Pre Eclampsia Eclampsia and Hypertension

Pregnancy and childbirth
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Pre-eclampsia, eclampsia, and hypertension

Search date July 2007 Lelia Duley ABSTRACT
INTRODUCTION: Pre-eclampsia (raised blood pressure and proteinuria) complicates 28% of pregnancies, and raises morbidity and mortality in the mother and child. Pre-eclampsia is more common in women with multiple pregnancy and in those who have conditions associates with microvascular disease. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of preventive interventions in women at risk of pre-eclampsia? What are the effects of interventions in women who develop mildmoderate hypertension during pregnancy? What are the effects of interventions in women who develop severe pre-eclampsia or very high blood pressure during pregnancy? What is the best choice of anticonvulsant for women with eclampsia? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2007 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 53 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: anticonvulsants, antihypertensive drugs, antioxidants, antiplatelet drugs, atenolol, bed rest, hospital admission or day care, calcium supplementation, choice of analgesia during labour, early delivery (interventionist care), evening primrose oil, fish oil, glyceryl trinitrate, magnesium supplementation, plasma volume expansion, and salt restriction.
QUESTIONS What are the effects of preventive interventions in women at risk of pre-eclampsia?. . . . . . . . . . . . . . . . . . . . . 3 What are the effects of interventions in women who develop mild to moderate hypertension during pregnancy?. . 8 What are the effects of interventions in women who develop severe pre-eclampsia or very high blood pressure during pregnancy?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 What is the best choice of anticonvulsant for women with eclampsia?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 INTERVENTIONS PREVENTION OF PRE-ECLAMPSIA Beneficial Antiplatelet drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Calcium supplementation . . . . . . . . . . . . . . . . . . . . . 4 Unknown effectiveness Unknown effectiveness Antioxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Glyceryl trinitrate . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Magnesium supplementation . . . . . . . . . . . . . . . . . . 7 Marine oil (fish oil) and other prostaglandin precursors (evening primrose oil) . . . . . . . . . . . . . . . . . . . . . . . . 5 Salt restriction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 ECLAMPSIA: ANTICONVULSANTS Unlikely to be beneficial Atenolol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 TREATMENTS FOR MILDMODERATE HYPERTENSION Unknown effectiveness Antihypertensive drugs for mild to moderate hypertension .......................................... 8 Bed rest/admission v day care . . . . . . . . . . . . . . . . . 8 TREATMENT OF SEVERE EPISODES OF PREECLAMPSIA Beneficial Prophylactic magnesium sulphate in severe preeclampsia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
BMJ Publishing Group Ltd 2008. All rights reserved.
Likely to be beneficial Antihypertensive drugs for very high blood pressure* . . 1 0
Antioxidants in severe pre-eclampsia . . . . . . . . . . . 11 Choice of analgesia during labour with severe preeclampsia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 Early delivery for severe early-onset pre-eclampsia . . 1 2 Plasma volume expansion in severe pre-eclampsia . . 1 3
Beneficial Magnesium sulphate for eclampsia (better and safer than other anticonvulsants) . . . . . . . . . . . . . . . . . . 13 To be covered in future updates Interventions in women with pre-existing hypertension Treatment of postpartum hypertension Footnote *There is consensus that women with severe hypertension during pregnancy should have antihypertensive treatment, and that women with eclampsia should have an anticonvulsant. Placebo-controlled trials would therefore be unethical.
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Clinical Evidence 2008;08:1402

Key points Pre-eclampsia (raised blood pressure and proteinuria) complicates 28% of pregnancies, and increases morbidity and mortality in the mother and child. Pre-eclampsia is more common in women with multiple pregnancy, and in people with conditions associated with microvascular disease. Antiplatelet drugs (primarily low-dose aspirin) reduce the risk of pre-eclampsia, death of the baby, and premature birth, without increasing the risks of bleeding, in women at high risk of pre-eclampsia. Calcium supplementation reduces the risk of pre-eclampsia compared with placebo. We don't know whether fish oil, evening primrose oil, salt restriction, magnesium supplementation, antioxidants, or glyceryl trinitrate are beneficial in high-risk women, because there are insufficient data to draw reliable conclusions. We don't know whether atenolol reduces the risk of pre-eclampsia, but it may worsen outcomes for babies. For women with mild to moderate hypertension during pregnancy, antihypertensive drugs reduce the risk of progression to severe hypertension, but may not improve other clinical outcomes. ACE inhibitors have been associated with fetal renal failure, and beta-blockers are associated with the baby being born small for its gestational age. We don't know whether bed rest or hospital admission are also beneficial. There is consensus that women who develop severe hypertension in pregnancy should receive antihypertensive treatment, but we don't know which antihypertensive agent is most effective. We don't know whether plasma volume expansion, antioxidants, epidural analgesia, or early delivery improve outcomes for women with severe pre-eclampsia. Magnesium sulphate reduces the risk of first or subsequent seizures in women with severe pre-eclampsia compared with placebo. Magnesium sulphate reduces the risk of subsequent seizures in women with eclampsia compared with either phenytoin or diazepam, with fewer adverse effects for the mother or baby. DEFINITION Hypertension during pregnancy may be associated with one of several conditions. Pregnancy-induced hypertension is a rise in blood pressure, without proteinuria, during the second half of pregnancy. Pre-eclampsia is a multisystem disorder, unique to pregnancy, that is usually associated with raised blood pressure and proteinuria. It rarely presents before 20 weeks' gestation. Eclampsia is one or more convulsions in association with the syndrome of pre-eclampsia. Preexisting hypertension (not covered in this review) is known hypertension before pregnancy, or raised blood pressure before 20 weeks' gestation. It may be essential hypertension or, less com[1] monly, secondary to underlying disease. Pregnancy-induced hypertension affects 10% of pregnancies, and pre-eclampsia complicates [2] 28% of pregnancies. Eclampsia occurs in about 1/2000 deliveries in resource-rich countries. [3] [4] In resource-poor countries, estimates of the incidence of eclampsia vary from 1/1001/1700.
[5]
INCIDENCE/ PREVALENCE
AETIOLOGY/ The cause of pre-eclampsia is unknown. It is likely to be multifactorial, and may result from deficient [6] RISK FACTORS placental implantation during the first half of pregnancy. Pre-eclampsia is more common among women likely to have a large placenta, such as those with multiple pregnancy, and among women with medical conditions associated with microvascular disease, such as diabetes, hypertension, [7] [8] and collagen vascular disease. Other risk factors include genetic susceptibility, increased [9] [10] parity, and older maternal age. Cigarette smoking seems to be associated with a lower risk of pre-eclampsia, but this potential benefit is outweighed by an increase in adverse outcomes such [11] as low birthweight, placental abruption, and perinatal death. PROGNOSIS The outcome of pregnancy in women with pregnancy-induced hypertension alone is at least as [7] [12] good as that for normotensive pregnancies. However, once pre-eclampsia develops, morbidity and mortality rise for both mother and child. For example, perinatal mortality for women with [7] severe pre-eclampsia is double that for normotensive women. Perinatal outcome is worse with [7] [9] [12] early gestational hypertension. Perinatal mortality also increases in women with severe [13] essential hypertension.
AIMS OF To delay or prevent the development of pre-eclampsia and eclampsia, and to improve outcomes INTERVENTION for women and their children. Once pre-eclampsia has occurred, to minimise morbidity and mortality for women and their children, and to ensure that health service resources are used appropriately.
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OUTCOMES For the woman: Mortality, rates of severe hypertension, rates of pre-eclampsia (proteinuria and hypertension), eclampsia, death, severe morbidity (such as renal failure, coagulopathy, cardiac failure, liver failure, and stroke), placental abruption, and caesarean section; use of resources (such as dialysis, ventilation, admission to intensive care, or length of stay); adverse effects of treatment. For the child: Mortality, intrauterine growth restriction, prematurity, and severe morbidity (such as intraventricular haemorrhage, respiratory distress syndrome, or asphyxia); measures of infant and child development (such as cerebral palsy or significant learning disability); use of resources (such as admission to special-care nursery, ventilation, length of stay in hospital, and special needs in the community); adverse effects of treatment. BMJ Clinical Evidence search and appraisal June 2007. The following databases were used to identify studies for this review: Medline 1966 to June 2007, Embase 1980 to June 2007, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials 2007, Issue 2. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and NICE. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using pre-determined criteria to identify relevant studies. Study design criteria for evaluation in this review were: published systematic reviews and RCTs in any language, at least single blinded, and containing any number of individuals of whom more than 80% were followed up. There was no minimum length of follow-up required to include studies. We excluded all studies described as open, open label, or not blinded unless blinding was impossible. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. In options where systematic reviews are reported and have pooled data for large numbers of women, we have reported data from subsequent RCTs sparingly so as not to give such smaller data undue prominence where larger more robust analysis exists, unless they have reported clinically meaningful data, or data not previously reported by the review. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table, p 18 ). What are the effects of preventive interventions in women at risk of pre-eclampsia? ANTIPLATELET DRUGS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
METHODS
QUESTION OPTION
Development of pre-eclampsia Compared with placebo/no antiplatelet drugs Antiplatelet drugs (mainly low-dose aspirin) are more effective at reducing pre-eclampsia in women at risk of pre-eclampsia (high-quality evidence). Preterm birth Compared with placebo/no antiplatelet drugs Antiplatelet drugs (mainly low-dose aspirin) are more effective at reducing the risk of babies being born small for their gestational age to women at risk of pre-eclampsia (high-quality evidence). Perinatal mortality Compared with placebo/no antiplatelet drugs Antiplatelet drugs (mainly low-dose aspirin) are more effective at reducing perinatal mortality (high-quality evidence). For GRADE evaluation of interventions for pre-eclampsia, eclampsia, and hypertension, see table, p 18 . Benefits: We found one systematic review (search date 2006, 59 RCTs, 37,560 women).
[14]
Antiplatelet drugs versus placebo/no antiplatelet drug: The systematic review found that antiplatelet agents (mainly aspirin, but also dipyridamole and ozagrel) significantly reduced pre-eclampsia, premature birth, the proportion of babies born small for gestational age, and infant mortality, in women considered at risk of pre-eclampsia (preeclampsia: 46 RCTs, 1081/16,396 [7%] with antiplatelet v 1292/16,194 [8%] with control; RR 0.83, 95% CI 0.77 to 0.89; NNT 72, 95% CI 52 to 119; premature birth: 29 RCTs, 2612/15,629 [17%] with antiplatelet v 2797/15,522 [18%] with control; RR 0.92, 95% CI 0.88 to 0.97; NNT 72, 95% CI 52 to 119; babies born small for gestational age: 36 RCTs, 983/11,904 [8%] with antiplatelet v 1062/11,734 [9%] with control; RR 0.90 95% CI 0.83 to 0.98; infant mortality: 40 RCTs, 414/16,607 [2.5%] with antiplatelet v 475/16,491 [2.9%] with control; RR 0.86, 95% CI 0.76 to 0.98; NNT 243, [14] 95% CI 131 to 1666). There were no clear effects on other important outcomes, and no clear benefit from starting treatment before 20 weeks compared with later in pregnancy. The systematic review also found similar relative risk reductions in pre-eclampsia for women at high and moderate risk of pre-eclampsia and its complications for antiplatelets compared with control (women at high risk: 18 RCTs, 323/2070 [16%] with antiplatelet v 425/2051 [21%] with control, RR 0.75, 95% CI BMJ Publishing Group Ltd 2008. All rights reserved. ........................................................... 3

