Table 1.

Overview of the studies included in this review.

Drug	Study	Study Design	Study Year and Location	Malaria Indicators	Safety on Pregnancy Outcomes	Tolerability	Conclusion
AQ	[26] Clerk et al., 2008	Double-blind, three-arm RCT IPTp-AQ IPTp-AQSP IPTp-SP (N = 3643)	2004–2007 Ghana	-The prevalence of peripheral and placental malaria and anemia at delivery was similar groups.	-There was no difference between groups with regard to the incidences of LBW.	Women who received AQ or SPAQ were more likely to report adverse events than were those who received SP. Symptoms were usually mild, including bodily pains and weakness, dizziness, vomiting, and nausea.	-The effects of IPTp-AQ or SPAQ were comparable to the effects of IPTp-SP.
MQ	[27] Briand et al., 2009	Open-label equivalence RCT IPTp-MQ IPTp-SP (N = 1601)	2005–2008 Benin	-Placental and peripheral parasitemia at delivery were significantly less prevalent in the MQ group than in the SP group. -Women in the MQ group were less likely to have anemia than were women in the SP group, (difference only marginally significant)	-The incidences of spontaneous abortions, stillbirths, and congenital anomalies did not differ significantly between groups. -The prevalence of LBW among infants born to women receiving MQ and to women receiving SP was not statistically different.	-The proportion of women who reported an AE was significantly higher in the MQ group than in the SP group. The most common complaints were vomiting, dizziness, tiredness, and nausea.	MQ proved to be highly efficacious for use as IPTp. Its low tolerability might impair its effectiveness.
	[28] González et al., 2014	Open label, Three-arm, RCT IPTp-SP IPTp-MQ full dose IPTp-MQ split-dose (N = 4749)	2009–2013 Benin, Gabon, Tanzania, Mozambique	-IPTp-MQ was associated with lower rates of -Peripheral malaria parasitemia at delivery -Maternal anemia at delivery -Clinical malaria episodes -All-cause outpatient attendances during pregnancy -There were no differences between groups in the prevalence of -placental infection -neonatal parasitemia -neonatal anemia	-There were no significant differences between the MQ and SP groups in either the prevalence of LBW infants or in mean birth weight. -There was no difference in the prevalence of adverse pregnancy outcomes between groups, including miscarriages, stillbirths, and congenital malformations.	-The immediate tolerability of IPTp was poorer in the two MQ groups as compared to the SP group, with no difference between the MQ full and split-dose groups. The most frequently reported related AEs were dizziness and vomiting.	The results of this study do not support a change in the current recommended IPTp policy.
	[29] González et al., 2014	Double-blind two arm RCT: IPTp-Placebo + CTX IPTp-MQ + CTX (N = 1071 HIV-infected women)	2009–2013 Kenya, Tanzania and Mozambique	IPTp-MQ was associated with reduced rates of -maternal parasitemia -placental malaria -hospital admissions HIV viral load at delivery was higher in the MQ group compared to the control group.	-There were no differences in the prevalence of adverse pregnancy outcomes between groups. -The mother-to-child transmission of HIV was twofold higher in the IPTp-MQ group.	Drug tolerability was poorer in the MQ group compared to the control group (dizziness and vomiting after the first IPTp-MQ administration).	Its potential for IPTp is limited given poor drug tolerability and given that MQ was associated with an increased risk of mother-to-child transmission of HIV.
