Comparison 1. Supplementation with any folate versus no intervention, placebo or other micronutrients without folate (five trials).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Neural tube defects (All)	5	6708	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.17, 0.58]
2 Neural tube defects (by scheme)	5	6708	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.17, 0.58]
2.1 Daily supplementation	5	6708	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.17, 0.58]
3 Neural tube defects (by daily dose)	5	6708	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.17, 0.58]
3.1 400 µg (0.4 mg) folic acid or less per day	1	261	Risk Ratio (M‐H, Random, 95% CI)	0.17 [0.01, 4.21]
3.2 More than 400 µg (0.4 mg) folic acid per day	4	6447	Risk Ratio (M‐H, Random, 95% CI)	0.32 [0.17, 0.60]
4 Neural tube defects (by timing of supplementation)	5	6708	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.17, 0.58]
4.1 Periconceptional period	5	6708	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.17, 0.58]
5 Neural tube defects (by history of an affected pregnancy ‐recurrence)	5	6708	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.17, 0.58]
5.1 Yes	4	1846	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.18, 0.64]
5.2 No	1	4862	Risk Ratio (M‐H, Random, 95% CI)	0.07 [0.00, 1.32]
6 Neural tube defects (by folate compound)	5	6708	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.17, 0.58]
6.1 Folic acid	5	6708	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.17, 0.58]
7 Neural tube defects (by micronutrient composition)	5	6623	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.18, 0.63]
7.1 Folate alone	2	709	Risk Ratio (M‐H, Random, 95% CI)	0.24 [0.08, 0.73]
7.2 Folate + multiple micronutrients	4	5914	Risk Ratio (M‐H, Random, 95% CI)	0.40 [0.18, 0.85]
8 Neural tube defects (by malaria setting at time of the study)	5	6708	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.17, 0.58]
8.1 No	5	6708	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.17, 0.58]
9 Cleft lip (All)	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.14, 4.36]
10 Cleft lip (by scheme)	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.14, 4.36]
10.1 Daily supplementation	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.14, 4.36]
11 Cleft lip (by daily dose)	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.14, 4.36]
11.1 400 µg (0.4 mg) folic acid or less per day	1	261	Risk Ratio (M‐H, Random, 95% CI)	0.17 [0.01, 4.21]
11.2 More than 400 µg (0.4 mg) folic acid per day	2	5351	Risk Ratio (M‐H, Random, 95% CI)	1.30 [0.29, 5.80]
12 Cleft lip (by timing of supplementation)	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.14, 4.36]
12.1 Periconceptional period	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.14, 4.36]
13 Cleft lip (by history of an affected pregnancy ‐recurrence)	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.14, 4.36]
13.1 Yes	2	1456	Risk Ratio (M‐H, Random, 95% CI)	0.17 [0.01, 4.21]
13.2 No	1	4156	Risk Ratio (M‐H, Random, 95% CI)	1.30 [0.29, 5.80]
14 Cleft lip (by folate compound)	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.14, 4.36]
14.1 Folic acid	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.14, 4.36]
15 Cleft lip (by micronutrient composition)	3	5527	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.26, 3.96]
15.1 Folate alone	1	598	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
15.2 Folate + multiple micronutrients	3	4929	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.26, 3.96]
16 Cleft lip (by malaria setting at the time of the study)	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.14, 4.36]
16.1 No	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.14, 4.36]
17 Cleft palate (All)	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.05, 10.89]
18 Cleft palate (by scheme)	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.05, 10.89]
18.1 Daily supplementation	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.05, 10.89]
19 Cleft palate (by daily dose)	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.05, 10.89]
19.1 More than 400 µg (0.4 mg) folic acid per day	2	5351	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.05, 10.89]
19.2 400 µg (0.4 mg) folic acid or less per day	1	261	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
20 Cleft palate (by timing of supplementation)	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.05, 10.89]
20.1 Periconceptional period	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.05, 10.89]
21 Cleft palate (by history of an affected pregnancy ‐recurrence)	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.05, 10.89]
21.1 Yes	2	1456	Risk Ratio (M‐H, Random, 95% CI)	3.05 [0.12, 74.61]
21.2 No	1	4156	Risk Ratio (M‐H, Random, 95% CI)	0.20 [0.01, 4.06]
22 Cleft palate (by folate compound)	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.05, 10.89]
22.1 Folic acid	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.05, 10.89]
23 Cleft palate (by micronutrient composition)	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.05, 10.76]
23.1 Folate alone	1	598	Risk Ratio (M‐H, Random, 95% CI)	3.02 [0.12, 73.84]
23.2 Folate + multiple micronutrients	3	5014	Risk Ratio (M‐H, Random, 95% CI)	0.20 [0.01, 4.06]
24 Cleft palate (by malaria setting at the time of the study)	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.05, 10.89]
24.1 No	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.05, 10.89]
25 Congenital cardiovascular anomalies (All)	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.24, 1.33]
26 Congenital cardiovascular anomalies (by scheme)	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.24, 1.33]
26.1 Daily supplementation	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.24, 1.33]
27 Congenital cardiovascular anomalies (by daily dose)	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.24, 1.33]
