Area definition

Parasite rates

Description

Geographical location

Hypoendemicity (also called designated unstable malaria)

10% or fewer children aged 2 to 9 years, but may be higher for part of the year

Areas where there is little transmission and during the average year the effects upon the general population are unimportant

AFRO: Chad
AMRO: Belize, Bolivia, El Salvador, Guatemala, Mexico, Nicaragua, Costa Rica, Paraguay
EMRO: Afghanistan, Iraq, Oman
EURO: Armenia, Azerbaijan, Georgia, Kyrgyzstan, Tajikistan
SEARO: Nepal
WPRO: China

Mesoendemicity (also called unstable and stable malaria)

11 to 50% of children aged 2 to 9 years

Typically found among rural communities in subtropical zones where wide geographical variations in transmission exist

AFRO: Angola, Botswana, Cape Verde, Chad, Eritrea, Ethiopia, Kenya (considered hyper‐ or holoendemic in review, as indicated in most of the trials), Mauritania, Namibia, Niger, Zambia, Zimbabwe
AMRO: Brazil, Colombia, Ecuador, Guyana, Panama, Peru, Venezuela
EMRO: Iran, Pakistan, Saudi Arabia
SEARO: Bangladesh, Bhutan, India, Indonesia, Sri Lanka, Thailand
WPRO: Malaysia

Hyperendemicity (also called stable malaria)

Consistently > 50% among children aged 2 to 9 years

Areas where transmission is intense but seasonal; immunity is insufficient in all age groups

AFRO: Angola, Benin, Burkina Faso, Cameroon, Central African Republic, Chad, Congo, Côte d'Ivoire, Equatorial Guinea, Gabon, Gambia, Ghana, Guinea, Guinea‐Bissau, Liberia, Madagascar, Malawi, Mali, Mozambique, Nigeria, Sao Tome and Principe, Senegal, Sierra Leone, Togo, Uganda,Tanzania, Zambia
SEARO: Timor‐Leste
WPRO: Papua New Guinea, Philippines, Solomon Islands, Vanuatu, Vietnam

Holoendemicity (also called stable malaria)

Consistently > 75% among infants aged 0 to 11 months

Intense transmission resulting in a considerable degree of immunity after early childhood

AFRO: Central African Republic, Democratic Republic of Congo, Tanzania, Uganda, Burundi, Madagascar, Malawi, Mozambique
AMRO: Dominican Republic, Suriname
EMRO: Djibouti, Somalia, Sudan, Yemen
SEARO: Myanmar
WPRO: Cambodia, Lao People's Democratic Republic

Age group

Minimal daily dose

< 6 months

2 mg/kg

6 to 24 months

12.5 mg or 2 mg/kg

2 to 5 years

20 mg

6 to 11 years

30 mg

11 to 18 years

60 mg

Search set

CIDG SR^a

CENTRAL

MEDLINE^b

EMBASE^b

LILACS^b

1

iron

iron

iron

iron

iron

2

ferrous

ferrous

ferrous

FERROUS‐SULPHATE

ferrous

3

1 or 2

IRON COMPOUNDS

IRON COMPOUNDS

1 or 2

1 or 2

4

malaria

1 or 2 or 3

1 or 2 or 3

supplem$

malaria

5

anaemia

supplem*

supplem*

3 and 4

anaemia

6

anaemia

4 and 5

4 and 5

malaria

anaemia

7

4 or 5 or 6

malaria

malaria

anaemia

4 or 5 or 6

8

3 and 7

anaemia

anaemia

6 or 7

3 and 7

9

—

anaemia

anaemia

5 and 8

—

10

—

7 or 8 or 9

7 or 8 or 9

child$

—

11

—

6 and 10

6 and 10

infant$

—

12

—

—

child*

10 or 11

—

13

—

—

infant*

9 and 12

—

14

—

—

12 or 13

—

—

15

—

—

11 and 14

—

—

Trial ID

Clinical definition

Laboratory definition

Malaria‐related outcomes reported

Time of assessment

Malaria prevention or management strategies

Malaria prevention or management

Adam 1997 (C)

Physician's diagnosis of malaria

Any parasitaemia (all malaria species, assumed most Plasmodium falciparum since trial conducted in same region as Gebreselassie 1996)

Clinical malaria; any parasitaemia; malaria necessitating hospitalization (used as severe malaria); parasite density (all N events/N individuals, unadjusted for clustering)

3 months to end of treatment

Blood smears for malaria obtained before, during and after treatment. Children with clinical malaria referred to local hospital and treated

No

Ayoya 2009

Fever > 37.5°C (axillary)

