the institutional review board of the University of Leiden and locally approved by the hospital board of the participating hospitals. The study protocol has previously been published. The current study is a follow-up of the Hypertension and Preeclampsia Intervention Trial at Term (HYPITAT) study (trial registration: ISRCTN08132825).
Participants
Hypertension in pregnancy cohort
From October 2005 through March 2008, the HYPITAT study, a multicenter, parallel, open-label randomized controlled trial of induction of labor vs expectant management, included women with gestational hypertension or preeclampsia at term (n = 1153). At baseline (randomization), these women consented to be contacted 2.5 years after their delivery to participate in the follow-up study.
The HYPITAT study
The HYPITAT study evaluated whether induction of labor improved maternal outcome in women with gestational hypertension or preeclampsia at term and included women with a singleton pregnancy at a gestational age between 36 +0 and 41 +0 weeks. The diastolic blood pressure thresholds for inclusion in the HYPITAT study differed between gestational hypertension and preeclampsia as diastolic blood pressure of 90 mm Hg without proteinuria was discussed and considered too mild and trivial for inclusion in the HYPITAT trial. Therefore, gestational hypertension was defined as a diastolic blood pressure of ≥95 mm Hg measured on 2 occasions at least 6 hours apart without proteinuria. Preeclampsia was defined as diastolic blood pressure of ≥90 mm Hg measured on 2 occasions at least 6 hours apart, combined with proteinuria (≥2 occurrences of protein on a dipstick, >300 mg total protein within a 24-hour urine collection, or ratio of protein to creatinine >30 mg/mmol).
Other exclusion criteria included: antihypertensive medication use for chronic hypertension, diabetes mellitus, gestational diabetes treated with insulin, renal disease, heart disease, previous cesarean section, HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets), oliguria of <500 mL per 24 hours, pulmonary edema or cyanosis, human immunodeficiency virus, use of intravenous antihypertensive medication, fetal anomalies, intrauterine growth restriction, and abnormal fetal-heart rate monitoring.
In the HYPITAT study, which was analyzed according to intention to treat, women allocated to expectant monitoring were induced if they developed severe preeclampsia. Patients who refused randomization were analyzed separately after informed consent as nonrandomized patients.
The follow-up study
From June 2008 through November 2010, women who had participated in the HYPITAT study were invited to participate in a longitudinal, follow-up study assessing cardiovascular risk factors 2.5 years after pregnancy. We used a follow-up period of 2.5 years as this time interval allows using pregnancy as a stress test to identify young women who are at high risk for CVD in later life. Furthermore, 2.5 years is long enough to ensure that pregnancy and lactation have no influence on biochemical cardiovascular risk factor levels. Three academic hospitals and 17 nonacademic hospitals across 4 geographical regions in The Netherlands (Leiden, Groningen, Amsterdam, Brabant) participated.
Normotensive pregnancy cohort
The normotensive pregnancies at term (NTP) women were either friends of the HTP women or women from midwifery practices. NTP women were required to have had only uncomplicated normotensive pregnancies. Exclusion criteria for the NTP cohort included HELLP syndrome, gestational hypertension, preeclampsia, preexisting hypertension, (gestational) diabetes, premature delivery, delivery of a neonate with intrauterine growth restriction (<5th percentile), renal disease, heart disease, and human immunodeficiency virus. Initially, we asked HTP women if they had a friend who had given birth in the same period as the HTP woman and who could function as NTP woman. We assumed that friends would be similar in terms of age, demographic region, and ethnic origin. If an HTP woman did not have a friend who could function as NTP woman, we searched for a NTP woman in a midwifery practice of the same demographic region and matched for elapsed time since delivery. It is common practice in The Netherlands for women with no medical history or obstetrical history to have their antenatal care provided by a midwife. Data were collected from their medical records in midwifery practices. We collected and reviewed the NTP women’s blood pressure measurements and their maternal and fetal outcomes of index and previous pregnancies and deliveries in thorough detail. Relatives of the HTP women were excluded from the NTP cohort. Furthermore, women who were pregnant or lactating within the last 3 months were excluded from our study (n = 101).
