1. Objectives

To evaluate the effects of malaria chemoprevention, malaria chemoprevention with sulfadoxine-pyrimethamine (SP), and malaria preventive regimens for Plasmodium vivax during pregnancy on maternal and infant health outcomes

2. How studies were identified

The following databases were searched in June 2014:

• Cochrane Infectious Diseases Group Specialized Register
• CENTRAL (The Cochrane Library 2014)
• MEDLINE
• EMBASE
• LILACS

Reference lists were also hand-searched and the authors directly contacted researchers

3. Criteria for including studies in the review

3.1 Study type

Randomized controlled trials and quasi-randomized controlled trials

3.2 Study participants

Pregnant women living in malaria-endemic areas

(Malaria-endemic areas were defined as regions where malaria transmission occurs and malaria is a feature of the region)

3.3 Interventions

Any antimalarial chemopreventive drug regimen given to pregnant women in comparison to no intervention or placebo

3.4 Primary outcomes

Maternal outcomes

• Maternal death (death during pregnancy or within 42 days of pregnancy termination)
• Severe malaria, which includes severe anaemia (haemoglobin <6 or <7 or <8 g/dL)
• Severe adverse events
• Anaemia (haemoglobin between 10 and 12 g/dL)
• Mean haemoglobin (g/dL) or mean packed cell volume (%)
• Clinical malaria during pregnancy (history of fever episodes prior to delivery)
• Adverse events

Infant outcomes

• Neonatal and infant mortality
• Fetal loss, including spontaneous abortion (spontaneous expulsion of a fetus before it is able to survive independently) and stillbirth (birth of a foetus with no vital signs, born after the 28th week of pregnancy)
• Perinatal mortality
• Severe adverse events, including congenital anomalies
• Preterm birth before 37 weeks’ gestation
• Low birth weight (<2500 g)
• Mean birth weight
• Cord blood anaemia
• Adverse events
• Placental malaria
• Haemoglobin concentrations (g/dL)
• Cord blood haemoglobin (g/dL)
• Cord blood packed cell volume (%)
• Cord blood parasitaemia

4. Main results

4.1 Included studies

Seventeen controlled trials, enrolling 20,256 pregnant women, were included in this review

• Six antimalarial agents were compared with placebo or no preventive intervention (i.e., passive case detection and treatment of clinical cases only): chloroquine (weekly), pyrimethamine (weekly or monthly), proguanil (daily), pyrimethamine-dapsone (weekly or fortnightly), SP (given twice, monthly or intermittently at least one month apart), and mefloquine (weekly)
• Six trials recruited only primiparous women, two trials recruited women having their first or second child, one trial recruited only multigravid women, and the remaining trials recruited women of any parity
• Four trials provided insecticide-treated bed nets to both treatment and control groups
• Iron and/or folic acid were given to women in eight trials, with one of these trials only providing supplements to anaemic women

4.2 Study settings

• Burkina Faso, Cameroon, Gambia (3 trials), Kenya (3 trials), Mozambique (2 trials), Nigeria (3 trials), Thailand (2 trials), and Uganda (2 trials)
• Included studies were conducted in malaria-endemic areas with varying levels of endemicity

4.3 Study settings

How the data were analysed
Three comparisons were made: i) malaria chemoprevention, using any drug regimen, versus placebo or no chemoprevention, ii) SP intermittent preventive therapy chemoprevention for women in their first or second pregnancy, and iii) chemoprevention for P. vivax. Dichotomous data were summarized using risk ratios (RR), continuous data were summarized using mean differences (MD), and count data were summarized using rate ratios. Corresponding 95% confidence intervals (CI) were also calculated. Although one trial was randomized by compound, the data were analyzed as for individually randomized studies. For trials with multiple treatment arms, the control group was divided between each treatment group for analysis of dichotomous outcomes, and for continuous outcomes, the denominator of the control group was divided in two. Comparisons were stratified by parity, grouping trials into low parity (recruiting women with 0 to 1 child), multigravidae (recruiting women with >1 child), and trials that recruited all women, regardless of parity. Trial results that were disaggregated by parity were analysed in the appropriate category. Where substantial heterogeneity was detected, random effects models were used. Packed cell volume values were converted to haemoglobin by dividing by three. Although subgroup analyses were planned by HIV status, risk of bias, geographical region, malaria transmission pattern, antimalarial resistance, insecticide-treated bed net use, and drug regimen, these were not performed due to insufficient data.

