Multiple micronutrient supplements: GRADE tables and forest plots

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WHO antenatal care recommendations for a positive pregnancy experience: Nutritional interventions update: Multiple micronutrient supplements during pregnancy [Internet]. Geneva: World Health Organization; 2020.

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WHO antenatal care recommendations for a positive pregnancy experience: Nutritional interventions update: Multiple micronutrient supplements during pregnancy [Internet].

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Annex 3Multiple micronutrient supplements: GRADE tables and forest plots

GRADE tables for effects of multiple micronutrient supplements (MMS) vs iron and folic acid supplements (IFAS): Comparison 1

Question: Antenatal MMS with 13–15 micronutrients, including iron (27 mg to 60 mg) and folic acid compared with iron (30 mg or 60 mg) and folic acid supplements.

Setting: Low- and middle-income countries.

Source: Guideline Development Group (GDG)-specified WHO analysis based on data found in: Keats EC, Haider BA, Tam E, Bhutta ZA. Multiple-micronutrient supplementation for women during pregnancy. Cochrane Database of Systematic Reviews. 2019;3(3):CD004905 [PMC free article: PMC6418471] [PubMed: 30873598] (13).

Certainty assessment							Number of participants		Effect		Certainty	Importance
Number of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Comparison 1: 13–15 micronutrients	IFAS	Relative (95% CI)	Absolute (95% CI)	Certainty	Importance
Maternal anaemia (third trimester Hb <110 g/L)
8	randomized trials	not serious	not serious	not serious	not serious	none	27 832	27 731	RR 1.03 (0.92 to 1.15)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗⊗⊗ HIGH	CRITICAL
Maternal anaemia (third trimester Hb <110 g/L) - versus 60 mg iron plus folic acid
7	randomized trials	not serious	serious^a	not serious	not serious	none	5332	5231	RR 1.04 (0.90 to 1.21)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗⊗◯ MODERATE	CRITICAL
Maternal anaemia (third trimester Hb <110 g/L) - versus 30 mg iron plus folic acid
1	randomized trial	not serious	not serious	not serious	not serious	none	22 500	22 500	RR 1.01 (0.89 to 1.14)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗⊗⊗ HIGH	CRITICAL
Mode of delivery: Caesarean section
4	randomized trials	serious^b	not serious	not serious	serious^c	none	3299	3374	RR 1.04 (0.76 to 1.43)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗◯◯ LOW	CRITICAL
Mode of delivery: Caesarean section - versus 60 mg iron plus folic acid
3	randomized trials	serious^b	not serious	not serious	serious^c	none	2462	2542	RR 1.06 (0.75 to 1.49)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗◯◯ LOW	CRITICAL
Mode of delivery: Caesarean section - versus 30 mg iron plus folic acid
0^d							0	0	not pooled	not pooled	-	CRITICAL
Mode of delivery: Caesarean section - iron dose not specified
1	randomized trial	serious^b	not serious	not serious	serious^c	none	837	832	RR 0.96 (0.41 to 2.25)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗◯◯ LOW	CRITICAL
Maternal mortality
6	randomized trials	serious^b	not serious	not serious	serious^c	none	42 494	41 375	RR 1.06 (0.72 to 1.54)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗◯◯ LOW	CRITICAL
Maternal mortality - versus 60 mg iron plus folic acid
4	randomized trials	very serious^e	not serious	not serious	serious^c	none	4190	3389	RR 0.88 (0.41 to 1.87)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗◯◯◯ VERY LOW	CRITICAL
Maternal mortality - versus 30 mg iron plus folic acid
2	randomized trials	serious^b	not serious	not serious	serious^c	none	38 304	37 986	RR 1.12 (0.73 to 1.74)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗◯◯ LOW	CRITICAL
Small for gestational age
15	randomized trials	not serious	not serious	not serious	not serious	publication bias strongly suspected^f	50 562	49 423	RR 0.98 (0.96 to 1.00)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗⊗◯ MODERATE	CRITICAL
Small for gestational age - versus 60 mg iron plus folic acid
11	randomized trials	serious^b	not serious	not serious	not serious	publication bias strongly suspected^f	10 197	9357	RR 0.95 (0.89 to 1.01)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗◯◯ LOW	CRITICAL
Small for gestational age - versus 30 mg iron plus folic acid
3	randomized trials	not serious	not serious	not serious	not serious	none	39 528	39 234	RR 0.98 (0.96 to 1.00)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗⊗⊗ HIGH	CRITICAL
