Michael Nambozi

Background: Despite widespread Plasmodium falciparum resistance, intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine–pyrimethamine is more protective against adverse pregnancy and birth outcomes compared to IPTp with dihydroartemisinin–piperaquine, even though dihydroartemisinin–piperaquine is superior against malaria-related outcomes. We assessed whether adding metronidazole to sulfadoxine–pyrimethamine is more protective against adverse pregnancy and birth outcomes compared to IPTp with dihydroartemisinin–piperaquine in an area of high malaria transmission and parasite resistance to sulfadoxine–pyrimethamine, and where curable sexually transmitted infections (STIs) in pregnancy, including bacterial vaginosis, are common. Methods: From December 2019 to March 2022, we enrolled pregnant women without HIV into ASPIRE, an individually randomised, double-blinded, three-arm, partly placebo-controlled trial in Zambia. Participants received monthly IPTp with standard sulfadoxine–pyrimethamine (3 tablets 500mg sulfadoxine and 25mg pyrimethamine) plus placebo metronidazole in Arm 1, or standard sulfadoxine–pyrimethamine plus metronidazole (4 tablets 500mg) in Arm 2, or dihydroartemisinin-piperaquine plus metronidazole (3 tablets 40mg dihydroartemisinin and 320mg piperaquine once daily for 3 consecutive days) plus metronidazole (4 tablets 500mg) in Arm 3. The primary outcome was any adverse pregnancy or birth outcome (spontaneous abortion, stillbirth, low birthweight, preterm birth, or neonatal death). Secondary outcomes included components of the primary outcome, small-for-gestational age, and day 28 treatment efficacy of IPTp regimens against asymptomatic Plasmodium falciparum malaria infection and asymptomatic curable STIs. We used a modified intention-to-treat analysis for the primary outcome. ClinicalTrials.gov: NCT04189744. Findings: 5436 pregnant women were allocated to three treatment-arms. Overall, 16·3% (288/1763) of women in Arm 1 (reference) had adverse pregnancy and birth outcomes compared to 16·6% (290/1745) in Arm 2 (p=0·82), and 16·0% (281/1755) in Arm 3 (p=0·79). Of individual components of adverse pregnancy and birth outcomes in the primary outcome, none differed across arms. However, women in Arm 3 were at greater risk of delivering small-for-gestational age newborns relative to Arm 1, 28·4% (476/1678) vs 24·5% (408/1663) (p=0·01). In Arms 1, 2, and 3, the day 28 clearance of asymptomatic peripheral malaria detected by PCR was 72·1% (555/770), 71·8% (541/754), and 93·5% (722/772), respectively. In Arm 1, day 28 clearance of asymptomatic STIs by PCR, and bacterial vaginosis by microscopy using the Nugent score, were: Chlamydia trachomatis 98·4% (60/61), Neisseria gonorrhoea 84·1% (95/113), Trichomonas vaginalis 75·0% (96/128), and bacterial vaginosis 34·3% (193/563). In Arm 2, day 28 clearance rates were: C. trachomatis 89·5% (51/57), N. gonorrhoea 84·2% (96/114), T. vaginalis 87·5% (105/120), and bacterial vaginosis 53·9% (289/536). In Arm 3, day 28 clearance rates were: C. trachomatis 80·8% (42/52), N. gonorrhoea 84·9% (84/99), T. vaginalis 89·8% (115/128), and bacterial vaginosis 62·2% (335/536). Interpretation: Neither Arm 2 nor 3 were superior to Arm 1 for protection against adverse pregnancy and birth outcomes. Arm 3 was superior to Arms 1 and 2 against malaria infection, whereas all IPTp regimens reduced curable STIs, including bacterial vaginosis. Sulfadoxine-pyrimethamine may serve as an important tool fo

