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Drugs for preventing malaria in pregnant women

  1. Paul Garner1,*,
  2. A Metin Gülmezoglu2

Editorial Group: Cochrane Infectious Diseases Group

Published Online: 18 OCT 2006

Assessed as up-to-date: 19 AUG 2006

DOI: 10.1002/14651858.CD000169.pub2


How to Cite

Garner P, Gülmezoglu AM. Drugs for preventing malaria in pregnant women. Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD000169. DOI: 10.1002/14651858.CD000169.pub2.

Author Information

  1. 1

    Liverpool School of Tropical Medicine, International Health Group, Liverpool, Merseyside, UK

  2. 2

    World Health Organization, Department of Reproductive Health and Research, Geneva, Switzerland

*Paul Garner, International Health Group, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, Merseyside, L3 5QA, UK. pgarner@liv.ac.uk.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 18 OCT 2006

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Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

Women who live in areas with endemic malaria and who are pregnant for the first or second time are more likely to be infected with Plasmodium falciparum malaria than non-pregnant women of a similar age (Brabin 1983). This infection contributes to antenatal anaemia (Brabin 1990; Duffy 2001) and slows fetal growth (Kramer 1987), which may harm the mother and baby.

Drugs have been widely used to prevent infection or its consequences. From the 1980s, prophylaxis to prevent, suppress, or eradicate malaria parasites with a variety of drugs has been tested. From the 1990s, a modification of this called intermittent preventive treatment (IPT) has been used, where women are treated for malaria presumptively at fixed times during the pregnancy, usually drugs with a long half life, such as sulfadoxine-pyrimethamine. There remains debate as to whether the mechanism of IPT actually differs a lot from prophylaxis (White 2005), but the regimens are very different. IPT requires just two or three doses during pregnancy, compared to prophylaxis regimens that may be daily (eg with proguanil) or weekly (eg with chloroquine). Prophylaxis and IPT are in addition to good care during pregnancy, which includes prompt treatment of women when they present clinically with fever or anaemia. Surprisingly, this latter area is remarkably under-researched (Orton 2005).

The research and policy question addressed in this review is whether giving drugs on a regular basis (prophylaxis or IPT) to prevent malaria has additional advantages in terms of health outcomes over prompt, appropriate treatment. The advantages with women taking regular, routine antimalarial drugs are that the drug will treat or suppress parasites in the blood and reduce the chances of illness or anaemia developing. In turn, this may ultimately benefit the fetus and impact on birthweight and long-term survival. The disadvantages of routine use of antimalarial drugs are that many drugs have adverse effects and that widespread use may contribute to the malaria parasite developing resistance to these drugs; and it requires health systems to help ensure their implementation. The question is first addressed in terms of all pregnant women, and then secondly in women of low parity, where the effects of malaria are more marked.

One of the main problems in evaluating the effects of routine antimalarial drugs on the mother and the infant is identifying meaningful outcomes in terms of the direct impact on mother or baby. This review has identified two pragmatic outcome measures:

  • Severe antenatal anaemia: there is a strong association between anaemia and poor maternal outcomes, so preventing severe anaemia is likely to be of benefit.
  • Perinatal death: preventing death of the fetus and in the first week of life is one of the main reasons for giving malaria prophylaxis.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

To assess drugs given to prevent malaria infection and its consequences in pregnant women living in malarial areas. This includes prophylaxis and intermittent preventive treatment (IPT).

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

Criteria for considering studies for this review

 

Types of studies

Randomized and quasi-randomized controlled trials.

 

Types of participants

Pregnant women living in endemic malaria areas.

 

Types of interventions

 

Interventions

Antimalarial drug prophylaxis (eg chloroquine given weekly) or IPT (typically sulfadoxine-pyrimethamine given two to three times during pregnancy).

 

Controls

  • No regular or routine antimalarial drugs given; women receive malaria treatments for fever, anaemia, or clinical malaria, according to local protocols.
  • Comparator regimens of prophylaxis or IPT.

 

Types of outcome measures

 

Mother

  • Death.
  • Antenatal hospital admission.
  • Obstetric complications:
    • Caesarean section.
    • Complicated labour.

  • Anaemia:
    • Severe anaemia*, defined as haemoglobin level less than 8 g/L; or haematocrit equivalent.
    • Anaemia (any).
    • Mean haematocrit.
    • Mean haemoglobin.
    • Need for a blood transfusion.

  • Malaria infection:
    • Antenatal parasitaemia.
    • Incidence (number of women infected at least once; number treated for suspected malaria).
    • Placental malaria.
    • Fever.

  • Adverse events leading to discontinuation of the drug or hospitalization.

 

Fetus

  • Death:
    • Perinatal death* (death of the baby after 22nd week of pregnancy and first seven days after birth).
    • Stillbirth.
    • Neonatal death.
    • Infant death.
    • Preterm birth.

  • Birthweight:
    • Mean birthweight.
    • Low birthweight.
    • High birthweight.

  • Malaria infection.

*Primary outcome measures for the review.

 

Search methods for identification of studies

We attempted to identify all relevant trials regardless of language or publication status (published, unpublished, in press, and in progress).

 

Databases

We searched the following databases using the search terms and strategy described in Appendix 1: Cochrane Infectious Diseases Group Specialized Register (March 2006); Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library (2006, Issue 1); MEDLINE (1966 to March 2006); EMBASE (1974 to March 2006); and LILACS (1982 to March 2006).

 

Researchers

We contacted researchers working in the field for unpublished data, confidential reports, and raw data of published trials.

 

Reference lists

We also checked the citations of literature reviews (Kramer 1987; Brabin 1990), and of all trials identified by the above methods, and asked the referees to check the search strategy.

 

Data collection and analysis

 

Selection of studies

Over the last 10 years, PG has periodically assessed titles and abstracts of articles identified by the literature search. Potentially relevant studies (describing the use of antimalarial drugs in pregnancy) were retrieved and examined. If they were potentially a trial, both authors applied the inclusion criteria and then compared their decisions; differences were resolved by discussion. Trials that appeared relevant but did not meet the inclusion criteria are listed in the 'Characteristics of excluded studies'.

 

Data extraction and management

Both authors extracted data in most updates; in the 2006 update, PG extracted data and MG cross checked the papers for accuracy. Data were entered into Review Manager 5.

