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Lancet (London, England) Nov 1996Opinion and policy over the use of amodiaquine for treating malaria vary. Amodiaquine is more palatable than chloroquine and may be more effective but serious adverse... (Comparative Study)
Comparative Study Review
BACKGROUND
Opinion and policy over the use of amodiaquine for treating malaria vary. Amodiaquine is more palatable than chloroquine and may be more effective but serious adverse events have been reported in travellers taking it as prophylaxis. It is not recommended as first-line treatment. In the light of the global debate over the use of this drug, we conducted a systematic review of the effectiveness and tolerability of amodiaquine in the treatment of uncomplicated falciparum malaria.
METHODS
This is a systematic review of published and unpublished randomised or pseudorandomised trials of amodiaquine. Observational reports were also systematically identified and reviewed to access evidence of serious adverse events.
FINDINGS
40 trials met the inclusion criteria. Symptomatic patients were enrolled in 24 studies in comparisons of amodiaquine (n = 1071) with chloroquine (n = 1097). Amodiaquine was significantly more effective than chloroquine, with odds ratios and 99% confidence intervals (OR [99% CI]) of 4.29 (3.30-5.58) on day 7 and 6.00 (3.97-9.06) on day 14. Time to parasite clearance was significantly shorter with amodiaquine and fever clearance times were marginally faster. Eight studies compared amodiaquine with chloroquine in asymptomatic parasitaemia, with effects on parasitological outcomes similar to those for symptomatic malaria. At twelve sites, 692 amodiaquine and 679 sulfadoxine/pyrimethamine (S/P) recipients were enrolled. The two drugs did not differ significantly on day 7 (OR 0.74 [0.48-1.15]) but the odds ratios favoured S/P on day 14 (OR 0.51 [0.28-0.93]) and on day 28 (OR 0.30 [0.16-0.55]). The time to parasitological clearance was similar in the two groups; fever clearance times were significantly shorter with amodiaquine. Tolerability was assessed for both comparative and non-comparative trials. The rates of adverse events in controlled trials were 10.7%, 8.8%, and 14.3% with amodiaquine, chloroquine, and S/P, respectively. No life-threatening adverse events and no significant shifts in laboratory indices were reported.
INTERPRETATION
This systematic review of published and unpublished trials supports the use of amodiaquine in the treatment of uncomplicated malaria. However, there is partial cross-resistance between chloroquine and amodiaquine, and monitoring of the effectiveness of this drug and surveillance for evidence of toxicity must continue.
Topics: Amodiaquine; Antimalarials; Chloroquine; Humans; Malaria, Falciparum; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 8898036
DOI: 10.1016/S0140-6736(96)06217-4 -
The Cochrane Database of Systematic... Jul 2009The World Health Organization recommends uncomplicated P. falciparum malaria is treated using Artemisinin-based Combination Therapy (ACT). This review aims to assist the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The World Health Organization recommends uncomplicated P. falciparum malaria is treated using Artemisinin-based Combination Therapy (ACT). This review aims to assist the decision making of malaria control programmes by providing an overview of the relative benefits and harms of the available options.
OBJECTIVES
To compare the effects of ACTs with other available ACT and non-ACT combinations for treating uncomplicated P. falciparum malaria.
SEARCH STRATEGY
We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; LILACS, and the metaRegister of Controlled Trials (mRCT) to March 2009.
SELECTION CRITERIA
Randomized head to head trials of ACTs in uncomplicated P. falciparum malaria.This review is limited to: dihydroartemisinin-piperaquine; artesunate plus mefloquine; artemether-lumefantrine (six doses); artesunate plus amodiaquine; artesunate plus sulfadoxine-pyrimethamine and amodiaquine plus sulfadoxine-pyrimethamine.
DATA COLLECTION AND ANALYSIS
Two authors independently assessed trials for eligibility and risk of bias, and extracted data. We analysed primary outcomes in line with the WHO 'Protocol for assessing and monitoring antimalarial drug efficacy' and compared drugs using risk ratios (RR) and 95% confidence intervals (CI). Secondary outcomes were effects on P. vivax, gametocytes, haemoglobin, and adverse events.