Results
Malaria chemoprevention, using any drug regimen, versus placebo or no chemoprevention
Chemoprevention for women having their first or second child
Maternal outcomes
Only 15 maternal deaths were reported among three trials involving 2097 participants, and chemoprevention did not demonstrate any statistically significant effect on maternal death (RR 1.15, 95% CI [0.44 to 3.06]). In comparison to placebo or no chemoprevention, malaria chemoprevention reduced the risk of moderate to severe anaemia by 40% in the third trimester (RR 0.60, 95% CI [0.47 to 0.75], p<0.00001; 3 trials/2503 participants). The risk of any anaemia (haemoglobin <12 g/dL or packed cell volume <33%) was also reduced with chemoprevention (RR 0.83, 95% CI [0.74 to 0.93], p=0.001; 5 trials/3662 participants), and mean haemoglobin in the third trimester was higher (MD 0.41 g/dL, 95% CI [0.29 to 0.54], p<0.00001; 5 trials/3363 participants). The risk of presumed clinical malaria, as indicated by a history of fever, was reduced with chemoprevention in two small trials (RR 0.37, 95% CI [0.18 to 0.74], p=0.0053; 307 participants). A 61% reduction in the risk of antenatal parasitaemia (parasitaemia at delivery or 34 to 36 weeks’ gestation) was found with chemoprevention (RR 0.39. 95% CI [0.26 to 0.58], p<0.00001; 8 trials/3663 participants), although this was subject to a high degree of heterogeneity (I²=82%).

Infant outcomes
Overall, few cases of spontaneous abortion, perinatal deaths, or neonatal deaths occurred, and effect estimates did not reach statistical significance (spontaneous abortion: RR 0.65, 95% CI [0.41 to 1.02], 5 trials/2876 participants; perinatal death: RR 0.73, 95% CI [0.54 to 1.00], 2 trials/1620 participants; neonatal deaths: RR 0.62, 95% CI [0.37 to 1.05], 2 trials/2156 participants). Preterm births were not significantly reduced with chemoprevention in comparison to placebo or no chemoprevention (RR 0.85, 95% CI [0.66 to 1.10], 2 trials/1493 participants). Mean birth weight was higher among infants whose mothers received chemoprevention (MD 92.7 g, 95% CI [62.1 to 123.4], p<0.00001; 9 trials/3936 participants), and the risk of low birth weight <2500 g was also reduced by 27% (RR 0.73, 95% CI [0.61 to 0.87], p=0.00065; 8 trials/3619 participants). Cord blood anaemia and haemoglobin were reported in one small trial; while no statistically significant effect of chemoprevention on cord blood anaemia was found (RR 2.94 95% CI [0.78 to 11.05], 64 infants), cord blood haemoglobin was reduced in the treatment group (MD -1.80 g/dL [-3.46 to -0.14], 64 infants). The risk of placental parasitaemia was reduced by 46% with the use of chemopreventive agents (RR 0.54, 95% CI [0.43 to 0.69], p<0.00001; 7 trials/2830 participants). Cord blood parasitaemia was reported in one trial in which no effect of chemoprevention was described, although few cases were occurred (RR 0.47, 95% CI [0.22 to 1.01], 1335 participants).

Chemoprevention for multigravidae
Maternal outcomes
Ten maternal deaths occurred in one trial of multigravid women, with no significant difference between treatment groups (RR 1.47, 95% CI [0.42 to 5.21], 2239 participants). Severe anaemia was reported in two trials, with pooled results providing no evidence of a treatment effect (RR 0.96, 95% CI [0.41 to 2.25], 2 trials/2682 participants). Mean haemoglobin at delivery was not different between treatment groups in two trials including 676 women (MD 0.01 g/dL, 95% CI [-0.23 to 0.24]). The risk of antenatal parasitaemia was reduced by 62% with chemoprevention in four trials including 3022 women (RR 0.38, 95% CI [0.28 to 0.50], p=0.00001).

