Drugs for treating uncomplicated malaria in pregnant women

Lois C Orton; Aika AA Omari

doi:10.1002/14651858.CD004912.pub3

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Figure 1

Artesunate plus atovaquone‐proguanil (AS+AP) vs quinine (QN): Treatment failure at day 63 (excludes new infections, detected by PCR)

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Figure 2

Artesunate plus mefloquine (AS+MQ) vs quinine (QN): Treatment failure at day 63 (excludes new infections, detected by PCR)

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Figure 3

Artesunate plus sulfadoxine‐pyrimethamine (AS+SP) vs sulfadoxine‐pyrimethamine (SP): Treatment failure at delivery or day 40 (excludes new infections, detected by PCR)

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Figure 4

Amodiaquine plus sulfadoxine‐pyrimethamine (AQ+SP) vs chloroquine (CQ): Treatment failure at day 28 (excludes new infections, detected by PCR)

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Figure 5

Amodiaquine (AQ) vs chloroquine (CQ): Treatment failure at day 28 (excludes new infections, detected by PCR)

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Figure 6

Azithromycin plus sulfadoxine‐pyrimethamine (AZM+SP) vs sulfadoxine‐pyrimethamine (SP): Treatment failure at delivery or day 40 (excludes new infections, detected by PCR)

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Analysis 1.1

Comparison 1 Artesunate plus atovaquone‐proguanil (AS+AP) vs quinine (QN), Outcome 1 Treatment failure at day 63.

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Analysis 1.2

Comparison 1 Artesunate plus atovaquone‐proguanil (AS+AP) vs quinine (QN), Outcome 2 Treatment failure at day 63 (excludes new infections, detected by PCR).

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Analysis 1.3

Comparison 1 Artesunate plus atovaquone‐proguanil (AS+AP) vs quinine (QN), Outcome 3 Anaemia.

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Analysis 1.4

Comparison 1 Artesunate plus atovaquone‐proguanil (AS+AP) vs quinine (QN), Outcome 4 Tinnitus.

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Analysis 1.5

Comparison 1 Artesunate plus atovaquone‐proguanil (AS+AP) vs quinine (QN), Outcome 5 Low birthweight.

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Analysis 1.6

Comparison 1 Artesunate plus atovaquone‐proguanil (AS+AP) vs quinine (QN), Outcome 6 Mean birthweight.

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Analysis 1.7

Comparison 1 Artesunate plus atovaquone‐proguanil (AS+AP) vs quinine (QN), Outcome 7 Preterm delivery.

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Analysis 1.8

Comparison 1 Artesunate plus atovaquone‐proguanil (AS+AP) vs quinine (QN), Outcome 8 Gestational age.

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Analysis 1.9

Comparison 1 Artesunate plus atovaquone‐proguanil (AS+AP) vs quinine (QN), Outcome 9 Intra‐uterine growth retardation.

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Analysis 1.10

Comparison 1 Artesunate plus atovaquone‐proguanil (AS+AP) vs quinine (QN), Outcome 10 Congenital abnormality.

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Analysis 2.1

Comparison 2 Artesunate plus mefloquine (AS+MQ) vs quinine (QN), Outcome 1 Treatment failure at day 63 (excludes new infections, detected by PCR).

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Analysis 2.2

Comparison 2 Artesunate plus mefloquine (AS+MQ) vs quinine (QN), Outcome 2 Anaemia.

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Analysis 2.3

Comparison 2 Artesunate plus mefloquine (AS+MQ) vs quinine (QN), Outcome 3 Nervous system adverse events.

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Analysis 2.4

Comparison 2 Artesunate plus mefloquine (AS+MQ) vs quinine (QN), Outcome 4 Gastrointestinal adverse events.

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Analysis 2.5

Comparison 2 Artesunate plus mefloquine (AS+MQ) vs quinine (QN), Outcome 5 Other adverse events.

