Antiplatelet agents for preventing pre‐eclampsia and its complications

Lelia Duley; David J Henderson‐Smart; Marian Knight; James F King

doi:10.1002/14651858.CD004659

Scolaris Content Display Scolaris Content Display

Analysis 1.1

Comparison 1 Antiplatelet agents versus placebo/no antiplatelet (subgrouped by maternal risk), Outcome 1 Pregnancy induced hypertension.

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Analysis 1.2

Comparison 1 Antiplatelet agents versus placebo/no antiplatelet (subgrouped by maternal risk), Outcome 2 Proteinuric pre‐eclampsia.

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Analysis 1.3

Comparison 1 Antiplatelet agents versus placebo/no antiplatelet (subgrouped by maternal risk), Outcome 3 Eclampsia.

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Analysis 1.4

Comparison 1 Antiplatelet agents versus placebo/no antiplatelet (subgrouped by maternal risk), Outcome 4 Maternal death.

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Analysis 1.5

Comparison 1 Antiplatelet agents versus placebo/no antiplatelet (subgrouped by maternal risk), Outcome 5 Placental abruption.

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Analysis 1.6

Comparison 1 Antiplatelet agents versus placebo/no antiplatelet (subgrouped by maternal risk), Outcome 6 Caesarean section.

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Analysis 1.7

Comparison 1 Antiplatelet agents versus placebo/no antiplatelet (subgrouped by maternal risk), Outcome 7 Induction of labour.

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Analysis 1.8

Comparison 1 Antiplatelet agents versus placebo/no antiplatelet (subgrouped by maternal risk), Outcome 8 Hospital admission for the woman during pregnancy.

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Analysis 1.9

Comparison 1 Antiplatelet agents versus placebo/no antiplatelet (subgrouped by maternal risk), Outcome 9 Preterm birth (< 37 weeks).

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Analysis 1.10

Comparison 1 Antiplatelet agents versus placebo/no antiplatelet (subgrouped by maternal risk), Outcome 10 Preterm birth (subgroups by gestational age).

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Analysis 1.11

Comparison 1 Antiplatelet agents versus placebo/no antiplatelet (subgrouped by maternal risk), Outcome 11 Fetal and neonatal deaths.

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Analysis 1.12

Comparison 1 Antiplatelet agents versus placebo/no antiplatelet (subgrouped by maternal risk), Outcome 12 Fetal, neonatal, infant and childhood deaths (subgroups by time of death).

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Analysis 1.13

Comparison 1 Antiplatelet agents versus placebo/no antiplatelet (subgrouped by maternal risk), Outcome 13 Deaths after discharge from hospital.

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Analysis 1.14

Comparison 1 Antiplatelet agents versus placebo/no antiplatelet (subgrouped by maternal risk), Outcome 14 Small for gestational age (any definition).

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Analysis 1.15

Comparison 1 Antiplatelet agents versus placebo/no antiplatelet (subgrouped by maternal risk), Outcome 15 Small for gestational age (subgroups by severity).

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Analysis 1.16

Comparison 1 Antiplatelet agents versus placebo/no antiplatelet (subgrouped by maternal risk), Outcome 16 Birthweight < 2500g.

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Analysis 1.17

Comparison 1 Antiplatelet agents versus placebo/no antiplatelet (subgrouped by maternal risk), Outcome 17 Admission to a special care baby unit.

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Analysis 1.18

Comparison 1 Antiplatelet agents versus placebo/no antiplatelet (subgrouped by maternal risk), Outcome 18 Intraventricular haemorrhage.

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Analysis 1.19

Comparison 1 Antiplatelet agents versus placebo/no antiplatelet (subgrouped by maternal risk), Outcome 19 Other neonatal bleed.

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Analysis 1.20

Comparison 1 Antiplatelet agents versus placebo/no antiplatelet (subgrouped by maternal risk), Outcome 20 Non‐routine GP consultation for child.

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Analysis 1.21

Comparison 1 Antiplatelet agents versus placebo/no antiplatelet (subgrouped by maternal risk), Outcome 21 Child admitted to hospital.

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Analysis 1.22

Comparison 1 Antiplatelet agents versus placebo/no antiplatelet (subgrouped by maternal risk), Outcome 22 Developmental problems at 18 months.