Any parasitaemia (P. falciparum)

Clinical malaria; clinical malaria with parasitaemia ≥ 5000/μL (used as severe malaria); parasite density

3 months to end of treatment

Malaria screening was done at baseline for all children and repeated throughout the study in children who had fever. Children infected with P. falciparum also were treated with sulfadoxine‐pyrimethamine

Yes

Berger 2000

Isolated fever

Parasite density > 3000 (P. falciparum, Plasmodium malariae and Plasmodium ovale assessed. Over 97% were P. falciparum)

Parasite index (%, used as parasitaemia); parasitaemia above 3000 /µL (used as severe malaria) and 10,000 / µL (%); parasite density

3 months to end of treatment

9 months to end of follow‐up (FU)

Blood smears for malaria obtained at baseline, end of treatment (3 months) and end of FU (6 months). Chloroquine treatment given for all isolated fevers

Yes

Desai 2003

Fever ≥37.5°C

Any parasitaemia (P. falciparum) with fever or parasitaemia > 5000/mm³ alone

Clinical malaria; any parasitaemia; hazard ratios for these; parasite density

3 months to end of treatment

Blood smears at baseline and every 4 weeks. Oral quinine given for any fever with parasitaemia and cases of severe malaria referred for further treatment

Yes

Esan 2013

No clinical definition

Any parasitaemia

All cause sick visits (including malaria),

3 months to end of treatment

6 months to end of FU

Routine trimethoprim ‐ sulfamethoxazole prophylaxis

Yes

Fahmida 2007

Not stated

Not stated

Participants with "malaria" (used primarily as clinical malaria)

6 months to end of treatment

Not stated

No

Gebreselassie 1996

Fever ≥ 37.5°C with signs and symptoms suggestive of malaria and other diagnoses ruled out

Presence of parasites in blood (all species, P. falciparum 88.9%)

Children with at least one episode of clinical malaria; cumulative incidence of parasitaemia; parasite density > 5000 µL (used as severe malaria); parasite density

3 months to end of treatment

6 months to end of FU

Blood smears negative at baseline and repeated weekly. Chloroquine with or without primaquine given for any positive smear

Yes

Harvey 1989

Fever and headache at the same time

Any parasitaemia (P. falciparum 67%, P. vivax 26.4%, P. malariae 6.6%)

First episodes of clinically suspected malaria (used primarily as clinical malaria); any parasitaemia

4 months to end of treatment

6 months to end of FU

Blood smears for malaria obtained at 0, 6, 16, and 24 weeks. Chloroquine given for any illness reported as fever or headache, or both

Yes

Latham 1990

Not assessed

Any positive smear (malaria species not stated)

Any positive smear; parasite density

8 months to end of FU

Blood smears for malaria obtained at baseline and end of treatment. Treatment not stated

Yes

Lawless 1994

Child's recall of clinical illness

Any positive blood smear (malaria species not stated)

Malaria is not defined (used as clinical malaria)

3.5 months to end of treatment

No blood smears at baseline or during the trial (only at end of treatment). Treatment not stated

No

Leenstra 2009

Fever ≥ 37.5°C

Positive blood smear (malaria species not stated)

Episodes of clinical malaria and RRs adjusted for school; episodes of malaria parasitaemia and parasitaemia > 500 parasites/mm³ (used as severe malaria) and RRs adjusted for school, age, and baseline parasitaemia

5 months to end of treatment

Blood smears for malaria at baseline (1/4 of participants positive) and monthly during the trial. No treatment offered for positive smears; symptomatic cases referred to physician

Yes

Massaga 2003

History of fever in the previous 24 to 72 hours or measured temperature of ≥ 37.5°C

Any level of parasitaemia (P. falciparum only)

Clinical malaria as first or only episode per participant (used as clinical malaria) and episodes of clinical malaria; episodes of clinical malaria associated with parasitaemia > 5000 parasites/μL (used as severe malaria)

6 months to end of treatment

Blood smears for malaria at baseline and every 2 weeks. Sulfadoxine‐pyrimethamine treatment given for uncomplicated cases; complicated and severe malaria referred to the hospital

Yes

Mebrahtu 2004 (C)

Not assessed

Any positive smear (P. falciparum only)

Parasitaemia as OR (95% CI) adjusted for repeated measurements in each child

12 months to end of treatment

Blood smears for malaria at baseline and end of treatment. In addition, monthly smears from a random sample (50% of randomized). Treatment not stated

Yes

Menendez 1997

Fever ≥ 37.5°C

Parasitaemia of any density (P. falciparum only)