Infant outcomes
Deaths in the first six weeks of life were not statistically significantly different between chemoprevention and control groups (RR 1.46, 95% CI [0.90 to 2.38], 1 trial/2017 participants). Meta-analysis of three trials demonstrated no clear benefit of chemoprevention in reducing the risk of low birth weight (RR 0.86, 95% CI [0.64 to 1.17], 3 trials/2743 participants).

Chemoprevention for all women
Maternal outcomes
Overall, nine maternal deaths occurred, with no evidence of a difference between treatment and control groups (RR 0.84, 95% CI [0.25 to 2.74], 4 trials/6026 women). The risk of severe maternal anaemia was statistically significantly reduced with chemopreventive treatment (RR 0.19, 95% CI [0.05 to 0.75], p=0.017; 2 trials/1327 participants), and mean haemoglobin was marginally improved (MD 0.13 g/dL, 95% C [0.00 to 0.25], p=0.042; 3 trials/2233 women), but no evidence of a difference was found for any anaemia (RR 1.03, 95% CI [0.87 to 1.23], 3 trials/3027 participants). No statistically significant difference between intervention and control groups was found for the risk of clinical malaria (RR 0.37, 95% CI [0.11 to 1.23], 4 trials/3455 women) or maternal parasitaemia (RR 0.70, 95% CI [0.44 to 1.13], 5 trials/3961 women).

Infant outcomes
The risk of spontaneous abortion (RR 0.89, 95% CI [0.58 to 1.36], 3 trials/5767 participants), stillbirth (RR 1.02, 95% CI [0.76 to 1.36], 5 trials/7130 participants), perinatal death (RR 1.24, 95% CI [0.94 to 1.63], 4 trials/5216 participants), and neonatal or infant death (RR 0.91, 95% CI [0.71 to 1.16], 5 trials/6313 participants), did not differ between treatment groups. Pooled analyses of these outcomes across all parity stratifications failed to provide any evidence of a benefit of chemopreventive therapy. Preterm birth (RR 0.95, 95% CI [0.65 to 1.38], 2 trials/1174 participants), low birth weight (RR 1.06, 95% CI [0.89 to 1.27], 4 trials/3644 participants), and mean birth weight (MD -0.54 g, 95% CI [-24.66 to 23.58], 5 trials/6007 participants) also did not differ between treatment groups. No statistically significant effect of chemoprevention on the risk of placental parasitaemia (RR 0.44, 95% CI [0.15 to 1.29], 4 trials/3200 participants) or cord blood parasitaemia (RR 0.73, 95% CI [0.47 to 1.14], 1 trial/2629 participants) was detected. A single trial including 870 women reported a 51% reduction in the risk of cord blood anaemia (RR 0.49, 95% CI [0.30 to 0.80], p=0.0044) with a corresponding increase in cord blood packed cell volume (MD 1.01%, 95% CI [0.05 to 1.97], p=0.039).

Sulfadoxine-pyrimethamine (SP) intermittent preventive therapy chemoprevention for women having their first or second child
Maternal outcomes
Ten maternal deaths occurred overall, with no difference between treatment and control groups (RR 0.99, 95% CI [0.30 to 3.22], 2 trials/1926 women). Severe anaemia (RR 0.60, 95% CI [0.47 to 0.75], p<0.00001; 4 trials/2503 participants), anaemia (RR 0.88, 95% CI [0.81 to 0.96], p=0.0054; 5 trials/3219 women), and mean haemoglobin (MD 0.41 g/dL, 95% CI [0.27 to 0.54], p<0.00001; 5 trials/2995 women) were all improved with SP treatment in comparison to no treatment or placebo. The risk of maternal parasitaemia was statistically significantly reduced with SP treatment (RR 0.38, 95% CI [0.24 to 0.59], p=0.000021; 7 trials/3456 women). Clinical malaria was reported in one trial of 174 women in which no clear benefit of SP treatment was observed (RR 0.24, 95% CI [0.05 to 1.12]).