	[30] Denoueud-Ndam 2014 et al. (I)	Open label, non-inferiority RCT daily CTX daily CTX + IPTp-MQ (N = 140 HIV-infected women)	2009–2011 Benin	-CTX efficacy for the prevention of placental parasitemia was not more than 5% inferior to the association of CTX + MQ-IPTp. -No differences were either observed regarding peripheral parasitemia at delivery and maternal hemoglobin between groups.	No statistically significant differences were either observed regarding birth weight, or prematurity.	Vomiting, nausea, dizziness, and fatigue were more frequently reported with MQ.	Small sample size MQ-IPTp may be an effective alternative given concern about parasite resistance to CTX
	[30] Denoueud-Ndam 2014 et al. (II)	Open label, non-RCT daily CTX IPTp-MQ (N = 292 HIV-infected women)	2009–2011 Benin	Because of the small sample size obtained, noninferiority could not be conclusively assessed. No statistically significant differences were observed regarding peripheral parasitemia at delivery and maternal hemoglobin	No statistically significant differences were either observed regarding birth weight, or prematurity.	Vomiting, nausea, dizziness, and fatigue were more frequently reported with MQ.	MQ-IPTp may be an effective alternative given concern about parasite resistance to CTX
	[31] Akinyotu et al., 2018	Open label RCT IPTp-MQ IPTp-SP (N = 142 HIV-infected women)	2016 Nigeria	-Presence of malaria parasites in peripheral blood at delivery or enrolment.	No statistically significant differences were found in the incidence of preterm birth and LBW.	There was no significant difference in the occurrence of vomiting, gastric pain, headache and dizziness. Nausea was eight times more likely to occur in the MQ group.	Outcomes following use of IPTp-PQ were comparable to IPTp-SP treatment. The authors concluded that MQ is a feasible alternative therapy.
DP	[32] Kakuru et al., 2016	Three-arm, double-blind, RCT IPTp-SP 3-dose IPTp-DP or monthly IPTp-DP (N = 300)	2014 Uganda	-The prevalence of placental malaria was significantly higher in the SP group than in the three-dose DP group or the monthly DP group. -During pregnancy, the incidence of symptomatic malaria was significantly higher in the SP group than in the three-dose DP or the monthly DP.	-The prevalence of a composite adverse birth outcome was lower in the monthly DP group than in the SP group or the three-dose DP group.	-In each treatment group, the risk of vomiting after administration of any dose of the study agents was very low. -There were no significant differences among the groups in the risk of adverse events.	IPTp-DP during pregnancy resulted in a lower burden of malaria than did treatment with SP.
	[33] Desai et al., 2016	Three-arm, open-label RCT IPTp-DP IPTp-SP IST-DP (N = 1546)	2012–2014 Kenya	-Compared with women who received IPTp-SP, prevalence of malaria infection at the time of delivery was lower in the IPTp-DP group -Women in IPTp-DP group had -fewer malaria infections -lower incidence of clinical malaria -fewer all-cause sick-clinic visits during pregnancy than those in the IPTp-SP group	Women in the IPTp-DP group had fewer stillbirths, and infant mortality than those in the IPTp-SP group. Prevalence of LBW, small for gestational age, and preterm delivery did not differ significantly between groups.	-DP was well tolerated by most women. Adverse events were more frequent in the IPTp-DP group.	DP is a promising alternative drug to replace SP for IPTp.
	[34] Natureeba et al., 2017	Double-blinded, RCT daily CTX + monthly DP daily CTX (N = 200 HIV-positive women)	2014–2015 Uganda	No statistically significant difference in -risk of placental malarial infection -incidence of malaria and parasite prevalence among both arms.	No statistically significant difference in the incidence of adverse birth outcomes among both arms.	There were no significant differences in the incidence of adverse events of any severity.	Adding monthly DP to daily CTX did not reduce the risk of placental or maternal malaria or improve birth outcomes.
	[35] Kajubi et al., 2019	Double-blind, RCT IPTp-SP IPTp-DP (N = 782)	2016–2017 Uganda	IPTp-DP was associated with lower: -incidence of symptomatic malaria during pregnancy. -prevalence of parasitaemia at the time of each routine visit. -risk of maternal anaemia during pregnancy	-There was no significant difference in the risk of LBW, preterm birth, small for gestational age, or composite adverse birth outcome between the treatment groups.	-Both drug regimens were well tolerated, with no significant differences in adverse events between the groups, with the exception of asymptomatic corrected QT interval prolongation (significantly higher in the DP group).	Monthly IPTp-DP was safe but did not lead to significant improvements in birth outcomes compared with SP.
	[36] Mlugu et al., 2021	Open-label RCT IPTp-DP IPTp-SP (N = 956)	2017–2019 Tanzania	IPTp-DP was associated with lower: -prevalence of maternal malaria at delivery. -incidence of symptomatic-malaria and parasitemia during pregnancy	The prevalence of any adverse birth outcomes was not significantly different between groups. The prevalence of LBW was significantly lower in IPTp-DP.	There was no significant difference in the prevalence of adverse drug events between the treatment groups.	There was a significantly higher protective efficacy of IPTp-DP compared to monthly IPTp-SP.