Follow-up study procedure and cardiovascular risk factor assessment
The study protocol has been previously published. We refer to the Appendix for a detailed description of the risk factor assessment methods and the laboratory methods.
In short, local research nurses counseled the participants, obtained written informed consent, monitored the study protocol in each center, and collected the data. After enrollment all participants were invited for cardiovascular risk factor assessment, including blood pressure measurement, weight, height, and hip and waist circumference. Furthermore, all participants were asked to complete a questionnaire. This questionnaire included: medical history, current use of medication, obstetric history, subsequent pregnancy after index pregnancy, and family history, including CVD.
Venous blood samples were collected after an overnight fast and assayed for: glucose, glycosylated hemoglobin (HbA 1c ), insulin, total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, and high-sensitivity C-reactive protein (hs-CRP). Insulin resistance was assessed by the homeostatic model assessment (HOMA): insulin concentration/(22.5 e–ln glucose concentration ). Urine was collected immediately after waking up for assessment of microalbuminuria. After immediately centrifuging, the blood and urine samples were sent to a central laboratory (Medical Center Haaglanden, The Hague, The Netherlands) and were analyzed within 36 hours after blood draw.
Definitions
Hypertension 2.5 years’ postpartum was defined as systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or current use of antihypertensive medication. Major independent risk factors were defined according to the American Heart Association, including blood pressure ≥140/90 mm Hg, HDL cholesterol <40 mg/dL, current smoking, and a family history of early CVD. Metabolic syndrome was defined as waist circumference ≥80 cm plus any 2 of: raised triglycerides (>150 mg/dL), reduced HDL cholesterol (<50 mg/dL), raised blood pressure (systolic ≥130 mm Hg and diastolic ≥85 mm Hg), treatment of previously diagnosed hypertension, raised fasting plasma glucose (≥100 mg/dL), or previously diagnosed type 2 diabetes.
Sample size considerations
Our power analysis was based on individual risk estimation from the Framingham Heart Study, rather than on cardiovascular risk factors alone. Due to the young age of our participants, the estimated absolute 10-year cardiovascular risk was likely to be low. Therefore, our approach was to estimate the risk for each woman as if the woman was 60 years old. This approach has been recommended in the cardiovascular risk factor management guidelines for young women with elevated risk factor levels.
For detecting an estimated absolute 10-year cardiovascular risk difference between the HTP and NTP cohorts of 10% increase after extrapolation, we needed a sample size of 456 women for 80% power and a 5% type 1 error probability (2-sided) for inclusion in 3:1 ratio (3 HTP: 1 NTP). This method was used according to an earlier study performed in severe early preeclampsia. According to earlier studies we expected a homogeneous effect with low prevalence of unfavorable cardiovascular risk factors in NTP women. Therefore, we used a 3:1 inclusion ratio instead of 1:1 as we assumed that including more NTP women in 1:1 ratio would have no additional value in this study as a result of homogeneous outcome of cardiovascular risks.
Statistical analysis
Data were analyzed using software (SPSS, version 18.0; IBM Corp, Armonk, NY). Baseline continuous data are expressed as means and SD or as medians with 25th–75th percentile (interquartile range) for the not normally distributed values; dichotomous data are presented as numbers and percentages. Differences between groups were tested with the Student t test and categorical data with χ 2 test. Comparisons of continuous data with a skewed distribution were performed using the nonparametric Mann-Whitney U test. We used logistic regression analyses and results were reported as odds ratios (ORs) with corresponding 95% confidence intervals (CIs). We made adjustments for potential confounders, where appropriate, ie, parity, body mass index (BMI), smoking, and age at follow-up; and BMI, systolic and diastolic blood pressure, and parity at booking. Furthermore, we performed a multicenter analysis that resulted in an intraclass correlation coefficient of 2-4%. Therefore, we did not use a multilevel model for our analyses. For all tests, a P value < .05 indicated statistical significance.