0.66 to 0.85; women at moderate risk: 25 RCTs, 758/14,326 [5%] with antiplatelet v 867/14,143 [6%] with control, RR 0.86, 95% CI 0.79 to 0.95). The benefit was greatest for women given more than 75 mg aspirin daily (above 75 mg aspirin: 16 RCTs, RR 0.64, 95% CI 0.51 to 0.80; above 75 mg aspirin plus dipyridamole: 5 RCTs, RR 0.30, 95% CI 0.15 to 0.60; 75 mg aspirin or less: 21 [14] RCTs, RR 0.88, 95% CI 0.81 to 0.95). Harms: The systematic review found no evidence that aspirin increased the risk of bleeding for mother or [14] baby. Two studies followed up children of mothers enrolled in trials comparing aspirin versus [15] [16] placebo for 1218 months. They found no significant difference between aspirin and placebo in children of treated mothers for: hospital visits for congenital malformations, motor deficit, developmental delay, respiratory problems, or bleeding problems; height or weight below the third centile; or bleeding rates. Almost all RCTs used low-dose aspirin 5075 mg daily, and most were placebo controlled. The RCTs included women with a variety of risk factors, including a history of previous early-onset disease, diabetes, or chronic hypertension, and were conducted in both resource-rich and resourcepoor countries. Women were categorised as high risk if they had previous severe pre-eclampsia, diabetes, chronic hypertension, renal disease, or autoimmune disease. The number-needed-totreat values cannot be applied directly to different populations of women; the values stated represent estimates for women with a risk of pre-eclampsia that is an average over all the participants in the RCTs. The absolute benefit was higher (and the NNT lower) in women at higher risk of preeclampsia. CALCIUM SUPPLEMENTATION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Comment:
OPTION
Development of pre-eclampsia Compared with placebo Calcium supplements are more effective at reducing the risk of pre-eclampsia, especially in women with low dietary calcium (high-quality evidence). Preterm birth Compared with placebo Calcium supplementation seems no more effective at reducing preterm birth (moderatequality evidence). Need for further interventions Compared with placebo Calcium supplements seem no more effective at reducing the risk of caesarean delivery (moderate-quality evidence). Maternal or perinatal mortality Compared with placebo Calcium supplements are more effective at reducing the risk of maternal death or serious morbidity (high-quality evidence). Calcium supplements seem no more effective at reducing stillbirth or death of the baby before discharge from hospital (moderate-quality evidence). For GRADE evaluation of interventions for pre-eclampsia, eclampsia, and hypertension, see table, p 18 . Benefits: Calcium supplementation versus placebo: We found one systematic review (search date 2006, 12 RCTs, 15,206 women; see comment below). [17] It found that calcium (mainly 1.52 g daily) significantly reduced the risk of pre-eclampsia compared with placebo (12 RCTs: 368/7578 [5%] with calcium supplementation v480/7628 [6%] with placebo; RR 0.48, 95% CI 0.33 to 0.69). Subgroup analysis found that the greatest reduction in risk of pre-eclampsia was for women with low dietary calcium (low dietary calcium: 198/5058 [4%] with calcium supplementation v 276/5096 [5%] with placebo, RR 0.36, 95% CI 0.18 to 0.70; normal dietary calcium: 169/2505 [7%] with calcium supplementation v 197/2517 [8%] with placebo, RR 0.62, 95% CI 0.32 to 1.20). The review found that, overall, compared with placebo, calcium supplementation significantly reduced the risk of maternal death or serious morbidity (4 RCTs: 167/4856 [3%] with calcium supplementation v 210/4876 [4%] with placebo; RR 0.80, 95% CI 0.65 to 0.97) It found no significant difference between calcium supplements and placebo for the risk of caesarean delivery, preterm birth, stillbirth or death of the baby before discharge from hospital, or birth weight below 2500 g (caesarean delivery: 7 RCTs, 14,710 women, RR 0.95, 95% CI 0.88 to 1.01; preterm birth: 10 RCTs, 14,751 women, RR 0.81, 95% CI 0.64 to 1.03; stillbirth or death of the baby before hospital discharge: 10 RCTs, 15,141 women, RR 0.89, 95% CI 0.73 to 1.09; birthweight below 2500 g: 8 RCTs, 14,359 women, RR 0.84, 95% CI 0.68 to 1.03). Follow-up of 514 children at age 7 years in a subset of one trial found that calcium supplementation was associated with fewer children having a distolic blood pressure above the 95th percentile (RR 0.59, 95% CI 0.39 to 0.91).
[17]
Harms:
After follow-up of 514 children to age 7 years, the review found no harms associated with maternal [17] calcium supplements. BMJ Publishing Group Ltd 2008. All rights reserved. ........................................................... 4

