Prevention and treatment of postpartum hypertension
Abstract
Background
Postpartum blood pressure (BP) is highest three to six days after birth when most women have been discharged home. A significant rise in BP may be dangerous (e.g., can lead to stroke), but there is little information about how to prevent or treat postpartum hypertension.
Objectives
To assess the relative benefits and risks of interventions to:
(1) prevent postpartum hypertension, by assessing whether 'routine' postpartum medical therapy is better than placebo/no treatment; and
(2) treat postpartum hypertension, by assessing whether (i) one antihypertensive therapy is better than placebo/no therapy for mild‐moderate postpartum hypertension; and (ii) one antihypertensive agent offers advantages over another for mild‐moderate or severe postpartum hypertension.
Search methods
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 January 2013), bibliographies of retrieved papers, and personal files.
Selection criteria
For women with antenatal hypertension, trials comparing a medical intervention with placebo/no therapy. For women with postpartum hypertension, trials comparing one antihypertensive with either another or placebo/no therapy.
Data collection and analysis
We extracted the data independently and were not blinded to trial characteristics or outcomes. We contacted authors for missing data when possible.
Main results
Nine trials are included.
Prevention: Four trials (358 women) compared furosemide, nifedipine capsules, or L‐arginine with placebo/no therapy. For women with antenatal pre‐eclampsia, postnatal furosemide is associated with a strong trend towards reduced use of antihypertensive therapy in hospital.
Treatment: For treatment of mild‐moderate postpartum hypertension, three trials (189 women) compared timolol, oral hydralazine, or oral nifedipine with methyldopa. Use of additional antihypertensive therapy did not differ between groups (risk ratio (RR) 0.92, 95% confidence interval (CI) 0.20 to 4.20; three trials), but the trials were not consistent in their effects. The drugs were well tolerated.
For treatment of severe postpartum hypertension, two trials (120 women) compared intravenous hydralazine with either sublingual nifedipine or intravenous labetalol. There were no maternal deaths or hypotension. Use of additional antihypertensive therapy did not differ between groups (RR 0.58, 95% CI 0.04 to 9.07; two trials), but the trials were not consistent in their effects.
Authors' conclusions
For women with pre‐eclampsia, postnatal furosemide may decrease the need for postnatal antihypertensive therapy in hospital, but more data are needed on substantive outcomes before this practice can be recommended. There are no reliable data to guide management of women who are hypertensive postpartum. Any antihypertensive agent used should be based on a clinician's familiarity with the drug. Future studies should include data on postpartum analgesics, severe maternal hypertension, breastfeeding, hospital length of stay, and maternal satisfaction with care.
PICOs
Plain language summary
Prevention and treatment of postpartum hypertension
Not enough evidence to know how best to treat women with hypertension after birth.
After birth, it is not uncommon for women to experience high blood pressure (hypertension), but it can have serious consequences. It can lead to stroke and, very rarely, death. It is unclear what causes hypertension after childbirth, or which women may develop the problem, although women with antenatal severe pre‐eclampsia appear to be at highest risk. The review of nine trials found no reliable evidence to guide care for these women. Further research is needed, particularly as the problem occurs most commonly three to six days after birth when most women have left hospital.
Authors' conclusions
Background
The hypertensive disorders of pregnancy are associated with increased morbidity and mortality. Research has focused on the antenatal complications, for both mother and baby, and the risks and benefits of administering antihypertensive therapy prior to delivery (Abalos 2007; Duley 2002). There is very little information on how best to manage postpartum hypertension, regardless of type or severity, to optimise maternal safety and minimise hospital stay.
The true prevalence of postpartum hypertension is difficult to ascertain, but the importance of monitoring women in the puerperium was highlighted by the Confidential Enquiries into Maternal Deaths in the United Kingdom (Conf Enq 94‐96), in which roughly 10% of maternal deaths due to a hypertensive disorder of pregnancy occurred in the postpartum period (Tan 2002). In the 1997 to 1999 triennial report, one of 15 deaths was attributed to severe hypertension that developed only postpartum in a woman with antenatal pre‐eclampsia (Conf Enq 97‐99). Other complications of severe postpartum hypertension include stroke, and possibly, eclampsia. In a survey of all cases of eclampsia in the United Kingdom, 1992, it was shown that 44% of eclampsia occurs in the postpartum period, usually in the first 48 hours after delivery (Douglas 1994). Women with postpartum hypertension may also experience longer hospital stays and possibly, heightened anxiety about their recovery.
Blood pressure rises progressively over the first five postnatal days, peaking on days three to six after delivery (Bayliss 2002; Walters 1986). This pattern of blood pressure is thought to result from mobilisation, from the extravascular to the intravascular space, of the six to eight litres of total body water and the 950 mEq of total body sodium accumulated during pregnancy. Excretion of urinary sodium (i.e., natriuresis) has been observed on days three to five postpartum (Davison 1984), and it has been postulated that this may result from an increase in atrial natriuretic peptide (ANP). ANP has roles in natriuresis and inhibition of aldosterone, angiotensin II and vasopressin (Bond 1989) and has been observed to rise during the first week postpartum (Castro 1994).