27.1 400 µg (0.4 mg) folic acid or less per day	1	261	Risk Ratio (M‐H, Random, 95% CI)	0.10 [0.01, 2.14]
27.2 More than 400 µg (0.4 mg) folic acid per day	2	5351	Risk Ratio (M‐H, Random, 95% CI)	0.66 [0.27, 1.60]
28 Congenital cardiovascular anomalies (by timing of supplementation)	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.24, 1.33]
28.1 Periconceptional period	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.24, 1.33]
29 Congenital cardiovascular anomalies (by history of an affected pregnancy ‐recurrence))	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.24, 1.33]
29.1 Yes	2	1456	Risk Ratio (M‐H, Random, 95% CI)	0.40 [0.08, 2.11]
29.2 No	1	4156	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.23, 1.82]
30 Congenital cardiovascular anomalies (by folate compound)	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.24, 1.33]
30.1 Folic acid	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.24, 1.33]
31 Congenital cardiovascular anomalies (by micronutrient composition)	2	5351	Risk Ratio (M‐H, Random, 95% CI)	0.66 [0.27, 1.60]
31.1 Folate alone	1	1195	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.11, 4.04]
31.2 Folate + multiple micronutrients	1	4156	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.23, 1.82]
32 Congenital cardiovascular anomalies (by malaria setting at the time of the study)	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.24, 1.33]
32.1 No	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.24, 1.33]
33 Other congenital anomalies (All)	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.53, 1.66]
34 Other congenital anomalies (by scheme)	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.53, 1.66]
34.1 Daily supplementation	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.53, 1.66]
35 Other congenital anomalies (by daily dose)	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.53, 1.66]
35.1 400 µg (0.4 mg) folic acid or less per day	1	261	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.32, 2.30]
35.2 More than 400 µg (0.4 mg) folic acid per day	2	5351	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.40, 2.42]
36 Other congenital anomalies (by timing of supplementation)	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.53, 1.66]
36.1 Periconceptional period	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.53, 1.66]
37 Other congenital anomalies (by history of an affected pregnancy ‐recurrence)	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.53, 1.66]
37.1 Yes	2	1456	Risk Ratio (M‐H, Random, 95% CI)	1.27 [0.69, 2.34]
37.2 No	1	4156	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.36, 1.18]
38 Other congenital anomalies (by folate compound)	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.53, 1.66]
38.1 Folic acid	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.53, 1.66]
39 Other congenital anomalies (by micronutrient composition)	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.58, 1.51]
39.1 Folate alone	1	598	Risk Ratio (M‐H, Random, 95% CI)	1.26 [0.34, 4.64]
39.2 Folate + other micronutrients	3	5014	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.50, 1.71]
40 Other congenital anomalies (by malaria setting at the time of the study)	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.53, 1.66]
40.1 No	3	5612	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.53, 1.66]
41 Miscarriage (All)	5	7391	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.94, 1.28]
42 Miscarriage (by scheme)	5	7391	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.94, 1.28]
42.1 Daily supplementation	5	7391	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.94, 1.28]
43 Miscarriage (by daily dose)	5	7391	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.94, 1.28]
43.1 400 µg (0.4 mg) folic acid or less per day	1	281	Risk Ratio (M‐H, Random, 95% CI)	1.31 [0.57, 3.03]
43.2 More than 400 µg (0.4 mg) folic acid per day	4	7110	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.86, 1.31]
44 Miscarriage (by timing of supplementation)	5	7391	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.94, 1.28]
44.1 Periconceptional period	5	7391	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.94, 1.28]
45 Miscarriage (by history of an affected pregnancy ‐recurrence)	5	7391	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.94, 1.28]
45.1 Yes	4	2033	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.68, 1.40]
45.2 No	1	5358	Risk Ratio (M‐H, Random, 95% CI)	1.15 [0.98, 1.34]
46 Miscarriage (by folate compound)	5	7391	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.94, 1.28]
46.1 Folic acid	5	7391	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.94, 1.28]
47 Miscarriage (by micronutrient compound)	5	7283	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.90, 1.28]
47.1 Folate alone	2	795	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.66, 1.44]
47.2 Folate + multiple micronutrients	4	6488	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.74, 1.42]
48 Miscarriage (by malaria setting at the time of the study)	5	7370	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.77, 1.33]
48.1 No	5	7370	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.77, 1.33]
49 Spina bifida	3	4546	Risk Ratio (M‐H, Random, 95% CI)	0.32 [0.06, 1.62]
50 Anencephaly	4	4807	Risk Ratio (M‐H, Random, 95% CI)	0.36 [0.13, 1.03]
51 Stillbirths	4	6597	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.54, 2.05]
52 Elective termination of pregnancy for fetal anomalies	4	7110	Risk Ratio (M‐H, Random, 95% CI)	0.29 [0.15, 0.56]
53 Low birthweight (less than 2500 g)	2	5048	Risk Ratio (M‐H, Random, 95% CI)	1.13 [0.84, 1.52]
54 Macrosomia (birthweight greater than 4000 g)	1	4862	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.79, 1.22]
55 Preterm birth (less than 37 weeks' gestation)	1	4862	Risk Ratio (M‐H, Random, 95% CI)	1.14 [0.93, 1.41]
56 Multiple pregnancy	4	7280	Risk Ratio (M‐H, Random, 95% CI)	1.38 [0.89, 2.14]