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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.

With the advent of rapid diagnostic tests (RDT) for malaria detection, parasitological confirmation of malaria diagnoses has become more readily accessible and increasingly more affordable. However, questions are being asked about how useful they are in screening programmes, particularly for pregnant women who very often may harbour placental malaria infections which may not be detected by peripheral blood smear microscopy. It is also necessary to examine how many malaria infections go undetected by RDTs and whether such undetected infections have any negative consequences for women who carry such RDT-negative infections. This sub-study was conducted as part of a large multi-country trial of intermittent preventive treatment with sulfadoxine pyrimethamine versus intermittent screening and treatment of malaria in pregnancy which in Burkina Faso, Gambia, Ghana and Mali. The study enrolled 5,354 primi- and secundigravidae who attended antenatal clinics at study sites in the four countries from May 2010 to October 2011. The sensitivity of the RDT to detect peripheral malaria in pregnancy using PCR as the reference declined from 89.3% (95% CI 85.5-92.4) on the day of enrollment to 57.7% (95% CI 46.5-73.0) at delivery. However, the sensitivity of the RDT to detect placental malaria was lower when placental histology was used as the reference ranging from 72% (95% CI 63.3-79.7) for any woman who tested RDT positive at any scheduled ANC visit, to 35.4% (95% CI 26.6-45.0) at the delivery visit. The prevalence of sub-RDT malaria was highest at delivery (6.3%). There was no significant association between sub-RDT malaria infection and low birth weight. Of the women in a sub-sample who were seen at first ANC visit, 39.0% had malaria infections out of which 1.7% were non-falciparum infections presenting as mono-infections or mixed infections with P. falciparum. Clinical symptoms and signs were not sensitive enough to predict a positive RDT test and therefore the presence of malaria parasites. Women whose malaria infections get missed by RDTs are not at great risk of developing adverse pregnancy outcomes when compared with women who had no malaria. All pregnant women should be screened with RDT if IST was considered to replace IPTp-SP in areas where SP resistance is too high or transmission intensity is very low.

A thesis presented on a clinical trial of amodiaquine (AQ) and sulphadoxine-pyrimethamine (SP) used singly and in combination (AQ+SP) compared with chloroquine (CQ) for the treatment of 900 pregnant women who had falciparum malaria infection detected by a screening programme using OptiMAL antigen dipsticks during routine antenatal clinic sessions at the St. Theresa's hospital. Enrolment into the study began in March 2003 and ended in September 2004 but follow up of treated women continued to March 2005.

The health situation in Sub-Saharan Africa is complex and multifactorial. Along with its poorly developed economy and lack of basic health services, vector-borne diseases and nutritional disorders are major contributors to the high morbidity and mortality seen today. Malaria and anaemia due to iron deficiency and/or to infectious diseases are rampant in the area affecting its population in general women and children in particular. Although the problem of iron deficiency and anaernia was dealt with varying strategies in different places iron supplementation is widely used in many developing countries and has become a routine procedure in maternal and child health programmes. In recent years, however, there has been a growing concern regarding this approach due to the emergence of conflicting evidence on the health outcome of iron supplementation. In addition to the beneficial effect of iron supplementation, a possible adverse effect on health, particularly on the risk to malaria, has been suggested. The continued controversy has raised doubts as to whether to implement iron supplementation programmes in malaria endemic areas. A randomised, placebo-controlled field trial was conducted in a malaria endemic area in the northwestern part of Ethiopia in May 1993-October 1995 to determine the haernatological response to oral iron supplementation and measure the risk of malarial illness associated with iron. The study involved 776 women and 841 children with low haemoglobin (HB) level who were randomly allocated to receive oral iron or a look alike placebo for a period of 12 weeks. The results of this study showed that anaernia is common in the study population with prevalences of 72.3% and 84.6% among women and children respectively. The content of the staple diet in the area was generally iron insufficient. The dietary iron insufficiency was further realised to be both due to inadequate intake and poor absorption of the iron ingested. The supplementation for 12 weeks was completed by 729 (93.9%) women and 740 (88%) children in the study. After supplementation more women (82.6%) and children (93.5%) in the iron group showed an improvement in their FIB compared with those women (54.6%) and children (43.7%) in the placebo respectively. The mean HB rise was also significantly higher in women and children in the iron than in the placebo group, 1.43 vs 0.28 g/dL, (t= 12.6; p<0.0001) for women and 1.38 vs 0.22 g/dL Q=21.3; p<0.0001) for children respectively. After supplementation women and children with severe anaemia were fewer in the iron (5.1% and 0.3%; x 17.2; p<0.001) than in the placebo group (13.5% and 8.0%; y, 2 =27.9; p<0.001) . After supplementation more women (9.6%) and children (18.2%) in the iron group reached the HB cut-off point showing no anaernia than women (1.4%) and children (9.6%) who received placebo (X2" =23.9; p<0.001 and X2 =34.3; p<0.001 for women and children respectively). Post-supplementation prevalences of clinical malaria among women in the iron and placebo groups were 24.2% and 18.3% respectively (RR=1.3, C1,1.0-1.8). The parasite rate was also higher in the iron supplemented women than those in the placebo, 29.4% and 20.2% respectively (RR=1.47, Cl, 1.4-1.9). During supplementation, women in the iron group experienced more frequent episodes of fever and spent more days with fever than women in the placebo group, (RR=1.16, CI, 1.03-1.30). Similarly, clinical malaria was diagnosed in 19.7% and 13.2% of children in the iron and placebo treatment groups respectively, (RR=1.49, CI, 1.07-2.08). Splenomegaly in children was detected in 27.3% of those in the iron 19.1% of those in the placebo, (RR=1.43, Cl, 1.1-1.9). The parasite rates for iron and placebo supplemented children were 34.5% and 27.1% respectively, (RR=1.28, Cly 1.0-1.6). Febrile episodes were experienced by 68.9% and 58.9% of children in the iron and placebo groups respectively, (RR=1.17; CI, 1.05-1.30. The results indicated not only that the dietary iron intake of the population was inadequate but also was poorly bioavailable due to lack of foods which enhance absorption and due to a high intake of food substances which interfere absorption all of which may have contributed to the anaernia. Study women and children who received iron supplementation have shown a substantial haernatological response (HB rise) and significantly improved their anaemia. The study has also demonstrated that there is a considerable risk of uncomplicated malaria associated with oral iron supplementation as malariometric indices used in this study were all significantly higher among women and children in the iron than in the placebo group. Intervention programmes involving iron supplementation in malaria endemic areas in the future need to weigh the health benefits and the malarial risk attributable to iron. In the present study area,w here nearly all women and children suffer from anaerniaa nd its consequenceso n health, the haematological response to iron supplementation outweighs the associated drawbacks. In such areas oral iron supplementation should therefore continue to be used to prevent and control iron deficiency and anaemia. Public health activities pertaining to the control and prevention of malaria and/or anaernia should, however, protect the population most at risk from malaria when implementing iron supplementation during the malaria transmission seasons.