Inequalities in sub-Saharan African women's and girls' health opportunities and outcomes: evidence from the Demographic and Health Surveys

BACKGROUND: Maternal and reproductive health services are far from universalization and important gaps exist in their distribution across groups of women in sub-Saharan Africa (SSA). The aim of this study is to determine the magnitude of this unequal distribution of maternal and reproductive health-related opportunities and outcomes and to identify the major sources of inequality. METHODS: Demographic and Health Surveys data were used to analyse 15 opportunities for women of reproductive age (15-49), pregnant women and older adolescent girls (15-19), across 29 SSA countries. The tool employed is the Human Opportunity Index (HOI), a composite indicator that combines the availability of an opportunity (the coverage rate) with a measure of how equitably it is distributed among groups of women with different characteristics (or circumstances). Decompositions are used to assess the contribution of each individual circumstance to inequality. RESULTS: The maternity care package of services is found to have lowest average HOI (26%), while exclusive breastfeeding among children aged 0-6 months has the highest HOI (77%). The other indicators show low HOIs, sometimes lower than 50%, indicating low coverage and/or high inequality. Wealth, education and area of residence are the main contributors to inequality for women of reproductive age. Among adolescent girls, marital status is the major contributor. CONCLUSIONS: Reproductive and maternal health opportunities for women in SSA are scarce and far from reaching the global goals set by the post 2015 agenda. Further progress in improving women's and adolescents' health and well-being can only be achieved by a strong expansion of coverage to produce a more equitable and efficient distribution of health care. Failure to do so will compromise the likelihood of achieving the post-2015 Sustainable Development Goals (SDG). New metrics such as the HOI allows better understanding of the nature of challenges to achieving equity in perinatal and reproductive health, and offers a tool for monitoring progress in implementing a strong equity agenda as a part of the SDG initiative