Results
From June 2008 through November 2010, 306 women with a history of gestational hypertension or preeclampsia at term and 99 women with a history of uncomplicated normotensive pregnancies at term were included in the follow-up study.
Of the 751 eligible HTP women for the 2.5-year follow-up study, 168 women refused participation, 175 women were lost to follow-up, and 101 pregnant or lactating women were excluded. One woman died in a car accident. The NTP cohort consisted of 40 women who were friends of the HTP women and 59 women who were identified from midwifery practices.
Baseline characteristics of the subjects are shown in Table 1 . At index pregnancy, HTP women were more often nulliparous and had higher BMI at booking, higher systolic and diastolic blood pressures at booking, lower gestational age at delivery, and lower birthweight compared with NTP women.
| Characteristic | NTP cohort (n = 99) | HTP cohort (n = 306) | P value |
|---|---|---|---|
| Maternal age, y | 31 (4.5) | 31 (5.1) | .70 |
| Ethnic origin | |||
| Caucasian | 94 (95%) | 273 (89%) | .15 |
| Other | 5 (5%) | 30 (10%) | |
| Unknown | 0 (0%) | 3 (1%) | |
| Nulliparous | 30 (30%) | 211 (69%) | < .001 |
| Systolic blood pressure at booking, mm Hg | 113 (11) | 120 (12) | < .001 |
| Diastolic blood pressure at booking, mm Hg | 66 (7.6) | 73 (9.0) | < .001 |
| Body mass index at booking, kg/m 2 | 24 (4.2) | 26 (4.9) | < .001 |
| Gestational age at delivery, wk | 39.9 (1.2) | 39.4 (1.3) | < .001 |
| Birthweight, g | 3630 (465) | 3395 (519) | < .001 |
At the 2.5-year follow-up study, HTP women were found to use more antihypertensive medication and had higher BMI, higher systolic and diastolic blood pressures, and higher waist circumferences compared with NTP women. There were no significant differences in maternal age, elapsed time since delivery, or smoking rates ( Table 2 ).
| Characteristic | NTP cohort (n = 99) | HTP cohort (n = 306) | P value |
|---|---|---|---|
| Maternal age at follow-up, y | 34 (4.7) | 34 (5.2) | .67 |
| Time elapsed since delivery, d | 965 (387) | 921 (161) | .11 |
| Primiparous | 30 (30%) | 123 (40%) | .04 |
| Antihypertensive medication use | 0 (0%) | 29 (9%) | < .001 |
| Systolic blood pressure at follow-up, mm Hg | 110 (9.3) | 124 (13) | < .001 |
| Diastolic blood pressure at follow-up, mm Hg | 72 (8.8) | 82 (9.6) | < .001 |
| Body mass index at follow-up, kg/m 2 | 24 (4.6) | 28 (5.5) | < .001 |
| Waist circumference, cm | 81 (12) | 90 (13) | < .001 |
| Hip circumference, cm | 104 (11) | 109 (12) | < .001 |
| Smoking | 19 (19%) | 60 (20%) | .89 |
Table 3 shows biochemical cardiovascular risk factors 2.5 years after index pregnancy in HTP and NTP women. Fasting blood glucose, HbA 1c , insulin, HOMA scores, total cholesterol, triglycerides, and hs-CRP were all significantly higher in HTP compared with NTP women. HDL cholesterol was significantly lower in HTP women. We found higher microalbumin levels in urine in HTP women, however this difference was not significant ( P = .06).
