Antihypertensive drug therapy for mild to moderate hypertension during pregnancy

Edgardo Abalos; Lelia Duley; D Wilhelm Steyn; Celina Gialdini

doi:10.1002/14651858.CD002252.pub4

. 2018 Oct 1;2018(10):CD002252. doi: 10.1002/14651858.CD002252.pub4

Antihypertensive drug therapy for mild to moderate hypertension during pregnancy

Edgardo Abalos ^1,^✉, Lelia Duley ², D Wilhelm Steyn ³, Celina Gialdini ⁴

Editor: Cochrane Pregnancy and Childbirth Group

PMCID: PMC6517078 PMID: 30277556

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 methods

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, orimpaired 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 oftotal 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 andeclampsia. 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.

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.

Plain language summary

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.

Summary of findings

Background

Description of the condition

Hypertension during pregnancy is common. One in 10 women will have high blood pressure at some time before delivery, and pre‐eclampsia complicates between 2% to 8% of all pregnancies worldwide (Abalos 2013). Hypertensive disorders of pregnancy, particularly pre‐eclampsia and eclampsia, constitute important causes of severe acute morbidity, long‐term disability and death among mothers and babies (Abalos 2014a; Khan 2006). Pre‐eclampsia is discussed in more detail in the generic protocol of interventions for prevention of pre‐eclampsia (Meher 2005).

There is a general consensus about the classification of hypertensive disorders during pregnancy (NHBPEP 2000) considering four broad categories: (a) gestational hypertension or pregnancy‐induced hypertension, which is hypertension newly diagnosed after 20 weeks of gestation without proteinuria; (b) pre‐eclampsia, which is hypertension developed after 20 weeks of gestation with proteinuria; (c) chronic hypertension, or essential hypertension, which is pre‐existing hypertension; and (d) chronic hypertension with superimposed pre‐eclampsia. Recently, the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy extended the diagnosis of pre‐eclampsia to those cases in which hypertension, in the absence of significant proteinuria, is associated with other systemic findings such as thrombocytopenia, worsening liver or renal function, pulmonary oedema or new‐onset cerebral or visual disturbances (ACOG Task Force 2013).

Moderate hypertension is defined as systolic blood pressure of 140 mmHg or more, and/or diastolic blood pressure of 90 mmHg or above on two consecutive occasions at least four hours apart. Severe hypertension is defined as systolic blood pressure of 160 mmHg or 170 mmHg and/or diastolic blood pressure of 110 mmHg or more two consecutive occasions up to 15 minutes apart (ACOG Task Force 2013; Canadian HDP Working Group 2014; NHBPEP 2000). Korotkoff phase V (disappearance of sounds) is now widely recommended as more reliable than phase IV (muffling) for measuring diastolic blood pressure (Canadian HDP Working Group 2014).

For this review we have accepted broad and pragmatic criteria for identifying women with mild to moderate hypertension during pregnancy. This reflects clinical practice, and is justifiable in the context of randomised trials as within each study the same criteria will have been used for women in both groups.

Description of the intervention

A wide variety of drugs have been advocated for lowering blood pressure in pregnant women with hypertension, and each group has different potential side‐effects and adverse events. In this review we evaluate individual agents within the class or family to which they belong, as each class has a similar mechanism of action.

How the intervention might work

Alpha agonists: inhibit vasoconstriction via a centrally mediated effect (Ingenito 1970). Methyldopa is the most widely used alpha agonist, and became available in 1963. Clonidine is also an alpha agonist, although it has the disadvantage that sudden withdrawal may cause a hypertensive crisis (Isaac 1980). Common side‐effects of methyldopa include dizziness, lightheadedness, drowsiness, headache, stuffy nose, and weakness, especially when starting this medication and when dosage is increased. Other side‐effects include swelling, muscle pain, dry mouth, swollen or "black" tongue, gastrointestinal symptoms and depression (depressed mood, unusual thoughts, and nightmares).

Beta blockers: beta‐adrenoceptor blocking drugs block adrenoceptors in the heart, peripheral blood vessels, airways, pancreas and liver (Frishman 1979). Labetalol has an additional arteriolar vasodilating action that lowers peripheral resistance, but is usually classified with the beta blockers. Side‐effects of beta blockers include oedema, postural hypotension, bradycardia, cold or cyanotic extremities, rashes, masking of the normal response to hypoglycaemia (sweating and tachycardia), nausea, dyspepsia, vomiting, difficulty in micturition (including acute urinary bladder retention, dizziness, headache, taste distortion, vertigo, and paraesthesia.

Calcium channel blockers: include amlodipine, isradipine, nifedipine, nicardipine, nimodipine and verapamil. These drugs inhibit influx of calcium ions to vascular smooth muscle resulting in arterial vasodilatation (Robinson 1980). Common side‐effects of calcium channel blockers include dizziness, giddiness, lightheadedness, headaches, heat sensation, weakness, flushing, palpitations, transient hypotension, heartburn, nausea, dyspnoea, nasal congestion, and muscle cramps.

Peripheral vasodilators: hydralazine is a vasodilator with a direct relaxing effect on smooth muscle in the blood vessels, predominantly in the arterioles (Stunkard 1954). The most frequently reported side‐effects are palpitations and tachycardia. Other side‐effects include flushing, hypotension, nausea, vomiting, diarrhoea, gastrointestinal disturbances, headache, arthralgia, joint swelling, myalgia, and anorexia.

Serotonin receptor antagonists: ketanserin is a selective serotonin receptor antagonist with weak adrenergic receptor blocking properties (Frishman 1995). The drug is effective in lowering blood pressure in essential hypertension. It also inhibits platelet aggregation. Side‐effects of ketanserin includes dizziness, headache, drowsiness, fatigue, dry mouth, sedation, lightheadedness, lack of concentration, gastrointestinal disturbances. Rare but serious side‐effects includes ventricular tachycardia.

Nitric‐oxid donors: glyceryl trinitrate is a nitric oxide donor with vasodilator effect in perivascular smooth‐muscle cells (Seligman 1994). Side‐effects include chest pain, hypoxaemia, difficulty breathing, cyanosis, tachycardia, throbbing headache, spinning sensation, postural hypotension, dizziness, drowsiness, and weakness.

Phosphodiesterase inhibitors: sildenafil (usually associated with treatment of erectile dysfunction in men) has been attracting the attention of clinicians and researchers. This is a phosphodiesterase type 5 inhibitor that increases intracellular cyclic guanosine monophosphate (cGMP) in the vascular smooth muscle, resulting in vasodilatation (Wareing 2004). The most common adverse reactions reported in clinical trials are headache, flushing, dyspepsia, abnormal vision, nasal congestion, back pain, myalgia, nausea, dizziness, and rash.

Why it is important to do this review

The role of antihypertensive therapy for pregnant women with mild to moderate hypertension is unclear. As there is no immediate need to lower mild to moderate rises in blood pressure, the rationale for treatment is that it will prevent or delay progression to more severe disease, thereby benefiting the woman or her baby, or both, and reducing consumption of health service resources. As well as reducing blood pressure, the belief has been that these drugs reduce the risk of preterm delivery and placental abruption and improve fetal growth. The aim of this review is to assess the potential benefits and hazards, to the woman and baby, of antihypertensive drugs for the treatment of mild to moderate hypertension during pregnancy. If antihypertensive agents are overall beneficial, a secondary aim will be to assess the comparative effects of alternative agents.

There are other types of interventions for women with mild to moderate hypertension during pregnancy that are not considered in this review. Interventions covered by other reviews include salt restriction (Duley 1999), antiplatelet agents (Duley 2007), abdominal decompression (Hofmeyr 2012), and bed rest, with or without hospitalisation (Meher 2005a). The role of diuretics for women with hypertension during pregnancy is covered by a separate Cochrane review (Churchill 2007), as is prevention and treatment of postpartum hypertension (Magee 2013).

For women with severe hypertension, usually defined as 170 mmHg or more systolic blood pressure or 110 mmHg or more diastolic blood pressure, there is a risk of direct arterial damage and so antihypertensive drugs are used to lower blood pressure (Gifford 1990; Redman 1993). The question of which drug is best in this situation is considered in another Cochrane review and not discussed further here (Duley 2013).

A separate review assessing the effect of alternative oral beta blocker regimens in mild to moderate hypertension during pregnancy is underway. Beta blockers are included in this review as part of all the spectrum of antihypertensive drugs.

Objectives

To determine the possible benefits, risks and side‐effects of antihypertensive drug treatments for women with mild to moderate hypertension during pregnancy (defined whenever possible as a systolic blood pressure of 140 to 169 mmHg or diastolic blood pressure of 90 to 109 mmHg, or both). Also, to compare the differential effects of alternative drug regimens.

The comparisons are of:

any antihypertensive drug with either no drug or placebo;
one antihypertensive drug compared with another. For this review, the commonly used group of drugs are regarded as controls and compared with all other group of drugs (for example, other antihypertensives versus methyldopa, other antihypertensives versus calcium channel blockers, and other antihypertensives versus beta blockers).

Methods

Criteria for considering studies for this review

Types of studies

All cluster‐ and‐ individually‐randomised trials evaluating any antihypertensive drug treatment for mild to moderate hypertension during pregnancy. Quasi‐randomised trials were excluded. Cross‐over trials were not eligible for inclusion.

Types of participants

The review includes women with mild to moderate hypertension during pregnancy, defined whenever possible as those with systolic blood pressure 140 to 169 mmHg and/or diastolic blood pressure 90 to 109 mmHg. Studies in which participants were described as having 'mild to moderate' hypertension but the range of blood pressures was not clearly specified were also included. Women were included regardless of whether they had proteinuria or not, and irrespective of previous antihypertensive treatment or whether the pregnancy was singleton or multiple.

Women who had given birth before trial entry were excluded, as were women with severe hypertension (defined whenever possible as either systolic blood pressure of 170 mmHg or more, or diastolic blood pressure 110 mmHg or more). Studies that included a substantial proportion of women who did not have mild to moderate hypertension were excluded, unless data were available on outcomes for those with mild to moderate hypertension only.

Types of interventions

Any comparison of one or more antihypertensive drug with either placebo or no antihypertensive drug was included, as were comparisons of one antihypertensive drug with another. Studies were excluded if the intention was to treat for less than seven days, as a longer period of treatment would be necessary for any substantive clinical effect. Comparisons of two drugs of the same class were also excluded, although these may be included in future updates if clinically relevant.    Drugs that aimed to reduce the risk of pregnancy‐induced hypertension progressing to pre‐eclampsia but are not antihypertensive agents were also excluded.

Types of outcome measures

Primary outcomes

Main outcomes were pre‐specified as follows.

Severe hypertension: defined whenever possible as either systolic blood pressure 170 mmHg or more, or diastolic blood pressure 110 mmHg or more. Trials where the definition of severe hypertension was not clear, or where the cut‐off was up to 10 mmHg lower were also included and were clearly documented.
Proteinuria/pre‐eclampsia: defined whenever possible as new proteinuria (1+ or more or 300 mg/24 hours).
Total reported fetal or neonatal death (including miscarriage): fetal deaths included miscarriage (fetal losses before viability, usually taken as 20 or 24 weeks) and stillbirths (after 24 weeks, or however defined). Perinatal deaths are stillbirths plus deaths in the first week of life. Neonatal deaths are deaths in the first 28 days.
Small‐for‐gestational age: low birthweight for gestational age, below the third, fifth or 10th percentile, using the most severe reported.
Preterm birth: all births before 37 completed weeks.

Secondary outcomes

For the woman

Maternal death.
Severe pre‐eclampsia: defined whenever possible as severe hypertension with proteinuria 2+ or more, or 2 g or more/24 hours, with or without other signs of symptoms, or as moderate hypertension with proteinuria 3+ or more. Haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome is a form of severe pre‐eclampsia and was therefore included here as well as a separate measure. Trials reporting imminent eclampsia, or where the definition of severe pre‐eclampsia was not clear were also included.
Eclampsia.
HELLP syndrome.
Severe maternal morbidity: such as liver or renal failure, disseminated intravascular coagulation and cerebrovascular accident (stroke).
Need for additional antihypertensive drug/s to control blood pressure.
Miscarriage (fetal losses before viability, usually taken as before 20 or 24 weeks).
Elective delivery: combines elective caesarean sections and elective induction of labour at term or before term.
Caesarean section.
Antenatal hospital admission and length of stay more than seven days: hospital and day care units were to be reported separately.
Placental abruption.
Side‐effects: any reported side‐effects or severe adverse events.
Changed/stopped drug due to maternal side‐effects.

For the baby

Very low, less than four, five‐minute Apgar score.
Severe prematurity, all births less than 32 or less than 34 weeks' gestation.
Admission to neonatal or intensive care nursery.
Respiratory distress syndrome.
Other morbidity possibly related to maternal drug therapy, such as hypo‐ or hypertension, hypoglycaemia and bradycardia (with beta blockers).
Impaired long‐term growth and development in infancy and childhood.

Search methods for identification of studies

The following search methods section of this review is based on a standard template used by Cochrane Pregnancy and Childbirth.

Electronic searches

For this update, we searched Cochrane Pregnancy and Childbirth’s Trials Register by contacting their Information Specialist (13 September 2017).

The Register is a database containing over 24,000 reports of controlled trials in the field of pregnancy and childbirth. For full search methods used to populate Pregnancy and Childbirth’s Trials Register including the detailed search strategies for CENTRAL, MEDLINE, Embase and CINAHL; the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service, please follow this link to the editorial information about the Cochrane Pregnancy and Childbirth in the Cochrane Library and select the ‘Specialized Register ’ section from the options on the left side of the screen.

Briefly, Cochrane Pregnancy and Childbirth’s Trials Register is maintained by their Information Specialist and contains trials identified from:

monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
weekly searches of MEDLINE (Ovid);
weekly searches of Embase (Ovid);
monthly searches of CINAHL (EBSCO);
handsearches of 30 journals and the proceedings of major conferences;
weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.

Search results are screened by two people and the full text of all relevant trial reports identified through the searching activities described above is reviewed. Based on the intervention described, each trial report is assigned a number that corresponds to a specific Pregnancy and Childbirth review topic (or topics), and is then added to the Register. The Information Specialist searches the Register for each review using this topic number rather than keywords. This results in a more specific search set that has been fully accounted for in the relevant review sections (Included studies; Excluded studies; Ongoing studies).

In addition, we searched ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) (13 September 2017) for unpublished, planned and ongoing trial reports (See: Appendix 1)

Searching other resources

We searched reference lists of retrieved studies.

We did not apply any language or date restrictions.

Data collection and analysis

For methods used in the previous version of this review, seeAbalos 2014.

For this update, the following methods were used for assessing the 45 reports that were identified as a result of the updated search.

The following methods section of this review is based on a standard template used by Cochrane Pregnancy and Childbirth.

