Invitations to all known contributors to the IST analysis were sent out in 2015 and data curating protocol writing are ongoing and the publications are planned for 2016. Data for the IPTp-DP analysis from new clinical trials are anticipated in 2018/19.

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 SP Resistance Study Group). 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, 2, 3, 4}and/or alternative ‘screen and treat’ strategies.

Alternative drugs for intermittent preventive treatment (IPTp)

Several alternatives to SP for IPTp have been evaluated in a series of intensive multicentre trials over the past decade. These trials have shown that neither amodiaquine, alone or combined with SP,⁵mefloquine (15 mg/kg),^{6, 7, 8, 9} or the fixed-dose combination of chloroquine-azithromycin^{10, 11} are tolerated well enough to replace SP for IPTp in Africa. More recently, two trials comparing DP to SP for IPTp in Kenya¹² and Uganda¹³ showed promising results and three other trials with IPTp-DP are scheduled to start in 2016 in East and southern Africa. In Asia, an IPTp trial with SP-azithromycin was recently completed in Papua New Guinea14 and another trial with DP is ongoing in Indonesia. No attempts have been made to combine this information.

Intermittent screening and treatment in pregnancy (ISTp)

Another proposed alternative strategy to IPTp with SP 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.¹⁵ 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.^{15, 16, 17, 18} Two other trials were completed in in east and southern Africa in areas with high grade SP resistance, which showed that ISTp with dihydro-artemisinin was not superior to IPT with SP.^{12, 19}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. Two other trials are ongoing in India and in Indonesia. These findings need to be combined to determine if ISTp has any role to play in the control of malaria in pregnancy with the current generation of RDTs, and if so, under which epidemiological settings, and/or if alternative strategies are required.

The Alternative MiP Prevention Strategies (AMPS) Study Group’s aim is to determine the safety and efficacy of novel strategies for the control of malaria in pregnancy including intermittent preventive therapy (IPTp) with dihydroartemisinin-piperaquine (DP) and intermittent screening and treatment (ISTp) with DP or artemether-lumefantrine (AL).

To achieve these important goals, we aim to pool individual patient data from these multicentre trials to increase the power to detect study outcomes than can be achieved by individual studies alone and take into account the range of epidemiological settings. The proposed work will provide evidence to help further refine WHO policy development.

The specific objectives are:

1. Conduct a IPD pooled meta-analysis of the safety and efficacy of ISTp with DP versus IPTp with SP for the control of malaria in pregnancy of completed trials in Africa (2016).
2. Conduct a prospective IPD pooled analysis of the safety and efficacy of IPTp with DP versus IPTp with SP for the control of malaria in pregnancy in Kenya, Uganda and three planned trial(s) in Uganda, Tanzania,  Kenya plus Malawi (pending completion in 2018/19).
3. Conduct an IPD pooled analysis of the safety and efficacy of ISTp vs current control strategies for the control of malaria in pregnancy in Asia (2017/18).

• Clinical trials of IPTp with DP or IST with an artemisinin combination therapy (ACT)  in pregnant women conduced in Africa or Asia

• Baseline data on patient demographics
• Information on dosing (mg/kg) and regimen
• Follow-up of pregnant women to delivery or termination of pregnancy
• Safety data to include information on  serious adverse events during follow-up

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. Data sets will be pooled into a single database of quality-assured individual patient data. 

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 on the WWARN website.

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  and Prof Feiko ter Kuile will co-lead the Study Group, and Dr Jenny Hill is the Study Group Coordinator.

For further information, email Jenny Hill: Jenny.Hill@lstmed.ac.uk or clinical@wwarn.org. 