Comment: Most trials in the systematic review were of good quality and included nulliparous or primiparous women. They were conducted largely in the USA and South America. They included mainly women at low risk, with low dietary calcium. Several studies reported that adherence to treatment was [17] 6090%. The proportion of women taking 90100% of all allocated treatment was 85% in the [17] largest study, but low in several others (20% in 1 study). The statistical heterogeneity for some outcomes seemed to be explained by differences between the small and large trials, with small trials of largely high-risk women having more positive results. ANTIOXIDANTS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
OPTION
Development of pre-eclampsia Compared with placebo/no antioxidant We don't know whether antioxidants are more effective at reducing the risk of pre-eclampsia (low-quality evidence). Preterm birth Compared with placebo/no antioxidant Vitamin C plus E seems no more effective at reducing preterm births (moderatequality evidence). Perinatal mortality Compared with placebo/no antioxidant Vitamin C plus E seems no more effective at reducing perinatal deaths (moderate-quality evidence). For GRADE evaluation of interventions for pre-eclampsia, eclampsia, and hypertension, see table, p 18 . Benefits: We found one systematic review (search date 2004, 7 RCTs, 6082 women) of antioxidant treatment [18] (largely either the combination of vitamins C and E or antioxidant minerals, such as selenium), one systematic review (search date 2006, 4 RCTs, 4680 women) reporting solely on the combination [19] of antioxidant vitamins C plus E, and one small subsequent RCT of multiple antioxidant vitamins [20] and minerals. Antioxidants versus placebo/ no antioxidant: The first systematic review found that, compared with no antioxidant, antioxidants significantly reduced the relative risk of pre-eclampsia, and of having a baby small for gestational age (preeclampsia: 7 RCTs, 134/3034 [4%] with antioxidants v 221/3048 [7%] with no antioxidants; RR 0.61, 95% CI 0.50 to 0.75; NNT 34, 95% CI 25 to 50; baby small for gestational age: 3 RCTs, 49/309 [13%] with antioxidants v 81/325 [25%] with no antioxidants; RR 0.64, 95% CI 0.47 to 0.87; [18] NNT 12, 95% CI 7 to 34). The second systematic review included 2 RCTs published subsequent [19] to the first review, and 2 RCTs included in the first review. The second systematic review (4680 women) found no significant difference between vitamin C plus E and placebo in the risk of preeclampsia, preterm birth, having a baby small for gestational age, or of the baby dying (preeclampsia: 4 RCTs, 11.0% with vitamins C and E v 11.4% with placebo; RR 0.97; 95% CI 0.82 to 1.13; absolute numbers not reported, results presented graphically; preterm birth: 4 RCTs: 19.5% with vitamins C and E v 18.0% with placebo; RR 1.07, 95% CI 0.96 to 1.20; absolute numbers not reported, results presented graphically; having a baby small for gestational age: 4 RCTs: 20.6% with vitamins C and E v 20.0% with placebo; RR 0.94, 95% CI 0.74 to 1.19; absolute numbers not reported, results presented graphically; baby death: 4 RCTs, 2.6% with vitamins C and E v 2.3% with placebo; RR 1.10, 95% CI 0.78 to 1.56; absolute numbers not reported, results presented [19] graphically). The small subsequent RCT (60 women) found that significantly fewer women taking a combination of antioxidants developed pre-eclampsia compared with placebo (2/29 [7%] [20] with antioxidants v 9/31 [29%] with placebo; P = 0.04). Harms: The first systematic review found that antioxidants significantly increased the risk of birth before 37 weeks' gestation (3 RCTs: 76/293 [26%] with antioxidants v 54/290 [19%] with no antioxidants; [18] RR 1.38, 95% CI 1.04 to 1.82). The second systematic review did not report further on adverse [19] effects. The largest trial (5021 women) in the first systematic review was quasi-random, and only three of the seven included trials were rated as high quality. There are insufficient data for reliable conclusions about the effects on other substantive outcomes, such as perinatal death. MARINE OIL (FISH OIL) AND OTHER PROSTAGLANDIN PRECURSORS (EVENING PRIMROSE OIL). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Comment:
OPTION
Development of pre-eclampsia Compared with placebo or no treatment Marine oil seems no more effective at reducing the risk of pre-eclampsia (moderate-quality evidence).
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Preterm birth Compared with placebo or no treatment Marine oil seems no more effective at reducing preterm birth (moderatequality evidence). For GRADE evaluation of interventions for pre-eclampsia, eclampsia, and hypertension, see table, p 18 . Benefits: Marine oil (fish oil) and other prostaglandin precursors (evening primrose oil) versus placebo or no treatment: We found one systematic review (search date 2005, 6 RCTs, 2783 women; see comment below) of marine oil and other prostaglandin precursors for the prevention of pre-eclampsia versus [21] placebo or no treatment. It included all pregnant women regardless of their risk for preeclampsia, preterm birth, or intrauterine growth retardation, and excluded women with established pre-eclampsia or suspected intrauterine growth retardation.The review found no significant difference between marine oil and placebo or no marine oil in the risk of pre-eclampsia (4 RCTs: 42/827 [5%] with marine oil v 51/856 [6%] with placebo or no marine oil; RR 0.86, 95% CI 0.59 to 1.27), or preterm birth (5 RCTs: 205/947 [22%] with marine oil v 228/969 [24%] with placebo or no marine [21] oil; RR 0.92, 95% CI 0.79 to 1.07). The review found that women allocated a marine oil supplement had a mean gestation 2.6 days longer than women allocated placebo or no treatment (3 RCTs, 1621 women; WMD 2.55 days, 95% CI 1.03 days to 4.07 days), and that their babies had [21] a slightly higher birthweight (3 RCTs, 2440 women, WMD 47 g, 95% CI 1 g to 93 g). We found a second systematic review (search date 2005, 6 RCTs, 1278 women) restricted to women with a low-risk pregnancy only, and which also included 3 RCTs of oil from non-marine sources, which [22] reached similar conclusions. Marine oil (fish oil) and other prostaglandin precursors (evening primrose oil) versus placebo or no treatment: The first review found that, compared with women allocated control oil, women allocated marine oil were more than three times more likely to report belching (3 RCTs: 320/762 with marine oil v 64/624 with placebo/no marine oil; RR 3.55, 95% CI 2.78 to 4.52), and six times more likely to complain of an unpleasant taste (3 RCTs: 193/743 with marine oil v 22/611 with placebo/no marine [21] oil; RR 6.17, 95% CI 4.03 to 9.44). The review found no significant difference between groups [21] in nausea, vomiting, stomach pain, diarrhoea or constipation. It also found no significant difference between groups in any bleeding complications such as nasal bleeding, antepartum vaginal [21] bleeding, maternal anaemia, vaginal blood loss after birth, and blood loss at birth. In the first review, of the six included RCTs, four RCTs used oil derived from the body of a fish, the fifth RCT used a combination of evening primrose oil and fish (body) oil, while the sixth RCT assessed the consumption of eggs enriched with docosanhexanoic acid (DHA) by feeding laying [21] hens with algal (marine) oil. RCTs of fish oil may have been difficult to blind because of the distinctive taste of fish oil. One RCT found that olive oil provided better masking than a non-oil [23] placebo. GLYCERYL TRINITRATE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Harms:
Comment:
OPTION
Development of pre-eclampsia Compared with placebo/no treatment Glyceryl trinitrate may be no more effective at reducing the risk of preeclampsia (low-quality evidence). For GRADE evaluation of interventions for pre-eclampsia, eclampsia, and hypertension, see table, p 18 . Benefits: Glyceryl trinitrate versus placebo/no treatment: [24] [25] We found no systematic review, but found two RCTs. The first RCT (40 women) found no significant difference in the risk of pre-eclampsia between glyceryl trinitrate patches and placebo [24] (RR 1.13, 95% CI 0.35 to 3.60), but the confidence interval was wide. The second RCT (68 [25] women) reported similar results (RR 1.35, 95% CI 0.61 to 3.01). Glyceryl trinitrate versus aspirin and dipyridamole: [26] We found one trial (76 women) that was too small to draw any reliable conclusions. Harms: Glyceryl trinitrate versus placebo/no treatment: The first RCT found similar rates of adverse events with glyceryl trinitrate and placebo (skin rash: 4/21 [19%] with glyceryl trinitrate v 4/19 [21%] with placebo; headache: 2/21 [10%] with glyceryl [24] trinitrate v 1/19 [5%] with placebo; significance not reported). The second RCT gave no infor[25] mation on adverse events. Glyceryl trinitrate versus aspirin and dipyridamole: [26] The RCT was too small to draw any reliable conclusions.
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Comment: OPTION None. MAGNESIUM SUPPLEMENTATION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Development of pre-eclampsia Compared with placebo Magnesium supplements seem no more effective at reducing the risk of pre-eclampsia (moderate-quality evidence). For GRADE evaluation of interventions for pre-eclampsia, eclampsia, and hypertension, see table, p 18 . Benefits: We found one systematic review (search date 2001, 2 RCTs, 474 women) comparing magnesium [27] supplements versus placebo. It found no significant difference in pre-eclampsia between groups [27] (34/235 [15%] with magnesium v 40/239 [17%] with placebo; RR 0.87, 95% CI 0.57 to 1.32). There was no significant difference between the groups in the number of reported gastrointestinal [27] side effects (RR 0.89, 95% CI 0.75 to 1.05). This review included seven trials with 2689 women, of which only two (474 women) reported data for pre-eclampsia. There is, therefore, also a possibility of bias, in that five trials did not report this outcome. SALT RESTRICTION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Harms:
Comment:
OPTION
Development of pre-eclampsia Compared with normal dietary intake A low-salt diet seems no more effective at reducing the risk of pre-eclampsia (moderate-quality evidence). For GRADE evaluation of interventions for pre-eclampsia, eclampsia, and hypertension, see table, p 18 . Benefits: We found one systematic review (search date 2005, 2 RCTs, 603 women) comparing reduced salt [28] (advice to restrict dietary salt intake to 20 or 50 mmol/day) with normal dietary salt intake. It found no significant difference for rates of pre-eclampsia, although the trials may have lacked power to detect clinically important effects (RR 1.11, 95% CI 0.46 to 2.66). We found no evidence of harmful effects in the trials.
[28]
Harms: Comment:
The trials of salt restriction were conducted in the Netherlands, where advice to restrict salt intake during pregnancy has been routine for many years. Such advice is no longer widespread elsewhere. ATENOLOL. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
OPTION
Development of pre-eclampsia Compared with placebo Atenolol seems no more effective at reducing the risk of pre-eclampsia in women without hypertension but with a cardiac output of over 7.4 L/minute (moderate-quality evidence). For GRADE evaluation of interventions for pre-eclampsia, eclampsia, and hypertension, see table, p 18 . Benefits: We found one small RCT (68 women without hypertension selected because they had a cardiac output of over 7.4 L/minute), which found no significant reduction in the risk of pre-eclampsia with atenolol 100 mg daily (1/28 [4%] with atenolol v 5/28 [18%] with placebo; RR 0.20, 95% CI 0.02 to [29] 1.60). This single study was too small for reliable estimates of clinically important effects on substantive outcomes. The RCT found that mean birthweight was significantly lower with atenolol for a subgroup of prim[29] iparous women (mean difference: 440 g; P = 0.02). Although the possible benefits of atenolol for prevention of pre-eclampsia remain unclear, the reduction in birthweight may be real. Concerns about the possible harmful effects of atenolol on fetal growth and development have been discussed for some time (see harms of antihypertensive [30] [31] agents, p 8 ).
Harms:
Comment:
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QUESTION What are the effects of interventions in women who develop mild to moderate hypertension during pregnancy? ANTIHYPERTENSIVE AGENTS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
OPTION
Development of severe hypertension or pre-eclampsia Compared with placebo/no antihypertensive drug Antihypertensive drugs may be more effective at reducing the risk of severe hypertension, but not of pre-eclampsia (very low-quality evidence). Mortality Compared with placebo/no antihypertensive drug We dont know whether antihypertensive drugs are more effective at reducing fetal or neonatal deaths (very low-quality evidence). For GRADE evaluation of interventions for pre-eclampsia, eclampsia, and hypertension, see table, p 18 . Benefits: We found two systematic reviews. The first systematic review (search date 2006, 46 RCTs, 4282 women with mild to moderate hypertension) included studies that compared any antihyper[32] tensive drug versus placebo or versus another antihypertensive drug. The second systematic review (search date 2004, 29 RCTs, 2500 women with mild to moderate hypertension) included only studies that compared beta-blockers versus no antihypertensive drug or versus another anti[33] hypertensive drug. Antihypertensive drugs versus placebo or no antihypertensive drug: The first review found that antihypertensive drugs significantly and substantially reduced the risk of developing severe hypertension compared with no antihypertensive drugs (19 RCTs, 2409 [32] women: RR 0.50, 95% CI 0.41 to 0.61; NNT 10, 95% CI 8 to 13). It found no significant difference between groups for pre-eclampsia or fetal or neonatal death (pre-eclampsia: 22 RCTs, 2702 women: RR 0.97, 95% CI 0.83 to 1.13; fetal or neonatal death: 26 RCTs, 3081 women: RR 0.73, [32] 95% CI 0.50 to 1.08). The second review found that beta-blockers significantly reduced the development of severe hypertension compared with no beta-blockers (11 RCTs, 1128 women: RR [33] 0.37, 95% CI 0.26 to 0.53). The review found insufficient evidence for other maternal outcomes. Antihypertensive drugs versus other antihypertensive agents: Neither systematic review found any clear difference among any of these drugs for the risk of de[32] [33] veloping severe hypertension or pre-eclampsia. Harms: The antihypertensive agents included in the systematic reviews seem to have been well tolerated during pregnancy, but adverse effects have not been reported in many RCTs. All antihypertensive drugs cross the placenta, but few trials reported possible adverse effects for the baby. The first review found that beta-blockers seem significantly better compared with methyl dopa for [32] reducing the risk of severe hypertension (8 RCTs, 493 women; RR 0.79, 95% CI 0.63 to 0.99). The second review found that beta-blockers significantly increased the baby's risk of being small [33] for its gestational age (13 RCTs, 854 women: RR 1.34, 95% CI 1.01 to 1.79). Meta regression within a systematic review suggested that lowering blood pressure for women with mild or moderate [34] hypertension may increase the risk of having a baby small for its gestational age. One systematic review (search date 1999, 13 small RCTs in women with pre-existing chronic hypertension) found that ACE inhibitors used in the second or third trimester were associated with fetal renal [35] [36] failure. Fetal exposure to these agents during the first trimester is associated with major [37] congenital malformations. If women using ACE inhibitors are contemplating pregnancy, it would seem advisable to switch them to another drug well in advance of conception. The RCTs were too small to exclude beneficial effects of antihypertensive agents. The trials had problems with methods. Many were not placebo controlled, and few attempted to blind blood pressure measurement. Many important outcomes were reported by only a few studies. We found little evidence about adherence to treatment. One systematic review found that the effects of antihypertensive agents in women with pre-existing chronic hypertension were similar to those described above for women with pregnancy-induced hypertension. The review did not establish or exclude [35] [36] benefit from treatment. We found one study in Russian that is awaiting translation and will [38] be included in future if relevant. BED REST/HOSPITAL ADMISSION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
[32] [33] [32] [33]
Comment:
OPTION
Development of severe hypertension or pre-eclampsia Compared with no hospital admission We dont know whether some rest in hospital is more effective than normal activity at home at reducing the incidence of severe hypertension in women with non-proteinuric hypertension (lowquality evidence).
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Preterm birth Compared with no hospital admission Some rest in hospital seems to be modestly more effective at lowering the risk of preterm birth in women with non-proteinuric hypertension (moderate-quality evidence). For GRADE evaluation of interventions for pre-eclampsia, eclampsia, and hypertension, see table, p 18 . Benefits: Bed rest/admission versus no hospital admission: We found one systematic review (search date 2005, 4 RCTs, 449 women) of hospital admission. [39] The systematic review compared some rest in hospital with normal activity at home for women with non-proteinuric hypertension. Women allocated some rest in hospital had fewer incidences of severe hypertension compared with those allocated normal activity at home (1 RCT, 218 women: 25/110 [23%] with some rest v 42/108 [39%] with normal activity; RR 0.58, 95% CI 0.38 to 0.89), and a lower risk of preterm birth that was borderline for statistical significance (1 RCT, 218 women: 13/110 [12%] with some rest v 24/108 [22%] with normal activity; RR 0.53, 95% CI 0.29 to 0.99). [39] There were no clear differences in any other outcomes. This systematic review also compared bed rest in hospital with normal ambulation in hospital for women with proteinuric hypertension (2 RCTs, 145 women), but the RCTs were too small for any reliable conclusions to be drawn. Bed rest/admission versus antenatal day-care units: [40] We found one systematic review (search date 2001, 1 RCT, 54 women). The RCT was too small to draw reliable conclusions. Harms: It has been suggested that hospital admission increases the risk of venous stasis, thromboembolic disease, or infection, but we found no evidence in this context. In the RCT of antenatal day care, [40] women preferred not to be admitted to hospital. Women allocated rest in hospital were less likely to say that they would choose this option for a future pregnancy than those allocated routine activity at home (1 RCT, 86 women, RR 3.00, 95% CI 1.43 to 6.31). We found no evidence from the other trials about the views of women and their families. Trials of hospital admission and bed rest in hospital were largely conducted before widespread introduction of day-care assessment units. Women with hypertension during pregnancy are now often seen in day-care units, but only one small RCT has compared day-care assessment versus assess[40] ment in an outpatient clinic. The reduction in severe hypertension for women allocated rest in hospital rather than routine activity at home should be interpreted with caution, as this may reflect 'white-coat' hypertension, ascertainment bias, or both, in that women at home had only weekly assessment of their blood pressure. What are the effects of interventions in women who develop severe pre-eclampsia or very high blood pressure during pregnancy? PROPHYLACTIC ANTICONVULSANTS FOR WOMEN WITH SEVERE PRE-ECLAMPSIA. . . .
Comment:
QUESTION
OPTION
Seizures Compared with placebo/no anticonvulsants Prophylactic magnesium sulphate is more effective at reducing the risk of eclampsia (high-quality evidence). Compared with phenytoin, nimodipine, or diazepam Magnesium sulphate is more effective than phenytoin and nimodipine at reducing the risk of eclampsia (high-quality evidence). Need for further interventions Compared with placebo/no anticonvulsants Magnesium sulphate increases the need for a caesarean section (highquality evidence). Maternal or perinatal mortality Compared with placebo/no anticonvulsants Prophylactic magnesium sulphate is no more effective at reducing stillbirths, maternal mortality, neonatal mortality, or neurosensory disability or mortality in children at 18 months (high-quality evidence). Adverse effects Compared with placebo/no anticonvulsants Magnesium sulphate causes more adverse effects, such as flushing, and respiratory depression (moderate-quality evidence). For GRADE evaluation of interventions for pre-eclampsia, eclampsia, and hypertension, see table, p 18 . Benefits: We found one systematic review (search date 2002, 13 RCTs, 15,558 women).
[41]
...........................................................

