Chronic hypertension affects approximately 8% of women of reproductive age and up to 6% of pregnancies in the United States.1–4 It is associated with a threefold to fivefold increase in several adverse pregnancy outcomes including preeclampsia, small-for-gestational age (SGA) neonates, indicated preterm birth, placental abruption, and intrauterine fetal demise compared with pregnancies uncomplicated by chronic hypertension.4–9 Although there is little debate that women with severe-range chronic hypertension (blood pressure [BP] 160/110 mm Hg or greater) should be treated, less is known regarding risks of mild-range chronic hypertension because some data suggest no increased risk in this range.3,8 The American College of Obstetricians and Gynecologists and other organizations specifically recommend against starting or continuing antihypertensive therapy for mild chronic hypertension (140/90–159/109 mm Hg) because there is no evidence that therapy during pregnancy benefits the mother and there is concern that the risk of antihypertensive medication may impair placental perfusion and fetal growth.2,4,10–15 However, actual practice varies and many women with mild chronic hypertension are treated to a BP goal of less than 140/90 mm Hg as generally recommended for the nonpregnant population.10
We conducted this study to further evaluate the relationship between BP level and outcomes among pregnant women with chronic hypertension. Our hypothesis is that BP less than 140/90 mm Hg is associated with lower risks, and increasing degrees of mild-range chronic hypertension (140–159/90–109 mm Hg) are associated with worse pregnancy outcomes. If proven, this would suggest a benefit to treating mild chronic hypertension to improve perinatal outcomes.
MATERIALS AND METHODS
We performed a secondary analysis of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network multicenter randomized trial evaluating the use of low-dose aspirin for preeclampsia prevention in high-risk women enrolled at 13–26 weeks of gestation.16 The database has been publicly released to individual study sites, and an institutional review board waiver was obtained at the University of Alabama at Birmingham. The primary study cohort included 2,539 women at high risk for the development of preeclampsia as a result of a history of chronic hypertension, pregestational diabetes mellitus, multiple gestations, or a history of preeclampsia. Of note, aspirin did not influence the risk of preeclampsia in any risk group. Only the subcohort of 776 women with chronic hypertension was eligible for this study. This remains arguably one of the best well-characterized cohorts of women with chronic hypertension in pregnancy, particularly with respect to prospectively ascertained and verified outcomes. Chronic hypertension diagnosed before 20 weeks of gestation was defined according to the primary study: a history of chronic hypertension with documentation of use of antihypertensive drug therapy by medical records or a new diagnosis with BP while sitting of at least 140/90 mm Hg taken on two occasions 4 hours apart, either before pregnancy or during pregnancy and before study entry.16 As part of prerandomization eligibility screening, medical records of potential participants were reviewed by research staff and a preenrollment BP measured during a preenrollment visit. Eligible women were enrolled approximately 1 week later if they passed a compliance test (pill count) given during the preenrollment visit. Because the preenrollment BP was not the diagnostic BP and women could be receiving antihypertensive therapy, some women with chronic hypertension naturally had a preenrollment BP less than 140/90 mm Hg. All women with severe preenrollment BP (160/110 mm Hg or greater) were excluded from this analysis. We examined preenrollment BP both as categories of increasing BP (defined as follows: less than 140/90, 140–150/90–99, or 151–159/100–109 mm Hg) and as a continuous exposure variable defined by 5-mm Hg increments in systolic or diastolic BP.
Study outcomes included a primary perinatal composite outcome defined as the presence of one or more of perinatal death, indicated preterm birth less than 35 weeks of gestation, placental abruption, and severe preeclampsia. We also examined SGA and the individual components of the primary perinatal composite as well as preeclampsia and any preterm birth. The definitions of the study outcomes and the detailed rigorous protocol for their ascertainment are detailed in the primary article.16 Perinatal death was defined as fetal or neonatal death occurring after 20 weeks of gestation. Preterm birth was defined as delivery before the completion of 37 weeks of gestation; indicated preterm births were centrally coded as preterm births resulting from reasons other than spontaneous labor or premature membrane rupture. Abruptio placenta was diagnosed according to clinical criteria (vaginal bleeding and uterine tenderness) and examination of the placenta. Preeclampsia was defined as BP elevation (BP 140/90 mm Hg or greater on two occasions at least 4 hours apart in those who were previously controlled) or worsening hypertension (two diastolic readings greater than 110 mm Hg taken 4 hours apart in the week before delivery) plus at least one of the following: new proteinuria or a sudden increase in proteinuria (either five times the baseline value or twice baseline if the baseline value exceeded 5 g per 24 hours), thrombocytopenia (less than 100,000 per cubic millimeter), a serum aspartate aminotransferase greater than 70 unit/L, symptoms (including severe headache or epigastric pain), eclamptic convulsion, HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome, or pulmonary edema. Proteinuria was defined as excretion of 300 mg of protein in a 24-hour urine collection or two dipstick test results of greater than 2+ (greater than 100 mg/dL), at least 4 hours apart, with no evidence of urinary tract infection. A neonate was considered SGA if its weight was below the 10th percentile of normative birth weights for singletons.
