Mass drug administration for malaria

Eugenie Poirot; Jacek Skarbinski; David Sinclair; S Patrick Kachur; Laurence Slutsker; Jimee Hwang

doi:10.1002/14651858.CD008846.pub2

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Figure 1

Study flow diagram.

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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 3

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Analysis 1.1

Comparison 1 MDA versus no MDA in areas of low endemicity (Stratified by study design), Outcome 1 Parasitaemia Prevalence: Cluster‐randomized trials.

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Analysis 1.2

Comparison 1 MDA versus no MDA in areas of low endemicity (Stratified by study design), Outcome 2 Parasitaemia Prevalence: Uncontrolled before‐and‐after studies.

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Analysis 1.3

Comparison 1 MDA versus no MDA in areas of low endemicity (Stratified by study design), Outcome 3 Gametocytaemia Prevalence: Cluster randomized trials.

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Analysis 2.1

Comparison 2 MDA versus no MDA in areas of moderate endemicity (Stratified by study design), Outcome 1 Parasitaemia Prevalence: Non‐randomized controlled studies.

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Analysis 2.2

Comparison 2 MDA versus no MDA in areas of moderate endemicity (Stratified by study design), Outcome 2 Parasitaemia Prevalence: Uncontrolled before‐and‐after studies.

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Analysis 2.3

Comparison 2 MDA versus no MDA in areas of moderate endemicity (Stratified by study design), Outcome 3 Gametocytaemia Prevalence: Non‐randomized controlled studies.

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Analysis 2.4

Comparison 2 MDA versus no MDA in areas of moderate endemicity (Stratified by study design), Outcome 4 Gametocytaemia Prevalence: Uncontrolled before‐and‐after studies.

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Analysis 3.1

Comparison 3 MDA versus no MDA in areas of high endemicity (Stratified by study design), Outcome 1 Parasitaemia Prevalence: Cluster‐randomized trials.

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Analysis 3.2

Comparison 3 MDA versus no MDA in areas of high endemicity (Stratified by study design), Outcome 2 Parasitaemia Prevalence: Non‐randomized controlled studies.

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Analysis 3.3

Comparison 3 MDA versus no MDA in areas of high endemicity (Stratified by study design), Outcome 3 Parasitaemia Prevalence: Uncontrolled before‐and‐after studies.

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Analysis 3.4

Comparison 3 MDA versus no MDA in areas of high endemicity (Stratified by study design), Outcome 4 Parasitaemia Incidence: Cluster‐randomized trials.

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Analysis 3.5

Comparison 3 MDA versus no MDA in areas of high endemicity (Stratified by study design), Outcome 5 Gametocytaemia Prevalence: Cluster‐randomized trials.

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Analysis 3.6

Comparison 3 MDA versus no MDA in areas of high endemicity (Stratified by study design), Outcome 6 Gametocytaemia Prevalence: Non‐randomized controlled studies.

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Analysis 3.7

Comparison 3 MDA versus no MDA in areas of high endemicity (Stratified by study design), Outcome 7 Gametocytaemia Prevalence: Uncontrolled before‐and‐after studies.

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Analysis 3.8

Comparison 3 MDA versus no MDA in areas of high endemicity (Stratified by study design), Outcome 8 Anaemia Prevalence: Cluster‐randomized trials.

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Analysis 3.9

Comparison 3 MDA versus no MDA in areas of high endemicity (Stratified by study design), Outcome 9 Mortality: Cluster‐randomized trials.

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Analysis 4.1

Comparison 4 MDA + vector control versus no intervention in areas of moderate endemicity (Stratified by study design), Outcome 1 Parasitaemia Prevalence: Non‐randomized controlled studies.

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Analysis 4.2

Comparison 4 MDA + vector control versus no intervention in areas of moderate endemicity (Stratified by study design), Outcome 2 Parasitaemia Prevalence: Uncontrolled before‐and‐after studies.

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Analysis 4.3

Comparison 4 MDA + vector control versus no intervention in areas of moderate endemicity (Stratified by study design), Outcome 3 Gametocytaemia Prevalence: Uncontrolled before‐and‐after studies.

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Analysis 5.1

Comparison 5 MDA + vector control versus no intervention in areas of high endemicity (Stratified by study design), Outcome 1 Parasitaemia Prevalence: Non‐randomized controlled studies.

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Analysis 5.2

Comparison 5 MDA + vector control versus no intervention in areas of high endemicity (Stratified by study design), Outcome 2 Parasitaemia Prevalence: Uncontrolled before‐and‐after studies.

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Analysis 5.3

Comparison 5 MDA + vector control versus no intervention in areas of high endemicity (Stratified by study design), Outcome 3 Gametocytaemia Prevalence: Non‐randomized controlled studies.

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Analysis 5.4

Comparison 5 MDA + vector control versus no intervention in areas of high endemicity (Stratified by study design), Outcome 4 Gametocytaemia Prevalence: Uncontrolled before‐and‐after studies.

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Analysis 6.1

Comparison 6 Parasitaemia Incidence studies, Outcome 1 MDA versus no MDA: Uncontrolled before‐and‐after studies.

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Analysis 6.2

Comparison 6 Parasitaemia Incidence studies, Outcome 2 MDA + vector control versus no MDA: Uncontrolled before‐and‐after studies.

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Analysis 7.1

Comparison 7 MDA versus no MDA in areas of moderate and high endemicity (Stratified by study design; subgrouped by 8‐aminoquinoline), Outcome 1 Parasitaemia Prevalence during MDA.

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Analysis 7.2

Comparison 7 MDA versus no MDA in areas of moderate and high endemicity (Stratified by study design; subgrouped by 8‐aminoquinoline), Outcome 2 Parasitaemia Prevalence 1‐3 months post MDA.

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Analysis 7.3

Comparison 7 MDA versus no MDA in areas of moderate and high endemicity (Stratified by study design; subgrouped by 8‐aminoquinoline), Outcome 3 Parasitaemia Prevalence during MDA.

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Analysis 7.4

Comparison 7 MDA versus no MDA in areas of moderate and high endemicity (Stratified by study design; subgrouped by 8‐aminoquinoline), Outcome 4 Parasitaemia Prevalence <1 month post MDA.

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Analysis 7.5

Comparison 7 MDA versus no MDA in areas of moderate and high endemicity (Stratified by study design; subgrouped by 8‐aminoquinoline), Outcome 5 Parasitaemia Prevalence 1‐3 months post MDA.

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Analysis 7.6

Comparison 7 MDA versus no MDA in areas of moderate and high endemicity (Stratified by study design; subgrouped by 8‐aminoquinoline), Outcome 6 Parasitaemia Prevalence 4‐6 months post MDA.

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Analysis 8.1

Comparison 8 MDA versus no MDA for all endemicity levels (Stratified by study design; subgrouped by plasmodium species), Outcome 1 Parasitaemia Prevalence at baseline.