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Analysis 1.23

Comparison 1 Antiplatelet agents versus placebo/no antiplatelet (subgrouped by maternal risk), Outcome 23 Behaviour problems at 18 months.

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Analysis 1.24

Comparison 1 Antiplatelet agents versus placebo/no antiplatelet (subgrouped by maternal risk), Outcome 24 Malformations at 18 months.

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Analysis 1.25

Comparison 1 Antiplatelet agents versus placebo/no antiplatelet (subgrouped by maternal risk), Outcome 25 Growth at 18 months.

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Analysis 2.1

Comparison 2 Antiplatelet agents versus placebo/no antiplatelet (subgrouped by gestation at entry), Outcome 1 Pregnancy induced hypertension.

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Analysis 2.2

Comparison 2 Antiplatelet agents versus placebo/no antiplatelet (subgrouped by gestation at entry), Outcome 2 Proteinuric pre‐eclampsia.

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Analysis 2.3

Comparison 2 Antiplatelet agents versus placebo/no antiplatelet (subgrouped by gestation at entry), Outcome 3 Placental abruption.

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Analysis 2.4

Comparison 2 Antiplatelet agents versus placebo/no antiplatelet (subgrouped by gestation at entry), Outcome 4 Preterm birth.

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Analysis 2.5

Comparison 2 Antiplatelet agents versus placebo/no antiplatelet (subgrouped by gestation at entry), Outcome 5 Fetal, neonatal or infant death.

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Analysis 2.6

Comparison 2 Antiplatelet agents versus placebo/no antiplatelet (subgrouped by gestation at entry), Outcome 6 Small‐for‐gestational age.

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Analysis 3.1

Comparison 3 Antiplatelet agents versus placebo/no treatment (subgrouped by use of placebo), Outcome 1 Pregnancy induced hypertension.

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Analysis 3.2

Comparison 3 Antiplatelet agents versus placebo/no treatment (subgrouped by use of placebo), Outcome 2 Proteinuric pre‐eclampsia.

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Analysis 3.3

Comparison 3 Antiplatelet agents versus placebo/no treatment (subgrouped by use of placebo), Outcome 3 Placental abruption.

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Analysis 3.4

Comparison 3 Antiplatelet agents versus placebo/no treatment (subgrouped by use of placebo), Outcome 4 Preterm birth.

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Analysis 3.5

Comparison 3 Antiplatelet agents versus placebo/no treatment (subgrouped by use of placebo), Outcome 5 Fetal, neonatal or infant death.

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Analysis 3.6

Comparison 3 Antiplatelet agents versus placebo/no treatment (subgrouped by use of placebo), Outcome 6 Small‐for‐gestational age.

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Analysis 4.1

Comparison 4 Aspirin versus placebo/no treatment (subgrouped by dose), Outcome 1 Pregnancy induced hypertension.

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Analysis 4.2

Comparison 4 Aspirin versus placebo/no treatment (subgrouped by dose), Outcome 2 Proteinuric pre‐eclampsia.

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Analysis 4.3

Comparison 4 Aspirin versus placebo/no treatment (subgrouped by dose), Outcome 3 Placental abruption.

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Analysis 4.4

Comparison 4 Aspirin versus placebo/no treatment (subgrouped by dose), Outcome 4 Preterm birth.

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Analysis 4.5

Comparison 4 Aspirin versus placebo/no treatment (subgrouped by dose), Outcome 5 Fetal, neonatal or infant death.

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Analysis 4.6

Comparison 4 Aspirin versus placebo/no treatment (subgrouped by dose), Outcome 6 Small‐for‐gestational age.

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Analysis 5.1

Comparison 5 Antiplatelet agent + other agents versus placebo/no treatment (subgrouped by type of agent), Outcome 1 Proteinuric pre‐eclampsia.

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Analysis 5.2

Comparison 5 Antiplatelet agent + other agents versus placebo/no treatment (subgrouped by type of agent), Outcome 2 Fetal or neonatal death.