Selection of studies

Two review authors independently assessed for inclusion all the potential studies identified as a result of the search strategy. We resolved any disagreement through discussion or, if required, we consulted a third review author.

Data extraction and management

We designed a form to extract data. For eligible studies, two review authors extracted the data using the agreed form. We resolved discrepancies through discussion or, if required, we consulted a third review author. Data were entered into Review Manager software (RevMan 2014) and checked for accuracy.

When information regarding any of the above was unclear, we planned 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) Random sequence generation (checking for possible selection bias)

We described for each included study the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.

We assessed the method as:

low risk of bias (any truly random process, e.g. random number table; computer random number generator);
high risk of bias (any non‐random process, e.g. odd or even date of birth; hospital or clinic record number);
unclear risk of bias.

(2) Allocation concealment (checking for possible selection bias)

We described for each included study the method used to conceal allocation to interventions prior to assignment and assessed whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.

We assessed the methods as:

low risk of bias (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);
high risk of bias (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth);
unclear risk of bias.

(3.1) Blinding of participants and personnel (checking for possible performance bias)

We described for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We considered that studies were at low risk of bias if they were blinded, or if we judged that the lack of blinding unlikely to affect results. We assessed blinding separately for different outcomes or classes of outcomes.

We assessed the methods as:

low, high or unclear risk of bias for participants;
low, high or unclear risk of bias for personnel.

(3.2) Blinding of outcome assessment (checking for possible detection bias)

We described for each included study the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received. We assessed blinding separately for different outcomes or classes of outcomes.

We assessed methods used to blind outcome assessment as:

low, high or unclear risk of bias.

(4) Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data)

We 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 stated whether attrition and exclusions were reported and 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 planned to re‐include missing data in the analyses which we undertook.

We assessed the methods as:

low risk of bias (e.g. no missing outcome data; missing outcome data balanced across groups);
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);
unclear risk of bias.

(5) Selective reporting (checking for reporting bias)

We described for each included study how we investigated the possibility of selective outcome reporting bias and what we found.

We assessed the methods as:
low risk of bias (where it is clear that all of the study’s pre‐specified outcomes and all expected outcomes of interest to the review have been reported);
high risk of bias (where not all the study’s pre‐specified outcomes have been reported; one or more reported primary outcomes were not pre‐specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);
unclear risk of bias.

(6) Other bias (checking for bias due to problems not covered by (1) to (5) above)

We described for each included study any important concerns we had about other possible sources of bias.

(7) Overall risk of bias

We made explicit judgements about whether studies were at high risk of bias, according to the criteria given in the Handbook (Higgins 2011). With reference to (1) to (6) above, we planned to assess the likely magnitude and direction of the bias and whether we considered it is likely to impact on the findings. In future updates, we will explore the impact of the level of bias through undertaking sensitivity analyses ‐ seeSensitivity analysis.

Assessment of the quality of the evidence using the GRADE approach

For this update the quality of the evidence was assessed using the GRADE approach as outlined in the GRADE handbook in order to assess the quality of the body of evidence relating to the following outcomes for the main comparison ‐ any hypertensive drug versus no antihypertensive drugs/placebo.

Primary outcomes

Severe hypertension
Proteinuria/pre‐eclampsia
Total reported fetal or neonatal (including miscarriage)
Small‐for‐gestational age
Preterm birth

Secondary outcomes

Maternal

Maternal death
Severe pre‐eclampsia
Eclampsia
Elective delivery
Changed/stopped drug due to maternal side‐effects

Fetal/infant outcomes

Admission to neonatal or intensive care nursery
Follow‐up of the children at one year: cerebral palsy

We used the GRADEpro Guideline Development Tool to import data from Review Manager 5.3 (RevMan 2014) in order to create ’Summary of findings’ tables. A summary of the intervention effect and a measure of quality for each of the above outcomes was produced using the GRADE approach. The GRADE approach uses five considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of the body of evidence for each outcome. The evidence can be downgraded from 'high quality' by one level for serious (or by two levels for very serious) limitations, depending on assessments for risk of bias, indirectness of evidence, serious inconsistency, imprecision of effect estimates or potential publication bias.

Measures of treatment effect

Dichotomous data

For dichotomous data, we presented results as summary risk ratio with 95% confidence intervals.

Continuous data

We planned to use the mean difference if outcomes were measured in the same way between trials. We would have used the standardised mean difference to combine trials that measured the same outcome, but used different methods.

Unit of analysis issues

Cluster‐randomised trials

Although there were no cluster‐randomised trials identified to date for inclusion, we will include them in future updates in the analyses along with individually‐randomised trials. We will adjust their sample sizes using the methods described in the Handbook [Section 16.3.4] 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.

Other unit of analysis issues

Dealing with more than two intervention groups

For multi‐arm studies, all intervention arms were mentioned and described in the Characteristics of included studies table, including the number of women randomised to each arm. Appropriate pair‐wise comparisons were selected for the meta‐analysis in order to avoid double‐counting of one of the arms. For example, when two different antihypertensive drugs were compared with placebo, the active drug groups were combined into one arm for the comparison antihypertensive drugs versus no antihypertensive drugs/placebo. These two arms, were included separately in the meta‐analysis of alternative regimens.

Dealing with missing data

For included studies, we noted levels of attrition. In future updates, if more eligible studies are included, we will explore the impact of including studies with high levels of missing data in the overall assessment of treatment effect by using sensitivity analysis.

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 Tau², I² and Chi² statistics. We regarded heterogeneity as substantial if an I² was greater than 30% and either a Tau² was greater than zero, or there was a low P value (less than 0.10) in the Chi² test for heterogeneity. If we identified substantial heterogeneity (above 30%), we planned to explore it by pre‐specified subgroup analysis.

Assessment of reporting biases

Where there were 10 or more studies in the meta‐analysis, we investigated reporting biases (such as publication bias) using funnel plots. We assessed funnel plot asymmetry visually. If asymmetry was suggested by a visual assessment, we performed exploratory analyses to investigate it.

Data synthesis

We carried out statistical analysis using the Review Manager software (RevMan 2014). We used fixed‐effect meta‐analysis for combining data where it was reasonable to assume that studies were estimating the same underlying treatment effect: i.e. where trials were examining the same intervention, and the trials’ populations and methods were judged sufficiently similar.

Where there was clinical heterogeneity sufficient to expect that the underlying treatment effects differed between trials, or if substantial statistical heterogeneity was detected, we used random‐effects meta‐analysis to produce an overall summary, if an average treatment effect across trials was considered clinically meaningful. The random‐effects summary was treated as the average range of possible treatment effects and we discussed the clinical implications of treatment effects differing between trials. If the average treatment effect was not clinically meaningful, we did not combine trials. Where we used random‐effects analyses, the results were presented as the average treatment effect with 95% confidence intervals, and the estimates of Tau² and I².

Subgroup analysis and investigation of heterogeneity

For the comparison of antihypertensive drug/s with placebo or no treatment the following subgroup analyses were pre‐specified:

by class of drug (such as alpha agonists, beta blockers and calcium channel blockers);
by type of hypertensive disorder at trial entry: mild to moderate hypertension alone; mild to moderate hypertension with proteinuria; chronic hypertension; unspecified;
by gestational age at trial entry: less than about 32 weeks' gestation; about 32 weeks or more gestation; or unclassified/mixed;
by whether a placebo was used: placebo, no placebo.

The subgroup analysis by type of drug is presented for all outcomes. The remaining subgroups are presented for the pre‐specified primary outcomes only.

We assessed subgroup differences by interaction tests available within RevMan (RevMan 2014). We reported the results of subgroup analyses quoting the Chi² statistic and P value, and the interaction test I² value.

Sensitivity analysis

We did not conducted sensitivity analyses. In future updates, we plan 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 (high and unclear risk of bias) being excluded from the analyses in order to assess whether this makes any difference to the overall result. If future updates include cluster‐randomised trials, we will also acknowledge heterogeneity in the randomisation unit and perform a sensitivity analysis to investigate the effects of the randomisation unit. In future updates, if more eligible studies are included, the impact of including studies with high levels of missing data in the overall assessment of treatment effect will be explored by using sensitivity analysis.

Results

Description of studies

Results of the search

See: Figure 1.

We retrieved 45 trial reports to assess from the updated search in September 2017 and we also reassessed one ongoing trial listed in the previous version of the review. We included nine new trials (14 reports), and five previously excluded studies in the qualitative synthesis and excluded 20 (23 reports) and added an additional reference to an already excluded study. Eight trials are ongoing.

Included studies

In total, 63 studies were included in this review. From these, 58 trials (5909 women) contributed data: 36 trials (3629 women) were conducted in high‐income countries (Australia, France, Hong Kong, Ireland, Israel, Italy, Sweden, UK and USA), and 22 trials (2280 women) in middle‐ or low‐income countries (Argentina, Brazil, Caribbean Islands, India, Pakistan, Panama, South Africa, Sudan and Venezuela).

Methods and trial dates

Three trials (405 women) were published in the 1960s and 1970s, 22 (1854 women) in the 1980s, 17 (1718 women) in the 1990s, and 16 (1927 women) after the year 2000. All included trials are small. The largest study recruited 314 women. Only six studies had comparison arms containing more than 100 women. Two three‐arm trials of methyldopa versus labetalol versus no treatment (India 2012; USA 1990a) were included in the comparison of any antihypertensive with placebo/no antihypertensive, and in the comparison of one drug with another. One three‐arm trial of nifedipine versus methyldopa versus labetalol (India 2015a), was included in the comparison one drug versus another. Another three‐arm trial of furosemide versus amlodipine versus aspirin (Panama 2014), was only included in the comparison one drug versus another (furosemide versus amlodipine), as aspirin is not an antihypertensive and was only prescribed in the third arm.

Funding sources

Six of the included trials reported to be funded by universities or non commercial organisations; 14 trials were funded by industry and two trials stated to have no funding source. The remaining trials provided no information about funding.

Trials authors' declaration of interest

Authors of UK 2017 declared that "C. Nelson‐Piercy reports personal fees from Alliance Pharmaceuticals, UCB Pharmaceuticals, LEO Pharmaceuticals, Sanofi Aventis, and Warner Chilcott outside the submitted work. J.K. Cruickshank is current President of the Artery Society which has had donations from Servier Pharmaceuticals" and that "the other authors report no conflicts". Authors of Brazil 2016, India 2012, India 2013c, India 2015a, India 2015b, Panama 2014 and UK 2009 declared that they had no conflicts of interest. Of the remaining studies, none included any declarations of interest.

Interventions and comparisons

The antihypertensive drugs used in these trials include: alpha agonists (methyldopa), beta blockers (acebutolol, atenolol, labetalol, mepindolol, metoprolol, pindolol, oxprenolol and propranolol), calcium channel blockers (amlodipine, isradipine, nicardipine, nifedipine, nimodipine and verapamil), vasodilators (hydralazine and prazozin), ketanserin, glyceryl trinitrate (GTN), furosemide and sildenafil. All drugs were given orally, except glyceryl trinitrate, which was given transdermally. The dose for several agents varied considerably between studies, in both amount and duration of therapy.

The antihypertensive drug was compared with placebo, or no antihypertensive drug, in 31 trials (3480 women). Of these trials, 17 evaluated beta blockers (1902 women), seven using a placebo for the control group and 10 comparing with no treatment. Methyldopa was evaluated in eight trials (986 women), one comparison with placebo, and seven with no antihypertensive treatment. One trial (118 women) compared isradipine with placebo, another trial (199 women) compared verapamil with placebo, and three studies (583 women) compared nifedipine with no drug treatment. Prazozin was compared with placebo in one trial (32 women), and GTN was compared with placebo patches in another (16 women). Two newly included trials (Brazil 2016; UK 2009) compared sildenafil with placebo in 130 women.

Alternative drug regimens were compared in 30 trials (3093 women). Twenty‐five of these studies compared methyldopa with another agent. In 19 trials (2041 women) the comparison was with beta blockers, in four it was nifedipine (389 women), in one (111 women) it was nimodipine, and in another ketanserin (20 women). Two trials (354 women) compared labetalol versus nifedipine. One small trial (36 women) compared nifedipine with GTN. In one study (100 women), metoprolol was compared with nicardipine and in another (42 women) furosemide was compared with amlodipine (the aspirin arm of this study was not considered for this review).

Gestation at trial entry

Twenty of the 58 included studies contributing to data recruited women during the second and third trimester of pregnancy, and 21 recruited only during the third trimester. Eight studies recruited women during the first and second trimester. Gestational age at trial entry was not reported in nine studies.

Severity and type of hypertension disease at trial entry

Mild to moderate hypertension was defined as a diastolic blood pressure of 90 mmHg or more in 42 studies. In five trials, the definition was 95 mmHg or more and in four it was 100 mmHg or more. In two trials, the cut‐off was 85 mmHg, In the remaining five studies, authors merely stated 'mild to moderate hypertension', or 'pregnancy‐induced hypertension', or 'diagnosed hypertension'. Women with proteinuria were excluded from trial entry in 19 studies, whilst in eight trials all women had proteinuria at recruitment. Fourteen trials included women regardless of whether or not they had proteinuria, and the proportion of women with proteinuria ranged from 4% to 47%. In the remaining 17 trials the presence of proteinuria at trial entry was not reported.

Ten studies only recruited women with chronic hypertension. Women with chronic hypertension were excluded from 22 trials. Ten trials included women regardless of whether or not they had chronic hypertension, although outcomes were often not reported separately. In the remaining 16 trials, chronic hypertension at trial entry was not mentioned.

Methods for measuring blood pressure

Only four trials masked the assessment of blood pressure by using a random zero sphygmomanometer (Australia 1983; UK 1976; UK 1983a; UK 1983b). For assessment of diastolic blood pressure, Korotkoff phase IV sound was used in 16 trials and Korotkoff phase V was used for 10 studies. Criteria for blood pressure measurement were not mentioned in 32 trials.

Definition of small‐for‐gestational age

Small‐for‐gestational age was defined in a variety of ways in the 34 trials reporting this outcome. Five studies used birthweight below the fifth centile and 14 below the 10th centile. Four trials used other definitions, and in the remaining 11 trials, small‐for‐gestational age was not defined.

One outcome specified in our protocol, very low (less than four) five‐minute Apgar score, is not included in this review as it was not reported by any trial.

When pooling the data, and in the absence of statistical heterogeneity, we used fixed‐effect meta‐analysis only for the outcome severe hypertension with the assumption that all drugs are expected to lower blood pressure. For the other outcomes, we used random‐effects meta‐analysis as different drugs' effects might vary due to their different mechanisms of action, dosages, length of treatment, etc.