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Analysis 2.6

Comparison 2 Artesunate plus mefloquine (AS+MQ) vs quinine (QN), Outcome 6 Low birthweight.

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Analysis 2.7

Comparison 2 Artesunate plus mefloquine (AS+MQ) vs quinine (QN), Outcome 7 Mean birthweight.

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Analysis 2.8

Comparison 2 Artesunate plus mefloquine (AS+MQ) vs quinine (QN), Outcome 8 Abortion.

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Analysis 2.9

Comparison 2 Artesunate plus mefloquine (AS+MQ) vs quinine (QN), Outcome 9 Neonatal jaundice.

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Analysis 3.1

Comparison 3 Artesunate plus sulfadoxine‐pyrimethamine (AS+SP) vs azithromycin plus sulfadoxine‐pyrimethamine (AZM+SP), Outcome 1 Treatment failure at delivery or day 40.

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Analysis 3.2

Comparison 3 Artesunate plus sulfadoxine‐pyrimethamine (AS+SP) vs azithromycin plus sulfadoxine‐pyrimethamine (AZM+SP), Outcome 2 Treatment failure at delivery or day 40 (excludes new infections, detected by PCR).

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Analysis 3.3

Comparison 3 Artesunate plus sulfadoxine‐pyrimethamine (AS+SP) vs azithromycin plus sulfadoxine‐pyrimethamine (AZM+SP), Outcome 3 Maternal anaemia.

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Analysis 3.4

Comparison 3 Artesunate plus sulfadoxine‐pyrimethamine (AS+SP) vs azithromycin plus sulfadoxine‐pyrimethamine (AZM+SP), Outcome 4 Low birthweight.

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Analysis 3.5

Comparison 3 Artesunate plus sulfadoxine‐pyrimethamine (AS+SP) vs azithromycin plus sulfadoxine‐pyrimethamine (AZM+SP), Outcome 5 Perinatal death.

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Analysis 3.6

Comparison 3 Artesunate plus sulfadoxine‐pyrimethamine (AS+SP) vs azithromycin plus sulfadoxine‐pyrimethamine (AZM+SP), Outcome 6 Neonatal death.

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Analysis 4.1

Comparison 4 Artesunate plus sulfadoxine‐pyrimethamine (AS+SP) vs sulfadoxine‐pyrimethamine (SP), Outcome 1 Treatment failure at delivery or 40 days.

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Analysis 4.2

Comparison 4 Artesunate plus sulfadoxine‐pyrimethamine (AS+SP) vs sulfadoxine‐pyrimethamine (SP), Outcome 2 Treatment failure at delivery or day 40 (excludes new infections, detected by PCR).

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Analysis 4.3

Comparison 4 Artesunate plus sulfadoxine‐pyrimethamine (AS+SP) vs sulfadoxine‐pyrimethamine (SP), Outcome 3 Maternal anaemia.

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Analysis 4.4

Comparison 4 Artesunate plus sulfadoxine‐pyrimethamine (AS+SP) vs sulfadoxine‐pyrimethamine (SP), Outcome 4 Low birthweight.

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Analysis 4.5

Comparison 4 Artesunate plus sulfadoxine‐pyrimethamine (AS+SP) vs sulfadoxine‐pyrimethamine (SP), Outcome 5 Perinatal death.

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Analysis 4.6

Comparison 4 Artesunate plus sulfadoxine‐pyrimethamine (AS+SP) vs sulfadoxine‐pyrimethamine (SP), Outcome 6 Neonatal death.

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Analysis 5.1

Comparison 5 Quinine plus spiramycin (QN+SPI) vs quinine (QN), Outcome 1 Mean parasite clearance time.

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Analysis 5.2

Comparison 5 Quinine plus spiramycin (QN+SPI) vs quinine (QN), Outcome 2 Mean gestational age at delivery.

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Analysis 6.1

Comparison 6 Artesunate (AS) vs quinine plus clindamycin (QN+CLD), Outcome 1 Treatment failure at 48 hours (excludes new infections, detected by PCR).

