Preeclampsia is linked to hypertension and stroke in the adult offspring.1–4 Furthermore, there is a growing body of evidence that the cardiometabolic health of the offspring of pregnancies affected by preeclampsia is impaired as early as childhood. In a systematic review, Davis et al5 surmised that preeclampsia is consistently associated with higher blood pressure (BP) and body mass index (BMI, calculated as weight (kg)/[height (m)]2) as early as 4–10 years of age. Even gestational hypertension, in the absence of proteinuria, elevated liver enzymes, or thrombocytopenia, is associated with higher BP in young offspring.6,7
Several mechanisms may explain the association between pregnancy-associated hypertension and offspring BP. The potential mechanisms likely represent a complex interplay of several mechanisms including fetal programming, genetics, and shared environment. Barker et al8 hypothesized that shallow invasion of the spiral arteries leads to fetal malnutrition. Fetal programming may also involve a response to inflammation and endothelial dysfunction associated with preclampsia.9
The association between pregnancy-associated hypertension (gestational hypertension and preeclampsia) and cardiometabolic markers other than BP such as lipid profile and glucose metabolism is less clear.5 Therefore, the objective of this study was to evaluate whether pregnancy-associated hypertension was associated with the cardiometabolic health of the offspring at 5–10 years of age.
MATERIALS AND METHODS
From February 2012 through September 2013, we conducted a prospective observational follow-up study of the offspring of women who participated in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network mild gestational diabetes mellitus (GDM) treatment trial and observational study.10,11 The follow-up study was not planned at the time of the original study. Both the original study and the follow-up study were approved by the institutional review board of all participating centers. From October 2002 through mid-November 2007, pregnant women with and without mild GDM who consented were enrolled in the Maternal-Fetal Medicine Units Network's mild GDM study, the methods of which have been previously described.10
Pregnancy complications were collected as part of the original study.10 Pregnancy-associated hypertension included both gestational hypertension and preeclampsia. Gestational hypertension was defined as meeting either of the following criteria: 1) diastolic BP 90 mm Hg or greater or systolic BP 140 mm Hg or greater on two occasions at least 4 hours apart or 2) one elevated BP subsequently treated with antihypertensive medication. Preeclampsia was defined as elevation in BP as defined previously plus meeting any of the following criteria: 1) proteinuria (24-hour urine protein 300 mg or greater/24 hours or 24-hour urine not done and 2+ or greater on dipstick in absence of a urinary tract infection, or 24-hour urine not done and protein:creatinine ratio 0.35 or greater), 2) elevated liver enzyme serum levels (serum glutamic oxaloacetic transaminase 70 units/L or greater or lactic acid dehydrogenase 600 units/L or greater), or 3) thrombocytopenia (platelet count less than 100,000/mm3) in absence of any other known cause of elevated BPs, proteinuria, elevated enzymes, or decreased platelets. All suspected cases of pregnancy-associated hypertension were centrally reviewed and adjudicated during the original study by two protocol subcommittee physician members who were masked to the participants' group assignment. Preterm delivery was defined as delivery less than 37 0/7 weeks of gestation with gestational age confirmed by ultrasonography before enrollment. For the present analysis, children were categorized into one of four groups according to their in utero exposure to maternal pregnancy–associated hypertension and the timing of their delivery: 1) maternal pregnancy–associated hypertension and delivered preterm, 2) maternal pregnancy–associated hypertension and delivered at term, 3) normotensive pregnancy and delivered preterm, or 4) normotensive pregnancy and delivered at term (reference group).
After parental informed consent, and child assent when appropriate, children of the index pregnancy were enrolled 5–10 years after delivery.11 Eligibility for the follow-up study included enrollment in the original study at a center still participating in the Maternal-Fetal Medicine Units Network at the time of the follow-up study (12 of 16 centers; 92% of the participants from the original study). At follow-up, parents were queried about breastfeeding and their child's current diet, physical activity, and whether anyone in the household was receiving public assistance (food stamps, Medicaid benefits, or welfare). Parents also were asked whether their child showed any signs of pubertal changes using drawings and descriptions of the five Tanner stages,12 and their responses were coded as no (Tanner equals 1) or yes (Tanner greater than 1) for any signs of puberty.
