Key messages
• For HIV-positive pregnant women, adding an antimalarial drug (such as mefloquine or dihydroartemisinin/piperaquine) to usual infection-prevention treatment for people with HIV (daily cotrimoxazole):
- probably reduces the risk of the mother being infected with malaria when she delivers her baby;
- probably reduces malarial infection in the placenta;
- probably does not affect the risk of losing the baby before delivery or after birth, or of the baby having a low birthweight.
• Although mefloquine, when added to daily cotrimoxazole, probably reduces the risk of malaria infection in HIV-positive women, it probably increases the risk of mother-to-child HIV transmission and may have a higher risk of negative drug reactions.
• Dihydroartemisinin/piperaquine, when added to daily cotrimoxazole, probably reduces the risk of malaria in the placenta of HIV-positive pregnant women. It probably makes no difference to the risk of low birth weight or losing the baby before or after birth, or the risk of minor side effects, such as vomiting.
Why is malaria prevention in HIV-positive pregnant women important?
HIV-positive pregnant women are vulnerable to malaria. Having both malaria and HIV can make malaria worse in pregnancy, increasing the risk of health complications for women and their babies. Daily intake of a drug called cotrimoxazole is recommended to prevent infections in people with HIV, including pregnant women, in many countries where malaria is common. The drug that is recommended to prevent malaria in pregnancy, sulfadoxine-pyrimethamine, cannot be taken by women on cotrimozaxole because of potential negative interactions between the two drugs.
What did we want to find out?
We wanted to know if antimalarial drugs currently available are effective and safe when used for preventing malaria in HIV-positive pregnant women. This is an update of a Cochrane Review published in 2011.
What did we do?
We searched for studies that investigated the benefits and harms of antimalarial drugs used for prevention of malaria among HIV-positive pregnant women. We combined the results of these studies.
What did we find?
We found 14 studies with 4976 HIV-positive pregnant women. The studies were conducted between 2002 and 2023 in sub-Saharan African countries: Benin, Central African Republic, Gabon, Malawi, Mozambique, Nigeria, Kenya, Tanzania, Togo, Uganda, and Zambia. The studies tested nine comparisons of different drug regimens.
What are our main results?
Adding an anti-malarial drug such as mefloquine or dihydroartemisinin/piperaquine to daily cotrimoxazole probably reduces the risk of malaria infection in the mother's blood at delivery and in the placenta. It probably does not increase or decrease the risk of having a baby with low birth weight, or of losing the baby before or after birth. It probably does not increase or decrease the mother's risk of anaemia (i.e. low level of iron in the blood). We do not know if it has any effect on the risk of malarial parasites in the baby's umbilical cord.
Although mefloquine probably reduces the risk of malarial infection, it probably increases the risk of mother-to-child HIV transmission and may be more likely to cause negative drug-related effects, when compared to daily cotrimoxazole alone.
When we looked separately at the studies that evaluated dihydroartemisinin/piperaquine, we found that dihydroartemisinin/piperaquine added to daily cotrimoxazole probably does not reduce the presence of the Plasmodium parasites in the mother's blood at delivery or her risk of anaemia, but it reduces malarial infection in the placenta. It probably does not increase or decrease the risk of low birth weight, or of losing the baby before or after birth. Dihydroartemisinin/piperaquine plus daily cotrimoxazole may not increase the risk of mother-to-child HIV transmission, compared to daily cotrimoxazole alone, and may not increase the risk of negative side effects from taking the drug.
What are the limitations of the evidence?
In terms of routine preventive treatment for HIV-positive women (daily cotrimoxazole) plus any other drug (mefloquine or dihydroartemisinin/piperaquine), we are confident in the evidence regarding maternal anaemia at delivery. We are moderately confident in the evidence regarding presence of parasites in the mother's blood and placenta, babies born with low birth weight, and stillbirths and spontaneous abortions. It is possible that people in one of the studies were aware of who had received each drug regimen, which could have affected the study results. We are less confident in our results for presence of parasites in the cord blood and the risk of the baby dying after birth, because the results from the studies varied widely.
In terms of routine preventive treatment (daily cotrimoxazole) plus dihydroartemisinin/piperaquine specifically, we are confident in the evidence regarding malaria infection detected by the presence of parasites in the mother's placenta. We are moderately confident in the evidence regarding presence of parasites in the mother's blood, maternal anaemia at delivery, babies born with low birth weight, stillbirths and spontaneous abortions, and infant deaths. We are less confident in our results for the drug's side effects, and HIV transmission from mother to baby.
How up to date is this evidence?
The review authors searched for studies up to 31 January 2024.
Dihydroartemisinin/piperaquine and mefloquine added to daily cotrimoxazole seem to be efficacious in preventing malaria infection in HIV-positive pregnant women compared to daily cotrimoxazole alone. However, increased risk of HIV transmission to the foetus and poor drug tolerability may be barriers to implementation of mefloquine in practice. In contrast, the evidence suggests that dihydroartemisinin/piperaquine does not increase the risk of HIV mother-to-child transmission and is well tolerated.
Malaria and HIV infection overlap geographically in sub-Saharan Africa and share risk factors. HIV infection increases malaria's severity, especially in pregnant women. The World Health Organization (WHO) recommends intermittent preventive treatment in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) for pregnant women living in areas of stable malaria transmission. However, HIV-positive women on daily cotrimoxazole prophylaxis (recommended for prevention of opportunistic infections in people with HIV) cannot receive SP due to adverse drug interactions, so malaria prevention in this vulnerable population currently relies on daily cotrimoxazole prophylaxis alone. This review is based on a new protocol and provides an update to the 2011 Cochrane Review that evaluated alternative drugs for IPTp to prevent malaria in HIV-positive women.
