Treatment of pregnancy-related hypertensive disorders, such as preeclampsia PE , remain a challenging problem in obstetrics. Typically, aggressive antihypertensive drug treatment options are avoided to prevent pharmacological-induced hypotension. Another major concern of administering antihypertensive drugs during pregnancy is possible adverse fetal outcome. In addition, management of hypertension during pregnancy in chronic hypertensive patients or in patients with prior kidney problems are carefully considered. Recent studies suggest that PE patients are at increased cardiovascular risk postpartum.
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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.
All randomized controlled trials evaluating antihypertensive treatments for chronic hypertension in pregnancy were included. Data were extracted and analyzed in Stata version 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. There remains some debate regarding the efficacy of treating chronic hypertension in pregnancy before it reaches severe levels due to concerns for fetal growth.
Given the physiological demands of pregnancy, duration of treatment and potential impacts on maternal and perinatal outcomes, there is a need for evidence on efficacy and safety of antihypertensive treatment specifically in pregnancy complicated by chronic hypertension. Current international guidance points to the lack of evidence for antihypertensive agent prescribing in chronic hypertension in pregnancy. No ethical approval was required.
A comprehensive literature review using Medline via Ovid , Embase via Ovid , and the Cochrane Trials Register from their earliest entries until the November 30, was performed.
Search strategies were adapted to each database. For Medline and Embase searches, a search filter for randomized controlled trials was then applied as recommended in the Cochrane Handbook for Systematic Reviews of Interventions. References of retrieved studies and relevant review articles were also searched using the snowballing approach. No language restrictions were applied. The study protocol including the literature search strategy is detailed in Data S1.
Comparisons with other antihypertensive drug s , placebo, no treatment, or an alternative such as bed rest were eligible for inclusion. Studies that included participants with gestational hypertension and chronic hypertension were only eligible for inclusion if the data for the women with chronic hypertension were reported separately to allow fair comparison. Studies that compared management strategies only but did not include a randomized comparison of drug treatments were not eligible for inclusion.
Trials that did not report any of the predefined outcomes were excluded. No other restrictions were applied to the study search. The titles, abstracts and selected full texts generated from the literature search were independently screened by authors L. The authors were not masked to the results of the study or authors.
Where 2 articles published results from the same study, individual pertinent outcomes were extracted from both articles without repetition of data extraction. Details of potential confounders maternal age, body mass index, ethnicity were recorded wherever provided in the manuscripts. Each trial was independently quality assessed using the Cochrane Collaboration Risk of Bias tool by L.
Data were analyzed in the statistical package Stata version Initial analysis of treatment effects was performed by class of antihypertensive agent and subsequently by active versus nonactive treatment. After removal of duplicates, the initial search generated titles and abstracts for review. Flowchart of articles identified reporting randomized controlled trials of antihypertensive agents for the treatment of chronic hypertension in pregnancy.
OR undocumented history of hypertension for which the patient was taking antihypertensive treatment before or during pregnancy.
Ten of the trials were conducted in a predefined chronic hypertension cohort alone, 1 and the remaining 5 reported outcomes for a subgroup of women with chronic hypertension.
Two studies excluded women with proteinuria, 33 , 44 3 studies included women with proteinuria at study entry, 32 , 35 , 43 and the remainder of studies did not specify presence or absence of proteinuria in their methods.
Six studies excluded multifetal pregnancies 30 , 32 , 40 , 41 , 44 , 45 ; the remainder either included women with multifetal pregnancies or did not specify inclusion or exclusion in their methods. Maternal age was the only potential confounding baseline characteristic consistently reported. Body mass index was not reported in any of the trials, but 6 studies reported maternal weight at trial entry.
Ethnicity of the participants was not considered or recorded in any of the trials. All studies were assessed to be at high risk of bias apart from Steyn and colleagues, 42 which was assigned unclear risk of bias. Randomized controlled trials are listed alphabetically by author name.
Antihypertensive treatment reduces the incidence of severe hypertension in pregnancy complicated by chronic hypertension compared with no antihypertensive or placebo, with a risk ratio of 0. Maternal outcomes: active vs nonactive treatment. A, Severe hypertension. Studies are listed in order of the year they were published. 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.