 

Assessment of risk of bias in included studies

We independently assessed the trials' methodological quality (risk of bias). We judged the method used to generate the allocation sequence to be adequate if it was described and the resulting sequences were unpredictable, unclear if it was stated that the trial is randomized but the method was not described, and inadequate if the sequences could be related to prognosis. We considered the method used to conceal allocation to be adequate if the participants and investigators enrolling participants could not foresee assignment, unclear if the trial was described as randomized but the method was not described, and inadequate if the participants and investigators enrolling participants could foresee the upcoming assignment. Blinding was classified as double (use a placebo or a double dummy technique such that neither the participant or care provider/assessor know which treatment is given), single (the participant or care provider/assessor is aware of the treatment given), or open (all parties are aware of treatment). In our assessment of losses to follow up, we assessed the loss between the initial cohort and those women included in the final analysis of outcomes. Where information appeared to have been collected but was not fully reported, we approached the trial authors for further details.

 

Data synthesis

We used Review Manager 5 for the analysis. We separated trials into those evaluating the intervention in all parity groups (generally the older trials) and those evaluating prophylaxis in low-parity women (parity one and two). Trials were grouped by those that evaluated prophylaxis and those evaluating IPT. We used risk ratios (RR) for dichotomous variables and mean differences (MD) for mean values. In the absence of heterogeneity we used a fixed-effect model with 95% confidence intervals (CI), and where we detected heterogeneity, we used a random-effects model for the meta-analysis. Weighted averages were calculated where required. In trials where standard deviations for birthweight were not available, we used an estimate of 500 g.

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of ongoing studies.

Sixteen trials met the inclusion criteria (see 'Characteristics of included studies'); one trial had two arms (Parise 1998i; Parise 1998ii), making 17 separate comparisons. One large trial with 4220 participants from Malawi was intended to be randomized (Steketee 1996), but this did not appear to happen in practice; this and the other excluded studies are detailed in the 'Characteristics of excluded studies'.

 

Trial location

One trial was carried out in an area with unstable malaria in Thailand (Nosten 1994). All other trials were carried out in highly endemic areas in countries in Africa: Burkina Faso (Cot 1992); Cameroon (Cot 1995); The Gambia (Greenwood 1989; Menendez 1994); Kenya (Parise 1998i; Parise 1998ii; Shulman 1999); Malawi (Schultz 1994); Mali (Kayentao 2005); Mozambique (Challis 2004); Nigeria (Morley 1964; Fleming 1985; Nahlen 1989); Tanzania (Mutabingwa 1991); and Uganda (Hamilton 1972; Ndyomugyenyi 2000). Drug resistance varied over time and was incompletely reported in the papers.

 

Participants

The review includes 12,638 women (Appendix 2). All women regardless of number of previous pregnancies were included in seven trials (Morley 1964; Hamilton 1972; Greenwood 1989; Nahlen 1989; Mutabingwa 1991; Cot 1992; Nosten 1994); however, two of these trials selected women in their first pregnancy for follow up or reporting (Greenwood 1989; Mutabingwa 1991). Women in their first pregnancy were exclusively recruited in six trials (Fleming 1985; Menendez 1994; Cot 1995; Shulman 1999; Ndyomugyenyi 2000; Challis 2004), and women in their first or second pregnancy were recruited in three trials (Parise 1998i; Parise 1998ii; Schultz 1994; Kayentao 2005).

 

Interventions

Ten prophylaxis trials used a placebo or no antimalarial drug as the control (Appendix 3) . Different intervention drugs were used: chloroquine (Hamilton 1972; Cot 1992; Cot 1995; Ndyomugyenyi 2000); pyrimethamine (Morley 1964; Nahlen 1989); proguanil (Fleming 1985); pyrimethamine-dapsone (Greenwood 1989; Menendez 1994); and mefloquine (Nosten 1994). One trial compared chloroquine prophylaxis with proguanil (Mutabingwa 1991).

Three trials evaluated IPT with sulfadoxine-pyrimethamine against placebo (Parise 1998; Shulman 1999; Challis 2004), and two evaluated IPT against chloroquine prophylaxis (Schultz 1994; Kayentao 2005).

Three trial reports describe access to treatment in the event of a malarial illness (Morley 1964; Nosten 1994; Shulman 1999), while the other trials did not describe the services available to the trial participants.

Oral iron and folic acid supplements were used in seven trials in various combinations.

 

Risk of bias in included studies

As shown in Appendix 4, three trials used an adequate method to generate the allocation sequence (Fleming 1985; Shulman 1999; Ndyomugyenyi 2000), seven used an inadequate method (alternate allocation or allocation by day of attendance at clinic), and the method was unclear in six trials. Only two trials concealed allocation (Nosten 1994; Shulman 1999), while 10 trials did not conceal allocation or used inadequate methods to do this, and the methods used were unclear in four trials. For blinding, three trials reported both that health staff and women were blinded from their intervention group (Nosten 1994; Shulman 1999; Challis 2004). One trial was described as double blind (Ndyomugyenyi 2000) and another blinded the patients but was not clear about health staff (Fleming 1985); the other trials did not use blinding.

The percentage of randomized participants included in the analyses varied from 24% to 100% for maternal outcomes, and 62% to 100% for fetal outcomes (Appendix 5).

The two trials from The Gambia trials were randomized by cluster (Greenwood 1989; Menendez 1994), but the analysis did not take the cluster-design effects into consideration. However, pregnancy is a relatively infrequent event and the compounds (which were the units of randomization) generally have only a small number of houses. We therefore used the data as they were presented in the paper and ignored any possible design effects.

 

Effects of interventions

We examined trials allocating women to prophylaxis or IPT versus a control (placebo or no routine drug), first in trials that recruited and reported women of all parity groups, and then those recruiting and reporting women of low parity. We then examined head-to-head comparisons.

 

1. Any antimalarial drug versus no drug

 

1.1. Women of all parity groups

Six trials tested the overall benefit to women of routine drugs given during pregnancy: five were carried out in Africa (Morley 1964; Hamilton 1972; Greenwood 1989; Nahlen 1989; Cot 1992); and one was carried out in an area with unstable malaria in Thailand (Nosten 1994).

 

1.1.1. Mother

 
Death

One trial, Greenwood 1989, recorded maternal death and did not demonstrate a difference (1049 participants,  Analysis 1.1).

 
Obstetric complications

There was no significant difference in the number of Caesarean sections in Hamilton 1972 (1137 participants,  Analysis 1.2) or complicated labours in Nosten 1994 (301 participants,  Analysis 1.3).

 
Anaemia

No statistically significant difference between the two groups was reported for women with any anaemia (Nosten 1994, 311 participants,  Analysis 1.4), mean values of haematocrit (Greenwood 1989, 276 participants,  Analysis 1.5), or the need for a blood transfusion (Nosten 1994, 339 participants,  Analysis 1.6).

