BACKGROUND: Malaria in pregnancy causes deleterious effects on the mother and has devastating consequences such as low birthweight (LBW), small-for-gestational age (SGA), or preterm birth. In addition, sexually transmitted and reproductive tract infections (STIs/RTIs) are also associated with adverse birth outcomes similar to malaria. A recent observational cohort study of pregnant women conducted in Nchelenge, Zambia, reported that 37.0% (345/941) of pregnant women were co-infected with malaria and at least one curable STI/RTI, 25.4% (237/941) had a curable STI/RTI alone, and 19.5% (182/941) had malaria alone. Of five common curable STIs/RTIs, Trichomonas vaginalis (TV) and bacterial vaginosis (BV) were most often implicated in co-infection with malaria. This established the biological basis for combination therapy among pregnant women aimed at reducing the dual burden of malaria and STIs/RTIs with a particular focus on TV and BV. The World Health Organization (WHO) recommends intermittent preventive treatment in pregnancy with sulfadoxine-pyrimethamine (IPT-SP) for asymptomatic women, but high-level parasite resistance to SP threatens its efficacy. Thus, it is applicable] to replace SP with a combination treatment that contains a highly efficacious antimalarial compound alongside an efficacious anti-STI/RTI therapy to produce better birth outcomes. Dihydroartemisinin-piperaquine (DP), has the potential to replace SP for IPTp. The WHO recommends metronidazole (MTZ) for the treatment of TV and BV in pregnancy which can be provided as a single observed treatment alongside IPTp with SP or DP. The objectives of my thesis were: 1. to determine the protective efficacy of IPTp with SP plus MTZ, or DP plus MTZ, was superior to SP alone in protecting against adverse pregnancy outcomes among pregnant women in Nchelenge district. 2. to determine the day-28 treatment efficacy against Plasmodium falciparum infection among pregnant women in who received either SP alone, SP plus MTZ, or DP plus MTZ . 3. to determine the prevalence of molecular markers of resistance to sulphadoxine-pyremethmine in P. falciparum samples found among pregnant women in Nchelenge district who received either SP alone, SP plus MTZ, or DP plus MTZ. 4. to compare the prevalence of STIs/RTIs at first and second antenatal care visits among pregnant women in Nchelenge district who received either SP alone, SP plus MTZ, or DP plus MTZ. METHODS: The data for this thesis were part of the individually randomized, 3-arm, partially-placebo controlled superiority trial comparing the efficacy, safety, and tolerance of IPTp-SP versus IPTp-SP plus MTZ, or IPTp-DP plus MTZ to reduce adverse birth outcomes attributable to malaria and curable STIs/RTIs in the Nchelenge District of Zambia. Eligible and consenting HIV-uninfected pregnant women (N=5,436) with gestational age between 16 and 28 weeks measured by ultrasound were enrolled consecutively and allocated to treatment groups in a 1:1:1 ratio during antenatal booking. Women received IPTp based on the arm to which they were allocated at each antenatal care visit from enrolment until delivery at monthly intervals. Biological samples for diagnosis of malaria and STIs/RTIs were collected for retrospective analyses. The primary endpoint was based on a composite measure of adverse pregnancy outcome: spontaneous abortion, stillbirth, preterm birth, low birthweight, and neonatal death. In addition, a sub-group of samples that were PCR-positive for P. falciparum malaria at enrolment were analysed to measure the frequency of point mutations on the dhps and dhfr genes for resistance for SP. RESULTS: Protective efficacy of IPTp: In the SP group, 18.8% (287/1,524) of women had an adverse pregnancy outcome compared