Methods

Randomized controlled trial

Generation of allocation sequence: no method reported

Allocation concealment: no method reported

Blinding: none

Inclusion of all randomized participants: 95% (for treatment failure)

Participants

Number: 60 randomized, 57 analysed

Inclusion criteria: pregnant women infected with P. falciparum; gestational age at least 28 weeks; not more than 4% parasitized red blood cells; could be followed up at Srisangwal Hospital; could take and tolerate oral form of the medicine and be admitted to the hospital for at least 7 days

Exclusion criteria: former medication with quinine, artesunate (including its derivatives), or mefloquine within 28 days; history of quinine, artesunate, or mefloquine allergy; malaria with complications such as shock, renal failure, pulmonary oedema, or cerebral malaria; mixed malarial infection

Age in years (mean): artesunate plus mefloquine group 27.207; quinine group 26.143

Parity (mean): artesunate plus mefloquine group 1.59; quinine group 1.36

Early/late pregnancy: second trimester

Symptomatic/asymptomatic malaria: number not reported

Anaemia on admission: number not reported

Interventions

1. Artesunate plus mefloquine
Artesunate: 2 mg/kg loading dose and 1 mg/kg every 12 hours for at least 5 days (until parasites are absent and there is clinical improvement)
Mefloquine: 15 mg/kg on day 6 and 10 mg/kg 6 hours later

2. Quinine sulfate: 10 mg/kg every 8 hours for at least 7 days (until clinically recovered)

Outcomes

1. Treatment failure at day 28
2. Fever clearance time
3. Parasite clearance time
4. Haematocrit
5. Birthweight
6. Gestational age at birth
7. Congenital abnormalities
8. Infant development
9. Adverse events

Not included in review:
10. Treatment time of parasite presentation
11. Intra‐uterine growth retardation

Notes

Location: Mae Hong Son, Thailand

Local malaria endemicity/transmission: not reported

Local antimalarial drug resistance: multiple‐drug resistance

Supervision of treatment: not reported

Methods

Randomized controlled trial

Generation of allocation sequence: computer‐generated, random‐number list

Allocation concealment: no method reported

Blinding: none

Inclusion of all randomized participants: 83% (for treatment failure)

Participants

Number: 147 randomized, 122 analysed

Inclusion criteria: primigravidae or secundigravidae; gestation 12 to 36 weeks (fundal height < 30 cm); axillary temperature ≥ 37.5 °C; recent history of fever (within 48 hours preceding enrolment); or presence of clinical malaria‐related symptoms; mono‐infection with P. falciparum density ≥ 2000 parasites/mm³ blood; absence of clinical signs of severe malaria; absence of other patent infections; absence of previous severe reaction to chloroquine or sulfadoxine‐pyrimethamine; staying in neighbouring district/village; able to come for follow up; consent

Exclusion criteria: other febrile disease than malaria; use of interfering treatment during follow‐up period; high‐risk pregnancy

Age in years (median (range)): 20 (15 to 29)

Parity: primigravidae and secundigravidae

Early/late pregnancy: second and third trimester

Symptomatic/asymptomatic malaria: all women symptomatic

Anaemia on admission: 81% (21% severe malaria)

Interventions

1. Sulfadoxine‐pyrimethamine: 25 mg/kg sulfadoxine and 1.25 mg/kg pyrimethamine in 1 dose
2. Chloroquine: 10 mg/kg on days 0 and 1; 5 mg/kg on day 2

Outcomes

1. Treatment failure at day 14
2. Treatment failure at day 28
3. Adverse reactions

Not included in review:
4. Anaemia
5. Parasitaemia
6. Gametocytaemia
7. Early treatment failure
8. Late clinical failure
9. Late parasitological failure

Notes

Location: Ouagadougou, Burkina Faso

Local malaria endemicity/transmission: endemic but seasonal

Local antimalarial drug resistance: increasing resistance to chloroquine; and some resistance to sulfadoxine‐pyrimethamine

Supervision of treatment: all treatments were supervised

Data awaiting: none

Additional notes: trial for monitoring of therapeutic efficacy; women who failed study treatment were given quinine

Methods

Randomized controlled trial

Generation of allocation sequence: random‐number list; block randomized

Allocation concealment: sealed envelopes

Blinding: outcome assessor

Inclusion of all randomized participants: 84% (for treatment failure)