Mefloquine for preventing malaria in pregnant women

Background: The World Health Organization recommends intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine for malaria for all women who live in moderate to high malaria transmission areas in Africa. However, parasite resistance to sulfadoxine-pyrimethamine has been increasing steadily in some areas of the region. Moreover, HIV-infected women on cotrimoxazole prophylaxis cannot receive sulfadoxine-pyrimethamine because of potential drug interactions. Thus, there is an urgent need to identify alternative drugs for prevention of malaria in pregnancy. One such candidate is mefloquine. Objectives: To assess the effects of mefloquine for preventing malaria in pregnant women, specifically, to evaluate: • the efficacy, safety, and tolerability of mefloquine for preventing malaria in pregnant women; and • the impact of HIV status, gravidity, and use of insecticide-treated nets on the effects of mefloquine.Search methods: We searched the Cochrane Infectious Diseases Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE, Embase, Latin American Caribbean Health Sciences Literature (LILACS), the Malaria in Pregnancy Library, and two trial registers up to 31 January 2018. In addition, we checked references and contacted study authors to identify additional studies, unpublished data, confidential reports, and raw data from published trials. Selection criteria: Randomized and quasi-randomized controlled trials comparing mefloquine IPT or mefloquine prophylaxis against placebo, no treatment, or an alternative drug regimen. Data collection and analysis: Two review authors independently screened all records identified by the search strategy, applied inclusion criteria, assessed risk of bias, and extracted data. We contacted trial authors to ask for additional information when required. Dichotomous outcomes were compared using risk ratios (RRs), count outcomes as incidence rate ratios (IRRs), and continuous outcomes using mean differences (MDs). We have presented all measures of effect with 95% confidence intervals (CIs). We assessed the certainty of evidence using the GRADE approach for the following main outcomes of analysis: maternal peripheral parasitaemia at delivery, clinical malaria episodes during pregnancy, placental malaria, maternal anaemia at delivery, low birth weight, spontaneous abortions and stillbirths, dizziness, and vomiting. Main results: Six trials conducted between 1987 and 2013 from Thailand (1), Benin (3), Gabon (1), Tanzania (1), Mozambique (2), and Kenya (1) that included 8192 pregnant women met our inclusion criteria. Two trials (with 6350 HIV-uninfected pregnant women) compared two IPTp doses of mefloquine with two IPTp doses of sulfadoxine-pyrimethamine. Two other trials involving 1363 HIV-infected women compared three IPTp doses of mefloquine plus cotrimoxazole with cotrimoxazole. One trial in 140 HIV-infected women compared three doses of IPTp-mefloquine with cotrimoxazole. Finally, one trial enrolling 339 of unknown HIV status compared mefloquine prophylaxis with placebo. Study participants included women of all gravidities and of all ages (four trials) or > 18 years (two trials). Gestational age at recruitment was > 20 weeks (one trial), between 16 and 28 weeks (three trials), or ≤ 28 weeks (two trials). Two of the six trials blinded participants and personnel, and only one had low risk of detection bias for safety outcomes. When compared with sulfadoxine-pyrimethamine, IPTp-mefloquine results in a 35% reduction in maternal peripheral parasitaemia at delivery (RR 0.65, 95% CI 0.48 to 0.86; 5455 participants, 2 studies; high-certainty evidence) but may have little or no effect on placental malaria infections (RR 1.04, 95% CI 0.58 to 1.86; 4668 participants, 2 studies; low-certainty evidence). Mefloquine results in little or no difference in the incidence of clinical malaria episodes during pregnancy (incidence rate ratio (IRR) 0.83, 95% CI 0.65 to 1.05, 2 studies; high-certainty evidence). Mefloquine decreased maternal anaemia at delivery (RR 0.84, 95% CI 0.76 to 0.94; 5469 participants, 2 studies; moderate-certainty evidence). Data show little or no difference in the proportions of low birth weight infants (RR 0.95, 95% CI 0.78 to 1.17; 5641 participants, 2 studies; high-certainty evidence) and in stillbirth and spontaneous abortion rates (RR 1.20, 95% CI 0.91 to 1.58; 6219 participants, 2 studies; I2 statistic = 0%; high-certainty evidence). IPTp-mefloquine increased drug-related vomiting (RR 4.76, 95% CI 4.13 to 5.49; 6272 participants, 2 studies; high-certainty evidence) and dizziness (RR 4.21, 95% CI 3.36 to 5.27; participants = 6272, 2 studies; high-certainty evidence). When compared with cotrimoxazole, IPTp-mefloquine plus cotrimoxazole probably results in a 48% reduction in maternal peripheral parasitaemia at delivery (RR 0.52, 95% CI 0.30 to 0.93; 989 participants, 2 studies; moderate-certainty evidence) and a 72% reduction in placental malaria (RR 0.28, 95% CI 0.14 to 0.57; 977 participants, 2 studies; high-certainty evidence) but has little or no effect on the incidence of clinical malaria episodes during pregnancy (IRR 0.76, 95% CI 0.33 to 1.76, 1 study; high-certainty evidence) and probably no effect on maternal anaemia at delivery (RR 0.94, 95% CI 0.73 to 1.20; 1197 participants, 2 studies; moderate-certainty evidence), low birth weight rates (RR 1.20, 95% CI 0.89 to 1.60; 1220 participants, 2 studies; moderate-certainty evidence), and rates of spontaneous abortion and stillbirth (RR 1.12, 95% CI 0.42 to 2.98; 1347 participants, 2 studies; very low-certainty evidence). Mefloquine was associated with higher risks of drug-related vomiting (RR 7.95, 95% CI 4.79 to 13.18; 1055 participants, one study; high-certainty evidence) and dizziness (RR 3.94, 95% CI 2.85 to 5.46; 1055 participants, 1 study; high-certainty evidence). Authors' conclusions: Mefloquine was more efficacious than sulfadoxine-pyrimethamine in HIV-uninfected women or daily cotrimoxazole prophylaxis in HIV-infected pregnant women for prevention of malaria infection and was associated with lower risk of maternal anaemia, no adverse effects on pregnancy outcomes (such as stillbirths and abortions), and no effects on low birth weight and prematurity. However, the high proportion of mefloquine-related adverse events constitutes an important barrier to its effectiveness for malaria preventive treatment in pregnant women

Association between HIV infection and socio-economic status: evidence from a semirural area of southern Mozambique

