Alternative strategies to prevent malaria in pregnancy Study Group

Update and overview

Invitations to contributors for the ISTp-Africa analysis will be sent out in Q1 2019. Data collation will close by the end of June 2019. The Statistical Analysis Plan and outcomes will be circulated among all participants for feedback prior analysis in Q3 2019. The publication is planned for Q4 2019 and approval prior to publication will be sought from all Study Group members.

Rationale

The World Health Organization (WHO) currently recommends intermittent preventive treatment for the prevention of malaria in pregnant women (IPTp) by administering treatment doses of an efficacious antimalarial drug during the second and third trimesters of pregnancy at predefined intervals at least a month apart. Sulphadoxine-pyrimethamine (SP) is the only antimalarial currently recommended for IPTp, however high-level parasite resistance to SP threatens the efficacy of the strategy.

In East and Southern Africa, the effectiveness of IPTp-SP to clear peripheral parasitaemia and prevent low birthweight (LBW) decreases with increasing population prevalence of the Plasmodium falciparum dihydropteroate synthase (dhps) K540E mutation (see also SP Molecular Surveyor). The continued use of SP for IPTp in these highly resistant areas has been a topic of recent debate, reflecting the urgent need for an effective, safe and affordable alternative to SP [1–4] and/or alternative ‘screen and treat’ strategies.

Intermittent screening and treatment in pregnancy (ISTp) consists of scheduled antenatal testing with rapid diagnostic tests (RDTs) and the treatment of RDT-positive women with artemisinin-based combination therapy (ACT), referred to as intermittent screening and treatment in pregnancy, or ISTp [5]. In West African settings where parasite resistance to SP is low, ISTp with artemether-lumefantrine (AL) was not inferior to IPTp-SP in reducing low birth weight and was well-accepted by providers and patients [5–8]. However, cost-effectiveness analysis found that in areas without SP resistance, ISTp was not cost-effective compared to IPTp-SP [9].

Two other trials were completed in east and southern Africa in areas with high grade SP resistance, which showed that ISTp with dihydroartemisinin-piperaquine (DP) was not superior to IPTp with SP [10,11]. The results from these trials were disappointing, showing no evidence that this strategy is a suitable alternative to IPTp-SP either in areas with high SP resistance and malaria transmission in East Africa nor in areas of low SP resistance in West Africa.

Aims and objectives

The Alternative Malaria in Pregnancy (MiP) Prevention Strategies (AMPS) Study Group’s aim is to determine the safety and efficacy of intermittent screening and treatment (ISTp) with DP or AL as an alternative to IPTp with SP in sub-Saharan Africa

To achieve these important goals, we aim to pool individual patient data from multicentre trials in Africa to increase the power to detect study outcomes beyond what can be achieved by individual studies alone, as well as take into account the range of epidemiological settings.

The specific objectives are:

1. Conduct an IPD pooled analysis of the safety and efficacy of ISTp vs IPTp with SP for the control of malaria in pregnancy in Africa.

Inclusion criteria for studies

• RCT Clinical trials of IST with an artemisinin combination therapy (ACT) in pregnant women conducted in Africa

Minimum required data

• Baseline data on patient demographics, including number of antenatal clinic visits
• Information on treatment dosing (mg/kg) and regimen
• Primary outcomes: malaria infection at delivery (composite of peripheral or placental parasitaemia detected by placental histology, microscopy, or RDT); Paucigravidae: adverse birth outcomes (low birth weight (LBW) or composite of small-for-gestation age, low birthweight or preterm birth); Multigravidae: P. falciparum infection at delivery.
• Follow-up of pregnant women to delivery or termination of pregnancy
• Safety data to include information on serious adverse events during follow-up

Data standardisation and analysis

Once uploaded into the WWARN Data Repository, datasets will be standardised according to the WWARN Clinical (and, if applicable, Pharmacology) Data Management and Statistical Analysis Plan. The WWWARN Clinical Data Management and Statistical Analysis Plan will be modified before analysis to reflect the variables and analyses relevant to the MiP studies. Data sets will be pooled into a single database of quality-assured individual patient data. 

Study Group governance and membership

The Study Group comprises investigators who contribute relevant data sets to the pooled analysis and invited technical experts. Data sets remain the property of the investigator. More details about sharing data with WWARN and how WWARN will use data are available.

The Study Group collectively makes decisions with respect to including additional studies, data analysis and plans for publication, in line with the WWARN Publication Policy. Dr Julie Gutman (fff2 [at] cdc [dot] gov) and Prof Feiko ter Kuile (feiko [dot] terkuile [at] LSTMed [dot] ac [dot] uk) will co-lead this Study Group. Dr Jenny Hill is the Study Group Coordinator. 

For further information, email Jenny Hill jenny [dot] hill [at] LSTMed [dot] ac [dot] uk and/or clinical [at] wwarn [dot] org.

References

1. Harrington WE. Fried M, Duffy PE. Defending the Use of Sulfadoxine-Pyrimethamine for Intermittent Preventive Treatment for Malaria in Pregnancy: A Short-Sighted Strategy. J Infect Dis. 213, 496-7 (2016)

2. Harrington W. et al. Intermittent preventive treatment in pregnancy with sulfadoxine-pyrimethamine: the times they are a-changin'. Clin Infect Dis. 55, 1025-6; author reply 1026-7 (2012).

3. Gutman J. et al. The A581G Mutation in the Gene Encoding Plasmodium falciparum Dihydropteroate Synthetase Reduces the Effectiveness of Sulfadoxine-Pyrimethamine Preventive Therapy in Malawian Pregnant Women. J Infect Dis. 211, 1997-2005 (2015).

4. Gutman J. et al. Reply to Harrington et al. J Infect Dis. 213, 497-8 (2016).

5. Tagbor H. et al. Intermittent screening and treatment versus intermittent preventive treatment of malaria in pregnancy: a randomised controlled non-inferiority trial. PLoS One. 5, e14425 (2010).

6. Smith LA. et al. Intermittent screening and treatment versus intermittent preventive treatment of malaria in pregnancy: user acceptability. Malar Journal 9, 18 (2010).

7. Smith Paintain L. et al. Intermittent screening and treatment versus intermittent preventive treatment of malaria in pregnancy: provider knowledge and acceptability. PLoS One. 6, e24035 (2011).

8. Tagbor H. et al. A Non-Inferiority, Individually Randomized Trial of Intermittent Screening and Treatment versus Intermittent Preventive Treatment in the Control of Malaria in Pregnancy. PLoS One. 10, e0132247 (2015).

9. Fernandes S. et al. Cost effectiveness of intermittent screening followed by treatment versus intermittent preventive treatment during pregnancy in West Africa: analysis and modelling of results from a non-inferiority trial. Malaria Journal. 15, 493 (2016).

10. Madanitsa M. et al. Submitted. Control of malaria in pregnancy with scheduled intermittent screening with rapid diagnostic tests and treatment with dihydroartemisinin-piperaquine versus intermittent preventive therapy with sulphadoxine-pyrimethamine in Malawi: a randomized clinical trial.

11. Desai M, Gutman J. et al. Intermittent screening and treatment or intermittent preventive treatment with dihydroartemisinin-piperaquine versus intermittent preventive treatment with sulfadoxine-pyrimethamine for the control of malaria during pregnancy in western Kenya: an open-label, three-group, randomised controlled superiority trial. Lancet. 386, 2507-19 (2015).