Excluded studies

Ninety‐six studies were excluded from the review. Of these, 41 were conducted in high‐income countries (Australia, Belgium, Denmark, Finland, France, Germany, Israel, Italy, Japan, Netherlands, Sweden, UK and USA), and 55 in low‐ and middle‐income countries (Argentina, Brazil, China, Cuba, Czech Republic, Dominican Republic, Egypt, Hungary, India, Iran, Kuwait, Mexico, Pakistan, Panama, Philippines, Russia, Singapore, Slovakia, South Africa, Sri Lanka, Uganda and Venezuela). The oldest excluded study was published 1957, one was published in 1978, 54 were published in the 1980s and 1990s, and 42 have been published since the millennium.

The language of publication was English (for 78 papers), Chinese (six), Spanish (five), Portuguese (three), Czech (two), French (one), and Russian (one). Language was not a reason for exclusion. Twenty‐six papers (21/101) were published only as congress abstracts, and 13 are protocols registered in ClinicalTrials.Gov or similar pages. They were excluded as the intervention is not eligible (i.e. severe hypertension, prevention trial in high‐risk women, etc). Three studies were excluded after personal communication with authors. Authors of 14 papers provided additional information about methods and/or clinical outcomes.    The reasons for exclusions were as follows.

Methodological problems (25 studies): either they were not randomised trials (12 studies) or they used quasi‐random methods for treatment allocation (nine studies), or more than 20% of women were excluded after randomisation (four studies).
Participants were not eligible for the review (18 studies): either some or all of the women had severe hypertension (nine studies), or some women had normal blood pressure, and data were not presented separately for the women with mild to moderate hypertension, or all women were at high risk of developing hypertension in a prophylactic trial (eight studies), or the intervention was administered postpartum (one).
Intervention was not eligible for the review (45 studies): either the comparison was of drugs within the same class (eight studies), or the allocated intervention was for less than seven days (15 trials), or it was not an antihypertensive drug (21) or the study had a mixed control group (one).
No clinical outcomes measured (eight studies): there are no data on clinical outcomes (three congress abstracts, of which authors were contacted but with no responses to date). Three reports were personal communications of planned randomised controlled trials, but no information could be found about their completion.

Risk of bias in included studies

Overall, the quality of the studies included in this review is moderate to poor (Figure 2; Figure 3).

'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

Sequence generation

Methods for generating the random sequence were described in 23 trials out of 63 (36.5%).

We assessed these trials as being at a low risk of bias ‐ methods included computer generation (Australia 2001, France 1994; India 2013a; Italy 1998; Panama 2014; UK 2009; UK 2017; USA 1987a; USA 1990a; USA 1992), random‐number tables (UK 1980; UK 1989; Venezuela 1988), series of random numbers (Australia 1985a; India 2013b; Israel 1992a). Although three studies did not describe the method used for allocation, the authors mentioned that it was in blocks of five (Brazil 2016), six (Sweden 1995), 10 (Caribbean Is.1990), or nine at each centre (France 1987).

We assessed three trials as being at a high risk of bias due to inadequate methods, namely "mixed‐up opaque envelopes" (India 2012), "lottery method" (Pakistan 2016) and "cards shuffled into a random order and numbered in sequence" (Ireland 1991). See Figure 2, Figure 3.

Methods for generating the random sequence were not described in the remaining 40 trials.

Allocation concealment

Concealment of allocation was adequate for only 22 of the 63 trials (34.9%), being unclear whether concealment was adequate in the remaining 41 trials. Methods for concealing the allocation included on‐line computer system (UK 2017), telephone randomisation (Australia 2001; Italy 1998; Sweden 1984; UK 2009), blinded treatment packs (Brazil 1988; Brazil 2000a; Caribbean Is.1990; Israel 1992a; Italy 2000; UK 1989), consecutive, sealed identical envelopes (UK 1992) or blinded or sealed envelopes (Brazil 2016; France 1987; France 1994; India 2012; Ireland 1991; Italy 1999; Panama 2014; USA 1987a; USA 1990a; USA 1992), or just "envelopes" (South Africa 1991a, Sweden 1985; UK 1982). Most trials with unclear concealment of allocation were described as 'randomised' with no details on how this was achieved. Some of these studies were stated to be double blind, but with no information about how this was achieved. Three trials with unclear concealment used random‐number tables without mentioning any attempt to conceal the allocation (Sweden 1995; UK 1980; Venezuela 1988). See Figure 2, Figure 3.

Blinding

Performance bias

From 31 trials evaluating whether or not hypertension should be treated with antihypertensives, only 14 (45%) compared the active drug with placebo, 12 of them were described by authors as double‐blind (Brazil 2000a; Brazil 2016; Caribbean Is.1990; Hong Kong 1990; Israel 1992a; Sweden 1984; Sweden 1995; UK 1983a; UK 1989; UK 1990; UK 2009; USA 1987b). One placebo‐controlled trial was reported as single‐blind (Australia 2001), and another, even though placebo‐controlled, did not mention whether it was single‐ or double‐blinded (South Africa 1991a). See Figure 2, Figure 3

Detection bias

All trials evaluating alternative treatments for mild/moderate hypertension during pregnancy were open‐label trials, and no attempts were made to blind outcome assessment in order to prevent detection bias. See Figure 2, Figure 3

Incomplete outcome data

As per protocol, trials were excluded from the review (or a particular outcome was excluded from the analysis) if it was not possible to enter data on an intention‐to‐treat basis, or lf 20% or more participants were excluded or withdrawn. We also downgraded the score of a trial to a high risk of bias status if more than 10% of randomised women were withdrawn from the analysis. Most trials reported the outcomes for all (or nearly all) women randomised (low risk of bias), although only six trials described the women who met the study eligibility criteria, but were not randomised (Sweden 1984; Sweden 1985; UK 1976; UK 1983a; UK 2009; UK 2017). Five trials reported losses greater than 10%: Italy 1999 (17%), South Africa 1993 (10.3%), UK 1990 (12%), UK 2009 (10.3%) and USA 1990a (12%), with high risk of bias. See Figure 2, Figure 3.

Selective reporting

Thirty‐three trials (52%) reported on the risk of a woman for developing severe hypertension (one of the primary outcomes of this review). However, most trials evaluated the effect that the antihypertensive under scrutiny may have on blood pressure (mean blood pressure after treatment, % fall in blood pressure, etc.). Proteinuria (either new proteinuria or the aggravation of previously existing) was reported in 46 trials. Total reported fetal or neonatal deaths were evaluated in 48 trials, preterm birth in 25 and small‐for‐gestational‐age babies in 28. Most analyses were carried out using data from published reports. Authors were contacted for unpublished information related to the methods and the main outcomes; we obtained data from Australia 2001; Brazil 1988; Brazil 2000a; Caribbean Is.1990; Ireland 1991; Italy 1999; Italy 2000; Sweden 1984; Sweden 1995; UK 1982; UK 1990; UK 1992; USA 1990a. See Figure 2, Figure 3,

Funnel plots were assessed, see Figure 4; Figure 5; Figure 6; Figure 7; Figure 8; Figure 9; Figure 10; Figure 11; Figure 12; Figure 13; Figure 14; Figure 15; Figure 16; Figure 17; Figure 18; Figure 19; Figure 20; Figure 21; Figure 22; Figure 23; Figure 24; Figure 25.

Funnel plot of comparison: 1 Any antihypertensive drug versus no antihypertensive drugs/placebo (subgrouped by class of drug), outcome: 1.1 Severe hypertension.

Funnel plot of comparison: 1 Any antihypertensive drug versus no antihypertensive drugs/placebo (subgrouped by class of drug), outcome: 1.2 Proteinuria/pre‐eclampsia.

Funnel plot of comparison: 1 Any antihypertensive drug versus no antihypertensive drugs/placebo (subgrouped by class of drug), outcome: 1.3 Total reported fetal or neonatal death (including miscarriage).

Funnel plot of comparison: 1 Any antihypertensive drug versus no antihypertensive drugs/placebo (subgrouped by class of drug), outcome: 1.5 Small‐for‐gestational age.

Funnel plot of comparison: 1 Any antihypertensive drug versus no antihypertensive drugs/placebo (subgrouped by class of drug), outcome: 1.7 Preterm birth (< 37 weeks).

Funnel plot of comparison: 1 Any antihypertensive drug versus no antihypertensive drugs/placebo (subgrouped by class of drug), outcome: 1.14 Need for additional antihypertensive drug/s.

Funnel plot of comparison: 1 Any antihypertensive drug versus no antihypertensive drugs/placebo (subgrouped by class of drug), outcome: 1.16 Caesarean section.

Funnel plot of comparison: 1 Any antihypertensive drug versus no antihypertensive drugs/placebo (subgrouped by class of drug), outcome: 1.19 Placental abruption.

Funnel plot of comparison: 1 Any antihypertensive drug versus no antihypertensive drugs/placebo (subgrouped by class of drug), outcome: 1.20 Maternal side‐effects.

Funnel plot of comparison: 1 Any antihypertensive drug versus no antihypertensive drugs/placebo (subgrouped by class of drug), outcome: 1.21 Changed/stopped drugs due to maternal side‐effects.

Funnel plot of comparison: 1 Any antihypertensive drug versus no antihypertensive drugs/placebo (subgrouped by class of drug), outcome: 1.22 Admission to neonatal or intensive care nursery.

Funnel plot of comparison: 5 Any antihypertensive versus methyldopa (subgrouped by class of drug), outcome: 5.1 Severe hypertension.

Funnel plot of comparison: 5 Any antihypertensive versus methyldopa (subgrouped by class of drug), outcome: 5.2 Proteinuria/pre‐eclampsia.

Funnel plot of comparison: 5 Any antihypertensive versus methyldopa (subgrouped by class of drug), outcome: 5.3 Total reported fetal or neonatal death (including miscarriage).

Funnel plot of comparison: 5 Any antihypertensive versus methyldopa (subgrouped by class of drug), outcome: 5.5 Preterm birth (< 37 weeks).

Funnel plot of comparison: 5 Any antihypertensive versus methyldopa (subgrouped by class of drug), outcome: 5.8 Need for additional antihypertensive drug/s.

Funnel plot of comparison: 5 Any antihypertensive versus methyldopa (subgrouped by class of drug), outcome: 5.10 Caesarean section.

Funnel plot of comparison: 7 Any antihypertensive versus beta blocker (subgrouped by class of drug), outcome: 7.1 Severe hypertension.

Funnel plot of comparison: 7 Any antihypertensive versus beta blocker (subgrouped by class of drug), outcome: 7.2 Proteinuria/pre‐eclampsia.

Funnel plot of comparison: 7 Any antihypertensive versus beta blocker (subgrouped by class of drug), outcome: 7.3 Total reported fetal or neonatal death (including miscarriage).

Funnel plot of comparison: 7 Any antihypertensive versus beta blocker (subgrouped by class of drug), outcome: 7.11 Need for additional antihypertensive drug/s.

Funnel plot of comparison: 7 Any antihypertensive versus beta blocker (subgrouped by class of drug), outcome: 7.13 Caesarean section.

Other potential sources of bias

Baseline characteristics were similar between groups in most trials, thus in the absence of other potential sources of bias they were scored as at low risk. In one trial (Australia 1985a) co‐interventions were unevenly distributed: 48% of oxprenolol group and 35% of methyldopa group received a second or third antihypertensive. In another study (Caribbean Is.1990), treatment was unblinded in 23 women (15%) and other treatment started, 16 for uncontrolled BP (five experimental, 11 control) and seven for poor compliance/side‐effects (four experimental, three control). In another trial (UK 2017) some baseline characteristics (such as smoking or chronic hypertension) were not balanced. So these three studies were assessed as high risk. In 13 trials, funding source included the Industry totally or partially (France 1987, India 1992 UK 1976; UK 1980; UK 1982; UK 1983a; UK 1983b; UK 1989; UK 1990; UK 1992; UK 2009; USA 1987b; Venezuela 1988), so they were assessed as high risk of bias. In 22 studies, the funding sources was not declared and theywere classified as unclear risk of bias.

Informed consent was mentioned in the majority of trials. In one study, informed consent was obtained only from women allocated to the treatment arm (Ireland 1991).

Sample size and power calculations were reported for nine trials (Brazil 2016; Caribbean Is.1990; France 1987; Ireland 1991; Italy 1998; Pakistan 2016; UK 1989; UK 2009; UK 2017).

Effects of interventions

See: Table 1; Table 2

Summary of findings for the main comparison. Any antihypertensive drug compared to no antihypertensive drugs/placebo for mild to moderate hypertension during pregnancy (primary outcomes).

Any antihypertensive drug compared to no antihypertensive drugs/placebo for mild to moderate hypertension during pregnancy
Patient or population: women with mild to moderate hypertension during pregnancy  Setting: hospital settings in high‐ low‐ and middle‐income countries  Intervention: any antihypertensive drug (beta blockers, methyldopa, calcium channel blockers, alpha blockers, glyceryl trinitrate, sildenafil) alone or in combination  Comparison: placebo or no antihypertensive drug
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	№ of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
	Risk with no drugs/placebo	Risk with any antihypertensive drug
Maternal
Severe hypertension	Study population		RR 0.49  (0.40 to 0.60)	2558  (20 RCTs)	⊕⊕⊕⊝  MODERATE ^{1 2}
	198 per 1000	97 per 1000  (79 to 119)
Proteinuria/pre‐eclampsia	Study population		RR 0.92  (0.75 to 1.14)	2851  (23 RCTs)	⊕⊕⊝⊝  LOW ^{1 2 3 4}
	185 per 1000	171 per 1000  (139 to 211)
Fetal/neonatal/infant
Total reported fetal or neonatal deaths (including miscarriage)	Study population		RR 0.72  (0.50 to 1.04)	3365  (29 RCTs)	⊕⊕⊕⊝  MODERATE ^{1 2}
	41 per 1000	28 per 1000  (20 to 40)
Small‐for‐gestational age	Study population		RR 0.96  (0.78 to 1.18)	2686  (21 RCTs)	⊕⊕⊕⊝  MODERATE ^{1 2}
	152 per 1000	149 per 1000  (125 to 176)
Preterm birth (< 37 weeks)	Study population		RR 0.96  (0.83 to 1.12)	2141  (15 RCTs)	⊕⊕⊕⊝  MODERATE ^{1 2}
	277 per 1000	266 per 1000  (236 to 305)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence  High certainty: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Date	Event	Description
12 January 2018	New citation required and conclusions have changed	New co‐author joined the team: Dr Celina Gialdini. Nine new studies included (two of sildenafil versus placebo, three of labetalol versus methyldopa, one of nifedipine versus methyldopa, one of nifedipine versus labetalol, one of amlodipine versus furosemide and a three‐arm trial of nifedipine versus labetalol versus methyldopa). Twenty new studies were excluded with reasons and there are eight new ongoing trials. Five studies Finland 1988b; France 1990; Hong Kong 1993; India 2011; Spain 1988, excluded in previous versions of this review for not reporting clinical outcomes, are now included, specifying that they do not contribute data. Figure 1: study flow diagram was added. The introduction was updated in line with new definitions for pre‐eclampsia, and the inclusion of new agents (amlodipine and sildenafil). Common side‐effects of each family of drugs were added in the introduction section "How the intervention might work". Conclusions changed: Implications for practice now reflect the benefits of avoiding hypertensive crises and use of additional antihypertensives, and the possible benefits of beta‐blockers and calcium channel blockers on avoiding a hypertensive crisis.
13 September 2017	New search has been performed	Search updated.