What causes a postpartum recurrence or de novo (i.e., new) postpartum presentation of hypertension is not known. Perhaps an attenuated increase in ANP plays a role. Five women with de novo postpartum hypertension were seen to have significantly lower ANP levels, compared with 10 normotensive controls (Nagai 1997). Another possibility is a failure to observe the expected postpartum fall in serum angiotensin I, an inactive intermediate of angiotensin II which is a potent vasoconstrictor. This was observed in 10 women with postpartum hypertension (recurrent or de novo) (Mizutani 1993).
There are iatrogenic causes of postpartum hypertension. Bromocriptine, to inhibit lactation, was withdrawn from the American market in 1994, because of numerous case reports of intracerebral haemorrhage and other vasospasm‐mediated adverse events (such as myocardial infarction). It is plausible that the administration of non‐steroidal anti‐inflammatory drugs (NSAIDs) for postpartum analgesia may contribute to the risk of postpartum hypertension by stimulating sodium retention (Makris 2004).
Postpartum hypertension may represent a continuation of an antenatal hypertensive disorder (regardless of type), or the appearance of a new hypertensive disorder after delivery. Although it is recognised that antenatal hypertension may continue into the postpartum period, the incidence with which this occurs and for what duration, have been poorly defined. For clarification, hypertension is defined as a blood pressure of 140/90 mmHg or more. Mild‐to‐moderate hypertension is usually defined as a blood pressure of 140 to 169/90 to 109 mmHg, and severe hypertension as 170/110 mmHg or more. Hypertension in pregnancy (or the puerperium) is classified as: pre‐existing hypertension (defined as that which antedated pregnancy or appeared before 20 weeks' gestation); gestational hypertension without proteinuria (defined as hypertension that appeared at or after 20 weeks, with less than 0.3 grams/day of urinary protein); gestational hypertension with proteinuria (also known as 'pre‐eclampsia' or 'toxaemia'); or pre‐eclampsia superimposed on pre‐existing hypertension. Eclampsia is included in the pre‐eclampsia category, and is defined as an otherwise unexplained seizure in a woman with pre‐eclampsia.
Prevention of postpartum hypertension for high‐risk groups
Women delivered with pre‐eclampsia appear to be at increased risk of postpartum hypertension (Tan 2002). This was recognized by JS Henry in 1936, who pointed out that, "... in toxaemic patients, the postpartum fall [in blood pressure] to normal is very variable, but is apt to take longer in eclamptics and in pre‐eclamptics" (Henry 1936). In the no treatment arm of a randomised controlled trial comparing furosemide with no treatment, 26% of women with pre‐eclampsia were observed to be on antihypertensive therapy at the time of hospital discharge (Ascarelli 1999). An observational study of 67 women with either proteinuric or non‐proteinuric gestational hypertension found that 50% of women had a blood pressure greater than 150/100 mmHg on day five postpartum (Walters 1987). In women who develop pre‐eclampsia antenatally, postnatal hypertension lasted approximately two weeks (mean ± standard deviation (SD) of 16 ± 9.5 days). Although blood pressure dropped significantly in the first two weeks postpartum, there was substantial variability between women (Bowler 2002; Ferrazzani 1994). Women at increased risk for recurrence of hypertension after delivery were those who delivered preterm, and those multiparous women with higher uric acid levels or blood urea nitrogen (Ferrazzani 1994). In a study of 80 women with pregnancy‐induced hypertension, the risk of developing postpartum morbidity increased with higher levels of urinary albumin and urinary immunoglobulin G (IgG), measured in the antepartum and intrapartum periods. In this study, postpartum morbidity was defined as one or more of the following: (1) need for greater than 24 hours of maternal postpartum intensive care or parenteral magnesium sulphate administration; (2) need for postpartum parenteral antihypertensive medication for blood pressure greater than 160/110 mmHg; (3) postpartum blood pressure of greater than 140/90 for more than three days; and/or (4) need for oral antihypertensive medication at the time of hospital discharge (Eden 1986).
Compared with women with pre‐eclampsia, fewer women with gestational hypertension appear to have postpartum hypertension. Also, the duration of this hypertension appeared to be shorter (mean ± SD of six days, SD 5.5 days) than in women with pre‐eclampsia. Again, the duration was highly variable (Ferrazzani 1994). Multiparous women with higher uric acid and blood urea nitrogen appeared to be at higher risk (Ferrazzani 1994).
It is not known whether or not antihypertensives should be routinely re‐instituted postpartum among women with antenatal hypertension in order to prevent postpartum hypertension. No international guidelines give guidance in this regard.