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Analysis 6.2

Comparison 6 Artesunate (AS) vs quinine plus clindamycin (QN+CLD), Outcome 2 Mean parasite clearance time.

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Analysis 6.3

Comparison 6 Artesunate (AS) vs quinine plus clindamycin (QN+CLD), Outcome 3 Anaemia at day 7.

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Analysis 6.4

Comparison 6 Artesunate (AS) vs quinine plus clindamycin (QN+CLD), Outcome 4 Low birthweight.

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Analysis 6.5

Comparison 6 Artesunate (AS) vs quinine plus clindamycin (QN+CLD), Outcome 5 Mean birthweight.

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Analysis 6.6

Comparison 6 Artesunate (AS) vs quinine plus clindamycin (QN+CLD), Outcome 6 Mean gestational age at delivery.

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Analysis 7.1

Comparison 7 Artemether plus mefloquine (ATM+MQ) vs artemether (ATM), Outcome 1 Mean fever clearance time.

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Analysis 7.2

Comparison 7 Artemether plus mefloquine (ATM+MQ) vs artemether (ATM), Outcome 2 Mean parasite clearance time.

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Analysis 7.3

Comparison 7 Artemether plus mefloquine (ATM+MQ) vs artemether (ATM), Outcome 3 Adverse events.

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Analysis 7.4

Comparison 7 Artemether plus mefloquine (ATM+MQ) vs artemether (ATM), Outcome 4 Mean birthweight.

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Analysis 8.1

Comparison 8 Amodiaquine plus sulfadoxine‐pyrimethamine (AQ+SP) vs chloroquine (CQ), Outcome 1 Treatment failure at day 28.

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Analysis 8.2

Comparison 8 Amodiaquine plus sulfadoxine‐pyrimethamine (AQ+SP) vs chloroquine (CQ), Outcome 2 Treatment failure at day 28 (excludes new infections, detected by PCR).

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Analysis 8.3

Comparison 8 Amodiaquine plus sulfadoxine‐pyrimethamine (AQ+SP) vs chloroquine (CQ), Outcome 3 Adverse events.

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Analysis 8.4

Comparison 8 Amodiaquine plus sulfadoxine‐pyrimethamine (AQ+SP) vs chloroquine (CQ), Outcome 4 Low birthweight.

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Analysis 8.5

Comparison 8 Amodiaquine plus sulfadoxine‐pyrimethamine (AQ+SP) vs chloroquine (CQ), Outcome 5 Preterm delivery.

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Analysis 9.1

Comparison 9 Amodiaquine (AQ) vs chloroquine (CQ), Outcome 1 Treatment failure at day 28.

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Analysis 9.2

Comparison 9 Amodiaquine (AQ) vs chloroquine (CQ), Outcome 2 Treatment failure at day 28 (excludes new infections, detected by PCR).

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Analysis 9.3

Comparison 9 Amodiaquine (AQ) vs chloroquine (CQ), Outcome 3 Adverse events.

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Analysis 9.4

Comparison 9 Amodiaquine (AQ) vs chloroquine (CQ), Outcome 4 Low birthweight.

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Analysis 9.5

Comparison 9 Amodiaquine (AQ) vs chloroquine (CQ), Outcome 5 Preterm delivery.

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Analysis 10.1

Comparison 10 Azithromycin plus sulfadoxine‐pyrimethamine (AZM+SP) vs sulfadoxine‐pyrimethamine (SP), Outcome 1 Treatment failure at delivery or day 40.

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Analysis 10.2

Comparison 10 Azithromycin plus sulfadoxine‐pyrimethamine (AZM+SP) vs sulfadoxine‐pyrimethamine (SP), Outcome 2 Treatment failure at delivery or day 40 (excludes new infections, detected by PCR).

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Analysis 10.3

Comparison 10 Azithromycin plus sulfadoxine‐pyrimethamine (AZM+SP) vs sulfadoxine‐pyrimethamine (SP), Outcome 3 Maternal anaemia.