The children had their height and weight measured using a hospital-grade scale and a stationary stadiometer, respectively, which were used to estimate child BMI. Waist circumference was measured just above the uppermost lateral border of the right ilium of the pelvis,13 and an average of three measurements was used in the analysis. Blood pressure was measured by auscultation using aneroid sphygmomanometer instruments or a hospital-grade BP or pulse machine, and an average of two measurements was used in the analysis.
After an 8-hour fast, the children had their blood drawn. Specimens were collected per a standardized approach and analyzed at the Northwest Lipid Metabolism and Diabetes Research Laboratories for lipid panel, glucose, and insulin. The glucose and insulin measurements were used to estimate homeostasis model assessment estimated insulin resistance, calculated as (fasting glucose [mmol/L]×fasting insulin [microunits/mL])/22.5.14 To minimize bias, research staff involved in data collection and laboratory analyses were masked to the participants' exposures during the original study.
Although several definitions of metabolic syndrome in children exist, there is no one standard, particularly in children younger than 10 years of age. Developmental and pubertal changes during childhood and adolescence, and differences between males and females, complicate the ability to establish appropriate cut points for cardiometabolic risk factors in children.15,16 Metabolic syndrome in children has generally included the following measures: BP, glucose, high-density lipoprotein cholesterol, triglycerides, and either waist circumference or BMI.15,17–19 We therefore evaluated each of these measures as well as homeostatic model assessment of insulin resistance, which is associated with other cardiometabolic risk factors and metabolic dysfunction in children.20,21
Baseline characteristics were compared between follow-up participants and nonparticipants using the χ2 test or Fisher exact test for categorical variables and the Wilcoxon rank-sum test for continuous variables. Descriptive analyses evaluating characteristics by exposure group used the χ2 test or Fisher exact test for categorical variables and the Kruskal-Wallis test for continuous variables. To describe shared health and lifestyle between the mother and child, we estimated the correlation (Spearman) between maternal and child BP, diet (vegetable consumption), and exercise (average exercise in the child and vigorous exercise in the mother). Continuous variables were assessed to evaluate whether they were normally distributed and log-transformed when appropriate.
The cardiometabolic outcomes were each evaluated as continuous outcomes using comparisons of least squares means based on multivariable linear regression models. Several variables were considered in the multivariable analysis, including maternal baseline characteristics during the index pregnancy (study group [mild GDM treated, mild GDM untreated, no GDM], self-reported race and ethnicity, BMI, and smoking). The child characteristics considered in the multivariable analysis included sex and age at follow-up. Child height at follow-up was considered for the BP models. For any statistically significant associations observed, we evaluated whether associations remained significant after further adjustment for the potentially mediating effect of either birth weight for gestational age or child BMI. Birth weight for gestational age was estimated per methods of Alexander et al22 (personal communication, G. Alexander, 2000) using neonatal gestational age at delivery, birth weight, and sex and maternal race and ethnicity to categorize newborns into three groups: small for gestational age (birth weight less than the 10th percentile for gestational age), appropriate for gestational age (birth weight 10th–90th percentile for gestational age; reference group), and large for gestational age (birth weight greater than the 90th percentile for gestational age). Multivariable models were developed for the cohort overall and to test for an interaction between pregnancy-associated hypertension and child sex and between pregnancy-associated hypertension and puberty status.
Our sample size was not large enough to evaluate gestational hypertension and preeclampsia separately in multivariable analysis; however, we conducted an unadjusted analysis to describe the cardiometabolic risk factors separately for gestational hypertension and preeclampsia.
A post hoc analysis was conducted to determine the frequency of hypertension by exposure group to aid in the clinical interpretation of the results. Hypertension was defined as either a systolic or diastolic value greater than the 95th percentile for gender, age, and height centile per the National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents.23 As a result of the small cell sizes, this analysis was descriptive only and did not include multivariable analysis.
SAS was used for the analyses. All tests were two-tailed and P<.05 was used to define statistical significance. No imputation for missing data was performed.
