Online link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4172436/#!po=31.9444

Randomized controlled trial

Background

Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is recommended by WHO to prevent malaria in African pregnant women. The spread of SP parasite resistance has raised concerns regarding long-term use for IPT. Mefloquine (MQ) is the most promising of available alternatives to SP based on safety profile, long half-life, and high efficacy in Africa. We evaluated the safety and efficacy of MQ for IPTp compared to those of SP in HIV-negative women.

Methods and Findings

A total of 4,749 pregnant women were enrolled in an open-label randomized clinical trial conducted in Benin, Gabon, Mozambique, and Tanzania comparing two-dose MQ or SP for IPTp and MQ tolerability of two different regimens. The study arms were: (1) SP, (2) single dose MQ (15 mg/kg), and (3) split-dose MQ in the context of long lasting insecticide treated nets. There was no difference on low birth weight prevalence (primary study outcome) between groups (360/2,778 [13.0%]) for MQ group and 177/1,398 (12.7%) for SP group; risk ratio [RR], 1.02 (95% CI 0.86–1.22; p = 0.80 in the ITT analysis). Women receiving MQ had reduced risks of parasitemia (63/1,372 [4.6%] in the SP group and 88/2,737 [3.2%] in the MQ group; RR, 0.70 [95% CI 0.51–0.96]; p = 0.03) and anemia at delivery (609/1,380 [44.1%] in the SP group and 1,110/2743 [40.5%] in the MQ group; RR, 0.92 [95% CI 0.85–0.99]; p = 0.03), and reduced incidence of clinical malaria (96/551.8 malaria episodes person/year [PYAR] in the SP group and 130/1,103.2 episodes PYAR in the MQ group; RR, 0.67 [95% CI 0.52–0.88]; p = 0.004) and all-cause outpatient attendances during pregnancy (850/557.8 outpatients visits PYAR in the SP group and 1,480/1,110.1 visits PYAR in the MQ group; RR, 0.86 [0.78–0.95]; p = 0.003). There were no differences in the prevalence of placental infection and adverse pregnancy outcomes between groups. Tolerability was poorer in the two MQ groups compared to SP. The most frequently reported related adverse events were dizziness (ranging from 33.9% to 35.5% after dose 1; and 16.0% to 20.8% after dose 2) and vomiting (30.2% to 31.7%, after dose 1 and 15.3% to 17.4% after dose 2) with similar proportions in the full and split MQ arms. The open-label design is a limitation of the study that affects mainly the safety assessment.

Conclusions

Women taking MQ IPTp (15 mg/kg) in the context of long-lasting insecticide treated nets had similar prevalence rates of low birth weight as those taking SP IPTp. MQ recipients had less clinical malaria than SP recipients, and the pregnancy outcomes and safety profile were similar. MQ had poorer tolerability even when splitting the dose over two days. These results do not support a change in the current IPTp policy.

Online link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517148/

Systematic review/meta-analysis

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.

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.

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.

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.

Online link: https://sci-hub.tw/10.1086/605474

Randomized controlled trial

Background. In the context of the increasing resistance to sulfadoxine-pyrimethamine (SP), we evaluated the efficacy of mefloquine (MQ) for intermittent preventive treatment during pregnancy (IPTp).

Methods. A multicenter, open-label equivalence trial was conducted in Benin from July 2005 through April 2008. Women of all gravidities were randomized to receive SP (1500 mg of sulfadoxine and 75 mg of pyrimethamine) or 15 mg/kg MQ in a single intake twice during pregnancy. The primary end point was the proportion of low– birth-weight (LBW) infants (body weight, !2500 g; equivalence margin, 5%).