Determining gestational age in resource-poor settings is challenging because of limited availability of ultrasound technology and late first presentation to antenatal clinic. Last menstrual period (LMP), symphysio-pubis fundal height (SFH) and Ballard Score (BS) at delivery are therefore often used. We assessed the accuracy of LMP, SFH, and BS to estimate gestational age at delivery and preterm birth compared to ultrasound (US) using a large dataset derived from a randomized controlled trial in pregnant malaria patients in four African countries. Mean and median gestational age for US, LMP, SFH and BS were calculated for the entire study population and stratified by country. Correlation coefficients were calculated using Pearson’s rho, and Bland Altman plots were used to calculate mean differences in findings with 95% limit of agreements. Sensitivity, specificity, positive predictive value and negative predictive value were calculated considering US as reference method to identify term and preterm babies. A total of 1630 women with P. falciparum infection and a gestational age > 24 weeks determined by ultrasound at enrolment were included in the analysis. The mean gestational age at delivery using US was 38.7 weeks (95%CI: 38.6–38.8), by LMP, 38.4 weeks (95%CI: 38.0–38.9), by SFH, 38.3 weeks (95%CI: 38.2–38.5), and by BS 38.0 weeks (95%CI: 37.9–38.1) (p < 0.001). Correlation between US and any of the other three methods was poor to moderate. Sensitivity and specificity to determine prematurity were 0.63 (95%CI 0.50–0.75) and 0.72 (95%CI, 0.66–0.76) for LMP, 0.80 (95%CI 0.74–0.85) and 0.74 (95%CI 0.72–0.76) for SFH and 0.42 (95%CI 0.35–0.49) and 0.77 (95%CI 0.74–0.79) for BS. In settings with limited access to ultrasound, and in women who had been treated with P. falciparum malaria, SFH may be the most useful antenatal tool to date a pregnancy when women present first in second and third trimester. The Ballard postnatal maturation assessment has a limited role and lacks precision. Improving ultrasound facilities and skills, and early attendance, together with the development of new technologies such as automated image analysis and new postnatal methods to assess gestational age, are essential for the study and management of preterm birth in low-income settings.

In Zambia, malaria is one of the leading causes of morbidity and mortality, especially among under five children and pregnant women. For the latter, the World Health Organization recommends the use of artemisinin-based combination therapy (ACT) in the second and third trimester of pregnancy. In a context of limited information on ACT, the safety and efficacy of three combinations, namely artemether–lumefantrine (AL), mefloquine–artesunate (MQAS) and dihydroartemisinin–piperaquine (DHAPQ) were assessed in pregnant women with malaria. The trial was carried out between July 2010 and August 2013 in Nchelenge district, Luapula Province, an area of high transmission, as part of a multi-centre trial. Women in the second or third trimester of pregnancy and with malaria were recruited and randomized to one of the three study arms. Women were actively followed up for 63 days, and then at delivery and 1 year post-delivery. Nine hundred pregnant women were included, 300 per arm. PCR-adjusted treatment failure was 4.7% (12/258) (95% CI 2.7–8.0) for AL, 1.3% (3/235) (95% CI 0.4–3.7) for MQAS and 0.8% (2/236) (95% CI 0.2–3.0) for DHAPQ, with significant risk difference between AL and DHAPQ (p = 0.01) and between AL and MQAS (p = 0.03) treatments. Re-infections during follow up were more frequent in the AL (HR: 4.71; 95% CI 3.10–7.2; p < 0.01) and MQAS (HR: 1.59; 95% CI 1.02–2.46; p = 0.04) arms compared to the DHAPQ arm. PCR-adjusted treatment failure was significantly associated with women under 20 years [Hazard Ratio (HR) 5.35 (95% CI 1.07–26.73; p = 0.04)] and higher malaria parasite density [3.23 (95% CI 1.03–10.10; p = 0.04)], and still women under 20 years [1.78, (95% CI 1.26–2.52; p < 0.01)] had a significantly higher risk of re-infection. The three treatments were generally well tolerated. Dizziness, nausea, vomiting, headache and asthenia as adverse events (AEs) were more common in MQAS than in AL or DHAPQ (p < 0.001). Birth outcomes were not significantly different between treatment arms. As new infections can be prevented by a long acting partner drug to the artemisinins, DHAPQ should be preferred in places as Nchelenge district where transmission is intense while in areas of low transmission intensity AL or MQAS may be used.

Intermittent preventive treatment of malaria in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) decreases placental parasitaemia, thus improving birth outcomes. Zambian policy recommends monthly SP-IPTp doses given presumptively during pregnancy at each antenatal examination, spaced one month apart after 16 weeks of gestation. The effectiveness of SP-IPTp was evaluated in Zambia where a recent study showed moderate prevalence of Plasmodium falciparum parasites with genetic mutations that confer SP resistance. HIV-negative women were enrolled at the time of delivery at two facilities in Mansa, Zambia, an area of high malaria transmission. Women were interviewed and SP exposure was determined by antenatal card documentation or self-reports. Using Poisson regression modelling, the effectiveness of SP-IPTp was evaluated for outcomes of parasitaemia (microscopic examination of maternal peripheral, cord, and placental blood films), maternal anaemia (Hb < 11 g/dl), placental infection (histopathology), and infant outcomes (low birth weight (LBW), preterm delivery, and small for gestational age) in women who took 0–4 doses of SP-IPTp. Participants included 435 women, with a median age of 23 years (range 16–44). Thirty-four women took zero doses of SP-IPTp, while 115, 142 and 144 women took one, two, or ≥ three doses, respectively. Multivariate Poisson regression models considering age, mosquito net usage, indoor residual spraying, urban home, gravidity, facility, wet season delivery, and marital status showed that among paucigravid women ≥ two doses of SP-ITPp compared to one or less doses was associated with a protective effect on LBW (prevalence ratio (PR) 0.33, 95% confidence interval (CI) 0.12–0.91) and any infection (PR 0.76, CI 0.58–0.99). Multivariate models considering SP-IPTp as a continuous variable showed a protective dose–response association with LBW (paucigravid women: PR 0.54, CI 0.33–0.90, multigravid women: PR 0.63, CI 0.41–0.97). In Mansa, Zambia, an area of moderate SP resistance, ≥ two doses of SP-IPTp were associated with a protective effect from malaria in pregnancy, especially among paucigravid women. Each dose of SP-IPTp contributed to a 46 and 37% decrease in the frequency of LBW among paucigravid and multigravid women, respectively. SP-IPTp remains a viable strategy in this context.