MAIN RESULTS
Fifty studies met the inclusion criteria. All five ACTs achieved PCR adjusted failure rates of < 10%, in line with WHO recommendations, at most study sites.Dihydroartemisinin-piperaquine performed well compared to the ACTs in current use (PCR adjusted treatment failure versus artesunate plus mefloquine in Asia; RR 0.39, 95% CI 0.19 to 0.79; three trials, 1062 participants; versus artemether-lumefantrine in Africa; RR 0.39, 95% CI 0.24 to 0.64; three trials, 1136 participants).ACTs were superior to amodiaquine plus sulfadoxine-pyrimethamine in East Africa (PCR adjusted treatment failure versus artemether-lumefantrine; RR 0.12, 95% CI 0.06 to 0.24; two trials, 618 participants; versus AS+AQ; RR 0.44, 95% CI 0.22 to 0.89; three trials, 1515 participants).Dihydroartemisinin-piperaquine (RR 0.32, 95% CI 0.24 to 0.43; four trials, 1442 participants) and artesunate plus mefloquine (RR 0.30, 95% CI 0.21 to 0.41; four trials, 1003 participants) were more effective than artemether-lumefantrine at reducing the incidence of P.vivax over 42 days follow up.
AUTHORS' CONCLUSIONS
Dihydroartemisinin-piperaquine is another effective first-line treatment for P. falciparum malaria.The performance of the non-ACT (amodiaquine plus sulfadoxine-pyrimethamine) falls below WHO recommendations for first-line therapy in parts of Africa.In areas where primaquine is not being used for radical cure of P. vivax, ACTs with long half-lives may provide some benefit.
Topics: Antimalarials; Artemisinins; Artesunate; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Fluorenes; Humans; Lumefantrine; Malaria; Malaria, Falciparum; Malaria, Vivax; Mefloquine; Parasitemia; Pyrimethamine; Quinolines; Randomized Controlled Trials as Topic; Sulfadoxine
PubMed: 19588433
DOI: 10.1002/14651858.CD007483.pub2 -
BMC Medicine Aug 2015It is known that antimalarial drugs reduce the risk of low birth weight (LBW) in pregnant patients. However, a previous Cochrane review did not evaluate whether the... (Meta-Analysis)
Meta-Analysis Review
Antimalarial drugs for preventing malaria during pregnancy and the risk of low birth weight: a systematic review and meta-analysis of randomized and quasi-randomized trials.
BACKGROUND
It is known that antimalarial drugs reduce the risk of low birth weight (LBW) in pregnant patients. However, a previous Cochrane review did not evaluate whether the level of antimalarial drug resistance could modify the protective effect of antimalarial drugs in this regard. In addition, no systematic review exists comparing current recommendations for malaria prevention during pregnancy to alternative regimens in Africa. Therefore, we conducted a comprehensive systematic review and meta-analysis to assess the efficacy of antimalarial drugs for malaria prevention during pregnancy in reducing the risk of LBW.
METHODS
We searched PubMed, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL) for articles published up to 21 November 2014, in English or French, and identified additional studies from reference lists. We included randomized and quasi-randomized studies reporting LBW as one of the outcomes. We extracted data and assessed the risk of bias in selected studies. All pooled analyses were based on a random effect model, and we used a funnel plot and trim and fill method to test and adjust for publication bias.
RESULTS
A total of 25 studies met the inclusion criteria (37,981 subjects). Compared to no use, all combined antimalarial drugs were associated with a 27% (RR 0.73, 95% CI 0.56-0.97, ten studies) reduction in the risk of LBW. The level of antimalarial drug resistance modified the protective effect of the antimalarial drug used for prevention of LBW during pregnancy. Sulfadoxine-pyrimethamine was not associated with a reduction in the risk of LBW in regions where the prevalence of the dihydropteroate synthase 540E mutation exceeds 50% (RR 0.99, 95% CI 0.80-1.22, three studies). The risk of LBW was similar when sulfadoxine-pyrimethamine was compared to mefloquine (RR 1.05, 95% CI 0.86-1.29, two studies).
CONCLUSION
Prophylactic antimalarial drugs and specifically sulfadoxine-pyrimethamine may no longer protect against the risk of LBW in areas of high-level resistance. In Africa, there are currently no suitable alternative drugs to replace sulfadoxine-pyrimethamine for malaria prevention during pregnancy.