CQ	[37] Divala et al., 2018	Three arm, open-label, RCT CQ-IPTp CQ chemoprophylaxis SP-IPTp (N = 900)	2012–2014 Malawi	There was no difference in the risk of -placental malaria detected by histopathology -malaria infection or clinical malaria illness.	There were no differences in adverse pregnancy outcomes between arms.	Both CQ treatment regimens were associated with higher rates of treatment-related adverse events than the SP-IPTp regimen.	This study did not have enough superiority evidence of chloroquine either as IPTp or as chemoprophylaxis versus SP-IPTp for prevention of malaria during pregnancy and associated maternal and infant adverse outcomes.
AZ	[38] Akinyotu et al., 2019	Open-label RCT IPTp-SP AZ (N = 180 HIV-infected women)	2015–2016 Nigeria	No statistically significant difference in the incidence of malaria parasitaemia at delivery and placental parasitization among arms.	No significant difference in preterm birth and LBW between both arms.	Nausea was significantly higher in the AZ group compared with the SP group. There were no statistically significant differences among groups in the presence of dizziness and headache.	The use of AZ for malaria prevention in HIV-positive pregnant women has a comparable outcome to SP. It is tolerable and has few maternal and foetal adverse effects
AZSP	[39] Luntamo et al., 2010	RCT Two-dose IPTp-SP Monthly IPTp-SP Monthly IPTp-AZSP (N = 1320)	2003–2006 Malawi	Compared with the controls, participants in the monthly SP and AZSP groups had a statistically significant lower prevalence of peripheral malaria parasitemia at 32 gestation weeks.	IPTp-SPAZ was associated with lower incidence of preterm delivery and LBWIPTp-SPAZ and monthly IPTp-SP were associated with higher mean duration of pregnancy.	Incidence of serious adverse events was low in all groups.	This intervention could be efficacious, but the impact would heavily depend on the local epidemiology and resistance of malaria.
AZCQ	[40] Kimani et al., 2016	Open-label RCT IPTp-SP IPTp-AZCQ (N = 2891)	2010–2013 Benin, Kenya, Tanzania, Uganda	Statistically significant reduction in -symptomatic malaria episodes -incidence of peripheral parasitemia at w. 36–38.	There was no significant difference in the incidence of LBW between treatment groups in the IPTp-AZCQ group.	AEs such as vomiting, dizziness, headache, and asthenia were reported more frequently by women receiving IPTp-AZCQ than those receiving IPTp-SP.	IPTp-AZCQ was not superior to IPTp-SP. The study was terminated earlier due to futility.

AQ: amodiaquine; AQSP: amodiaquine-sulfadoxine/pyrimethamine; IPTp: intermittent preventive treatment of malaria in pregnancy; LBW: low birth weight; MQ: mefloquine; RCT: randomized clinical trial; SP: sulfadoxine-pyrimethamine. CTX: cotrimoxazole; IPTp: intermittent preventive treatment of malaria in pregnancy; LBW: low birth weight; MQ: mefloquine; RCT: randomized clinical trial; SP: sulfadoxine-pyrimethamine. CTX: cotrimoxazole; DP: dihydroartemisinin-piperaquine; IPTp: intermittent preventive treatment of malaria in pregnancy; IST: intermittent screening and treatment; RCT: randomized clinical trial; SP: sulfadoxine-pyrimethamine. CQ: chloroquine; DP: dihydroartemisinin-piperaquine; IPTp: intermittent preventive treatment of malaria in pregnancy; LBW: low birthweight; RCT: randomized clinical trial; SP: sulfadoxine-pyrimethamine. AZ: azithromycin; AZCQ: azithromyicin/chloroquine; AZSP: azithromycin/sulfadoxine-pyrimethamine; IPTp: intermittent preventive treatment of malaria in pregnancy; LBW: low birthweight; RCT: randomized clinical trial; SP: sulfadoxine-pyrimethamine; w.: week.