Artemisinin-based combination therapy in pregnant women in Zambia: efficacy, safety and risk of recurrent malaria.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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

Artemisinin-based combination therapy during pregnancy: outcome of pregnancy and infant mortality: a cohort study.

BACKGROUND: The World Health Organization (WHO) recommendation of treating uncomplicated malaria during the second and third trimester of pregnancy with an artemisinin-based combination therapy (ACT) has already been implemented by all sub-Saharan African countries. However, there is limited knowledge on the effect of ACT on pregnancy outcomes, and on newborn and infant's health. METHODS: Pregnant women with malaria in four countries (Burkina Faso, Ghana, Malawi and Zambia) were treated with either artemether-lumefantrine (AL), amodiaquine-artesunate (ASAQ), mefloquine-artesunate (MQAS), or dihydroartemisinin-piperaquine (DHA-PQ); 3127 live new-borns (822 in the AL, 775 in the ASAQ, 765 in the MQAS and 765 in the DHAPQ arms) were followed-up until their first birthday. RESULTS: Prevalence of placental malaria and low birth weight were 28.0% (738/2646) and 16.0% (480/2999), respectively, with no significant differences between treatment arms. No differences in congenital malformations (p = 0.35), perinatal mortality (p = 0.77), neonatal mortality (p = 0.21), and infant mortality (p = 0.96) were found. CONCLUSIONS: Outcome of pregnancy and infant survival were similar between treatment arms indicating that any of the four artemisinin-based combinations could be safely used during the second and third trimester of pregnancy without any adverse effect on the baby. Nevertheless, smaller safety differences between artemisinin-based combinations cannot be excluded; country-wide post-marketing surveillance would be very helpful to confirm such findings. Trial registration ClinicalTrials.gov, NCT00852423, Registered on 27 February 2009, https://clinicaltrials.gov/ct2/show/NCT00852423

The assessment of gestational age: a comparison of different methods from a malaria pregnancy cohort in sub-Saharan Africa.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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