Nosten 1994 THA

Methods	Trial design: double‐blind, placebo‐controlled trial. Phase 1 and phase 2 Follow‐up: in both phases, weekly visits included assessment of weight, temperature, pulse, blood pressure, fundal height, presence of oedema and anaemia, a symptom questionnaire on gastrointestinal and central nervous system side effects, malaria blood smear, electrocardiogram, and haematology and biochemistry every 2 weeks. Treatment of malaria and anaemia and food supply were provided when needed. At phase 2, expanded questionnaires and Romberg test were used. At delivery, measurement of newborn weight, details of labour, cord and maternal blood samples (malaria and anaemia), and placental biopsy were included. At phase 2, autopsy of death was performed in newborns. Follow‐up consisted of different measurements in children until 2 years of age (weight, height, head and arm circumferences) and determination of age when baby could first crawl, sit, walk, and talk. At phase 2, age at first symptomatic malaria, malaria blood smear, haematocrit, and full clinical examination were performed. Adverse event monitoring: weekly symptom questionnaire focusing on gastrointestinal, neurological, dermatological, and systemic symptoms
Participants	Numbers of participants randomized: 170 (mefloquine ‐ 60 phase 1, 110 phase 2), 169 (placebo ‐ 59 phase 1, 110 phase 2) Inclusion criteria: women of all gravidities and unknown HIV status (not tested) who attended the ANC clinic and were at > 20 weeks of estimated gestation. Exclusion criteria: women not meeting inclusion criteria.
Interventions	IPTp with mefloquine Phase 1: 500 mg of base loading dose followed by 250 mg weekly for 4 weeks and thereafter 125 mg weekly until delivery Phase 2: 250 mg of base weekly given for 4 weeks followed by 125 mg weekly until delivery IPTp with placebo Identical to mefloquine tablets (weekly dosage) The first dose was given at > 20 weeks of gestation. Anaemia was treated with ferrous sulphate and folic acid. Uncomplicated Plasmodium falciparum malaria was treated with quinine sulphate, P vivax with chloroquine sulphate, and severe malaria with intravenous quinine dihydrochloride.
Outcomes	Maternal peripheral parasitaemia during pregnancy Placental malaria Mean birth weight Low birth weight Prematurity Stillbirths Spontaneous abortions Congenital malformations Maternal mortality Infant mortality
Notes	Country: Thailand Setting: 3 camps for displaced people: phase 1 antenatal clinics, phase 2 hospital Dates: 1987 to 1990 Transmission: seasonal malaria transmission (mesoendemic) Resistance: resistances to mefloquine, quinine, chloroquine, and antifolates Funding: United Nations Development Programme/World Bank/World Health Organization Special Programme for Research and Training in Tropical Diseases; Wellcome Trust of Great Britain; Prevention Fundation
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Women were randomized to receive mefloquine or placebo. Not well explained how women were randomized
Allocation concealment (selection bias)	Unclear risk	Not explained
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind trial Quote: "The investigators were unaware of the randomization". Placebo tablets were identical to mefloquine tablets.
Blinding of outcome assessment (detection bias) Efficacy	Unclear risk	Not explained
Blinding of outcome assessment (detection bias) Safety	Unclear risk	Not explained
Incomplete outcome data (attrition bias) All outcomes	Low risk	All excluded participants and those who decided to drop out are correctly reported along with reasons. Missing outcome data were balanced in numbers across groups.
Selective reporting (reporting bias)	Unclear risk	Results of cord and maternal blood smears are not shown (published elsewhere?). No protocol is available. Nothing else was observed.
Other bias	Low risk	The study appears to be free of other sources of bias.

Abbreviations: AE: adverse event; AECID: Spanish Agency for International Cooperation; ANC: antenatal care; ATP: adenosine triphosphate; CISM: Centro de Investigação em Saúde da Manhiça; IPTp: intermittent preventive treatment for malaria in pregnancy; IPTp‐mefloquine: intermittent preventive mefloquine treatment in pregnancy; IPTp‐sulfadoxine‐pyrimethamine: intermittent preventive sulfadoxine‐pyrimethamine treatment in pregnancy; ITT: intention‐to‐treat; LLITN: long‐lasting insecticide‐treated net; PCR: polymerase chain reaction; PMTCT: prevention of mother‐to‐child transmission; SAE: serious adverse event.