Antiplatelet drugs for prevention of pre-eclampsia and its consequences: systematic reviewBMJ 2001; 322 doi: https://doi.org/10.1136/bmj.322.7282.329 (Published 10 February 2001) Cite this as: BMJ 2001;322:329
Study identifier (quality score)* Methods Participants Interventions Outcomes Australia 1988w1
Women given identification number at trial entry. Randomisation in pharmacy using a random number sequence linked to this number. Two groups: high umbilical artery systolic:diastolic ratio (>95th <99.5th centile) and umbilical artery systolic:diastolic ratio >99.5th centile. Data incomplete for second group, outcome only included if data for all women 46 women. Singleton pregnancy at 28-36 weeks and concern about fetal welfare. Umbilical artery velocity waveform systolic:diastolic ratio >95th centile
Exclusions: diastolic pressure >110 mm Hg or >90 mm Hg with proteinuria, and maternal condition likely to lead to delivery
Aspirin 150 mg/day v placebo Women: caesarean section, induction, placental weight Babies: stillbirth, neonatal death, ventilation, admission to SCBU, intraventricular haemorrhage, birth weight, gestation at delivery, head circumference, Apgar scores Australia 1990w2
Randomised trial; no other information. 1/21 women (5%) excluded as miscarriage at 20 weeks. Published as abstract only 21 women with renal disease. 20 had previous early onset pre-eclampsia Dipyridamole (dose not known) + subcutameous heparin 15 000 u/day v no treatment Women: hypertension, proteinuria, "complications" Babies: neonatal death Australia 1995w3
Instructions about the tablets in numbered sealed opaque envelopes. Women shown 5 envelopes and asked to choose 1 51 women at 28-36 weeks with ultrasound diagnosis of restricted fetal growth, umbilical artery Doppler systolic:diastolic ratio >95th centile. No previous aspirin during pregnancy Aspirin 100 mg v starch tablets Women: none Babies: mean gestation at delivery, small for gestational age (<3rd, <10th centile), 5 min Apgar score, admission to SCBU, intraventricular haemorrhage Australia 1996w4
Randomisation by taking the next in a series of numbered identical blister packs. 2 women withdrew, one from each group 104 women. Primiparous with abnormal uterine Doppler flow at 18 weeks (systolic:diastolic ratio >3.3 or systolic:diastolic >3 and early diastolic notch). Selected from 955 women screened, 186 with abnormal waveforms Aspirin 100 mg /day v placebo Women: pregnancy induced hypertension, pre-eclampsia, eclampsia, antepartum haemorrhage Babies: preterm birth, small for gestational age Australia 1997w5
Allocated by a series of random numbers. 10% (12/120) of women excluded as withdrew before starting treatment 120 women with one of: pre-existing hypertension (³140/90 mm Hg before pregnancy on ³2 occasions or antihypertensive therapy), renal disease, previous early severe pre-eclampsia
Exclusions: aspirin allergy, aspirin-sensitive asthma, pre-existing bleeding diathesis, or multiple pregnancy
Aspirin 100 mg modified release daily from 17-19 weeks until delivery v placebo Women: proteinuria, duration of pregnancy, indications delivery, caesarean section, maximum antenatal blood pressure, "complications" Babies: perinatal death, birth weight, Apgar scores Austria 1992w6
Randomised by coded packages of medication; assessment of primary outcome blinded 41 women. Primigravidas with positive roll over test (increase of 20 mm Hg in diastolic pressure) at 28-32 weeks
Exclusions: existing hypertension, renal gut lung or heart disease, intrauterine growth retardation, impending preterm birth
Aspirin 80 mg/day until 37 weeks v placebo Women: pregnancy induced hypertension, pre-eclampsia, caesarean section, preterm birth (<37 weeks), Babies: stillbirths, neonatal death, small for gestational age (<10th centile), neonatal bleeding, admission to SCBU Barbados 1998w7
Single centre, treatment packs randomly numbered by computer in clinic and dispensed by pharmacist. 55/3697 women (1.5%) excluded after randomisation: 42 pack labelling errors, 8 women not pregnant and 6 lost to follow up. 3697 women at 12-32 weeks gestation
Exclusions: increased risk of bleeding, aspirin allergy, high likelihood of immediate delivery, or previous placental abruption
