DOI: 10.25934/pr00007552
title: Impact of Malaria in Pregnancy on Infants Study Group

description: Malaria is a parasitic infection, transmitted to humans by mosquitoes. Once a human is infected, the infection passes through a development stage in the liver, and after a period of days or weeks depending on the species, can start infecting blood cells and affect haemoglobin (the blood level), causing anaemia (a too low blood level) and fever. There are four species of malaria, of which Plasmodium falciparum is the most dangerous and the most common in Africa; Plasmodium vivax is more common outside of Africa. Although malaria can lead to severe illness, some infections do not lead to symptoms but can still be harmful, and it can lead to severe adverse consequences in pregnant women. Approximately 31 million pregnant women in malaria-endemic regions in Africa were estimated to be at risk of infection with malaria in 2015. Infections in pregnancy can lead to maternal anaemia and infant low birthweight, a risk factor for infant mortality, in addition to premature birth and stillbirth. Although the effects of malaria during pregnancy on birth outcomes have been well described, the long term impact of maternal malaria exposure during pregnancy on the infant and on child development are not clear. There are multiple reports that exposure in utero to malaria and other infections affects the developments of the fetal immune system (summarised by Harrington et al. 2018) and may affect the acquisition of malaria in the first year of life. In the early months of life, the prevalence of clinical malaria is low, as the transfer of maternal malaria antibodies leads to protection of the infant during this period, and foetal haemoglobin may not support the development of the pathology of malaria. Placental malaria does not seem to have a consistent effect on the transfer of antimalarial antibodies to the infant but cellular responses to malaria antigens may differ depending on intra-uterine exposure. Malaria in pregnancy was a risk factor for the acquisition of infant malaria in several studies, but in some studies the higher risk was only detected late in infancy or an increased risk was only seen after the first year of life for infants of primigravidae, or differed by gravidity, or intra-uterine foetal sensitization to malaria. Other studies reported a shorter time to first clinical malaria infection, or higher odds of clinical or any malaria, and for some this was modified by the timing of the exposure during pregnancy or compartment of detected infection. 
It has been argued that it is difficult to disentangle the effect of the environment from the effect of intra-uterine malaria exposure; pregnant women with malaria are more likely to live in an environment with a higher risk of malaria; some studies have taken this into account by including an environmental malaria risk factor in the analytical model. Some studies reported observing no association between maternal malaria and infant malaria incidence, or only an association between maternal and infant malaria among small-for-gestational-age infants. A recent review noted that evidence of an association between malaria in pregnancy or intermittent preventive treatment and risk of malaria in infancy is limited and of variable quality; however, one trial comparing intermittent preventive treatment with sulfadoxine pyrimethamine vs. dihydroartemisinin-piperaquine (DP) noted gender differences in susceptibility to malaria in infancy, with placental malaria potentially more severe among male infants. 
Malaria during pregnancy may also affect the risk of other infections during infancy such as diarrhoea, gastrointestinal and acute respiratory infections, and all-cause febrile episodes, by modulating of the foetal immune system or transfer of maternal antibodies. 
Heterogeneity in study results has also been reported for the associations between malaria exposure during pregnancy and infant anaemia or haemoglobin levels, with some studies reporting an association between maternal malaria and infant anaemia or haemoglobin levels, but not others. Similarly, the reported associations between maternal malaria and infant growth have been variable. 

We propose an individual participant data (IPD) meta-analysis to better understand the effects of malaria during pregnancy on infant outcomes. An IPD approach is needed to enable standardisation of outcomes across studies, to be able to adjust for exposures and confounders appropriately, and provide greater scope for subgroup analyses.