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Comparison 1. Antiplatelet agents versus placebo/no antiplatelet (subgrouped by maternal risk)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Pregnancy induced hypertension Show forest plot	31	21754	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.90, 1.06]

1.1 moderate‐risk women	22	21107	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.93, 1.09]
1.2 high‐risk women	9	647	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.44, 0.83]
2 Proteinuric pre‐eclampsia Show forest plot	43	33439	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.75, 0.88]

2.1 moderate‐risk women	24	29217	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.77, 0.94]
2.2 high‐risk women	19	4222	Risk Ratio (M‐H, Fixed, 95% CI)	0.73 [0.64, 0.83]
3 Eclampsia Show forest plot	12	14977	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.53, 1.38]

4 Maternal death Show forest plot	3	12709	Risk Ratio (M‐H, Fixed, 95% CI)	2.57 [0.39, 17.06]

5 Placental abruption Show forest plot	16	25806	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.85, 1.32]

5.1 moderate‐risk women	12	23066	Risk Ratio (M‐H, Fixed, 95% CI)	1.13 [0.89, 1.44]
5.2 high‐risk women	4	2740	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.40, 1.29]
6 Caesarean section Show forest plot	23	29406	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.98, 1.06]

7 Induction of labour Show forest plot	5	19295	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.98, 1.08]

8 Hospital admission for the woman during pregnancy Show forest plot	2	9323	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.97, 1.14]

9 Preterm birth (< 37 weeks) Show forest plot	28	31845	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.89, 0.98]

9.1 moderate‐risk women	19	28693	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.89, 0.99]
9.2 high‐risk women	9	3152	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.83, 0.99]
10 Preterm birth (subgroups by gestational age) Show forest plot	25		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

10.1 delivery < 37 completed weeks	24	31522	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.89, 0.98]
10.2 delivery < 34 completed weeks	5	5248	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.64, 1.20]
10.3 delivery < 32 completed weeks	7	15180	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.80, 1.15]
11 Fetal and neonatal deaths Show forest plot	38	34010	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.74, 0.96]

11.1 moderate‐risk women	21	29364	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.78, 1.06]
11.2 high‐risk women	17	4646	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.53, 0.87]
12 Fetal, neonatal, infant and childhood deaths (subgroups by time of death) Show forest plot	34		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

12.1 stillbirths	27	18892	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.78, 1.20]
12.2 perinatal deaths	15	16028	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.73, 1.09]
12.3 neonatal deaths	20	12968	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.61, 1.14]
13 Deaths after discharge from hospital Show forest plot	2	5886	Risk Ratio (M‐H, Fixed, 95% CI)	0.53 [0.21, 1.34]

13.1 deaths 8 days to 18 months	1	788	Risk Ratio (M‐H, Fixed, 95% CI)	1.69 [0.15, 18.57]
13.2 hospital discharge ‐ 12 months	1	4688	Risk Ratio (M‐H, Fixed, 95% CI)	0.28 [0.08, 0.99]
13.3 hospital discharge ‐ 18 months	1	410	Risk Ratio (M‐H, Fixed, 95% CI)	2.16 [0.20, 23.66]
14 Small for gestational age (any definition) Show forest plot	32	24310	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.85, 1.00]

14.1 moderate‐risk women	20	20111	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.85, 1.02]
14.2 high‐risk women	12	4199	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.75, 1.09]
15 Small for gestational age (subgroups by severity) Show forest plot	26	25005	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.86, 1.01]

15.1 birthweight < 10th centile	14	8905	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.82, 1.04]
15.2 birthweight < 5th centile	3	1390	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.77, 1.44]
15.3 birthweight < 3rd centile	7	12938	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.81, 1.07]
15.4 definition not stated	4	1772	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.68, 1.27]
16 Birthweight < 2500g Show forest plot	6	7577	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.82, 1.02]

17 Admission to a special care baby unit Show forest plot	15	29092	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.91, 1.02]

18 Intraventricular haemorrhage Show forest plot	10	26184	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.63, 1.22]

19 Other neonatal bleed Show forest plot	7	26896	Risk Ratio (M‐H, Fixed, 95% CI)	1.13 [0.83, 1.52]

20 Non‐routine GP consultation for child Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

20.1 at 12 months	1	4168	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.99, 1.02]
20.2 at 18 months	1	4365	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.96, 1.04]
21 Child admitted to hospital Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

21.1 at 12 months	1	4168	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.83, 1.08]
21.2 at 18 months	1	4365	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.89, 1.11]
22 Developmental problems at 18 months Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