Treatment of postpartum hypertension
The incidence of de novo postpartum hypertension has also been poorly defined. In an observational study of 136 primarily Caucasian women who were normotensive antenatally, 12% had a diastolic blood pressure (dBP) greater than 100 mmHg during the first five postpartum days, with an average rise in blood pressure of 6 mmHg systolic and 4 mmHg diastolic (Walters 1986). In contrast, postpartum hypertension occurred in only 3.5% of 210 Nigerian women who were normotensive during pregnancy. However, excluded were women who were hypertensive within 48 hours of delivery. Of note, is the fact that of the two thirds of women who became hypertensive within six weeks postpartum, 70% did so between days two and seven postpartum (Ojugwu 1993). Long‐term follow‐up was available for only 35 of the women (17%), most of whom developed gestational hypertension (N = 8) or recurrent isolated postpartum hypertension (N = 17) in subsequent pregnancies. Finally, in a case‐control study of women readmitted to hospital with postpartum pre‐eclampsia after a normotensive pregnancy (versus controls who were normotensive throughout pregnancy and the postpartum period), a rise in mean arterial pressure of more than 10 mmHg between the intrapartum and postpartum periods was associated with a greater than threefold increased risk of readmission postpartum with severe pre‐eclampsia or eclampsia (Atterbury 1996).
For manifest postpartum hypertension, there is general consensus that severe hypertension should be treated (to prevent acute maternal vascular complications such as stroke), but no such consensus exists for mild‐moderate postpartum hypertension (whether de novo or not and regardless of type), needs to be treated. The Canadian Hypertension Society recommends treatment for women with severe hypertension or symptoms, and those with target organ damage and moderate gestational hypertension (i.e., dBP greater than 99 mmHg) three days after delivery (Rey 1997). The American and Australasian guidelines acknowledge the postnatal rise in blood pressure and the possibility that antihypertensive medication may need to be increased in women with antenatal (even chronic) hypertension, but they make no specific recommendations about when treatment should be started and what the therapeutic goal should be (Brown 2000; NHBPEPWG 2000).
Despite widespread use of antihypertensives in the postpartum period, there is limited evidence to support their safety for babies of breastfeeding mothers. A review of the available observational literature (37 reports covering 41 different antihypertensives) concluded that the following drugs have minimal milk to maternal plasma ratios to make breastfeeding acceptable: methyldopa, beta‐blockers with high protein binding (e.g., oxprenolol), angiotensin converting enzyme inhibitors and some dihydropyridine calcium channel blockers (Beardmore 2002). All of these drugs are used commonly in the postpartum period.
This review focuses on the benefits and risks of antihypertensive therapy for the prevention or treatment of postpartum hypertension. We will not address other therapeutic approaches (e.g., postpartum curettage) (Hunter 1961; Magann 1993; Magann 1994; Robinson 1964) or magnesium sulphate therapy (Livingston 2003; Ehrenberg 2006).
Objectives
To assess the relative benefits and risks of interventions to prevent postpartum hypertension, by assessing whether or not 'routine' postpartum administration of oral antihypertensive therapy is better than placebo/no treatment.
To assess the relative benefits and risks of treatment of postpartum hypertension by assessing whether or not:
(i) oral antihypertensive therapy is better than placebo/no therapy for mild‐moderate postpartum hypertension; and
(ii) one antihypertensive agent offers any advantages over another for either mild‐moderate or severe postpartum hypertension.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials. Quasi‐random designs were excluded.
Types of participants
Women with either:
(i) an antenatal hypertensive disorder of pregnancy; or
(ii) women with de novo postpartum hypertension.
Postpartum hypertension was defined as an elevated blood pressure (140/90 mmHg or more) measured twice at least four hours apart, between delivery and six weeks postpartum.
Types of interventions
For prevention of postpartum hypertension
Comparisons of:
(i) routine postpartum antihypertensive therapy versus placebo/no therapy;
(ii) routine postpartum antihypertensive therapy of one agent versus another.
For treatment of postpartum hypertension
Comparisons of:
(i) oral antihypertensive agents with placebo or no therapy; or
(ii) oral antihypertensive agent(s) versus another.
Any pharmacological therapy that was given to reduce blood pressure was acceptable for this review, and was considered as a source of between‐trial heterogeneity in outcome. Also recorded were other aspects of postpartum management, including use of non‐steroidal anti‐inflammatories (NSAIDs), bromocriptine, and/or ergot alkaloids. Interventions used to treat the syndrome of pre‐eclampsia (e.g., endometrial curettage) were not included in the review.