 
Malaria infection

Fewer women in the group that received antimalarial drugs had antenatal parasitaemia (RR 0.53, 95% CI 0.33 to 0.86; 328 participants, 2 trials,  Analysis 1.7), at least one malaria infection (RR 0.14, 95% CI 0.06 to 0.34; 337 participants, 1 trial,  Analysis 1.8), placental malaria (RR 0.34, 95% CI 0.26 to 0.45; 1236 participants, 3 trials,  Analysis 1.9), and episodes of fever (RR 0.42, 95% CI 0.27 to 0.66; 227 participants, 1 trial,  Analysis 1.10).

 

1.1.2. Fetal

 
Death

There was no statistically significant difference in the number of perinatal deaths in the meta-analysis of the four trials that reported this (2890 participants, 4 trials,  Analysis 2.1), with no significant heterogeneity. Nosten 1994 had a trend of more perinatal deaths in the prophylaxis group that bordered on significance (RR 3.51, 95% CI 1.00 to 12.32; 311 participants). The analyses for stillbirth (1493 participants, 2 trials,  Analysis 2.2), neonatal death (419 participants, 1 trial,  Analysis 2.3), and infant death (288 participants, 2 trials,  Analysis 2.4) were underpowered and infrequently reported, with no significant differences demonstrated.

 
Preterm birth

Nosten 1994 reported on the number of preterm births, and no significant difference was demonstrated (199 participants,  Analysis 2.5).

 
Birthweight

Four trials reported mean birthweight (2671 participants, Analysis 2.6). There was no significant difference in number with low birthweight (1438 participants,  Analysis 2.7) or high birthweight (287 participants,  Analysis 2.8, although there was significant heterogeneity between the trials (P = 0.010).

 

1.2. Women having their first or second baby

Seven trials reported on women in their first or second pregnancy (Fleming 1985; Greenwood 1989; Menendez 1994; Cot 1995; Shulman 1999; Ndyomugyenyi 2000; Challis 2004). In the analyses, we have stratified trials by whether women were given prophylaxis or IPT.

 

1.2.1. Mother

 
Death

The two trials that reported this outcome measure both used prophylaxis (Greenwood 1989; Ndyomugyenyi 2000). They had too few participants to detect an effect on maternal death (772 participants, 2 trials,  Analysis 3.1).

 
Obstetric complications

Two small trials that used prophylaxis measured the number of women having a Caesarean section (Fleming 1985; Cot 1995) and the meta-analysis showed no significant difference (294 participants,  Analysis 3.2).

 
Anaemia

The group of women who received antimalarial drugs had fewer instances of severe antenatal anaemia (RR 0.62, 95% CI 0.50 to 0.78; 2809 participants, 1 prophylaxis trial, 2 IPT trials,  Analysis 3.3) and any anaemia (RR 0.67, 95% CI 0.47 to 0.95; 566 participants, 1 prophylaxis trial,  Analysis 3.4. This was also the case for mean haematocrit (MD 2.63, 95% CI 1.36 to 3.90; 118 participants, 2 prophylaxis trials,  Analysis 3.5) and mean haemoglobin (MD 0.40, 95% CI 0.23 to 0.56; 1677 participants, 1 prophylaxis trial and 1 IPT trial,  Analysis 3.6.

 
Malaria infection

Routine drug administration was associated with fewer women with parasites in the antenatal period (RR 0.27, 95% CI 0.17 to 0.44, random-effects model; 2906 participants, 3 prophylaxis trials and 3 IPT trials, Analysis 3.7); there was heterogeneity between the trials, but the direction of effect was consistent. The antimalarial drugs also had an effect on reducing the incidence of women having at least one malaria infection (RR 0.12, 95% 0.02 to 0.93; 83 participants, 1 prophylaxis trial,  Analysis 2.8), the need for treatment for suspected malaria (RR 0.41, 95% CI 0.18 to 0.91; 133 participants, 1 prophylaxis trial, Analysis 3.9, and the number of women with placental malaria in the three prophylaxis trials (RR 0.71, 95% CI 0.60 to 0.85; 573 participants) and the two IPT trials (RR 0.35, 95% CI 0.27 to 0.47; 1232 participants;  Analysis 3.10).

 

1.2.2. Fetus

 
Death

A meta-analysis of two prophylaxis trials and one IPT trial found that the use of antimalarial drugs is associated with fewer perinatal deaths (RR 0.73, 95% CI 0.53 to 0.99; 1986 participants, 2 prophylaxis and 1 IPT trial,  Analysis 4.1). A sensitivity analysis of the one adequately concealed trial showed that the effect on perinatal deaths was smaller than in the other two trials (RR 0.78, 95% CI 0.52 to 1.17; 1237 participants, Shulman 1999,  Analysis 4.1). For stillbirth, no impact was detected (3454 participants,  Analysis 4.2. In the three trials reporting neonatal deaths, the trend was towards protection, but again this was not statistically significant (2505 participants,  Analysis 4.3). There was also no significant difference in the number of infant deaths in one small trial (349 participants,  Analysis 4.4).

 
Preterm births

One prophylaxis trial reported no statistically significant difference in the number of preterm births (1051 participants,  Analysis 4.5).

 
Birthweight

Babies born to women using antimalarial drugs had a higher mean birthweight (MD 126.70 g, 95% CI 88.64 to 164.75; 2648 participants, 8 trials,  Analysis 4.6 and were less likely to have a low birthweight (RR 0.57, 95% CI 0.46 to 0.72; 2350 participants, 6 trials,  Analysis 4.7. One small trial reported on high birthweight, but there was no significant difference between the groups (121 participants,  Analysis 4.8).

 
Malaria infection

Two trials reported on newborn malaria infection; one suggesting an effect and the other not showing a significant difference (639 participants,  Analysis 4.9).

 

2. Head-to-head comparisons

 

2.1. Proguanil versus chloroquine

One trial carried out in Tanzania in women of all parities examined this comparison (Mutabingwa 1991). Compared with chloroquine, proguanil was associated with fewer fever episodes (RR 0.69, 95% CI 0.59 to 0.81; 223 participants,  Analysis 5.3) and fewer women with antenatal parasitaemia (RR 0.80, 95% CI 0.71 to 0.91; 223 participants,  Analysis 5.4), but there was no difference for haemoglobin (200 participants,  Analysis 5.2). The difference in mean birthweight tended towards favouring proguanil, but this was not significant (197 participants,  Analysis 6.3).