To compare the safety and efficacy of intermittent preventive treatment regimens for malaria prevention in HIV-positive pregnant women.
We searched CENTRAL, MEDLINE, Embase, three other databases, and two trial registries to 31 January 2024. To identify relevant additional studies or unpublished work, we checked references and contacted study authors and other researchers working on malaria and HIV.
We included randomized controlled trials (RCTs) comparing any intermittent preventive treatment regimen for preventing malaria in HIV-positive pregnant women against daily cotrimoxazole prophylaxis alone, placebo, current or previous standard of care, or combinations of these options. By 'standard of care' we refer to the country's recommended drug regimen to prevent malaria in pregnancy among HIV-positive women, or the treatment that a trial's research team considered to be the standard of care.
Review authors, in pairs, independently screened all records identified by the search strategy, applied inclusion criteria, assessed risk of bias in included trials, and extracted data. We contacted trial authors when additional information was required. We presented dichotomous outcomes using risk ratios (RRs), count outcomes as incidence rate ratios (IRRs), and continuous outcomes as mean differences (MDs). We presented all measures of effect with 95% confidence intervals (CIs). We assessed the certainty of the evidence using the GRADE approach for what we considered to be the main comparisons and outcomes.
We included 14 RCTs, with a total of 4976 HIV-positive pregnant women initially randomized. All trials assessed the efficacy and safety of one antimalarial used as IPTp (mefloquine, dihydroartemisinin/piperaquine, SP, or azithromycin) with or without daily cotrimoxazole, compared to daily cotrimoxazole alone, placebo, or a standard of care regimen. We grouped the trials into nine comparisons. Our main comparison evaluated the current standard of care (daily cotrimoxazole) with another drug regimen (mefloquine or dihydroartemisinin/piperaquine) versus daily cotrimoxazole with or without placebo. In this comparison, two trials evaluated mefloquine and three evaluated dihydroartemisinin/piperaquine. We conducted meta-analyses that included trials evaluating dihydroartemisinin/piperaquine plus cotrimoxazole, and trials that evaluated mefloquine plus cotrimoxazole, as we considered there to be no qualitative or quantitative heterogeneity among trials for most outcomes. We considered drug-related adverse events and HIV-related outcomes to be drug-specific.
Daily cotrimoxazole prophylaxis plus another drug regimen (mefloquine or dihydroartemisinin/piperaquine) probably results in lower risk of maternal peripheral parasitaemia at delivery (RR 0.62, 95% CI 0.41 to 0.95; 2406 participants, 5 trials; moderate-certainty evidence). It results in little or no difference in maternal anaemia cases at delivery (RR 0.98, 95% CI 0.90 to 1.07; 2417 participants, 3 trials; high-certainty evidence). It probably results in a decrease in placental malaria measured by blood smear (RR 0.54, 95% CI 0.31 to 0.93; 1337 participants, 3 trials; moderate-certainty evidence), and probably results in little or no difference in low birth weight (RR 1.16, 95% CI 0.95 to 1.41; 2915 participants, 5 trials; moderate-certainty evidence). There is insufficient evidence to ascertain whether daily cotrimoxazole prophylaxis plus another drug regimen affects the risk of cord blood parasitaemia (RR 0.27, 95% CI 0.04 to 1.64; 2696 participants, 5 trials; very low-certainty evidence).
Daily cotrimoxazole prophylaxis plus another drug regimen probably results in little or no difference in foetal loss (RR 1.03, 95% CI 0.73 to 1.46; 2957 participants, 5 trials; moderate-certainty evidence), and may result in little or no difference in neonatal mortality (RR 1.21, 95% CI 0.68 to 2.14; 2706 participants, 4 trials; low-certainty evidence).
Due to the probability of an increased risk of mother-to-child HIV transmission and some adverse drug effects noted with mefloquine, we also looked at the results for dihydroartemisinin/piperaquine specifically.
Dihydroartemisinin/piperaquine plus daily contrimoxazole probably results in little to no difference in maternal peripheral parasitaemia (RR 0.59, 95% CI 0.31 to 1.11; 1517 participants, 3 trials; moderate-certainty evidence) or anaemia at delivery (RR 0.95, 95% CI 0.82 to 1.10; 1454 participants, 2 trials; moderate-certainty evidence), but leads to fewer women having placental malaria when measured by histopathologic analysis (RR 0.67, 95% CI 0.50 to 0.90; 1570 participants, 3 trials; high-certainty evidence). The addition of dihydroartemisinin/piperaquine to daily cotrimoxazole probably made little to no difference to rates of low birth weight (RR 1.13, 95% CI 0.87 to 1.48; 1695 participants, 3 trials), foetal loss (RR 1.14, 95% CI 0.68 to 1.90; 1610 participants, 3 trials), or neonatal mortality (RR 1.03, 95% CI 0.39 to 2.72; 1467 participants, 2 trials) (all moderate-certainty evidence). We found low-certainty evidence of no increased risk of gastrointestinal drug-related adverse events (RR 1.42, 95% CI 0.51 to 3.98; 1447 participants, 2 trials) or mother-to-child HIV transmission (RR 1.54, 95% CI 0.26 to 9.19; 1063 participants, 2 trials).