Perinatal outcomes were assessed to determine the potential fetal and neonatal risks associated with antihypertensive use when compared to nonactive treatment. The analysis of stillbirth and neonatal death demonstrated a nonsignificant reduction with the use of antihypertensive treatment: risk ratio 0. Perinatal outcomes: active vs nonactive treatment. A, Stillbirth or neonatal death. B, Birth weight. There were no additional significant differences. Risk ratios provided where binary data were analyzed, and weighted mean difference given for continuous outcomes.
There was no difference in incidence of severe hypertension between agents when methyldopa was compared with other antihypertensive treatments. There were additionally no significant differences in perinatal outcomes between antihypertensive agents. Maternal outcomes: comparison of methyldopa vs other antihypertensive agents.
Perinatal outcomes: comparison of methyldopa vs other antihypertensive agents. A, Stillbirth and neonatal death. This is the largest systematic review of the evidence from randomized controlled trials to guide antihypertensive treatment specifically for chronic hypertension in pregnancy. Other systematic reviews have pooled results for chronic and gestational hypertension, but given the different etiology and duration of treatment, there are concerns with this approach.
The paucity of data to guide selection of antihypertensive treatment for chronic hypertension in pregnancy is also highlighted.
Given the changes in management of hypertension both inside and outside pregnancy and that all of these trials were published between and , optimal antihypertensive therapy for treating chronic hypertension in pregnancy warrants further investigation through large randomized controlled trials. Antihypertensive use in pregnancy complicated by chronic hypertension does not increase the risk of stillbirth or neonatal death.
This strengthens the finding that antihypertensive agents do not significantly affect perinatal morbidity; agent selection and higher than recommended dose are likely to account for the evidence from Butters and colleagues, who published data from a study of 29 participants randomized in the second trimester to atenolol or placebo.
The primary results for this analysis have been presented without the inclusion of this study for these reasons. Therefore, a substantial proportion of the evidence for treatment of hypertension in pregnancy is based on outdated drugs and outdated doses. It is difficult to draw conclusions over the effect of antihypertensive agents on other maternal and perinatal outcomes. In addition, the planned adjustment for potential confounders such as body mass index was not possible due to inconsistent or absent reporting in the trial manuscripts.
Further studies are needed to answer these questions and assess the potential impact of maternal characteristics such as obesity and other medical comorbidities. This is primarily due to assignment of unclear risk of bias to many areas of study conduct and restrictions in the Cochrane tool.
Additionally, the studies are not uniform in their reported outcome measures, which reflect the large time frame and variation in geographical setting of the studies. In addition, a considerable portion of women will cross over from 1 group to the other, making analysis problematic.
Earlier systematic reviews have focused on magnitude of initial hypertension rather than the underlying condition causing the hypertension. However, separating chronic and gestational hypertension, given the differing pathophysiological pathways and implications of treatment, allows focus on optimizing treatment for each condition and is much more relevant to clinical practice. In addition, further consideration of the impact of maternal demographic factors should be considered such as body mass index and ethnicity.
This systematic review provides evidence to recommend that women with chronic hypertension in pregnancy should receive antihypertensive treatment to reduce the incidence of severe hypertension and its associated maternal morbidity without adversely affecting perinatal outcome.
A considerable paucity of data exists from randomized controlled trials to guide choice of antihypertensive agent for chronic hypertension in pregnancy. Data were analyzed by Seed with contributions from other authors. The guarantor of the review is Professor Lucy Chappell. All authors had full access to all of the data including statistical reports and take responsibility for the integrity of the data and accuracy of the data analysis.
The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research, or the Department of Health. Paul Seed is partly funded by Tommy's Registered charity no. Open access for this article was funded by King's College London.
The other authors report no disclosures. J Am Heart Assoc. National Center for Biotechnology Information , U. Published online May Louise M. Seed , CStat, 1 Andrew J. Paul T. Andrew J. Lucy C. Author information Article notes Copyright and License information Disclaimer. Webster, Email: ku. Corresponding author. Received Feb 15; Accepted Mar Published on behalf of the American Heart Association, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
This article has been cited by other articles in PMC. Study Protocol. Conclusions Antihypertensive treatment reduces the risk of severe hypertension in pregnant women with chronic hypertension.
Use of Antihypertensive Drugs During Preeclampsia
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