OBJECTIVES: To analyse the association between socio-economic status (SES) and HIV in Manhica, a district of Southern Mozambique with one of the highest HIV prevalences in the world. METHODS: Data were gathered from two cross-sectional surveys performed in 2010 and 2012 among 1511 adults and from the household census of the district's population. Fractional polynomial logit models were used to analyse the association between HIV and SES, controlling for age and sex and taking into account the nonlinearity of covariates. The inequality of the distribution of HIV infection with regard to SES was computed through a concentration index. RESULTS: Fourth and fifth wealth quintiles, the least poor, were associated with a reduced probability of HIV infection compared to the first quintile (OR = 0.595, P-value = 0.009 and OR = 0.474, P-value < 0.001, respectively). Probability of HIV infection peaked at 36 years and then fell, and was always higher for women regardless of age and SES. HIV infection was unequally distributed across the SES strata. CONCLUSIONS: Despite the high HIV prevalence across the entire population of Manhica, the poorest are at greatest risk of being HIV infected. While women have a higher probability of being HIV positive than men, both sexes showed the same infection reduction at higher levels of SES. HIV interventions in the area should particularly focus on the poorest and on women without neglecting anyone else, as the HIV risk is high for everyone

Hydroxychloroquine efficacy and safety in preventing SARS-CoV-2 infection and COVID-19 disease severity during pregnancy (COVID-Preg) : A structured summary of a study protocol for a randomised placebo controlled trial

Objectives: The primary objectives of the study are: 1. To assess the effect of hydroxychloroquine (HCQ) in reducing SARS-CoV-2 viral shedding by PCR in infected pregnant women with mild symptoms. 2. To assess the efficacy of HCQ to prevent SARS-CoV-2 infection in pregnant women in contact with an infected or suspected case. 3. To evaluate the effect of HCQ in preventing the development of the COVID-19 disease in asymptomatic SARS-CoV-2-infected pregnant women. The secondary objectives are: 1. To determine the effect of HCQ on the clinical course and duration of the COVID-19 disease in SARS-CoV-2-infected pregnant women. 2. To determine the impact of HCQ on the risk of hospitalization and mortality of SARS-CoV-2-infected pregnant women. 3. To assess the safety and tolerability of HCQ in pregnant women. 4. To describe the clinical presentation of SARS-CoV-2 infection during pregnancy. 5. To describe the effects of maternal SARS-CoV-2 infection on pregnancy and perinatal outcomes by treatment group. 6. To determine the risk of vertical transmission (intra-utero and intra-partum) of SARS-CoV-2. Trial design: Randomized double-blind placebo-controlled two-arm multicentre clinical trial to evaluate the safety and efficacy of HCQ to prevent and/or minimize SARS-CoV-2 infection during pregnancy. Participants will be randomized to receive a 14-day oral treatment course of HCQ or placebo, ratio 1:1. Participants: Study population: pregnant women undergoing routine prenatal follow up or attending emergency units at the participating hospitals who report either symptoms/signs suggestive of COVID-19 disease or close contact with a suspected or confirmed COVID-19 case. Inclusion criteria Women will be invited to participate in the trial and sign an informed consent if they meet the following inclusion criteria. •Presenting with fever (≥37.5°C) and/or one mild symptom suggestive of COVID-19 disease (cough, dyspnoea, chills, odynophagia, diarrhoea, muscle pain, anosmia, dysgeusia, headache) OR being contact*of a SARS-CoV-2 confirmed or suspected case in the past 14 days •More than 12 weeks of gestation (dated by ultrasonography) •Agreement to deliver in the study hospitals Exclusion criteria •Known hypersensitivity to HCQ or other 4-amonoquinoline compounds •History of retinopathy of any aetiology •Concomitant use of digoxin, cyclosporine, cimetidine •Known liver disease •Clinical history of cardiac pathology including known long QT syndrome •Unable to cooperate with the requirements of the study •Participating in other intervention studies •Delivery onset (characterized by painful uterine contractions and variable changes of the cervix, including some degree of effacement and slower progression of dilatation up to 5 cm for first and subsequent labours) The study participants will be stratified by clinical presentation and SARS-CoV-2 PCR results. Assignment of participants to study groups will be as follows: •SARS-CoV-2-PCR confirmed, infected pregnant women: a. symptomatic (n=100) b. asymptomatic (n=100) •SARS-CoV-2 PCR negative pregnant women in contact*with a SARS-CoV-2-infected confirmed or suspected case (n=514).*The ECDC definition of close contact will be followed. The trial will be conducted in five hospitals in Spain: Hospital Clínic of Barcelona, Hospital Sant Joan de Déu and Hospital de la Santa Creu i Sant Pau, in Barcelona, and HM Puerta del Sur and Hospital Universitario de Torrejón, in Madrid. Intervention and comparator: Participants will be randomized to HCQ (400 mg/day for three days, followed by 200 mg/day for 11 days) or placebo (2 tablets for three days, followed by one tablet for 11 days). Main outcomes: The primary outcome is the number of PCR-confirmed infected pregnant women assessed from collected nasopharyngeal and oropharyngeal swabs at day 21 after treatment start (one week after treatment is completed). Randomisation: Allocation of participants to study arms will be done centrally by the trial's Sponsor (the Barcelona Institute for Global Health, ISGlobal) by block randomization. This method will ensure balanced allocation to both arms. The electronic CRF will automatically assign a study number to each participant, depending on her study group and recruitment site. Each number will be related to a treatment number, which assigns them to one of the study arms. Blinding (masking): Participants, caregivers, investigators and those assessing the outcomes will be blinded to group assignment. Study tablets (HCQ and placebo) will be identically packaged in small opaque bottles. Numbers to be randomised (sample size): This study requires 200 SARS-CoV-2 infected and 514 contact pregnant women, randomised 1:1 with 100 and 227 respectively in each study arm. Trial Status: Protocol version 1.0, from May 8th, 2020. Recruitment is ongoing (first patient recruited the 19th May 2020 and recruitment end anticipated by December 2020). Trial registration: EudraCT number: 2020-001587-29, registered 2 April 2020. Clinicaltrials.gov identifier: NCT04410562, retrospectively registered 1 June 2020. Full protocol: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol

