Comparison of ISTp- PYRAMAX-US-RDT to IPTp-SP to Prevent Malaria in Pregnant Women in DRC (ULTRAPYRAPREG)

• Introduction Malaria is a threat for pregnant women and their offspring in endemic settings (1, 2). Plasmodium falciparum (Pf) can sequester in the placenta during pregnancy, resulting in low peripheral parasitemia. As a consequence, malaria diagnostic tests are often false negative in pregnant women who actually do have a Pf malaria infection (3, 4).

Intermittent Preventive Treatment in pregnant women with Sulfadoxine-Pyrimethamine (IPTp-SP) is one of the World Health Organization (WHO)'s recommended malaria control strategies in sub-Saharan African countries (2). The IPTp-SP strategy surmounts the potential misdiagnosis of malaria in pregnant women by treating them all with SP at pre-determined schedules during the antenatal care (ANC) visits. The efficacy of IPTp-SP is dose dependent and relies on ANC coverage. However, the spread of Plasmodium SP resistant strains now threatens the efficacy of the IPTp-SP and can lead to the proliferation of placental resistant parasites in pregnant women (5-9).

As an alternative for IPTp-SP, Intermittent Screening and Treatment in pregnancy (ISTp) may be considered as an option (10). ISTp comprises of monthly screening of pregnant women with a malaria RDT and treatment of positive cases with an artemisinin-based combination therapy (ACT) regardless of the presence of symptoms. The ISTp depends on the performance of the diagnostic tests and the use of ultrasensitive RDTs (us-RDTs), which have a higher sensitivity than conventional RDTs (11, 12), can avoid false negative that would prevent the method from being effective.

Unlike IPTp-SP, ISTp prevents overuse of antimalarials and, thus, limits drug pressure on malaria parasites (10). This advantage could be potentiated by using an ACT that is not yet used or should not be used by the national malaria control for other strata of the population than pregnant women. Pyronaridine - Artesunate (Pyramax®), a newly approved antimalarial is the ideal candidate for this purpose in Democratic Republic of Congo (DRC). Pyramax®, approved for use in malaria endemic countries since 2015, is used in the field to treat malaria in children and adults (13). There is little information on the safety of Pyramax® during pregnancy, however, Pyronaridine unintentionally administered successfully treated at least 40 cases of malaria in late pregnancy (14) and, a review reported that ACTs, although Pyramax® was not included in, are generally very effective and well tolerated during the second and third trimesters (15).

The hypothesis of this study is that the ISTp using Pyramax® for the treatment and performed with the us-RDT (ISTp-US-Py) is non inferior than IPTp-SP for the prevention of maternal malaria (malaria infection, parasite density), maternal anemia, spontaneous abortions or intrauterine death during pregnancy, fetal morbidity (premature birth, low birth weight, small for gestational age) and neonatal mortality at childbirth.

Inclusion criteria

• Gestation ≥16 weeks;
• Age: ≥18 years;
• Residence within the health facility catchment area;
• Willing to adhere to study requirements and to deliver at the health facility.
• Willing to provide written informed consent; if the woman is illiterate, she can choose an impartial witness, not related to the study, to accompany her during the informant consent process and they will both sign the informed consent form

Exclusion criteria

• Known history of allergy to SP or to an ACT
• An ongoing antibioprophylaxis with cotrimoxazole,
• Current issue requiring hospital admission (including severe malaria as defined by WHO)
• Pregnancy at high risk