 

2.2. Sulfadoxine-pyrimethamine versus chloroquine

Two trials examined this comparison; both were conducted in Africa in low-parity women (Schultz 1994; Kayentao 2005). There was no significant difference between the two interventions for the number of women with severe anaemia (717 participants, 1 trial,  Analysis 5.1), but fewer women in the sulfadoxine-pyrimethamine group had antenatal parasitaemia (RR 0.71, 95% CI 0.56 to 0.91; 848 participants, 2 trials,  Analysis 5.4) and placental malaria (RR 0.75, 95% CI 0.60 to 0.95; 831 participants, 2 trials  Analysis 5.5).

There was no significant difference for the number of neonatal deaths (696 participants, 1 trial,  Analysis 6.1), preterm births (828 participants, 2 trials,  Analysis 6.2), or mean birthweight (719 participants, 1 trial,  Analysis 6.3); however, low birthweight was less common with sulfadoxine-pyrimethamine (RR 0.77, 95% CI 0.61 to 0.97; 828 participants, 2 trials,  Analysis 6.4).

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

Prophylaxis with a variety of antimalarial drugs or IPT with sulfadoxine-pyrimethamine in women having their first or second baby is associated with fewer women having severe anaemia and fewer perinatal deaths. The size of the effect for severe anaemia is considerable, while the size of the effect with perinatal mortality is more modest. There was no obvious effect when prophylaxis or IPT was given to all women regardless of the number of previous pregnancies. Malaria parasitaemia in the blood or the placenta is also less common with prophylaxis or IPT.

For infants, the review shows emerging evidence of an effect on perinatal death in low-parity women. This also corresponds with the effect seen on birthweight, with fewer low birthweight infants in these women. Women with more than two previous pregnancies may accrue small benefits from prophylaxis, but there are insufficient data to demonstrate or refute this.

In Fleming 1985, some women in the intervention group also received iron or folic acid, or both, and in these women growth (height) also increased during pregnancy. The nutritional supplementation (not the prophylaxis) appeared to assist maternal growth in pregnancy and reduce the risk of Caesarean section.

We anticipated that there may be differences in effect between women living in areas where malaria is endemic and those living in epidemic areas. We know that host immunity means that malaria illness in semi-immune women is less severe than in women who have no host immunity. Thus it is reasonable to expect there to be differences in effects of preventive measures for malaria in pregnancy between women living in areas where malaria is highly endemic and women have acquired some host resistance compared with women living in areas where malaria is less common or occurs in epidemics and a malaria infection is likely to be associated with a more severe illness. We were unable to stratify the analysis to explore for these differences because there were too few trials.

Trials on this question are not easy to conduct, particularly when mortality outcomes are sought, and a meta-analysis has something to offer by combining results from the different trials. Apart from the trial from The Gambia (Greenwood 1989), the recording of pregnancy outcome data in the trials was largely dependent on delivery in hospital. The large number of women lost or excluded from the final analyses could potentially mean the more disadvantaged groups were excluded from the results.

Much of the research emphasis has been on drugs for prevention, rather than prompt and appropriate treatment of illness episodes, including anaemia. Pregnant women need access to services that can provide treatment for illness episodes and anaemia. It may be that prophylaxis is an appropriate approach where such services are not available because the health system is insufficient to provide clinical care for illness episodes. An additional advantage of IPT could be in terms of adherence.

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

 

Implications for practice

Routine antimalarial drugs have been shown to reduce antenatal parasitaemia and fever in pregnant women living in areas with endemic malaria. For women in their first or second pregnancy, this intervention reduces the instances of severe antenatal anaemia, antenatal parasitaemia, and perinatal deaths, and it has a positive effect on birthweight.

Even if quite modest, these effects may well be worth pursuing. The sulfadoxine-pyrimethamine regimen is feasible and practical to implement. There are public health consequences to giving drugs regularly to women during pregnancy in terms of increasing the risk of drug resistance developing.

There remains a question over what policies to adopt when sulfadoxine-pyrimethamine resistance rises. As impregnated mosquito nets have been shown to be effective in pregnancy (Gamble 2006), then IPT may be used in combination with them. Nets, if used in combination with IPT or prophylaxis, may assist in preventing drug resistant strains of the parasite from spreading.

 
Implications for research

The confidence intervals for the meta-analysis for perinatal death in women in their first or second pregnancy just reaches statistical significance, but the point estimate indicates that the potential impact of this intervention on death could be high. Until the appropriate research is done, we cannot be sure how effective the intervention is in reducing perinatal deaths.

Large simple trials implemented through routine health services measuring mortality outcomes are widely used in areas outside malaria. Such a trial could compare prophylaxis or IPT with prompt regular treatment of morbidity in the mother (usually fever or anaemia). The outcomes should examine the effects on pregnancy outcome and death in the neonate and infant. Establishing whether there is an impact of routine prophylaxis or IPT is likely to re-emerge as an issue if sulfadoxine-pyrimethamine becomes ineffective through drug resistance, and policy makers are then faced with the potential of changing to effective drugs.

Iron deficiency is an important cause of anaemia in areas with malaria, so researchers contemplating a trial should consider a factorial design to examine also the impact of routine iron supplementation in malaria areas.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

On earlier versions of this review, we thank Iain Chalmers and Bernard Brabin for their helpful comments; and François Nosten, Alice Greenwood, TK Mutabingwa, Michel Cot, Caroline Shulman, and Monica Parise for contributing unpublished data; and funding from the European Commission (Directorate General XII) in Belgium and the World Health Organization.

This document is an output from a project funded by the UK Department for International Development (DFID) for the benefit of developing countries. The views expressed are not necessarily those of DFID.

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
Download statistical data

 
Comparison 1. Any antimalarial drug versus no drug (women of all parity groups): maternal outcomes

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Death1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 2 Caesarean section1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 3 Complicated labour1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 4 Anaemia (any)1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 5 Haematocrit1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 6 Need for blood transfusion1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 7 Antenatal parasitaemia2328Risk Ratio (M-H, Fixed, 95% CI)0.53 [0.33, 0.86]

 8 At least one malaria infection1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 9 Placental malaria31236Risk Ratio (M-H, Fixed, 95% CI)0.34 [0.26, 0.45]

 10 Fever episodes1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 
Comparison 2. Any antimalarial drug versus no drug (women of all parity groups): fetal outcomes

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Perinatal death42890Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.73, 1.43]

 2 Stillbirth21493Risk Ratio (M-H, Fixed, 95% CI)1.51 [0.80, 2.84]

 3 Neonatal death1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 4 Infant death1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 5 Preterm birth1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 6 Mean birthweight42671Mean Difference (IV, Fixed, 95% CI)19.10 [-19.08, 57.27]