Small for gestational age - iron dose not specified
1	randomized trial	serious^b	not serious	not serious	serious^c	none	837	832	RR 0.81 (0.51 to 1.28)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗◯◯ LOW	CRITICAL
Low birthweight
16	randomized trials	not serious	not serious	not serious	not serious	none	56 814	55 689	RR 0.88 (0.86 to 0.91)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗⊗⊗ HIGH	CRITICAL
Low birthweight - versus 60 mg iron plus folic acid
11	randomized trials	serious^b	not serious	not serious	not serious	publication bias strongly suspected^f	10 197	9357	RR 0.90 (0.82 to 0.98)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗◯◯ LOW	CRITICAL
Low birthweight - versus 30 mg iron plus folic acid
4	randomized trials	not serious	not serious	not serious	not serious	none	45 780	45 500	RR 0.88 (0.85 to 0.91)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗⊗⊗ HIGH	CRITICAL
Low birthweight - iron dose not specified
1	randomized trial	serious^b	not serious	not serious	serious^c	none	837	832	RR 0.74 (0.45 to 1.22)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗◯◯ LOW	CRITICAL
Preterm births
16	randomized trials	serious^b	not serious	not serious	not serious	none	56 814	55 689	RR 0.94 (0.88 to 1.00)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗⊗◯ MODERATE	CRITICAL
Preterm births - versus 60 mg iron plus folic acid
11	randomized trials	serious^b	not serious	not serious	not serious	publication bias strongly suspected^f	10 197	9357	RR 0.99 (0.92 to 1.07)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗◯◯ LOW	CRITICAL
Preterm births - versus 30 mg iron plus folic acid
4	randomized trials	not serious	serious^g	not serious	not serious	none	45 780	45 500	RR 0.90 (0.80 to 1.01)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗⊗◯ MODERATE	CRITICAL
Preterm births - iron dose not specified
1	randomized trial	serious^b	not serious	not serious	serious^c	none	837	832	RR 0.79 (0.55 to 1.13)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗◯◯ LOW	CRITICAL
Congenital anomalies - versus 60 mg iron plus folic acid
2	randomized trials	serious^b	not serious	not serious	serious^c	none	1039	1041	RR 1.34 (0.25 to 7.12)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗◯◯ LOW	CRITICAL
Perinatal mortality
13	randomized trials	not serious	not serious	not serious	not serious	seriousⁱ	53 920	52 934	Subgroup data not pooled (tests for subgroup differences P = 0.05, I² = 73.4%)	0 fewer per 1000 (from 0 fewer to 0 fewer)	-	CRITICAL
Perinatal mortality - versus 60 mg iron plus folic acid
9	randomized trials	not serious	not serious	not serious	serious^c	none	8140	7434	RR 1.15 (0.93 to 1.42)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗⊗◯ MODERATE	CRITICAL
Perinatal mortality - versus 30 mg iron plus folic acid
4	randomized trials	not serious	not serious	not serious	not serious	serious^h	45 780	45 500	RR 0.92 (0.86 to 0.98)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗⊗◯ MODERATE	CRITICAL
Neonatal mortality
13	randomized trials	not serious	not serious	not serious	not serious	seriousⁱ	53 920	52 934	Subgroup data not pooled (tests for subgroup differences P = 0.08, I² = 68.4%)	0 fewer per 1000 (from 0 fewer to 0 fewer)	-	CRITICAL
Neonatal mortality - versus 60 mg iron plus folic acid
9	randomized trials	not serious	not serious	not serious	serious^c	none	8140	7434	RR 1.22 (0.94 to 1.56)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗⊗◯ MODERATE	CRITICAL
Neonatal mortality - versus 30 mg iron plus folic acid
4	randomized trials	not serious	not serious	not serious	not serious	serious^h	45 780	45 500	RR 0.95 (0.87 to 1.04)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗⊗◯ MODERATE	CRITICAL
Stillbirths
15	randomized trials	not serious	not serious	not serious	not serious	none	56 650	55 543	RR 0.98 (0.87 to 1.10)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗⊗⊗ HIGH	CRITICAL
Stillbirths - versus 60 mg iron plus folic acid
10	randomized trials	not serious	not serious	not serious	serious^c	none	10 033	9211	RR 1.11 (0.89 to 1.37)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗⊗◯ MODERATE	CRITICAL
Stillbirths - versus 30 mg iron plus folic acid
4	randomized trials	not serious	not serious	not serious	not serious	serious^h	45 780	45 500	RR 0.89 (0.82 to 0.97)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗⊗◯ MODERATE	CRITICAL
Stillbirths - iron dose not specified
1	randomized trials	serious^b	not serious	not serious	serious^c	none	837	832	RR 1.98 (0.37 to 10.76)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗◯◯ LOW	CRITICAL