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Analysis 8.2

Comparison 8 MDA versus no MDA for all endemicity levels (Stratified by study design; subgrouped by plasmodium species), Outcome 2 Parasitaemia Prevalence during MDA.

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Analysis 8.3

Comparison 8 MDA versus no MDA for all endemicity levels (Stratified by study design; subgrouped by plasmodium species), Outcome 3 Parasitaemia Prevalence <1 month post MDA.

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Analysis 8.4

Comparison 8 MDA versus no MDA for all endemicity levels (Stratified by study design; subgrouped by plasmodium species), Outcome 4 Parasitaemia Prevalence 1‐3 months post MDA.

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Analysis 8.5

Comparison 8 MDA versus no MDA for all endemicity levels (Stratified by study design; subgrouped by plasmodium species), Outcome 5 Parasitaemia Prevalence 4‐6 months post MDA.

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Analysis 8.6

Comparison 8 MDA versus no MDA for all endemicity levels (Stratified by study design; subgrouped by plasmodium species), Outcome 6 Parasitaemia Prevalence >12 months post MDA.

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Table 1. Overview of studies conducted in areas of low endemicity

Study ID	Design	Country	Year	Endemicity	MDA group						Control group/ Baseline
Study ID	Design	Country	Year	Endemicity	Drug (dose)	Interval	No. of rounds	Population targeted	Coverage	Co‐intervention	Control group/ Baseline
Shekalaghe 2011	CRT	Tanzania	2008	0%*	AS (4 mg/kg/day for 3 days) +SP (25 mg/1.25 mg on day 1) +PQ (0.75 mg on day 3)	‐	1	1110	93%	Background ITN use	Placebo + Background ITN use
Malaria_Taiwan 1991	BAS	Taiwan	1955	3‐4%*	CQ (12 mg/kg)	‐	1	1520	ND	IRS	IRS
CRT = Cluster‐randomized trial; BAS = Uncontrolled before‐and‐after study; AS = Artesunate; SP = Sulfadoxine‐Pyrimethamine; PQ = Primaquine; CQ = Chloroquine; ND = Not described; IRS = Indoor Residual Spraying. *In all ages

Table 1. Overview of studies conducted in areas of low endemicity

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Table 2. Overview of studies conducted in areas of moderate endemicity

Study ID	Design	Country	Year	Endemicity	MDA group						Control group/baseline
Study ID	Design	Country	Year	Endemicity	Drug (dose)	Interval	No. of rounds	Population targeted	Coverage	Co‐intervention	Control group/baseline
Najera 1973	N‐RCS	Nigeria	1966‐68	29%*	CQ (450 mg) + Pyr (45 mg)	2 months	11	52,000	78‐92%	IRS	IRS alone
Singh 1953	N‐RCS	India	1952‐53	22%*	AQ (600 mg)	2 weeks	5	125	ND	None	No intervention
Jones 1958	N‐RCS	Kenya	1952‐53	34%†	Pyr (100 mg)	6 months	3	3721‐4500	ND	None	No intervention
Roberts 1964	N‐RCS	Kenya	1953	28%*	Pyr (50 mg)	‐	1	101,000	95%	None	No intervention
Roberts 1964	N‐RCS	Kenya	1954	22%*	Pyr (50 mg)	‐	1	99,000	95%	None	No intervention
Archibald 1960	BAS	Nigeria	1958	29%†	CQ (600 mg) + Pyr (25 mg)	1 month	5	10,000	ND	IRS	IRS
Cavalie 1962	BAS	Cameroon	1960‐61	20%†	CQ (600 mg) + Pyr (50 mg)	4 months	2	22,500	76‐92%	IRS	IRS
Houel 1954	BAS	Morocco	1953	14%†	Pyr (100 mg)	‐	1	9999	ND	IRS	IRS
Metselaar 1961	BAS	New Guinea	1958‐59	13‐21%†	CQ (450 mg) +Pyr (50 mg)	1 week	6	2500	90%	IRS	IRS
Jones 1954	BAS	Kenya	1952‐53	35%†	Pyr (100 mg)	6 months	3	3721	ND	None	‐
van Dijk 1961	BAS	Papua New Guinea	1960	39%†	CQ (450 mg)	4 weeks	11	1250	97%	None	‐
Comer 1971	BAS	Panama	1965‐68	17%*	Pyr (50 mg / 75 mg) + PQ (40 mg)	2 weeks	49	1709	61‐87%	None	‐
N‐RCS = Non‐randomized controlled study; BAS = Uncontrolled before‐and‐after study; AQ = Amodiaquine; Pyr = Pyrimethamine; CQ = Chloroquine; PQ = Primaquine; ND = Not described; IRS = Indoor Residual Spraying. *In all ages †Amongst children only

Table 2. Overview of studies conducted in areas of moderate endemicity

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Table 3. Overview of studies conducted in areas of high endemicity

Study ID	Design	Country	Year	Endemicity	MDA group						Control group
Study ID	Design	Country	Year	Endemicity	Drug (dose)	Interval	No. of rounds	Population targeted	Coverage	Co‐intervention	Control group
Von Seidlein 2003	CRT	Gambia	1999	43%†	AS (4 mg/kg/day for 3 days) +SP (25 mg/1.25 mg on day 1)	‐	1	1969	89%	None	Placebo
Molineaux 1980	N‐RCS	Nigeria	1970‐75	46%*	SP (500 mg/25 mg)	10 weeks	9‡	14,129	85%	IRS	IRS alone
Molineaux 1980	N‐RCS	Nigeria	1970‐75	46%*	SP (500 mg/25 mg)	2‐10 weeks	23‡	1810	85%	IRS	IRS alone
Escudie 1962	N‐RCS	Burkina Faso	1960‐61	56.1%†	CQ (600 mg)/AQ (600 mg) +PQ (15 mg)	1 month	8	1890	75‐92%	None	No intervention
					CQ (600 mg)/AQ (600 mg) +PQ (15 mg)	2 weeks	15	2560	84‐97%	None	No intervention
					CQ (600 mg)/AQ (600 mg) +PQ (15 mg)	1 month	8	5400	81‐92%	IRS	IRS alone‐
					CQ (600 mg)/AQ (600 mg) +PQ (15 mg)	2 weeks	15	3490	82‐94%	IRS	IRS alone‐
Schneider 1961	N‐RCS	Burkina Faso	1960‐61	59%†	CQ (600 mg)/AQ (600 mg) +PQ (15 mg)	2 weeks	15	2500	90%	None	No intervention
Archibald 1960	BAS	Nigeria	1957‐59	64%†	CQ (600 mg) +Pyr (25 mg)	6 months	4	1300	ND	IRS	IRS‐
Cavalie 1962	BAS	Cameroon	1960‐61	65%*	CQ (600 mg) +Pyr (50 mg)	‐	1	7000	100%	IRS	IRS
Gaud 1953	BAS	Morocco	1952	42%*	AQ (600 mg)	‐	1	3000	ND	None	‐
Ricosse 1959	BAS	Burkina Faso	1958‐59	56%†	Pyr (50 mg)	2 weeks	8	3000	82‐91%	None	‐
Song 2010	BAS	Cambodia	2003‐06	56%†	AS (125 mg/day for 2 days) + PIP (750 mg/day for 2 days) + PQ (9 mg every 10 days)	‐	1	3653	ND	None	‐
Hii 1987	BAS	Malaysia	1984‐85	56%†	SP (1500 mg / 75 mg) + PQ (30 mg)	‐	1	148	76%	None	‐
Kligler 1931	BAS	Palestine	1930	67%†	Plas (30 mg) + Q (900 mg) twice daily for 5 days	3 weeks	3	953	79%	None	‐
CRT= Cluster‐randomized trial; N‐RCS = Non‐randomized controlled study; BAS = Uncontrolled before‐and‐after study; AS = Artesunate; SP = Sulfadoxine (or sulfalene)‐Pyrimethamine; Pyr = Pyrimethamine; CQ = Chloroquine; AQ = Amodiaquine; PQ = Primaquine; Pip = Piperaquine; Plas = Plasmochin; Q = Quinine; ND = Not described; IRS = Indoor Residual Spraying. *In all ages †Amongst children only ‡Estimated from the data provided

