Methodology of assessment and reporting of safety in anti-malarial treatment efficacy studies of uncomplicated falciparum malaria in pregnancy: a systematic literature review

Makoto Saito, Mary Ellen Gilder, François Nosten, Philippe J. Guérin, Rose McGready

Considering the uncertainty of safety of anti-malarial drugs in pregnancy, efficacy studies are one of the few sources of clinical safety data. Complete safety evaluation is not usually incorporated in efficacy studies due to financial and human resource constraints. This review reports the methods used for the assessment of safety of artemisinin-based and quinine-based treatments in efficacy studies in pregnancy. Methodology of assessment and reporting of safety in efficacy studies of artemisinin-based and quinine-based treatment in pregnancy was reviewed using seven databases and two clinical trial registries. The protocol was registered to PROSPERO (CRD42017054808). Of 48 eligible efficacy studies the method of estimation of gestational age was reported in only 32 studies (67%, 32/48) and ultrasound was used in 18 studies (38%, 18/48). Seventeen studies (35%, 17/48) reported parity, 9 (19%, 9/48) reported gravidity and 13 (27%, 13/48) reported both. Thirty-eight studies (79%, 38/48) followed participants through to pregnancy outcome. Fetal loss was assessed in 34 studies (89%, 34/38), but the definition of miscarriage and stillbirth were defined only in 11 (32%, 11/34) and 7 (21%, 7/34) studies, respectively. Preterm birth was assessed in 26 studies (68%, 26/38) but was defined in 16 studies (62%, 16/26). Newborn weight was assessed in 30 studies (79%, 30/38) and length in 10 studies (26%, 10/38). Assessment of birth weight took gestational age into account in four studies (13%, 4/30). Congenital abnormalities were reported in 32 studies (84%, 32/38). Other common risk factors for adverse pregnancy outcomes were not well-reported. Incomplete reporting and varied methodological assessment of pregnancy outcomes in anti-malarial drug efficacy studies limits comparison across studies. A standard list of minimal necessary parameters to assess and report the safety component of efficacy studies of anti-malarials in pregnancy is proposed.