First or only episode of clinical malaria

1 year (6 months after end of treatment)

Blood smears for malaria at baseline, week 8 and for any fever. Chloroquine treatment given for clinical malaria

Yes

Richard 2006

Any fever within the previous 72 hours

P. falciparum (29%) or P. vivax (71%), any density

Episodes of falciparum or vivax malaria, or both (used primarily as clinical malaria)

7 months to end of treatment

Blood smears for malaria at baseline and whenever febrile. Treatment given for all clinical cases

Yes

Sazawal 2006 (C)a

Fever > 38°C and

Parasitaemia > 1000 or history of fever and parasitaemia > 3000 or parasitaemia > 10,000 parasites/mm³ regardless of fever (mostly P. falciparum)

Malaria‐related adverse events, defined as hospital admission or death due to malaria (used primarily as clinical malaria). RRs with 95% CI adjusted for multiple events per child and clustering; cerebral malaria (used as severe malaria)

Not fixed. End of treatment about 1 year and end of FU about 18 months

No baseline or routine surveillance for malaria during the trial. Treatment given only if admitted to the hospital and malaria diagnosed

No

Sazawal 2006 (C)b

Fever > 38°C

Parasitaemia > 1000 or history of fever and parasitaemia > 3000 or parasitaemia > 10,000 parasites/mm³ regardless of fever (mostly P. falciparum)

Malaria‐related adverse events, defined as hospital admission or death due to malaria (used primarily as clinical malaria). RRs with 95% CI adjusted for multiple events per child and clustering; cerebral malaria (used as severe malaria)

Not fixed. End of treatment about 1 year and end of FU about 18 months

Blood smear for malaria at baseline, and at 6 and 12 months. Sulfadoxine‐pyrimethamine treatment delivered to home to all slide‐confirmed malaria participants or clinical disease presenting during the study

Yes

Smith 1989 (C)

Fever > 37.5°C

> 500 parasites/mm³ (mostly P. falciparum)

Visits for clinical malaria; parasitaemia > 500/µL; fever with parasitaemia > 5000 parasites/mm³ (used as severe malaria (all N events/N individuals, unadjusted for clustering)

3 months to end of treatment

Blood smear for malaria at baseline, 2 weeks and end of treatment. No treatment at baseline; clinical malaria referred to local healthcare services

No

Verhoef 2002

Axillary temperature ≥ 37.5°C

Dipstick test for P. falciparum

Number of children with malaria infection (used primarily as clinical malaria)

3 months to end of treatment

Dipstick for P. falciparum tested at baseline, 4, 8, and 12 weeks. Confirmed with blood smear if febrile and treated with sulfadoxine‐pyrimethamine, amodiaquine or halofantrine

Yes

Zlotkin 2013 (C)

Axillary temperature ≥ 37.5°C

Parasitaemia of any density (mostly P. falciparum)

Incidence of clinical malaria, malaria with parasite density > 5000/µL, cerebral malaria

5 months to end of treatment

6 months to end of FU

Insecticide‐treated bed nets supplied with instructions for use. Children with malaria treated with artemisinin combination therapy

Yes

Trial ID

Outcome

n Int reported

N Int reported

n Cont reported

N Cont reported

Average cluster size

DE

Unadjusted RR (95% CI)

ln(RR)

Unadjusted SE(lnRR)

Adjusted SE(lnRR)/ sample size

Adam 1997 (C)

Clinical malaria

72

366

49

372

Household (used 1.5)

1.34

1.49 (1.07 to 2.08)

0.40

0.17

0.20

Adam 1997 (C)

Parasitaemia

127

368

101

372

Household (used 1.5)

1.34

1.27 (1.02 to 1.58)

0.24

0.11

0.13

Adam 1997 (C)

Clinical malaria necessitating hospitalization

41

405

32

382

Household (used 1.5)

1.34

1.21 (0.78 to 1.88)

0.19

0.22

0.26

Mebrahtu 2004 (C)

Parasitaemia

—

307

—

307

1.5

1.34

OR 0.9 (0.72 to 1.19) Converted to RR 0.98

0.47

0.28

0.32

Mebrahtu 2004 (C)

High‐grade parasitaemia

—

307

—

307

1.5

1.34

OR 1.04 (0.82 to 1.34) Converted to RR 1.03

0.03

0.12

0.14

Sazawal 2006 (C)a

Clinical malaria

467

7950

411

8006

1.4

—

1.16 (1.00 to 1.34)

0.15

—

0.07

Sazawal 2006 (C)a

Severe malaria (cerebral)