Table 3. Overview of studies conducted in areas of high endemicity

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Table 4. Overview of studies comparing MDA + vector control versus no intervention

Study ID	Design	Country	Year	Endemicity	MDA group						Control group/ baseline
Study ID	Design	Country	Year	Endemicity	Drug (dose)	Interval	No. of rounds	Population targeted	Coverage	Co‐intervention	Control group/ baseline
Moderate Endemicity
Kaneko 2000	N‐RCS	Vanuatu	1991‐99	29%*	CQ (600 mg) + SP (1500 mg/75 mg) + PQ (45 mg) weeks 1, 5, and 9; CQ (300 mg) + PQ (45 mg) weeks 2, 3, 4, 6, 7, and 8	1 week	9	718	79‐92%	ITN + larvivorous fish	low baseline coverage of ITNs
Ricosse 1959	BAS	Burkina Faso	1958‐59	15%†	Pyr (50 mg)	2 weeks	8	5000	82‐91%	IRS	None
De Zulueta 1961	BAS	Uganda	1959‐60	34%†	CQ (600 mg) + Pyr (50 mg)	3 months	4	30,384	80%	IRS	None
De Zulueta 1964	BAS	Uganda	1960	23%†	CQ (600 mg) + Pyr (50 mg)	5 months	2	16,000	50%	IRS	None
Paik 1974a	BAS	Solomon Islands	1972	28%*	CQ (600 mg) +Pyr (50 mg)	1 month	4	ND	90%	IRS	None
High Endemicity
Molineaux 1980	N‐RCS	Nigeria	1970‐75	46%*	SP (500 mg/25 mg)	10 weeks	9‡	14,129	85%	IRS	None
Molineaux 1980	N‐RCS	Nigeria	1970‐75	46%*	SP (500 mg/25 mg)	2‐10 weeks	23‡	1810	85%	IRS	None
Escudie 1962	N‐RCS	Burkina Faso	1960‐61	56.1%†	CQ (600 mg) /AQ (600 mg) + PQ (15 mg)	1 month	8	5400	81‐92%	IRS	None
Escudie 1962	N‐RCS	Burkina Faso	1960‐61	56.1%†	CQ (600 mg)/AQ (600 mg) + PQ (15 mg)	2 weeks	15	3490	82‐94%	IRS	None
Schneider 1961	N‐RCS	Burkina Faso	1960‐61	59%†	AQ (600 mg) + PQ (15 mg)	2 weeks	8	3525	ND	IRS	None
Metselaar 1961	BAS	New Guinea	1958‐59	46%*	CQ (450 mg) +Pyr (50 mg)	1 week	6	2500	90%	IRS	None
Hii 1987	BAS	Malaysia	1984‐85	46%†	SP (1500 mg / 75 mg) + PQ (30 mg)	‐	1	754	87%	ITN	None
N‐RCS = Non‐randomized controlled study; BAS = Uncontrolled before‐and‐after study; AQ = Amodiaquine; Pyr = Pyrimethamine; CQ = Chloroquine; SP = Sulfadoxine (or sulfalene)‐Pyrimethamine; PQ = Primaquine; ND = Not described; IRS = Indoor Residual Spraying; ITN = Insecticide Treated Net. *In all ages †Amongst children only ‡Estimated from the data provided

Table 4. Overview of studies comparing MDA + vector control versus no intervention

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Table 5. Overview of studies assessing parasitaemia incidence only

Study ID	Design	Country	Year	Baseline Incidence	MDA group						Baseline
Study ID	Design	Country	Year	Baseline Incidence	Drug (dose)	Interval	No. of rounds	Population targeted	Coverage	Co‐intervention	Baseline
Garfield 1983	BAS	Nicaragua	1981‐82	0.4/1000	CQ (500 mg/day for 3 days) + PQ (15 mg/day for 3 days)	‐	1	2,300,000	70‐80%	Larval control	None
Simeons 1938	BAS	India	1935	156/1000	Ate (300 mg) + Plas (60 mg)	‐	1	5650	100%	Larval control	None
Gabaldon 1959	BAS	Venezuela	1956‐57	0.4/1000	Pyr (50 mg)	1 week	24	111,995	ND	IRS	IRS
Kondrashin 1985	BAS	India	1981	4/1000	CQ (600 mg) + PQ (45 mg)	6 months	2	51,325	85%	IRS	IRS
Paik 1974b	BAS	Solomon Islands	1972‐73	15/1000	CQ (300 mg/day for 5 days) + PQ (15 mg/day for 5 days)	3 months	3	1200	90%	None	‐
Cáceres Garcia 2008	BAS	Venezuela	2002‐07	22/1000	CQ (25 mg/kg over 3 days) +PQ (3.5 mg/kg over 7 days)	‐	1	22,941	77%	None	‐
BAS = Uncontrolled before‐and‐after study; PQ = Primaquine; CQ = Chloroquine; Pyr = Pyrimethamine; Plas = Plasmochin; Ate = Atebrin; ND = Not described; IRS = Indoor Residual Spraying. †Amongst children only

Table 5. Overview of studies assessing parasitaemia incidence only

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Table 6. Summary of findings table: Mass drug administration in areas of low endemicity (≤5%)