: CI: confidence interval; RR: risk ratio
: Explanations
a: Serious unexplained heterogeneity (I² = 61%).
b: Most of the pooled effect provided by studies with some risk of bias but without a substantial proportion (i.e. < 50%) from studies with a high risk of bias (“C” studies).
c: Wide CI crossing the line of no effect.
d: No studies were found that evaluated this subgroup for this outcome.
e: Most of the pooled effect provided by “B” or “C” studies but with a substantial proportion (i.e. > 50%) from “C” studies.
f: Evident asymmetry in funnel plot.
g: Serious unexplained heterogeneity (I² = 86%).
h: The study contributing the most weight (West et al., 2014) used 27 mg iron in the IFA arm, not 30 mg.
i: Substantial subgroup differences.

Forest plots for effects of MMS vs IFAS: Comparison 1

a. Anaemia

b. Caesarean section

c. Maternal mortality

d. Small for gestational age

e. Low birthweight

f. Preterm birth

g. Congenital anomalies

h. Perinatal mortality

i. Neonatal mortality

j. Stillbirth

GRADE tables for effects of MMS vs IFAS: Comparison 2

Question: Antenatal MMS with UNIMMAP (containing 30 mg iron/0.4 mg folic acid) compared with iron (30 mg or 60 mg) and folic acid supplements.

Setting: Low- and middle-income countries.

Source: GDG-specified WHO analysis based on data found in Keats EC, Haider BA, Tam E, Bhutta ZA. Multiple-micronutrient supplementation for women during pregnancy. Cochrane Database of Systematic Reviews. 2019;3(3):CD004905 [PMC free article: PMC6418471] [PubMed: 30873598] (13).

