Improving Neonatal Health Through Rapid Malaria Testing in Early Pregnancy With High-Sensitivity Diagnostics

NCT05757167 | Recruiting Phase 4 DMC

• 5 other identifiers: Pro001107711U01AI162463-01A15U01AI162463-025U01AI162463-035U01AI162463-04
• Study Type: interventional
• Target: 2,500
• Locations: 2 countries
• Sites: 2

Brief Summary

The purpose of the INTREPiD study is to compare 1st trimester screening for malaria parasites with a high-sensitivity malaria rapid diagnostic test followed by treatment of test-positive women with artemether-lumefantrine (AL) against usual antenatal care on a composite adverse pregnancy outcome including low birth weight, small for gestational age, preterm, fetal loss, or neonatal death.

Conditions

Malaria in Childbirth; Pregnancy; Neonatal Health; Malaria,Falciparum; Malaria in Pregnancy; Low Birthweight; Stillbirth; Gestational Age and Weight Conditions; Preterm Birth

Outcome Measures

Primary Outcomes (1)

• Composite number of adverse pregnancy outcomes

  Adverse pregnancy outcomes defined as low birth weight (\<2500 grams) OR preterm (\< 37 0/7 weeks) OR small for gestational age (GA) (\< 10th percentile weight for GA) OR pregnancy loss, defined as a. spontaneous abortion ( loss \< 22 0/7 weeks gestation) OR b. stillbirth (loss ≥ 22 0/7 weeks gestation) OR neonatal death (livebirth with death prior to the 28th day of life).

  Enrollment to 28 days Post-delivery (including each antenatal care visit)

Secondary Outcomes (18)

• Birthweight

  Delivery

• Number of infants with low birthweight

  Delivery

• Gestational age (GA)

  Delivery

• Preterm

  Delivery

• Number of infants that are small for gestational age

  Delivery

Other Outcomes (3)

• Number of maternal serious adverse events

  Enrollment to 28 days Post-delivery

• Number of infants with congenital malformations

  Delivery to 28 days Post-delivery

• Number of offspring with the need for hospitalization or acute medical evaluation

  Delivery to 28 days Post-delivery

Study Arms (2)

HS-RDT screening/AL treatment

EXPERIMENTAL

Pregnant women will be screened with a malaria HS-RDT and, if positive, treated with artemether-lumefantrine

Diagnostic Test: Malaria High-Sensitivity Rapid Diagnostic Test (HS-RDT); Drug: Artemether-lumefantrine (AL)

Usual antenatal care

NO INTERVENTION

Pregnant women will receive usual antenatal care

Interventions

Malaria High-Sensitivity Rapid Diagnostic Test (HS-RDT) DIAGNOSTIC_TEST

Detection of Plasmodium falciparum HRP-II antigen1 Method: Lateral Flow; Time to Result: 20 minutes; Sample Type: Fingerstick Whole Blood; Sample Volume: 5µl; Storage Conditions: 1-30°C; Shelf Life: 12 months; Sensitivity/Specificity: 99.0%/98.6%

Also known as: NxTek™ Eliminate Malaria P.f, 05FK140 (Global), 05FK141 (Global), 05FK142 (Global), 05FK143 (Global), Alere Malaria Ag P.f

HS-RDT screening/AL treatment

Artemether-lumefantrine (AL) DRUG

oral tablets: 6 doses of 80/480 mg over 3 days

Also known as: AL

HS-RDT screening/AL treatment

Eligibility Criteria

• Age: 16 Years - 40 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Aged between 16 years and 40 years (inclusive)
• Viable singleton pregnancy with gestational age estimated less than 13 6/7 weeks (inclusive) by ultrasound
• HIV-uninfected
• Willing to participate in the study schedule
• Planning to remain in the study area for the duration of pregnancy and 1 month after delivery
• Willing to deliver in a study-affiliated health facility

You may not qualify if:

• High risk pregnancy that requires referral for specialized care by local guidelines
• Active medical problem at the time of screening requiring higher level care
• Antimalarial receipt in the 2 weeks prior to screening
• Past allergy to Artemether or Lumefantrine or another condition that prohibits the receipt of either drug
• Current participation in another clinical research study

Sponsors & Collaborators

• Duke University: lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator

Study Sites (2)

Kinshasa School of Public Health

Kinshasa, Democratic Republic of the Congo

RECRUITING

Moi University

Eldoret, Kenya

RECRUITING

Related Publications (57)

• Lawn JE, Blencowe H, Oza S, You D, Lee AC, Waiswa P, Lalli M, Bhutta Z, Barros AJ, Christian P, Mathers C, Cousens SN; Lancet Every Newborn Study Group. Every Newborn: progress, priorities, and potential beyond survival. Lancet. 2014 Jul 12;384(9938):189-205. doi: 10.1016/S0140-6736(14)60496-7. Epub 2014 May 19.