The economic costs of malaria in pregnancy: evidence from four sub-Saharan countries [version 2; peer review: 2 approved]

Background Malaria in pregnancy is a major public health problem in sub-Saharan Africa (SSA), which imposes a significant economic burden. We provide evidence on the costs of malaria care in pregnancy to households and the health system in four high-burden countries in SSA.  Methods Household and health system economic costs associated with malaria control in pregnancy were estimated in selected areas of the Democratic Republic of Congo (DRC), Madagascar (MDG), Mozambique (MOZ) and Nigeria (NGA). An exit survey was administered to 2,031 pregnant women when leaving the antenatal care (ANC) clinic from October 2020 to June 2021. Women reported the direct and indirect costs associated to malaria prevention and treatment in pregnancy. To estimate health system costs, we interviewed health workers from 133 randomly selected health facilities. Costs were estimated using an ingredients-based approach. Results Average household costs of malaria prevention per pregnancy were USD6.33 in DRC, USD10.06 in MDG, USD15.03 in MOZ and USD13.33 in NGA. Household costs of treating an episode of uncomplicated/complicated malaria were USD22.78/USD46 in DRC, USD16.65/USD35.65 in MDG, USD30.54/USD61.25 in MOZ and USD18.92/USD44.71 in NGA, respectively. Average health system costs of malaria prevention per pregnancy were USD10.74 in DRC, USD16.95 in MDG, USD11.17 in MOZ and USD15.64 in NGA. Health system costs associated with treating an episode of uncomplicated/complicated malaria were USD4.69/USD101.41 in DRC, USD3.61/USD63.33 in MDG, USD4.68/USD83.70 in MOZ and USD4.09/USD92.64 in NGA. These estimates resulted in societal costs of malaria prevention and treatment per pregnancy of USD31.72 in DRC, USD29.77 in MDG, USD31.98 in MOZ and USD46.16 in NGA. Conclusions Malaria in pregnancy imposes a high economic burden on households and the health system. Findings emphasize the importance of investing in effective strategies that improve access to malaria control and reduce the burden of the infection in pregnancy

Burden of malaria in pregnancy among adolescent girls compared to adult women in 5 sub-Saharan African countries: A secondary individual participant data meta-analysis of 2 clinical trials