to 19.4% (292/1,501) in the SP-MTZ group [RR 1.04, 95% CI 0.90 to 1.20], p=0.62) and 18.6% (280/1,504) in the DP-MTZ group [RR 0.99 95% CI 0.85 to 1.14, p=0.76]. The risks of individual adverse pregnancy outcomes of spontaneous abortion, stillbirth, preterm birth, low birthweight, and neonatal death did not differ between the treatment groups. Day-28 SP efficacy against Plasmodium falciparum infection: Plasmodium falciparum infection prevalence at visit 1 (day 0) and visit 2 (day 28) by treatment group were as follows: SP 45.7% (844/1,847) and 20.5% (336/1,640), p=<0.001; SP+MTZ 46.4% (840/1,810) and 19.1% (311/1,628) at visit 2, p=<0.001; DP+MTZ 47.1% (850/1,806) and 5.3% (87/1,642) at visit 2, p=<0.001. Genotypes of P. falciparum: The genotypes present in P. falciparum samples were analysed among two separate sub-groups of women who were parasite-positive at the enrolment visit. In a sub-group of 200 women who had malaria parasitaemia at enrolment, the prevalence of dhps 540 mutations and dhfr581 mutation was 66.8% (133/199, 95% CI: 59.8, 73.3) and 5.0% (10/199, 95% CI: 2.4, 9.0), respectively. The second set of samples consisted of 176 falciparum PCR-positive samples collected that were analysed at the University of Copenhagen. The Pfdhfr SNPs in codons 51,59, 108 and 164 were observed at 84.09% and 0% respectively. In the Pfdhps gene, codons 431, 436, 437, 540, 581 and 613 were analyzed. While the rest neither showed any mutations nor had any insignificant proportions. Codons 540 and 581 showed much higher prevalence point mutations at 74.24% and 9.45% respectively. Ultimately, the study showed quintuple and sextuple mutations at 66% and 11% respectively. Prevalence of curable STIs/RTIs at first and second antenatal care visits: The prevalence of STIs/RTIs between visit 1 (day 0) and visit 2 (day 28) was significantly lower across treatment groups except for Chlamydia trachomatis in the DP-MTZ arm. For TV visit 1 versus visit 2 the prevalence was as follows: SP group 13.7% (248/1,807) versus 10.5% (100/955, p=0.014); SP-MTZ group 13.7% (248/1,810) versus 7.6% (72/945, p=<0.001); DP+MTZ 14.3 (258/1,806) versus 8.4% (80/957, p=<0.001). For BV visit 1 versus visit 2 was as follows: SP arm 35.5% (644/1,807) versus 29.7% (488/1,643, p=<0.001); SP-MTZ arm 34.6% (626/1,810) versus 23.1% (377/1,632, p=<0.001); DP-MTZ arm 33.4% (606/1,806) versus 19.2% (315/1,640, p=<0.001). For Neisseria gonorrhoeae, visit 1 versus visit 2 prevalence was as follow: SP group 13.1% (237/1,807) versus 6.8% (65/955, p=<0.001); SP-MTZ group 12.7% (229/1,807) versus 7.4% (70/945, p=<0.001); DP-MTZ group 11.7% (211/1,806) versus 6.8% (65/957, p=<0.001). Chlamydia infection was similar in the DP-MTZ arm between visit 1 and visit 2, 5.7% (103/1,806) versus 4.4% (42/957, p=0.14), respectively. However, in the SP group prevalence was 7.1% (129/1,807) versus 2.1% (20/955, p=<0.001), and the SP-MTZ group 6.0% (109/1,080) versus 3.0% (28/945, p= <0.001) respectively. CONCLUSIONS: Despite the parasite resistance to SP, current WHO guidelines do not recommend withdrawing IPTp-SP even when there is a high prevalence of mutations associated with SP resistance (In 2013, the WHO recommended that countries consider discontinuing IPTp-SP once the population prevalence of the pfdhps 540E mutation is 95% and the prevalence of the pfdhps 581G mutation is 10%) and despite DP being better at reducing maternal malaria, SP was not inferior in protecting against adverse pregnancy outcomes. SP significantly reduced the day 28 population prevalence of STIs/RTIs suggesting specific non-malarial pathways to reducing adverse pregnancy outcomes. Alternative regimens to address the dual burden of malaria and STIs/RTIs are still needed in this setting.