  PMID: 24853593 BACKGROUND

• Rogerson SJ, Desai M, Mayor A, Sicuri E, Taylor SM, van Eijk AM. Burden, pathology, and costs of malaria in pregnancy: new developments for an old problem. Lancet Infect Dis. 2018 Apr;18(4):e107-e118. doi: 10.1016/S1473-3099(18)30066-5. Epub 2018 Jan 31.

  PMID: 29396010 BACKGROUND

• Lawn JE, Blencowe H, Waiswa P, Amouzou A, Mathers C, Hogan D, Flenady V, Froen JF, Qureshi ZU, Calderwood C, Shiekh S, Jassir FB, You D, McClure EM, Mathai M, Cousens S; Lancet Ending Preventable Stillbirths Series study group; Lancet Stillbirth Epidemiology investigator group. Stillbirths: rates, risk factors, and acceleration towards 2030. Lancet. 2016 Feb 6;387(10018):587-603. doi: 10.1016/S0140-6736(15)00837-5. Epub 2016 Jan 19.

  PMID: 26794078 BACKGROUND

• van Eijk AM, Larsen DA, Kayentao K, Koshy G, Slaughter DEC, Roper C, Okell LC, Desai M, Gutman J, Khairallah C, Rogerson SJ, Hopkins Sibley C, Meshnick SR, Taylor SM, Ter Kuile FO. Effect of Plasmodium falciparum sulfadoxine-pyrimethamine resistance on the effectiveness of intermittent preventive therapy for malaria in pregnancy in Africa: a systematic review and meta-analysis. Lancet Infect Dis. 2019 May;19(5):546-556. doi: 10.1016/S1473-3099(18)30732-1. Epub 2019 Mar 25.

  PMID: 30922818 BACKGROUND

• Gonzalez R, Mombo-Ngoma G, Ouedraogo S, Kakolwa MA, Abdulla S, Accrombessi M, Aponte JJ, Akerey-Diop D, Basra A, Briand V, Capan M, Cot M, Kabanywanyi AM, Kleine C, Kremsner PG, Macete E, Mackanga JR, Massougbodgi A, Mayor A, Nhacolo A, Pahlavan G, Ramharter M, Ruperez M, Sevene E, Vala A, Zoleko-Manego R, Menendez C. Intermittent preventive treatment of malaria in pregnancy with mefloquine in HIV-negative women: a multicentre randomized controlled trial. PLoS Med. 2014 Sep 23;11(9):e1001733. doi: 10.1371/journal.pmed.1001733. eCollection 2014 Sep.

  PMID: 25247709 BACKGROUND

• Divala TH, Mungwira RG, Mawindo PM, Nyirenda OM, Kanjala M, Ndaferankhande M, Tsirizani LE, Masonga R, Muwalo F, Boudova S, Potter GE, Kennedy J, Goswami J, Wylie BJ, Muehlenbachs A, Ndovie L, Mvula P, Mbilizi Y, Tomoka T, Laufer MK. Chloroquine as weekly chemoprophylaxis or intermittent treatment to prevent malaria in pregnancy in Malawi: a randomised controlled trial. Lancet Infect Dis. 2018 Oct;18(10):1097-1107. doi: 10.1016/S1473-3099(18)30415-8. Epub 2018 Sep 5.

  PMID: 30195996 BACKGROUND

• Kimani J, Phiri K, Kamiza S, Duparc S, Ayoub A, Rojo R, Robbins J, Orrico R, Vandenbroucke P. 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. 2016 Jun 21;11(6):e0157045. doi: 10.1371/journal.pone.0157045. eCollection 2016.

  PMID: 27326859 BACKGROUND

• Tagbor H, Bruce J, Agbo M, Greenwood B, Chandramohan D. Intermittent screening and treatment versus intermittent preventive treatment of malaria in pregnancy: a randomised controlled non-inferiority trial. PLoS One. 2010 Dec 28;5(12):e14425. doi: 10.1371/journal.pone.0014425.