Date	Event	Description
14 June 2013	New citation required but conclusions have not changed	Three new trials were added for this update: one of beta blockers versus methyldopa; one of calcium channel blockers versus methyldopa; and a three‐arm trial of labetalol versus methyldopa versus no treatment.
31 May 2013	New search has been performed	Review authors updated. April 2013: search updated. Nineteen trials added to excluded studies (not all are new studies as, for some, new information has become available leading them to be reclassified as excluded). Four figures added: 'Risk of bias' graph, 'Risk of bias' summary, and two funnel plots.
6 August 2012	Amended	Search updated. Nineteen new reports added to Studies awaiting classification.
8 May 2008	Amended	Converted to new review format.
14 November 2006	New search has been performed	March 2006: Search updated. Six new trials were added to included studies. Twenty‐seven new trials added to excluded studies (not all are new studies as, for some, new information has become available leading them to be reclassified as excluded). Changes in the outcome tree (calcium channel blockers versus beta blockers are no longer referred to the beta blockers review (Magee 2000) as this comparison is now part of the group 'any antihypertensive versus calcium channel blockers'). Changes in the text to reflect new data. An entire section describing the general characteristics of the excluded trials has been added in the text. Acknowledgements to authors for unpublished data.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Severe hypertension	20	2558	Risk Ratio (M‐H, Fixed, 95% CI)	0.49 [0.40, 0.60]
1.1 Beta blocker versus no antihypertensive drugs/placebo	8	762	Risk Ratio (M‐H, Fixed, 95% CI)	0.38 [0.26, 0.57]
1.2 Beta blocker + other drug versus no antihypertensive drugs/placebo	2	322	Risk Ratio (M‐H, Fixed, 95% CI)	0.30 [0.12, 0.77]
1.3 Methyldopa versus no antihypertensive drugs/placebo	2	310	Risk Ratio (M‐H, Fixed, 95% CI)	0.32 [0.17, 0.58]
1.4 Methyldopa + other drug versus no antihypertensive drugs/placebo	1	58	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.12, 3.70]
1.5 Beta blocker or methyldopa versus no antihypertensive drugs/placebo	2	412	Risk Ratio (M‐H, Fixed, 95% CI)	0.43 [0.25, 0.74]
1.6 Calcium channel blocker versus no antihypertensive drugs/placebo	4	662	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.60, 1.11]
1.7 Alpha blocker versus no antihypertensive drugs/placebo	1	32	Risk Ratio (M‐H, Fixed, 95% CI)	0.07 [0.00, 1.09]
2 Proteinuria/pre‐eclampsia	23	2851	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.75, 1.14]
2.1 Beta blocker versus no antihypertensive drugs/placebo	8	883	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.56, 0.99]
2.2 Beta blocker + other drug versus no antihypertensive drugs/placebo	2	322	Risk Ratio (M‐H, Random, 95% CI)	1.25 [0.63, 2.51]
2.3 Methyldopa versus no antihypertensive drugs/placebo	2	267	Risk Ratio (M‐H, Random, 95% CI)	1.21 [0.55, 2.64]
2.4 Methyldopa + other drug versus no antihypertensive drugs/placebo	2	158	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.44, 1.34]
2.5 Beta blocker or methyldopa versus no antihypertensive drugs/placebo	2	412	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.28, 1.79]
2.6 Calcium channel blocker versus no antihypertensive drugs/placebo	4	725	Risk Ratio (M‐H, Random, 95% CI)	1.40 [1.02, 1.92]
2.7 Alpha blocker versus no antihypertensive drugs/placebo	1	32	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.04, 2.52]
2.8 Glyceryl trinitrate versus no antihypertensive drugs/placebo	1	16	Risk Ratio (M‐H, Random, 95% CI)	0.43 [0.06, 3.28]
2.9 Regular antihypertensive therapy versus no antihypertensive drugs/placebo	1	36	Risk Ratio (M‐H, Random, 95% CI)	0.19 [0.02, 1.39]
3 Total reported fetal or neonatal death (including miscarriage)	29	3365	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.50, 1.04]
3.1 Beta blocker versus no antihypertensive drugs/placebo	11	1045	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.45, 2.53]
3.2 Beta blocker + other drug versus no antihypertensive drugs/placebo	2	322	Risk Ratio (M‐H, Random, 95% CI)	1.15 [0.28, 4.76]
3.3 Methyldopa versus no antihypertensive drugs/placebo	3	337	Risk Ratio (M‐H, Random, 95% CI)	0.35 [0.06, 2.10]
3.4 Methyldopa + other drug versus no antihypertensive drugs/placebo	2	158	Risk Ratio (M‐H, Random, 95% CI)	0.58 [0.23, 1.46]
3.5 Beta blocker or methyldopa versus no antihypertensive drugs/placebo	2	443	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.21, 1.54]
3.6 Calcium channel blocker versus no antihypertensive drugs/placebo	5	857	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.28, 2.10]
3.7 Alpha blocker versus no antihypertensive drugs/placebo	1	32	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.25, 2.73]
3.8 Regular antihypertensive therapy versus no antihypertensive drugs/placebo	1	36	Risk Ratio (M‐H, Random, 95% CI)	2.24 [0.22, 22.51]
3.9 Sildenafil versus no antihypertensive drugs/placebo	2	135	Risk Ratio (M‐H, Random, 95% CI)	0.51 [0.13, 1.95]
4 Fetal or neonatal death (subgrouped by time of death)	27		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
4.1 Miscarriage	7	1058	Risk Ratio (M‐H, Random, 95% CI)	0.46 [0.18, 1.15]
4.2 Stillbirth	18	2480	Risk Ratio (M‐H, Random, 95% CI)	1.15 [0.58, 2.30]
4.3 Perinatal death	22	2517	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.56, 1.41]
4.4 Neonatal death	6	692	Risk Ratio (M‐H, Random, 95% CI)	0.60 [0.19, 1.87]
5 Small‐for‐gestational age	21	2686	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.78, 1.18]
5.1 Beta blocker versus no antihypertensive drugs/placebo	9	904	Risk Ratio (M‐H, Random, 95% CI)	1.30 [0.86, 1.97]
5.2 Beta blocker + other drug versusno antihypertensive drugs/placebo	2	322	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.45, 2.01]
5.3 Methyldopa versus no antihypertensive drugs/placebo	2	227	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.02, 47.65]
5.4 Methyl dopa + other drug versus no antihypertensive drugs/placebo	1	58	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.28, 3.62]
5.5 Beta blocker or methyldopa versus no antihypertensive drugs/placebo	2	412	Risk Ratio (M‐H, Random, 95% CI)	0.64 [0.42, 0.98]
5.6 Calcium channel blocker versus no antihypertensive drugs/placebo	3	640	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.60, 1.16]
5.7 Alpha blocker versus no antihypertensive drugs/placebo	1	23	Risk Ratio (M‐H, Random, 95% CI)	0.43 [0.05, 3.57]
5.8 Sildenafil versus no antihypertensive drugs/placebo	1	100	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.75, 1.43]
6 Small‐for‐gestational age (subgrouped by severity)	20		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
6.1 Birthweight < 10th centile	11	1365	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.80, 1.21]
6.2 Birthweight < 5th centile	3	287	Risk Ratio (M‐H, Random, 95% CI)	3.00 [0.87, 10.32]
6.3 Unspecified	7	1090	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.50, 1.11]
7 Preterm birth (< 37 weeks)	15	2141	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.83, 1.12]
7.1 Beta blocker versus no antihypertensive drugs/placebo	4	361	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.61, 1.32]
7.2 Beta blocker + other drug versusno antihypertensive drugs/placebo	2	322	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.64, 1.48]
7.3 Methyldopa versus no antihypertensive drugs/placebo	2	272	Risk Ratio (M‐H, Random, 95% CI)	1.61 [0.73, 3.57]
7.4 Beta blocker or methyldopa versus no antihypertensive drugs/placebo	2	412	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.22, 2.06]
7.5 Calcium channel blocker versus no antihypertensive drugs/placebo	4	742	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.86, 1.18]
7.6 Alpha blocker versus no antihypertensive drugs/placebo	1	32	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.27, 1.66]
8 Preterm birth (subgrouped by gestational age)	15		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
8.1 < 37 weeks	10	1569	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.85, 1.12]
8.2 < 36 weeks	2	304	Risk Ratio (M‐H, Random, 95% CI)	0.46 [0.04, 5.68]
8.3 < 34 weeks	5	792	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.62, 1.94]
8.4 Unspecified	4	423	Risk Ratio (M‐H, Random, 95% CI)	1.21 [0.85, 1.73]
9 Maternal death	5	525	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.18, 7.02]
10 Severe pre‐eclampsia	3	416	Risk Ratio (M‐H, Random, 95% CI)	0.56 [0.15, 2.02]
11 Eclampsia	7	713	Risk Ratio (M‐H, Random, 95% CI)	0.52 [0.13, 2.06]
12 HELLP syndrome	3	332	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.32, 3.50]
12.1 Calcium channel blocker versus no antihypertensive drugs/placebo	1	197	Risk Ratio (M‐H, Random, 95% CI)	2.02 [0.38, 10.78]
12.2 Sildenafil versus no antihypertensive drugs/placebo	2	135	Risk Ratio (M‐H, Random, 95% CI)	0.53 [0.10, 2.97]
13 Pulmonary oedema	2	325	Risk Ratio (M‐H, Random, 95% CI)	1.22 [0.13, 11.75]
13.1 Beta blocker versus no antihypertensive drugs/placebo	1	176	Risk Ratio (M‐H, Random, 95% CI)	5.23 [0.25, 107.39]
13.2 Beta blocker or methyldopa versus no antihypertensive drugs/placebo	1	149	Risk Ratio (M‐H, Random, 95% CI)	0.51 [0.07, 3.48]
14 Need for additional antihypertensive drug/s	11	1385	Risk Ratio (M‐H, Random, 95% CI)	0.49 [0.38, 0.65]
14.1 Beta blocker versus no antihypertensive drugs/placebo	3	245	Risk Ratio (M‐H, Random, 95% CI)	0.45 [0.24, 0.82]
14.2 Beta blocker + other drug versusno antihypertensive drugs/placebo	2	315	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.10, 1.15]
14.3 Methyldopa + other drug versus no antihypertensive drugs/placebo	1	58	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.11, 0.83]
14.4 Beta blocker or methyldopa versus no antihypertensive drugs/placebo	1	263	Risk Ratio (M‐H, Random, 95% CI)	0.52 [0.22, 1.20]
14.5 Calcium channel blocker versus no antihypertensive drugs/placebo	2	372	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.35, 1.28]
14.6 Alpha blocker versus no antihypertensive drugs/placebo	1	32	Risk Ratio (M‐H, Random, 95% CI)	0.07 [0.00, 1.09]
14.7 Sildenafil versus no antihypertensive drugs/placebo	1	100	Risk Ratio (M‐H, Random, 95% CI)	0.55 [0.35, 0.88]
15 Elective delivery (induction of labour + elective caesarean section)	4	710	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.84, 1.04]
15.1 Beta blocker versus no antihypertensive drugs/placebo	2	240	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.84, 1.12]
15.2 Beta blocker + other drug versus no antihypertensive drugs/placebo	3	470	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.70, 1.10]
16 Caesarean section	21	2724	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.84, 1.03]
16.1 Beta blocker versusno antihypertensive drugs/placebo	8	850	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.86, 1.31]
16.2 Beta blocker + other drug versus no antihypertensive drugs/placebo	2	322	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.38, 0.85]
16.3 Methyldopa versus no antihypertensive drugs/placebo	2	272	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.59, 1.34]
16.4 Methyldopa + other drug versus no antihypertensive drugs/placebo	1	58	Risk Ratio (M‐H, Random, 95% CI)	1.8 [0.69, 4.72]
16.5 Beta blocker or methyldopa versus no antihypertensive drugs/placebo	2	412	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.45, 1.52]
16.6 Calcium channel blocker versus no antihypertensive drugs/placebo	3	642	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.79, 1.11]
16.7 Alpha blocker versus no antihypertensive drugs/placebo	1	32	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.20, 1.91]
16.8 Regular antihypertensive therapy versus no antihypertensive drugs/placebo	1	36	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
16.9 Sildenafil versus no antihypertensive drugs/placebo	1	100	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.81, 1.12]
17 Induction of labour	5	563	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.75, 1.15]
17.1 Beta blocker versus no antihypertensive drugs/placebo	3	384	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.83, 1.17]
17.2 Beta blocker + other drug versus no antihypertensive drugs/placebo	1	154	Risk Ratio (M‐H, Random, 95% CI)	0.49 [0.26, 0.90]
17.3 Methyldopa versus no antihypertensive drugs/placebo	1	25	Risk Ratio (M‐H, Random, 95% CI)	1.54 [0.46, 5.09]
18 Antenatal hospital admission	4	455	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.71, 1.08]
18.1 Beta blocker versus no antihypertensive drugs/placebo	1	52	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.57, 1.24]
18.2 Beta blocker + other drug versus no antihypertensive drugs/placebo	2	254	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.79, 1.18]
18.3 Beta blocker or methyldopa versus no antihypertensive drugs/placebo	1	149	Risk Ratio (M‐H, Random, 95% CI)	0.51 [0.26, 0.98]
19 Placental abruption	13	1568	Risk Ratio (M‐H, Random, 95% CI)	1.49 [0.70, 3.17]
19.1 Beta blocker versus no antihypertensive drugs/placebo	3	364	Risk Ratio (M‐H, Random, 95% CI)	5.11 [0.25, 104.96]
19.2 Beta blocker + other drug versus no antihypertensive drugs/placebo	2	322	Risk Ratio (M‐H, Random, 95% CI)	2.22 [0.33, 14.97]
19.3 Methyldopa versus no antihypertensive drugs/placebo	1	70	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
19.4 Beta blocker or methyldopa versus no antihypertensive drugs/placebo	2	412	Risk Ratio (M‐H, Random, 95% CI)	0.52 [0.13, 2.16]
19.5 Calcium blocker versus no antihypertensive drugs/placebo	1	197	Risk Ratio (M‐H, Random, 95% CI)	1.52 [0.26, 8.87]
19.6 Alpha blocker versus no antihypertensive drugs/placebo	1	32	Risk Ratio (M‐H, Random, 95% CI)	3.33 [0.34, 32.96]
19.7 Regular antihypertensive therapy versus no antihypertensive drugs/placebo	1	36	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
19.8 Sildenafil versus no antihypertensive drugs/placebo	2	135	Risk Ratio (M‐H, Random, 95% CI)	2.06 [0.39, 10.75]
20 Maternal side‐effects	11	934	Risk Ratio (M‐H, Random, 95% CI)	1.99 [0.89, 4.43]
20.1 Beta blocker versusno antihypertensive drugs/placebo	7	554	Risk Ratio (M‐H, Random, 95% CI)	3.14 [0.66, 15.02]
20.2 Beta blocker + other drug versusno antihypertensive drugs/placebo	1	154	Risk Ratio (M‐H, Random, 95% CI)	1.30 [0.30, 5.61]
20.3 Methyldopa versus no antihypertensive drugs/placebo	1	25	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
20.4 Calcium channel blocker versus no antihypertensive drugs/placebo	1	185	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.60, 1.52]
20.5 Glyceryl trinitrate versus no antihypertensive drugs/placebo	1	16	Risk Ratio (M‐H, Random, 95% CI)	18.75 [1.25, 281.11]
21 Changed/stopped drugs due to maternal side‐effects	16	1503	Risk Ratio (M‐H, Random, 95% CI)	1.93 [0.92, 4.06]
21.1 Beta blocker versus no antihypertensive drugs/placebo	9	745	Risk Ratio (M‐H, Random, 95% CI)	1.85 [0.61, 5.57]
21.2 Beta blocker + other drug versus no antihypertensive drugs/placebo	2	315	Risk Ratio (M‐H, Random, 95% CI)	1.30 [0.30, 5.61]
21.3 Methyldopa versus no antihypertensive drugs/placebo	1	25	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
21.4 Calcium channel blocker versus no antihypertensive drugs/placebo	2	302	Risk Ratio (M‐H, Random, 95% CI)	4.02 [0.45, 35.97]
21.5 Glyceryl trinitrate versus no antihypertensive drugs/placebo	1	16	Risk Ratio (M‐H, Random, 95% CI)	18.75 [1.25, 281.11]
21.6 Sildenafil versus no antihypertensive drugs/placebo	1	100	Risk Ratio (M‐H, Random, 95% CI)	0.5 [0.05, 5.34]
22 Admission to neonatal or intensive care nursery	10	1570	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.83, 1.22]
22.1 Beta blocker versus no antihypertensive drugs/placebo	3	449	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.82, 1.41]
22.2 Beta blocker + other drug versus no antihypertensive drugs/placebo	1	151	Risk Ratio (M‐H, Random, 95% CI)	0.66 [0.38, 1.14]
22.3 Methyldopa versus no antihypertensive drugs/placebo	2	272	Risk Ratio (M‐H, Random, 95% CI)	1.56 [0.88, 2.78]
22.4 Beta blocker or methyldopa versus no antihypertensive drugs/placebo	1	149	Risk Ratio (M‐H, Random, 95% CI)	0.51 [0.27, 0.95]
22.5 Calcium channel blocker versus no antihypertensive drugs/placebo	2	449	Risk Ratio (M‐H, Random, 95% CI)	1.18 [0.87, 1.62]
22.6 Sildenafil versus no antihypertensive drugs/placebono antihypertensive drugs/placebo	1	100	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.69, 1.15]
23 Respiratory distress syndrome	6	925	Risk Ratio (M‐H, Random, 95% CI)	0.53 [0.29, 0.99]
23.1 Beta blocker versus no antihypertensive drugs/placebo	3	412	Risk Ratio (M‐H, Random, 95% CI)	0.32 [0.13, 0.83]
23.2 Beta blocker + other drug versus no antihypertensive drugs/placebo	1	157	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.03, 3.10]
23.3 Calcium channel blocker versus no antihypertensive drugs/placebo	1	256	Risk Ratio (M‐H, Random, 95% CI)	0.20 [0.01, 4.06]
23.4 Sildenafil versus no antihypertensive drugs/placebo	1	100	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.51, 1.42]
24 Neonatal hypoglycaemia	6	962	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.51, 1.15]
24.1 Beta blocker versus no antihypertensive drugs/placebo	2	261	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.13, 3.83]
24.2 Beta blocker + other drug versus no antihypertensive drugs/placebo	1	157	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.35, 1.84]
24.3 Beta blocker or methyldopa versus no antihypertensive drugs/placebo	1	261	Risk Ratio (M‐H, Random, 95% CI)	2.07 [0.23, 18.24]
24.4 Calcium channel blocker versus no antihypertensive drugs/placebo	1	183	Risk Ratio (M‐H, Random, 95% CI)	0.69 [0.39, 1.21]
24.5 Sildenafil versus no antihypertensive drugs/placebo	1	100	Risk Ratio (M‐H, Random, 95% CI)	0.8 [0.23, 2.81]
25 Neonatal bradycardia	3	418	Risk Ratio (M‐H, Random, 95% CI)	1.28 [0.31, 5.24]
25.1 Beta blocker versus no antihypertensive drugs/placebo	2	261	Risk Ratio (M‐H, Random, 95% CI)	2.20 [0.68, 7.16]
25.2 Beta blocker + other drug versusno antihypertensive drugs/placebo	1	157	Risk Ratio (M‐H, Random, 95% CI)	0.25 [0.03, 2.16]
26 Neonatal jaundice	3	529	Risk Ratio (M‐H, Random, 95% CI)	0.78 [0.53, 1.15]
26.1 Beta blocker versus no antihypertensive drugs/placebo	1	144	Risk Ratio (M‐H, Random, 95% CI)	0.53 [0.19, 1.47]
26.2 Methyldopa versus no antihypertensive drugs/placebo	1	202	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.65, 1.61]
26.3 Calcium channel blocker versus no antihypertensive drugs/placebo	1	183	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.35, 1.10]
27 Follow‐up of the children at 1 year: cerebral palsy	1	110	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.01, 8.01]
28 Follow‐up of the children at 7 1/2 years	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
28.1 Chronic ill health	1	190	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.16, 3.06]