Mass drug administration in areas of low endemicity
Patient or population: People living in malaria endemic areas Settings: Areas with low (≤5%) endemicity Intervention: Mass drug administration (any regimen) Comparison: Placebo or no intervention (or baseline data in before‐and‐after studies)
Timepoint post MDA	Outcomes	Study design	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of studies	Quality of the evidence (GRADE)
			Assumed risk	Corresponding risk
			Control	MDA
<1 month	Parasite prevalence	Before‐and‐after	50 per 1000¹	14 per 1000 (7 to 25)	RR 0.27 (0.14 to 0.50)	1 study	⊕⊝⊝⊝ very low^2,3,4,5
	Parasite incidence	‐	‐	‐	‐	0 studies	^‐
	Gametocyte prevalence	‐	‐	‐	‐	0 studies²	‐
12 months	Parasite prevalence	Before‐and‐after	50 per 1000¹	1 per 1000 (0 to 6)	RR 0.02 (0 to 0.12)	1 study	⊕⊝⊝⊝ very low^2,3,4,5
	Parasite incidence	‐	‐	‐	‐	0 studies	‐
	Gametocyte prevalence	‐	‐	‐	‐	0 studies²	‐
The assumed risk has been set at 5%. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk Ratio.
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: 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. Very low quality: We are very uncertain about the estimate.
¹ For illustrative purposes the control group prevalence has been set at 5%. ² Only one cluster‐randomized trial from Tanzania has evaluated MDA in a setting of low endemicity and this study recorded no episodes of parasitaemia or gametocytaemia at baseline or throughout six months follow‐up in either the control or intervention groups. ³ Downgrade by 1 for serious risk of bias: This study is uncontrolled, and so at very high risk of confounding. ⁴ Downgraded by 1 for serious indirectness: This singe study from Taiwan reported the effects of MDA administered as a single dose of chloroquine (12 mg/kg). Further trials are needed from a variety of settings to have confidence in the results. ⁵ Compared to baseline data a large reduction in parasite prevalence was seen at 1 month and 12 months post‐MDA.

Table 6. Summary of findings table: Mass drug administration in areas of low endemicity (≤5%)

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Table 7. Summary of findings table: Mass drug administration in areas of moderate endemicity (6 to 39%)

Mass drug administration in areas of moderate endemicity
Patient or population: People living in malaria endemic areas Settings: Areas with moderate malaria endemicity (6‐39%) Intervention: Mass drug administration (any regimen) Comparison: No intervention (or baseline data in before‐and‐after studies)
Timepoint post MDA	Outcomes	Study design	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of studies	Quality of the evidence (GRADE)
			Assumed risk	Corresponding risk
			Control	MDA
<1 month	Parasitaemia prevalence	Non‐randomized	250 per 1000	5 per 1000 (3 to 15)	RR 0.03 (0.01 to 0.08)	3 studies	⊕⊕⊕⊝ moderate^1,2,3,4
	Parasitaemia prevalence	Before‐and‐after	250 per 1000	73 per 1000 (43 to 120)	RR 0.29 (0.17 to 0.48)	3 studies	⊕⊕⊝⊝ low^5,3,6
	Parasitaemia incidence	‐		‐	‐	0 studies	‐
	Gametocytaemia prevalence	Non‐randomized	100 per 1000	28 per 1000 (10 to 82)	RR 0.28 (0.1 to 0.82)	1 study	⊕⊝⊝⊝ very low^1,7
	Gametocytaemia prevalence	Before‐and‐after	100 per 1000	47 per 1000 (25 to 87)	RR 0.47 (0.25 to 0.87)	3 studies	⊕⊕⊝⊝ low^5,6,8
4‐6 months	Parasitaemia prevalence	Non‐randomized	250 per 1000	70 per 1000 (53 to 95)	RR 0.18 (0.10 to 0.33)	2 studies	⊕⊕⊝⊝ low^1,3,9
	Parasitaemia prevalence	Before‐and‐after	250 per 1000	438 per 1000 (103 to 1000)	RR 1.75 (0.41 to 7.41)	2 studies	⊕⊝⊝⊝ very low^5,10,11
	Parasitaemia incidence	‐	‐	‐	‐	0 studies	‐
	Gametocytaemia prevalence	Non‐randomized	100 per 1000	52 per 1000 (24 to 111)	RR 0.52 (0.24 to 1.11)	1 study	⊕⊝⊝⊝ very low¹²
	Gametocytaemia prevalence	Before‐and‐after	100 per 1000	35 per 1000 (12 to 101)	RR 0.35 (0.12 to 1.01)	1 study	⊕⊝⊝⊝ very low¹²
The assumed risk for parasitaemia prevalence has been set at 25%. Gametocytaemia prevalence was generally lower in the included studies and the assumed risk has therefore been set at 10%. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk Ratio.
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: 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. Very low quality: We are very uncertain about the estimate.
¹ No serious risk of bias: Although there were some differences in prevalence at baseline, these were much smaller in size than the large effects seen post‐intervention. ² No serious indirectness: These three studies were conducted in Kenya in 1953 and 1954 (pyrimethamine administered every six months for three rounds), and in India in 1953 (amodiaquine administered every two weeks for five rounds). A fourth study from Nigeria in 1973 reported a similar reduction in prevalence during an ongoing MDA program. Although these studies are old, similar effects might be expected today with effective anti‐malarials. ³ No serious inconsistency: Consistent and large reductions were seen in these studies. ⁴ Upgraded by 1 for large effect size: Very large effects were seen consistently across both controlled and uncontrolled studies. ⁵ No serious risk of bias: These studies are uncontrolled, and so are at very high risk of confounding. However, as the GRADE approach automatically downgrades non‐randomized controlled studies by two levels for risk of bias we did not further downgrade. ⁶ No serious indirectness: These three studies were conducted between 1953 and 1961, and administered MDA as: Pyrimethamine once only (Morocco), chloroquine plus pyrimethamine every month for five rounds (Nigeria) and chloroquine every four weeks for 11 rounds (Papua New Guinea). Although these studies are old, similar effects might be expected today with effective anti‐malarials. ⁷ Downgraded by 1 for serious indirectness: This single trial in Kenya gave pyrimethamine every six months for three rounds. Different regimens may have different effects and primaquine, a drug with gametocytocidal properties, was not given. One further trial from Nigeria in the 1960s, which only reported on prevalence during an ongoing MDA programme, also administered MDA without primaquine. ⁸ No serious inconsistency: Gametocyte prevalence was lower post‐intervention in all four trials, however there was variation in the size of this effect. ⁹ No serious indirectness: These two studies are both from Kenya in the 1950s, and both administer MDA as pyrimethamine alone. One study continued follow‐up for > 6 months when an effect was still present. ¹⁰ No serious indirectness: These two studies were conducted between 1959 and 1961, and administered MDA as: chloroquine plus pyrimethamine every four months for two rounds (Cameroon), chloroquine plus pyrimethamine every month for five rounds (Nigeria). ¹¹ Downgraded by 1 for serious inconsistency: At this time point results were mixed. One study found a higher prevalence at this time point and one found no difference. ¹² Downgraded by 1 for serious indirectness: This single trial found no substantial difference between groups at 4‐6 months. Modern trials with different regimens may have different effects. This study did not administer primaquine as part of MDA.