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Analysis 10.4

Comparison 10 Azithromycin plus sulfadoxine‐pyrimethamine (AZM+SP) vs sulfadoxine‐pyrimethamine (SP), Outcome 4 Low birthweight.

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Analysis 10.5

Comparison 10 Azithromycin plus sulfadoxine‐pyrimethamine (AZM+SP) vs sulfadoxine‐pyrimethamine (SP), Outcome 5 Perinatal death.

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Analysis 10.6

Comparison 10 Azithromycin plus sulfadoxine‐pyrimethamine (AZM+SP) vs sulfadoxine‐pyrimethamine (SP), Outcome 6 Neonatal death.

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Analysis 11.1

Comparison 11 Sulfadoxine‐pyrimethamine (SP) vs chloroquine (CQ), Outcome 1 Treatment failure at day 14.

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Analysis 11.2

Comparison 11 Sulfadoxine‐pyrimethamine (SP) vs chloroquine (CQ), Outcome 2 Treatment failure at day 28.

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Analysis 11.3

Comparison 11 Sulfadoxine‐pyrimethamine (SP) vs chloroquine (CQ), Outcome 3 Treatment failure at day 28 (excludes new infections, detected by PCR).

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Analysis 11.4

Comparison 11 Sulfadoxine‐pyrimethamine (SP) vs chloroquine (CQ), Outcome 4 Adverse events.

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Analysis 11.5

Comparison 11 Sulfadoxine‐pyrimethamine (SP) vs chloroquine (CQ), Outcome 5 Low birthweight.

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Analysis 11.6

Comparison 11 Sulfadoxine‐pyrimethamine (SP) vs chloroquine (CQ), Outcome 6 Preterm delivery.

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Analysis 12.1

Comparison 12 Chloroquine plus clindamycin (CQ+CLD) for 3 or 5 days vs chloroquine (CQ), Outcome 1 Treatment failure at day 14.

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Analysis 12.2

Comparison 12 Chloroquine plus clindamycin (CQ+CLD) for 3 or 5 days vs chloroquine (CQ), Outcome 2 Adverse event: itching.

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Analysis 12.3

Comparison 12 Chloroquine plus clindamycin (CQ+CLD) for 3 or 5 days vs chloroquine (CQ), Outcome 3 Adverse event: diarrhoea.

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Table 1. Detailed search strategies

Search set	CIDG SR^a	CENTRAL	MEDLINE^b	EMBASE^b	LILACS^b
1	malaria	malaria	malaria	malaria	malaria
2	pregnan*	pregnan*	Exp MALARIA	MALARIA	pregnan*
3	—	1 and 2	pregnan*	pregnan$	1 and 2
4	—	—	PREGNANCY	PREGNANCY	—
5	—	—	1 or 2	1 or 2	—
6	—	—	3 or 4	3 or 4	—
7	—	—	5 and 6	5 and 6	—
8	—	—	Limit 7 to human	Limit 7 to human	—
^aCochrane Infectious Diseases Group Specialized Register. ^bSearch terms used in combination with the search strategy for retrieving trials developed by The Cochrane Collaboration (Lefebvre 2008); upper case: MeSH or EMTREE heading; lower case: free text term.

Table 1. Detailed search strategies

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Table 2. Risk of bias of included trialsa

Trial	Generation of allocation sequence	Allocation concealment	Blinding	Inclusion of all randomized participants in the final analysis^b
Bounyasong 2001	Unclear	Unclear	None	Adequate
Coulibaly 2006	Adequate	Unclear	None	Inadequate
Kalilani 2007	Adequate	Adequate	Outcome assessor	Inadequate
Mbanzulu 1993	Inadequate	Unclear	Outcome assessor	Adequate
McGready 2000	Adequate	Unclear	None	Adequate
McGready 2001a	Unclear	Unclear	None	Inadequate
McGready 2005	Adequate	Adequate	Outcome assessor	Adequate
Nosten 1993b	Inadequate	Unclear	None	Inadequate
Sowunmi 1998a	Unclear	Unclear	None	Adequate
Tagbor 2006	Adequate	Adequate	Participant, treatment provider, outcome assessor, data analyst	Adequate
^aSee 'Assessment of risk of bias in included studies' for the assessment methods, and the 'Characteristics of included studies' for the methods used in each trial. ^bFor primary outcomes.