Types of outcome measures
Primary outcomes
Maternal outcomes
Measures that evaluated the effectiveness and safety of antihypertensive therapy for the woman:
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stroke (acute neurological deficit of vascular origin, which lasts more than 48 hours);
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maternal mortality;
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severe hypertension (blood pressure of greater than or equal to 170/110 for four hours or more);
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eclampsia, haemolysis;
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elevated liver enzymes;
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low platelets syndrome;
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the need for additional antihypertensive therapy (according to criteria defined by respective researchers);
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the need to change therapy due to maternal side‐effects of antihypertensive therapy;
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maternal hypotension
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duration of postpartum hospital stay (days);
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incidence of readmission to hospital after discharge postpartum;
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measures of maternal anxiety or well‐being as defined by respective researchers.
Measures not prespecified were:
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Maternal end‐organ failure (any);
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Use of NSAIDs for postpartum analgesia;
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Maternal side effects to antihypertensive medication;
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Severe maternal hypotension.
Secondary outcomes
Breastfeeding and neonatal outcomes
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Proportion of mothers who breastfed their babies and among them, neonatal side‐effects such as:
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bradycardia;
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hypotension;
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hypothermia;
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hypoglycaemia, as defined by respective researchers.
Search methods for identification of studies
Electronic searches
We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register by contacting the Trials Search Co‐ordinator (31 January 2013).
The Cochrane Pregnancy and Childbirth Group’s Trials Register is maintained by the Trials Search Co‐ordinator and contains trials identified from:
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monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
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weekly searches of MEDLINE;
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weekly searches of EMBASE;
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handsearches of 30 journals and the proceedings of major conferences;
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weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.
Details of the search strategies for CENTRAL, MEDLINE and EMBASE, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the ‘Specialized Register’ section within the editorial information about the Cochrane Pregnancy and Childbirth Group.
Trials identified through the searching activities described above are each assigned to a review topic (or topics). The Trials Search Co‐ordinator searches the register for each review using the topic list rather than keywords.
For previous versions of this review, we searched PubMed (2002 to 2009) and MEDLINE (1966 to May 2003), EMBASE (1980 to January 2003) using the search strategies listed in Appendix 1 and Appendix 2.
Searching other resources
We searched the bibliographies of retrieved papers and personal files.
We did not apply any language restrictions.
Data collection and analysis
For methods used in previous versions of this review seeAppendix 3. For this 2013 update, the following methods were used.
Selection of studies
Two review authors independently assessed for inclusion all the potential studies we identified as a result of the search strategy. We resolved any disagreement through discussion, or, if required, we consulted a third person.
Data extraction and management
We designed a form to extract data. For eligible studies, at least two review authors (S Sadeghi and LA Magee (LAM), or LAM and P von Dadelszen) extracted the data using the agreed form. We resolved discrepancies through discussion or, if required, we consulted a third person. For this update, data were entered into Review Manager (RevMan 2012) software and checked for accuracy.
When information regarding any of the above was unclear, we attempted to contact authors of the original reports to provide further details.
Assessment of risk of bias in included studies
Two review authors independently assessed risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Any disagreement was resolved by discussion or by involving a third assessor.
(1) Sequence generation (checking for possible selection bias)
We have described for each included study, the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should have produced comparable groups.
We assessed the method as:
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low risk of bias (any truly random process, e.g., random number table; computer random number generator);
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high risk of bias (any non‐random process, e.g., odd or even date of birth; hospital or clinic record number);
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unclear risk of bias.
(2) Allocation concealment (checking for possible selection bias)
We have described for each included study the method used to conceal the allocation sequence in sufficient detail and determine whether intervention allocation could have been foreseen in advance, or during recruitment, or changed after assignment.
We assessed the methods as:
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low risk of bias (e.g., telephone or central randomisation; consecutively numbered sealed opaque envelopes);
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high risk of bias (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth);
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unclear risk of bias.
(3.1) Blinding (checking for possible performance bias)
We have described for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. Studies were judged at low risk of bias if they were blinded, or we judged that the lack of blinding could not have affected the results. Blinding was assessed separately for different outcomes or classes of outcomes.
We assessed the methods as:
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low, high or unclear risk of bias for participants;
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low, high or unclear risk of bias for personnel.
(3.2) Blinding (checking for possible detection bias)
We have described for each included study the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received. We planned to assess blinding separately for different outcomes or classes of outcomes.
We assessed the methods used to blind outcome assessment as:
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low, high or unclear risk of bias.
(4) Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations)
We have described for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We have stated whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported, or could be supplied by the trial authors, we re‐included missing data in the analyses which we undertook.
We assessed methods as:
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low risk of bias (e.g. no missing outcome data; missing outcome data balanced across groups; less than 2.5% of women were excluded from the analysis);
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high risk of bias (e.g. numbers or reasons for missing data imbalanced across groups; "as treated" analysis done with substantial departure of intervention received from that assigned at randomisation);
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unclear risk of bias.
(5) Selective reporting bias
We have described for each included study how we investigated the possibility of selective outcome reporting bias and what we found.