—

7950

—

8006

1.4

—

1.32 (1.02 to 1.70)

0.28

—

0.13

Sazawal 2006 (C)b

Clinical malaria

14

815

30

804

1.2

—

0.46 (0.24 to 0.88)

‐0.78

—

0.33

Sazawal 2006 (C)b

Severe malaria (cerebral)

4

815

15

804

1.2

—

0.26 (0.09 to 0.81)

‐1.35

—

0.56

Smith 1989 (C)

Clinical malaria

14

97

8

89

Household (used 1.5)

1.34

1.60 (0.42 to 0.71)

0.47

0.42

0.48

Smith 1989 (C)

Parasitaemia

28

97

16

89

Household (used 1.5)

1.34

1.61 (0.93 to 2.76)

0.47

0.28

0.32

Smith 1989 (C)

High‐grade parasitaemia

17

97

11

89

Household (used 1.5)

1.34

1.42 (0.70 to 2.86)

0.35

0.13

0.15

Zlotkin 2013 (C)

Clinical malaria

338

966

392

989

Compounds

—

0.87 (0.79 to 0.97)

‐0.14

—

0.05

Zlotkin 2013 (C)

Clinical malaria with high grade parasitaemia

273

966

308

989

Compounds

—

0.89 (0.80 to 1.00)

‐0.12

—

0.06

Study ID

Outcome

n Int reported

N Int reported

n Cont reported

N Cont reported

Average cluster size

DE

n Int adjusted

N Int adjusted

n Cont adjusted

N Cont adjusted

Adam 1997 (C)

Anaemia

364

368

357

374

Household (used 1.5)

1.4

260

263

255

267

Hall 2002 (C)

Anaemia

273

551

356

562

20

2.77

99

199

129

203

Mebrahtu 2004 (C)

All‐cause mortality

0

340

2

344

1.5

1.001

0

340

2

344

Mebrahtu 2004 (C)

Anaemia

180

232

172

272

1.5

1.4

129

166

123

194

Roschnik 2003 (C)

Anaemia

133

224

110

203

30

3.70

36

61

30

55

Sazawal 2006 (C)a

All‐cause mortality

149

7950

130

8006

1.4

1.001

149

7941

130

7996

Sazawal 2006 (C)b

All‐cause mortality

8

815

9

804

1.2

1.0004

8

815

9

804

Sazawal 2006 (C)b

Anaemia

4

308

7

327

1.2

1.4

3

220

5

234

Zlotkin 2013 (C)

All‐cause mortality

3

967

2

991

Compound

1.001

3

966

2

990

Trial ID

Intervention

Unit of measurement

Iron

Control

No. iron

No. control

Favours

For prevention or treatment of anaemia

Adam 1997 (C)

Iron versus placebo

Geometric mean, parasites/μL

15,059

8225

368 slides

372 slides

Control

Ayoya 2009

Iron versus placebo

Geometric mean, parasites/μL ± SD

2733 ± 1459

2648 ± 1562

105 children

97 children

Control

Berger 2000

Iron versus placebo

Geometric mean, RBC/mm³

61.2

25.7

49 children with malarial index

39 children with malarial index

Controlor similar

Desai 2003

Iron plus antimalaria versus antimalaria

Iron versus placebo (with single‐dose antimalarial treatment)

Geometric mean, parasites/mm³

1705

2569

2485

3778

129 children

127 children

127 children

108 children

Iron

Gebreselassie 1996

Iron versus placebo

Average parasite density class (parasite density classified in ascending order from 1 to 10)

5.2

5.0

239 children

241 children

Control or similar

Latham 1990

Iron versus placebo

Geometric mean, infected RBCs/100 WBC

4.8

1.9

28 children

26 children

Control

Mebrahtu 2004 (C)

Iron versus placebo

Geometric mean, parasites/μL (counting against 200 to 500 WBC, assuming 8000 WBC/μL

Age < 30 months 3402

Age > 30 months 2188

Age < 30 months 3422

Age > 30 months 2046

273 children (225 households)

265 children (225 households)

Similar

For treatment of malaria

Nwanyanwu 1996

Iron daily plus antimalarial versus iron weekly plus antimalarial versus antimalarial

Mean, parasites/μL (counting against 300 WBC, assuming 6000 WBC/μL

4927 (daily)

2207 (weekly)

1812

77 (daily)

63 (weekly)

children

75 children

Control

van den Hombergh 1996

Iron plus antimalarial plus folic acid versus antimalarial plus folic acid

Geometric mean, parasites/μL

5308

9302

48 children

47 children

Iron (at baseline groups unbalanced favouring placebo)