Table 2. Risk of bias of included trialsa

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Comparison 1. Artesunate plus atovaquone‐proguanil (AS+AP) vs quinine (QN)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Treatment failure at day 63 Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2 Treatment failure at day 63 (excludes new infections, detected by PCR) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3 Anaemia Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

4 Tinnitus Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

5 Low birthweight Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

6 Mean birthweight Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

7 Preterm delivery Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

8 Gestational age Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

9 Intra‐uterine growth retardation Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

10 Congenital abnormality Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 1. Artesunate plus atovaquone‐proguanil (AS+AP) vs quinine (QN)

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Comparison 2. Artesunate plus mefloquine (AS+MQ) vs quinine (QN)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Treatment failure at day 63 (excludes new infections, detected by PCR) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2 Anaemia Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2.1 On admission	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.2 Day 7	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.3 Day 28	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.4 Day 42	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.5 Day 63	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3 Nervous system adverse events Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3.1 Abnormal neurology	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 Blurring vision	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.3 Dizziness	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.4 Headache	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.5 Tinnitus	2		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.6 Vertigo	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Gastrointestinal adverse events Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

4.1 Abdominal pain	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 Anorexia	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.3 Nausea	2		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.4 Vomiting	2		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 Other adverse events Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

5.1 Hypoglycaemia	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.2 Muscle and joint pain	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.3 Palpitations	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6 Low birthweight Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

7 Mean birthweight Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

8 Abortion Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

9 Neonatal jaundice Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 2. Artesunate plus mefloquine (AS+MQ) vs quinine (QN)

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Comparison 3. Artesunate plus sulfadoxine‐pyrimethamine (AS+SP) vs azithromycin plus sulfadoxine‐pyrimethamine (AZM+SP)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Treatment failure at delivery or day 40 Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2 Treatment failure at delivery or day 40 (excludes new infections, detected by PCR) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3 Maternal anaemia Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

4 Low birthweight Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

5 Perinatal death Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

6 Neonatal death Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 3. Artesunate plus sulfadoxine‐pyrimethamine (AS+SP) vs azithromycin plus sulfadoxine‐pyrimethamine (AZM+SP)

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Comparison 4. Artesunate plus sulfadoxine‐pyrimethamine (AS+SP) vs sulfadoxine‐pyrimethamine (SP)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Treatment failure at delivery or 40 days Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2 Treatment failure at delivery or day 40 (excludes new infections, detected by PCR) Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3 Maternal anaemia Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

4 Low birthweight Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

5 Perinatal death Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

6 Neonatal death Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 4. Artesunate plus sulfadoxine‐pyrimethamine (AS+SP) vs sulfadoxine‐pyrimethamine (SP)

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Comparison 5. Quinine plus spiramycin (QN+SPI) vs quinine (QN)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mean parasite clearance time Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

2 Mean gestational age at delivery Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

Comparison 5. Quinine plus spiramycin (QN+SPI) vs quinine (QN)

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Comparison 6. Artesunate (AS) vs quinine plus clindamycin (QN+CLD)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Treatment failure at 48 hours (excludes new infections, detected by PCR) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2 Mean parasite clearance time Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

3 Anaemia at day 7 Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

4 Low birthweight Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

5 Mean birthweight Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

6 Mean gestational age at delivery Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

Comparison 6. Artesunate (AS) vs quinine plus clindamycin (QN+CLD)

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Comparison 7. Artemether plus mefloquine (ATM+MQ) vs artemether (ATM)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mean fever clearance time Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