Table 7. Summary of findings table: Mass drug administration in areas of moderate endemicity (6 to 39%)

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Table 8. Summary of findings table: Mass drug administration in areas of high endemicity (≥40%)

Mass drug administration in areas of high endemicity
Patient or population: People living in malaria endemic areas Settings: Areas with high malaria endemicity (≥ 40%) Intervention: Mass drug administration (any regimen) Comparison: No intervention (or baseline data in before‐and‐after studies)
Timepoint post MDA	Outcomes	Study design	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of studies	Quality of the evidence (GRADE)
			Assumed risk	Corresponding risk
			Control	MDA
< 1 month	Parasitaemia prevalence	Cluster‐randomized	500 per 1000	410 per 1000 (335 to 505)	RR 0.82 (0.67 to 1.01)	1 study	⊕⊕⊝⊝ low^1,2,3
		Non‐randomized	500 per 1000	85 per 1000 (50 to 140)	RR 0.17 (0.10 to 0.28)	3 studies	⊕⊕⊕⊝ moderate^4,5,6,7
		Before‐and‐after	500 per 1000	185 per 1000 (140 to 245)	RR 0.37 (0.28 to 0.49)	4 studies	⊕⊕⊝⊝ low^8,9,10
	Parasitaemia incidence	Cluster‐randomized	60 per 1000	25 per 1000 (14 to 44)	RR 0.41 (0.23 to 0.73)	1 study	⊕⊕⊕⊝ moderate^1,2,11
	Gametocytaemia prevalence	Non‐randomized	100 per 1000	16 per 1000 (8 to 30)	RR 0.16 (0.08 to 0.30)	3 studies	⊕⊕⊕⊝ moderate^4,5,6,7
	Gametocytaemia prevalence	Before‐and‐after	100 per 1000	38 per 1000 (13 to 108)	RR 0.38 (0.13 to 1.08)	3 studies	⊕⊕⊝⊝ low^8,12
4‐6 months	Parasitaemia prevalence	Cluster‐randomized	500 per 1000	580 per 1000 (465 to 720)	RR 1.16 (0.93 to 1.44)	1 study	⊕⊕⊕⊝ moderate^1,2,13
		Non‐randomized	‐	‐	‐	0 studies	‐
		Before‐and‐after	500 per 1000	205 per 1000 (120 to 360)	RR 0.41 (0.24 to 0.72)	3 studies	⊕⊕⊝⊝ low^8,14
	Parasitaemia incidence	Cluster‐randomized	60 per 1000	67 per 1000 (52 to 85)	RR 1.11 (0.87 to 1.41)	1 study	⊕⊕⊕⊝ moderate^1,2,13
	Gametocytaemia prevalence	Cluster‐randomized	100 per 1000	107 per 1000 (62 to 185)	RR 1.07 (0.62 to 1.85)	1 study	⊕⊕⊝⊝ low^1,2,3
		Non‐randomized	‐	‐	‐	0 studies	‐
		Before‐and‐after	100 per 1000	35 per 1000 (10 to 128)	RR 0.35 (0.10 to 1.28)	2 studies	⊕⊝⊝⊝ very low^8,15
The assumed risk for parasitaemia prevalence has been set at 50%. Gametocytaemia prevalence was generally lower in the included studies and the assumed risk has therefore been set at 10%. The assumed risk for parasitaemia incidence is taken from the control group of the single trial. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio.
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: 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. Very low quality: We are very uncertain about the estimate.
¹ No serious risk of bias: This cluster‐randomized trial was at low risk of bias. ² Downgraded by 1 for serious indirectness: This single study from the Gambia in 1999 administered MDA as AS+SP. The findings may not be easily generalized to other settings, or to alternative MDA regimens. The first time point measured post‐MDA was 1‐3 months. ³ Downgraded by 1 for serious imprecision: The result was not statistically significant but the 95% CI is wide and includes important effects. ⁴ No serious risk of bias: Although there was some evidence of baseline imbalance between the intervention and control areas, these were generally of smaller magnitude than the effects seen. ⁵ No serious indirectness: The data presented here were measured during ongoing multiple‐round MDA programmes, not at one month post‐intervention. The studies were conducted in Burkina Faso in 1961 (CQ or AQ plus PQ every two to four weeks), and Nigeria in 1975 (SP given every two weeks or every 10 weeks). Although these studies are old, similar effects might be expected today with effective anti‐malarials. ⁶ No serious inconsistency: The observed effects were consistently large in all three trials. ⁷ Upgraded by 1 for the large effect size: Large effects seen in all trials. ⁸ No serious risk of bias: These studies are uncontrolled, and so are at very high risk of confounding. However, as the GRADE approach automatically downgrades non‐randomized controlled studies by two levels for risk of bias we did not further downgrade. ⁹ No serious indirectness: These four studies were conducted in Palestine in 1930 (plasmoquine plus quinine every three weeks for three rounds), Burkina Faso in 1959 (pyrimethamine every two weeks), in Malaysia in 1985 (SP + PQ once only), and Cambodia in 2006 (AS + piperaquine once only plus PQ every 10 days). ¹⁰ No serious inconsistency: Three studies observed large effects, while one small study found no effect. ¹¹ No serious imprecision: The result is statistically significant. ¹² No serious indirectness: Two large studies found large effects in Burkina Faso in the 1950s (pyrimethamine every 2 weeks for 8 rounds), and Palestine in the 1930s (plasmoquine plus quinine every three weeks for three rounds). One small study from Malaysia in the 1980s found no effect. ¹³ No serious imprecision: The 95% CI excludes clinically important reductions at this time point. ¹⁴ No serious inconsistency: The two large studies from Palestine and Cambodia still demonstrated a large reduction at 4‐6 months while the small study from Malaysia found no difference ¹⁵ Downgraded by 1 for serious indirectness: Benefits beyond three months have only been demonstrated in this single study from Cambodia. MDA was administered as artesunate plus piperaquine once only followed by primaquine every 10 days for six months.