  PMID: 21203389 BACKGROUND

• Madanitsa M, Kalilani L, Mwapasa V, van Eijk AM, Khairallah C, Ali D, Pace C, Smedley J, Thwai KL, Levitt B, Wang D, Kang'ombe A, Faragher B, Taylor SM, Meshnick S, Ter Kuile FO. Scheduled Intermittent Screening with Rapid Diagnostic Tests and Treatment with Dihydroartemisinin-Piperaquine versus Intermittent Preventive Therapy with Sulfadoxine-Pyrimethamine for Malaria in Pregnancy in Malawi: An Open-Label Randomized Controlled Trial. PLoS Med. 2016 Sep 13;13(9):e1002124. doi: 10.1371/journal.pmed.1002124. eCollection 2016 Sep.

  PMID: 27622558 BACKGROUND

• 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. 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. 2015 Dec 19;386(10012):2507-19. doi: 10.1016/S0140-6736(15)00310-4. Epub 2015 Sep 28.

  PMID: 26429700 BACKGROUND

• Kajubi R, Ochieng T, Kakuru A, Jagannathan P, Nakalembe M, Ruel T, Opira B, Ochokoru H, Ategeka J, Nayebare P, Clark TD, Havlir DV, Kamya MR, Dorsey G. Monthly sulfadoxine-pyrimethamine versus dihydroartemisinin-piperaquine for intermittent preventive treatment of malaria in pregnancy: a double-blind, randomised, controlled, superiority trial. Lancet. 2019 Apr 6;393(10179):1428-1439. doi: 10.1016/S0140-6736(18)32224-4. Epub 2019 Mar 22.

  PMID: 30910321 BACKGROUND

• 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. Dihydroartemisinin-Piperaquine for the Prevention of Malaria in Pregnancy. N Engl J Med. 2016 Mar 10;374(10):928-39. doi: 10.1056/NEJMoa1509150.

  PMID: 26962728 BACKGROUND

• Desai M, Gutman J, Taylor SM, Wiegand RE, Khairallah C, Kayentao K, Ouma P, Coulibaly SO, Kalilani L, Mace KE, Arinaitwe E, Mathanga DP, Doumbo O, Otieno K, Edgar D, Chaluluka E, Kamuliwo M, Ades V, Skarbinski J, Shi YP, Magnussen P, Meshnick S, Ter Kuile FO. Impact of Sulfadoxine-Pyrimethamine Resistance on Effectiveness of Intermittent Preventive Therapy for Malaria in Pregnancy at Clearing Infections and Preventing Low Birth Weight. Clin Infect Dis. 2016 Feb 1;62(3):323-333. doi: 10.1093/cid/civ881. Epub 2015 Oct 20.

  PMID: 26486699 BACKGROUND

• Leuba SI, Westreich D, Bose CL, Powers KA, Olshan A, Taylor SM, Tshefu A, Lokangaka A, Carlo WA, Chomba E, Liechty EA, Bucher SL, Esamai F, Jessani S, Saleem S, Goldenberg RL, Moore J, Nolen T, Hemingway-Foday J, McClure EM, Koso-Thomas M, Derman RJ, Hoffman M, Bauserman M. Predictors of Plasmodium falciparum Infection in the First Trimester Among Nulliparous Women From Kenya, Zambia, and the Democratic Republic of the Congo. J Infect Dis. 2022 Jun 1;225(11):2002-2010. doi: 10.1093/infdis/jiab588.

  PMID: 34888658 BACKGROUND

• Jafari-Guemouri S, Courtois L, Mama A, Rouas B, Neto Braga G, Accrombessi M, Massougbodji A, Ding XC, Tuikue Ndam N, Fievet N, Briand V. A Genotyping Study in Benin Comparing the Carriage of Plasmodium falciparum Infections Before Pregnancy and in Early Pregnancy: Story of a Persistent Infection. Clin Infect Dis. 2021 Jul 15;73(2):e355-e361. doi: 10.1093/cid/ciaa841.

  PMID: 32569359 BACKGROUND

• Hounkonnou CPA, Briand V, Fievet N, Accrombessi M, Yovo E, Mama A, Sossou D, Vianou B, Massougbodji A, Ndam NT, Cot M, Cottrell G. Dynamics of Submicroscopic Plasmodium falciparum Infections Throughout Pregnancy: A Preconception Cohort Study in Benin. Clin Infect Dis. 2020 Jun 24;71(1):166-174. doi: 10.1093/cid/ciz748.