Aspirin 75 mg controlled release daily until delivery v placebo Women: pre-eclampsia, antepartum haemorrhage, postpartum haemorrhage, caesarean section, duration of pregnancy, use of antihypertensive and anticonvulsant drugs Babies: stillbirth, death before hospital discharge, days in SCBU, bleeding problems, birth weight Brazil 1996w8
Central telephone randomisation; 39/1009 women (4%) lost to follow up. Conducted in 12 university teaching hospitals and 182 obstetric offices 1009 women at 12-32 weeks gestation (41% £20 weeks) at risk of pre-eclampsia: generally low/moderate risk (47% primiparous, 47% chronic hypertension, 6% diabetes). Exclusions: bleeding risk, asthma, allergy to aspirin, gastric ulcer, placenta praevia Aspirin 60 mg/day v placebo Women: pre-eclampsia, caesarean section, antepartum haemorrhage Babies: small for gestational age, perinatal death, preterm birth, neonatal bleeding China 1996w9
Prospective randomised double-blind study 84 women with singleton pregnancy at high risk of intrauterine growth retardation at 28-32 weeks gestation Aspirin 75 mg daily from 28-34 weeks for 6-8 weeks v placebo Women: pregnancy induced hypertension, caesarean section, preterm delivery. Babies: neonatal death, intrauterine growth retardation, intraventricular haemorrhage China 1999w10
Randomisation by offering woman 5 sealed envelopes (2 aspirin, 2 calcium, 1 placebo). 132 women allocated aspirin, 154 calcium, and 83 control. Calcium group excluded from this review. 22 women lost to follow up (14 aspirin, 8 control) 215 primigravid women with mean arterial pressure >80 mm Hg and <106 mm Hg early in second trimester and >60 mm Hg at 22-24 weeks Aspirin 80 mg /day until delivery v control, no placebo mentioned Women: pregnancy induced hypertension, pre-eclampsia, eclampsia, caesarean section. Babies: gestation at delivery (mean), birth weight, Apgar scores CLASP 1994w11
By telephoning central computerised randomisation service. 0.6% (55/9364) lost to follow up. International study. Compliance: 96% started treatment, 88% took it ³80% of time from entry-delivery. Follow up of surviving children with GP letter at 12 months in UK (4688 with 4675 alive at 12 months) and parental questionnaire at 18 months in UK and Canada (410 with 407 alive at 18 months). For GP letter, 89% response, for parental questionnaire 86% response 9364 women at 12-32 weeks gestation at risk of pre-eclampsia or intrauterine growth retardation or women with established pre-eclampsia or intrauterine growth retardation. Only 7974 women randomised for prevention included in review Aspirin 60 mg daily until delivery v placebo Women: Death, eclampsia, pre-eclampsia, bleeding complications, caesarean section, induction, problems with epidural, postpartum haemorrhage, transfusion, use of antihypertensive or anticonvulsant drugs, compliance Babies: death (stillbirth, neonatal, one year), small for gestational age (<3rd centile), gestation at delivery, admission to SCBU, intraventricular haemorrhage, other neonatal bleeding. At 12-18 months: developmental delay, congenital malformations, respiratory problems, hospital admissions Colorado 1993w12
RandomisedCno further information; completeness of follow up unclear. Multicentre trial, stopped early due to slow recruitment 100 nulliparous women with multiple pregnancy in early pregnancy Aspirin 81 mg/day v placebo Women: pregnancy induced hypertension, pre-eclampsia Babies: none reported EPREDA 1991w13
Randomised by centre with stratification for one or two previous poor outcomes. 1 woman excluded after randomisation. Two studies within the report. Only data for placebo study included in review. 323 women at 15-18 weeks gestation with poor outcome in previous 2 pregnancies, at least 1 being intrauterine growth retardation or intrauterine growth retardation in previous pregnancy. Aspirin 150 mg /day, or aspirin 150 mg + dipyridamole 225 mg/day v placebo Women: death, diastolic pressure >90 mm Hg, proteinuria, abruption, caesarean section <34 weeks, "poor outcome" Exclusions: twins, uterine malformation, renal disease, secondary hypertension, diabetes, cardiac disease Aspirin 150 mg + dypridamole 225 mg/day v aspirin 150 mg/day Babies: stillbirth, neonatal death, ventilation, admission to SCBU, small for gestational age (<10th centile), duration of hospital stay (mean) Finland 1993w14