Topics: Africa; Antimalarials; Drug Resistance; Female; Humans; Infant, Low Birth Weight; Infant, Newborn; Malaria; Pregnancy; Randomized Controlled Trials as Topic
PubMed: 26275820
DOI: 10.1186/s12916-015-0429-x -
The Cochrane Database of Systematic... May 2016Acute toxoplasma retinochoroiditis causes transient symptoms of ocular discomfort and may lead to permanent visual loss. Antibiotic treatment aims primarily to reduce... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Acute toxoplasma retinochoroiditis causes transient symptoms of ocular discomfort and may lead to permanent visual loss. Antibiotic treatment aims primarily to reduce the risk of permanent visual loss, recurrent retinochoroiditis, and the severity and duration of acute symptoms. There is uncertainty about the effectiveness of antibiotic treatment.
OBJECTIVES
To compare the effects of antibiotic treatment versus placebo or no treatment for toxoplasma retinochoroiditis.
SEARCH METHODS
We searched CENTRAL (which contains the Cochrane Eyes and Vision group Trials Register) (2016, Issue 1), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to February 2016), EMBASE (January 1980 to February 2016), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to February 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 22 February 2016. We searched the reference lists of identified articles and contacted pharmaceutical companies for unpublished trials.
SELECTION CRITERIA
We included randomised controlled trials that compared any antibiotic treatment against placebo or no treatment. We excluded trials that included immunocompromised participants. We considered any antibiotic treatment known to be active against Toxoplasma gondii. Antibiotic treatment could be given in any dose orally, by intramuscular injection, by intravenous infusion, or by intravitreal injection.
DATA COLLECTION AND ANALYSIS
The primary outcomes for this review were visual acuity at least three months after treatment and risk of recurrent retinochoroiditis. Secondary outcomes were improvement in symptoms and signs of intraocular inflammation, size of lesion, and adverse events. We used standard methodological procedures expected by Cochrane.
MAIN RESULTS
Four trials that randomised a total of 268 participants met the inclusion criteria. In all four studies antibiotic was administered orally.One study conducted in Brazil in both adults and children compared trimethoprim-sulfamexacocol over 20 months to no treatment and was judged to be at high risk of performance, detection, and attrition bias. The other three studies compared antibiotic treatment to placebo. We judged these three studies to be at a mixture of low or unclear risk of bias due to poor reporting. One study conducted in the US in adults studied pyrimethamine-trisulfapyrimidine for eight weeks; one study conducted in the UK in children and adults evaluated pyrimethamine for four weeks; and one study conducted in Brazil in adults investigated trimethoprim-sulfamethoxazole for 12 months. In the last study, all participants had active retinochoroiditis and were treated with antibiotics for 45 days prior to randomisation to trimethoprim-sulfamethoxazole versus placebo.Only the study in Brazil of trimethoprim-sulfamethoxazole over 12 months, in participants with healed lesions, reported the effect of treatment on visual acuity. People treated with antibiotics may have a similar change in visual acuity compared with people treated with placebo at one year (mean difference -1.00 letters, 95% confidence interval (CI) -7.93 to 5.93 letters; 93 participants; low-quality evidence).Treatment with antibiotics probably reduces the risk of recurrent retinochoroiditis compared with placebo (risk ratio (RR) 0.26, 95% CI 0.11 to 0.63; 227 participants; 3 studies; I(2) = 0%; moderate-quality evidence); similar results were seen for acute and chronic retinochoroiditis.The UK study of pyrimethamine for four weeks reported an improvement in intraocular inflammation in treated compared with control participants (RR 1.76, 95% CI 0.98 to 3.19; 29 participants; low-quality evidence). The study in Brazil of trimethoprim-sulfamethoxazole for 12 months stated that the severity of inflammation was higher in the comparator group when compared to the antibiotic-treated group but did not provide further details. In the US study of pyrimethamine-trisulfapyrimidine for eight weeks intraocular inflammation had almost completely resolved by eight weeks in all participants, however in this study all participants received steroid treatment.Two studies (UK and US studies) reported an increased risk of adverse events in treated participants. These were a fall in haemoglobin, leucocyte, and platelet count, nausea, loss of appetite, rash, and arthralgia.
AUTHORS' CONCLUSIONS
Treatment with antibiotics probably reduces the risk of recurrent toxoplasma retinochoroiditis, but there is currently no good evidence that this leads to better visual outcomes. However, absence of evidence of effect is not the same as evidence of no effect. Further trials of people with acute and chronic toxoplasma retinochoroiditis affecting any part of the retina are required to determine the effects of antibiotic treatment on visual outcomes.