We assessed the methods as:
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low risk of bias (where it was clear that all of the study’s pre‐specified outcomes and all expected outcomes of interest to the review were reported);
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high risk of bias (where not all of the study’s pre‐specified outcomes were reported; one or more reported primary outcome(s) was(were) not pre‐specified; outcomes of interest were reported incompletely and so cannot be used; study failed to include results of a key outcome that would have been expected to have been reported);
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unclear risk of bias.
(6) Other sources of bias
We described for each included study any important concerns we had about other possible sources of bias.
We assessed whether each study was free of other problems that could put it at risk of bias:
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low risk of other bias;
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high risk of other bias;
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unclear whether there is risk of other bias.
(7) Overall risk of bias
We made explicit judgments about whether studies were at high risk of bias, according to the criteria given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). With reference to (1) to (6) above, we assessed the likely magnitude and direction of the bias and whether we considered it likely to impact on the findings.
Measures of treatment effect
Dichotomous data
For dichotomous data, we presented results as summary risk ratio with 95% confidence intervals.
Continuous data
No trials provided continuous data. In future updates, if continuous data are analysed, we will use the mean difference if outcomes are measured in the same way between trials. We will use the standardised mean difference to combine trials that measure the same outcome, but use different methods.
Unit of analysis issues
Cluster‐randomised trials
In future updates, if identified and eligible for inclusion, we will include cluster‐randomised trials in the analyses along with individually‐randomised trials. We will adjust their sample sizes using the methods described in the Cochrane Handbook for Systematic Reviews of Interventions using an estimate of the intracluster correlation co‐efficient (ICC) derived from the trial (if possible), from a similar trial or from a study of a similar population. If we use ICCs from other sources, we will report this and conduct sensitivity analyses to investigate the effect of variation in the ICC. If we identify both cluster‐randomised trials and individually‐randomised trials, we plan to synthesise the relevant information. We will consider it reasonable to combine the results from both if there is little heterogeneity between the study designs and the interaction between the effect of intervention and the choice of randomisation unit is considered to be unlikely. We will also acknowledge heterogeneity in the randomisation unit and perform a sensitivity analysis to investigate the effects of the randomisation unit.
Cross‐over Trials
Cross‐over trials were excluded from this review.
Other unit of analysis issues
None identified.
Dealing with missing data
For included studies, levels of attrition were noted.
For all outcomes, analyses were carried out, as far as possible on an intention‐to‐treat basis (i.e., we attempted to include all participants randomised to each group in the analyses). The denominator for each outcome in each trial was the number randomised minus any participants whose outcomes were known to be missing.
Assessment of heterogeneity
We assessed statistical heterogeneity in each meta‐analysis using the T², I² and Chi² statistics. We regarded heterogeneity as substantial if the I² was greater than 50% and either the T² was greater than zero, or there was a low P value (< 0.10) in the Chi² test for heterogeneity.
Assessment of reporting biases
There were too few studies included and too few outcomes reported to assess the impact of potential reporting bias on outcomes. In future updates, if more studies are included, we will assess reporting biases.
If there are 10 or more studies in the meta‐analysis, we will investigate reporting biases (such as publication bias) using funnel plots. We will assess funnel plot asymmetry visually.
Data synthesis
We carried out statistical analysis using the Review Manager software (RevMan 2012). We used fixed‐effect inverse variance meta‐analysis for combining data where trials examined the same intervention, and the trials’ populations and methods were judged sufficiently similar. Where we suspected clinical or methodological heterogeneity between studies sufficient to suggest that treatment effects may differ between trials, we used random‐effects meta‐analyses. The random‐effects summary was treated as the average range of possible treatment effects. If the average treatment effect was not clinically meaningful, we did not combine trials.
If we used random‐effects analyses, the results were presented as the average treatment effect with 95% confidence intervals, and the estimates of T² and I².
Subgroup analysis and investigation of heterogeneity
If we identified substantial heterogeneity, we investigated it using the following subgroup analyses:
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type of agent used to prevent postpartum hypertension (i.e., furosemide versus an antihypertensive);
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treatment of mild‐to‐moderate versus severe postpartum hypertension.
The following outcomes were used in subgroup analyses:
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maternal death;
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maternal organ failure;
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severe hypotension;
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antihypertensive use in hospital;
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and antihypertensive use at hospital discharge.
We assessed subgroup differences by interaction tests available within RevMan (RevMan 2012). We reported the results of subgroup analyses quoting the χ2 statistic and P value, and the interaction test I² value.
Sensitivity analysis
We planned to carry out sensitivity analyses to explore the effect of trial quality assessed by concealment of allocation, high attrition rates, or both, with poor quality studies being excluded from the analyses in order to assess whether this made any difference to the overall result. Poor quality was defined as studies being at high risk of bias for allocation concealment, or incomplete outcome data, or both.
Results
Description of studies
Included studies
Nine trials were included.
SeeCharacteristics of included studies.
