Objective
Hyperhomocysteinemia is associated with an elevated cardiovascular disease risk. We examined whether women with a history of hypertension in pregnancy are more likely to have a high level of serum homocysteine decades after pregnancy.
Study Design
Serum homocysteine was measured at a mean age of 60 years in nulliparous women (n = 216), and women with a history of normotensive (n = 1825) or hypertensive (n = 401) pregnancies who participated in the Genetic Epidemiology Network of Arteriopathy (GENOA) study. Relationships between homocysteine and pregnancy history were examined by linear and logistic regression, controlling for multiple covariates including personal and family history of hypertension, diabetes, obesity, tobacco use, and demographics.
Results
A history of hypertension in pregnancy, when compared with normotensive pregnancy, was associated with a 4.5% higher serum homocysteine level ( P = .015) and 1.60-fold increased odds of having an elevated homocysteine (95% confidence interval, 1.15–2.21; P = .005) after adjusting for potentially confounding covariates. In contrast, a history of normotensive pregnancy, as compared with nulliparity, was associated with a 6.1% lower serum homocysteine level ( P = .005) and a 0.49-fold reduced odds of elevated homocysteine levels (95% confidence interval, 0.32–0.74; P < .001).
Conclusion
Homocysteine levels decades after pregnancy are higher in women with a history of pregnancy hypertension, even after controlling for potential confounders. Thus, pregnancy history may prompt homocysteine assessment and risk modification in an attempt at primary prevention of cardiovascular disease.
Hypertension in pregnancy increasingly is recognized as a predictor of future cardiovascular disease (CVD). A spectrum of hypertensive disorders can be seen in pregnancy including gestational hypertension, preeclampsia, eclampsia, and HELLP syndrome (with clinical features of hemolysis, elevated liver enzymes, and low platelet count), either de novo or superimposed on preexisting chronic hypertension. The signs and symptoms of multisystem organ dysfunction associated with preeclampsia usually abate soon after delivery. However, both retrospective and prospective studies have shown that a history of a hypertensive disorder in pregnancy predicts an increased risk for future cardiovascular morbidity, including hypertension, cardiac disease, and cerebrovascular events. The increased risk for CVD persists even after controlling for traditional risk factors, including hypertension and family history. Clearly, there are mediators that link hypertensive disorders in pregnancy and future CVD risk. Biomarkers, such as homocysteine, may play a role.
Homocysteine is a metabolite of the essential amino acid, methionine. Blood homocysteine levels are influenced by a variety of nutritional factors, including folate and cobalamin intake, and genetic polymorphisms, such as the 677 C → T change in the MTHFR gene. Several studies have demonstrated that serum homocysteine levels are elevated in preeclampsia at the time of symptoms compared to gestational age–matched normotensive pregnancies, but these elevations do not appear to predate the disease. High levels of serum homocysteine are associated with oxidative stress and endothelial dysfunction, biological processes common to both preeclampsia and CVD. Therefore, high homocysteine levels that persist after preeclamptic pregnancies may be mechanistically related to an increased CVD risk in these women.
To date, limited data are available regarding homocysteine level trends after preeclamptic pregnancies. Sep et al showed that 21% of 40 women with preeclampsia had persistent elevations in homocysteine >15 mmol/L at 6-10 months’ postpartum. Girouard et al found homocysteine to be increased as much as 8 years’ postpartum, although neither of these studies adjusted for known confounders.
The aim of this study was to determine if a history of hypertension in pregnancy is an independent risk factor for hyperhomocysteinemia later in life. We postulate that a high level of plasma homocysteine may serve as a biomarker for an increased risk of CVD and cerebrovascular disease among women with a history of hypertensive pregnancy disorders, years after their affected pregnancies.
Materials And Methods
Participants
The participants were obtained from the Genetic Epidemiology Network of Arteriopathy (GENOA) study, which was part of the Family Blood Pressure Program established in 1995 to investigate the genetics of hypertension across multiple ethnicities. The GENOA study included recruitment sites in Jackson, MI; Starr County, Texas; and Rochester, MN; representing African Americans, Hispanics, and non-Hispanic whites, respectively. The specific recruitment strategy to identify sibships with multiple hypertensive siblings at each site has been described previously. The present study included 2442 women who participated in the second GENOA study examination (2000 through 2004), which included a questionnaire regarding pregnancy and hypertension in pregnancy (as described below).
All individuals gave informed consent and institutional review board–approved protocols were used. At the second GENOA examination (2000 through 2004), data regarding personal and family medical history, medication use, menopausal status, pregnancy, and hypertension history were gathered using validated questionnaires administered by trained examiners.