Magnesium sulphate versus placebo or no anticonvulsant: In the review, six RCTs (11,444 women) compared magnesium sulphate versus placebo. Prophylactic magnesium sulphate significantly reduced the risk of eclampsia compared with placebo (43/5722 [1%] with magnesium sulphate v 107/5722 [2%] with placebo; RR 0.41, 95% CI 0.29 to 0.58; NNT 100, 95% CI 50 to 100). Magnesium sulphate also reduced maternal mortality compared with placebo, although the results were not significant (2 RCTs: 11/5400 [0.2%] with magnesium sulphate v 21/5395 [0.4%] with placebo; RR 0.54, 95% CI 0.26 to 1.10). For women randomised before delivery, there was no significant difference in the risk of stillbirth or neonatal death (3 RCTs: 634/5003 [13%] with magnesium sulphate v 611/4958 [12%] with placebo; RR 1.04, 95% CI 0.93 [41] [42] [43] to 1.15). We found two reports of long-term follow-up for women and children recruited [44] to a large RCT included in the review. The first report in women found no significant difference between the groups in the risk of death or serious morbidity potentially related to pre-eclampsia when the children were 2 years old (58/1650 [4%] with magnesium sulphate v 72/1725 [4%] with [42] placebo; RR 0.84, 95% CI 0.60 to 1.18). Of those women selected for follow-up (4782 of 7927 women randomised at centres participating in the follow-up study), the results were based on 3375/4782 (71%) of women who responded. The second follow-up report in children found no significant difference between the groups in the risk of death or neurosensory disability when the children were 18 months old (245/1635 [15%] allocated magnesium sulphate v 233/1648 [14%] [43] allocated placebo; RR 1.06, 95% CI 0.90 to 1.25). Of those children selected for follow-up (4483 of 6922 children of women randomised before delivery at centres participating in the follow-up study), the results were based on 3283/4483 (73%) of children for whom data were available. Magnesium sulphate versus phenytoin, nimodipine, or diazepam: Two RCTs (2241 women) included in the review found that magnesium sulphate significantly reduced the risk of eclampsia compared with phenytoin (0/1109 [0%] with magnesium sulphate v 10/1132 [41] [0.8%] with phenytoin; RR 0.05, 95% CI 0.00 to 0.84). Another RCT (1650 women) found that magnesium sulphate significantly reduced the risk of eclampsia compared with nimodipine (7/831 [41] [1%] with magnesium sulphate v 21/819 [3%] with nimodipine; RR 0.33, 95% CI 0.14 to 0.77). There was insufficient evidence for reliable conclusions about magnesium sulphate compared with [41] diazepam (2 RCTs, 66 women). Harms: Magnesium sulphate versus placebo or no anticonvulsant: [44] One large, placebo-controlled trial in the review reported adverse effects in detail. In this RCT, more women had adverse effects with magnesium sulphate compared with placebo (1201/4999 [44] [24%] with magnesium sulphate v 228/4993 [5%] with placebo). By far the most common reported adverse effect was flushing (2 RCTs: 1032/5066 [20%] with magnesium sulphate v 110/5061 [41] [2%] with placebo). Respiratory depression was rare in both treatment groups, although the relative risk was significantly lower for women allocated placebo (2 RCTs: 52/5344 [1.0%] with [41] magnesium sulphate v 26/5333 [0.5%] with placebo, RR 1.98, 95% CI 1.24 to 3.15). Magnesium sulphate slightly increased the risk of caesarean section compared with placebo (2528/5082 [50%] with magnesium sulphate v 2370/5026 [47%] with placebo; RR 1.05, 95% CI 1.01 to 1.10; NNH 34, 95% CI 25 to 100). There were no clear differences in outcome between the two groups at two [42] [43] years for the women, and at age 18 months for the children (see benefits section, above). Magnesium sulphate versus phenytoin, nimodipine, or diazepam: The review found that, compared with phenytoin, magnesium sulphate was also associated with an increased risk of caesarean section (RR 1.21, 95% CI 1.05 to 1.41; NNH 21, 95% CI 12 to 83). [41] Compared with nimodipine, magnesium sulphate was associated with an increase in respiratory problems (11/831 [1.3%] with magnesium sulphate v 3/819 [0.4%] with nimodipine; RR 3.61, 95% [41] CI 1.01 to 12.91). One small RCT evaluated magnesium sulphate for preventing and treating preterm labour in women who did not have pre-eclampsia. It found an increase in infant mortality [45] for babies born to these women. Many of the infants had low birthweight (below 1500 g). Comment: Most of the data in these trials refer to women with relatively severe pre-eclampsia. One small study recruited only women with mild pre-eclampsia. Long-term follow-up of women and children in one large RCT is reassuring, in that the lower risk of eclampsia is not associated with any clear [43] [42] difference in longer-term outcome for the women or children. Weak evidence from two case control studies suggested that magnesium sulphate may be associated with a decreased risk [46] [47] of cerebral palsy in babies weighing less than 1500 g. This hypothesis has been tested in [48] a large RCT. The RCT found that magnesium sulphate was associated with a non-significant reduction in the composite outcome of death or cerebral palsy compared with placebo (123/629 [48] [20%] with magnesium sulphate v 149/626 [24%] with placebo; RR 0.83, 95% CI 0.66 to 1.03). ANTIHYPERTENSIVE DRUGS FOR VERY HIGH BLOOD PRESSURE. . . . . . . . . . . . . . . . . . . .
OPTION Seizures
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10