Nine hundred eighty-one children participated in the follow-up study (56% of the 1,737 children born to women enrolled in the original study at a center that participated in the follow-up portion) (Fig. 1). One child was excluded from this analysis because of missing anthropometric data and another child was excluded as a result of missing data regarding exposure to pregnancy complications, leaving 979 children included in this analysis. All 979 of these children had anthropometric measurements, including height, weight, and waist circumference. Blood pressure was measured in 974 of the children and a blood specimen was collected in 765 of the children.
The maternal baseline characteristics were generally similar between the children who did and did not participate, although some differences were observed. Most notably, a higher percentage of the children of non-Hispanic white women participated in the follow-up study (Appendix 2, available online at http://links.lww.com/AOG/B50). Still, this was an ethnically diverse cohort with 56% of participating children born to women of Hispanic ethnicity. The percent of children whose mothers experienced pregnancy-associated hypertension or were delivered preterm was similar between participants and nonparticipants.
The children were evaluated at a median 7 years of age (interquartile range 6–8). The number of children in each exposure group was 23 (2%) from a hypertensive pregnancy and born preterm, 73 (7%) from a hypertensive pregnancy and born at term, 58 (6%) from a normotensive pregnancy and born preterm, and 825 (84%) from a normotensive pregnancy and born at term. Among the mothers with a hypertensive pregnancy, 57% of the mothers who delivered preterm had preeclampsia and 30% of the mothers who delivered at term had preeclampsia. Among the mothers who delivered preterm, 69% of the mothers with a normotensive pregnancy experienced spontaneous preterm birth, whereas 13% of the mothers with a hypertensive pregnancy experienced spontaneous preterm birth. Twenty-four percent of the children showed some signs of puberty (Table 1). The women who had pregnancy-associated hypertension and delivered preterm had the highest BMI. A significant correlation was observed between maternal and child diet (vegetable consumption); weak correlations between mother and child were observed for exercise and systolic BP.
When evaluating unadjusted outcomes, mean systolic BP was significantly higher in the children who were born at term to mothers who experienced pregnancy-associated hypertension compared with those born at term to normotensive mothers (systolic BP of 104 mm Hg, 95% CI 101–106 vs systolic BP of 99 mm Hg, 95% CI 98–100, P=.002) (Table 2). The multivariable models were adjusted for maternal baseline self-reported race and ethnicity and BMI and child sex. The BP models were also adjusted for child height at follow-up; all other models were also adjusted for child age at follow-up. The results were similar if further adjusted for study group (mild GDM treated, mild GDM untreated, no GDM) and smoking during pregnancy; therefore, these variables were excluded as adjusters to maintain a more parsimonious model. Results of the adjusted models were similar to the unadjusted results. Mean adjusted systolic BP was significantly higher in the children who were born at term to mothers who experienced pregnancy-associated hypertension compared with those born at term to normotensive mothers (systolic BP of 104 mm Hg, 95% CI 101–106 vs systolic BP of 99 mm Hg, 95% CI 99–100, P=.001) (Table 3). Results were consistent across child sex and Tanner stage groups. The other cardiometabolic risk factors did not significantly differ between exposure groups. No significant differences were observed when comparing the children who were born preterm (from either a hypertensive pregnancy or a normotensive pregnancy) with those born at term to normotensive mothers. The association between pregnancy-associated hypertension at term and systolic BP (Appendix 3 [Panel A], available online at http://links.lww.com/AOG/B50) was not attenuated after further adjustment for the potentially mediating effect of either birth weight for gestational age (Appendix 3 [Panel B], available online at http://links.lww.com/AOG/B50) or child BMI (Appendix 3 [Panel C], available online at http://links.lww.com/AOG/B50). Overall, 11% of the children had hypertension, which ranged from 10% in those born at term to a normotensive pregnancy to 23% in those born at term to a hypertensive pregnancy (Appendix 4, available online at http://links.lww.com/AOG/B50).
Descriptive results evaluating gestational hypertension and preeclampsia separately for systolic BP are presented in Appendix 5, available online at http://links.lww.com/AOG/B50. Elevated systolic BP was observed in the children born at term to mothers with gestational hypertension and preeclampsia.