Determination of exposure
A validated questionnaire was used to determine history of nulliparity, normotensive pregnancy, or hypertensive pregnancy. Female participants were asked, “Have you had at least 1 pregnancy that lasted >6 months?” Women who answered “yes” were asked to report the number of pregnancies and to answer whether or not they had developed hypertension during any of their pregnancies that had lasted >6 months. Preeclampsia was defined either by self-report or by self-report of proteinuria during the pregnancy with hypertension. This questionnaire was previously shown to be 80% sensitive and 96% specific to assess hypertension in pregnancy.
Determination of confounders
Demographics and covariates were assessed by structured interviews and the information obtained included age at assessment, education level, race, and family history. Standardized physical examinations were performed and the body mass index (BMI) was calculated as weight/height in kg/m 2 .
Hypertension was defined in 1 of 2 ways: a history of such and concurrent use of an antihypertensive, or a blood pressure measurement of 140 mm Hg systolic and/or at least 90 mm Hg diastolic. Diabetes mellitus was self-reported.
Smoking was coded as “ever” if >100 cigarettes had been used in the past. The diagnosis of dyslipidemia was confirmed if ≥1 of the following criteria were met: (a) the use of lipid-lowering drugs; or (b) total cholesterol of ≥200 mg/dL, triglycerides of ≥150 mg/dL, or a high-density lipoprotein of ≤40 mg/dL, collected at the time of the phase II examination.
Laboratory methods
Blood work was drawn by venipuncture in the fasting state. Serum homocysteine was measured by the Mayo Clinic high-performance liquid chromatography method and an elevated homocysteine level was defined as >13 μmol/L. Serum total cholesterol, high-density lipoprotein cholesterol, and triglyceride concentrations were measured by standard methods on a Hitachi 911 Chemistry Analyzer (Roche Diagnostics, Indianapolis, IN).
Statistical analysis
Women were grouped as nulliparous (no pregnancy lasting >6 months), having a history of a normotensive pregnancy (normotensive in all pregnancies >6 months), and having a history of a hypertensive pregnancy (hypertensive in at least 1 pregnancy >6 months). Means ± SD and counts (percentages) are summarized within the pregnancy group. Pairwise differences in age among the 3 groups were assessed with 2-sample t tests and pairwise differences in race and education among the 3 groups were assessed with χ tests. Due to significant differences in age, race, and education among the pregnancy groups, pairwise differences in all other variables among the pregnancy groups were adjusted for age, race, and education using logistic regression for binary variables or linear regression for continuous variables. No adjustment was made for multiple comparisons.
Linear regression was used for predicting continuous homocysteine levels and logistic regression was used for predicting homocysteine levels >13 μmol/L. Associations between the levels of homocysteine and pregnancy groups were assessed using 3 separate models: 1 with no adjustment for covariates; 1 adjusting for age, race, and education; and a full model adjusting for age, race, education, smoking, hypertension, diabetes, BMI, dyslipidemia, statin use, hormone replacement therapy use, family history of hypertension, and family history of coronary heart disease. For the linear regression models, a log transformation was used for homocysteine levels due to a skewed distribution. The adjusted mean ± SD homocysteine and adjusted percentage with homocysteine >13 μmol/L are shown within pregnancy groups for all models. All linear and logistic models were fit with generalized estimating equations to account for relationships among siblings.
Results
There were 2442 women in the GENOA cohort available for analysis. There were a total of 1273 families among the 2442 subjects in the study. The median number of siblings in a family was 2 (minimum 1, maximum 8). The demographic characteristics of the cohort are shown in Table 1 . In all, 216 (9%) were nulliparous, 1825 (75%) had histories of normotensive pregnancies, and 401 (16%) had histories of hypertensive pregnancies.
| Variable | Nulliparous (n = 216) | Normotensive pregnancy (n = 1825) | Hypertensive pregnancy (n = 401) |
|---|---|---|---|
| Race, n (%) | |||
| Hispanic | 69 (32) | 543 (30) | 112 (28) |
| Non-Hispanic white | 83 (38) | 508 (28) | 112 (28) |
| Non-Hispanic black | 64 (30) | 774 (42) | 177 (44) |
| Significance | a | a | |
| Age, y | 57 ± 13 | 61 ± 10 a | 57 ± 11 b |
| BMI, kg/m 2 | 33 ± 8 | 32 ± 7 | 34 ± 7 a,b |
| Education, n (%) | |||
| <High school (≤8 y) | 39 (18) | 456 (25) | 85 (21) |
| Some high school (9-11 y) | 14 (6) | 208 (11) | 61 (15) |
| High school graduate or GED (12 y) | 51 (24) | 543 (30) | 116 (29) |
| >High school (>12 y) | 112 (52) | 618 (34) | 139 (35) |
| Significance | a | a | |
| Ever smoked, n (%) | 69 (32) | 574 (31) | 106 (26) a,b |
| Diabetes, n (%) | 63 (29) | 592 (32) | 152 (38) a,b |
| Hypertension, n (%) | 152 (70) | 1245 (68) a | 329 (82) a,b |
| Dyslipidemia, n (%) | 176 (81) | 1414 (78) | 297 (74) |
| Statins, n (%) | 40 (19) | 402 (22) | 92 (23) |
| Family history of hypertension, n (%) | 162 (75) | 1291 (71) | 331 (83) b |
| Family history of coronary heart disease, n (%) | 108 (50) | 786 (43) | 210 (52) b |
| Hormone replacement therapy, n (%) | 56 (26) | 452 (25) | 91 (23) |
a Significant difference from nulliparous, P < .05
b Significant difference from normotensive pregnancy, P < .05.