Compared with each other We don't know whether one antihypertensive (such as labetalol, nifedipine, methyldopa, diazoxide, urapidil, magnesium sulphate, prazosin, nimodipine, or ketanserin) is more effective than the others at reducing blood pressure (low-quality evidence). Note There is consensus that women with severe hypertension during pregnancy should have antihypertensive treatment. For GRADE evaluation of interventions for pre-eclampsia, eclampsia, and hypertension, see table, p 18 . Benefits: We found one systematic review (search date 2006, 24 RCTs, 2949 women) and two subsequent [50] [51] RCTs. The review compared many antihypertensives (such as labetalol, nifedipine, methyldopa, diazoxide, urapidil, magnesium sulphate, prazosin, nimodipine, and ketanserin) [49] mainly versus hydralazine. It found that all the antihypertensives reduced blood pressure. The review found that women allocated calcium channel blockers were significantly less likely to have persistent high blood pressure compared with hydralazine (5 RCTs: 8/135 [6%] with calcium channel blockers v 23/128 [18%] with hydralazine; RR 0.33, 95% CI 0.15 to 0.70), but there were [49] no significant differences in other reported outcomes. The review found that the risk of persistent high blood pressure was significantly lower for nimodipine compared with magnesium sulphate (1 RCT: 374/819 [47%] with nimodipine v 451/831 [65%] with magnesium sulphate; RR 0.84, 95% CI 0.76 to 0.93), although nimodipine was associated with a significantly higher risk of eclampsia (2 RCTs: 21/837 [3%] with nimodipine v 9/846 [1%] with magnesium sulphate; RR 2.24, 95% CI 1.06 to 4.73). It found that nimodipine was associated with a significantly lower risk of respiratory difficulties for the woman compared with magnesium sulphate (1 RCT: 3/819 [0.4%] with nimodipine v 11/831 [1.3%] with magnesium sulphate; RR 0.28, 95% CI 0.08 to 0.99), and significantly less postpartum haemorrhage (1 RCT: 8/819 [1%] with nimodipine v 20/831 [2%] with magnesium sulphate; RR 0.41, 95% CI 0.18 to 0.92). Overall, there was no clear evidence that one drug in the [49] review was better than another. The first subsequent RCT (200 women) compared intravenous [50] bolus doses of labetalol versus hydralazine, repeated after 20 minutes if required. It found no clear differences between groups in persistent hypertension, need for additional doses, or hypotension. The second subsequent RCT (42 women) compared intravenous urapidil versus hydralazine, [51] and reported that no women had hypotension in the first 6 hours of treatment. The systematic review found that the use of ketanserin was associated with significantly more persistent hypertension compared with hydralazine (3 RCTs: 26/96 [27%] with ketanserin v 5/84 [6%] with hydralazine; RR 4.79, 95% CI 1.95 to 11.73), but with significantly fewer maternal adverse effects (3 RCTs: 13/64 [20%] with ketanserin v 36/56 [64%] with hydralazine; RR 0.32, 95% CI [49] 0.19 to 0.53). Labetalol was associated with less hypotension requiring treatment than diazoxide [49] (1 RCT, 90 women, RR 0.06, 95% CI 0 to 0.99). Hypotension may compromise fetoplacental blood flow.The review found that nimodipine was associated with significantly less flushing compared with magnesium sulphate (1 RCT: 13/819 [2%] with nimodpine v 59/831 [7%] with magnesium sulphate; RR 0.22, 95% CI 0.12 to 0.40), although there was no significant difference between [49] groups in the risk of headache, or nausea and vomiting. Few other RCTs reported adverse effects or events. The frequency of adverse effects varied from 264%. Antihypertensive drugs cross the placenta, but we found little evidence about effects on the baby. There is consensus that women with severe hypertension during pregnancy should have antihypertensive treatment. Placebo-controlled trials would therefore be unethical. Women in these studies had blood pressures high enough to merit immediate treatment, and many also had proteinuria or severe pre-eclampsia. The trials were small and reported few outcomes other than control of blood pressure. In most trials, there was no blinding after trial entry. ANTIOXIDANTS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
[49]
Harms:
Comment:
OPTION
We found no direct information about whether a combination of vitamin E plus vitamin C plus allopurinol is better than no active treatment. For GRADE evaluation of interventions for pre-eclampsia, eclampsia, and hypertension, see table, p 18 . Benefits: We found no systematic review. We found one RCT (56 women with severe pre-eclampsia at [52] 2432 weeks' gestation) comparing vitamin E plus vitamin C plus allopurinol versus placebo. It was too small for reliable conclusions to be drawn. We found insufficient evidence to draw reliable conclusions. None.
Harms: Comment:
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11