Both the preenrollment BP and the previously mentioned study outcomes were key variables of the primary trial. These data were abstracted by trained and certified research nurses, entered by trained data abstractors, and securely transmitted to the biostatistics coordinating center. To ensure consistency in the ascertainment of outcomes, particularly preeclampsia and abruption, in the primary study, the records of all the women with suspected preeclampsia or abruption were reviewed centrally and independently by two to three physicians unaware of the treatment group assignments. They had to agree unanimously on the validity of the designated outcomes.
For data analysis, comparisons among BP groups were performed using a combination of analysis of variance, χ2 test, and Fisher's exact test as relevant. Outcomes were also compared using the Cochrane-Armitage test of trend. Multivariable logistic regression was conducted for each outcome comparing those with mildly elevated preenrollment BP, 140–150/90–99 mm Hg and 151–159/100–109 mm Hg, with those with BP less than 140/90 mm Hg as the referent group. Adjustments were made for potential confounders including age (continuous variable), parity (nulliparous compared with multiparous), race or ethnicity (non-Hispanic white as referent, black, Hispanic, and other), body mass index ([calculated as weight (kg)/[height (m)]2] continuous variable), gestational age (weeks) at randomization, use of antihypertensive medications (none, initiated before pregnancy or initiated during pregnancy), aspirin use (study intervention), smoking during pregnancy (smoker or nonsmoker), and baseline proteinuria (presence or absence). All analyses were performed using SAS 9.2. Statistical significance was defined as P<.05; no adjustments were made for multiple comparisons.
Of the 776 patients with chronic hypertension in the Maternal-Fetal Medicine Units Network High Risk Aspirin Database, 17 patients were excluded (two for severe preenrollment hypertension 160/110 mm Hg or greater, four for multifetal gestation, and 11 who had no outcome data available), leaving a total of 759 (97.8%) women with mild chronic hypertension during pregnancy for data analysis. The characteristics of the cohort by preenrollment BP categories are shown in Table 1. Preenrollment BP differed by ethnicity, smoking status, history of preeclampsia, and antihypertensive use. Women with preenrollment BP less than 140/90 mm Hg were most likely to have started antihypertensive therapy before pregnancy and less likely to be Hispanic compared with the other categories, whereas those with BP 151–159/100–109 mm Hg were less likely to be non-Hispanic whites. Women with BP 140–150/90–99 or 151–159/100–109 mm Hg were less likely to be smokers or to have been on antihypertensive therapy before pregnancy but more likely to have a history of prior preeclampsia and to have antihypertensive therapy started during pregnancy as compared with those with BP less than 140/90 mm Hg. The study groups did not differ by gestational age at randomization or by who received aspirin or placebo.
The incidence of each adverse pregnancy outcome including the primary perinatal composite by BP category is presented in Table 2. The incidence of the composite outcome and specific components including perinatal death and indicated preterm birth before 35 weeks of gestation were lowest with BP less than 140/90 mm Hg and increased with increasing BP category. Similar findings were observed for SGA as well as for preeclampsia, preterm births overall, and any indicated preterm births less than 37 weeks of gestation.
Results of multivariable regression relating BP categories to selected outcomes while adjusting for potential confounders are shown in Table 3. These findings support the dose–response increase observed in Table 2. As compared with BP less than 140/90 mm Hg, elevated BPs 140–150/90–99 mm Hg and 151–159/100–109 mm Hg at preenrollment were associated with a 2.0- and 3.2-fold increase, respectively, in the primary composite perinatal outcome. The increases in the odds of the other outcomes ranged from 1.6- to 2.6-fold and 2.4- to 3.8-fold for elevated BP categories, respectively, as compared with BP less than 140/90 mm Hg.
Results from similar multivariable models in which BP categories were replaced with diastolic and systolic BPs as continuous variables are shown in Table 4. With each 5-mm Hg rise in diastolic BP, there was a 19% increase in the primary composite, 29% increase in perinatal death, 21% increase in indicated preterm birth less than 35 weeks of gestation, 22% increase in SGA neonates, 20% increase in preeclampsia, 18% increase in any indicated preterm birth, and 17% increase in any preterm birth. A statistically significant increase in each of these adverse outcomes was not detected with similar rises in systolic BP.
In additional analyses, results relating BP category and the primary composite outcome did not vary by the gestational age at randomization (less than 20 or 20 weeks of gestation or greater; P value for interaction=.28; the exact gestational age corresponding to the preenrollment BP was not available in the released database but was at least 1 week before randomization).