Participants

Number: 141 randomized, 118 analysed

Inclusion criteria: peripheral parasitaemia; P. falciparum; aged 15 to 49 years; estimated fetal gestational age 14 to 26 weeks; mother had felt fetal movement; available for follow up until delivery

Exclusion criteria: multiple gestations; history of chronic disease such as tuberculosis or diabetes; mental health disorder; known allergies to drugs containing sulfonamides; macrolides or pyrimethamine; pregnancy complications; taken antimalarial drugs within 28 days before enrolment

Age in years (median (interquartile range)): 20 (17 to 24)

Parity: mostly primigravidae, some secundigravidae

Early/late pregnancy: mainly third trimester

Symptomatic/asymptomatic malaria: not stated

Anaemia on admission: not stated

Interventions

1. Sulfadoxine‐pyrimethamine: 1500 mg sulfadoxine, 75 mg pyrimethamine in 1 dose
2. Sulfadoxine‐pyrimethamine and azithromycin: 1500 mg sulfadoxine, 75 mg pyrimethamine in 1 dose, and 1 g/day azithromycin for 2 days
3. Sulfadoxine‐pyrimethamine and artesunate: 1500 mg sulfadoxine, 75 mg pyrimethamine in 1 dose, and artesunate 200 mg/day for 3 days

All treatment courses given twice, at least 4 weeks apart

All participants also given 200 mg ferrous sulfate and 0.25 mg folic acid for daily administration, and insecticide‐treated bed nets

Outcomes

1. Treatment failure at delivery or 40 days
2. Treatment failure at delivery or 40 days (excludes new infections using PCR)
3. Maternal anaemia
4. Low birthweight
5. Perinatal death
6. Neonatal death

Not included in review:
7. Placental parasite clearance

Notes

Location: Mpemba and Madziabango health centres, Blantyre District, Malawi

Local malaria endemicity/transmission: perennial, peaks in rainy season

Local antimalarial drug resistance: not reported

Supervision of treatment: directly observed

Additional notes: pilot for larger study of intermittent preventive treatment, therefore two treatment courses given; trial authors report that statistically significantly more women who received sulfadoxine‐pyrimethamine or azithromycin plus sulfadoxine‐pyrimethamine were diagnosed as HIV positive than those who received artesunate plus sulfadoxine‐pyrimethamine (but many women refused the routine testing)

Methods

Quasi‐randomized controlled trial

Generation of allocation sequence: alternate allocation

Allocation concealment: no method reported

Blinding: assessor blinded

Inclusion of all randomized participants: 100% (for treatment failure)

Participants

Number: 132 randomized and analysed

Inclusion criteria: at least 18 weeks pregnant; 1000 parasites per mm³; no prior antimalarial; not vomiting; consent

Exclusion criteria: none reported

Average age in years (mean (range)): not reported; most between 17 and 24 (15 to 40)

Parity: 0 to 7; most 0 to 1

Early/late pregnancy: at least 18 weeks

Symptomatic/asymptomatic malaria: number not reported

Anaemia on admission: number not reported

Interventions

1. Chloroquine plus clindamycin (for 3 days)
Chloroquine: 10 mg/kg on days 1 and 2; 5 mg/kg on day 3
Clindamycin: 10 mg/kg for 3 days

2. Chloroquine plus clindamycin (for 5 days)
Chloroquine: 10 mg/kg on days 1 and 2; 5 mg/kg on day 3
Clindamycin: 10 mg/kg for 5 days

3. Chloroquine: 10 mg/kg on days 1 and 2; 5 mg/kg on day 3

Outcomes

1. Treatment failures at day 14
2. Adverse events

Notes

Location: Kinshasa, Democratic Republic of the Congo

Local malaria endemicity/transmission: not reported

Local antimalarial drug resistance: some resistance to chloroquine, amodiaquine, and quinine

Supervision of treatment: not reported

Data awaiting: authors contacted 2005, awaiting additional trial data

Methods

Randomized controlled trial

Generation of allocation sequence: block randomization

Allocation concealment: no method reported

Blinding: none

Inclusion of all randomized participants: 92% (for treatment failure) and 75% (for low birthweight)