We found that pregnancy-associated hypertension in women who deliver at term was associated with higher systolic BP in the offspring; however, no association was observed in those born preterm. It is possible that an earlier delivery may protect a fetus from continued in utero exposure to the sequelae of pregnancy-associated hypertension; however, the relatively modest sample size of those born preterm limits our interpretation. In an analysis from this same study, we found that pregnancy-associated hypertension was associated with subsequent maternal BP in the mothers who delivered preterm.24 This difference in at-risk groups for higher systolic BP between mothers and their offspring may argue against a strong genetic or shared environment mechanism in our population. We observed no significant association between pregnancy-associated hypertension and the other cardiometabolic measures evaluated, suggesting that the adverse consequences of in utero exposure to pregnancy-associated hypertension are specific to child BP.
Our findings of an association between pregnancy-associated hypertension with offspring systolic BP, but not other cardiometabolic markers, are consistent with other studies. The United Kingdom Avon Longitudinal Study followed up more than 6,000 offspring of women with preeclampsia, gestational hypertension, or normotension from 7 to 18 years after birth.6,25–27 Maternal gestational hypertension and preeclampsia were associated with higher systolic BP in the 7-, 9-, and 11-year-old offspring.6,25,27 Endothelial function, markers of inflammation, and lipids were also measured in the 11-year-old offspring and none was significant.25 In a study conducted in Finland in 60 12-year-old children born after a preeclamptic pregnancy and 60 children in a matched control group, preeclampsia was associated with offspring BP and epinephrine, but not with total cholesterol, low-density lipoprotein cholesterol, or insulin.28
Whether elevations in cardiometabolic risk factors other than BP may emerge later in adolescence or early adulthood remains inconclusive. In a cohort of 5,573 16-year-old adolescents part of the Northern Finland Birth Cohort 1986, gestational hypertension was associated with higher BP, total cholesterol, and apolipoprotein B, but no statistically significant association was observed for insulin, glucose, homeostatic model assessment of insulin resistance, high-density lipoprotein cholesterol, or triglycerides.7 In the 17-year-old adolescents enrolled in the Avon Longitudinal Study, gestational hypertension and preeclampsia were associated with offspring BP, but not with insulin, glucose, or lipids.26 A subgroup of these adolescents had echocardiography, and gestational hypertension and preeclampsia were associated with offspring cardiac wall thickness, but not cardiac function.29 In a cohort of 2,868 20-year-old adults in Australia, pregnancy-associated hypertension was associated with offspring hypertension, BMI, and a global lifetime risk score above the 75th percentile, but not with the individual measures of insulin, glucose, or lipids.4 In the Helsinki Health Cohort of more than 5,000 older adults, exposure to in utero gestational hypertension and preeclampsia was associated with hypertension and stroke in the offspring, but not with coronary heart disease,1 and gestational hypertension was associated with type 2 diabetes medication use before age 62 years.30
Limitations of this study are acknowledged. The sample size was relatively small for those born preterm and those exposed to preeclampsia. Because the follow-up study was not planned at the time of the original study, 44% were lost to follow-up. This could lead to bias in the results, although it is noted that the children included in the analysis and the children not included in the analysis were similar with respect to exposure to pregnancy-associated hypertension and preterm birth. In addition, our results may be specific to children born to women with mild GDM or lesser degrees of carbohydrate intolerance, although our results are consistent with the literature.
There are numerous strengths of this study. Our study provided an opportunity to evaluate the association between pregnancy-associated hypertension and cardiometabolic health of offspring. The mothers of the index children were enrolled during pregnancy and therefore pregnancy outcomes were prospectively collected and defined using rigorous criteria and under a standardized research setting rather than relying on maternal self-report, vital statistics, or administrative data sets. Cases of pregnancy-associated hypertension were reviewed and adjudicated and gestational age at delivery was based on dating confirmed by ultrasonography. Likewise, data at the follow-up visit were prospectively and rigorously collected, trained research staff performed anthropometric and BP measurements, and cardiometabolic markers were measured at a central laboratory.
Our findings suggest that children born to mothers experiencing pregnancy-associated hypertension may be candidates for regular BP measurements, even if not overweight. Furthermore, these findings, coupled with other studies, can inform hypertension prevention strategies that may affect maternal hypertension as well as offspring hypertension.
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