Results. A total of 1601 women were randomized to receive MQ ( ) or SP ( ). In the modified n p 802 n p 799 intention-to-treat analysis, which assessed only live singleton births, 59 (8%) of 735 women who were given MQ and 72 (9.8%) of 730 women who were given SP gave birth to LBW infants (difference between low birth weights in treatment groups, 1.8%; 95% confidence interval [CI], 4.8% to 1.1%]), establishing equivalence between the drugs. The per-protocol analysis showed consistent results. MQ was more efficacious than SP in preventing placental malaria (prevalence, 1.7% vs 4.4% of women; ), clinical malaria (incidence rate, 26 cases/10,000 P p .005 person-months vs. 68 cases/10,000 person-months; ), and maternal anemia at delivery (as defined by a P p .007 hemoglobin level !10 g/dL) (prevalence, 16% vs 20%; marginally significant at ). Adverse events (mainly P p .09 vomiting, dizziness, tiredness, and nausea) were more commonly associated with the use of MQ (prevalence, 78% vs 32%; ). One woman in the MQ group had severe neuropsychiatric symptoms. 3 P ! 10

Conclusions. MQ proved to be highly efficacious—both clinically and parasitologically—for use as IPTp. However, its low tolerability might impair its effectiveness and requires further investigations.

Online link:  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764647/

Prospective Cohort Study.

Background: Little is known about the effects of intermittent preventive treatment of malaria in pregnancy (IPTp) on the health of sub-Saharan African infants. We have evaluated the safety of IPTp with mefloquine (MQ) compared to sulfadoxine-pyrimethamine (SP) for important infant health and developmental outcomes.

Methods and findings: In the context of a multicenter randomized controlled trial evaluating the safety and efficacy of IPTp with MQ compared to SP in pregnancy carried out in four sub-Saharan countries (Mozambique, Benin, Gabon, and Tanzania), 4,247 newborns, 2,815 born to women who received MQ and 1,432 born to women who received SP for IPTp, were followed up until 12 mo of age. Anthropometric parameters and psychomotor development were assessed at 1, 9, and 12 mo of age, and the incidence of malaria, anemia, hospital admissions, outpatient visits, and mortality were determined until 12 mo of age. No significant differences were found in the proportion of infants with stunting, underweight, wasting, and severe acute malnutrition at 1, 9, and 12 mo of age between infants born to women who were on IPTp with MQ versus SP. Except for three items evaluated at 9 mo of age, no significant differences were observed in the psychomotor development milestones assessed. Incidence of malaria, anemia, hospital admissions, outpatient visits, and mortality were similar between the two groups. Information on the outcomes at 12 mo of age was unavailable in 26% of the infants, 761 (27%) from the MQ group and 377 (26%) from the SP group. Reasons for not completing the study were death (4% of total study population), study withdrawal (6%), migration (8%), and loss to follow-up (9%).

Conclusions: No significant differences were found between IPTp with MQ and SP administered in pregnancy on infant mortality, morbidity, and nutritional outcomes. The poorer performance on certain psychomotor development milestones at 9 mo of age in children born to women in the MQ group compared to those in the SP group may deserve further studies.

(# of subjects/ studies, cohort definition etc)

This study was divided into 3-arm trials: 1) Preventative treatment in pregnancy with sulfadoxine-pyrimethamine, 2) Preventative treatment in pregnancy with mefloquine (15mg/kg full dose) and 3) Preventative treatment in pregnancy with mefloquine (15 mg/kg split dose over 2 days).

4,749 pregnant women who lived in the sub-Saharan region, where exposure to malaria is high, were randomized to receive preventative treatment. 1,578 of them received sulfadoxine-pyrimethamine, 1,580 received mefloquine full dose and 1,591 received mefloquine at split dose.

2) Risk of maternal peripheral malaria parasitemia during delivery.

3) Risk and frequency of maternal anemia.

4) Risk of placental infection, neonatal anemia and neonatal parasitemia.

5) Number of miscarriages, stillbirths, or congenital malformations.

6) Tolerability of sulfadoxine-pyrimethamine and mefloquine.

2) Maternal peripheral malaria parasitemia risk during delivery was reduced by 30% more in women with mefloquine than those who received sulfadoxine-pyrimethamine.

3) The risk and frequency of maternal anemia was also lower in those patients who received mefloquine when compared to those who received sulfadoxine-pyrimethamine.