Topics: Administration, Oral; Adult; Anti-Bacterial Agents; Child; Chorioretinitis; Drug Combinations; Humans; Pyrimethamine; Randomized Controlled Trials as Topic; Recurrence; Secondary Prevention; Sulfadiazine; Sulfamerazine; Sulfamethazine; Toxoplasmosis, Ocular; Trimethoprim, Sulfamethoxazole Drug Combination; Visual Acuity; Watchful Waiting
PubMed: 27198629
DOI: 10.1002/14651858.CD002218.pub2 -
EClinicalMedicine Nov 2021In sub-Saharan Africa, the efficacy of intermittent preventive therapy in pregnancy with sulphadoxine-pyrimethamine (IPTp-SP) for malaria in pregnancy is threatened by...
Intermittent screening and treatment with artemisinin-combination therapy versus intermittent preventive treatment with sulphadoxine-pyrimethamine for malaria in pregnancy: a systematic review and individual participant data meta-analysis of randomised clinical trials.
BACKGROUND
In sub-Saharan Africa, the efficacy of intermittent preventive therapy in pregnancy with sulphadoxine-pyrimethamine (IPTp-SP) for malaria in pregnancy is threatened by parasite resistance. We conducted an individual-participant data (IPD) meta-analysis to assess the efficacy of intermittent screening with malaria rapid diagnostic tests (RDTs) and treatment of RDT-positive women with artemisinin-based combination therapy (ISTp-ACT) compared to IPTp-SP, and understand the importance of subpatent infections.
METHODS
We searched MEDLINE and the Malaria-in-Pregnancy Library on May 6, 2021 for trials comparing ISTp-ACT and IPTp-SP. Generalised linear regression was used to compare adverse pregnancy outcomes (composite of small-for-gestational-age, low birthweight (LBW), or preterm delivery) and peripheral or placental at delivery. The effects of subpatent (PCR-positive, RDT/microscopy-negative) infections were assessed in both arms pooled using multi-variable fixed-effect models adjusting for the number of patent infections. PROSPERO registration: CRD42016043789.
FINDINGS
Five trials conducted between 2007 and 2014 contributed (10,821 pregnancies), two from high SP-resistance areas where quintuple mutant parasites are saturated, but sextuple mutants are still rare (Kenya and Malawi), and three from low-resistance areas (West-Africa). Four trials contributed IPD data (N=10,362). At delivery, the prevalence of any malaria infection (relative risk [RR]=1.08, 95% CI 1.00-1.16, I=67.0 %) and patent infection (RR=1.02, 0.61-1.16, I=0.0%) were similar. Subpatent infections were more common in ISTp recipients (RR=1.31, 1.05-1.62, I=0.0%). There was no difference in adverse pregnancy outcome (RR=1.00, 0.96-1.05; studies=4, N=9,191, I=54.5%). Subpatent infections were associated with LBW (adjusted RR=1.13, 1.07-1.19), lower mean birthweight (adjusted mean difference=32g, 15-49), and preterm delivery (aRR=1.35, 1.15-1.57).
INTERPRETATION
ISTp-ACT was not superior to IPTp-SP and may result in more subpatent infections than the existing IPTp-SP policy. Subpatent infections were associated with increased LBW and preterm delivery. More sensitive diagnostic tests are needed to detect and treat low-grade infections.
FUNDING
Centers for Disease Control and Prevention and Worldwide Antimalarial Resistance Network.
PubMed: 34746720
DOI: 10.1016/j.eclinm.2021.101160 -
The Cochrane Database of Systematic... 2000Amodiaquine has been widely used to treat malaria. Due to reports of fatal adverse drug reactions, discontinuation or modification of its use has been suggested. (Review)
Review
BACKGROUND
Amodiaquine has been widely used to treat malaria. Due to reports of fatal adverse drug reactions, discontinuation or modification of its use has been suggested.
OBJECTIVES
The objective of this review was to assess the effects of amodiaquine for treating malaria.
SEARCH STRATEGY
We searched the Cochrane Infectious Diseases Group trials register and Medline. We also contacted researchers in the field and drug companies.
SELECTION CRITERIA
Randomised and quasi-randomised trials comparing amodiaquine with other treatment for uncomplicated malarial infections in adults and children.