Sealed envelopes, no further details. 3 centres. 5.3% (11/208) women excluded: 6 from aspirin group (1 miscarriage, 1 anencephaly, 4 discontinued due to urticaria, raised aspartate transaminase or prolonged bleeding time), 5 from placebo group (1 miscarriage, 3 raised aspartate transaminase or prolonged bleeding time, 1 lost to follow up) 208 women with pre-existing hypertension (>140/90 mm Hg before pregnancy) or previous severe pre-eclampsia (in immediately preceding pregnancy), and 12-18 weeks gestation
Excluded: women proteinuric before pregnancy
Aspirin 50 mg/day v placebo Women: exacerbation of hypertension +/- proteinuria, caesarean section, blood loss at delivery (mean), hospital admission during pregnancy, bleeding time and diastolic pressure at 36 weeks Babies: perinatal death, admission to SCBU, birth weight, small for gestational age, gestation at delivery Finland 1997w15
Randomised–no other information 26 high risk women with uterine artery bilateral notches on Doppler, at 22-24 weeks. Aspirin 50 mg v no treatment Women: pregnancy induced hypertension, pre-eclampsia, abruption, delivery <37 weeks Babies: stillbirth, intrauterine growth retardation (<10th centile), intraventricular haemorrhage on ultrasonography, gestation at delivery (mean), birth weight France 1985w16
Randomly allocated to group A or B–no other information. 9% (9/102) excluded from analysis (2 controls lost to follow up, 4 treatment and 3 controls had miscarriage <16 weeks). 102 women at high risk of pre-eclampsia or intrauterine growth retardation
Exclusions: secondary hypertension, or known or suspected renal disease.
Aspirin 150 mg + dipyridamole 300 mg daily, from 3 months until delivery v no treatment Women: pregnancy induced hypertension (³140/85 mm Hg), pre-eclampsia, caesarean section, abnormal bleeding during delivery or caesarean section, abruption, headache Babies: stillbirth, neonatal death, fetal malformation, small for gestational age (<10th <3rd centile, live births only), haemorrhagic complication (undefined) France 1990w17
Randomised study–no other information. Published in abstract form only 91 women at high risk of pregnancy induced hypertension because of previous early onset pre-eclampsia, severe intrauterine growth retardation, or fetal death due to placental insufficiency Aspirin 100 mg + dipyridamole 300 mg daily until delivery v no antiplatelet Women: pregnancy induced hypertension , duration of pregnancy (mean) Babies: fetal death, birth weight Israel 1989w18
Coded packages of 100 pills allocated according to a computer-generated randomisation list 65 women with either twin pregnancy, history of pre-eclampsia in first pregnancy, and a positive rollover test at 28-29 weeks gestation Aspirin 100 mg daily v placebo Women: pregnancy induced hypertension, pre-eclampsia, caesarean section, days in hospital (mean) Babies: stillbirth, neonatal death, gestation at birth (mean), preterm (<37 weeks), small for gestational age (<10th centile), Apgar score, ventilation, admission to SCBU, intraventricular haemorrhage, haematuria, sepsis work up Israel 1994w19
Allocated to a coded package according to randomisation list. 1 women withdrawn from placebo group due to thrombocytopenia–
outcomes included where possible
48 women with twin pregnancies at about 18 weeks Aspirin 100 mg/day v placebo Women: pregnancy induced hypertension, pre-eclampsia, caesarean section, intrauterine growth retardation Babies: preterm birth, perinatal mortality, birth weight discordancy Italy 1989w20
Randomly assigned–no other information given 33 women at risk of hypertension because of essential hypertension or previous obstetric history (placental insufficiency causing fetal death, severe intrauterine growth retardation, or pre-eclampsia <32 weeks)
Excluded if antiphospholipid antibodies present
Aspirin 60 mg/day from 12 weeks until delivery v placebo Women: pregnancy induced hypertension (>140/90 mm Hg and previously normal) Babies: perinatal death, assisted ventilation, haemorrhagic complications, birth weight <10th centile, preterm (<37 weeks), Apgar scores, respiratory distress syndrome Italy 1993w21
Allocation by a telephone call to one of two randomisation centres. 5.8% (64/1106) of women lost to follow up (18/523 aspirin, 46/583 control).