Prevention of postpartum hypertension
Four trials studied (358 women) interventions for prevention of postpartum hypertension in women with antenatal pre‐eclampsia (defined as pregnancy‐induced hypertension with either proteinuria or adverse features such as haemolysis, elevated liver enzymes, low platelets syndrome). Women with pre‐existing hypertension were excluded from one trial and those with chronic kidney disease from another.
Two trials (282 women) compared routine postnatal furosemide therapy (20 to 40 mg orally per day, for five to seven days) with either placebo or no therapy. In one trial (Ascarelli 2005), 20 mEq orally per day of supplemental potassium was administered, and in the other (Matthews 1997), intravenous magnesium sulphate was given if the woman was considered to be at 'high risk' of eclampsia. Neither trial reported mean and standard deviation (SD) of baseline blood pressure, but one trial (Matthews 1997) reported the change in blood pressure (BP) on days one, three and seven after delivery (i.e., ‐6.5 mmHg (furosemide) versus ‐3.5 (placebo) on day one, ‐10.6 (furosemide) versus ‐9.75 (placebo) on day three, and ‐11.5 (furosemide) versus ‐7.8 (placebo) on day seven). Follow‐up ranged from day 10 postpartum (Ascarelli 2005) to six weeks postpartum (Matthews 1997).
A third trial (31 women) compared nifedipine capsules (10 mg orally every four hours for 48 hours) with placebo (Barton 1990). Women had mild hypertension at baseline, and at 18 to 24 hours following delivery, mean (±SD) diastolic BP was 93.9 ± 1.6 mmHg (nifedipine) versus 100.2 ± 2.6 (placebo). All women in this trial were on magnesium sulphate. Women were followed until hospital discharge.
A fourth trial (45 women) compared L‐arginine (a nitric oxide donor) with placebo. Women had pre‐eclampsia antenatally or postnatally and a mean pre‐treatment BP of 169 ± 15mmHg systolic and 105 ± 8mmHg diastolic at a mean gestational age of 34.7 ± 4.0 weeks. Women received L‐arginine before delivery and for three days postpartum; most women (30/45) were treated only postpartum. Women were followed to day three and day 10 postpartum.
No trials were identified that compared routine postpartum administration of one antihypertensive agent versus another.
Treatment of postpartum hypertension
No trials were identified that compared antihypertensive therapy with placebo/no therapy.
Five trials (480 women) studied treatment of postpartum hypertension by comparing different oral antihypertensive agents.
Women in these trials were hypertensive postpartum, but the nature of the hypertensive disorder was not well described, and included both women who were normotensive ante and intrapartum, and those who had severe antenatal pre‐eclampsia. Diastolic BP was moderate to severe in nature. Approximately half of the women delivered their first child in the two trials that reported parity. Women with comorbid conditions were usually excluded, due to pre‐existing hypertension (Griffis 1989; Walss Rodriguez 1991), renal disease (Fidler 1992; Walss Rodriguez 1991), hepatic dysfunction (Griffis 1989), need for intensive care (Walss Rodriguez 1991), or diabetes or multiple pregnancy (Fidler 1992). One trial reported a average gestational age at delivery which was at term [38.6 ± 1.26 (nifedipine sublingual) versus 37.6 ± 2.4 (hydralazine sublingual)] (Walss Rodriguez 1991). Another reported an average gestational age at delivery that was preterm [33.2 ± 4.1 (methyldopa) versus 33.5 ± 4.3 (nifedipine)] (Sayin 2005).
Five trials compared one oral antihypertensive agent with another. In three trials, methyldopa was compared with either timolol (Fidler 1992), hydralazine (Griffis 1989), or nifedipine (oral) (Sayin 2005). In two trials, hydralazine (parenteral) was compared with either nifedipine (sublingual) (Walss Rodriguez 1991) or labetalol (iv) (Vigil‐De Gracia 2007). Follow‐up appeared to occur until hospital discharge (Griffis 1989; Sayin 2005; Vigil‐De Gracia 2007; Walss Rodriguez 1991) or until two to six weeks postpartum (Fidler 1992).
Excluded studies
Twenty trials were excluded based on: applying a surgical intervention (i.e., endometrial curettage), incomplete information about clinical outcomes, failure to report outcomes among women treated only postpartum, or the absence of abstractable data on clinical outcomes. SeeCharacteristics of excluded studies.
Risk of bias in included studies
All included trials were small, with a median sample size of 45 women (range 18 to 264). The quality of the trials was poor. No trials reported the potential co‐intervention of non‐steroidal anti‐inflammatory drug (NSAID) use for postnatal analgesia.
SeeFigure 1 and Figure 2 for summaries of 'Risk of bias' assessment.
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
Allocation
Four trials described a random component in the sequence generation process. Four trials described adequate concealment of allocation.
Blinding
Three of the nine trials reported outcome assessment blinding and most outcomes included data from only one trial.
Incomplete outcome data
There was adequate follow‐up (less than 2.5% loss to follow‐up) in all but one trial.
