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Drugs for treatment of very high blood pressure during pregnancy

RHL Commentary by Oladapo OT and Adetoro O

1. EVIDENCE SUMMARY

This review (1) included twenty-four trials in which the antihypertensive effect of different drugs for the management of very high blood pressure during pregnancy was compared. For only few outcomes in four of the 12 drug–drug comparisons in the review could inferences be drawn about comparative effect: (i) calcium channel blockers (nifedipine and isradipine) are associated with less risk of persistent hypertension compared with hydralazine (6% versus 18%); (ii) Ketanserin is associated with almost fivefold risk of persistent hypertension compared with hydralazine (27% versus 6%), though side-effects are less common; (iii) diazoxide tends to cause more hypotension compared with labetalol; and (iv) nimodipine and magnesium sulfate are both associated with high levels of persistent hypertension (47% versus 65%), though nimodipine is less likely to cause respiratory difficulties, postpartum haemorrhage and side-effects. Overall, there is insufficient evidence to conclude that any one antihypertensive drug is clearly better those others for the treatment of women with very high blood pressure in pregnancy. Inclusion of more trials in the updated version of the review has not changed the conclusion of the initial review.

The criteria employed for identifying eligible studies in the review allowed inclusion of relevant trials. Though only short-term outcomes were reported in the included trials, the review also set out to compare long-term effects of antihypertensive drugs. Assessment of methodological quality of studies was based on stringent criteria that aimed at including only trials of high quality. However, the robustness of the results is diminished by the fact that majority of the included studies are of uncertain methodological quality as evident from the proportion of trials with adequate allocation concealment (5/24) and those that blinded intervention or outcome assessment. The findings of the review were summarized with appropriate statistical methods and the data were separately presented for each drug–drug comparison for clear understanding. However, there are contradictions between the findings reported in the body of the review and the abstract with respect to the risk of hypotension for labetalol and diazoxide and risk of persistent high blood pressure for nimodipine and magnesium sulfate. For the purpose of this commentary, we presumed the report in the text of the review is accurate as it is more elaborate and in keeping with the authors’ discussion of their findings. These disparities would subsequently need to be amended for the benefit of the readers of Cochrane reviews who limit reading to the abstract alone.

2. RELEVANCE TO UNDER-RESOURCED SETTINGS

2.1. Magnitude of the problem

Hypertension in pregnancy occurs in approximately 6–8% of all pregnant women (2) and ranks high as a cause of maternal morbidity and mortality worldwide, but especially in under-resourced settings. According to a WHO systematic analysis of the causes of maternal death, hypertensive disorders are among the leading causes of maternal death in developing countries, particularly in Africa, Latin America and the Caribbean (3). In South Africa alone, a total of 507 maternal deaths were associated with hypertensive disorders over the triennium 1999–2001 (4).

2.2. Applicability of the results

Most (16/24) of the trials in the review were conducted in developing-country settings and therefore the results are applicable to women in such settings. With the exception of nimodipine, which was compared with magnesium sulfate in the largest trial included, most of the drugs that were compared in the included trials are available in developing countries. Majority of the trials compared hydralazine, a widely available and relatively cheap drug in under-resourced settings, with other drugs. However, the results of the review are only applicable to women who present with severe hypertension while still pregnant and not to postpartum women with severe hypertension. Similarly, since the main concern is blood pressure reduction in many of the included trials with little or no documentation of safety and acceptability of the drugs for the mother and the fetus, it would not be justified to select any antihypertensive drug on the premise that it is likely to reduce the risk of severe maternal or fetal complications than other drugs.

2.3. Implementation of the intervention

Since the review indicates that no antihypertensive drug is better than the rest, the use of a particular drug would in the meantime depend on the physician’s experience and availability of the drug. In under-resourced settings where women pay for the services they receive, it is important for clinicians to familiarize themselves with the cost of available antihypertensive drugs. Although the trials showed that most of the drugs are effective for the control of severe hypertension in pregnancy, to be considered for a wider usage in pregnancy they need to be proven safe, readily available, affordable, and easy to administer. Of all the antihypertensive drugs in this review, hydralazine is the only one that is readily available in most under-resourced settings and, apart from magnesium sulfate; it is relatively cheaper than others. On the whole, hydralazine should be considered as the drug of choice for the management of severe high blood pressure in pregnancy in under-resourced settings because of its effectiveness, low cost, and relative safety. Although, calcium channel blockers appear to fair better than hydralazine with respect to reducing the risk of persistent hypertension, their cost is likely to limit their widespread use in under-resourced settings. Besides, concern has been raised about the concurrent use of calcium channel blockers and magnesium sulfate, an important drug for preventing convulsions in women with severe preeclampsia and eclampsia. It has been suggested that there could be increased risk of cardiac function depression because of the synergistic effects of the two drugs on neuromuscular system (5, 6). Therefore, these drugs should be used with extreme caution if they are to be used concurrently.

3. RESEARCH

Future trials should include the effect of the drugs on the mother and the fetus (both short-term and long-term effects) as part of their main outcome measures, in addition to their effect on blood pressure.

Sources of support: UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Geneva, Switzerland, and Liverpool School of Tropical Medicine, International Health Division, Liverpool, United Kingdom.

Acknowledgement: This commentary was initially written by Dr Olalekan Adetoro for an earlier version of the Cochrane review. It was partly prepared during the Fellowship Programme organized by the Cochrane Infectious Diseases Group in collaboration with the UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Geneva, Switzerland, in August 2006. The United Kingdom Department for International Development (DFID) supports HRP through the Effective Health Care Alliance Programme at the Liverpool School of Tropical Medicine for the benefit of developing countries. The views expressed are not necessarily those of DFID.

References

• Duley L, Henderson-Smart DJ, Meher S. Drugs for treatment of very high blood pressure during pregnancy (Cochrane Review). The Cochrane Database of Systematic Reviews;Issue 3, 2006.
• Sibai BM. Prevention of pre-eclampsia: a big disappointment. Am J Obstet Gynecol 1998;179:1275-1278.
• Khan KS, Wojdyla D, Say L, Gülmezoglu AM, Van Look PFA. WHO analysis of causes of maternal death: a systematic review. Lancet 2006;367:1066-1074.
• Moodley J. Maternal deaths associated with hypertensive disorders of pregnancy: a population-based study. Hypertens Pregnancy 2004;23:247-256.
• Davis WB, Wells SR, Kuller JA, Thorp JM Jr. Analysis of risks associated with calcium channel blockade: implications for the obstretrician-gynecologist. Obstet Gynecol Surv 1997;52:198-201.
• Snyder SW, Cardwell MS. Neuromuscular blockade with magnesium sulfate and nifedipine. Am J Obstet Gynecol 1989;161:35-36.

This document should be cited as: Olufemi T. Oladapo and Olalekan Adetoro. Drugs for treatment of very high blood pressure during pregnancy: RHL commentary (last revised: 15 December 2006). The WHO Reproductive Health Library; Geneva: World Health Organization.

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