2 Mean parasite clearance time Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

3 Adverse events Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3.1 Abdominal discomfort	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 Dizziness	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Mean birthweight Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

Comparison 7. Artemether plus mefloquine (ATM+MQ) vs artemether (ATM)

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Comparison 8. Amodiaquine plus sulfadoxine‐pyrimethamine (AQ+SP) vs chloroquine (CQ)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Treatment failure at day 28 Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2 Treatment failure at day 28 (excludes new infections, detected by PCR) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3 Adverse events Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3.1 Any "side effect" at day 3	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 Any "side effect" at day 7	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.3 General weakness at day 3	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.4 General weakness at day 7	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.5 Dizziness at day 3	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.6 Dizziness at day 7	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.7 Vomiting day 3	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.8 Vomiting at day 7	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.9 Itching at day 3	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.10 Itching at day 7	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.11 Nausea at day 3	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.12 Nausea at day 7	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Low birthweight Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

5 Preterm delivery Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 8. Amodiaquine plus sulfadoxine‐pyrimethamine (AQ+SP) vs chloroquine (CQ)

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Comparison 9. Amodiaquine (AQ) vs chloroquine (CQ)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Treatment failure at day 28 Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2 Treatment failure at day 28 (excludes new infections, detected by PCR) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3 Adverse events Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3.1 Any "side effect" at day 3	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 Any "side effect" at day 7	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.3 General weakness at day 3	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.4 General weakness at day 7	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.5 Dizziness at day 3	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.6 Dizziness at day 7	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.7 Vomiting at day 3	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.8 Vomiting at day 7	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.9 Itching at day 3	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.10 Itching at day 7	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.11 Nausea at day 3	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.12 Nausea at day 7	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Low birthweight Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

5 Preterm delivery Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 9. Amodiaquine (AQ) vs chloroquine (CQ)

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Comparison 10. Azithromycin plus sulfadoxine‐pyrimethamine (AZM+SP) vs sulfadoxine‐pyrimethamine (SP)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Treatment failure at delivery or day 40 Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2 Treatment failure at delivery or day 40 (excludes new infections, detected by PCR) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3 Maternal anaemia Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

4 Low birthweight Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

5 Perinatal death Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

6 Neonatal death Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 10. Azithromycin plus sulfadoxine‐pyrimethamine (AZM+SP) vs sulfadoxine‐pyrimethamine (SP)

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Comparison 11. Sulfadoxine‐pyrimethamine (SP) vs chloroquine (CQ)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Treatment failure at day 14 Show forest plot	2	544	Risk Ratio (M‐H, Fixed, 95% CI)	0.56 [0.29, 1.09]

2 Treatment failure at day 28 Show forest plot	2	538	Risk Ratio (M‐H, Fixed, 95% CI)	0.46 [0.33, 0.64]

3 Treatment failure at day 28 (excludes new infections, detected by PCR) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

4 Adverse events Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

4.1 Any "side effect" at day 3	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 Any "side effect" at day 7	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.3 General weakness at day 3	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.4 General weakness at day 7	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.5 Dizziness at day 3	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.6 Dizziness at day 7	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.7 Vomiting at day 3	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.8 Vomiting at day 7	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.9 Itching at day 3	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.10 Itching at day 7	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.11 Nausea at day 3	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.12 Nausea at day 7	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 Low birthweight Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

6 Preterm delivery Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 11. Sulfadoxine‐pyrimethamine (SP) vs chloroquine (CQ)

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Comparison 12. Chloroquine plus clindamycin (CQ+CLD) for 3 or 5 days vs chloroquine (CQ)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Treatment failure at day 14 Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

1.1 3‐day clindamycin	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.2 5‐day clindamycin	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2 Adverse event: itching Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2.1 3‐day clindamycin	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.2 5‐day clindamycin	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3 Adverse event: diarrhoea Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3.1 3‐day clindamycin	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 5‐day clindamycin	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 12. Chloroquine plus clindamycin (CQ+CLD) for 3 or 5 days vs chloroquine (CQ)

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