Selective reporting
Only two trials were deemed to be at low risk of bias for selective reporting. The risk of bias was unclear for five of the nine trials; they were published prior to the year 2000 and, as such, did not have published study protocols with which to compare reported outcomes in the manuscripts. One trial did not describe all pre‐specified outcomes and another did not report all outcomes according to randomised group.
Other potential sources of bias
No other sources of bias were identified.
Effects of interventions
Nine trials are included.
(A) Routine postnatal antihypertensive therapy in women with antenatal pre‐eclampsia, in order to prevent postpartum hypertension
Four trials (358 women) compared routine antihypertensive therapy (furosemide, nifedipine capsules, or L‐arginine) with an approach that dictated antihypertensive treatment only for severely elevated blood pressure postpartum. There are insufficient data for any conclusions about the possible benefits and harms of these management strategies.
There were no maternal deaths (Analysis 1.1), serious maternal morbidity (Analysis 1.2), or severe maternal hypotension reported (Analysis 1.3) but the data are limited and not consistent with either benefit or risk.
With use of routine postnatal furosemide, there was a strong trend for a decrease in the need for additional antihypertensive therapy (for blood pressure 150 systolic or 100 diastolic, or higher) on the postnatal wards (risk ratio (RR) 0.74, 95% confidence interval (CI) 0.55 to 1.00; one trial, N = 264 women) (Analysis 1.5). The direction of effect was the same for antihypertensive therapy at hospital discharge but the results were not statistically significant (RR 0.81, 95% CI 0.59 to 1.12; two trials, N = 282 women) (Analysis 1.6.1). The mean number of medical attendances during hospitalisation did not differ between the furosemide (14.9 attendances) and control (18.0 attendances) groups in one trial (Matthews 1997); however, statistical comparisons were not possible because standard deviations were not reported. Mean postnatal hospital stay did not appear to differ in one trial (7.3 versus 7.6 days) but SD were not reported (Matthews 1997).
The trial of routine nifedipine capsules reported no significant difference in the occurrence of severe hypertension treatment between groups, but data were not provided (Barton 1990). The trial of L‐arginine versus placebo did not find a between‐group difference in severe hypertension (or use of antihypertensive therapy on day three postpartum).
None of the 31 women in the nifedipine versus placebo trial changed drugs due to side‐effects (Analysis 1.7).
No differences between subgroups were observed (Analysis 1.6).
None of the aforementioned trials reported: whether or not women used NSAIDs for postpartum analgesia, the incidence of adverse drug reactions, or the incidence of breastfeeding.
(B) Antihypertensive therapy for women with postpartum hypertension
No trials were located that compared antihypertensive with placebo or no therapy for mild‐to‐moderate postpartum hypertension, of any type.
For treatment of mild‐moderate postpartum hypertension, three trials (189 women) compared timolol, hydralazine (oral), or nifedipine (oral) with methyldopa. Magnesium sulphate therapy was administered for 12 hours postpartum in one trial (Griffis 1989). There were no maternal deaths (Analysis 2.1). The need for additional antihypertensive therapy did not differ between the groups (average RR 0.92, 95% CI 0.20 to 4.20; three trials, 189 women; heterogeneity: Tau² = 0.75; Chi² = 2.09, df = 1 (P = 0.15); I² = 52%); however, the trials were more different in their effects than could be expected by chance alone (Analysis 2.3). The need to change drugs due to side‐effects was infrequent (Analysis 2.4).
For treatment of severe postpartum hypertension, two trials (120 women) compared intravenous hydralazine with either sublingual nifedipine (Walss Rodriguez 1991) or intravenous labetalol (Vigil‐De Gracia 2007). Magnesium sulphate therapy was given for 24 hours postpartum in one trial (Vigil‐De Gracia 2007). There were no maternal deaths and no reported maternal hypotension (Vigil‐De Gracia 2007) (Analysis 2.1) (Analysis 2.2). The need for additional antihypertensive therapy did not differ between groups (average RR 0.58, 95% CI 0.04 to 9.07; two trials, 120 women; heterogeneity: Tau² = 2.24; Chi² = 2.21, df = 1 (P = 0.14); I² = 55%), but the trials were not consistent in their effects (Analysis 2.3). The need to change drugs due to side‐effects was not reported.
No differences between subgroups were observed (Analysis 2.3).
None of these trials reported whether or not women used NSAIDs for postpartum analgesia.
Discussion
From the few trials that focused on the prevention or management of postpartum hypertension, there are insufficient data for any reliable conclusions to be drawn about the relative benefits and risks of different management strategies.
Prevention of postpartum hypertension
For women with antenatal hypertension, even that of pre‐eclampsia, there is a strong trend towards reduced use of antihypertensive therapy in hospital with use of routine postnatal furosemide (with routine potassium supplementation). It is unclear whether there may be other potential benefits (e.g., reduced antihypertensive use at hospital discharge and/or length of maternal hospital stay) or potential harms (e.g., on breastfeeding).