 7 Low birthweight21438Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.83, 1.34]

 8 High birthweight1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 
Comparison 3. Any antimalarial drug prevention versus no drug (women in first or second pregnancy): maternal outcomes

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Death2772Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.32, 2.98]

    1.1 Prophylaxis
2772Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.32, 2.98]

 2 Caesarean section (prophylaxis only)2294Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.35, 2.59]

 3 Severe antenatal anaemia42809Risk Ratio (M-H, Fixed, 95% CI)0.62 [0.50, 0.78]

    3.1 Prophylaxis
1566Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.41, 2.03]

    3.2 Intermittent preventive treatment
32243Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.48, 0.76]

 4 Anaemia (any)1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    4.1 Prophylaxis
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 5 Mean haematocrit2Mean Difference (IV, Fixed, 95% CI)Subtotals only

    5.1 Prophylaxis
2118Mean Difference (IV, Fixed, 95% CI)2.63 [1.36, 3.90]

 6 Mean haemoglobin31677Mean Difference (IV, Fixed, 95% CI)0.40 [0.23, 0.56]

    6.1 Prophylaxis
1566Mean Difference (IV, Fixed, 95% CI)0.40 [0.14, 0.66]

    6.2 Intermittent preventive treatment
21111Mean Difference (IV, Fixed, 95% CI)0.40 [0.19, 0.61]

 7 Antenatal parasitaemia72906Risk Ratio (M-H, Random, 95% CI)0.27 [0.17, 0.44]

    7.1 Prophylaxis
3334Risk Ratio (M-H, Random, 95% CI)0.23 [0.05, 1.18]

    7.2 Intermittent preventive treatment
42572Risk Ratio (M-H, Random, 95% CI)0.27 [0.17, 0.45]

 8 Women infected at least once (prophylaxis only)1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 9 Treatment for suspected malaria (prophylaxis only)1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 10 Placental malaria61805Risk Ratio (M-H, Random, 95% CI)0.52 [0.38, 0.72]

    10.1 Prophylaxis
3573Risk Ratio (M-H, Random, 95% CI)0.71 [0.60, 0.85]

    10.2 Intermittent preventive treatment
31232Risk Ratio (M-H, Random, 95% CI)0.35 [0.27, 0.47]

 
Comparison 4. Any antimalarial drug prevention versus no drug (women in first or second pregnancy): fetal outcomes

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Perinatal death31986Risk Ratio (M-H, Fixed, 95% CI)0.73 [0.53, 0.99]

    1.1 Prophylaxis
2749Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.41, 1.06]

    1.2 Intermittent preventive treatment
11237Risk Ratio (M-H, Fixed, 95% CI)0.78 [0.52, 1.17]

 2 Stillbirth63454Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.62, 1.21]

    2.1 Prophylaxis
3882Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.45, 1.24]

    2.2 Intermittent preventive treatment
32572Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.62, 1.50]

 3 Neonatal death42505Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.44, 1.05]

    3.1 Prophylaxis
1349Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.39, 1.88]

    3.2 Intermittent preventive treatment
32156Risk Ratio (M-H, Fixed, 95% CI)0.62 [0.37, 1.05]

 4 Infant death1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    4.1 Prophylaxis
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 5 Preterm birth2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    5.1 Intermittent preventive treatment
21051Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.64, 1.29]

 6 Mean birthweight92648Mean Difference (IV, Fixed, 95% CI)126.70 [88.64, 164.75]

    6.1 Prophylaxis
61249Mean Difference (IV, Fixed, 95% CI)130.60 [81.01, 180.20]

    6.2 Intermittent preventive treatment
31399Mean Difference (IV, Fixed, 95% CI)121.11 [61.76, 180.45]

 7 Low birthweight72350Risk Ratio (M-H, Fixed, 95% CI)0.57 [0.46, 0.72]

    7.1 Prophylaxis
4951Risk Ratio (M-H, Fixed, 95% CI)0.57 [0.40, 0.79]

    7.2 Intermittent preventive treatment
31399Risk Ratio (M-H, Fixed, 95% CI)0.58 [0.43, 0.78]

 8 High birthweight1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 9 Newborn malaria infection2639Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.69, 1.16]

    9.1 Prophylaxis
1337Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.78, 1.31]

    9.2 Intermittent preventive treatment
1302Risk Ratio (M-H, Fixed, 95% CI)0.11 [0.01, 0.82]

 
Comparison 5. Any antimalarial regimen versus weekly chloroquine: maternal outcomes

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Severe anaemia1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    1.1 Sulfadoxine-pyrimethamine
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 2 Haemoglobin1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    2.1 Proguanil
1Mean Difference (IV, Fixed, 95% CI)Not estimable

 3 Fever episodes1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    3.1 Proguanil
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 4 Antenatal parasitaemia3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 Proguanil
1223Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.71, 0.91]

    4.2 Sulfadoxine-pyrimethamine
2848Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.56, 0.91]

 5 Placental malaria2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    5.1 Sulfadoxine-pyrimethamine
2831Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.60, 0.95]

 
Comparison 6. Any antimalarial regimen versus weekly chloroquine: fetal outcomes

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Neonatal death1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    1.1 Sulfadoxine-pyrimethamine
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 2 Preterm birth2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Sulfadoxine-pyrimethamine
2828Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.52, 1.49]

 3 Mean birthweight2Mean Difference (IV, Fixed, 95% CI)Totals not selected

    3.1 Proguanil
1Mean Difference (IV, Fixed, 95% CI)Not estimable

    3.2 Sulfadoxine-pyrimethamine
1Mean Difference (IV, Fixed, 95% CI)Not estimable

 4 Low birthweight3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 Proguanil
1134Risk Ratio (M-H, Fixed, 95% CI)1.27 [0.54, 3.00]

    4.2 Sulfadoxine-pyrimethamine
2828Risk Ratio (M-H, Fixed, 95% CI)0.77 [0.61, 0.97]

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

Appendix 1. Search methods: detailed search strategies


Search setCIDG SRaCENTRALMEDLINEbEMBASEbLILACSb

1malariaMALARIAMALARIAMALARIAmalaria

2pregnan*malariamalariamalariapregnan*

31 and 21 or 21 or 21 or 21 and 2

4PREGNANCYPREGNANCYPREGNANCY

5pregnan*pregnan*pregnan$

64 or 54 or 54 or 5

73 and 63 and 63 and 6

8Limit 7 to humanLimit 7 to human



aCochrane Infectious Diseases Group Specialized Register.
bSearch terms used in combination with the search strategy for retrieving trials developed by The Cochrane Collaboration (Higgins 2005); upper case: MeSH or EMTREE heading; lower case: free text term.

