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

Abstract

BackgroundConsidering 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.MethodsMethodology 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).ResultsOf 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.ConclusionIncomplete 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.Electronic supplementary materialThe online version of this article (10.1186/s12936-017-2136-x) contains supplementary material, which is available to authorized users.

Pregnancy outcomes and risk of placental malaria after artemisinin-based and quinine-based treatment for uncomplicated falciparum malaria in pregnancy: a WorldWide Antimalarial Resistance Network systematic review and individual patient data meta-analysis

“…Gestational age was strictly defined and assessed with ultrasound for > 90% of women included. Individual studies used different cut-offs or definitions [11]; thus, aggregated data metaanalysis was difficult. With IPD, standardized definitions for both exposures and outcomes were applied.…”

“…The use of insecticide-treated bed nets and the history of malaria and antimalarial use including IPTp before and after the study period were not always available (or not systematically collected). As IPTp is associated with a lower risk of LBW [57], it is possible that we have underestimated the impact of malaria on the pregnancy outcomes by missing some unreported IPTp intervention [11]. However, these two preventive measures can be regarded as an unmeasured study-level information and was statistically taken into account by mixed-effects model.…”

“…The most widely reported adverse impact of malaria in pregnancy is low birthweight (LBW), commonly defined as birthweight less than 2500 g and used as a proxy for foetal growth [11,12]. However, LBW does not distinguish between being "born to early" (or PTB) or "born to small" (or IUGR), or both, which are associated with different neonatal mortality and morbidity.…”

Systematic review of statistical methods for safety data in malaria chemoprevention in pregnancy trials

“…Recent review indicates that methodological issues in studying anti-malarial drugs in pregnancy have prevented firm conclusions on the safety of new anti-malarial drugs in pregnancy [11]. Previous efforts have attempted to standardize safety assessment methodology for anti-malarial drug trials in pregnancy, including study designs and data collection [12,13]. However, literature remains limited in describing the standard practice in the statistical analysis of safety data that are collected on anti-malarial drugs during pregnancy trials.…”

Systematic review of statistical methods for safety data in malaria chemoprevention in pregnancy trials

“…Recent review indicates that methodological issues in studying antimalarial drugs in pregnancy have prevented firm conclusions on the safety of new anti-malarial drugs in pregnancy [11]. Previous efforts have attempted to standardize safety assessment methodology for antimalarial drug trials in pregnancy, including study designs and data collection [12,13]. However, literature remains limited in describing the standard practice in the statistical analysis of safety data that are collected on anti-malarial drugs during pregnancy trials.…”