Infant outcomes
In five trials including 2572 participants, the risk of spontaneous abortion was reduced by 39%, although the CI was wide (RR 0.61, 95% CI [0.38 to 0.99], p=0.044). The risks of perinatal death (RR 0.78, 95% CI [0.52 to 0.17], 1 trial/1237 women), neonatal and infant mortality (RR 0.62, 95% CI [0.37 to 1.05], 3 trials/2156 women), and preterm birth (RR 0.85, 95% CI [0.66 to 1.10], 3 trials/1493 women) were not reduced with SP treatment. Low birth weight and mean birth weight were both statistically significantly improved with SP treatment in comparison to no treatment or placebo (RR 0.81, 95% CI [0.67 to 0.99], p=0.035; 7 trials/3043 participants and MD 105.5 g, 95% CI [68 to 143], p<0.00001; 6 trials/2693 women, respectively). SP treatment statistically significantly reduced the risk of placental parasitaemia (RR 0.45, 95% CI [0.33 to 0.61], p<0.00001; 6 trials/2257 women). A similar effect size was found for cord blood parasitaemia in a single trial, although it did not reach statistical significance (RR 0.47, 95% CI [0.22 to 1.01], p=0.052; 1 trial/1335 women).

Chemoprevention for P. vivax
One trial conducted in Thailand was identified for this comparison, in which the chemopreventive chloroquine was used. A 99% reduction in the risk of malaria was reported (RR 0.01, 95% CI [0.00 to 0.20], 942 participants), but no effect on maternal anaemia, low birth weight, or mean birth weight was found.

Adverse effects
Few identified trials reported on adverse effects and therefore analyses were not stratified by parity. For the chemopreventive agent mefloquine, maternal dizziness, vertigo, vomiting, itching, and visual abnormalities were reported in one trial on 339 participants, in which no differences between women in treatment and control groups were found. For the chemopreventive agent SP, maternal skin reactions (RR 0.85, 95% [0.27 to 2.65], 2 trials/1472 participants), maternal nausea and vomiting (RR 1.69, 95% CI [0.22 to 12.81], 2 trials/1472 participants), and any adverse effects for the mother (RR 0.72, 95% CI [0.38 to 1.36], 3 trials/2599 participants) were not different between treatment and control groups. Among infants whose mothers received SP treatment, no statistically significant differences were found for neonatal icterus (RR 0.84, 95% CI [0.63 to 1.13], 3 trials/2233 participants) or congenital anomalies (RR 2.94, 95% CI [0.12 to 71.90], 1 trial/1017 participants).

5. Additional author observations*

Almost all trials were conducted in Africa, and only one trial was identified reporting on the effects of chemoprevention for P. vivax. The review was underpowered to detect or exclude clinically important effects for many outcomes. For women having their first or second child, the outcomes placental parasitaemia (any chemopreventive agent), antenatal parasitaemia (any chemopreventive agent or SP treatment), severe anaemia (any chemopreventive agent or SP treatment), and anaemia (any chemopreventive agent) were rated as high quality using GRADE quality of evidence criteria. All other outcomes assessed using these criteria were rated as being of very low to moderate quality. Only six of the 17 trials reported adequate allocation concealment, and six trials were at high risk of performance and detection bias for lack of blinding. Included trials did not systematically report on adverse events.

Current evidence shows a benefit of malaria chemoprevention for maternal anaemia and parasitaemia, and for infant birth weight. However, it is possible that with reduced malaria transmission and improved antenatal services the benefits of chemoprevention will be attenuated.

Intermittent preventive treatment during pregnancy with SP is currently recommended by the WHO in all areas with moderate to high malaria transmission in Africa. The results of this review indicate there may be justification for investigating other chemopreventive agents in areas where SP resistance exists. Data on adverse effects and long-term outcomes should be recorded in future trials, and more evidence is needed from areas of malaria endemicity outside of Africa.