Treatment of postpartum hypertension
For women with manifest postpartum hypertension (whether or not they were hypertensive before delivery), there are no data that inform whether or not mild‐to‐moderate hypertension should be treated, and if so, whether or not one agent is preferable to another. Certainly, two of the agents studied (timolol and methyldopa) are not in common usage postpartum. Regardless of the approach taken, the currently evaluated antihypertensive therapies appear to be associated with few women changing drugs due to maternal side‐effects.
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
Comparison 1 Routine postnatal oral antihypertensive therapy for prevention of postpartum hypertension, Outcome 1 Maternal death.
Comparison 1 Routine postnatal oral antihypertensive therapy for prevention of postpartum hypertension, Outcome 2 Maternal organ failure.
Comparison 1 Routine postnatal oral antihypertensive therapy for prevention of postpartum hypertension, Outcome 3 Severe hypotension.
Comparison 1 Routine postnatal oral antihypertensive therapy for prevention of postpartum hypertension, Outcome 4 Severe hypertension.
Comparison 1 Routine postnatal oral antihypertensive therapy for prevention of postpartum hypertension, Outcome 5 Postnatal antihypertensive use in hospital.
Comparison 1 Routine postnatal oral antihypertensive therapy for prevention of postpartum hypertension, Outcome 6 Postnatal antihypertensive use at hospital DISCHARGE.
Comparison 1 Routine postnatal oral antihypertensive therapy for prevention of postpartum hypertension, Outcome 7 Medication changed secondary to maternal side‐effects.
Comparison 2 Oral antihypertensive therapy for treatment of postpartum hypertension, Outcome 1 Maternal death.
Comparison 2 Oral antihypertensive therapy for treatment of postpartum hypertension, Outcome 2 Maternal hypotension.
Comparison 2 Oral antihypertensive therapy for treatment of postpartum hypertension, Outcome 3 Need for additional antihypertensive therapy.
Comparison 2 Oral antihypertensive therapy for treatment of postpartum hypertension, Outcome 4 Medication changed secondary to maternal side‐effects.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Maternal death Show forest plot | 2 | 295 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 1.1 Furosemide versus placebo/no therapy | 1 | 264 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 1.2 Routine antihypertensive versus placebo | 1 | 31 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 2 Maternal organ failure Show forest plot | 1 | 264 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 2.1 Furosemide versus placebo/no therapy | 1 | 264 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 3 Severe hypotension Show forest plot | 1 | 31 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 3.1 Routine antihypertensive versus placebo | 1 | 31 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 4 Severe hypertension Show forest plot | 1 | 45 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.91 [0.60, 1.39] |
| 4.1 L‐arginine vs. placebo | 1 | 45 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.91 [0.60, 1.39] |
| 5 Postnatal antihypertensive use in hospital Show forest plot | 1 | 264 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.74 [0.55, 1.00] |
| 5.1 Furosemide versus placebo/no therapy | 1 | 264 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.74 [0.55, 1.00] |
| 6 Postnatal antihypertensive use at hospital DISCHARGE Show forest plot | 3 | 325 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.79 [0.58, 1.08] |
| 6.1 Furosemide vs. placebo/no therapy | 2 | 282 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.81 [0.59, 1.12] |
| 6.2 L‐arginine vs. placebo | 1 | 43 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.64 [0.21, 1.94] |
| 7 Medication changed secondary to maternal side‐effects Show forest plot | 1 | 31 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 7.1 Routine antihypertensive versus placebo | 1 | 31 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Maternal death Show forest plot | 2 | 106 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 1.1 Antihypertensive agent versus another for mild‐moderate postpartum hypertension | 2 | 106 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 2 Maternal hypotension Show forest plot | 1 | 82 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 2.1 Antihypertensive agent versus another for severe postpartum hypertension | 1 | 82 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 3 Need for additional antihypertensive therapy Show forest plot | 5 | 309 | Risk Ratio (M‐H, Random, 95% CI) | 0.70 [0.25, 1.96] |
| 3.1 Antihypertensive agent versus another for mild‐moderate postpartum hypertension | 3 | 189 | Risk Ratio (M‐H, Random, 95% CI) | 0.92 [0.20, 4.20] |
| 3.2 Antihypertensive agent versus another for severe postpartum hypertension | 2 | 120 | Risk Ratio (M‐H, Random, 95% CI) | 0.58 [0.04, 9.07] |
| 4 Medication changed secondary to maternal side‐effects Show forest plot | 2 | 106 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.5 [0.05, 5.30] |
| 4.1 Antihypertensive agent versus another for mild‐moderate postpartum hypertension | 2 | 106 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.5 [0.05, 5.30] |
| 4.2 Antihypertensive therapy for severe postpartum hypertension | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