28.2 Impaired hearing	1	190	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.38, 3.14]
28.3 Impaired vision	1	190	Risk Ratio (M‐H, Random, 95% CI)	0.47 [0.20, 1.11]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Severe hypertension	11	638	Risk Ratio (M‐H, Fixed, 95% CI)	0.70 [0.56, 0.88]
1.1 Beta blocker versus methyldopa	9	592	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.59, 0.93]
1.2 Calcium channel blockers versus methyldopa	2	46	Risk Ratio (M‐H, Fixed, 95% CI)	0.23 [0.04, 1.22]
2 Proteinuria/pre‐eclampsia	11	997	Risk Ratio (M‐H, Random, 95% CI)	0.78 [0.58, 1.06]
2.1 Beta blocker versus methyldopa	10	903	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.58, 1.16]
2.2 Calcium channel blockers versus methyldopa	1	94	Risk Ratio (M‐H, Random, 95% CI)	0.66 [0.34, 1.27]
3 Total reported fetal or neonatal death (including miscarriage)	22	1791	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.52, 1.14]
3.1 Beta blocker versus methyldopa	16	1280	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.43, 1.50]
3.2 Calcium channel blocker versus methyldopa	4	251	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.04, 2.65]
3.3 Beta blockers or calcium channel blockers versus methyldopa	1	240	Risk Ratio (M‐H, Random, 95% CI)	0.76 [0.46, 1.27]
3.4 Ketanserin versus methyldopa	1	20	Risk Ratio (M‐H, Random, 95% CI)	3.0 [0.14, 65.90]
4 Small‐for‐gestational age	7	597	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.52, 1.20]
4.1 Beta blocker versus methyldopa	6	577	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.54, 1.31]
4.2 Calcium channel blocker versus methyldopa	1	20	Risk Ratio (M‐H, Random, 95% CI)	0.4 [0.10, 1.60]
5 Preterm birth (< 37 weeks)	11	835	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.68, 1.22]
5.1 Beta blocker versus methyldopa	8	694	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.62, 1.29]
5.2 Calcium channel blocker versus methyldopa	3	141	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.44, 1.64]
6 Severe pre‐eclampsia	1	311	Risk Ratio (M‐H, Random, 95% CI)	1.15 [0.56, 2.33]
6.1 Beta blocker versus methyldopa	1	311	Risk Ratio (M‐H, Random, 95% CI)	1.15 [0.56, 2.33]
7 Eclampsia	1	92	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
7.1 Calcium channel blockers versus methyldopa	1	92	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
8 Need for additional antihypertensive drug/s	13	1081	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.47, 1.13]
8.1 Beta blocker versus methyldopa	10	853	Risk Ratio (M‐H, Random, 95% CI)	0.76 [0.45, 1.28]
8.2 Calcium channel blocker versus methyldopa	3	228	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.30, 1.28]
9 Elective delivery (induction of labour + elective caesarean section)	7	655	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.90, 1.09]
9.1 Beta blocker versus methyldopa	5	453	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.90, 1.12]
9.2 Calcium channel blocker versus methyldopa	2	202	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.65, 1.63]
10 Caesarean section	13	1330	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.74, 0.95]
10.1 Beta blocker versus methyldopa	10	972	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.81, 1.13]
10.2 Calcium channel blocker versus methyldopa	2	118	Risk Ratio (M‐H, Random, 95% CI)	0.66 [0.38, 1.16]
10.3 Beta blocker or calcium channel blocker versus methyldopa	1	240	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.57, 0.86]
11 Induction of labour	3	452	Risk Ratio (M‐H, Random, 95% CI)	1.14 [0.89, 1.45]
11.1 Beta blocker versus methyldopa	1	120	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.65, 1.53]
11.2 Calcium channel blocker versus methyldopa	1	92	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.75, 1.57]
11.3 Beta blocker or calcium channel blocker versus methyldopa	1	240	Risk Ratio (M‐H, Random, 95% CI)	1.54 [0.89, 2.64]
12 Antenatal hospital admission	2	275	Risk Ratio (M‐H, Random, 95% CI)	0.56 [0.17, 1.86]
12.1 Beta blocker versus methyldopa	2	275	Risk Ratio (M‐H, Random, 95% CI)	0.56 [0.17, 1.86]
13 Placental abruption	1	173	Risk Ratio (M‐H, Random, 95% CI)	2.02 [0.19, 21.90]
13.1 Beta blocker versus methyldopa	1	173	Risk Ratio (M‐H, Random, 95% CI)	2.02 [0.19, 21.90]
14 Maternal side‐effects	6	412	Risk Ratio (M‐H, Random, 95% CI)	0.22 [0.02, 2.09]
14.1 Beta blocker versus methyldopa	5	302	Risk Ratio (M‐H, Random, 95% CI)	0.22 [0.02, 2.09]
14.2 Calcium channel blockers versus methyldopa	1	110	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
15 Changed/stopped drugs due to maternal side‐effects	4	272	Risk Ratio (M‐H, Random, 95% CI)	2.80 [0.12, 67.91]
15.1 Beta blocker versus methyldopa	4	272	Risk Ratio (M‐H, Random, 95% CI)	2.80 [0.12, 67.91]
16 Admission to neonatal or intensive care nursery	6	688	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.72, 1.27]
16.1 Beta blocker versus methyldopa	4	571	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.67, 1.25]
16.2 Calcium channel blocker versus methyldopa	2	117	Risk Ratio (M‐H, Random, 95% CI)	1.22 [0.56, 2.64]
17 Respiratory distress syndrome	1	118	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.31, 2.40]
17.1 Beta blocker versus methyldopa	1	118	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.31, 2.40]
18 Neonatal hypoglycaemia	5	439	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.47, 2.05]
18.1 Beta blocker versus methyldopa	5	439	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.47, 2.05]
19 Neonatal bradycardia	2	146	Risk Ratio (M‐H, Random, 95% CI)	3.0 [0.12, 72.18]
19.1 Beta blocker versus methyldopa	2	146	Risk Ratio (M‐H, Random, 95% CI)	3.0 [0.12, 72.18]
20 Neonatal jaundice	2	146	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.48, 2.29]
20.1 Beta blocker versus methyldopa	2	146	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.48, 2.29]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Severe hypertension	5	223	Risk Ratio (M‐H, Fixed, 95% CI)	1.86 [1.09, 3.15]
1.1 Glyceryl trinitrate versus calcium channel blockers	1	36	Risk Ratio (M‐H, Fixed, 95% CI)	1.56 [0.07, 35.67]
1.2 Beta blockers versus calcium channel blockers	1	100	Risk Ratio (M‐H, Fixed, 95% CI)	2.14 [0.96, 4.80]
1.3 Furosemide versus calcium channel blockers	1	41	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.48, 2.44]
1.4 Methyldopa versus calcium channel blockers	2	46	Risk Ratio (M‐H, Fixed, 95% CI)	4.33 [0.82, 22.86]
2 Proteinuria/pre‐eclampsia	5	375	Risk Ratio (M‐H, Random, 95% CI)	1.24 [0.70, 2.19]
2.1 Glyceryl trinitrate versus calcium channel blockers	1	36	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.10, 9.96]
2.2 Beta blockers versus calcium channel blockers	2	204	Risk Ratio (M‐H, Random, 95% CI)	1.12 [0.24, 5.23]
2.3 Furosemide versus calcium channel blockers	1	41	Risk Ratio (M‐H, Random, 95% CI)	1.67 [0.57, 4.83]
2.4 Merthyldopa versus calcium channel blockers	1	94	Risk Ratio (M‐H, Random, 95% CI)	1.52 [0.79, 2.93]
3 Total reported fetal or neonatal death (including miscarriage)	9	700	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.52, 1.57]
3.1 Glyceryl trinitrate versus calcium channel blockers	1	36	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.2 Beta blockers versus calcium channel blockers	3	372	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.46, 1.46]
3.3 Furosemide versus calcium channel blockers	1	41	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.4 Methyldopa versus calcium channel blockers	4	251	Risk Ratio (M‐H, Random, 95% CI)	3.21 [0.38, 27.40]
4 Small‐for‐gestational age	4	200	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.64, 1.73]
4.1 Glyceryl trinitrate versus calcium channel blockers	1	36	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.10, 9.96]
4.2 Beta blockers versus calcium channel blockers	1	103	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.55, 1.68]
4.3 Furosemide versus calcium channel blockers	1	41	Risk Ratio (M‐H, Random, 95% CI)	0.48 [0.05, 4.85]
4.4 Methyldopa versus calcium channel blockers	1	20	Risk Ratio (M‐H, Random, 95% CI)	2.5 [0.63, 10.00]
5 Preterm birth (< 37 weeks)	6	330	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.59, 1.23]
5.1 Glyceryl trinitrate versus calcium channel blockers	1	36	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.20, 1.91]
5.2 Beta blockers versus calcium channel blockers	1	112	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.34, 1.15]
5.3 Furosemide versus calcium channel blockers	1	41	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.22, 4.18]
5.4 Methyldopa versus calcium channel blockers	3	141	Risk Ratio (M‐H, Random, 95% CI)	1.18 [0.61, 2.30]
6 Maternal death	1	112	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
6.1 Beta blockers versus calcium channel blockers	1	112	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
7 Eclampsia	2	204	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
7.1 Beta blockers versus calcium channel blockers	1	112	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
7.2 Methyldopa versus calcium channel blockers	1	92	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
8 HELLP syndrome	2	212	Risk Ratio (M‐H, Random, 95% CI)	1.78 [0.38, 8.20]
8.1 Beta blockers versus calcium channel blockers	2	212	Risk Ratio (M‐H, Random, 95% CI)	1.78 [0.38, 8.20]
9 Pulmonary oedema	1	112	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
9.1 Beta blockers versus calcium channel blockers	1	112	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
10 Need for additional antihypertensive drug/s	5	440	Risk Ratio (M‐H, Random, 95% CI)	1.36 [0.78, 2.36]
10.1 Beta blockers versus calcium channel blockers	2	212	Risk Ratio (M‐H, Random, 95% CI)	1.27 [0.51, 3.20]
10.2 Methyldopa versus calcium channel blockers	3	228	Risk Ratio (M‐H, Random, 95% CI)	1.61 [0.78, 3.34]
11 Elective delivery (induction of labour + elective caesarean section)	3	302	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.82, 1.17]
11.1 Beta blockers versus calcium channel blockers	1	100	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.69, 1.15]
11.2 Methyldopa versus calcium channel blockers	2	202	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.61, 1.54]
12 Caesarean section	6	531	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.86, 1.29]
12.1 Beta blockers versus calcium channel blockers	3	372	Risk Ratio (M‐H, Random, 95% CI)	1.04 [0.77, 1.39]
12.2 Furosemide versus calcium channel blockers	1	41	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.57, 1.59]
12.3 Methyldopa versus calcium channel blockers	2	118	Risk Ratio (M‐H, Random, 95% CI)	1.51 [0.87, 2.65]
13 Induction of labour	2	252	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.74, 1.34]
13.1 Beta blockers versus calcium channel blockers	1	160	Risk Ratio (M‐H, Random, 95% CI)	1.15 [0.69, 1.92]
13.2 Methyldopa versus calcium channel blockers	1	92	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.64, 1.33]
14 Placental abruption	3	253	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.16, 6.86]
14.1 Beta blockers versus calcium channel blockers	2	212	Risk Ratio (M‐H, Random, 95% CI)	0.35 [0.01, 8.30]
14.2 Furosemide versus calcium channel blockers	1	41	Risk Ratio (M‐H, Random, 95% CI)	1.90 [0.19, 19.40]
15 Maternal side‐effects	3	322	Risk Ratio (M‐H, Random, 95% CI)	1.40 [0.85, 2.29]
15.1 Beta blockers versus calcium channel blockers	2	212	Risk Ratio (M‐H, Random, 95% CI)	1.40 [0.85, 2.29]
15.2 Methyldopa versus calcium channel blockers	1	110	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
16 Changed/stopped drug due to side‐effects	3	248	Risk Ratio (M‐H, Random, 95% CI)	1.55 [0.56, 4.31]
16.1 Glyceryl trinitrate versus calcium channel blockers	1	36	Risk Ratio (M‐H, Random, 95% CI)	2.6 [0.13, 50.25]
16.2 Beta blockers versus calcium channel blockers	2	212	Risk Ratio (M‐H, Random, 95% CI)	1.45 [0.49, 4.30]
17 Admission to neonatal or intensive care nursery	4	319	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.54, 1.37]
17.1 Beta blockers versus calcium channel blockers	2	202	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.49, 1.58]
17.2 Methyldopa versus calcium channel blockers	2	117	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.38, 1.78]
18 Respiratory distress syndrome	1	103	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.27, 1.54]
18.1 Beta blockers versus calcium channel blockers	1	103	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.27, 1.54]
19 Neonatal hypoglycaemia	1	103	Risk Ratio (M‐H, Random, 95% CI)	0.76 [0.29, 2.05]
19.1 Beta blockers versus calcium channel blockers	1	103	Risk Ratio (M‐H, Random, 95% CI)	0.76 [0.29, 2.05]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Severe hypertension	10	692	Risk Ratio (M‐H, Fixed, 95% CI)	1.18 [0.95, 1.48]
1.1 Methyldopa versus beta blocker	9	592	Risk Ratio (M‐H, Fixed, 95% CI)	1.36 [1.08, 1.71]
1.2 Calcium channel blocker versus beta blocker	1	100	Risk Ratio (M‐H, Fixed, 95% CI)	0.47 [0.21, 1.05]
2 Proteinuria/pre‐eclampsia	12	1107	Risk Ratio (M‐H, Random, 95% CI)	1.21 [0.88, 1.67]
2.1 Methyldopa versus beta blockers	10	903	Risk Ratio (M‐H, Random, 95% CI)	1.22 [0.86, 1.72]
2.2 Calcium channel blocker versus beta blocker	2	204	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.19, 4.17]
3 Total reported fetal or neonatal death (including miscarriage)	19	1652	Risk Ratio (M‐H, Random, 95% CI)	1.23 [0.81, 1.88]
3.1 Methyldopa versus beta blockers	16	1280	Risk Ratio (M‐H, Random, 95% CI)	1.25 [0.67, 2.34]
3.2 Calcium channel blokers versus beta blockers	3	372	Risk Ratio (M‐H, Random, 95% CI)	1.21 [0.68, 2.16]
4 Small‐for‐gestational age	7	680	Risk Ratio (M‐H, Random, 95% CI)	1.13 [0.80, 1.60]
4.1 Methyldopa versus beta blockers	6	577	Risk Ratio (M‐H, Random, 95% CI)	1.19 [0.76, 1.84]
4.2 Calcium channel blockers versus beta blockers	1	103	Risk Ratio (M‐H, Random, 95% CI)	1.04 [0.59, 1.83]
5 Preterm birth (< 37 weeks)	9	806	Risk Ratio (M‐H, Random, 95% CI)	1.22 [0.90, 1.67]
5.1 Methyldopa versus beta blockers	8	694	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.77, 1.60]
5.2 Calcium channel blockers versus beta blockers	1	112	Risk Ratio (M‐H, Random, 95% CI)	1.61 [0.87, 2.97]
6 Maternal death	1	112	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
6.1 Calcium channel blockers versus beta blockers	1	112	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
7 Severe pre‐eclampsia	1	311	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.43, 1.77]
7.1 Methyldopa versus beta blockers	1	311	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.43, 1.77]
8 Eclampsia	1	112	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
8.1 Calcium channel blockers versus beta blockers	1	112	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
9 HELLP syndrome	2	212	Risk Ratio (M‐H, Random, 95% CI)	0.56 [0.12, 2.60]
9.1 Calcium channel blockers versus beta blockers	2	212	Risk Ratio (M‐H, Random, 95% CI)	0.56 [0.12, 2.60]
10 Pulmonary oedema	1	112	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
10.1 Calcium channel blockers versus beta blockers	1	112	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
11 Need for additional antihypertensive drug/s	12	1065	Risk Ratio (M‐H, Random, 95% CI)	1.15 [0.76, 1.75]
11.1 Methyldopa versus beta blockers	10	853	Risk Ratio (M‐H, Random, 95% CI)	1.31 [0.78, 2.20]
11.2 Calcium channel blockers versus beta blockers	2	212	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.31, 1.97]
12 Elective delivery (induction of labour + elective caesarean section)	6	553	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.91, 1.12]
12.1 Methyldopa versus beta blockers	5	453	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.89, 1.11]
12.2 Calcium channel blockers versus beta blockers	1	100	Risk Ratio (M‐H, Random, 95% CI)	1.12 [0.87, 1.45]
13 Caesarean section	13	1344	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.90, 1.17]
13.1 Methyldopa versus beta blockers	10	972	Risk Ratio (M‐H, Random, 95% CI)	1.04 [0.88, 1.23]
13.2 Calcium channel blockers versus beta blockers	3	372	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.72, 1.29]
14 Induction of labour	2	280	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.68, 1.31]
14.1 Methyldopa versus beta blockers	1	120	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.65, 1.53]
14.2 Calcium channel blockers versus beta blockers	1	160	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.52, 1.45]
15 Antenatal hospital admission	2	275	Risk Ratio (M‐H, Random, 95% CI)	1.78 [0.54, 5.90]
15.1 Methyldopa versus beta blockers	2	275	Risk Ratio (M‐H, Random, 95% CI)	1.78 [0.54, 5.90]
16 Placental abruption	3	385	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.14, 6.28]
16.1 Methyldopa versus beta blockers	1	173	Risk Ratio (M‐H, Random, 95% CI)	0.49 [0.05, 5.35]
16.2 Calcium channel blockers versus beta blockers	2	212	Risk Ratio (M‐H, Random, 95% CI)	2.90 [0.12, 69.62]
17 Maternal side‐effects	7	514	Risk Ratio (M‐H, Random, 95% CI)	1.27 [0.64, 2.53]
17.1 Methyldopa versus beta blockers	5	302	Risk Ratio (M‐H, Random, 95% CI)	4.55 [0.48, 43.24]
17.2 Calcium channel blockers versus beta blockers	2	212	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.44, 1.17]
18 Changed/stopped drugs due to maternal side‐effects	6	484	Risk Ratio (M‐H, Random, 95% CI)	0.64 [0.23, 1.80]
18.1 Methyldopa versus beta blockers	4	272	Risk Ratio (M‐H, Random, 95% CI)	0.36 [0.01, 8.64]
18.2 Calcium channel blockers versus beta blockers	2	212	Risk Ratio (M‐H, Random, 95% CI)	0.69 [0.23, 2.04]
19 Admission to neonatal or intensive care nursery	6	773	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.84, 1.45]
19.1 Methyldopa versus beta blockers	4	571	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.80, 1.49]
19.2 Calcium channel blockers versus beta blockers	2	202	Risk Ratio (M‐H, Random, 95% CI)	1.14 [0.63, 2.05]
20 Respiratory distress syndrome	2	221	Risk Ratio (M‐H, Random, 95% CI)	1.37 [0.71, 2.66]
20.1 Methyldopa versus beta blockers	1	118	Risk Ratio (M‐H, Random, 95% CI)	1.17 [0.42, 3.26]
20.2 Calcium channel blockers versus beta blockers	1	103	Risk Ratio (M‐H, Random, 95% CI)	1.54 [0.65, 3.66]
21 Neonatal hypoglycaemia	6	542	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.62, 2.00]
21.1 Methyldopa versus beta blockers	5	439	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.49, 2.11]
21.2 Calcium channel blockers versus beta blockers	1	103	Risk Ratio (M‐H, Random, 95% CI)	1.31 [0.49, 3.50]
22 Neonatal bradycardia	2	146	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.01, 8.02]
22.1 Methyldopa versus beta blockers	2	146	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.01, 8.02]
23 Neonatal jaundice	2	146	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.44, 2.09]
23.1 Methyldopa versus beta blockers	2	146	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.44, 2.09]

