Comparative analysis of the safety and tolerability of fixed-dose artesunate/amodiaquine versus artemether/lumefantrine combinations for uncomplicated <em>falciparum</em> malaria in pregnancy: a randomized open label study

Abstract

A comparative clinical study was conducted to evaluate the safety and tolerability of two commonly used fixed dose artemisinin-based combinations for the treatment of uncomplicated Plasmodium falciparum malaria in the second and third trimester of pregnancy. To achieve this, a total of 155 participants were recruited for the study. Eighty of these were drawn from pregnant women who came for routine antenatal care while 40 nonpregnant participants were recruited from apparently healthy females in the community. Eighty pregnant participants with uncomplicated P. falciparum malaria were randomized into artesunate/amodiaquine (AA) and artemether/lumefantrine (AL) treatment arms while 40 nonpregnant and 35 nonmalarious pregnant women were used as control. The interventional groups received standard fixed dose combinations of AA (100/270 mg) daily or AL (20/120 mg) twice daily for 3 days. Blood samples were collected on day 4 and patients were followed-up closely to ascertain the safety of the drugs. The study showed a significant (p<0.0001) elevation of alkaline phosphatase in the AA and AL group compared to the nonpregnant control and a significant (p<0.05) elevation of alanine transaminase and aspartate transaminase level in the AL combination group when compared with the AA group. The elevated hepatic enzymes were within the normal range for pregnancy and were not clinically significant. Adverse event rate was higher in the AA group (n=28 [70%]) when compared to the AL group (n=4 [10%]) although the drugs were well-tolerated in both treatment arms. In conclusion, the use of these combinations is safe in the second and third trimester of pregnancy. However, we recommend active pharmacovigilance and spontaneous drug reporting of the agents in order to continuously monitor safety in the vastly heterogeneous population.

Systematic literature review and meta-analysis of the efficacy of artemisinin-based and quinine-based treatments for uncomplicated falciparum malaria in pregnancy: methodological challenges

“…Between different ACTs, lower parasite clearance on day 1 was reported with AL compared to ASAQ, ASMQ and dihydroartemisinin–piperaquine (DP), although this was not significant on day 2 [ 50 ]. Other two RCTs also showed no difference in parasite clearance on day 3 between AL and ASAQ [ 54 , 55 ]. The median or mean time to fever and parasite clearance were not different between artesunate monotherapy and AL [ 45 ], and between intramuscular artemether with or without mefloquine, respectively [ 38 ].…”

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

“…Thirty-nine (81%, 39/48) studies reported haematological assessment at least once during the study. Of them, 20 studies (51%, 20/39) used haematocrit [ 28 – 33 , 36 , 48 , 49 , 51 – 53 , 66 – 71 , 73 ], 17 studies (44%, 17/39) used haemoglobin [ 34 , 35 , 37 , 39 – 41 , 43 , 50 , 54 , 56 , 57 , 60 – 64 , 75 ] and two studies (5%, 2/39) used both [ 46 , 65 ]. Four published studies did not report haematological assessment [ 26 , 38 , 59 , 74 ] and information was not available in five unpublished studies [ 27 , 44 , 47 , 55 , 72 ].…”

“…One study reported the proportion of women with diabetes [ 74 ] and another study reported there were no women with chronic diseases included [ 56 ]. No studies reported the history of non-malarial febrile illness during the pregnancy but two studies excluded women with other diseases associated with fever [ 46 ] or severe underlying diseases presenting with fever [ 65 ]. Ten studies mentioned HIV status of the participants.…”

“…Women with a history of alcohol (or narcotic abuse) were excluded in four studies (8%, 4/48) [ 33 , 36 , 48 , 49 ], and alcohol consumption was not reported in any other studies. One study reported the use of traditional medicine in the description of a stillbirth [ 35 ], and two studies excluded women who used herbal medicine in the past 4 weeks at enrolment [ 46 , 65 ]. Marital status was reported in three studies (6%, 3/48) [ 35 , 54 , 75 ].…”

“…Education level was reported in eight studies (17%, 8/48) [ 35 , 37 , 38 , 43 , 48 , 51 , 54 , 75 ]. Maternal height was assessed in eleven studies (23%, 11/48) [ 30 , 43 , 46 , 48 , 50 , 51 , 53 , 54 , 56 , 65 , 67 ], and five of them also reported body mass index (BMI) [ 46 , 51 , 54 , 56 , 65 ]. Three studies reported BMI without the maternal height [ 36 , 52 , 57 ].…”