Antihypertensive drug therapy for mild to moderate hypertension during pregnancy

What is the issue?

The aim of this review was to determine the benefits and adverse effects of blood pressure-lowering drugs (antihypertensive drugs) for pregnant women with mild to moderate hypertension (high blood pressure). The other aim was to assess the benefits and adverse effects of these drugs for their babies.

Why is this important?

During pregnancy, up to one in 10 women have blood pressure readings that are above normal. For some women, their blood pressure remains slightly high (termed ‘mild to moderate high blood pressure’), with no apparent complications. Some of these women go on to develop very high blood pressure. Very high blood pressure can result in a medical emergency if it affects the woman’s organs (such as her liver, or brain in the form of a stroke). Also, it can seriously affect the growth and health of her baby.

Drugs that lower blood pressure are used to treat mild to moderate high blood pressure, in the belief that this treatment will prevent the blood pressure from continuing to rise. Over the years, information from good quality research studies has been contradictory, so we cannot be sure if this drug treatment is worthwhile.

What evidence did we find?

This Cochrane Review is an update of a review that was first published in 2001 and updated in 2007 and 2014. We searched for randomised controlled trials in September 2017, and this review now includes data from 58 trials involving more than 5900 women. A total of 31 trials with 3485 women compared a number of different blood pressure-lowering drugs to a placebo or no treatment. There were a further 29 trials involving 2774 women which compared one blood pressure-lowering drug with another one.

The evidence showed that treating pregnant women who had moderately raised blood pressure with blood pressure-lowering drugs probably halved the number of the women developing severe high blood pressure (20 trials, 2558 women). However, blood pressure-lowering drugs probably had little or no effect on the risk of the baby dying (29 trials, 3365 women), and there is insufficient data on maternal deaths to make a judgement on whether this risk is lowered (five trials, 525 women).

The use of blood pressure-lowering drugs may have little or no effect on the number of the women developing pre-eclampsia (23 trials, 2851 women), or the number of women who had to change drugs because of side-effects (16 trials, 1503 women).

We found no difference in the number of babies born preterm, that is before 37 weeks (15 trials, 2141 women). There was also no difference in the number of babies born small for their gestational age (21 trials, 2686 babies).

The quality of the evidence was mostly moderate (but for pre-eclampsia it was low). This was due to a number of small studies, and problems with the way the studies were undertaken.

The available evidence is still insufficient to demonstrate if there is any antihypertensive drug that is better than another. However, beta blockers and calcium channel blockers seem to be better than the alternative drugs for blood pressure control.

What does this mean?

More research is needed in order to confirm the true effect of antihypertensive drugs in mothers and in their babies, and to identify the drug which would be best.

Authors' conclusions: 

Antihypertensive drug therapy for mild to moderate hypertension during pregnancy reduces the risk of severe hypertension. The effect on other clinically important outcomes remains unclear. If antihypertensive drugs are used, beta blockers and calcium channel blockers appear to be more effective than the alternatives for preventing severe hypertension. High-quality large sample-sized randomised controlled trials are required in order to provide reliable estimates of the benefits and adverse effects of antihypertensive treatment for mild to moderate hypertension for both mother and baby, as well as costs to the health services, women and their families.

Read the full abstract...
Background: 

Antihypertensive drugs are often used in the belief that lowering blood pressure will prevent progression to more severe disease, and thereby improve pregnancy outcome. This Cochrane Review is an updated review, first published in 2001 and subsequently updated in 2007 and 2014.

Objectives: 

To assess the effects of antihypertensive drug treatments for women with mild to moderate hypertension during pregnancy.

Search strategy: 

We searched Cochrane Pregnancy and Childbirth’s Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (13 September 2017), and reference lists of retrieved studies.

Selection criteria: 

All randomised trials evaluating any antihypertensive drug treatment for mild to moderate hypertension during pregnancy, defined as systolic blood pressure 140 to 169 mmHg and/or diastolic blood pressure 90 to 109 mmHg. Comparisons were of one or more antihypertensive drug(s) with placebo, with no antihypertensive drug, or with another antihypertensive drug, and where treatment was planned to continue for at least seven days.

Data collection and analysis: 

Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy.

Main results: 

For this update, we included 63 trials (data from 58 trials, 5909 women), with moderate to high risk of bias overall.

We carried out GRADE assessments for the main 'antihypertensive drug versus placebo/no antihypertensive drug' comparison only. Evidence was graded from very low to moderate certainty, with downgrading mainly due to design limitations and imprecision.For many outcomes, trials contributing data evaluated different hypertensive drugs; while we did not downgrade for this indirectness, results should be interpreted with caution.