22.1 poor gross motor function	1	4365	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.57, 1.17]
22.2 poor fine motor function	1	4365	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.84, 1.14]
22.3 poor gross or fine motor function	1	788	Risk Ratio (M‐H, Fixed, 95% CI)	0.49 [0.26, 0.91]
22.4 respiratory problems	1	788	Risk Ratio (M‐H, Fixed, 95% CI)	1.48 [0.98, 2.23]
22.5 poor language expression	1	4365	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.74, 1.19]
22.6 poor language comprehension	1	4365	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.80, 1.13]
22.7 language problems ‐ undefined	1	788	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.69, 1.42]
22.8 hearing problems	1	788	Risk Ratio (M‐H, Fixed, 95% CI)	2.54 [0.10, 62.10]
22.9 sight problems	1	788	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.25, 2.90]
23 Behaviour problems at 18 months Show forest plot	1	4365	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.75, 1.01]

23.1 poor sleep pattern	1	4365	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.75, 1.01]
24 Malformations at 18 months Show forest plot	1	788	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.27, 2.02]

25 Growth at 18 months Show forest plot	2	10306	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.84, 1.07]

25.1 height < 3rd or 10th centile	2	5153	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.80, 1.09]
25.2 weight < 3rd or 10th centile	2	5153	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.79, 1.16]

Comparison 1. Antiplatelet agents versus placebo/no antiplatelet (subgrouped by maternal risk)

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Comparison 2. Antiplatelet agents versus placebo/no antiplatelet (subgrouped by gestation at entry)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Pregnancy induced hypertension Show forest plot	31	21754	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.90, 1.06]

1.1 entered into the study < 20 weeks	13	7787	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.84, 1.07]
1.2 entered into the study > 20 weeks	12	3886	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.74, 1.06]
1.3 unclassified	7	10081	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.93, 1.20]
2 Proteinuric pre‐eclampsia Show forest plot	43	33439	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.75, 0.88]

2.1 entered into the study < 20 weeks	20	17455	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.76, 0.94]
2.2 entered into the study > 20weeks	21	10263	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.70, 0.91]
2.3 unclassified	7	5721	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.56, 0.89]
3 Placental abruption Show forest plot	16	25806	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.85, 1.32]

3.1 entered into study at < 20 weeks	5	3735	Risk Ratio (M‐H, Fixed, 95% CI)	1.11 [0.60, 2.05]
3.2 entered into study at > 20 weeks	4	290	Risk Ratio (M‐H, Fixed, 95% CI)	1.19 [0.37, 3.81]
3.3 unclassified	7	21781	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.82, 1.33]
4 Preterm birth Show forest plot	28	31845	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.89, 0.97]

4.1 entered into the study < 20 weeks	14	16644	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.88, 1.01]
4.2 entered into the study > 20 weeks	15	9708	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.82, 0.96]
4.3 unclassified	4	5493	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.88, 1.15]
5 Fetal, neonatal or infant death Show forest plot	38	34010	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.75, 0.97]

5.1 entered into the study < 20 weeks	16	17501	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.69, 0.99]
5.2 entered into the study > 20 weeks	21	10857	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.67, 1.03]
5.3 unclassified	6	5652	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.73, 1.72]
6 Small‐for‐gestational age Show forest plot	32	24310	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.85, 1.00]

6.1 entered into the study < 20 weeks	15	12150	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.79, 1.00]
6.2 entered into the study > 20 weeks	17	6634	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.81, 1.08]
6.3 unclassified	3	5526	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.82, 1.21]

Comparison 2. Antiplatelet agents versus placebo/no antiplatelet (subgrouped by gestation at entry)

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Comparison 3. Antiplatelet agents versus placebo/no treatment (subgrouped by use of placebo)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Pregnancy induced hypertension Show forest plot	31	21754	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.90, 1.06]

1.1 placebo	25	20411	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.89, 1.06]
1.2 no placebo	6	1343	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.80, 1.30]
2 Proteinuric pre‐eclampsia Show forest plot	43	33439	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.75, 0.88]

2.1 placebo	35	31958	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.77, 0.90]
2.2 no placebo	8	1481	Risk Ratio (M‐H, Fixed, 95% CI)	0.46 [0.30, 0.70]
3 Placental abruption Show forest plot	16	25806	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.85, 1.32]