Table 8. Summary of findings table: Mass drug administration in areas of high endemicity (≥40%)

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Comparison 1. MDA versus no MDA in areas of low endemicity (Stratified by study design)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Parasitaemia Prevalence: Cluster‐randomized trials Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 At baseline	1	496	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.2 <1 month post MDA	1	484	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.3 1‐3 months post MDA	1	794	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.4 4‐6 months post MDA	1	660	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2 Parasitaemia Prevalence: Uncontrolled before‐and‐after studies Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 <1 month post MDA	1	3039	Risk Ratio (M‐H, Random, 95% CI)	0.27 [0.14, 0.50]
2.2 >12 months post MDA	1	3509	Risk Ratio (M‐H, Random, 95% CI)	0.02 [0.00, 0.12]
3 Gametocytaemia Prevalence: Cluster randomized trials Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 At baseline	1	496	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.2 < 1 month post MDA	1	484	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.3 1‐3 months post MDA	1	794	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.4 4‐6 months post MDA	1	660	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 1. MDA versus no MDA in areas of low endemicity (Stratified by study design)

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Comparison 2. MDA versus no MDA in areas of moderate endemicity (Stratified by study design)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Parasitaemia Prevalence: Non‐randomized controlled studies Show forest plot	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 At baseline	4	3123	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.43, 1.24]
1.2 During MDA	1	47014	Risk Ratio (M‐H, Random, 95% CI)	0.27 [0.25, 0.28]
1.3 < 1 month post MDA	3	1934	Risk Ratio (M‐H, Random, 95% CI)	0.03 [0.01, 0.08]
1.4 1‐3 months post MDA	2	1557	Risk Ratio (M‐H, Random, 95% CI)	0.15 [0.10, 0.23]
1.5 4‐6 months post MDA	2	1610	Risk Ratio (M‐H, Random, 95% CI)	0.18 [0.10, 0.33]
1.6 7‐12 months post MDA	1	600	Risk Ratio (M‐H, Random, 95% CI)	0.19 [0.11, 0.33]
2 Parasitaemia Prevalence: Uncontrolled before‐and‐after studies Show forest plot	7		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 During MDA	2	7965	Risk Ratio (M‐H, Random, 95% CI)	0.17 [0.02, 1.47]
2.2 <1 month post MDA	3	3096	Risk Ratio (M‐H, Random, 95% CI)	0.29 [0.17, 0.48]
2.3 1‐3 months post MDA	4	7925	Risk Ratio (M‐H, Random, 95% CI)	0.16 [0.08, 0.31]
2.4 4‐6 months post MDA	2	3797	Risk Ratio (M‐H, Random, 95% CI)	1.75 [0.41, 7.41]
3 Gametocytaemia Prevalence: Non‐randomized controlled studies Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 At baseline	2	1622	Risk Ratio (M‐H, Random, 95% CI)	1.40 [0.76, 2.57]
3.2 During MDA	1	47014	Risk Ratio (M‐H, Random, 95% CI)	0.48 [0.42, 0.54]
3.3 <1 month post MDA	1	433	Risk Ratio (M‐H, Random, 95% CI)	0.28 [0.10, 0.82]
3.4 1‐3 months post MDA	1	357	Risk Ratio (M‐H, Random, 95% CI)	0.17 [0.03, 0.86]
3.5 4‐6 months post MDA	1	410	Risk Ratio (M‐H, Random, 95% CI)	0.52 [0.24, 1.11]
4 Gametocytaemia Prevalence: Uncontrolled before‐and‐after studies Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

4.1 <1 month post MDA	3	3096	Risk Ratio (M‐H, Random, 95% CI)	0.47 [0.25, 0.87]
4.2 1‐3 months post MDA	1	294	Risk Ratio (M‐H, Random, 95% CI)	0.36 [0.12, 1.12]
4.3 4‐6 months post MDA	1	204	Risk Ratio (M‐H, Random, 95% CI)	0.35 [0.12, 1.01]

Comparison 2. MDA versus no MDA in areas of moderate endemicity (Stratified by study design)

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Comparison 3. MDA versus no MDA in areas of high endemicity (Stratified by study design)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Parasitaemia Prevalence: Cluster‐randomized trials Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 At baseline	1	1376	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.86, 1.10]
1.2 1‐3 months post MDA	1	1800	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.67, 1.01]
1.3 4‐6 months post MDA	1	1089	Risk Ratio (M‐H, Random, 95% CI)	1.16 [0.93, 1.44]
2 Parasitaemia Prevalence: Non‐randomized controlled studies Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 At baseline	3	9395	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.70, 1.00]
2.2 During MDA	3	12561	Risk Ratio (M‐H, Random, 95% CI)	0.17 [0.11, 0.27]
2.3 1‐3 months post MDA	2	7197	Risk Ratio (M‐H, Random, 95% CI)	0.52 [0.33, 0.81]
3 Parasitaemia Prevalence: Uncontrolled before‐and‐after studies Show forest plot	7		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 During MDA	2	2011	Risk Ratio (M‐H, Random, 95% CI)	0.10 [0.03, 0.34]
3.2 <1 month post MDA	4	3863	Risk Ratio (M‐H, Random, 95% CI)	0.37 [0.28, 0.49]
3.3 1‐3 months post MDA	4	5132	Risk Ratio (M‐H, Random, 95% CI)	0.35 [0.15, 0.84]
3.4 4‐6 months post MDA	3	2979	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.24, 0.72]
3.5 7‐12 months post MDA	1	75	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.43, 1.20]
3.6 >12 months post MDA	1	2375	Risk Ratio (M‐H, Random, 95% CI)	0.10 [0.07, 0.12]
4 Parasitaemia Incidence: Cluster‐randomized trials Show forest plot	1		Rate Ratio (Random, 95% CI)	0.84 [0.53, 1.32]

4.1 < 1 month post MDA	1		Rate Ratio (Random, 95% CI)	0.41 [0.23, 0.74]
4.2 1‐3 months post MDA	1		Rate Ratio (Random, 95% CI)	1.03 [0.75, 1.41]
4.3 4‐6 months post MDA	1		Rate Ratio (Random, 95% CI)	1.11 [0.84, 1.45]
5 Gametocytaemia Prevalence: Cluster‐randomized trials Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

5.1 At baseline	1	1376	Risk Ratio (M‐H, Random, 95% CI)	0.66 [0.33, 1.29]
5.2 4‐6 months post MDA	1	1414	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.62, 1.85]
6 Gametocytaemia Prevalence: Non‐randomized controlled studies Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

6.1 At baseline	3	9395	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.55, 0.95]
6.2 During MDA	3	12561	Risk Ratio (M‐H, Random, 95% CI)	0.17 [0.10, 0.28]
6.3 1‐3 months post MDA	2	7197	Risk Ratio (M‐H, Random, 95% CI)	0.55 [0.28, 1.07]
7 Gametocytaemia Prevalence: Uncontrolled before‐and‐after studies Show forest plot	5		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

7.1 During MDA	2	2011	Risk Ratio (M‐H, Random, 95% CI)	0.35 [0.09, 1.40]
7.2 <1 month post MDA	3	2582	Risk Ratio (M‐H, Random, 95% CI)	0.38 [0.13, 1.08]
7.3 1‐3 months post MDA	2	1199	Risk Ratio (M‐H, Random, 95% CI)	1.14 [0.64, 2.01]
7.4 4‐6 months post MDA	2	2789	Risk Ratio (M‐H, Random, 95% CI)	0.35 [0.10, 1.28]
7.5 7‐12 months post MDA	1	75	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.41, 1.79]
7.6 >12 months post MDA	1	2269	Risk Ratio (M‐H, Random, 95% CI)	0.09 [0.05, 0.15]
8 Anaemia Prevalence: Cluster‐randomized trials Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