| Biochemical cardiovascular risk factor | NTP cohort (n = 99) | HTP cohort (n = 306) | P value |
|---|---|---|---|
| Microalbumin urine, a mmol/L | 4.0 (3.0–8.0) | 5.0 (3.0–10.0) | .06 |
| Fasting blood glucose, b mg/dL | 85 (79–88) | 85 (81–92) | .01 |
| HbA 1c , c % | 5.3 (5.1–5.5) | 5.3 (5.1–5.6) | .04 |
| Insulin, d mU/L | 2.9 (2.0–5.0) | 4.4 (2.0–7.6) | .003 |
| HOMA score e | 0.6 (0.4–1.0) | 1.0 (0.4–1.6) | .001 |
| hs-CRP, f mg/L | 0.9 (0.4–2.2) | 2.2 (1.0–5.0) | < .001 |
| Total cholesterol, g mg/dL | 178 (151–197) | 182 (162–207) | .02 |
| HDL cholesterol, h mg/dL | 56 (50–63) | 54 (46–62) | .03 |
| Triglycerides, h mg/dL | 63 (48–91) | 81 (58–110) | < .001 |
a Missing data of 6 NTP women and 9 HTP women;
b Missing data of 11 NTP women and 15 HTP women. Majority of missing data was caused by fact that urine and blood samples were only processed within 36 h after sampling. Samples that arrived after this period were cancelled for analysis. Table shows median (interquartile range, 25th–75th percentile). Differences were tested with nonparametric Mann-Whitney U test. HTP women;
c Missing data of 6 NTP women and 14 HTP women;
d Missing data of 9 NTP women and 24 HTP women;
e Missing data of 11 NTP women and 25 HTP women;
f Missing data of 7 NTP women and 10 HTP women;
g Missing data of 5 NTP women and 5 HTP women;
The prevalence of 4 major cardiovascular risk factors, multiple major cardiovascular risk factors, and metabolic syndrome in HTP and NTP women are summarized in Table 4 . The adjusted OR of HTP women for hypertension 2.5 years’ postpartum was 48. On the contrary, there were no significant differences between HTP and NTP women in the other 3 major independent risk factors: HDL cholesterol, currently smoking, or family history of early CVD. Multiple risk factors were present in 18% of the HTP women compared with 7% of NTP women ( P = .01), including 4% of HTP women with ≥3 independent risk factors compared to 0% in NTP women. Metabolic syndrome was found in 25% of HTP and in 5% of NTP women (OR, 6.0; 95% CI, 2.3–15.3) even after adjustment for maternal age and baseline differences.
| Independent CVD risk factor and metabolic syndrome | NTP cohort (n = 99) | HTP cohort (n = 306) | Unadjusted OR (95% CI) | Adjusted OR a (95% CI) | Adjusted OR b (95% CI) | P value |
|---|---|---|---|---|---|---|
| Blood pressure, c ≥140/90 mm Hg | 1 (1%) | 105 (34%) | 51.5 (7.1–374) | 47.5 d (6.5–350) | 36.4 (4.8–276) | < .001 |
| HDL cholesterol, e <40 mg/dL | 10 (11%) | 37 (12%) | 1.2 (0.6–2.5) | 0.8 d (0.3–1.8) | 1.1 (0.4–2.8) | .53 |
| Current smoking, f % | 19 (19%) | 60 (21%) | 1.1 (0.6–1.9) | 1.01 g (0.6–1.1) | 1.1 (0.5–2.1) | .98 |
| Family history of early CVD, h % | 11 (11%) | 48 (16%) | 1.6 (0.8–3.1) | 1.7 g (0.8–3.5) | 2.0 (0.9–4.2) | .15 |
| ≥1 independent risk factor e | 32 (34%) | 184 (61%) | 3.0 (1.9–4.9) | 3.2 (1.9–5.3) | 2.7 (1.5–4.9) | < .001 |
| ≥2 independent risk factors e | 7 (7%) | 54 (18%) | 2.7 (1.2–6.2) | 3.1 i (1.3–7.5) | 3.0 (1.0–9.0) | .01 |
| Metabolic syndrome j | 5 (5%) | 73 (25%) | 6.0 (2.3–15) | 5.9 k (2.3–15) | 3.3 (1.2–9.1) | < .001 |
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