4) Women who received mefloquine reported lower malaria episodes than those who received sulfadoxine-pyrimethamine during pregnancy.

5) When it came to adverse effects and adverse pregnancy outcomes, there was no significant difference between the two preventative treatments.

6) Patients who took mefloquine showed a poorer tolerability in both full and split doses than patients who took sulfadoxine-pyrimethamine.

(2018)

Participating women in both treatment groups were HIV uninfected women and came from Thailand, Benin, Gabon, Tanzania, Mozambique and Kenya.

Inclusion criteria included randomized and quasi‐randomized controlled trials comparing mefloquine IPT or mefloquine prophylaxis against placebo, no treatment, or an alternative drug regimen.

Two independent authors reviewed and screened all records before including them in this systematic review for further analysis.

2) Clinical malaria episodes during pregnancy.

3) Number of low birth weight infants from each treatment group.

4) Number of stillbirth and spontaneous abortion rates from each treatment group.

5) Adverse effects from each treatment group.

2) Little to no significant difference in clinical malaria episodes between the two treatment groups.

3) Little to no significant difference in low birth wight infants between the two treatment groups.

4) There was also no significant difference between the two treatments when it came to stillbirth and spontaneous abortion rates. Both groups reported very low rates of stillbirths and spontaneous abortions.

5) Mefloquine showed a few non-life-threatening adverse effects such as drug-related vomiting and dizziness which were more frequently present in comparison to those patients who were treated with sulfadoxine-pyrimethamine.

6) Although overall mefloquine showed better effectiveness as a malaria preventative treatment than  sulfadoxine-pyrimethamine, its use is limited due to higher rates of adverse events.

(2009)

Participating patients were divided into two groups: 805 pregnant women were assigned to 15mg/kg of mefloquine treatment and 804 pregnant women were assigned to the sulfadoxine-pyrimethamine group which included 1500 mg of sulfadoxine and 75 mg of pyrimethamine per dose.

Women of all gravidities of 16–28 weeks’ gestation who had no prior history of a neurologic disorder and who never been on either sulfadoxine-pyrimethamine or mefloquine and had no allergic reaction to neither drug,

were eligible to participate.

2) Rate of placental and peripheral parasitemia.

3) Developing rate of anemia.

4) Rate of adverse effects associated with each treatment group.

5) Number of adverse delivery outcomes such as: spontaneous abortions, stillbirths, and congenital anomalies.

2) Mefloquine treatment group reported lower cases of placental and peripheral parasitemia than those treated with sulfadoxine-pyrimethamine. (1.7% in mefloquine group vs. 4.4% in the sulfadoxine-pyrimethamine group).

3) Women treated with mefloquine were less likely to develop anemia (16% of the cases) than those treated with sulfadoxine-pyrimethamine (more than 20% of the cases).

4) When it came to delivery outcomes (spontaneous abortions, stillbirths, and congenital anomalies), both treatment groups reported similar outcomes and no significant differences between the two groups were noted.

5) As for adverse effects, mefloquine group reported a significantly higher rate of adverse effects than those in the sulfadoxine-pyrimethamine group. To be more specific, 78% in the mefloquine group reported adverse effects vs 32% in the sulfadoxine-pyrimethamine group.

6) The most common adverse effects reported from mefloquine group were: vomiting, dizziness, tiredness, and nausea and lasted for an average of 24 to 48 hrs

2) Psychomotor ability of infants in both treatment groups.

3)  Number of clinical malaria, anemia, hospital admissions, or mortality between the two groups.

2)There was no significant difference between the two treatment groups in underweight, wasted or severely acute malnutrition newborns.

3) The ability to stand without help, walk without support and consumption of solid foods when assessed at 9 months of age were more frequent seen on  infants in the mefloquine group when compared to those infants in the sulfadoxine-pyrimethamine group.

4) No significant differences were observed in the incidences of clinical malaria, anemia, hospital admissions, outpatient visits, or mortality between the groups.