Women were 60 ± 11 (mean ± SD) years of age across the entire cohort, with women with a history of hypertension in pregnancy being younger than those with a normotensive pregnancy. Women with previous hypertensive pregnancies were also more likely to have hypertension and diabetes, less likely to have ever smoked, and had higher BMIs than women in the other 2 groups. Compared to women with previous normotensive pregnancies, women with previous hypertensive pregnancies were more likely to have a family history of hypertension or coronary heart disease. The dyslipidemia rates and the percentage of women taking statins or hormone replacement therapy were not significantly different among the 3 groups. Nulliparous women were significantly more likely to be white and have higher levels of education than women in the other 2 groups, and were significantly younger and were more likely to have hypertension than women with previous normotensive pregnancies ( Table 1 ).
There were no differences in fasting serum homocysteine between women with a history of hypertensive disorders in pregnancy and those who were nulliparous. Women with a history of normotensive pregnancy had the lowest values. This relationship persisted after adjustments for basic demographic factors of age, race, and education, as well as other potential covariates. Results were similar for the categorical variable of elevated homocysteine ( Table 2 ).
| Parameter | Model | Nulliparous | Normotensive pregnancy | HTN pregnancy | P value overall | P value normal vs null | P value HTN vs null | P value HTN vs normal |
|---|---|---|---|---|---|---|---|---|
| Log(homocysteine) | Unadjusted | 2.24 ± 0.37 | 2.21 ± 0.32 | 2.24 ± 0.36 | .11 | .15 | .88 | .09 |
| Log(homocysteine) | Age, race, education adjusted | 2.26 ± 0.34 | 2.19 ± 0.30 | 2.25 ± 0.33 | < .001 | .002 | .69 | < .001 |
| Log(homocysteine) | Full | 2.26 ± 0.33 | 2.19 ± 0.29 | 2.24 ± 0.33 | .002 | .005 | .47 | .015 |
| Homocysteine >13 μmol/L | Unadjusted | 16% | 11% | 15% | .012 | .018 | .74 | .011 |
| Homocysteine >13 μmol/L | Age, race, education adjusted | 19% | 11% | 17% | < .001 | < .001 | .64 | < .001 |
| Homocysteine >13 μmol/L | Full | 18% | 11% | 15% | < .001 | < .001 | .34 | .005 |
The multivariable linear regression model that predicts the impacts of pregnancy history and each of the clinical characteristics on serum homocysteine and the multivariable logistic regression model predicting the odds ratio for having elevated homocysteine are detailed in Tables 3 and 4 .
| Parameter | Beta coefficient | % difference | P value |
|---|---|---|---|
| Normotensive pregnancy (vs nulliparous) | –0.0633 | –6.1 | .005 |
| Hypertensive pregnancy (vs normotensive) | 0.0435 | 4.5 | .015 |
| Race | .001 | ||
| Non-Hispanic, white | ref | ||
| Hispanic | –0.0876 | –8.4 | < .001 |
| Non-Hispanic, black | –0.0293 | –2.9 | .07 |
| Age, per 10 y | 0.1022 | 10.8 | < .001 |
| Education level | .032 | ||
| High school graduate or GED (12 y) | ref | ||
| <High school education (≤8 y) | 0.0515 | 5.3 | .017 |
| Partial high school education (9-11 y) | 0.0651 | 6.7 | .011 |
| >High school education (>12 y) | 0.0164 | 1.7 | .22 |
| Ever smoked | 0.0454 | 4.6 | < .001 |
| Current hypertension | 0.0727 | 7.5 | < .001 |
| Diabetes | 0.0352 | 3.6 | .028 |
| Log (BMI) | 0.0520 | 5.3 | .12 |
| Dyslipidemia | 0.0048 | 0.5 | .74 |
| Statins | –0.0116 | –1.2 | .49 |
| Hormone replacement therapy | –0.0704 | –6.8 | < .001 |
| Family history of hypertension | –0.0175 | –1.7 | .25 |
| Family history of coronary heart disease | 0.0153 | 1.5 | .29 |
| Intercept | 1.4255 | < .001 |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