 

Appendix 2. Trial participants: number of previous pregnancies


No. of pregnanciesTrials

All womenMorley 1964, Hamilton 1972 Nahlen 1989, Cot 1992,Nosten 1994; Greenwood 1989, and Mutabingwa 1991 selected women in their first pregnancy for follow up or reporting

First pregnancyFleming 1985, Menendez 1994, Cot 1995, Shulman 1998, Ndyomugyenyi 2000, Challis 2004

First or second pregnancySchultz 1994, Parise 1998i, Parise 1998ii, Kayentao 2005



 

Appendix 3. Comparisons evaluated in the trials


ControlInterventionTrials

Placebo or no active drugChloroquineHamilton 1972, Cot 1992, Cot 1995, Ndyomugyenyi 2000

PyrimethamineMorley 1964, Nahlen 1989

ProguanilFleming 1985

Pyrimethamine-dapsoneGreenwood 1989, Menendez 1994

Sulfadoxine-pyrimethamineParise 1998i, Parise 1998ii, Shulman 1999, Challis 2004

MefloquineNosten 1994

ChloroquineProguanilMutabingwa 1991

Sulfadoxine-pyrimethamineSchultz 1994, Kayentao 2005



 

Appendix 4. Methodological quality (risk of bias)


TrialSequence generationConceal allocationBlinding

Challis 2004UnclearUnclearDouble (women; health worker)

Cot 1992Inadequate (alternate allocation)Inadequate (not concealed)None

Cot 1995Inadequate (alternate allocation)Inadequate (not concealed)None

Fleming 1985Adequate (random-number table)UnclearPatients blind; not clear if health staff blinded

Greenwood 1989Unclear (allocated by compound)Inadequate (not concealed)None

Hamilton 1972Inadequate (day of the week attending clinic; based on referral to 1 of 3 clinics)Inadequate (not concealed)None

Kayentao 2005Unclear ("by block")UnclearNone

Menendez 1994Unclear (allocated by compound)Inadequate (not concealed)None

Morley 1964Inadequate (alternate assignment at registration)InadequateNone

Mutabingwa 1991Inadequate (alternate allocation)Inadequate (not concealed)None

Nahlen 1989UnclearInadequate (not concealed)None

Ndyomugyenyi 2000Adequate ("using a random sequence")UnclearDouble

Nosten 1994UnclearAdequate (investigators unaware of randomization)Patients and health staff blind

Parise 1998i, Parise 1998iiInadequate (based on day of clinic attendance)Inadequate (not concealed)None

Shulman 1999Adequate (blocks of 10) from statisticianAdequate (code held by statistician)Patients, investigator, and health staff blind

Schultz 1994Inadequate (sequential assignment based on the day of clinic attendance)Inadequate (not concealed)None



 

Appendix 5. Percentage of randomized participants included in the analyses


TrialWomenNewborns


Outcomen/Na% in analysisOutcomen/Na% in analysis

Challis 2004Parasitaemia411/60069Low birthweight403/60067

Cot 1992Placental malaria904/146462Birthweight1148/1148100

Cot 1995Placental malaria120/26657Birthweight209/26679

Fleming 1985Haemoglobin107/20045Perinatal death152/20076

Greenwood 1989Parasitaemia257/104924Birthweight877/103485

Hamilton 1972Birthweight1149/184662

Kayentao 2005Severe anaemia717/116361BirthweightAppears completeAppears complete

Menendez 1994Placental malaria116/23050Birthweight182/20390

Morley 1964Antenatal parasitaemia227/42953Birthweight429/429100

Mutabingwa 1991Antenatal parasitaemia367/42387Birthweight312/42374

Nahlen 1989Parasitaemia71/71100

Ndyomugyenyi 2000Anaemia510/86059Congenital malaria337/51066

Nosten 1994Parasitaemia399/399100Birthweight290/290100

Parise 1998i, Parise 1998iiHaemoglobin1378/207766

Shulman 1999Severe anaemia1132/126490

Schultz 1994Parasitaemia159/35744BirthweightNot knownNot known



aNumber analysed/number randomized.

 

What's new

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

Last assessed as up-to-date: 19 August 2006.


DateEventDescription

16 September 2008AmendedConverted to new review format with minor editing.



 

History

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

Protocol first published: Issue 1, 1995
Review first published: Issue 1, 1995


DateEventDescription

20 August 2006Amended2006, Issue 4: added Challis 2004 and Kayentao 2005; meta-analysis stratified by prophylaxis and intermittent preventive treatment; review title shortened.

20 November 2002Amended2003, Issue 1: Review overhauled to reflect current methods; title was altered to "Drugs for preventing malaria-related illness in pregnant women and death in the newborn" (from "Prevention versus treatment for malaria in pregnant women"); we excluded mosquito nets as these are now covered by Gamble 2006; primary outcome measures were adjusted following feedback from readers; methodological quality of trials reassessed; Martin 1982 trial previously included, but now excluded because it is not randomized.

28 February 2001AmendedPrimary outcome measures defined; Parise 1998 trial added.



 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

Paul Garner wrote the first version of this review in 1995. Metin Gülmezoglu carried out the first update, and Paul Garner has been updating the review since then in consultation with Metin Gülmezoglu.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

None known.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

Internal sources

  • Liverpool School of Tropical Medicine, UK.
  • HRP-UNDP/UNFPA/WHO/World Bank Special Programme in Human Reproduction, Geneva, Switzerland.

 

