Gonzalez 2014a BEN GAB MOZ TAN

Methods	Trial design: open‐label, randomized, 3‐arm trial of 2 doses of IPTp Follow‐up: at each scheduled and unscheduled visit, a standardized symptom questionnaire was completed, as were blood smears for malaria parasites, and haemoglobin if symptoms and/or signs were suggestive of malaria. At delivery, blood samples were collected for haematological and parasitological evaluation. Weighting of newborns and gestational age at birth were recorded. Malaria parasite was determined 6 weeks after the end of pregnancy. Adverse event monitoring: home visits by field workers were done 2 days after IPTp administration to assess drug tolerability. Solicited and unsolicited adverse events (AEs) were assessed. The former were assessed by directed questioning regarding malaria‐related signs and symptoms during unscheduled visits, whereas the latter were assessed through open questioning during scheduled visits.
Participants	Numbers of participants randomized: 1578 (sulfadoxine‐pyrimethamine), 1580 (mefloquine full dose), 1591 (mefloquine split) Inclusion criteria: HIV‐uninfected women of all gravidities attending the antenatal care clinic for the first time, did not receive IPTp during current pregnancy, permanent residence in the study area, gestational age of ≤ 28 weeks Exclusion criteria: HIV‐positive; history of allergy to sulfa drugs or mefloquine; history of severe renal, hepatic, psychiatric, or neurological disease; mefloquine or halofantrine treatment in the preceding 4 weeks; participating in other intervention studies
Interventions	IPTp with sulfadoxine‐pyrimethamine, 3 tablets 500 mg/25 mg Two doses 1 month apart IPTp with mefloquine 15 mg/kg given once as a full dose (250‐mg tablets) Two doses 1 month apart IPTp with mefloquine (split dose) 15 mg/kg given as a split dose over 2 days (250‐mg tablets) Two doses 1 month apart All study participants were given LLITNs. The first dose was given at > 13 weeks of gestation. All women were observed for 60 minutes following IPT administration. Women vomiting within the first 30 minutes were given a second full IPT dose, and those vomiting 30 to 60 minutes after drug intake were given a half replacement dose. Uncomplicated malaria episodes were treated with oral quinine (first trimester) or artemether‐lumefantrine (second and third trimesters); severe malaria episodes were treated with parenteral quinine.
Outcomes	Maternal peripheral parasitaemia at delivery Placental parasitaemia at delivery Mean maternal haemoglobin at delivery Maternal anaemia (< 10 g/dL) at delivery Clinical malaria episodes during pregnancy Cord blood parasitaemia at delivery Cord blood anaemia Mean birth weight Low birth weight (< 2500 g) Low birth weight by gravidity Prematurity Malaria in first year of life Hospital admissions in first year of life Malaria in first year of life (infant morbidity) Hospital admissions in first year of life (infant morbidity) Serious adverse events (SAEs) during pregnancy Spontaneous abortions (< 20 complete weeks of gestation) Stillbirths (> 20 complete weeks of gestation) Congenital malformations Maternal mortality Neonatal mortality Infant mortality Vomiting Headache Fatigue/weakness Dizziness
Notes	Country: Tanzania, Mozambique, Benin, and Gabon Setting: antenatal care clinics Transmission: mesoendemic in Tanzania and Mozambique, hyperendemic in Benin and Gabon Resistance: resistance to sulfadoxine‐pyrimethamine due to long‐term sulfadoxine‐pyrimethamine for IPTp Dates: 2009 to 2013 Funding: this study was funded by the European Developing Countries Clinical Trials Partnership (EDCTP; IP.2007.31080.002), the Malaria in Pregnancy Consortium, and the Instituto de Salud Carlos III (PI08/0564), in Spain. RG and MR were partially supported by grants from the Spanish Ministry of Health (ref. CM07/0015 and CM11/00278, respectively). The CISM receives core funding from the Spanish Agency for International Cooperation (AECID). LLITNs (Permanet) were donated by Vestergaard Frandsen.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The allocation of the participants to the study arms was done centrally by randomization stratified by country according to a 1:1:1 scheme. The sponsor’s institution biostatistician produced the computer‐generated randomization list for each recruiting site".
Allocation concealment (selection bias)	Low risk	Quote: "Treatment allocation for each participant was concealed in opaque sealed envelopes that were opened only after recruitment. Study participants were assigned a unique study number linked to the allocated treatment group".
Blinding of participants and personnel (performance bias) All outcomes	High risk	Quote: "The study was designed as an open‐label, randomized, three‐arm trial to compare two‐dose mefloquine with two‐dose SP for IPTp".
Blinding of outcome assessment (detection bias) Efficacy	Low risk	No blinding of outcome assessment was reported, but the review authors judge that the efficacy outcome measurement is not likely to be influenced by lack of blinding.
Blinding of outcome assessment (detection bias) Safety	High risk	No blinding of outcome assessment was reported; thus the review authors judge that the safety outcome measurement is likely to be influenced by lack of blinding.
Incomplete outcome data (attrition bias) All outcomes	Low risk	All excluded participants, at any stage of the trial, are counted in the flow chart (both ITT and ATP cohorts). Missing outcome data were balanced in numbers across groups.
Selective reporting (reporting bias)	Low risk	Not observed. Protocol available
Other bias	Low risk	The study appears to be free of other sources of bias.