We found that in pregnant women with nonsevere chronic hypertension, the incidence of each of the several adverse perinatal outcomes including a primary perinatal composite and SGA was higher with elevated BP as compared with BP less than 140/90 mm Hg at the study preenrollment visit. The risk increased with increasing BP category. This finding was particularly true with increasing diastolic compared with systolic BPs when examined for small (5 mm Hg) increments. More than 83% of women with BP less than 140/90 mm Hg were on antihypertensive therapy initiated before or during pregnancy.
The strengths of our study include the relatively large well-characterized population of pregnant women with chronic hypertension. Data were prospectively assembled by trained and certified research staff as part of a clinical trial. Preenrollment BP was collected in a standardized fashion and outcomes were centrally reviewed and validated. We had detailed information on, and adjusted for, several potential confounders. These strengthen the validity of our findings. However, we acknowledge a number of study limitations. First, apart from the preenrollment BPs, we do not have information on BPs at other times or over the course of pregnancy (although collected as part of the primary trial, they were not available in the publicly released data set). Information regarding antihypertensive therapy initiated during pregnancy served as a limited proxy for elevated BP during pregnancy. Second, the precise gestational age data corresponding to preenrollment BPs were also not available in the released database. Therefore, we were unable to fully assess how findings varied by gestational age. However, results did not vary by gestational age at randomization before or after 20 weeks of gestation. Therefore, gestational age at preenrollment BP is unlikely to be a major influence because study groups did not differ by gestational age at randomization and in general women were randomized 1 week after the preenrollment visit.16 Third, we did not have granular information on the type and number of antihypertensive medications used or the study site. We were therefore unable to assess the effects of different sites or specific medications such as β-blockers (associated with SGA).17 Finally, we do not have a comparison group of healthy women (without chronic hypertension). However, considering the primary focus on BP level in women with chronic hypertension, such a comparison group is not critical because we are not also studying BP level in otherwise healthy women with de novo preeclampsia.
Whereas chronic hypertension is associated with several adverse pregnancy outcomes,4–9 specific information regarding the safety and efficacy of BP-lowering therapy during pregnancy are scarce and limited.13,14,18 Considering the lack of evidence of a salutary effect of BP control on pregnancy outcomes and the safety concerns regarding increased SGA,17,19 the American College of Obstetricians and Gynecologists and others recommend against starting or continuing antihypertensive therapy for mild chronic hypertension during pregnancy.2,4,11 Our current findings are consistent with those of other studies demonstrating the deleterious pregnancy-specific effects of chronic hypertension.6–9 These results demonstrate that adverse outcomes are increased even with mild BP elevation in treated or untreated women with chronic hypertension. Because women were randomized at 13–26 weeks of gestation, approximately 1 week after the preenrollment visit, the BPs correspond mainly to the midtrimester. Furthermore, because the mean gestational age was similar between BP groups, our findings are unlikely to be the result of a differential effect of the midtrimester nadir in BP. Suggestions of a lack of increase in adverse outcomes with isolated mild chronic hypertension have been based on outcomes in those without superimposed preeclampsia (a retrospective diagnosis). Furthermore, besides highlighting the health consequences and public health import of mild chronic hypertension, our findings reveal additional new information to guide future action. Specifically, the dose–response increase in several adverse outcomes with BP suggests that BP levels within the broad category considered “mild” BP elevation (140–159/90–109 mm Hg) are not equivalent. If confirmed, this could have important clinical implications going forward because BPs corresponding to this broad category are commonly managed equivalently. More importantly, the finding also leads to the hypothesis that BP control of mild chronic hypertension during pregnancy may improve pregnancy outcomes. Relevant trials focusing specifically on women with chronic hypertension have had inadequate power or methodologic limitations.14,18 For example, in a small meta-analysis that included seven trials and a total of 623 women with mild chronic hypertension, the incidence of severe hypertension (relative risk [RR]=0.3) was significantly reduced by BP-lowering therapy, but specific adverse outcomes including perinatal death (RR=0.4) and preeclampsia (RR=0.7) were not significantly reduced.18 Still, those RRs suggested the potential for these outcomes to be significantly reduced with adequate power. Our findings further support the preceding hypothesis. However, the aforementioned limitations of our study and other pitfalls inherent in the observational design do not support a uniform policy of BP-lowering therapy to achieve BP less than 140/90 mm Hg during pregnancy to reduce adverse pregnancy outcomes at this time. For example, it is plausible that pregnant women with uncontrolled hypertension may already have an inherent risk (vascular or otherwise) for adverse pregnancy outcomes that may not be amenable to BP-lowering therapy. Our findings do further underscore the urgent need to address long-standing calls from professional and other organizations for well-designed and adequately powered randomized trials to assess the efficacy and safety of BP-lowering therapy during pregnancy complicated by chronic hypertension.2,4,10–12,20–22
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