8.1 4‐6 months post MDA	1	1414	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.75, 0.93]
9 Mortality: Cluster‐randomized trials Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

9.1 4‐6 months post MDA	1	3655	Risk Ratio (M‐H, Random, 95% CI)	1.43 [0.34, 5.96]

Comparison 3. MDA versus no MDA in areas of high endemicity (Stratified by study design)

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Comparison 4. MDA + vector control versus no intervention in areas of moderate endemicity (Stratified by study design)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Parasitaemia Prevalence: Non‐randomized controlled studies Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 At baseline	1	1080	Risk Ratio (M‐H, Random, 95% CI)	2.09 [1.48, 2.98]
1.2 >12 months post MDA	1	1331	Risk Ratio (M‐H, Random, 95% CI)	0.10 [0.05, 0.20]
2 Parasitaemia Prevalence: Uncontrolled before‐and‐after studies Show forest plot	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 During MDA	2	2336	Risk Ratio (M‐H, Random, 95% CI)	0.12 [0.02, 0.62]
2.2 <1 month post MDA	3	5006	Risk Ratio (M‐H, Random, 95% CI)	0.06 [0.01, 0.33]
2.3 1‐3 months post MDA	3	4724	Risk Ratio (M‐H, Random, 95% CI)	0.14 [0.04, 0.57]
2.4 4‐6 months post MDA	1	939	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.39, 0.85]
2.5 >12 months post MDA	1	1758	Risk Ratio (M‐H, Random, 95% CI)	0.00 [0.00, 0.03]
3 Gametocytaemia Prevalence: Uncontrolled before‐and‐after studies Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 During MDA	2	4425	Risk Ratio (M‐H, Random, 95% CI)	0.13 [0.06, 0.27]
3.2 < 1 month post MDA	1	1907	Risk Ratio (M‐H, Random, 95% CI)	0.01 [0.00, 0.16]
3.3 1‐3 months post MDA	1	1941	Risk Ratio (M‐H, Random, 95% CI)	0.22 [0.11, 0.41]

Comparison 4. MDA + vector control versus no intervention in areas of moderate endemicity (Stratified by study design)

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Comparison 5. MDA + vector control versus no intervention in areas of high endemicity (Stratified by study design)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Parasitaemia Prevalence: Non‐randomized controlled studies Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 At baseline	3	8042	Risk Ratio (M‐H, Random, 95% CI)	0.56 [0.37, 0.84]
1.2 During MDA	3	9493	Risk Ratio (M‐H, Random, 95% CI)	0.10 [0.06, 0.16]
1.3 1‐3 months post MDA	2	4455	Risk Ratio (M‐H, Random, 95% CI)	0.12 [0.06, 0.23]
1.4 7‐12 months post MDA	1	3154	Risk Ratio (M‐H, Random, 95% CI)	0.60 [0.55, 0.67]
1.5 >12 months post MDA	1	3261	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.70, 0.84]
2 Parasitaemia Prevalence: Uncontrolled before‐and‐after studies Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 During MDA	2	5437	Risk Ratio (M‐H, Random, 95% CI)	0.17 [0.09, 0.31]
2.2 1‐3 months post MDA	2	5440	Risk Ratio (M‐H, Random, 95% CI)	0.13 [0.01, 2.51]
2.3 4‐6 months post MDA	1	415	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.66, 1.04]
2.4 7‐12 months post MDA	1	412	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.75, 1.16]
3 Gametocytaemia Prevalence: Non‐randomized controlled studies Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 At baseline	3	8042	Risk Ratio (M‐H, Random, 95% CI)	0.53 [0.31, 0.90]
3.2 During MDA	3	9493	Risk Ratio (M‐H, Random, 95% CI)	0.08 [0.03, 0.20]
3.3 1‐3 months post MDA	2	4455	Risk Ratio (M‐H, Random, 95% CI)	0.08 [0.05, 0.14]
3.4 7‐12 months post MDA	1	3154	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.73, 1.05]
3.5 > 12 months post MDA	1	3261	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.81, 1.14]
4 Gametocytaemia Prevalence: Uncontrolled before‐and‐after studies Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

4.1 During MDA	1	437	Risk Ratio (M‐H, Random, 95% CI)	0.29 [0.17, 0.50]
4.2 1‐3 months post MDA	1	440	Risk Ratio (M‐H, Random, 95% CI)	0.52 [0.34, 0.80]
4.3 4‐6 months post MDA	1	415	Risk Ratio (M‐H, Random, 95% CI)	0.76 [0.52, 1.12]
4.4 7‐12 months post MDA	1	412	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.65, 1.33]

Comparison 5. MDA + vector control versus no intervention in areas of high endemicity (Stratified by study design)

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Comparison 6. Parasitaemia Incidence studies

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 MDA versus no MDA: Uncontrolled before‐and‐after studies Show forest plot	4		Rate Ratio (Random, 95% CI)	Subtotals only

1.1 During MDA	3		Rate Ratio (Random, 95% CI)	0.29 [0.07, 1.14]
1.2 < 1 month post MDA	4		Rate Ratio (Random, 95% CI)	0.21 [0.05, 0.84]
1.3 1‐3 months post MDA	4		Rate Ratio (Random, 95% CI)	0.61 [0.26, 1.40]
1.4 4‐6 months post MDA	1		Rate Ratio (Random, 95% CI)	0.65 [0.41, 1.02]
1.5 7‐12 months post MDA	1		Rate Ratio (Random, 95% CI)	0.15 [0.07, 0.34]
1.6 >12 months post MDA	1		Rate Ratio (Random, 95% CI)	0.48 [0.42, 0.55]
2 MDA + vector control versus no MDA: Uncontrolled before‐and‐after studies Show forest plot	2		Rate Ratio (Random, 95% CI)	Subtotals only

2.1 During MDA	2		Rate Ratio (Random, 95% CI)	0.92 [0.49, 1.75]
2.2 < 1 month post MDA	2		Rate Ratio (Random, 95% CI)	0.04 [0.00, 1.54]
2.3 1‐3 months post MDA	2		Rate Ratio (Random, 95% CI)	0.08 [0.01, 0.98]
2.4 4‐6 months post MDA	2		Rate Ratio (Random, 95% CI)	0.11 [0.01, 1.97]
2.5 7‐12 months post MDA	2		Rate Ratio (Random, 95% CI)	0.16 [0.01, 3.10]
2.6 > 12 months post MDA	1		Rate Ratio (Random, 95% CI)	0.04 [0.03, 0.07]

