Dihydroartemisinin-Piperaquine for Intermittent Preventive Treatment in Pregnancy (IPTp-DP) Study Group

Dihydroartemisinin-Piperaquine for Intermittent Preventive Treatment in Pregnancy (IPTp-DP) Study Group

The Dihydroartemisinin-Piperaquine for Intermittent Preventive Treatment in Pregnancy Study Group aims to determine the safety and efficacy of intermittent preventive treatment in pregnancy (IPTp) with dihydroartemisinin-piperaquine (DP) compared to IPTp with sulfadoxine-pyrimethamine (SP), for the prevention of malaria and adverse birth outcomes among pregnant women in sub-Saharan Africa.

Update and overview

Invitations to contributors to the IPTp-DP versus IPTp-SP meta-analysis were sent out in Q1 2020. Data collation will close by Q4 2020. The statistical analysis plan and outcomes will be circulated among all participants for feedback prior to analysis in Q3 2020. The publication is planned for Q4 2020 and approval to submit for publication will be sought from all Study Group members.


The World Health Organization recommends the provision of intermittent preventive treatment (IPTp) with sulfadoxine-pyrimethamine (SP) to all pregnant women living in areas of moderate and high malaria transmission, starting as early as possible in the second trimester until delivery with doses given at least one month apart [1].


SP is the only antimalarial currently recommended for IPTp. However, growing parasite resistance to SP, particularly in eastern and southern Africa, has led researchers to evaluate alternative drug regimens for IPTp. Dihydroartemisinin-piperaquine (DP) remains the most promising candidate given its long-acting prophylactic effect and highly efficacious antimalarial activity [2]. To date, three trials [3-5] have demonstrated the superiority of DP compared to SP for the prevention of malaria in pregnancy, but none of these studies were independently powered to detect differences in birth outcomes. Since the publication of these three trials, additional trials have been conducted or are currently ongoing across Africa (e.g. Kenya, Uganda, Tanzania, Malawi and Nigeria) that aim to evaluate the efficacy of DP versus SP for IPTp.  


By pooling data from these studies, we aim to achieve the following objectives: (1) obtain more statistical power to assess differences in birth outcomes; (2) better understand differences in safety outcomes; and (3) assess whether the effect of IPTp-DP versus IPTp-SP is modified by any other factors (e.g. gravidity, frequency of IPTp dosing regimen, and level of SP resistance). In addition, other IPTp studies have assessed additional outcomes, including the effect of IPTp on non-malarial infections/conditions [6] and infant malaria incidence [7, 8], which will be further explored in the meta-analysis.


Aims and objectives

The overall aim of the Dihydroartemisinin-Piperaquine for Intermittent Preventive Treatment in Pregnancy (IPTp-DP) Study Group is to determine the safety and efficacy of DP as an alternative to SP for IPTp in sub-Saharan Africa. To achieve this goal, we will conduct meta-analyses using individual participant data (where available) and aggregated summary estimates from multiple trials to inform the following objectives:


  1. Determine the efficacy of DP versus SP for IPTp.
  2. Determine the safety of DP versus SP for IPTp.
  3. Examine whether the effect of DP versus SP is modified by other factors (e.g. gravidity, frequency of IPTp dosing regimen, and level of SP resistance).
  4. In the subset of trials where data is available, determine the efficacy of DP versus SP on the prevention of infant malaria incidence.
  5. Conduct mediation analyses to estimate the indirect and direct effects of IPTp on birth outcomes that is mediated through malaria and other potential, ‘non-malarial’ mechanisms.
Inclusion criteria for studies

Randomised controlled trials conducted in sub-Saharan Africa evaluating IPTp-DP versus IPTp-SP among HIV-negative pregnant women. Studies/arms will only be included if there was a study-specific comparison group with the same IPTp dosing regimen. For example, a study arm will be excluded if women of the IPTp-DP arm were administered DP every 4 weeks and the only comparator IPTp-SP arm was one where women were administered SP every 8 weeks. Studies will be excluded if DP or SP was co-administered with another intervention (e.g. azithromycin or metronidazole).