Methods	Allocation concealment: not stated. Authors state"...randomly divided into two groups...".Two arms.
Participants	60 women with SBP >/= 160 mmHg and/or DBP >/= 100 mmHg x 2, 24 hrs apart, with or without proteinuria at trial entry.  Excluded: > 1 drug to control BP, or contraindication for beta blockers.
Interventions	Exp: oral atenolol 50 mg/day to 250 mg/day (30 women)  Control: oral methyldopa 750 mg/day to 2000 mg/day (30 women)
Outcomes	Women: BP (mean).  Babies: gestational age, birthweight, Apgar score, stillbirth, neonatal deaths.
Notes	Main paper in Spanish. Methods for measuring BP not mentioned. Funding: no information about funding source. Declaration of interests not described
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described.
Allocation concealment (selection bias)	Unclear risk	Not described: "...randomly divided into two groups..." no further details.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label trial.
Blinding of outcome assessment (detection bias)   All outcomes	High risk	No.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No.
Selective reporting (reporting bias)	Unclear risk	Assessment from published study report.
Other bias	Unclear risk	No information about funding source. Declaration of interests not described.

Methods	Allocation concealment: central telephone randomisation Although authors stated it was a placebo‐controlled trial, data provided by authors suggest that they may have used a patch for the control, but not a matching placebo. Two arms
Participants	16 women with gestational HT, defined as quote: "de novo" HT after 20 weeks' gestation of > 140 and/or 90 mmHg on 2 readings, 6 hrs apart; or a rise in systolic pressure of > 25 mmHg or a diastolic of 15 mmHg from a BP pre‐pregnancy or in the first trimester.
Interventions	Exp: transdermal GTN patches 10 mg. (7 women)  Control: patch for the control, but not a matching placebo. (9 women)
Outcomes	Women: PE, side‐effects.  Babies: not reported.
Notes	Trial planned to recruit 220 women and stopped early due to side‐effects (headache) in the treatment group. Additional data provided by authors. Funding: no information about funding source. Declaration of interests not described.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Central telephone randomisation.
Allocation concealment (selection bias)	Low risk	Central telephone randomisation.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Described as quote: "...single blind, placebo controlled trial...".
Blinding of outcome assessment (detection bias)   All outcomes	High risk	No.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No.
Selective reporting (reporting bias)	Unclear risk	Assessment from published study letter to editor.
Other bias	Unclear risk	No information about funding source. Declaration of interests not described

Methods	Allocation concealment: consecutive numbered treatment boxes. Two arms
Participants	40 pregnant women with chronic HT with DBP =/> 95 mmHg, without proteinuria.
Interventions	Exp: oral pindolol 10 mg/day to 30 mg/day. (20 women)  Control: oral methyldopa 500 mg/day to 2000 mg/day. (20 women)
Outcomes	Women: BP, need for additional antihypertensives, severe HT, superimposed PE.  Babies: birthweight, Apgar score, fetal and neonatal death, preterm birth, SGA (undefined).
Notes	Main paper in Portuguese. Methods for measuring BP not mentioned. Additional data provided by authors. Funding: no information about funding source. Declaration of interests not declared
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not stated.
Allocation concealment (selection bias)	Low risk	Consecutive numbered treatment boxes (personal communication).
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label trial.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No.
Selective reporting (reporting bias)	Low risk	Published and unpublished data provided by author.
Other bias	Unclear risk	No information about funding source. Declaration of interests not described.