External sources

  • Department for International Development (DFID), UK.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. Abstract摘要
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to ongoing studies
  21. Additional references
  22. References to other published versions of this review
Challis 2004 {published data only}
Cot 1992 {published data only}
  • Cot M, Roisin A, Barro D, Yada A, Verhave J, Carnevale P, et al. Effect of chloroquine chemoprophylaxis during pregnancy on birth weight: results of a randomized trial. American Journal of Tropical Medicine and Hygiene 1992;46(1):21-7.
Cot 1995 {published data only}
  • Cot M, Le Hesran JY, Miailhes P, Esveld M, Etya'ale D, Breart G. Increase of birth weight following chloroquine chemoprophylaxis during the first pregnancy: results of a randomized trial in Cameroon. American Journal of Tropical Medicine and Hygiene 1995;53(6):581-5.
Fleming 1985 {published data only}
  • Fleming A, Ghatoura G, Harrison K, Briggs N, Dunn D. The prevention of anaemia in pregnancy in primigravidae in the guinea savanna of Nigeria. Annals of Tropical Medicine and Parasitology 1986;80(2):211-33.
  • Harrison KA, Fleming AF, Briggs ND, Rossiter CE. Growth during pregnancy in Nigerian teenage primigravidae. British Journal of Obstetric Gynaecol 1985;92 Suppl 5:32-9.
Greenwood 1989 {published and unpublished data}
  • Greenwood AM, Menendez C, Todd J, Greenwood BM. The distribution of birthweights in Gambian women who received malaria chemoprophylaxis during their first pregnancy and in control women. Transactions of the Royal Society of Tropical Medicine and Hygiene 1994;88(3):311-2.
  • Greenwood BM, Greenwood AM, Snow RW, Byass P, Bennett S, Hatib-N'Jie AB. The effects of malaria chemoprophylaxis given by traditional birth attendants on the course and outcome of pregnancy. Transactions of the Royal Society of Tropical Medicine and Hygiene 1989;83(5):589-94.
  • Menendez C, Todd J, Alonso P, Lulat S, Francis N, Greenwood BM. Malaria prophylaxis, infection of the placenta and birth weight in Gambian primigravidae. Journal of Tropical Medicine and Hygiene 1994;97(4):244-8.
Hamilton 1972 {published data only}
  • Hamilton P, Gebbie D, Wilks N, Lothe F. The role of malaria, folic acid deficiency and haemoglobin AS in pregnancy at Mulago Hospital. Transactions of the Royal Society of Tropical Medicine and Hygiene 1972;66(4):594-602.
Kayentao 2005 {published data only}
  • Kayentao K, Kodio M, Newman RD, Maiga H, Doumtabe D, Ongoiba A, et al. Comparison of intermittent preventive treatment with chemoprophylaxis for the prevention of malaria during pregnancy in Mali. Journal of Infectious Diseases 2005;191(1):109-16.
Menendez 1994 {published data only}
  • Menendez C, Todd J, Alonso PL, Lulat S, Francis N, Greenwood BM. Malaria chemoprophylaxis, infection of the placenta and birth weight in Gambian primigravidae. Journal of Tropical Medicine and Hygiene 1994;97(4):244-8.
Morley 1964 {published data only}
  • Morley D, Woodland M, Cuthbertson WF. Controlled trial of pyrimethamine in pregnant women in an African village. British Medical Journal 1964;5384:667-8.
Mutabingwa 1991 {published data only}
  • Mutabingwa T, Malle L, De Goos GA, Oosting J. Malaria chemosuppression in pregnancy. I. The effect of chemosuppressive drugs on maternal parasitaemia. Tropical and Geographical Medicine 1991;45(1):6-14.
Nahlen 1989 {published data only}
Ndyomugyenyi 2000 {published data only}
  • Ndyomugyenyi R, Magnussen P. Chloroquine prophylaxis, iron/folic-acid supplementation or case management of malaria attacks in primigravidea in western Uganda: effects on congenital malaria and infant haemoglobin concentrations. Annals of Tropical Medicine and Parasitology 2000;94(8):759-70.
  • Ndyomugyenyi R, Magnussen P. Chloroquine prophylaxis, iron-folic acid supplementation or case management of malaria attacks in primigravidae in western Uganda: effects on maternal parasitaemia and haemoglobin levels and on birthweight. Transactions of the Royal Society of Tropical Medicine and Hygiene 2000;94(4):413-8.
Nosten 1994 {published data only}
  • Nosten F, ter Kuile F, Maelankiri L, Chongsuphajaisiddhi T, Nopdonrattakoon L, Tangkitchot S, et al. Mefloquine prophylaxis in pregnancy: a double blind placebo controlled trial. Journal of Infectious Diseases 1994;169(3):595-603.
Parise 1998i {published and unpublished data}
  • Parise ME, Ayisi JG, Nahlen BL, Schultz LJ, Roberts JM, Misore A, et al. Efficacy of sulfadoxine-pyrimethamine for prevention of placental malaria in an area of Kenya with a high prevalence of malaria and human immunodeficiency virus infection. American Journal of Tropical Medicine and Hygiene 1998;59(5):813-22.
Parise 1998ii {published and unpublished data}
  • Parise ME, Ayisi JG, Nahlen BL, Schultz LJ, Roberts JM, Misore A, et al. Efficacy of sulfadoxine-pyrimethamine for prevention of placental malaria in an area of Kenya with a high prevalence of malaria and human immunodeficiency virus infection. American Journal of Tropical Medicine and Hygiene 1998;59(5):813-22.
Schultz 1994 {published data only}
  • Schultz LJ, Steketee RW, Macheso A, Kazembe P, Chitsulo L, Wirima JJ. The efficacy of antimalarial regimens containing sulfadoxine-pyrimethamine and/or chloroquine in preventing peripheral and placental Plasmodium falciparum infection among pregnant women in Malawi. American Journal of Tropical Medicine and Hygiene 1994;51(5):515-22.
Shulman 1999 {published data only}
  • Shulman CE, Dorman EK, Cutts F, Kawuondo K, Bulmer JN, Peshu N, et al. Intermittent sulpadoxine-pyrimethamine to prevent severe anaemia secondary to malaria in pregnancy: a randomised placebo-controlled trial. Lancet 1999;353(9153):632-6.