Participants

Number: 115 randomized, 108 analysed (86 and 108 for primary outcomes)

Inclusion criteria: pregnant women in their second or third trimester seen at antenatal clinics of Shoklo and Maela camps; microscopy‐confirmed uncomplicated P. falciparum infection; fully informed verbal consent

Exclusion criteria: severe complicated malaria; intercurrent infection requiring hospitalization; allergy to quinine or mefloquine; < 12 weeks gestation; history of mental disorder or mefloquine‐induced psychosis

Age in years (median (range)): artesunate plus mefloquine group 24 (15 to 37); quinine group 23 (16 to 36)

Parity: artesunate plus mefloquine group 18/66 primapara; quinine group 12/42 primapara

Early/late pregnancy: second and third trimester

Symptomatic/asymptomatic malaria: many women oligosymptomatic or asymptomatic

Anaemia on admission: artesunate plus mefloquine group 33/66 anaemic; quinine group 22/42 anaemic

Interventions

1. Artesunate plus mefloquine
Artesunate: 4 mg/kg on days 0, 1, and 2
Mefloquine: 15 mg/kg on day 1 and 10 mg/kg on day 2

2. Quinine sulfate: 10 mg/kg every 8 hours for 7 days

Outcomes

1. Treatment failure at day 28 (excludes new infections using PCR)
2. Treatment failure at day 63 (excludes new infections using PCR)
3. Abortion
4. Stillbirth
5. Congenital abnormalities
6. Mean birthweight
7. Anaemia and haematocrit
8. Perinatal death
9. Adverse events

Not included in review:
10. Treatment failure at 48 hours
11. Gametocyte positivity
12. Person‐gametocyte‐weeks
13. Placental weight
14. Estimated gestational age
15. Infant development

Notes

Location: Maela and Shoklo camps for displaced people of the Karen ethnic minority on the north‐west border of Thailand

Local malaria endemicity/transmission: low and seasonal

Local antimalarial drug resistance: multiple‐drug resistance

Supervision of treatment: all treatments supervised

Data awaiting: authors contacted, awaiting additional trial data

Additional notes: Médecins Sans Frontières is the main provider of medicine; treatment failures (up to day 63) were given artesunate for a further 7 days; all mothers requested to deliver at clinic

Methods

Randomized controlled trial

Generation of allocation sequence: no method reported

Allocation concealment: no method reported

Blinding: none

Inclusion of all randomized participants: 71% (for treatment failure) and 83% (for low birthweight)

Participants

Number: 131 randomized, 129 analysed (93 and 109 for primary outcomes)

Inclusion criteria: pregnant women; second or third trimester; seen at antenatal clinics of Shoklo and Maela camps; microscopy‐confirmed uncomplicated P. falciparum infection; consent

Exclusion criteria: severe or complicated malaria; intercurrent infections requiring hospitalization; allergy to quinine, artesunate, clindamycin; major liver or kidney disease; gestation < 12 weeks

Age in years (median (range)): artesunate group 25 (15 to 41); quinine plus clindamycin group 24 (15 to 41)

Parity: artesunate group 26.2% primipara; quinine plus clindamycin group 26.6% primipara

Early/late pregnancy: second and third trimester

Symptomatic/asymptomatic malaria: many women are oligosymptomatic or asymptomatic

Anaemia on admission: number not reported

Interventions

1. Artesunate: 2 mg/kg on days 0 to 4; 1 mg/kg on days 5 and 6
2. Quinine plus clindamycin
Quinine: 10 mg/kg every 8 hours for 7 days
Clindamycin: 5 mg/kg every 8 hours for 7 days

Outcomes

1. Treatment failure at day 42
2. Treatment failure (excludes new infections using PCR) at day 42
3. Congenital abnormalities
4. Stillbirth
5. Infant mortality
6. Low birthweight and mean birthweight
7. Anaemia
8. Haematocrit

Not included in review:
9. Mean placental weight
10. Estimated gestational age at delivery

Notes

Location: Maela and Shoklo camps for displaced people of the Karen ethnic minority on the north‐west border of Thailand