Asymptomatic and symptomatic malaria during pregnancy has consequences for both mother and her offspring. Unfortunately, there is insufficient information on the safety and efficacy of most antimalarials in pregnancy. Indeed, clinical trials assessing antimalarial treatments systematically exclude pregnancy for fear of teratogenicity and embryotoxicity. The little available information originates from South East Asia while in sub-Saharan Africa such information is still limited and needs to be provided.

Intermittent preventive treatment of malaria in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) decreases adverse effects of malaria during pregnancy. Zambia implemented its IPTp-SP programme in 2003. Emergence of SP-resistant Plasmodium falciparum threatens this strategy. The quintuple mutant haplotype (substitutions in N51I, C59R, S108N in dhfr and A437G and K540E in dhps genes), is associated with SP treatment failure in non-pregnant patients with malaria. This study examined efficacy of IPTp-SP and presence of the quintuple mutant among pregnant women in Mansa, Zambia.

Malaria is considered as one of the major public health problems and among the diseases of poverty. In areas of stable and relatively high transmission, pregnant women and their newborn babies are among the higher risk groups. A multicentre trial on the safety and efficacy of several formulations of artemisinin-based combination therapy (ACT) during pregnancy is currently on-going in four African countries, including Zambia, whose study site is in Nchelenge district. As the study outcomes may be influenced by the local malaria endemicity, this needs to be characterized. A cross-sectional survey to determine the prevalence and intensity of infection among <10 years old was carried out in March-April 2012 in Nchelenge district.

Malaria in Zambia remains a public health and developmental challenge, affecting mostly children under five and pregnant women. In 2002, the first-line treatment for uncomplicated malaria was changed to artemether-lumefantrine (AL) that has proved to be highly efficacious against multidrug resistant Plasmodium falciparum. The study objective was to determine whether dihydroartemisinin-piperaquine (DHA/PQP) had similar efficacy, safety and tolerability as AL for the treatment of children with uncomplicated P. falciparum malaria in Ndola, Zambia. Between 2005 and 2006, 304 children (6-59 months old) with uncomplicated P. falciparum were enrolled, randomized to AL (101) or DHA/PQP (203) and followed up for 42 days. Outcome of treatment was defined according to the standard WHO classification, i.e. early treatment failure (ETF), late clinical failure (LCF, late parasitological failure (LPF) and adequate clinical and parasitological response (ACPR). Recurrent infections were genotyped to distinguish between recrudescence and new infection. No ETF was observed. At day 28, PCR-uncorrected ACPR was 92% in the DHA/PQP and 74% in the AL arm (OR: 4.05; 95%CI: 1.89-8.74; p < 0.001). Most failure were new infections and PCR-corrected ACPR was similar in the two study arms (OR: 0.69; 95%CI: 0.22-2.26; p = 0.33). Similar results were observed for day 42, i.e. higher PCR-uncorrected ACPR for DHA/PQP, mainly due to the difference observed up to day 28, while the PCR-corrected ACPR was similar: DHA/PQP: 93% (179/192), AL: 93% (84/90), (OR: 0.92; 95%CI: 0.30-2.64; p = 0.85). Except for cough, more frequent in the DHA/PQP arm (p = 0.04), there were no differences between treatment arms in the occurrence of adverse events. Two serious adverse events were probably associated to AL treatment. DHA/PQP was as efficacious, safe and well tolerated in treatment of uncomplicated malaria as AL, though in the latter group more new infections during the follow up were observed. DHA/PQP seems a potential candidate to be used as an alternative first-line or rescue treatment in Zambia. ISRCTN16263443, at http://www.controlled-trials.com/isrctn