Minimum required data
  • Baseline data on participant demographics
  • Treatment allocation and information on treatment dosing and regimen
  • Delivery information or data on termination of pregnancy, especially in reference to the following outcomes: foetal and neonatal outcomes (i.e. miscarriage, stillbirth, birthweight at delivery, gestational age delivery and method used to assess gestational age, or neonatal loss)
  • Maternal malaria infection, defined as peripheral or placental parasitaemia detected by placental histology, microscopy, rapid diagnostic test (RDT), and/or molecular methods
  • Safety data, including information on the frequency and severity of adverse events during follow-up, maternal mortality, and presence and type of neonatal congenital malformations
Data standardisation and analysis

Once uploaded into the WWARN Data Repository, WWARN will standardise datasets and pooled into a single database of quality-assured individual participant data. Prior to analyses, a detailed statistical analysis plan will be developed and shared among data contributors.

Study group governance and membership

The study group comprises of participating investigators who contribute relevant data sets to the pooled analyses, invited technical experts, and investigators contributing statistical support. Data sets remain the property of the investigator. The study group collectively make decisions with respect to including additional studies, data analysis and plans for publications in line with the WWARN Publication Policy.

Dr Julie Gutman (fff2@cdc.gov) and Prof Feiko ter Kuile (feiko.terkuile@lstmed.ac.uk) will co-lead this Study Group. Dr Jenny Hill (jenny.hill@lstmed.ac.uk) is the Study Group Coordinator. 



1. World Health Organization: WHO policy brief for the implementation of intermittent preventive treatment of malaria in pregnancy using sulfadoxine-pyrimethamine (IPTp-SP).  (World Health Organization ed. Geneva, Switzerland2013.

2. Hill J, ter Kuile FO: Dihydroartemisinin–piperaquine holds promise as an option for malaria prevention in pregnancy. BMJ Evid Based Med 2016, 21:146-147.

3. Desai M, Gutman J, L'lanziva A, Otieno K, Juma E, Kariuki S, Ouma P, Were V, Laserson K, Katana A: 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 2016, 386:2507-2519.

4. Kakuru A, Jagannathan P, Muhindo MK, Natureeba P, Awori P, Nakalembe M, Opira B, Olwoch P, Ategeka J, Nayebare P: Dihydroartemisinin–piperaquine for the prevention of malaria in pregnancy. N Engl J Med 2016, 374:928-939.

5. Kajubi R, Ochieng T, Kakuru A, Jagannathan P, Nakalembe M, Ruel T, Opira B, Ategeka J, Nayabare P, Clark TD, et al: Monthly sulfadoxine-pyrimethamine versus dihydroartemisinin-piperaquine for intermittent preventive treatment of malaria in pregnancy: A randomized controlled trial. In preparation 2018.

6. Chico RM, Chaponda EB, Ariti C, Chandramohan D: Sulfadoxine-Pyrimethamine Exhibits Dose-Response Protection Against Adverse Birth Outcomes Related to Malaria and Sexually Transmitted and Reproductive Tract Infections. Clin Infect Dis 2017, 64:1043-1051.

7. Kakuru A, Staedke SG, Dorsey G, Rogerson S, Chandramohan D: Impact of Plasmodium falciparum malaria and intermittent preventive treatment of malaria in pregnancy on the risk of malaria in infants: a systematic review. Malar J 2019, 18:304.

8. Jagannathan P, Kakuru A, Okiring J, Muhindo MK, Natureeba P, Nakalembe M, Opira B, Olwoch P, Nankya F, Ssewanyana I: Dihydroartemisinin-piperaquine for intermittent preventive treatment of malaria during pregnancy and risk of malaria in early childhood: a randomized controlled trial. PLoS Med 2018, 15.