Methods	Allocation concealment: trial drug supplied by pharmacy in packs with serial numbers.  Withdrawals: 15 women (7.5%) excluded from the analysis (5 delivered in other hospitals, 9 dropped out of the study or failed to comply with treatment, 1 due to side‐effects). Two arms
Participants	199 singleton pregnant women with mild/moderate chronic HT (DBP > 90 mmHg and =/< 110 mmHg before 20 weeks' gestation, or with history of chronic HT), before 25 weeks' gestation and giving informed consent. Excluded: renal, cardiac or hepatic disease, IUGR diagnosed before trial entry, alcohol/drug abuse.
Interventions	Exp: oral verapamil 240 mg x 3/day. (90 women)  Control: oral placebo. (94 women)
Outcomes	Women: BP, heart rate, severe HT, superimposed PE, side‐effects, mode of delivery.  Babies: birthweight, gestational age, SGA, Apgar score, jaundice, hypoglycaemia, mortality.
Notes	Korotkoff phase IV used for DBP. Main report in Portuguese, presented as a Doctoral Thesis. Additional data provided by authors. Funding: no information about funding source. Declaration of interests not described.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described.
Allocation concealment (selection bias)	Low risk	Consecutive numbered treatment packs containing the study drug or placebo.
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blind, only pharmacist providing treatment packs aware of the codes.
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Double‐blind, only pharmacist providing treatment packs aware of the codes.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	15 withdrawals (7.5%): 5 women delivered in other hospitals, 10 withdrew consent (1 due to side‐effects).
Selective reporting (reporting bias)	Unclear risk	Assessment from published study thesis.
Other bias	Unclear risk	Groups appear comparable at baseline. No information about funding source. Declaration of interests not described.

Methods	Allocation concealment: sealed and numbered opaque envelopes. Two arms
Participants	100 singleton pregnant women with PE, defined as development of HT after 20 weeks of gestation (DBP blood pressure 90 mmHg or greater, SBP 140 mmHg or greater, or both) with associated proteinuria (greater than 300 mg in 24 hours), at 24 to 33 weeks' gestation. Excluded: history of HT, chronic disorders such as diabetes, fetal malformations, or maternal or fetal comorbidities or both, use of erythromycin, ketoconazole, itraconazole, antiretroviral agents, or any other medication that could interact with sildenafil, patients using antihypertensive medications other than a‐methyldopa, not giving consent.
Interventions	Exp: oral sildenafil citrate at 50 mg every 8 hours. (50 women) Control: identical placebo capsules. (50 women)
Outcomes	Women: time interval between randomisation and delivery, MAP, Doppler velocimetry of the uterine, umbilical, and middle cerebral arteries, need for an additional antihypertensive drug, caesarean section, eclampsia, placental abruption, maternal cardiac failure, HELLP syndrome, PPH, maternal side‐effects. Babies: IUGR (< 10th centile), birthweight, Apgar score, NICU admission, days in NICU, neonatal infection, IVH, thrombocytopenia, hypotension, necrotising enterocolitis, hypoglycaemia, pneumothorax, convulsions, neonatal demise, neonatal side‐effects.
Notes	Korotkoff phase IV used for DBP. Funding: funded by university or non commercial organisation. The authors reported no potential conflicts of interest.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Blocked randomisation (blocks of 5).
Allocation concealment (selection bias)	Low risk	Sealed and numbered opaque envelopes.
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Study investigators, attending physicians, ultrasonographers, neonatologists, and patients were blinded regarding allocation to placebo or sildenafil groups until the end of the study.
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Study investigators, attending physicians, ultrasonographers, neonatologists, and patients were blinded regarding allocation to placebo or sildenafil groups until the end of the study.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	7 women (7%) discontinued treatment due to concerns about the possibility of being allocated to a placebo (2 in each group), or due to side‐effects (1 in treatment group, 2 in placebo group). However, authors stated that women consent in the use of their data and presented results in 100 women randomised.
Selective reporting (reporting bias)	Unclear risk	Assessment from published study report.
Other bias	Low risk	Groups appear comparable at baseline. Funded by university or non commercial organisation. Authors stated not potential conflict of interests.

Methods	Allocation concealment: women given number corresponding to sealed envelope and treatment batch. Envelope contained unblinding, kept by investigator and only opened when necessary. Envelopes collected at end of study. 2 centres.  Withdrawals: 1 woman, from placebo group. Two arms
Participants	155 women with singleton pregnancy at 20 to 36 weeks' gestation, DBP < 85 mmHg x 2 before 20 weeks and > 84 mmHg after 20 weeks.  Excluded: type I diabetes, congestive heart failure, cardiac block, asthma, pre‐pregnancy HT, antihypertensive treatment during current pregnancy.
Interventions	Exp: oral oxprenolol 160 mg x 2/day to 320 mg x 2/day. Hydralazine 50 mg to 100 mg added if necessary to keep DBP < 86 mmHg. (78 women) Control: oral placebo, identical appearance. (77 women)
Outcomes	Women: death, mean BP, severe HT, proteinuria (> 1+ or 0.25 g/L), additional antihypertensive, eclampsia, changed drugs due to side‐effects, elective delivery, caesarean section, hospital admission, days in hospital, placental abruption.  Babies: perinatal death, preterm delivery (< 37 weeks), birthweight (mean), SGA (undefined, excludes stillbirth), 5 mins Apgar < 7, admission to SCBU, RDS.
Notes	Korotkoff phase IV used for DBP. For 23 women (15%), treatment unblinded and other treatment started. 16 for uncontrolled BP (5 exp, 11 control) and 7 for poor compliance/side‐effects (4 exp, 3 control). Additional data provided by authors. Funding: funded by industry.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomisation was in stratified blocks of ten..."
Allocation concealment (selection bias)	Low risk	Quote: "...sealed envelopes and individual batch of drugs containing either the maximum amount of active drug that could be used in 20 weeks of treatment or placebos of identical appearance."
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blind, placebo‐controlled.
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Yes.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	1 women (0.6%) lost to follow‐up.
Selective reporting (reporting bias)	Low risk	Published and unpublished data provided by author.
Other bias	High risk	For 23 women (15%), treatment unblinded and other treatment started. 16 for uncontrolled BP (5 exp, 11 control) and 7 for poor compliance/side‐effects (4 exp, 3 control). Funded by industry.

Methods	Quote: "randomised pilot trial". No further information.
Participants	25 women with PIH.
Interventions	Exp: oral nifedipine, 30 mg to 60 mg. daily (13 women)  Control: no treatment (12 women)
Outcomes	mean DBP, birthweight (mean).
Notes	Available as abstract only. Not possible to extract data. Reported as an ongoing study.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described.
Allocation concealment (selection bias)	Unclear risk	Not described.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Not described.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Not described.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Not described.
Selective reporting (reporting bias)	Unclear risk	Not described.
Other bias	Unclear risk	Funding source and declaration of interests not described.

Methods	Allocation concealment: quote "blinded envelopes". Stratified in blocks of 10 at each clinic. Multicentre, 12 hospitals.  Withdrawals: 12 women (6%). 5 labetalol (3 lost to follow‐up and 2 given methyldopa) and 7 methyldopa (all lost to follow‐up). Two arms
Participants	188 women with singleton pregnancy at 12 to 34 weeks' gestation, booked < 20 weeks and DBP >/= 90 mmHg.  Excluded: previous antihypertensive treatment this pregnancy, diabetes, depression, contraindication to beta blockers.
Interventions	Exp: oral labetalol 200 mg x 2/day to 600 mg x 2/day. (96 women)  Control: oral methyldopa 250 mg x 2/day to 750 mg x 2/day. (92 women)
Outcomes	Women: proteinuria (> 2+ or 0.5 g/L), admission to hospital, caesarean section, elective delivery, additional antihypertensive, side‐effects, changed drugs due to side‐effects.  Babies: stillbirth, neonatal death, admission to SCBU, SGA (< 5th centile, excludes stillbirths), preterm delivery (< 37 weeks), 5 mins Apgar < 8.
Notes	Korotkoff phase IV used for DBP. Funding: funded by industry.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "...stratified blocks of ten at each clinic..."
Allocation concealment (selection bias)	Low risk	Blinded envelopes.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label trial.
Blinding of outcome assessment (detection bias)   All outcomes	High risk	No.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	12 women (6.4%) excluded from analysis: 10 lost to follow‐up (3 from labetalol and 7 from methyldopa group), and 2 quote: "protocol violation".
Selective reporting (reporting bias)	Unclear risk	Assessment from published study report.
Other bias	High risk	Groups appear comparable at baseline. Funded by industry.

Methods	Quote "randomised protocol". No further details.
Participants	21 women with moderate HT (SBP 140‐180 mmHg and DBP 90‐120 mmHg).
Interventions	EXP: oral atenolol (n = 12) (no doses reported) CONT: oral nifedipine (n = 9) (no doses reported)
Outcomes	BP, Doppler measures, birthweight and length, Apgar score, admission to SCBU.
Notes	Not possible to extract data. Available as congress abstracts only (1 in English, 3 in French)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described.
Allocation concealment (selection bias)	Unclear risk	Not described.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Not described.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Not described.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Not described.
Selective reporting (reporting bias)	Unclear risk	Not described.
Other bias	Unclear risk	Funding source and declaration of interests not described.

Methods	Allocation concealment: sealed envelopes drawn by physician. Ordered using list of computer‐generated random numbers. Two arms
Participants	100 women with singleton pregnancy at > 20 weeks' gestation and mild‐moderate HT (BP >/= 140/90 mmHg x 2). No other antihypertensive medication at trial entry.
Interventions	Exp: oral nicardipine 20 mg x 3/day.(50 women)  Control: oral metoprolol (slow release) 200 mg/day.(50 women)
Outcomes	Women: severe HT, proteinuria (undefined), HELLP syndrome, additional antihypertensive, changed drug due to side‐effects, induction of labour, caesarean section.  Babies: perinatal death, umbilical Doppler, admission to SCBU.
Notes	Korotkoff phase IV used for DBP. Funding: no information about funding source. Declaration of interests not described.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	List of computer‐generated random numbers.
Allocation concealment (selection bias)	Low risk	Sealed envelopes.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label trial.
Blinding of outcome assessment (detection bias)   All outcomes	High risk	No.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No.
Selective reporting (reporting bias)	Unclear risk	Assessment from published study report.
Other bias	Unclear risk	Groups appear comparable at baseline. No information about funding source. Declaration of interests not described.

Methods	Allocation concealment: not stated.  Authors state: "randomised double‐blind". Two arms
Participants	41 healthy nulliparous women admitted for PE (BP >/= 140/90 mmHg x 2 within 24 hours).
Interventions	Exp: oral labetalol 200 mg x 3/day. (20 women)  Control: oral placebo (character not stated). (21 women)
Outcomes	Women: mean BP, severe HT, additional antihypertensive.  Babies: birthweight (mean), SGA (< 10th centile), gestation at delivery (mean).
Notes	Trial reported as in progress in 1990. Missing data for some babies. No description of how BP measured. Available only as an abstract. Funding: no information about funding source. Declaration of interests not described.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described.
Allocation concealment (selection bias)	Unclear risk	Not described: authors only state: "randomised double‐blind controlled study".
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blind, placebo‐controlled study.
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Yes.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No.
Selective reporting (reporting bias)	Unclear risk	Assessment from published study abstract.
Other bias	Unclear risk	No information about funding source. Declaration of interests not described.

Methods	Allocated in quote"randomised double manner". No further information. 4 women (6.2%) excluded after randomisation. No further details.
Participants	65 primigravid women with a singleton pregnancy at > 20 weeks' gestation and BP 140‐165/90‐105 mmHg x 2, 6 hrs apart but no proteinuria.
Interventions	Exp: oral labetalol. No dose specified. Number of women not specified.  Control: oral placebo. No dose specified. Number of women not specified
Outcomes	BP, need for additional antihypertensives, induction of labour, proteinuria, gestational age, mode of delivery, birthweight, Apgar score
Notes	Available as abstract only. Not possible to extract data. Declaration of interests not described.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described.
Allocation concealment (selection bias)	Unclear risk	Not described.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Not described.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Not described.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Not described.
Selective reporting (reporting bias)	Unclear risk	Not described.
Other bias	Unclear risk	Funding source and declaration of interests not described.

Methods	Methods not stated, authors only state "...randomised by number..." Two arms
Participants	118 primigravid women with HT (BP > 140/90 x 2, 60 hours apart) during pregnancy with and without proteinuria at > 20 weeks' gestation. Excluded: 2nd or more pregnancies, history of chronic HT, use of anti HT drugs.
Interventions	Exp: oral Nimodipine 30 mg every 6 hrs. (54 women) Control: oral methyldopa 250 mg every 6 hrs. (56 women)
Outcomes	MAP, additional antihypertensives, serum creatinine and liver enzymes, induction of labour, serious maternal side‐effects, perinatal deaths.
Notes	Method for measuring BP not mentioned. Funding: no information about funding source. Declaration of interests not described.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described.
Allocation concealment (selection bias)	Unclear risk	Not described: quote: "...randomised by number...". No further details.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label trial.
Blinding of outcome assessment (detection bias)   All outcomes	High risk	No.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	7 dropouts (6%), not specified in which group.
Selective reporting (reporting bias)	Unclear risk	Assessment from published study report.
Other bias	Unclear risk	Groups appear comparable at baseline. No information about funding source. Declaration of interests not described.

Methods	Prospective randomised comparative study. No further details
Participants	200 women with singleton pregnancy, 28 to 40 weeks' gestation with PIH.
Interventions	Exp: oral labetalol. No dose specified. Number of women not specified.  Control: oral methyldopa. No dose specified. Number of women not specified.
Outcomes	BP, control of proteinuria, mode of delivery, neonatal Apgar score, NICU admission, neonatal complications, perinatal deaths.
Notes	Available as abstract only. Not possible to extract data.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described
Allocation concealment (selection bias)	Unclear risk	Not described
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Not described
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Not described
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Not described
Selective reporting (reporting bias)	Unclear risk	Not described
Other bias	Unclear risk	Funding source and declaration of interests not described

PERMALINK

Antihypertensive drug therapy for mild to moderate hypertension during pregnancy

Edgardo Abalos

Lelia Duley

D Wilhelm Steyn

Celina Gialdini

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

For the woman

For the baby

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

(1) Random sequence generation (checking for possible selection bias)

(2) Allocation concealment (checking for possible selection bias)

(3.1) Blinding of participants and personnel (checking for possible performance bias)

(3.2) Blinding of outcome assessment (checking for possible detection bias)

(4) Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data)

(5) Selective reporting (checking for reporting bias)

(6) Other bias (checking for bias due to problems not covered by (1) to (5) above)

(7) Overall risk of bias

Assessment of the quality of the evidence using the GRADE approach

Primary outcomes

Secondary outcomes

Maternal

Fetal/infant outcomes

Measures of treatment effect

Dichotomous data

Continuous data

Unit of analysis issues

Cluster‐randomised trials

Other unit of analysis issues

Dealing with more than two intervention groups

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Results

Description of studies

Results of the search

1.