Antihypertensive drug versus placebo/no antihypertensive drug (31 trials, 3485 women)

Primary outcomes: moderate-certainty evidence suggests that use of antihypertensive drug(s) probably halves the risk of developing severe hypertension (risk ratio (RR) 0.49; 95% confidence interval (CI) 0.40 to 0.60; 20 trials, 2558 women), but may have little or no effect on the risk of proteinuria/pre-eclampsia (average risk ratio (aRR) 0.92; 95% CI 0.75 to 1.14; 23 trials, 2851 women; low-certainty evidence). Moderate-certainty evidence also shows that antihypertensive drug(s) probably have little or no effect in the risk of total reported fetal or neonatal death (including miscarriage) (aRR 0.72; 95% CI 0.50 to 1.04; 29 trials, 3365 women), small-for-gestational-age babies (aRR 0.96; 95% CI 0.78 to 1.18; 21 trials, 2686 babies) or preterm birth less than 37 weeks (aRR 0.96; 95% CI 0.83 to 1.12; 15 trials, 2141 women).

Secondary outcomes: we are uncertain of the effect of antihypertensive drug(s) on the risk of maternal death, severe pre-eclampsia, or eclampsia, or impaired long-term growth and development of the baby in infancy and childhood, because the certainty of this evidence is very low. There may be little or no effect on the risk of changed/stopped drugs due to maternal side-effects, or admission to neonatal or intensive care nursery (low-certainty evidence). There is probably little or no difference in the risk of elective delivery (moderate-certainty evidence).

Antihypertensive drug versus another antihypertensive drug (29 trials, 2774 women)

Primary outcomes: beta blockers and calcium channel blockers together in the meta-analysis appear to be more effective than methyldopa in avoiding an episode of severe hypertension (RR 0.70; 95% CI 0.56 to 0.88; 11 trials, 638 women). There was also an increase in this risk when other antihypertensive drugs were compared with calcium channel blockers (RR 1.86; 95% CI 1.09 to 3.15; 5 trials, 223 women), but no evidence of a difference when methyldopa and calcium channel blockers together were compared with beta blockers (RR1.18, 95% CI 0.95 to 1.48; 10 trials, 692 women). No evidence of a difference in the risk of proteinuria/pre-eclampsia was found when alternative drugs were compared with methyldopa (aRR 0.78; 95% CI 0.58 to 1.06; 11 trials, 997 women), with calcium channel blockers (aRR: 1.24, 95% CI 0.70 to 2.19; 5 trials, 375 women), or with beta blockers (aRR 1.21, 95% CI 0.88 to 1.67; 12 trials, 1107 women).

For the babies, we found no evidence of a difference in the risk of total reported fetal or neonatal death (including miscarriage) when comparing other antihypertensive drugs with methyldopa (aRR 0.77, 95% CI 0.52 to 1.14; 22 trials, 1791 babies), with calcium channel blockers (aRR 0.90, 95% CI 0.52 to 1.57; nine trials, 700 babies), or with beta blockers (aRR: 1.23, 95% CI 0.81 to 1.88; 19 trials, 1652 babies); nor in the risk for small-for-gestational age in the comparison with methyldopa (aRR 0.79, 95% CI 0.52 to 1.20; seven trials, 597 babies), with calcium channel blockers (aRR 1.05, 95% CI 0.64 to 1.73; four trials, 200 babies), or with beta blockers (average RR 1.13, 95% CI 0.80 to 1.60; 7 trials, 680 babies). No evidence of an overall difference among groups in the risk of preterm birth (less than 37 weeks) was found in the comparison with methyldopa (aRR: 0.91; 95% CI 0.68 to 1.22; 11 trials, 835 women), with calcium channel blockers (aRR 0.85, 95% CI 0.59 to 1.23; six trials, 330 women), or with beta blockers (aRR 1.22, 95% CI 0.90 to 1.66; 9 trials, 806 women).

Secondary outcomes: There were no cases of maternal death and eclampsia. There is no evidence of a difference in the risk of severe pre-eclampsia, changed/stopped drug due to maternal side-effects, elective delivery, admission to neonatal or intensive care nursery when other antihypertensive drugs are compared with methyldopa, calcium channel blockers or beta blockers. Impaired long-term growth and development in infancy and childhood was not reported for these comparisons.

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