  PMID: 32215629 BACKGROUND

• Tuikue Ndam N, Tornyigah B, Dossou AY, Escriou G, Nielsen MA, Salanti A, Issifou S, Massougbodji A, Chippaux JP, Deloron P. Persistent Plasmodium falciparum Infection in Women With an Intent to Become Pregnant as a Risk Factor for Pregnancy-associated Malaria. Clin Infect Dis. 2018 Nov 28;67(12):1890-1896. doi: 10.1093/cid/ciy380.

  PMID: 29733338 BACKGROUND

• Briand V, Cottrell G, Tuike Ndam N, Martianez-Vendrell X, Vianou B, Mama A, Kouwaye B, Houze S, Bailly J, Gbaguidi E, Sossou D, Massougbodji A, Accrombessi M, Mayor A, Ding XC, Fievet N. Prevalence and clinical impact of malaria infections detected with a highly sensitive HRP2 rapid diagnostic test in Beninese pregnant women. Malar J. 2020 May 24;19(1):188. doi: 10.1186/s12936-020-03261-1.

  PMID: 32448310 BACKGROUND

• Tagbor H, Cairns M, Bojang K, Coulibaly SO, Kayentao K, Williams J, Abubakar I, Akor F, Mohammed K, Bationo R, Dabira E, Soulama A, Djimde M, Guirou E, Awine T, Quaye S, Njie F, Ordi J, Doumbo O, Hodgson A, Oduro A, Meshnick S, Taylor S, Magnussen P, ter Kuile F, Woukeu A, Milligan P, Chandramohan D, Greenwood B. A Non-Inferiority, Individually Randomized Trial of Intermittent Screening and Treatment versus Intermittent Preventive Treatment in the Control of Malaria in Pregnancy. PLoS One. 2015 Aug 10;10(8):e0132247. doi: 10.1371/journal.pone.0132247. eCollection 2015.

  PMID: 26258474 BACKGROUND

• Taylor SM, Madanitsa M, Thwai KL, Khairallah C, Kalilani-Phiri L, van Eijk AM, Mwapasa V, Ter Kuile FO, Meshnick SR. Minimal Impact by Antenatal Subpatent Plasmodium falciparum Infections on Delivery Outcomes in Malawian Women: A Cohort Study. J Infect Dis. 2017 Aug 1;216(3):296-304. doi: 10.1093/infdis/jix304.

  PMID: 28658935 BACKGROUND

• Cottrell G, Moussiliou A, Luty AJ, Cot M, Fievet N, Massougbodji A, Deloron P, Tuikue Ndam N. Submicroscopic Plasmodium falciparum Infections Are Associated With Maternal Anemia, Premature Births, and Low Birth Weight. Clin Infect Dis. 2015 May 15;60(10):1481-8. doi: 10.1093/cid/civ122. Epub 2015 Feb 18.

  PMID: 25694651 BACKGROUND

• Dorman EK, Shulman CE, Kingdom J, Bulmer JN, Mwendwa J, Peshu N, Marsh K. Impaired uteroplacental blood flow in pregnancies complicated by falciparum malaria. Ultrasound Obstet Gynecol. 2002 Feb;19(2):165-70. doi: 10.1046/j.0960-7692.2001.00545.x.

  PMID: 11876809 BACKGROUND

• Umbers AJ, Stanisic DI, Ome M, Wangnapi R, Hanieh S, Unger HW, Robinson LJ, Lufele E, Baiwog F, Siba PM, King CL, Beeson JG, Mueller I, Aplin JD, Glazier JD, Rogerson SJ. Does malaria affect placental development? Evidence from in vitro models. PLoS One. 2013;8(1):e55269. doi: 10.1371/journal.pone.0055269. Epub 2013 Jan 31.

  PMID: 23383132 BACKGROUND

• Conroy AL, Silver KL, Zhong K, Rennie M, Ward P, Sarma JV, Molyneux ME, Sled J, Fletcher JF, Rogerson S, Kain KC. Complement activation and the resulting placental vascular insufficiency drives fetal growth restriction associated with placental malaria. Cell Host Microbe. 2013 Feb 13;13(2):215-26. doi: 10.1016/j.chom.2013.01.010.

  PMID: 23414761 BACKGROUND

• Elphinstone RE, Weckman AM, McDonald CR, Tran V, Zhong K, Madanitsa M, Kalilani-Phiri L, Khairallah C, Taylor SM, Meshnick SR, Mwapasa V, Ter Kuile FO, Conroy AL, Kain KC. Early malaria infection, dysregulation of angiogenesis, metabolism and inflammation across pregnancy, and risk of preterm birth in Malawi: A cohort study. PLoS Med. 2019 Oct 1;16(10):e1002914. doi: 10.1371/journal.pmed.1002914. eCollection 2019 Oct.