Background Malaria is among the top causes of death in adolescent girls (10 to 19 years) globally. Adolescent motherhood is associated with increased risk of adverse maternal and neonatal outcomes. The interaction of malaria, adolescence, and pregnancy is especially relevant in malaria endemic areas, where rates of adolescent pregnancy are high. However, data on burden of malaria among adolescent girls are limited. This study aimed at investigating whether adolescent girls were at a greater risk of experiencing malaria-related outcomes in pregnancy—parasitaemia and clinical disease—than adult women. Methods and findings An individual secondary participant-level meta-analysis was conducted using data from 5,804 pregnant women participating in 2 malaria prevention clinical trials in Benin, Gabon, Kenya, Mozambique, and Tanzania between 2009 and 2014. Of the sample, 1,201 participants were adolescent girls with a mean age of 17.5 years (standard deviation (SD) 1.3) and 886 (73.8%) of them primigravidae. Among the 4,603 adult women with mean age of 27.0 years (SD 5.4), 595 (12.9%) were primigravidae. Mean gestational age at enrolment was 20.2 weeks (SD 5.2) and 1,069 (18.4%) participants were HIV-infected. Women were followed monthly until the postpartum visit (1 month to 6 weeks after delivery). This study considered outcomes including clinical episodes during pregnancy, peripheral parasitaemia at delivery, and placental malaria. A 2-stage meta-analysis approach was followed by pooling single multivariable regression results into standard DerSimonian–Laird random-effects models. Adolescent girls were more likely than adult women to present with clinical malaria during pregnancy (incidence risk ratio (IRR) 1.70, 95% confidence interval (CI) 1.20; 2.39, p-value = 0.003, I2 = 0.0%, N = 4,092), peripheral parasitaemia at delivery (odds ratio (OR) 2.28, 95% CI 1.46; 3.55, p-value &lt; 0.001, I2 = 0.0%, N = 3,977), and placental infection (OR 1.97, 95% CI 1.31; 2.98, p-value = 0.001, I2 = 1.4%, N = 4,797). Similar associations were observed among the subgroup of HIV-uninfected participants: IRR 1.72 (95% CI 1.22; 2.45, p-value = 0.002, I2 = 0.0%, N = 3,531) for clinical malaria episodes, OR 2.39 (95% CI 1.49; 3.86, p-value &lt; 0.001, I2 = 0.0%, N = 3,053) for peripheral parasitaemia, and OR 1.88 (95% CI 1.06 to 3.33, p-value = 0.03, I2 = 34.9%, N = 3,847) for placental malaria. Among HIV-infected subgroups statistically significant associations were not observed. Similar associations were found in the subgroup analysis by gravidity. The small sample size and outcome prevalence in specific countries limited the inclusion of some countries in the meta-analysis. Furthermore, peripheral parasitaemia and placental malaria presented a considerable level of missing data—12.6% and 18.2% of participants had missing data on those outcomes, respectively. Given the original scope of the clinical trials, asymptomatic malaria infection was only assessed at the end of pregnancy through peripheral and placental parasitaemia. Conclusions In this study, we observed that adolescent girls in sub-Saharan Africa (SSA) are more prone to experience clinical malaria episodes during pregnancy and have peripheral malaria and placental infection at delivery than adult women. Moreover, to the best of our knowledge, for the first time this study disaggregates figures and stratifies analyses by HIV infection. Similar associations were found for both HIV-infected and uninfected women, although those for HIV-infected participants were not statistically significant. Our finding suggests that adolescent girls may benefit from targeted malaria prevention strategies even before they become pregnant

Drugs for Intermittent Preventive Treatment of Malaria in Pregnancy: Current Knowledge and Way Forward

Malaria infection during pregnancy is an important driver of maternal and neonatal health in endemic countries. Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is recommended for malaria prevention at each scheduled antenatal care visit, starting at the second trimester, in areas of high and moderate transmission. However, the increased resistance to SP in some endemic areas challenges its effectiveness. Furthermore, SP is contraindicated in the first trimester of pregnancy and in HIV-infected women on co-trimoxazole prophylaxis due to potential drug&ndash;drug interactions. Thus, in recent last decades, several studies evaluated alternative drugs that could be used for IPTp. A comprehensive literature review was conducted to summarize the evidence on the efficacy and safety of antimalarial drugs being evaluated for IPTp. Chloroquine, amodiaquine, mefloquine and azithromycin as IPTp have proven to be worse tolerated than SP. Mefloquine was found to increase the risk of mother-to-child transmission of HIV. Dihydroartemisin-piperaquine currently constitutes the most promising IPTp drug alternative; it reduced the prevalence of malaria infection, and placental and clinical malaria in studies among HIV-uninfected women, and it is currently being tested in HIV-infected women. Research on effective antimalarial drugs that can be safely administered for prevention to pregnant women should be prioritized. Malaria prevention in the first trimester of gestation and tailored interventions for HIV-infected women remain key research gaps to be addressed

