Impact of Antihypertensive Treatment on Maternal and Perinatal Outcomes in Pregnancy Complicated by Chronic Hypertension: A Systematic Review and Meta-Analysis

Abstract

Background: Chronic hypertension complicates around 3% of all pregnancies. There is evidence that treating severe hypertension reduces maternal morbidity. This study aimed to systematically review randomized controlled trials of antihypertensive agents treating chronic hypertension in pregnancy to determine the effect of this intervention.

Methods and results: Medline (via OVID), Embase (via OVID) and the Cochrane Trials Register were searched from their earliest entries until November 30, 2016. All randomized controlled trials evaluating antihypertensive treatments for chronic hypertension in pregnancy were included. Data were extracted and analyzed in Stata (version 14.1). Fifteen randomized controlled trials (1166 women) were identified for meta-analysis. A clinically important reduction in the incidence of severe hypertension was seen with antihypertensive treatment versus no antihypertensive treatment/placebo (5 studies, 446 women; risk ratio 0.33, 95%CI 0.19-0.56; I² 0.0%). There was no difference in the incidence of superimposed pre-eclampsia (7 studies, 727 women; risk ratio 0.74, 95%CI 0.49-1.11; I² 28.1%), stillbirth/neonatal death (4 studies, 667 women; risk ratio 0.37, 95%CI 0.11-1.26; I² 0.0%), birth weight (7 studies, 802 women; weighted mean difference -60 g, 95%CI -200 to 80 g; I² 0.0%), or small for gestational age (4 studies, 369 women; risk ratio 1.01, 95%CI 0.53-1.94; I² 0.0%) with antihypertensive treatment versus no treatment/placebo.

Conclusions: Antihypertensive treatment reduces the risk of severe hypertension in pregnant women with chronic hypertension. A considerable paucity of data exists to guide choice of antihypertensive agent. Adequately powered head-to-head randomized controlled trials of commonly used antihypertensive agents are required to inform prescribing.

Keywords: antihypertensive agent; hypertension; meta‐analysis; pregnancy; systematic review.

Figure 1

Flowchart of articles identified reporting randomized controlled trials of antihypertensive agents for the treatment of chronic hypertension in pregnancy.

Figure 2

Risk‐of‐bias assessment of each study included in the meta‐analysis. A, Risk‐of‐bias assessment by individual assessment of criteria for each study. Randomized controlled trials are listed alphabetically by author name. B, Risk‐of‐bias items presented as percentages across all included studies. *Redman et al39 and Mutch et al37 both publish data from the same study; only the Redman article has been assessed for risk of bias. Risk‐of‐bias summary shows review authors’ judgments about each risk‐of‐bias domain in randomized controlled trials on efficacy of antihypertensive treatment for chronic hypertension in pregnancy.

Figure 3

Maternal outcomes: active vs nonactive treatment. A, Severe hypertension. B, Superimposed pre‐eclampsia. *Where studies had more than 1 active treatment arm, the data from the active treatment arms were pooled and compared with the non‐active‐treatment data. Studies are listed in order of the year they were published. Antihypertensive agents used in each study are listed in Table 1. The numbers of participants experiencing severe hypertension or superimposed pre‐eclampsia in each treatment group are denoted as “n,” with the total number of participants with chronic hypertension in each study arm denoted as “N.” Forest plots of the meta‐analysis for each maternal outcome: active vs nonactive treatment. The gray rectangles represent the risk ratio for each study and are sized in proportion to the weight assigned to the study within the analysis. The red dotted line represents to overall risk ratio for each outcome and the lateral tips of the diamond represent the 95% confidence interval for the summary measure.

Figure 4

Perinatal outcomes: active vs nonactive treatment. A, Stillbirth or neonatal death. B, Birth weight. C, Small‐for‐gestational‐age infants. *Where studies had more than 1 active treatment arm, the data from the active treatment arms were pooled and compared with the nonactive treatment data. Studies are listed in order of the year they were published. Antihypertensive agents used in each study are listed in Table 1. The numbers of participants experiencing a stillbirth/neonatal death or small‐for‐gestational‐age infant in each treatment group are denoted as “n,” with the total number of participants with chronic hypertension in each study arm denoted as “N.” Forest plots of the meta‐analysis for each perinatal outcome: active vs nonactive treatment. The gray rectangles represent the risk ratio for each study and are sized in proportion to the weight assigned to the study within the analysis. The red dotted line represents to overall risk ratio for each outcome and the lateral tips of the diamond represent the 95% confidence interval for the summary measure.

Figure 5

Funnel plot comparing birth‐weight difference between studies. Funnel plot demonstrates that Butters and colleagues31 (atenolol vs placebo) is an outlier within the meta‐analysis of birth weight when comparing active and nonactive treatment. Antihypertensive agents used in each study are listed in Table 1.

Figure 6

Maternal outcomes: comparison of methyldopa vs other antihypertensive agents. A, Severe hypertension. B, Superimposed pre‐eclampsia. Studies are listed in order of the year they were published. Antihypertensive agents used in each study are listed in Table 1. The number of participants experiencing severe hypertension or superimposed pre‐eclampsia in each treatment group are denoted as “n,” with the total number of participants with chronic hypertension in each study arm denoted as “N.” Forest plots of the meta‐analysis for each maternal outcome: comparison of methyldopa vs other antihypertensive agents. The gray rectangles represent the risk ratio for each study and are sized in proportion to the weight assigned to the study within the analysis. The red dotted line represents to overall risk ratio for each outcome and the lateral tips of the diamond represent the 95% confidence interval for the summary measure.

Figure 7

Perinatal outcomes: comparison of methyldopa vs other antihypertensive agents. A, Stillbirth and neonatal death. B, Birth weight. *Comparison made between methyldopa and beta‐blockers as these were the only agents used in head‐to‐head trials reporting birth weight. Studies are listed in order of the year they were published. Antihypertensive agents used in each study are listed in Table 1. The number of participants experiencing a stillbirth/neonatal death in each treatment group are denoted as “n,” with the total number of participants with chronic hypertension in each study arm denoted as “N.” Forest plots of the meta‐analysis for each perinatal outcome: comparison of methyldopa vs other antihypertensive agents. The gray rectangles represent the risk ratio for each study and are sized in proportion to the weight assigned to the study within the analysis. The red dotted line represents to overall risk ratio for each outcome and the lateral tips of the diamond represent the 95% confidence interval for the summary measure.