Follow up: postal questionnaire for 1083 children at 18 months (excludes 41 born before follow up started). 427 aspirin responders (72%) and 361 no treatment (73%). Data not presented separately for prophylaxis and treatment, all women included in this review
1106 women at 16-32 weeks gestation. Prophylactic: age <18 or >40 years, mild-moderate chronic hypertension, nephropathy with normal renal function and blood pressure, pregnancy induced hypertension or intrauterine growth retardation in previous pregnancy, twins. Therapeutic: pregnancy induced hypertension (diastolic pressure 90-110 mm Hg) or early intrauterine growth retardation (fetal abdominal circumference ³2 SD below mean for gestational age)
Excluded: Chronic disease, allergy to aspirin, fetal malformation
Aspirin 50 mg/day v no treatment Women: pregnancy induced hypertension +/- proteinuria, abruption, induced or spontaneous abortion, caesarean section Babies: Perinatal mortality, gestation at delivery, birth weight <5th centile, admission to SCBU, intraventricular haemorrhage, gastric bleed. At 18 months: death, malformations, height and weight <10th centile, and respiratory, motor, sight, hearing or language problems Italy 1999w22
Randomised. 9 women stopped treatment early (4 aspirin, 5 placebo) 216 women aged 18-36, pre-existing hypertension or previous severe pre-eclampsia at 12-26 weeks Aspirin 50 mg/day v placebo Jamaica 1998w23
Women given sequential numbers on admission which identified a bottle containing either aspirin or placebo. 179/6275 (3%) lost to follow up. 50 women with multiple pregnancy excluded. Some women entered twice, but numbers not given 6275 primiparous women <32 weeks and no contraindication to aspirin. 144 aspirin women and 161 placebo randomised after 32 weeks but included in analysis Aspirin 60 mg/day until delivery v placebo Women: Hypertension (diastolic ³90 mm Hg or systolic ³140 mmHg or rise of 25 mm Hg diastolic or 40 mm Hg systolic), pre-eclampsia, eclampsia, caesarean section, antenatal admission, postpartum haemorrhage Baby: perinatal death, preterm delivery, birth weight <2500 g, admission to SCBU, 5 min Apgar <5, intraventricular haemorrhage, other neonatal bleeding Japan 1999w24
Enrolled randomly–no further information 40 women with severe pre-eclampsia in previous pregnancy. Enrolled at 6-18 weeks, treatment started at 20 weeks Ozagrel hydrochloride (thromboxane synthetase inhibitor) 400 mg/day from 20 weeks–delivery v placebo Women: pre-eclampsia Babies: Preterm delivery, delivery <32 weeks, small for gestational age Netherlands 1986w25
Coded packages, allocated according to a randomisation list. 2 women in treatment group excluded because of non-compliance, but data for some clinical outcomes reported 46 angiotensin II sensitive primigravid women at 28 weeks gestation with uncomplicated pregnancies, no history of hypertension, cardiovascular or renal disease, diastolic pressure <80 mm Hg, and taking no drugs except iron Aspirin 60 mg/day v placebo Women: eclampsia, pregnancy induced hypertension (diastolic pressure ³95 mm Hg on two or more occasions 6 hours apart), pre-eclampsia (hypertension as above plus proteinuria >0.5 g/l), preterm delivery (<37 weeks), caesarean section Babies: stillbirth, neonatal death, respiratory distress syndrome, small for gestational age (<10th, <3rd centile) Netherlands 1989w26