OPTION CHOICE OF ANALGESIA DURING LABOUR. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . We found no clinically important results about analgesia in women with severe pre-eclampsia. For GRADE evaluation of interventions for pre-eclampsia, eclampsia, and hypertension, see table, p 18 . Benefits: We found two RCTs comparing epidural analgesia with patient-controlled intravenous analgesia. [53] [54] The first RCT (116 women with severe pre-eclampsia) found that epidural analgesia significantly reduced mean pain scores, but the clinical importance of the difference is unclear. The trial [53] was too small for reliable conclusions to be drawn about other outcomes. The second RCT (738 women with pregnancy-induced hypertension) found that epidural analgesia reduced pain compared with intravenous analgesia (proportion of women reporting excellent pain relief: 54% [54] with epidural analgesia v 19% with intravenous analgesia; P less than 0.001). We found no RCTs of other forms of intrapartum analgesia for this group of women. In the first RCT, epidural analgesia significantly increased the chance of having hypotension requiring intravenous ephedrine (5/56 [9%] with epidural analgesia v 0/60 [0%] with iv analgesia; reported [53] as significant). However, the number of events is too small to draw reliable conclusions. Neonatal naloxone was more likely to be given after intravenous analgesia (5/56 [9%] with epidural analgesia v 31/60 [54%] with iv analgesia; RR 5.71, 95% CI 2.39 to 13.60; NNH 3, 95% CI 2 to 4). The trial was too small for reliable conclusions about other outcomes. In the second RCT, epidural analgesia increased the duration of the second stage of labour (mean length: 53 minutes with epidural analgesia v 40 minutes with iv analgesia), the risk of intrapartum fever (76/372 [22%] with epidural analgesia v 26/366 [8%] with iv analgesia; RR 2.88, 95% CI 1.89 to 4.38), the risk of forceps delivery (51/372 [14%] with epidural analgesia v 27/366 [7%] with iv analgesia; RR 1.86, 95% CI 1.19 to 2.90), and the need for treatment for hypotension (40/372 [11%] with epidural analgesia v 0/366 [0%] with iv analgesia; P less than 0.001). Neonatal naloxone was more likely to be given after intravenous analgesia (2/372 [1%] with epidural analgesia v 40/366 [12%] with iv analgesia).
[54] [53]
Harms:
Comment:
The drug used for patient-controlled intravenous analgesia was not reported in the first RCT. [54] Pethidine was used in the second RCT.
OPTION
INTERVENTIONIST CARE FOR SEVERE EARLY-ONSET PRE-ECLAMPSIA. . . . . . . . . . . . . .
Perinatal mortality Compared with expectant management We dont know whether interventionist management is more effective at reducing stillbirths or perinatal deaths in babies born to mothers with severe early-onset pre-eclampsia (low-quality evidence). Neonatal morbidity Compared with expectant management Interventionist management may increase the risk of respiratory distress syndrome, necrotising enterocolitis, and rates of admission to neonatal intensive care in babies born to mothers with severe pre-eclampsia (low-quality evidence). For GRADE evaluation of interventions for pre-eclampsia, eclampsia, and hypertension, see table, p 18 . Benefits: We found one systematic review (search date 2006, 2 RCTs, 133 women at 2834 weeks' gestation), which compared a policy of early elective delivery by induction or caesarean section depending on individual obstetric circumstances (interventionist management) versus a policy of delayed delivery to allow more time for fetal maturation (expectant management) in women with severe pre[55] eclampsia. It found that, for the baby, there was no significant difference in rates of stillbirth or death after delivery for interventionist management compared with expectant care (RR of death or stillbirth for interventional v expectant care 1.50, 95% CI 0.42 to 5.41). Babies of mothers in the interventionist-management group were significantly less likely to be small for gestational age than those in the expectant group (RR for interventionist v expectant management 0.36, 95% CI 0.14 to 0.90). The review found insufficient evidence about effects on maternal outcomes. The review found that interventionist management significantly increased risks of respiratory distress syndrome (34/66 [52%] babies with interventionist management v 15/67 [22%] babies with expectant care; RR 2.30, 95% CI 1.39 to 3.81), necrotising enterocolitis (RR 5.5, 95% CI 1.04 to 29.56), and rate of admission to neonatal intensive care (RR 1.32, 95% CI 1.13 to 1.55) in babies born to [55] mothers with severe pre-eclampsia. We found insufficient evidence for reliable conclusions about effects of expectant management on maternal morbidity. None. .......................................................... 12
Harms:
Comment:

OPTION PLASMA VOLUME EXPANSION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Seizures Compared with control We don't know whether plasma volume expansion using colloids is more effective at reducing the proportion of women who develop eclampsia (low-quality evidence). Maternal morbidity Compared with control We don't know whether plasma volume expansion using colloids is more effective at reducing the proportion of women who develop haemolysis, elevated liver enzymes and lowered platelets (HELLP) syndrome or other serious maternal morbidities (low-quality evidence). Perinatal mortality Compared with control We don't know whether plasma volume expansion using colloids is more effective at reducing infant mortality (low-quality evidence). For GRADE evaluation of interventions for pre-eclampsia, eclampsia, and hypertension, see table, p 18 . Benefits: We found one systematic review (search date 2000, 3 RCTs, 61 women; see comment below) [57] evaluating colloid solutions compared with placebo or no infusion, and one subsequent RCT. The systematic review found insufficient evidence for reliable conclusions, but suggested that [56] plasma volume expansion is not beneficial. The subsequent RCT (216 women) found no significant difference between plasma volume expansion and control in the proportion of women who developed eclampsia (2/111 [2%] with plasma volume expansion v 2/105 [2%] with no expansion), haemolysis, elevated liver enzymes and lowered platelets (HELLP) syndrome (19/111 [17%] with plasma volume expansion v 20/105 [19%] with no expansion), other serious maternal morbidity (13/111 [12%] with plasma volume expansion v 11/105 [10%] with no expansion), or infant mortality (23/111 [21%] with plasma volume v 15/105 [14%] with no expansion; differences reported as [57] not significant, P values not provided). The systematic review found no significant difference between plasma volume expansion and either placebo or no infusion in the risk of caesarean section (RR 1.5, 95% CI 0.8 to 2.9), or in the need [56] for additional treatment (RR 1.5, 95% CI 0.7 to 3.1). In one RCT included in the review, all women had severe pre-eclampsia. In the other two RCTs, some women did not have proteinuria at trial entry, and those with severe hypertension were ex[56] cluded. These three RCTs all used a colloid rather than crystalloid solution. The subsequent RCT included women with severe early-onset pre-eclampsia, and also used a colloid solution for [57] [58] [59] plasma volume expansion. Two systematic reviews (search dates 2004 and 2002 ) of plasma volume expansion in critically ill men and non-pregnant women have found an increased mortality with albumin (a colloid) when compared with either no expansion or expansion with crystalloid. What is the best choice of anticonvulsant for women with eclampsia? ANTICONVULSANTS FOR WOMEN WITH ECLAMPSIA. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
[56]
Harms:
Comment:
QUESTION OPTION
Seizures Compared with diazepam Magnesium sulphate is more effective at reducing further fits (high-quality evidence). Compared with phenytoin Magnesium sulphate is more effective at reducing further fits (high-quality evidence). Compared with lytic cocktail Magnesium sulphate seems more effective at reducing further fits (moderate-quality evidence). Neonatal morbidity Compared with diazepam Magnesium sulphate is more effective at reducing the proprotion of babies with Apgar scores less than 7 at 5 minutes, and at reducing the proportion of babies with a length of stay in a special-care baby unit for more than 7 days (high-quality evidence). Compared with phenytoin Magnesium sulphate seems more effective at reducing pneumonia, requirement for ventilation, and admission to an intensive-care unit, and at reducing the proportion of babies with a composite outcome of death or staying in a special-care baby unit for more than 7 days (moderate-quality evidence). Compared with lytic cocktail Magnesium sulphate is more effective at reducing pneumonia and respiratory depression (high-quality evidence). .......................................................... 13

