Intermittent preventive treatment of malaria in pregnancy and infectious causes of adverse birth outcomes in sub-Saharan Africa

Background: The World Health Organization recommends intermittent preventive treatment of malaria in pregnancy (IPTp) using sulphadoxine-pyrimethamine (SP) during antenatal visits in moderate to high transmission areas. In some areas of Africa, recent efforts to control and eliminate malaria have yielded historic reductions in transmission intensity that have occurred alongside concomitant increases in parasite resistance to SP, compromising the efficacy of IPTp. Nevertheless, IPTp-SP continues to have beneficial effect on birth outcomes, and there is a suspicion that SP may protect against adverse birth outcomes attributable to curable sexually transmitted and reproductive tract infections (STIs/RTIs). This doctoral thesis explores five research questions related to IPTp with methods noted in parentheses. Research questions and methods: 1. In the context of declining malaria transmission, is there a threshold of malaria transmission intensity below which IPTp-SP may no longer protect against the incidence of low birth weight? (Methods: systematic review, meta-analysis, and meta-regression analysis) 2. In the context of declining parasite sensitivity to SP, is there a threshold of the Plasmodium falciparum resistance to SP defined by the prevalence of dhps mutation at codon A581G above which IPTp-SP may no longer protect against the incidence of low birth weight? (Methods: systematic review and meta-analysis) 3. In the context of declining malaria transmission and parasite sensitivity to SP, might protection conferred by IPTp-SP be explained partially by an effect against malaria infection as well as STIs/RTIs? (Methods: descriptive analysis and multivariate logistic regression) 4. In the context of pregnant women attending antenatal care in sub-Saharan Africa, what is the prevalence of malaria infection and curable STIs/RTIs? (Methods: systematic review and meta-analysis) 5. In the context of a high dual burden of malaria infection and curable STIs/RTIs amongst pregnant women in sub-Saharan Africa, would azithromycin be an efficacious drug to be included as part of IPTp? (Methods: systematic review and selected meta-analysis) Results: Evidence suggests that IPTp-SP protects against low birth weight in all gravidae regardless of transmission intensity. This protection persists among primi- and secundigravidae irrespective of the prevalence of the A581G mutation. Protection appears to wane, however, as there is no evidence of protective effect against low birth weight amongst multigravidae where the prevalence of A581G is >10.1%. Despite this finding, data from Zambia suggests that the protective effect of IPTp-SP may safeguard pregnancies against more than just the effects of malaria infection; women who received more doses of IPTp-SP during pregnancy were protected against adverse birth outcomes attributable to co-infection with malaria and several curable STIs/RTIs. Meta-analysis of data from pregnant women attending antenatal care facilities in sub-Saharan Africa suggests that malaria infection and curable STIs/RTIs amongst pregnant women attending antenatal care facilities in sub-Saharan Africa is very high and, when considered collectively, curable STIs/RTIs may be more prevalent than malaria infection during pregnancy. A potential response to this dual burden of disease in pregnancy is to explore combination therapies that address malaria and curable STIs/RTIs jointly and more effectively than IPTp-SP. Research presented in this thesis suggests that curable STIs/RTIs are sensitive to azithromycin and that policymakers need additional evidence to consider adding azithromycin to IPTp regimens. Conclusions: Despite evidence of parasite resistance, IPTp-SP remains protective against the effects of malaria infection in most pregnant women, even where transmission intensities are very low, and may also reduce the burden of curable STIs/RTIs. However, this protection is likely sub-optimal and, given the high prevalence of malaria and curable STIs/RTIs among pregnant women in sub-Saharan Africa, alternative therapies that include azithromycin merit investigation in clinical trials with robust microbiological components.