Coded packages containing trial drug allocated according to a randomisation list 10 primigravid women with chronic hypertension and a positive angiotensin II sensitivity test at 26 weeks. No proteinuria, diastolic pressure <90 mm Hg, serum creatinine <70 μmol/l, and fetus adequately grown Aspirin 60 mg v placebo Women: pregnancy induced hypertension (diastolic increase ³20 mm Hg), pre-eclampsia (hypertension as before plus proteinuria ³500 mg/l), caesarean section Babies: small for gestational age (<10th centile) Netherlands 1991w27
Coded packages allocated according to randomisation sheet. Code broken at 34 weeks, some women then started aspirin 36 women with a positive angiotensin II sensitivity test at 28 weeks Aspirin 60 mg/day from 28-32 weeks v placebo Women: hypertension at 34 weeks Babies: stillbirth South Africa 1988w28
By computer generated random numbers, no other information. One woman lost to follow up. Published only as abstract 44 women with elevated mid-trimester blood pressure, 12-28 weeks gestation, diastolic pressure 80-105 mm Hg, and otherwise normal aspirin 81 mg/day or aspirin 81 mg + dipyridamole 200 mg/day v no antiplatelet drug Women: pre-eclampsia Babies: stillbirth Tanzania 1995w29
Coded packages, A and B. No other information 127 women with a positive roll over test
Exclusions: hypertension or increased blood pressure before screening, proteinuria >300 mg
Aspirin 80 mg/day v placebo Women: pregnancy induced hypertension, pre-eclampsia Babies: none Thailand 1996†w30
Identical treatment and placebo tablets (22 weeks supply) in identical containers (100 per box)–patient chose a container at random. Compliance testing: 86% aspirin, 81% placebo. 10% lost after randomisation (aspirin: 106 returned home, 1 rubella, 2 rashes. Placebo: 38 returned home, 1 twin, 1 abortion, 1 HIV, 1 fetal abnormality, 1 stillbirth) 1500 low risk nulliparous women at 18-22 weeks, ultrasonography to confirm dates (mean at randomisation 20.7 weeks)
Exclusions: renal or cardiovascular disease, diabetes, twins, hypertension
Aspirin 60 mg/day, until birth v placebo Women: Death, pregnancy induced hypertension, pre-eclampsia, eclampsia, caesarean section, antepartum haemorrhage Babies: stillbirth, preterm birth, small for gestational age UK 1990w31
Computer generated randomisation list. Serially numbered bottles dispensed by pharmacist. 5.7% (6/106) excluded after randomisation (5 women moved house, 1 withdrew after 3 weeks) 106 primigravid women with persistently abnormal Doppler waveform studies at 24 weeks Aspirin 75 mg/day v placebo Women: pregnancy induced hypertension, proteinuria, hypertension <37 weeks gestation, caesarean section for hypertension Exclusions: Aspirin allergy, diabetes, bleeding disorders, peptic ulceration, systemic lupus erythematosus Babies: perinatal death, small for gestational age (<5th centile) UK 1992w32
Simply randomised with block size four 18 normal primigravid women, 16 weeks gestation, and 16 primigravid women with pregnancy induced hypertension but no proteinuria at >20 weeks Aspirin 60 mg/day until delivery v placebo Women: duration of labour, blood loss at delivery Babies: <36 weeks at delivery, small for gestational age (<10th centile), minor bruising UK 1992bw33
Randomly allocated–no other information. 26 women with history of recurrent miscarriage or connective tissue disorder and positive for anticardiolipin antibodies Aspirin 75 mg/day v no treatment Women: miscarriage Babies: neonatal death UK 1995w34