Inequalities in sub-Saharan African women's and girls' health opportunities and outcomes: evidence from the Demographic and Health Surveys

BACKGROUND: Maternal and reproductive health services are far from universalization and important gaps exist in their distribution across groups of women in sub-Saharan Africa (SSA). The aim of this study is to determine the magnitude of this unequal distribution of maternal and reproductive health-related opportunities and outcomes and to identify the major sources of inequality. METHODS: Demographic and Health Surveys data were used to analyse 15 opportunities for women of reproductive age (15-49), pregnant women and older adolescent girls (15-19), across 29 SSA countries. The tool employed is the Human Opportunity Index (HOI), a composite indicator that combines the availability of an opportunity (the coverage rate) with a measure of how equitably it is distributed among groups of women with different characteristics (or circumstances). Decompositions are used to assess the contribution of each individual circumstance to inequality. RESULTS: The maternity care package of services is found to have lowest average HOI (26%), while exclusive breastfeeding among children aged 0-6 months has the highest HOI (77%). The other indicators show low HOIs, sometimes lower than 50%, indicating low coverage and/or high inequality. Wealth, education and area of residence are the main contributors to inequality for women of reproductive age. Among adolescent girls, marital status is the major contributor. CONCLUSIONS: Reproductive and maternal health opportunities for women in SSA are scarce and far from reaching the global goals set by the post 2015 agenda. Further progress in improving women's and adolescents' health and well-being can only be achieved by a strong expansion of coverage to produce a more equitable and efficient distribution of health care. Failure to do so will compromise the likelihood of achieving the post-2015 Sustainable Development Goals (SDG). New metrics such as the HOI allows better understanding of the nature of challenges to achieving equity in perinatal and reproductive health, and offers a tool for monitoring progress in implementing a strong equity agenda as a part of the SDG initiative