Comparison 6. Parasitaemia Incidence studies

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Comparison 7. MDA versus no MDA in areas of moderate and high endemicity (Stratified by study design; subgrouped by 8‐aminoquinoline)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Parasitaemia Prevalence during MDA Show forest plot	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 Non‐randomized controlled studies ‐ with 8‐aminoquinoline	2	6634	Risk Ratio (M‐H, Random, 95% CI)	0.20 [0.12, 0.32]
1.2 Non‐randomized controlled studies ‐ without 8‐aminoquinoline	2	52941	Risk Ratio (M‐H, Random, 95% CI)	0.16 [0.08, 0.31]
2 Parasitaemia Prevalence 1‐3 months post MDA Show forest plot	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 Non‐randomized controlled studies ‐ with 8‐aminoquinoline	2	7197	Risk Ratio (M‐H, Random, 95% CI)	0.52 [0.33, 0.81]
2.2 Non‐randomized controlled studies ‐ without 8‐aminoquinoline	2	1557	Risk Ratio (M‐H, Random, 95% CI)	0.15 [0.10, 0.23]
3 Parasitaemia Prevalence during MDA Show forest plot	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 Uncontrolled before‐and‐after studies ‐ with 8‐aminoquinoline	1	2965	Risk Ratio (M‐H, Random, 95% CI)	0.06 [0.03, 0.10]
3.2 Uncontrolled before‐and‐after studies ‐ without 8‐aminoquinoline	3	7011	Risk Ratio (M‐H, Random, 95% CI)	0.17 [0.06, 0.51]
4 Parasitaemia Prevalence <1 month post MDA Show forest plot	7		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

4.1 Uncontrolled before‐and‐after studies ‐ with 8‐aminoquinoline	3	2650	Risk Ratio (M‐H, Random, 95% CI)	0.42 [0.29, 0.61]
4.2 Uncontrolled before‐and‐after studies ‐ without 8‐aminoquinoline	4	4309	Risk Ratio (M‐H, Random, 95% CI)	0.29 [0.22, 0.38]
5 Parasitaemia Prevalence 1‐3 months post MDA Show forest plot	7		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.1 Uncontrolled before‐and‐after studies ‐ with 8‐aminoquinoline	1	98	Risk Ratio (M‐H, Fixed, 95% CI)	0.65 [0.41, 1.01]
5.2 Uncontrolled before‐and‐after studies ‐ without 8‐aminoquinoline	6	12959	Risk Ratio (M‐H, Fixed, 95% CI)	0.32 [0.29, 0.34]
6 Parasitaemia Prevalence 4‐6 months post MDA Show forest plot	5		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

6.1 Uncontrolled before‐and‐after studies ‐ with 8‐aminoquinoline	3	2979	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.24, 0.72]
6.2 Uncontrolled before‐and‐after studies ‐ without 8‐aminoquinoline	2	3797	Risk Ratio (M‐H, Random, 95% CI)	1.75 [0.41, 7.41]

Comparison 7. MDA versus no MDA in areas of moderate and high endemicity (Stratified by study design; subgrouped by 8‐aminoquinoline)

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Comparison 8. MDA versus no MDA for all endemicity levels (Stratified by study design; subgrouped by plasmodium species)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Parasitaemia Prevalence at baseline Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 Non‐randomized controlled studies ‐ falciparum	2	1537	Risk Ratio (M‐H, Random, 95% CI)	1.34 [1.03, 1.74]
1.2 Non‐randomized controlled studies ‐ vivax	2	1537	Risk Ratio (M‐H, Random, 95% CI)	3.84 [1.33, 11.04]
2 Parasitaemia Prevalence during MDA Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 Uncontrolled before‐and‐after studies ‐ falciparum	2	5561	Risk Ratio (M‐H, Random, 95% CI)	0.40 [0.08, 1.97]
2.2 Uncontrolled before‐and‐after studies ‐ vivax	2	5561	Risk Ratio (M‐H, Random, 95% CI)	0.60 [0.40, 0.90]
3 Parasitaemia Prevalence <1 month post MDA Show forest plot	5		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 Non‐randomized controlled studies ‐ falciparum	1	433	Risk Ratio (M‐H, Random, 95% CI)	0.02 [0.00, 0.08]
3.2 Non‐randomized controlled studies ‐ vivax	1	433	Risk Ratio (M‐H, Random, 95% CI)	0.05 [0.00, 0.82]
3.3 Uncontrolled before‐and‐after studies ‐ falciparum	4	7367	Risk Ratio (M‐H, Random, 95% CI)	0.22 [0.18, 0.29]
3.4 Uncontrolled before‐and‐after studies ‐ vivax	4	7367	Risk Ratio (M‐H, Random, 95% CI)	0.50 [0.41, 0.61]
4 Parasitaemia Prevalence 1‐3 months post MDA Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

4.1 Non‐randomized controlled studies ‐ falciparum	1	357	Risk Ratio (M‐H, Random, 95% CI)	0.03 [0.01, 0.12]
4.2 Non‐randomized controlled studies ‐ vivax	1	357	Risk Ratio (M‐H, Random, 95% CI)	1.37 [0.46, 4.11]
4.3 Uncontrolled before‐and‐after studies ‐ falciparum	2	5754	Risk Ratio (M‐H, Random, 95% CI)	0.22 [0.09, 0.51]
4.4 Uncontrolled before‐and‐after studies ‐ vivax	2	5754	Risk Ratio (M‐H, Random, 95% CI)	0.49 [0.32, 0.76]
5 Parasitaemia Prevalence 4‐6 months post MDA Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

5.1 Non‐randomized controlled studies ‐ falciparum	1	410	Risk Ratio (M‐H, Random, 95% CI)	0.22 [0.14, 0.33]
5.2 Non‐randomized controlled studies ‐ vivax	1	410	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.31, 2.08]
5.3 Uncontrolled before‐and‐after studies ‐ falciparum	2	3642	Risk Ratio (M‐H, Random, 95% CI)	0.40 [0.13, 1.23]
5.4 Uncontrolled before‐and‐after studies ‐ vivax	2	3642	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.24, 0.39]
6 Parasitaemia Prevalence >12 months post MDA Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

6.1 Non‐randomized controlled studies ‐ falciparum	1	1331	Risk Ratio (M‐H, Random, 95% CI)	0.01 [0.00, 0.13]
6.2 Non‐randomized controlled studies ‐ vivax	1	1331	Risk Ratio (M‐H, Random, 95% CI)	0.36 [0.15, 0.86]
6.3 Uncontrolled before‐and‐after studies ‐ falciparum	2	5884	Risk Ratio (M‐H, Random, 95% CI)	0.06 [0.04, 0.09]
6.4 Uncontrolled before‐and‐after studies ‐ vivax	2	5884	Risk Ratio (M‐H, Random, 95% CI)	0.17 [0.12, 0.24]

Comparison 8. MDA versus no MDA for all endemicity levels (Stratified by study design; subgrouped by plasmodium species)

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