1. Objectives

To compare intermittent preventive treatment regimens for malaria in pregnant women with HIV infection living in malaria-endemic areas

2. How studies were identified

The following databases were searched in June 2011:

• Cochrane Infectious Diseases Group Specialized Register
• CENTRAL (The Cochrane Library 2011)
• MEDLINE
• EMBASE
• LILACS
• mRCT

Relevant conference proceedings and reference lists were searched and the authors contacted researchers and organizations in the field

3. Criteria for including studies in the review

3.1 Study type

Randomized controlled trials

3.2 Study participants

Pregnant women with HIV infection living in regions where there is stable transmission of Plasmodium falciparum

3.3 Interventions

Three or more doses of sulfadoxine-pyrimethamine (SP) (25 mg/kg sulphadoxine and 1.25 mg/kg pyrimethamine) during the second and third trimester compared with a control of two doses of SP

In addition, other antimalarial regimens for this population compared with a standard regimen for the same antimalarial agents

3.4 Primary outcomes

• Maternal anaemia at delivery (haemoglobin <11 g/dL)
• Low birth weight (<2500 g)

Secondary outcomes included maternal and neonatal mortality, placental malaria, peripheral parasitaemia on blood smears, birth weight, maternal haemoglobin concentrations, maternal viral load, and adverse events: serious adverse events, adverse events leading to discontinuation of the medication, and other adverse events

4. Main results

4.1 Included studies

Two randomized controlled trials, enrolling 722 HIV-positive women, were included in this review

• One trial recruited women having their first or second child, while the other trial recruited women regardless of their parity
• Both studies compared the impact of monthly SP to the standard WHO recommendation of two doses of SP
• Both trials employed directly observed treatment
• HIV status was determined in both trials using rapid diagnostic tests in parallel, with further testing for discordant results

4.2 Study settings

• Rural Malawi and urban Zambia
• Transmission of P. falciparum was considered stable in both countries
• Resistance of P. falciparum to SP was high in both countries at the time the studies were conducted (2002 to 2005 in Malawi and 2003 to 2004 in Zambia), with both Malawi and Zambia changing to artemisinin combination therapy for treatment of malaria in 2007 and 2002, respectively

4.3 Study settings

How the data were analysed
Monthly intermittent preventive treatment during pregnancy using SP was compared to the standard two-dose regimen of SP. For dichotomous outcomes, risk ratios (RR) with corresponding 95% confidence intervals (CI) were calculated, and for continuous outcomes, mean differences (MD) and 95% CI were calculated. Subgroup analyses were conducted stratifying by parity. Sensitivity analyses for dichotomous outcomes were undertaken as follows:

• Complete case: participants with missing data were excluded from analyses
• Best-case scenario: participants with missing data in the monthly SP group were assumed to have good outcomes while participants with missing data in the two-dose SP group were assumed to have poor outcomes
• Worst-case scenario: participants with missing data in the monthly SP group were assumed to have poor outcomes while participants with missing data in the two-dose SP group were assumed to have good outcomes

Results
Monthly sulfadoxine-pyrimethamine (SP) compared to a standard two-dose regimen
Maternal anaemia
No evidence of a difference in the risk of maternal anaemia was found between women treated with monthly SP in comparison to those receiving the two-dose regimen (RR 0.97, 95% CI [0.84 to 1.12], 2 trials/604 participants). Subgroup analyses by parity did not reveal any significant difference between treatment groups, and nor did sensitivity analysis for the best-case scenario, where all women receiving monthly SP with missing data were treated as having had good outcomes. In pooled analysis of the worst-case scenario, where women with missing data in the monthly SP group were assumed to have poor outcomes, a statistically significant 32% increase in the risk of maternal anaemia with monthly SP was found (RR 1.32, 95% CI [1.05 to 1.66], 2 trials/722 women).

Low birth weight <2500 g
The risk of low birth weight did not differ between treatment groups (RR 0.88, 95% CI [0.59 to 1.32], 2 trials/624 participants). Subgroup analysis by parity did not meaningfully alter the results, and nor did sensitivity analysis of the worst-case scenario. Sensitivity analysis of the best-case scenario demonstrated a 57% reduction in the risk of low birth weight with monthly SP treatment (RR 0.43, 95% CI [0.24 to 0.77], 2 trials/722 participants).

Additional outcomes
Pooled analysis did not demonstrate a statistically significant difference between treatment groups for the outcome neonatal mortality, although few cases occurred. Placental parasitaemia was reduced with SP treatment overall (RR 0.42, 95% CI [0.23 to 0.76], p=0.004; 2 trials/612 participants), and among women having their first or second child (RR 0.38 [0.21 to 0.70], p=0.0019; 2 trials/459 participants), but not among multigravid women (RR 1.87, 95% CI [0.17 to 20.23], 1 trial/153 women). Similar results were found for maternal peripheral parasitaemia (overall: RR 0.26, 95% CI [0.15 to 0.45], p<0.00001; 2 trials/622 participants; primigravidae/secundigravidae: RR 0.25, 95% CI [0.14 to 0.43], p<0.00001; 2 trials/463 participants); multigravidae: RR 0.94, 95% CI [0.06 to 14.75], 1 trial/159 women). Birth weight was significantly improved with SP treatment overall (MD 0.10, 95% CI [0.09 to 0.11], p<0.00001; 2 trials/640 participants), and among women having their first or second child (MD 0.13 [0.12 to 0.15], p<0.00001; 2 trials/474 participants), but not among multigravid women (MD 0.01, 95% CI [-0.01 to 0.03], 1 trial/166 women). Maternal haemoglobin was also significantly improved with SP treatment overall (MD 0.18, 95% CI [0.13 to 0.24], p<0.00001; 2 trials/640 participants), and among multigravid women (MD 0.21 [0.15 to 0.27], p<0.00001; 1 trial/166 participants), but not among women having their first or second child (MD 0.05, 95% CI [-0.09 to 0.18], 2 trials/474 women).

Adverse effects
Both trials reported that adverse effects did not differ between treatment groups.

5. Additional author observations*

Only two trials were identified for inclusion in the review. Both compared monthly SP to the standard two-dose regimen; no trials comparing regimens for other antimalarial agents were identified. GRADE quality of evidence assessments ranged from low to very low for all outcomes. Monthly dosing of SP in comparison to two doses appeared to be more beneficial in the study set in a rural location. The review authors suggested that this might be due to low transmission in the urban area along with an increase in the use of insecticide-treated bed nets and indoor spraying.

Overall, low quality evidence suggests that for HIV-positive women having their first or second child, monthly SP may reduce maternal parasitaemia and placental parasitaemia at delivery, and may increase birth weight. Larger trials are needed to confirm these findings.

SP cannot be co-administered with co-trimoxazole, a drug that is commonly used for infection prophylaxis in HIV-infected pregnant women. In addition, data from Malawi suggest that daily co-trimoxazole in HIV-positive pregnant women is more effective at reducing malaria infections and anaemia compared with intermittent preventive treatment using SP. As SP cannot be used with co-trimoxazole and resistance to SP is increasing, further trials assessing other antimalarial agents are warranted.