Local malaria endemicity/transmission: low and seasonal

Local antimalarial drug resistance: multiple‐drug resistance

Supervision of treatment: all treatments were supervised

Data awaiting: authors contacted 2005, awaiting additional trial data

Additional notes: Médecins Sans Frontières main provider of medicine; treatment given orally with a small amount of sugar and water; women asked to deliver at clinic (although usually deliver at home)

Methods

Randomized controlled trial

Generation of allocation sequence: computer generated in blocks of 10

Allocation concealment: envelopes

Blinding: outcome assessor

Inclusion of all randomized participants: 99% (for treatment failure)

Participants

Number: 81 randomized, 80 analysed

Inclusion criteria: healthy; first episode of (uncomplicated) falciparum or mixed malaria detected by weekly screening; haematocrit level ≥ 20%; second (> 13 weeks) or early third (< 32 weeks) trimester of pregnancy

Exclusion criteria: known chronic disease; inability to follow antenatal clinic consultation; history of alcohol abuse; imminent delivery; inability to tolerate oral treatment

Age in years (mean (standard deviation)): 26 (7) vs 26 (6)

Parity: just under 1/3 primigravida

Early/late pregnancy: second and third trimester

Symptomatic/asymptomatic malaria: detected by screening so likely to be asymptomatic

Anaemia on admission: not severe anaemia

Interventions

1. Quinine sulfate: 10 mg/kg every 8 hours for 7 days
2. Atovaquone‐proguanil plus artesunate
Atovaquone‐proguanil: fixed‐dose tablet (atovaquone 20 mg/kg and primaquine 8 mg/kg) once a day for 3 days
Artesunate: 4 mg/kg once a day for 3 days

Outcomes

1. Treatment failure at day 63
2. Treatment failure at day 63 (excludes new infections using PCR)
3. Fever clearance time
4. Low birthweight and mean birthweight
5. Anaemia (and severe anaemia)
6. Prematurity and estimated gestational age at delivery
7. Intra‐uterine growth retardation
8. Congenital abnormality
9. Tinnitus

Not included in review:
10. Stillbirth
11. Infant death in first 12 months (neonatal)
12. Total infant developmental score at 12 months
13. Vomiting drugs
14. Urticaria

Notes

Location: Maela and Shoklo camps for displaced people of the Karen ethnic minority on the north‐west border of Thailand

Local malaria endemicity/transmission: low and seasonal

Local antimalarial drug resistance: multiple‐drug resistance (only artemisinin therapies known to be effective)

Supervision of treatment: all treatments supervised

Additional notes: treatment given orally with sugar and water (quinine) or chocolate milk (atovaquone proguanil plus artesunate); any women with reappearance of parasites after the primary treatment were retreated with artesunate and clindamycin for 7 days

Methods

Quasi‐randomized controlled trial

Generation of allocation sequence: paired, restricted, sequential trial

Allocation concealment: no method reported

Blinding: none

Inclusion of all randomized participants: 74.4% (for treatment failure)

Participants

Number: 43 randomized, 32 analysed

Inclusion criteria: uncomplicated P. falciparum malaria; second or third trimester; fully informed consent

Exclusion criteria: none reported

Average age in years (mean (standard devation)): quinine plus spiramycin group 26 (6.2); quinine plus placebo group 28 (6.8)

Parity (median): quinine plus spiramycin group 2; quinine plus placebo group 4

Early/late pregnancy in gestation weeks (median): second and third trimester

Symptomatic/asymptomatic malaria: many women oligosymptomatic or asymptomatic

Anaemia on admission: number not reported

Interventions

1. Quinine plus spiramycin
Quinine sulfate salt: 30 mg/kg every day for 5 days
Spiramycin: 2 "Miu" 3 times a day for 5 days

2. Quinine plus placebo
Quinine sulfate salt: 30 mg/kg every day for 5 days

Outcomes

1. Treatment failure at day 28
2. Parasite clearance time
3. Abortion
4. Adverse events

Notes

Location: Shoklo camp, Thai‐Burmese border

Local malaria endemicity/transmission: not reported

Local antimalarial drug resistance: multiple‐drug resistance (unsupervised 7‐day quinine treatment has a failure rate of 50% in pregnant women with uncomplicated malaria)