1. Harrington WE, Fried M, Duffy PE, 2016. Defending the Use of Sulfadoxine-Pyrimethamine for Intermittent Preventive Treatment for Malaria in Pregnancy: A Short-Sighted Strategy. J Infect Dis 213: 496-7.
2. Harrington W, McGready R, Muehlenbachs A, Fried M, Nosten F, Duffy P, 2012. Intermittent preventive treatment in pregnancy with sulfadoxine-pyrimethamine: the times they are a-changin'. Clin Infect Dis 55: 1025-6; author reply 1026-7.
3. Gutman J, Kalilani L, Taylor S, Zhou Z, Wiegand RE, Thwai KL, Mwandama D, Khairallah C, Madanitsa M, Chaluluka E, Dzinjalamala F, Ali D, Mathanga DP, Skarbinski J, Shi YP, Meshnick S, ter Kuile FO, 2015. 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.
4. Gutman J, Taylor S, Meshnick SR, Ter Kuile FO, 2016. Reply to Harrington et al. J Infect Dis 213: 497-8.
5. Clerk CA, Bruce J, Affipunguh PK, Mensah N, Hodgson A, Greenwood B, Chandramohan D, 2008. A randomized, controlled trial of intermittent preventive treatment with sulfadoxine-pyrimethamine, amodiaquine, or the combination in pregnant women in Ghana. J Infect Dis 198: 1202-11.
6. Briand V, Bottero J, Noel H, Masse V, Cordel H, Guerra J, Kossou H, Fayomi B, Ayemonna P, Fievet N, Massougbodji A, Cot M, 2009. Intermittent treatment for the prevention of malaria during pregnancy in Benin: a randomized, open-label equivalence trial comparing sulfadoxine-pyrimethamine with mefloquine. J Infect Dis 200: 991-1001.
7. Gonzalez R, Desai M, Macete E, Ouma P, Kakolwa MA, Abdulla S, Aponte JJ, Bulo H, Kabanywanyi AM, Katana A, Maculuve S, Mayor A, Nhacolo A, Otieno K, Pahlavan G, Ruperez M, Sevene E, Slutsker L, Vala A, Williamsom J, Menendez C, 2014. Intermittent preventive treatment of malaria in pregnancy with mefloquine in HIV-infected women receiving cotrimoxazole prophylaxis: a multicenter randomized placebo-controlled trial. PLoS Med 11: e1001735.
8. Gonzalez R, Hellgren U, Greenwood B, Menendez C, 2014. Mefloquine safety and tolerability in pregnancy: a systematic literature review. Malar J 13: 75.
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11. Kimani J, Phiri K, Kamiza S, Duparc S, Ayoub A, Rojo R, Robbins J, Orrico R, Vandenbroucke P, Hassan P, 2016 (in press). Efficacy and Safety of Azithromycin/Chloroquine Versus Sulfadoxine/Pyrimethamine for Intermittent Preventive Treatment of Plasmodium falciparum Malaria Infection in Pregnant Women in Africa: an Open-Label, Randomized Trial. PLoS One.
12. Desai M, Gutman J, L'Lanziva A, Otieno K, Juma E, Kariuki S, Ouma P, Were V, Laserson K, Katana A, Williamson J, ter Kuile FO, 2015. 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.
13. Kakuru A, Jagannathan P, Muhindo MK, Natureeba P, Awori P, Nakalembe M, Opira B, Olwoch P, Ategeka J, Nayebare P, Clark TD, Feeney ME, Charlebois ED, Rizzuto G, Muehlenbachs A, Havlir DV, Kamya MR, Dorsey G, 2016. Dihydroartemisinin-Piperaquine for the Prevention of Malaria in Pregnancy. N Engl J Med 374: 928-39.
14. Unger HW, Ome-Kaius M, Wangnapi RA, Umbers AJ, Hanieh S, Suen CS, Robinson LJ, Rosanas-Urgell A, Wapling J, Lufele E, Kongs C, Samol P, Sui D, Singirok D, Bardaji A, Schofield L, Menendez C, Betuela I, Siba P, Mueller I, Rogerson SJ, 2015. Sulphadoxine-pyrimethamine plus azithromycin for the prevention of low birthweight in Papua New Guinea: a randomised controlled trial. BMC Med 13: 9.
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19. Madanitsa M, Kalilani M, L., Mwapasa V, van Eijk A, Khairallah C, Ali D, Pace C, Smedley J, Thwai KL, Wang D, Kang'ombe A, Faragher B, Taylor SM, Steve Meshnick S, ter Kuile FO, 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.