Mefloquine for preventing malaria in pregnant women

Background: The World Health Organization recommends intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine for malaria for all women who live in moderate to high malaria transmission areas in Africa. However, parasite resistance to sulfadoxine-pyrimethamine has been increasing steadily in some areas of the region. Moreover, HIV-infected women on cotrimoxazole prophylaxis cannot receive sulfadoxine-pyrimethamine because of potential drug interactions. Thus, there is an urgent need to identify alternative drugs for prevention of malaria in pregnancy. One such candidate is mefloquine. Objectives: To assess the effects of mefloquine for preventing malaria in pregnant women, specifically, to evaluate: • the efficacy, safety, and tolerability of mefloquine for preventing malaria in pregnant women; and • the impact of HIV status, gravidity, and use of insecticide-treated nets on the effects of mefloquine.Search methods: We searched the Cochrane Infectious Diseases Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE, Embase, Latin American Caribbean Health Sciences Literature (LILACS), the Malaria in Pregnancy Library, and two trial registers up to 31 January 2018. In addition, we checked references and contacted study authors to identify additional studies, unpublished data, confidential reports, and raw data from published trials. Selection criteria: Randomized and quasi-randomized controlled trials comparing mefloquine IPT or mefloquine prophylaxis against placebo, no treatment, or an alternative drug regimen. Data collection and analysis: Two review authors independently screened all records identified by the search strategy, applied inclusion criteria, assessed risk of bias, and extracted data. We contacted trial authors to ask for additional information when required. Dichotomous outcomes were compared using risk ratios (RRs), count outcomes as incidence rate ratios (IRRs), and continuous outcomes using mean differences (MDs). We have presented all measures of effect with 95% confidence intervals (CIs). We assessed the certainty of evidence using the GRADE approach for the following main outcomes of analysis: maternal peripheral parasitaemia at delivery, clinical malaria episodes during pregnancy, placental malaria, maternal anaemia at delivery, low birth weight, spontaneous abortions and stillbirths, dizziness, and vomiting. Main results: Six trials conducted between 1987 and 2013 from Thailand (1), Benin (3), Gabon (1), Tanzania (1), Mozambique (2), and Kenya (1) that included 8192 pregnant women met our inclusion criteria. Two trials (with 6350 HIV-uninfected pregnant women) compared two IPTp doses of mefloquine with two IPTp doses of sulfadoxine-pyrimethamine. Two other trials involving 1363 HIV-infected women compared three IPTp doses of mefloquine plus cotrimoxazole with cotrimoxazole. One trial in 140 HIV-infected women compared three doses of IPTp-mefloquine with cotrimoxazole. Finally, one trial enrolling 339 of unknown HIV status compared mefloquine prophylaxis with placebo. Study participants included women of all gravidities and of all ages (four trials) or > 18 years (two trials). Gestational age at recruitment was > 20 weeks (one trial), between 16 and 28 weeks (three trials), or ≤ 28 weeks (two trials). Two of the six trials blinded participants and personnel, and only one had low risk of detection bias for safety outcomes. When compared with sulfadoxine-pyrimethamine, IPTp-mefloquine results in a 35% reduction in maternal peripheral parasitaemia at delivery (RR 0.65, 95% CI 0.48 to 0.86; 5455 participants, 2 studies; high-certainty evidence) but may have little or no effect on placental malaria infections (RR 1.04, 95% CI 0.58 to 1.86; 4668 participants, 2 studies; low-certainty evidence). Mefloquine results in little or no difference in the incidence of clinical malaria episodes during pregnancy (incidence rate ratio (IRR) 0.83, 95% CI 0.65 to 1.05, 2 studies; high-certainty evidence). Mefloquine decreased maternal anaemia at delivery (RR 0.84, 95% CI 0.76 to 0.94; 5469 participants, 2 studies; moderate-certainty evidence). Data show little or no difference in the proportions of low birth weight infants (RR 0.95, 95% CI 0.78 to 1.17; 5641 participants, 2 studies; high-certainty evidence) and in stillbirth and spontaneous abortion rates (RR 1.20, 95% CI 0.91 to 1.58; 6219 participants, 2 studies; I2 statistic = 0%; high-certainty evidence). IPTp-mefloquine increased drug-related vomiting (RR 4.76, 95% CI 4.13 to 5.49; 6272 participants, 2 studies; high-certainty evidence) and dizziness (RR 4.21, 95% CI 3.36 to 5.27; participants = 6272, 2 studies; high-certainty evidence). When compared with cotrimoxazole, IPTp-mefloquine plus cotrimoxazole probably results in a 48% reduction in maternal peripheral parasitaemia at delivery (RR 0.52, 95% CI 0.30 to 0.93; 989 participants, 2 studies; moderate-certainty evidence) and a 72% reduction in placental malaria (RR 0.28, 95% CI 0.14 to 0.57; 977 participants, 2 studies; high-certainty evidence) but has little or no effect on the incidence of clinical malaria episodes during pregnancy (IRR 0.76, 95% CI 0.33 to 1.76, 1 study; high-certainty evidence) and probably no effect on maternal anaemia at delivery (RR 0.94, 95% CI 0.73 to 1.20; 1197 participants, 2 studies; moderate-certainty evidence), low birth weight rates (RR 1.20, 95% CI 0.89 to 1.60; 1220 participants, 2 studies; moderate-certainty evidence), and rates of spontaneous abortion and stillbirth (RR 1.12, 95% CI 0.42 to 2.98; 1347 participants, 2 studies; very low-certainty evidence). Mefloquine was associated with higher risks of drug-related vomiting (RR 7.95, 95% CI 4.79 to 13.18; 1055 participants, one study; high-certainty evidence) and dizziness (RR 3.94, 95% CI 2.85 to 5.46; 1055 participants, 1 study; high-certainty evidence). Authors' conclusions: Mefloquine was more efficacious than sulfadoxine-pyrimethamine in HIV-uninfected women or daily cotrimoxazole prophylaxis in HIV-infected pregnant women for prevention of malaria infection and was associated with lower risk of maternal anaemia, no adverse effects on pregnancy outcomes (such as stillbirths and abortions), and no effects on low birth weight and prematurity. However, the high proportion of mefloquine-related adverse events constitutes an important barrier to its effectiveness for malaria preventive treatment in pregnant women