Computer generated randomisation list used to produce sealed envelopes. 4/122 women (3%) withdrew after randomisation 122 women with no previous pregnancy proceeding beyond 12 weeks, haemoglobin >132 g/l at 12-19 weeks gestation, diastolic pressure <90 mm Hg, and no proteinuria
Exclusions: multiple pregnancy, diabetes, recurrent miscarriage, or contraindication to aspirin
Aspirin 75 mg from 18 weeks until delivery v placebo. Women: pregnancy induced hypertension, pre-eclampsia, eclampsia, abruption, caesarean section, induction of labour, side effects Babies: perinatal mortality, delivery <34 weeks gestation, admission to SCBU, small for gestational age (<5th centile) USA 1993w35
Efforts were made to conceal randomisation; placebo controlled; <1% lost to follow up 604 primiparous women in single antenatal clinic
Exclusions: renal or collagen disease, diabetes, essential hypertension, multiple pregnancy
Aspirin 60 mg/day, from 22 weeks v placebo Women: pregnancy induced hypertension, pre-eclampsia, eclampsia, antepartum haemorrhage, Caesarean section, preterm delivery (<37, <34, <32 weeks) Babies: perinatal death, small for gestational age USA 1993aw36
Assigned randomly–no further details. 150/3135 (4.8%) lost to follow up: 85 from aspirin group and 65 from placebo. 3135 nulliparous women at 13-25 weeks with blood pressure <135/85 mm Hg and no proteinuria; out of the 4241 entered into a run-in compliance phase
Exclusions: chronic hypertension, diabetes, renal disease, other medical illness
Aspirin 60 mg/day v placebo. Women: pregnancy induced hypertension, pre-eclampsia, eclampsia, caesarean section, abruption, preterm delivery, postpartum haemorrhage. Babies: stillbirths, neonatal deaths, small for gestational age (<10th centile), bleeding USA 1994w37
Randomised, no further details. 5/54 (9%) women lost to follow up. Published as abstract only 54 women with chronic hypertension or previous severe pre-eclampsia, enrolled at 13-15 weeks Aspirin 100 mg sustained release/day until 37 weeks v placebo Women: pre-eclampsia Babies: Stillbirth, small for gestational age USA 1998†w38
Packets prepared using computer generated random numbers. Opened consecutively in each centre. Multicentre study. 36/2539 women (1%) lost to follow up 2539 women 13-26 weeks gestation with insulin treated diabetes, chronic hypertension, multiple pregnancy, or pre-eclampsia in previous pregnancy
Exclusions: Women with multiple pregnancy, if also diabetes, chronic hypertension, or proteinuria
Aspirin 60 mg/day v placebo Women: pregnancy induced hypertension, pre-eclampsia, abruption, preterm delivery, postpartum haemorrhage Baby: death, intrauterine growth retardation (<10th centile), intraventricular haemorrhage, other neonatal bleeding Zimbabwe 1998w39
Randomisation list used to determine sequence of numbered containers. 20/250 (8%) women lost to follow up 250 women at 20-28 weeks and pre-eclampsia in previous pregnancy, especially if <32 weeks, or chronic hypertension
Exclusions: aspirin hypersensitivity, pre-eclampsia, bleeding, or peptic disorder
Aspirin 75 mg/day v placebo Women: pre-eclampsia, antihypertensive drug, preterm delivery, postpartum haemorrhage, caesarean section Babies: death, Intrauterine growth retardation, admission to SCBU
*Score for quality of concealment of allocation: a=adequate, b=unclear, c=inadequate.
†Additional data provided by the authors.
SCBU=special care baby unit.
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