Supervision of treatment: supervised

Data awaiting: authors contacted, awaiting additional trial data

Additional notes: despite high resistance, quinine is the only treatment available for pregnant women in the area; quinine was given as a supervised 5‐day course as this is the average actual intake when the standard 7‐day regimen is not supervised (usual practice)

Methods

Randomized controlled trial

Generation of allocation sequence: no method reported

Allocation concealment: no method reported

Blinding: none

Inclusion of all randomized participants: 100% (for treatment failure)

Participants

Number: 55 randomized, 55 analysed

Inclusion criteria: non‐response to chloroquine or sulfadoxine‐pyrimethamine, or both, as shown by failure of complete clearance of parasitaemia in the 2 weeks following a course of treatment; oral fluid intolerance; no history of allergy to known antimalarial drugs; second or third trimester pregnancy; consent of patients

Exclusion criteria: none reported

Average age in years (mean (standard deviation; range)): artemether plus mefloquine group 29.9 (6.1; 21 to 41); artemether group 28.9 (5.1; 20 to 40)

Parity: mostly primigravidae (29/45)

Early/late pregnancy: second and third trimester

Symptomatic/asymptomatic malaria: symptomatic

Anaemia on admission: number not reported

Interventions

1. Artemether plus mefloquine
Artemether: 3.2 mg/kg intramuscularly on day 0
Mefloquine: 7.5 mg/kg on days 1 and 2

2. Artemether: 3.2 mg/kg intramuscularly on day 0; 1.6 mg/kg daily for next 4 days

Outcomes

1. Treatment failure at day 14 (for artemether plus mefloquine group) and day 28 (for artemether group)
2. Fever clearance time
3. Parasite clearance time
4. Stillbirth
5. Mean birthweight
6. Congenital (physical) abnormalities
7. Neonatal malaria
8. Haematocrit
9. Adverse events

Not included in review:
10. Intra‐uterine growth retardation
11. Icterus in newborns
12. Infant development

Notes

Location: Nigeria

Local malaria endemicity/transmission: not reported

Local antimalarial drug resistance: multiple‐drug resistance (artemether and mefloquine resistance low, no artemisinin―mefloquine cross‐resistance)

Supervision of treatment: supervised

Methods

Randomized controlled trial

Generation of allocation sequence: randomized‐number list in blocks of 16

Allocation concealment: envelopes

Blinding: participant, treatment provider, outcome assessor, and data analyst

Inclusion of all randomized participants: 93% (for treatment failure)

Participants

Number: 900 randomized; 838 analysed

Inclusion criteria: pregnant; gestational age ≥16 weeks; attended antenatal clinic between March 2003 and September 2004; with peripheral blood parasitaemia

Exclusion criteria: multiple pregnancy; severe malaria; enrolled previously in the current study

Age in years: roughly 23

Parity: all parities, about half primigravida

Early/late pregnancy: 16 weeks plus, second and third trimester

Symptomatic/asymptomatic malaria: detected by screening so likely to be asymptomatic

Anaemia on admission: number not reported

Interventions

1. Chloroquine: 600 mg on days 1 and 2; 300 mg on day 3

2. Amodiaquine: 600 mg on days 1 and 2; 300 mg on day 3

3. Sulfadoxine‐pyrimethamine
Sulfadoxine: single dose 1500 mg
Pyrimethamine: single dose 75 mg

4. Amodiaquine plus sulfadoxine‐pyrimethamine
Amodiaquine: 600 mg on days 1 and 2; 300 mg on day 3
Sulfadoxine: single dose 1500 mg on day 1
Pyrimethamine: single dose 75 mg on day 1

Outcomes

1. Treatment failure at day 14
2. Treatment failure at day 28
3. Treatment failure at day 28 (excludes new infections using PCR)
4. Placental parasitaemia
5. Low birthweight
6. Preterm delivery
7. Adverse events

Not included in review:
8. Placental parasite clearance
9. Birthweight
10. Abortion
11. Stillbirth
12. Perinatal death
13. Neonatal death
14. Congenital abnormality

Notes

Location: St Theresa's Hospital, Nkoranza, Ghana

Local malaria endemicity/transmission: perennial (peaks in rainy season – July and August)

Local antimalarial drug resistance: unclear

Supervision of treatment: first dose supervised (given by study team) second and third doses taken at home