Maternal or perinatal mortality Compared with diazepam Magnesium sulphate is more effective at reducing maternal mortality (high-quality evidence). Compared with phenytoin Magnesium sulphate and phenytoin seem equally effective at reducing maternal deaths (moderate-quality evidence). Compared with lytic cocktail Magnesium sulphate seems more effective at reducing fetal or infant deaths, but we don't know whether it is more effective at reducing maternal deaths (moderate-quality evidence). For GRADE evaluation of interventions for pre-eclampsia, eclampsia, and hypertension, see table, p 18 . Benefits: Magnesium sulphate versus diazepam: [60] We found one systematic review (search date 2002, 7 RCTs, 1441 women). It found that magnesium sulphate significantly reduced both maternal mortality (6 RCTs: 26/677 [4%] with magnesium sulphate v 42/659 [6%] with diazepam; RR 0.59, 95% CI 0.37 to 0.94) and further fits (7 RCTs: 71/737 [10%] with magnesium sulphate v 162/704 [23%] with diazepam; RR 0.44, 95% CI 0.34 to 0.57) compared with diazepam. It found no significant differences in any other outcomes for the mother. For the babies, it found that magnesium sulphate significantly reduced the proportion of babies with Apgar scores less than seven at 5 minutes compared with diazepam (2 RCTs: 69/309 [22%] with magnesium sulphate v 90/288 [31%] with diazepam; RR 0.72, 95% CI 0.55 to 0.94), and significantly reduced the proportion of babies with a length of stay in a special-care baby unit of more than 7 days compared with diazepam (3 RCTs: 42/329 [13%] with magnesium sulphate v [60] 59/302 [20%] with diazepam; RR 0.66, 95% CI 0.46 to 0.95). Magnesium sulphate versus phenytoin: [61] We found one systematic review (search date 2002, 6 RCTs, 897 women) and one subsequent [62] RCT. The systematic review found that, compared with phenytoin, magnesium sulphate significantly reduced the risk of further fits (5 RCTs: 25/448 [6%] with magnesium sulphate v 83/447 [19%] with phenytoin; RR 0.31, 95% CI 0.20 to 0.47), pneumonia (1 RCT, 775 women: RR 0.44, 95% CI 0.24 to 0.79), requirement for ventilation (1 RCT, 775 women: RR 0.66, 95% CI 0.49 to 0.90), and admission to intensive-care unit (1 RCT, 775 women: RR 0.67, 95% CI 0.50 to 0.89). [61] It also found that, compared with phenytoin, magnesium sulphate significantly reduced the proportion of babies with the composite outcome of death or staying in a special-care baby unit for more than 7 days (1 RCT, 643 babies: RR 0.77, 95% CI 0.63 to 0.95). The lower maternal death rate with magnesium sulphate compared with phenytoin was not significant, but the confidence interval was wide, and a clinically important effect could not be excluded (2 RCTs: 10/399 [3%] [61] with magnesium sulphate v 20/398 [5%] with phenytoin; RR 0.50, 95% CI 0.24 to 1.05). We [62] found one subsequent RCT (77 women), which was too small for reliable conclusions, although reported results were consistent with the systematic review. Magnesium sulphate versus lytic cocktail: [63] We found one systematic review (search date 2000, 2 RCTs, 199 women) and one additional [64] RCT (199 women). In the systematic review, when compared with lytic cocktail, magnesium sulphate significantly reduced further fits (4/96 [4%] with magnesium sulphate v 49/102 [48%] with lytic cocktail; RR 0.09, 95% CI 0.03 to 0.24), pneumonia (1/51 [2%] with magnesium sulphate v 11/57 [19%] with lytic cocktail; RR 0.08, 95% CI 0.02 to 0.42), respiratory depression (0/96 [0%] with magnesium sulphate v 8/102 [8%] with lytic cocktail; RR 0.12, 95% CI 0.02 to 0.91), and fetal or infant death (14/89 [16%] with magnesium sulphate v 30/88 [34%] with lytic cocktail; RR 0.45, 95% CI 0.26 to 0.79). There was a non-significant reduction in maternal deaths (1/96 [1%] with magnesium sulphate v 6/102 [6%] with lytic cocktail; RR 0.25, 95% CI 0.04 to 1.43). The additional RCT found that, compared with lytic cocktail, magnesium sulphate significantly reduced recurrence of convulsions, maternal deaths, and perinatal deaths (recurrence of convulsions: 2% with magnesium sulphate v 62% with lytic cocktail; absolute numbers not reported, P less than 0.001; maternal deaths: 0/101 [0%] with magnesium sulphate v 8/98 [8%] with lytic cocktail, P less than 0.005; perinatal deaths: 10% with magnesium sulphate v 23% with lytic cocktail, absolute numbers not [64] reported, P less than 0.05). Harms: The systematic reviews suggested that magnesium sulphate is safer for women at least in the short term than diazepam, phenytoin, or lytic cocktail. It also seemed to be safer for babies than [60] [61] [63] phenytoin or lytic cocktail. We found no evidence from RCTs about longer-term adverse effects in women or children. Most information about the comparisons with diazepam and phenytoin came from one large multicentre trial, in which adherence to treatment was 99%. Most of the data came from trials that included women with antepartum or postpartum eclampsia.
Comment:
..........................................................
14

GLOSSARY
Lytic cocktail A mixture of pethidine, chlorpromazine, and promethazine. High-quality evidence Further research is very unlikely to change our confidence in the estimate of effect. Low-quality evidence Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Moderate-quality evidence Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Very low-quality evidence Any estimate of effect is very uncertain.
SUBSTANTIVE CHANGES
Anticonvulsants for women with eclampsia One RCT including 199 women added comparing magnesium sulphate [64] versus lytic cocktail. Categorisation of magnesium sulphate for eclampsia (better and safer than other anticonvulsants) unchanged (Beneficial). Antihypertensive agents (under question in women who develop mildmoderate hypertension during pregnancy) One already-included systematic review comparing antihypertensive drug versus placebo/no antihypertensive [32] drug or versus other antihypertensives updated, and six new RCTs added to its analysis. The overall conclusions [32] of the review unchanged, in that it found antihypertensive drugs significantly reduced the risk of developing severe hypertension compared with no antihypertensive drugs, but it found no significant difference between antihypertensive drugs and no hypertensive drugs in pre-eclampsia or fetal or neonatal death. Categorisation of antihypertensive drugs for mild to moderate hypertension unchanged (Unknown effectiveness). [49] Antihypertensive drugs for very high blood pressure One already-included systematic review updated and [50] [51] two subsequent RCTs added. All the additional data compares different antihypertensives versus each other. Categorisation of antihypertensive drugs for very high blood pressure unchanged (Likely to be beneficial). Antioxidents (under question on the effects of preventative interventions in women at risk of pre-eclampsia) [19] One systematic review comparing the combination of vitamin C and E versus placebo and one small subsequent [20] RCT comparing the effects of a combination of different antioxidents versus placebo added to an already reported [19] systematic review comparing antioxidents versus no antioxidents. The new review found no significant difference between vitamin C plus E and placebo in the risk of pre-eclampsia, preterm birth, having a baby small for gestational age, or in the risk of the baby dying. Categorisation of antioxidants unchanged (Unknown effectiveness). Antiplatelet drugs One already reported systematic review updated and 8 RCTs added to the review and its analysis. [14] Overall conclusions of the review unchanged: antiplatelet drugs still categorised as Beneficial. Calcium supplementation One already-included systematic review updated with one large RCT added to its anal[17] ysis. Overall conclusions of the review unchanged: calcium supplementation still categorised as Beneficial. Interventionist care for severe early-onset pre-eclampsia Option title changed to Interventionist care, which involves a policy of early elective delivery by induction of caesarean section depending on individual obstetric circumstances. [55] One already-reported systematic review updated. No new data added. Categorisation of early delivery for severe early-onset pre-eclampsia unchanged (Unknown effectiveness). Marine oil (fish oil), and other prostaglandin precursors (evening primrose oil) Option title clarified and changed from 'Fish oil, evening primrose oil, or both' to 'marine oil (fish oil), and other prostaglandin precursors (evening [22] [21] primrose oil)'. Two systematic reviews added and benefits and harms data enhanced. Categorisation of marine oil (fish oil), and other prostaglandin precursors (evening primrose oil) unchanged (Unknown effectiveness). [57] Plasma volume expansion (in severe pre-eclampsia) One RCT including 216 women added. Benefits and harms data enhanced, categorisation unchanged (Unknown effectiveness). Prophylactic anticonvulsants for women with severe pre-eclampsia Two long-term follow-up studies in women [42] [43] and children from one large already-included RCT added. Categorisation of prophylactic magnesium sulphate in severe pre-eclampsia unchanged (Beneficial).
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45.
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24.
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49.
50.
27.
51.
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29.
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55.
56.
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Lelia Duley Obstetric Epidemiologist University of Leeds Academic unit Leeds UK
Competing interests: LD is the author of studies included in this review.
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
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17