DATA COLLECTION AND ANALYSIS
Both reviewers independently extracted data and assessed trial quality.
MAIN RESULTS
Forty trials were included. Allocation was adequately concealed in three trials. Amodiaquine was more effective than chloroquine for parasite clearance. The combined results of parasite clearance at seven days from 24 trials was 83% for amodiaquine and 56% for chloroquine (odds ratio 4.29, 95% confidence interval 3.51 to 5.24). The odds ratio for parasite clearance at 14 days was 6.00, 95% confidence interval 4.38 to 8.21. Amodiaquine and sulfadoxine/pyrimethamine showed similar results for parasite clearance on day seven, but sulfadoxine/pyrimethamine appeared to be more effective on day 14 and 28. No significant difference for adverse events was observed between amodiaquine and chloroquine and sulfadoxine/pyrimethamine. Reported adverse effects were minor or moderate, not life threatening.
REVIEWER'S CONCLUSIONS
There is some evidence to support the continued use of amodiaquine in the treatment of uncomplicated malaria, although drug resistance should be considered. Monitoring for toxicity should also continue.
Topics: Amodiaquine; Antimalarials; Humans; Malaria
PubMed: 10796468
DOI: 10.1002/14651858.CD000016 -
The American Journal of Tropical... Jan 2024Seasonal malaria chemoprevention (SMC) for children under 5 years of age for up to four monthly cycles during malaria transmission season was recommended by the WHO in... (Meta-Analysis)
Meta-Analysis
Seasonal malaria chemoprevention (SMC) for children under 5 years of age for up to four monthly cycles during malaria transmission season was recommended by the WHO in 2012 and has been implemented in 13 countries in the Sahel, reaching more than 30 million children annually. Malaria control programs implementing SMC have asked the WHO to consider expanding the age range or number of monthly cycles. We conducted a systematic review and meta-analysis of SMC among children up to 15 years of age and up to six monthly cycles. Twelve randomized studies were included, with outcomes stratified by age (< 5/≥ 5 years), by three or four versus five or six cycles, and by drug where possible. Drug regimens included sulfadoxine-pyrimethamine + amodiaquine, amodiaquine-artesunate, and sulfadoxine-pyrimethamine + artesunate. Included studies were all conducted in Sahelian countries in which high-grade resistance to sulfadoxine-pyrimethamine was rare and in zones with parasite prevalence ranging from 1% to 79%. Seasonal malaria chemoprevention resulted in substantial reductions in uncomplicated malaria incidence measured during that transmission season (rate ratio: 0.27, 95% CI: 0.25-0.29 among children < 5 years; rate ratio: 0.27, 95% CI: 0.25-0.30 among children ≥ 5 years) and in the prevalence of malaria parasitemia measured within 4-6 weeks from the final SMC cycle (risk ratio: 0.38, 95% CI: 0.34-0.43 among children < 5 years; risk ratio: 0.23, 95% CI: 0.11-0.48 among children ≥ 5 years). In high-transmission zones, SMC resulted in a moderately reduced risk of any anemia (risk ratio: 0.77, 95% CI: 0.72-0.83 among children < 5 years; risk ratio: 0.70, 95% CI: 0.52-0.95 among children ≥ 5 years [one study]). Children < 10 years of age had a moderate reduction in severe malaria (risk ratio: 0.53, 95% CI: 0.37-0.76) but no evidence of a mortality reduction. The evidence suggests that in areas in which sulfadoxine-pyrimethamine and amodiaquine remained efficacious, SMC effectively reduced malaria disease burden among children both < 5 and ≥ 5 years old and that the number of cycles should be commensurate with the length of the transmission season, up to six cycles.
Topics: Child; Child, Preschool; Humans; Amodiaquine; Antimalarials; Artesunate; Chemoprevention; Drug Combinations; Malaria; Pyrimethamine; Seasons; Sulfadoxine; Adolescent
PubMed: 38081050
DOI: 10.4269/ajtmh.23-0481 -
The Cochrane Database of Systematic... Oct 2006A malaria vaccine is needed because of the heavy burden of mortality and morbidity due to this disease. This review describes the results of trials of blood... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
A malaria vaccine is needed because of the heavy burden of mortality and morbidity due to this disease. This review describes the results of trials of blood (asexual)-stage vaccines. Several are under development, but only one (MSP/RESA, also known as Combination B) has been tested in randomized controlled trials.