Certainty assessment							Number of participants		Effect		Certainty	Importance
Number of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Comparison 2: UNIMMAP	IFAS	Relative (95% CI)	Absolute (95% CI)	Certainty	Importance
Maternal anaemia (third trimester Hb <110 g/L)
2	randomized trials	serious^a	not serious	not serious	not serious	none	2499	2512	RR 0.90 (0.77 to 1.05)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗⊗◯ MODERATE	CRITICAL
Maternal anaemia (third trimester Hb <110 g/L) - versus 60 mg iron plus folic acid
2	randomized trials	serious^a	not serious	not serious	not serious	none	2499	2512	RR 0.90 (0.77 to 1.05)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗⊗◯ MODERATE	CRITICAL
Maternal anaemia (third trimester Hb <110 g/L) - versus 30 mg iron plus folic acid
0^b							0	0	not pooled	not pooled	-	CRITICAL
Mode of delivery: Caesarean section
3	randomized trials	serious^a	not serious	not serious	serious^c	none	2462	2542	RR 1.06 (0.75 to 1.49)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗◯◯ LOW	CRITICAL
Mode of delivery: Caesarean section - versus 60 mg iron plus folic acid
3	randomized trials	serious^a	not serious	not serious	serious^c	none	2462	2542	RR 1.06 (0.75 to 1.49)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗◯◯ LOW	CRITICAL
Mode of delivery: Caesarean section - versus 30 mg iron plus folic acid
0^b							0	0	not pooled	not pooled	-	CRITICAL
Maternal mortality
3	randomized trials	serious^a	not serious	not serious	serious^c	none	19 089	17 971	RR 0.97 (0.63 to 1.48)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗◯◯ LOW	CRITICAL
Maternal mortality - versus 60 mg iron plus folic acid
2	randomized trials	serious^a	not serious	not serious	serious^c	none	3285	2485	RR 0.77 (0.30 to 1.97)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗◯◯ LOW	CRITICAL
Maternal mortality - versus 30 mg iron plus folic acid
1	randomized trial	serious^a	not serious	not serious	serious^c	none	15 804	15 486	RR 1.03 (0.64 to 1.66)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗◯◯ LOW	CRITICAL
Small for gestational age
9	randomized trials	serious^a	not serious	not serious	not serious	none	25106	24084	RR 0.91 (0.85 to 0.98)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗⊗◯ MODERATE	CRITICAL
Small for gestational age - versus 60 mg iron plus folic acid
7	randomized trials	not serious	not serious	not serious	not serious	none	8078	7350	RR 0.89 (0.81 to 0.97)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗⊗⊗ HIGH	CRITICAL
Small for gestational age - versus 30 mg iron plus folic acid
2	randomized trials	serious^a	not serious	not serious	not serious	none	17 028	16 734	RR 0.95 (0.85 to 1.06)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗⊗◯ MODERATE	CRITICAL
Low birthweight
10	randomized trials	serious^a	not serious	not serious	not serious	none	31 358	30 350	RR 0.87 (0.81 to 0.94)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗⊗◯ MODERATE	CRITICAL
Low birthweight - versus 60 mg iron plus folic acid
7	randomized trials	serious^a	not serious	not serious	not serious	none	8078	7350	RR 0.84 (0.75 to 0.94)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗⊗◯ MODERATE	CRITICAL
Low birthweight - versus 30 mg iron plus folic acid
3	randomized trials	serious^a	not serious	not serious	not serious	none	23 280	23 000	RR 0.89 (0.81 to 0.98)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗⊗◯ MODERATE	CRITICAL
Preterm births
10	randomized trials	serious^a	not serious	not serious	not serious	none	31 358	30 350	RR 1.00 (0.96 to 1.03)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗⊗◯ MODERATE	CRITICAL
Preterm births - versus 60 mg iron plus folic acid
7	randomized trials	serious^a	not serious	not serious	not serious	none	8078	7350	RR 1.04 (0.96 to 1.12)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗⊗◯ MODERATE	CRITICAL
Preterm births - versus 30 mg iron plus folic acid
3	randomized trials	serious^a	serious^d	not serious	not serious	none	23 280	23 000	RR 0.93 (0.82 to 1.05)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗◯◯ LOW	CRITICAL
Congenital anomalies - versus 60 mg iron plus folic acid
1	randomized trial	serious^a	not serious	not serious	serious^c	none	600	600	RR 0.99 (0.14 to 7.04)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗◯◯ LOW	CRITICAL
Perinatal mortality
9	randomized trials	serious^a	not serious	not serious	not serious	serious^e	29 465	28 573	Subgroup data not pooled (tests for subgroup differences P = 0.03, I² = 77.9%)	0 fewer per 1000 (from 0 fewer to 0 fewer)	-	CRITICAL
Perinatal mortality - versus 60 mg iron plus folic acid
6	randomized trials	not serious	not serious	not serious	serious^c	none	6185	5573	RR 1.20 (0.95 to 1.51)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗⊗◯ MODERATE	CRITICAL
Perinatal mortality - versus 30 mg iron plus folic acid
3	randomized trials	serious^a	not serious	not serious	not serious	none	23 280	23 000	RR 0.90 (0.80 to 1.01)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗⊗◯ MODERATE	CRITICAL
Neonatal mortality
9	randomized trials	serious^a	not serious	not serious	serious^c	none	29 465	28 573	Subgroup data not pooled (tests for subgroup differences P = 0.05, I² = 74.4%)	0 fewer per 1000 (from 0 fewer to 0 fewer)	-	CRITICAL
Neonatal mortality - versus 60 mg iron plus folic acid
6	randomized trials	not serious	not serious	not serious	serious^c	none	6185	5573	RR 1.25 (0.94 to 1.67)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗⊗◯ MODERATE	CRITICAL
Neonatal mortality - versus 30 mg iron plus folic acid
3	randomized trials	serious^a	not serious	not serious	not serious	none	23 280	23 000	RR 0.90 (0.78 to 1.05)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗⊗◯ MODERATE	CRITICAL
Stillbirths
10	randomized trials	serious^a	not serious	not serious	not serious	publication bias strongly suspected^f	31 358	30 350	RR 1.00 (0.86 to 1.17)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗◯◯ LOW	CRITICAL
Stillbirths - versus 60 mg iron plus folic acid
7	randomized trials	serious^a	not serious	not serious	serious^c	none	8078	7350	RR 1.10 (0.86 to 1.41)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗◯◯ LOW	CRITICAL
Stillbirths - versus 30 mg iron plus folic acid
3	randomized trials	serious^a	serious^g	not serious	not serious	none	23 280	23 000	RR 0.91 (0.77 to 1.07)	0 fewer per 1000 (from 0 fewer to 0 fewer)	⊗⊗◯◯ LOW	CRITICAL

: CI: confidence interval; RR: risk ratio
: Explanations
a: Most of the pooled effect provided by studies with some risk of bias but without a substantial proportion (i.e. < 50%) from studies with a high risk of bias (“C” studies).
b: No studies were found that included data for this subgroup analysis.
c: Wide CI crossing the line of no effect.
d: Serious unexplained heterogeneity (I² = 60%).
e: Substantial subgroup differences.
f: Evident asymmetry in funnel plot.
g: Serious unexplained heterogeneity (Chi² = 0.02).