TABLE GRADE evaluation of interventions for pre-eclampsia, eclampsia, and hypertension
Development of pre-eclampsia, seizures, morbidity, prematurity, use of resources, mortality, adverse effects Type of evidence Consistency Directness Effect size Important outcomes Number of studies (participants)
Outcome
Comparison
Quality
GRADE
Comment
What are the effects of preventive interventions in women at risk of pre-eclampsia? at least 46 RCTs (at least [14] 32,590 women) 29 (31,151) 40 (33,098) 12 (15,206) 4 (9722)
[17] [17] [14]
Development of preeclampsia Preterm birth Perinatal mortality Development of preeclampsia Maternal mortality Perinatal mortality Preterm birth Need for other interventions Development of preeclampsia Preterm birth Perinatal mortality
Antiplatelet drugs v placebo/no antiplatelet drugs Antiplatelet drugs v placebo/no antiplatelet drugs Antiplatelet drugs v placebo/no antiplatelet drugs Calcium supplementation v placebo Calcium supplementation v placebo Calcium supplementation v placebo Calcium supplementation v placebo Calcium supplementation v placebo Antioxidants v placebo/no antioxidant
4 4 4 4 4 4 4 4 4
0 0 0 0 0 1 1 1 1
0 0 0 0 0 0 0 0 1
0 0 0 0 0 0 0 0 0
0 0 0 +1 0 0 0 0 0
High High High High High Moderate Moderate Moderate Low Quality point deducted for incomplete reporting of results Quality point deducted for incomplete reporting of results Quality point deducted for incomplete reporting of results Quality point deducted for methodological weaknesses. Consistency point deducted for conflicting results Quality point deducted for incomplete reporting of results Quality point deducted for incomplete reporting of results Quality point deducted for uncertainty about blinding Quality point deducted for uncertainty about blinding Quality points deducted for sparse data and incomplete reporting of results Quality point deducted for uncertainty about bias Quality point deducted for incomplete reporting of results Quality point deducted for sparse data Effect-size point added for RR less than 0.5
[14]
[17]
10 (15,141) 10 (14,751) 7 (14,710)
[17]
[17]
at least 7 RCTs (at least [18] [19] 6082 women)

[20]
4 (?) 4 (?)
[19]
Antioxidants v placebo/no antioxidant Antioxidants v placebo/no antioxidant Marine oil and other prostaglandin precursors v placebo/no treatment Marine oil and other prostaglandin precursors v placebo/no treatment Glyceryl trinitrate v placebo/no treatment Magnesium supplementation v placebo Salt restriction v normal dietary salt intake Atenolol v placebo
4 4 4 4 4 4 4 4
1 1 1 1 2 1 1 1
0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0
Moderate Moderate Moderate Moderate Low Moderate Moderate Moderate
[20]
4 (1683) 5 (1916) 2 (108) 2 (474) 2 (603) 1 (68)
[21]
Development of preeclampsia Preterm birth

[25]
[21]
[24]
Development of preeclampsia Development of preeclampsia Development of preeclampsia Development of preeclampsia
[27]
[28]
[29]
What are the effects of interventions in women who develop mildmoderate hypertension during pregnancy?
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

Important outcomes Number of studies (participants) at least 22 RCTs (at least [32] [33] 2702 women) Development of pre-eclampsia, seizures, morbidity, prematurity, use of resources, mortality, adverse effects Type of evidence 4 Consistency 0 Directness 0 Effect size 0 Outcome Development of severe hypertension or preeclampsia Perinatal mortality Comparison Antihypertensive drugs v placebo/no antihypertensive drug Quality 3 GRADE Very low Comment Quality points deducted for incomplete reporting of results, methodological weaknesses, and uncertainty about adherence to treatment Quality points deducted for incomplete reporting of results, methodological weaknesses, and uncertainty about adherence to treatment Quality points deducted for uncertainty about bias and for differences in frequency of blood pressure measurement Quality point deducted for uncertainty about bias
26 (3081)
[32]
Antihypertensive drugs v placebo/no antihypertensive drug
Very low
1 (218)
[39]
Development of severe hypertension or preeclampsia Preterm birth
Bed rest/hospital admission v no hospital admission Bed rest/hospital admission v no hospital admission
Low
1 (218)
[39]
Moderate
What are the effects of interventions in women who develop severe pre-eclampsia or very high blood pressure during pregnancy? 6 (11,444) We found two reports of long-term [42] follow-up for women 1 (3283)
[43] [41]
Seizures
Magnesium sulphate v placebo/no anticonvulsant Magnesium sulphate v placebo/no anticonvulsant Magnesium sulphate v placebo/no anticonvulsant Magnesium sulphate v placebo/no anticonvulsant Magnesium sulphate v phenytoin, nimodipine, or diazepam Magnesium sulphate v placebo/no anticonvulsant Magnesium sulphate v placebo/no anticonvulsant Antihypertensive drugs v each other
+1
High
Effect-size point added for RR less than 0.5 Quality point deducted for poor follow-up
Child development Maternal mortality Perinatal mortality Seizures Need for further interventions Adverse effects Seizures
4 4 4 4 4 4 4
1 0 0 0 0 1 1
0 0 0 0 0 0 0
0 0 0 0 0 0 1
0 0 0 +1 0 0 0
Moderate High High High High Moderate Low
2 (10,795) 3 (9961) 3 (3891)
[41]
[41]
[41]
Effect-size point added for RR less than 0.5
at least 1 RCT (at least [41] 10,108 women) at least 1 RCT (9092 [41] women) 3 (505)
[49] [50] [51]
Quality point deducted for incomplete reporting of results Quality point deducted for incomplete reporting of results. Directness point deducted for no direct comparison between drugs Quality points deducted for incomplete reporting of results and for sparse data Quality points deducted for incomplete reporting of results and for sparse data Quality point deducted for incomplete reporting of results. Directness point deducted for differences in disease severities
2 (133) 2 (133) 4 (277)
[55]
Perinatal mortality Neonatal morbidity

[57]
Interventionist management v expectant management Interventionist management v expectant management Plasma volume expansion v control
4 4 4
2 2 1
0 0 0
0 0 1
0 0 0
Low Low Low
[55]
[56]
Seizures
............................................................................................................
19

Important outcomes Number of studies (participants) 4 (277)
[56] [57]
Development of pre-eclampsia, seizures, morbidity, prematurity, use of resources, mortality, adverse effects Type of evidence 4 Consistency 0 Directness 1 Effect size 0
Outcome Perinatal mortality
Comparison Plasma volume expansion v control
Quality 1
GRADE Low
Comment Quality point deducted for incomplete reporting of results. Directness point deducted for differences in disease severities Quality point deducted for incomplete reporting of results. Directness point deducted for differences in disease severities
4 (277)
[56]
[57]
Maternal morbidity
Plasma volume expansion v control
Low
What is the best choice of anticonvulsant for women with eclampsia? 7 (1441) 2 (597) 3 (631)
[60]
Seizures Neonatal morbidity Duration of hospital stay Maternal mortality Seizures Need for further interventions Maternal mortality Perinatal mortality
[64]
Magnesium sulphate v diazepam Magnesium sulphate v diazepam Magnesium sulphate v diazepam Magnesium sulphate v diazepam Magnesium sulphate v phenytoin Magnesium sulphate v phenytoin Magnesium sulphate v phenytoin Magnesium sulphate v phenytoin Magnesium sulphate v lytic cocktail Magnesium sulphate v lytic cocktail Magnesium sulphate v lytic cocktail
4 4 4 4 4 4 4 4 4 4 4
0 0 0 0 0 1 0 1 1 0 1
0 0 0 0 0 0 0 0 0 1 0
0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0 0
High High High High High Moderate High Moderate Moderate Moderate Moderate Quality point deducted for incomplete reporting of results Quality point deducted for incomplete reporting of results Consistency point deducted for conflicting results Quality point deducted for incomplete reporting of results Quality point deducted for incomplete reporting of results
[60] [60] [60]
6 (1336)
5 RCTs (at least 895 [62] women) 1 (775) 2 (797) 1 (643) 2 (397) 2 (397) 2 (397)
[61]
[62] [62]
[63]
Seizures Maternal mortality Perinatal mortality
[63]
[64]
[63]
[64]
Type of evidence: 4 = RCT; 2 = Observational Consistency: similarity of results across studies Directness: generalisability of population or outcomes Effect size: based on relative risk or odds ratio
............................................................................................................
20

Pre Eclampsia Eclampsia and Hypertension

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Pregnancy and childbirth