References to studies excluded from this review

  1. Top of page
  2. Abstract摘要
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to ongoing studies
  21. Additional references
  22. References to other published versions of this review
Dolan 1993 {published data only}
  • Dolan G, ter Kuile FO, Jacoutot V, White NJ, Luxemburger C, Malankirii L, et al. Bed nets for the prevention of malaria and anaemia in pregnancy. Transactions of the Royal Society of Tropical Medicine and Hygiene 1993;87(6):620-6.
Helitzer 1994 {published data only}
Martin 1982 {published data only}
  • Martin GE, Nkwate CC. [Administration de la dose unique mensuelle de 600 mg de chloroquine base dans le controle du paludisme chez les femmes enceintes]. CEAC Bulletin 1982;53:41-7.
McDermott 1988 {published data only}
  • McDermott JM, Heymann DL, Wirima JJ, Macheso AP, Wahl RD, Steketee RW, et al. Efficacy of chemoprophylaxis in preventing Plasmodium falciparum parasitaemia and placental infection in pregnant women in Malawi. Transactions of the Royal Society of Tropical Medicine and Hygiene 1988;82(4):520-3.
McGready 2001 {published data only}
  • McGready R, Hamilton KA, Simpson JA, Cho T, Luxemburger C, Edwards R, et al. Safety of the insect repellent N,N-diethyl-M-toluamide (DEET) in pregnancy. American Journal of Tropical Medicine and Hygiene 2001;65(4):285-9.
Pertet 1994 {unpublished data only}
Shulman 1998 {published data only}
Steketee 1996 {published data only}
  • Bloland P, Slutsker L, Steketee RW, Wirima JJ, Heymann DL, Breman JG. Rates and risk factors for mortality during the first two years of life in rural Malawi. American Journal of Tropical Medicine and Hygiene 1996;55 Suppl 1:82-6.
  • Mangochi Malaria Research Project. Malaria prevention in pregnancy: the effects of treatment and chemoprophylaxis on placental malaria infection, low birth weight, and fetal, infant, and child survival. U.S. Agency for International Development in conjunction with Centers for Disease Control and Prevention, Atlanta, Ga; Africa Regional Project (698-0421) 1996.
  • McDermott JM, Slutsker L, Steketee RW, Wirima JJ, Breman JG, Heymann DL. Prospective assessment of mortality among a cohort of pregnant women in rural Malawi. American Journal of Tropical Medicine and Hygiene 1996;55 Suppl 1:66-70.
  • McDermott JM, Wirima JJ, Steketee RW, Breman JG, Heymann DL. The effect of placental malaria infection on perinatal mortality in rural Malawi. American Journal of Tropical Medicine and Hygiene 1996;55 Suppl 1:61-5.
  • Redd SC, Wirima JJ, Steketee RW, Breman JG, Heymann DL. Transplacental transmission of Plasmodium falciparum in rural Malawi. American Journal of Tropical Medicine and Hygiene 1996;55 Suppl 1:57-60.
  • Steketee RW, Wirima JJ, Bloland PB, Chilima B, Mermin JH, Chitsulo L, et al. Impairment of a pregnant woman's acquired ability to limit Plasmodium falciparum by infection with human immunodeficiency virus type-1. American Journal of Tropical Medicine and Hygiene 1996;55 Suppl 1:42-9.
  • Steketee RW, Wirima JJ, Campbell CC. Developing effective strategies for malaria prevention programs for pregnant African women. American Journal of Tropical Medicine and Hygiene 1996;55 Suppl 1:95-100.
  • Steketee RW, Wirima JJ, Hightower AW, Slutsker L, Heymann DL, Breman JG. The effect of malaria and malaria prevention in pregnancy on offspring birthweight, prematurity, and intrauterine growth retardation in rural Malawi. American Journal of Tropical Medicine and Hygiene 1996;55 Suppl 1:33-41.
  • Steketee RW, Wirima JJ, Slutsker L, Breman JG, Heymann DL. Comparability of treatment groups and risk factors for parasitemia at the first antenatal clinic visit in a study of malaria treatment and prevention in pregnancy in rural Malawi. American Journal of Tropical Medicine and Hygiene 1996;55 Suppl 1:17-23.
  • Steketee RW, Wirima JJ, Slutsker L, Khoromana CO, Heymann DL, Breman JG. Malaria treatment and prevention in pregnancy: indications for use and adverse events associated with use of chloroquine or mefloquine. American Journal of Tropical Medicine and Hygiene 1996;55 Suppl 1:50-6.
  • Steketee RW, Wirima JJ, Slutsker L, Roberts JM, Khoromana CO, Heymann DL, et al. Malaria parasite infection during pregnancy and at delivery in mother, placenta, and newborn: efficacy of chloroquine and mefloquine in rural Malawi. American Journal of Tropical Medicine and Hygiene 1996;55 Suppl 1:24-32.
  • Steketee RW, Wirima JJ, Slutsker WL, Khoromana CO, Breman JG, Heymann DL. Objectives and methodology in a study of malaria treatment and prevention in pregnancy in rural Malawi: The Mangochi Malaria Research Project. American Journal of Tropical Medicine and Hygiene 1996;55 Suppl 1:8-16.

References to ongoing studies

  1. Top of page
  2. Abstract摘要
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to ongoing studies
  21. Additional references
  22. References to other published versions of this review
Mnyika 2000 {published data only}
  • Mnyika SK, Kabalimu TK, Mbaruku G, Masisila R, Mpanju-Shumbusho W. Randomised trial of alternative malaria chemoprophylaxis strategies among pregnant women in Kigoma, Tanzania: II. Results from baseline studies. East African Medical Journal 2000;77(2):105-10.

Additional references

  1. Top of page
  2. Abstract摘要
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to ongoing studies
  21. Additional references
  22. References to other published versions of this review
Brabin 1983
Brabin 1990
  • Brabin BJ. The risks and severity of malaria in pregnant women: including a summary of current field research with identificatiion of research priorities related to appropriate methods of prevention of malaria in pregnancy [TDR/FIELDMAL/1]. Geneva: World Health Organization, 1991.
Duffy 2001
  • Duffy PE, Fried M, editors. Malaria in pregnancy. London: Taylor and Francis, 2001.
Gamble 2006
Higgins 2005
  • Higgins J, Green S, editors. Highly sensitive search strategies for identifying reports of randomized controlled trials in MEDLINE. Cochrane Handbook for Systematic Reviews of Interventions 4.2.5 [updated May 2005]; Appendix 5b. www.cochrane.org/resources/handbook/hbook.htm (accessed 1 March 2006).
Kramer 1987
Orton 2005
  • Orton L, Garner P. Drugs for treating uncomplicated malaria in pregnant women. Cochrane Database of Systematic Reviews 2005, Issue 3. [DOI: DOI: 10.1002/14651858]
Review Manager 5
  • The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). 5.0. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2008.
White 2005

References to other published versions of this review

  1. Top of page
  2. Abstract摘要
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to ongoing studies
  21. Additional references
  22. References to other published versions of this review
Garner 1994
  • Garner P, Brabin B. A review of randomized controlled trials of routine antimalarial drug prophylaxis during pregnancy in endemic malarious areas. Bulletin of the World Health Organization 1994;72(1):89-99.
Garner 1995
  • Garner P. Routine antimalarial drug chemoprophylaxis during pregnancy in endemic malarious areas. Cochrane Database of Systematic Reviews 1995, Issue 1.
Garner 2000
  • Garner P, Gulmezoglu AM. Prevention versus treatment for malaria in pregnant women. Cochrane Database of Systematic Reviews 2000, Issue 2. [DOI: DOI: 10.1002/14651858]
Garner 2003
  • Garner P, Gulmezoglu AM. Drugs for preventing malaria-related illness in pregnant women and death in the newborn. Cochrane Database of Systematic Reviews 2003, Issue 1. [DOI: DOI: 10.1002/14651858]