Included studies

Methods and trial dates

Funding sources

Trials authors' declaration of interest

Interventions and comparisons

Gestation at trial entry

Severity and type of hypertension disease at trial entry

Methods for measuring blood pressure

Definition of small‐for‐gestational age

Excluded studies

Risk of bias in included studies

Methods	Mixed sealed envelopes containing the assigned intervention. 3‐arm trial.
Participants	149 women with PIH (140‐159/90 to 109 mmHg x 2, 6 hrs apart, without proteinuria) at 20‐38 weeks' gestation. Excluded: chronic HT, previous anti HT medication, secondary HT, UTI, diabetes, known medical/psychiatric disorders, multiple pregnancy, placenta previa, Rh isoimmunisation, congenital abnormality.
Interventions	Exp 1: oral labetalol 100 mg x 2/day (up to 2500 mg). (50 women) Exp 2: oral methyldopa 250 mg x 2/day (up to 2000 mg). (49 women) Control: no treatment. (50 women)
Outcomes	BP, laboratory parameters, gestational age at delivery, birthweight, 5‐min Apgar score, maternal adverse events, maternal death, major morbidity, severe HT, proteinuria, severe PE, antenatal hospital admission, caesarean section, perinatal death, SGA, preterm babies, Admission to NICU.
Notes	Korotkoff phase V for DBP. Funding: funded by university or non commercial organisation. Authors declared no conflict of interest
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Quote: "Allocation cards labelled L (labetalol), M (methyldopa) or N (no antihypertensive) were prepared by a staff clerk in equal numbers of 50 each and put into opaque envelopes that were subsequently sealed, mixed up and numbered 1‐150."
Allocation concealment (selection bias)	Low risk	Consecutively numbered opaque sealed envelopes.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label trial.
Blinding of outcome assessment (detection bias)   All outcomes	High risk	No.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	1 woman withdrew consent in methyldopa group.
Selective reporting (reporting bias)	Unclear risk	Assessment from published study report.
Other bias	Low risk	Groups appear comparable at baseline. Funded by university or non commercial organisation. Authors declared no conflict of interest.

Methods	Allocation concealment: not described, quote: "...prospective randomized study,.." no further details. Two arms
Participants	120 pre‐eclamptic women after 20 weeks of gestation with BP more than 140/90 mmHg on 2 separate occasion 6 hrs apart, proteinuria +1 dipstick in 2 midstream samples collected 4 hrs apart. Singleton with vertex presentation. Excluded: diabetes, Rh isoimmunisation, multi‐fetal pregnancy, thyrotoxicosis, cardiac disease, chronic HT, renal disease, bronchial asthma, antepartum haemorrhage, malnutrition, poli‐hydramnios, already receiving antihypertensive drugs.
Interventions	Exp: oral labetalol 100 mg 3 times a day. (90 women) Control: oral methyldopa 250 mg 3 times a day. (90 women)
Outcomes	Women: response in lowering BP over a period of 7 days, blood urea and serum creatinine, platelet count, mode of onset of labour, gestational age at delivery, mode of delivery, side‐effects. Babies: birthweight, stillbirth, preterm delivery, Apgar score, RDS, jaundice, bradycardia, hypoglycaemia, need for NICU.
Notes	Method for measuring BP not mentioned. Funding: no information about funding source. Declaration of interests not described.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated sequence of random numbers.
Allocation concealment (selection bias)	Unclear risk	Not described. Quote:"...prospective randomized study,.." no further details.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Not described.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Not described.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No.
Selective reporting (reporting bias)	Unclear risk	Assessment from published study report.
Other bias	Unclear risk	Groups appear comparable at baseline. No information about funding source. Declaration of interests not described.

Methods	Allocation concealment: not described. Authors state "randomized, double‐blind, comparative trial". Two arms
Participants	100 singleton pregnant women with sitting SBP of 150 to 169 mmHg or DBP (disappearance of sounds phase V, Korotkoff sounds) of 100 mmHg to 109 mmHg on 2 occasions at least 4 hrs apart. All patients in the study were more than 32 weeks pregnant and were normotensive before 20 weeks of pregnancy. Excluded: past history of HT, diabetes, renal disease, asthma, congestive heart failure, known atrioventricular block, other illness, or fetal congenital abnormality including intrauterine growth retardation
Interventions	Exp: 10 mg oral nifedipine four times a day. (50 women) Control: 250 mg oral methyldopa 3 times a day. (50 women)
Outcomes	Women: successful control of SBP < 150 mmHg and DBP < 100 mmHg without using additional drugs, maternal side‐effects such as hypotension, maternal tachycardia, headache, flushing, nausea and vomiting, dizziness, abnormal cardiotocogram or cardiovascular accidents after starting the antihypertensive medication. Babies: mean birth weight (kg), Apgar score at 5 minutes, Abnormal CTG, NICU admission, stillbirths.
Notes	Korotkoff phase V for DBP. Funding: no information about funding source. Declaration of interests not described.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "...by a series of random numbers".
Allocation concealment (selection bias)	Unclear risk	Not described.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Quote: "The patient and the investigator were blinded regarding treatment". No further details. However, the dosage of comparative treatments was different (nifedipine four times a day versus methyldopa 3 times a day).
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Not described.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	8 women (8%) excluded from analysis for failure to comply regular follow‐up, 3 in methyldopa and 5 in nifedipine group.
Selective reporting (reporting bias)	Unclear risk	Assessment from published study reports.
Other bias	Unclear risk	Groups appear comparable at baseline. No information about funding source. Declaration of interests not described.

Methods	Quote: "...patients were divided into two groups randomly..." Two arms
Participants	180 pregnant women at > 20 weeks' gestation with BP > 140/90 mmHg x 2, 6 hours apart and proteinuria 1+ on dipstick x 2, 4 hours apart.
Interventions	Exp: oral Labetalol 100 mg three times daily (doubled every 48 hours until BP control). (90 women) Control: oral Methyldopa 250 mg three times daily (doubled every 48 hours until BP control). (90 women)
Outcomes	Fall in BP after 7 days treatment, average dose of drug used, induction of labour, maternal side‐effects.
Notes	Method for measuring BP not mentioned. Funding: no funding source. Authors declared no conflict of interest.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described.
Allocation concealment (selection bias)	Unclear risk	Not described: quote: "...patients were divided into two groups randomly...". No further details.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label trial.
Blinding of outcome assessment (detection bias)   All outcomes	High risk	No.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No.
Selective reporting (reporting bias)	Unclear risk	Assessment from published study report.
Other bias	Low risk	Groups appear comparable at baseline. No funding source. Authors declared no conflict of interests.

Methods	Allocation concealment: Not described. Quote "...Patients (80 each) were randomised to each of the three treatment arms..." No further details. Three arms
Participants	240 pregnant women with SBP of ≥140 mmHg and a DBP of ≥ 90 mmHg requiring medication and gestational age more than 20 weeks of pregnancy. Excluded: bronchial asthma, any pre‐existing cardiovascular disorder, diabetes, Rh isoimmunisation, patients at risk of major obstetric complications ‐ antepartum haemorrhage, malnutrition, multifetal gestation and hydramnios during the current pregnancy and patients who had already received antihypertensive drugs.
Interventions	Group 1: oral nifedipine 10 mg twice daily (80 women) Group 2: oral methyldopa 250 mg three times daily (80 women) Group 3: oral labetalol 100 mg twice daily (80 women)
Outcomes	Women: control of BP over a period of 7 days, time required to control BP, average dose of drugs required to control BP, onset of labour‐spontaneous/induced or caesarean section, adverse effects of drugs Babies: Stillbirth
Notes	Korotkoff phase IV for DBP. Funding: no funding source. Authors declared no conflict of interests.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described. Quote: "...patients randomly divided in three groups..."
Allocation concealment (selection bias)	Unclear risk	Not described.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Ope label trial (different dosages).
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Not described.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No.
Selective reporting (reporting bias)	Unclear risk	Assessment from published study report.
Other bias	Low risk	Groups appear comparable at baseline. No funding source. Authors declared no conflict of interests.

Methods	Allocation concealment: not described.Quote: "...prospective randomized controlled parallel group study...". No further details. Two arms
Participants	100 pregnant women with SBP ≥160 mmHg and DBP ≥110 mmHg after 20 weeks of gestation. Excluded: history of pre‐existing HT, renal diseases, immunological disorders, liver diseases, diabetes mellitus, epilepsy, thyroid diseases, eclampsia, unwilling or unable to comply with the study proceedings.
Interventions	Exp: oral labetalol 100 mg twice a day (up to 800 mg). (50 women) Control: oral methyldopa 250 mg 3 times a day (up to 3 g). (50 women)
Outcomes	Women: the mean SBP, mean DBP, and MAP at time of delivery, adverse events.
Notes	Korotkoff phase V for DBP. Funding: no funding source. Authors declared no conflict of interests.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described. Quote: "...prospective randomized controlled parallel group study...". No further details.
Allocation concealment (selection bias)	Unclear risk	Not described
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label trial (different dosages)
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Not described
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No
Selective reporting (reporting bias)	Unclear risk	Assessment from published study report.
Other bias	Unclear risk	Baseline characteristics at study entry (apart from BP) not reported. No funding source. Authors declared no conflict of interests.

Methods	Allocation concealment: cards with 'test' or 'control' sealed in envelopes, shuffled and then numbered in sequence. Consecutive envelopes opened.Two arms
Participants	36 women < 38 weeks' gestation with BP >/= 140/90 mmHg on 2 separate days, without proteinuria.  Excluded: if lived too far from the hospital to attend for frequent examinations.
Interventions	Exp: choice between oral atenolol 50 mg/day to 100 mg/day and oral methyldopa 750 mg/day to 2250 mg/day. If monotherapy inadequate, 2 drugs combined. Oral bendrofluazide 2.5 mg to 5.0 mg added as a third agent when necessary. (17 women)  Control: no antihypertensive. (19 women)
Outcomes	Women: MAP, proteinuria.   Babies: perinatal death, Apgar, gestation age at delivery, birthweight, birthweight < 50th centile.
Notes	Korotkoff phase V used for DBP. Additional data provided by authors. Funding: no information about funding source. Declaration of interests not described.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Quote: "...shuffled into random order..."
Allocation concealment (selection bias)	Low risk	Sealed, identical numbered envelopes.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label trial.
Blinding of outcome assessment (detection bias)   All outcomes	High risk	No.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No.
Selective reporting (reporting bias)	Unclear risk	Assessment from published study report.
Other bias	Unclear risk	Groups appear comparable at baseline. No information about funding source. Declaration of interests not described.

Methods	Allocation concealment: consecutive‐numbered, opaque, sealed envelopes. 3‐arm study. 6 women (17%) left the study due to side‐effects (2 women) or mother's or baby's worsening conditions (4). Three arms
Participants	36 women with singleton pregnancy, gestation > 24 weeks and PIH or PE (BP 140/90 mmHg or more, PE if proteinuria > 300 mg/24 hr).  Excluded: fetal abnormalities or chromosomal disorders, renal or hepatic disease, chronic HT.
Interventions	Exp (1): transdermal GTN 10 mg continuously 24 hr/day (12 women). Exp (2): transdermal GTN 10 mg intermittently for 16 hrs/day.(12 women)  Control: oral nifedipine 40 mg/day orally. (12 women)
Outcomes	Women: caesarean section, BP (mean), stopped drug due to side‐effects, severe HT, proteinuria/PE.  Babies: birthweight, fetal/neonatal deaths, preterm birth, IUGR, gestation at birth (mean).
Notes	Korotkoff phase IV used for DBP. In the analysis the 2 GTN arms have been combined. Additional data provided by authors. Funding: no information about funding source. Declaration of interests not described.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described.
Allocation concealment (selection bias)	Low risk	Consecutive opaque sealed envelopes (personal communication).
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label trial.
Blinding of outcome assessment (detection bias)   All outcomes	High risk	No.
Incomplete outcome data (attrition bias)   All outcomes	High risk	6 withdrawals (16.6%). 3 in group 1, 1 in group 2 and 2 in group 3.
Selective reporting (reporting bias)	Low risk	Additional data provided by authors.
Other bias	Unclear risk	No information about funding source. Declaration of interests not described.

Methods	Allocation concealment quote: "...concealed through the use of sealed envelopes."
Participants	63 pregnant women with singleton or twin pregnancy and mild/moderate chronic HT at 20 weeks of gestation.  Excluded: chronic HT with BP 160 mmHg systolic or 110 mmHg diastolic; renal failure or pre‐existing renal disease; diabetes mellitus; autoimmune disease; major fetal abnormalities; oligohydramnios; fetal death. Three arms
Interventions	Exp 1: 20 mg of oral furosemide a day. (21 women) Exp 2: 5 mg of oral amlodipine a day. (21 women) Control: 75 mg of orally administered acetylsalicylic acid a day.(21 women)
Outcomes	Women: gestational age at delivery, indication for delivery, hospitalisation during pregnancy and mode of delivery, placental abruption, severe HT, aggregate PE, pulmonary oedema, HELLP syndrome, renal insufficiency, eclampsia, disseminated intravascular coagulation.  Babies: fetal or neonatal death, birthweight, Apgar scores, RDS, intraventricular haemorrhage grade III and IV, necrotising enterocolitis, neonatal sepsis.
Notes	Methods for measuring BP not stated. Funding: no information about funding source. Authors declared no conflict of interests.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated code with block size of 6. The other investigators did not have access to the randomisation sequence.
Allocation concealment (selection bias)	Low risk	Quote: "...concealed through the use of sealed envelopes."
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label trial.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Not described.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	3 women (5%) refused to continue in the study (one in the amlodipine group and 2 in the AAS group).
Selective reporting (reporting bias)	Unclear risk	Assessment from published study report.
Other bias	Unclear risk	Groups appear comparable at baseline. No information about funding source. Authors declared no conflict of interests.

Methods	Allocation concealment: cards labelled R and Q picked blindly from a box, these identified drug container. Two arms
Participants	32 women at 12 to 30 weeks' gestation with a singleton pregnancy and BP >/= 140/90 mmHg x 2 at least 6 hrs apart, no proteinuria, no antihypertensive therapy and no other drug treatment.
Interventions	Exp: oral prazosin 1 mg to 5 mg x 3/day. (12 women)  Control: oral identical placebo. (20 women)
Outcomes	Women: severe HT, proteinuria, duration of treatment, placental abruption, caesarean section.  Babies: perinatal death, gestation at delivery (mean), birthweight, SGA (< 10th centile) preterm delivery (< 37 weeks).
Notes	Method for measuring BP not mentioned. The trial stopped early. Funding: no information about funding source. Declaration of interests not described.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described.
Allocation concealment (selection bias)	Unclear risk	Not described. Quote: "...in a randomised way, participants either received...". No further details.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Although identical placebo tablets were used, there is no information about whether it was a double‐blind or a single‐blind trial.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Not described.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No.
Selective reporting (reporting bias)	Unclear risk	Assessment from published study report.
Other bias	Unclear risk	No information about funding source. Declaration of interests not described.