3.1 placebo	13	24644	Risk Ratio (M‐H, Fixed, 95% CI)	1.08 [0.86, 1.36]
3.2 no placebo	3	1162	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.35, 1.87]
4 Preterm birth Show forest plot	28	31845	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.88, 0.98]

4.1 placebo	23	30464	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.88, 0.98]
4.2 no placebo	5	1381	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.76, 1.08]
5 Fetal, neonatal or infant death Show forest plot	38	34010	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.75, 0.97]

5.1 placebo	30	32381	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.76, 1.00]
5.2 no placebo	8	1629	Risk Ratio (M‐H, Fixed, 95% CI)	0.56 [0.33, 0.94]
6 Small‐for‐gestational age Show forest plot	32	24310	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.88, 1.04]

6.1 placebo	27	22830	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.87, 1.03]
6.2 no placebo	5	1480	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.83, 1.31]

Comparison 3. Antiplatelet agents versus placebo/no treatment (subgrouped by use of placebo)

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Comparison 4. Aspirin versus placebo/no treatment (subgrouped by dose)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Pregnancy induced hypertension Show forest plot	30	21715	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.91, 1.06]

1.1 75 mg or less aspirin	18	17287	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.92, 1.10]
1.2 > 75 mg aspirin	12	4428	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.78, 1.07]
2 Proteinuric pre‐eclampsia Show forest plot	41	33369	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.76, 0.89]

2.1 75 mg or less aspirin	22	28404	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.79, 0.93]
2.2 > 75 mg aspirin	19	4965	Risk Ratio (M‐H, Fixed, 95% CI)	0.49 [0.38, 0.65]
3 Placental abruption Show forest plot	16	25806	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.85, 1.32]

3.1 75 mg or less aspirin	11	22071	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.83, 1.33]
3.2 > 75 mg aspirin	5	3735	Risk Ratio (M‐H, Fixed, 95% CI)	1.11 [0.60, 2.05]
4 Preterm birth Show forest plot	27	31787	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.89, 0.99]

4.1 75 mg or less aspirin	18	27823	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.89, 0.99]
4.2 > 75 mg aspirin	9	3964	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.76, 1.16]
5 Fetal, neonatal or infant death Show forest plot	37	33990	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.74, 0.96]

5.1 75 mg or less aspirin	25	29722	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.74, 0.97]
5.2 > 75 mg aspirin	12	4268	Risk Ratio (M‐H, Fixed, 95% CI)	0.79 [0.48, 1.28]
6 Small‐for‐gestational age Show forest plot	30	24242	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.85, 1.00]

6.1 75 mg or less aspirin	18	19663	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.84, 1.02]
6.2 > 75 mg aspirin	12	4579	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.78, 1.05]

Comparison 4. Aspirin versus placebo/no treatment (subgrouped by dose)

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Comparison 5. Antiplatelet agent + other agents versus placebo/no treatment (subgrouped by type of agent)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Proteinuric pre‐eclampsia Show forest plot	6	589	Risk Ratio (M‐H, Fixed, 95% CI)	0.20 [0.10, 0.39]

1.1 aspirin + dipyridamole	4	442	Risk Ratio (M‐H, Fixed, 95% CI)	0.29 [0.14, 0.61]
1.2 aspirin + fish oil + vit C + vit E	1	127	Risk Ratio (M‐H, Fixed, 95% CI)	0.07 [0.01, 0.54]
1.3 dipyridamole + heparin	1	20	Risk Ratio (M‐H, Fixed, 95% CI)	0.09 [0.01, 1.45]
2 Fetal or neonatal death Show forest plot	5	462	Risk Ratio (M‐H, Fixed, 95% CI)	0.49 [0.23, 1.03]

2.1 aspirin + dipyridamole	4	442	Risk Ratio (M‐H, Fixed, 95% CI)	0.52 [0.24, 1.13]
2.2 dipyridamole + heparin	1	20	Risk Ratio (M‐H, Fixed, 95% CI)	0.24 [0.01, 4.44]

Comparison 5. Antiplatelet agent + other agents versus placebo/no treatment (subgrouped by type of agent)

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