OBJECTIVES
To assess the effect of blood-stage malaria vaccines in preventing infection, disease, and death.
SEARCH STRATEGY
In March 2006, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2006, Issue 1), MEDLINE, EMBASE, LILACS, and the Science Citation Index. We also searched conference proceedings and reference lists of articles, and contacted organizations and researchers in the field.
SELECTION CRITERIA
Randomized controlled trials comparing blood-stage vaccines (other than SPf66) against P. falciparum, P. vivax, P. malariae, or P. ovale with placebo, control vaccine, or routine antimalarial control measures in people of any age receiving a challenge malaria infection.
DATA COLLECTION AND ANALYSIS
Both authors independently assessed trial quality and extracted data. Results for dichotomous data were expressed as relative risks (RR) with 95% confidence intervals (CI).
MAIN RESULTS
Five trials of MSP/RESA vaccine with 217 participants were included; all five reported on safety, and two on efficacy. No severe or systemic adverse effects were reported at doses of 13 to 15 microg of each antigen (39 to 45 microg total). One small efficacy trial with 17 non-immune participants with blood-stage parasites showed no reduction or delay in parasite growth rates after artificial challenge. In the second efficacy trial in 120 children aged five to nine years in Papua New Guinea, episodes of clinical malaria were not reduced, but MSP/RESA significantly reduced parasite density only in children who had not been pretreated with an antimalarial drug (sulfadoxine-pyrimethamine). Infections with the 3D7 parasite subtype of MSP2 (the variant included in the vaccine) were reduced (RR 0.38, 95% CI 0.26 to 0.57; 719 participants) while those with the other main subtype, FC27, were not (720 participants).
AUTHORS' CONCLUSIONS
The MSP/RESA (Combination B) vaccine shows promise as a way to reduce the severity of malaria episodes, but the effect of the vaccine is MSP2 variant-specific. Pretreatment for malaria during a vaccine trial makes the results difficult to interpret, particularly with the relatively small sample sizes of early trials. The results show that blood-stage vaccines may play a role and merit further development.
Topics: Antigens, Protozoan; Humans; Malaria; Malaria Vaccines; Merozoites; Protozoan Proteins; Randomized Controlled Trials as Topic; Vaccines, Combined
PubMed: 17054281
DOI: 10.1002/14651858.CD006199 -
Lancet (London, England) Jan 2023Malaria in the first trimester of pregnancy is associated with adverse pregnancy outcomes. Artemisinin-based combination therapies (ACTs) are a highly effective,... (Meta-Analysis)
Meta-Analysis
Pregnancy outcomes after first-trimester treatment with artemisinin derivatives versus non-artemisinin antimalarials: a systematic review and individual patient data meta-analysis.
BACKGROUND
Malaria in the first trimester of pregnancy is associated with adverse pregnancy outcomes. Artemisinin-based combination therapies (ACTs) are a highly effective, first-line treatment for uncomplicated Plasmodium falciparum malaria, except in the first trimester of pregnancy, when quinine with clindamycin is recommended due to concerns about the potential embryotoxicity of artemisinins. We compared adverse pregnancy outcomes after artemisinin-based treatment (ABT) versus non-ABTs in the first trimester of pregnancy.
METHODS
For this systematic review and individual patient data (IPD) meta-analysis, we searched MEDLINE, Embase, and the Malaria in Pregnancy Library for prospective cohort studies published between Nov 1, 2015, and Dec 21, 2021, containing data on outcomes of pregnancies exposed to ABT and non-ABT in the first trimester. The results of this search were added to those of a previous systematic review that included publications published up until November, 2015. We included pregnancies enrolled before the pregnancy outcome was known. We excluded pregnancies with missing estimated gestational age or exposure information, multiple gestation pregnancies, and if the fetus was confirmed to be unviable before antimalarial treatment. The primary endpoint was adverse pregnancy outcome, defined as a composite of either miscarriage, stillbirth, or major congenital anomalies. A one-stage IPD meta-analysis was done by use of shared-frailty Cox models. This study is registered with PROSPERO, number CRD42015032371.
FINDINGS
We identified seven eligible studies that included 12 cohorts. All 12 cohorts contributed IPD, including 34 178 pregnancies, 737 with confirmed first-trimester exposure to ABTs and 1076 with confirmed first-trimester exposure to non-ABTs. Adverse pregnancy outcomes occurred in 42 (5·7%) of 736 ABT-exposed pregnancies compared with 96 (8·9%) of 1074 non-ABT-exposed pregnancies in the first trimester (adjusted hazard ratio [aHR] 0·71, 95% CI 0·49-1·03). Similar results were seen for the individual components of miscarriage (aHR=0·74, 0·47-1·17), stillbirth (aHR=0·71, 0·32-1·57), and major congenital anomalies (aHR=0·60, 0·13-2·87). The risk of adverse pregnancy outcomes was lower with artemether-lumefantrine than with oral quinine in the first trimester of pregnancy (25 [4·8%] of 524 vs 84 [9·2%] of 915; aHR 0·58, 0·36-0·92).
INTERPRETATION
We found no evidence of embryotoxicity or teratogenicity based on the risk of miscarriage, stillbirth, or major congenital anomalies associated with ABT during the first trimester of pregnancy. Given that treatment with artemether-lumefantrine was associated with fewer adverse pregnancy outcomes than quinine, and because of the known superior tolerability and antimalarial effectiveness of ACTs, artemether-lumefantrine should be considered the preferred treatment for uncomplicated P falciparum malaria in the first trimester. If artemether-lumefantrine is unavailable, other ACTs (except artesunate-sulfadoxine-pyrimethamine) should be preferred to quinine. Continued active pharmacovigilance is warranted.
FUNDING
Medicines for Malaria Venture, WHO, and the Worldwide Antimalarial Resistance Network funded by the Bill & Melinda Gates Foundation.
Topics: Female; Pregnancy; Humans; Antimalarials; Pregnancy Outcome; Quinine; Pregnancy Trimester, First; Abortion, Spontaneous; Stillbirth; Prospective Studies; Artemether; Artemether, Lumefantrine Drug Combination; Malaria, Falciparum; Malaria; Drug Combinations; Ethanolamines
PubMed: 36442488
DOI: 10.1016/S0140-6736(22)01881-5 -
Malaria Journal Oct 2015This study aimed to synthesize the existing evidence on the efficacy and safety of a single dose artemisinin-naphthoquine (ASNQ) for treatment of uncomplicated malaria... (Comparative Study)
Comparative Study Meta-Analysis Review
BACKGROUND
This study aimed to synthesize the existing evidence on the efficacy and safety of a single dose artemisinin-naphthoquine (ASNQ) for treatment of uncomplicated malaria in endemic countries.
METHODS
A meta-analysis of randomized, controlled trials (RCT), assessing efficacy and safety of single dose ASNQ was carried out. Comparator drugs included artemether-lumefentrine (AL), chloroquine plus sulfadoxine-pyrimethamine (CQSP) and dihydroartemisinin-piperaquine (DHP). The efficacy and safety profile of non-comparator, single-arm studies on the single dose ASNQ was also assessed. The primary endpoint was efficacy defined as an absence of PCR-confirmed parasitaemia. The methodological quality of the included studies was assessed using the six domains for the risk of bias.
RESULTS
Five RCTs and three single-arm studies were included in this review. As RCT studies did not compare the same anti-malarial drugs, it was difficult to do a pooled analysis. At day 28, a pooled analysis of two RCTs (n = 271) showed a comparable efficacy on PCR-confirmed parasitaemia between ASNQ and AL. Another RCT, which compared ASNQ and CQSP or ASNQ and DHP, also showed comparable efficacy. At day 42, one RCT comparing ASNQ and DHP and another RCT comparing ASNQ and AL reported comparable levels of efficacy. The proportion of parasite clearance was faster in the ASNQ groups than the comparators at day 1, and almost all parasites were cleared by day 3 in the ASNQ groups.
CONCLUSIONS
The present review provides some evidence to support that there is similar efficacy and safety of the single dose ASNQ compared to other anti-malarial drugs in treating uncomplicated malaria. Larger, adequately powered, well-designed studies are recommended to substantiate the efficacy and safety in different populations and in different epidemiological settings. As the potential evolution of drug resistance is a great concern and this cannot be addressed in a short-term study, the use of single dose ASNQ needs further evaluation.
Topics: Antimalarials; Artemisinins; Humans; Malaria; Naphthoquinones; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 26445424
DOI: 10.1186/s12936-015-0919-5