  PMID: 31574087 BACKGROUND

• Moeller SL, Nyengaard JR, Larsen LG, Nielsen K, Bygbjerg IC, Msemo OA, Lusingu JPA, Minja DTR, Theander TG, Schmiegelow C. Malaria in Early Pregnancy and the Development of the Placental Vasculature. J Infect Dis. 2019 Sep 26;220(9):1425-1434. doi: 10.1093/infdis/jiy735.

  PMID: 30590576 BACKGROUND

• Rijken MJ, Papageorghiou AT, Thiptharakun S, Kiricharoen S, Dwell SL, Wiladphaingern J, Pimanpanarak M, Kennedy SH, Nosten F, McGready R. Ultrasound evidence of early fetal growth restriction after maternal malaria infection. PLoS One. 2012;7(2):e31411. doi: 10.1371/journal.pone.0031411. Epub 2012 Feb 9.

  PMID: 22347473 BACKGROUND

• Griffin JB, Lokomba V, Landis SH, Thorp JM Jr, Herring AH, Tshefu AK, Rogerson SJ, Meshnick SR. Plasmodium falciparum parasitaemia in the first half of pregnancy, uterine and umbilical artery blood flow, and foetal growth: a longitudinal Doppler ultrasound study. Malar J. 2012 Sep 10;11:319. doi: 10.1186/1475-2875-11-319.

  PMID: 22963509 BACKGROUND

• Das S, Jang IK, Barney B, Peck R, Rek JC, Arinaitwe E, Adrama H, Murphy M, Imwong M, Ling CL, Proux S, Haohankhunnatham W, Rist M, Seilie AM, Hanron A, Daza G, Chang M, Nakamura T, Kalnoky M, Labarre P, Murphy SC, McCarthy JS, Nosten F, Greenhouse B, Allauzen S, Domingo GJ. Performance of a High-Sensitivity Rapid Diagnostic Test for Plasmodium falciparum Malaria in Asymptomatic Individuals from Uganda and Myanmar and Naive Human Challenge Infections. Am J Trop Med Hyg. 2017 Nov;97(5):1540-1550. doi: 10.4269/ajtmh.17-0245. Epub 2017 Aug 18.

  PMID: 28820709 BACKGROUND

• Landier J, Haohankhunnatham W, Das S, Konghahong K, Christensen P, Raksuansak J, Phattharakokoedbun P, Kajeechiwa L, Thwin MM, Jang IK, Imwong M, Wiladphaingern J, Lwin KM, Ling C, Proux S, Domingo GJ, Delmas G, Nosten FH. Operational Performance of a Plasmodium falciparum Ultrasensitive Rapid Diagnostic Test for Detection of Asymptomatic Infections in Eastern Myanmar. J Clin Microbiol. 2018 Jul 26;56(8):e00565-18. doi: 10.1128/JCM.00565-18. Print 2018 Aug.

  PMID: 29898998 BACKGROUND

• Slater HC, Ding XC, Knudson S, Bridges DJ, Moonga H, Saad NJ, De Smet M, Bennett A, Dittrich S, Slutsker L, Domingo GJ. Performance and utility of more highly sensitive malaria rapid diagnostic tests. BMC Infect Dis. 2022 Feb 4;22(1):121. doi: 10.1186/s12879-021-07023-5.

  PMID: 35120441 BACKGROUND

• Vasquez AM, Velez G, Medina A, Serra-Casas E, Campillo A, Gonzalez IJ, Murphy SC, Seilie AM, Ding XC, Tobon Castano A. Evaluation of highly sensitive diagnostic tools for the detection of P. falciparum in pregnant women attending antenatal care visits in Colombia. BMC Pregnancy Childbirth. 2020 Jul 31;20(1):440. doi: 10.1186/s12884-020-03114-4.

  PMID: 32736543 BACKGROUND

• Vasquez AM, Medina AC, Tobon-Castano A, Posada M, Velez GJ, Campillo A, Gonzalez IJ, Ding X. Performance of a highly sensitive rapid diagnostic test (HS-RDT) for detecting malaria in peripheral and placental blood samples from pregnant women in Colombia. PLoS One. 2018 Aug 2;13(8):e0201769. doi: 10.1371/journal.pone.0201769. eCollection 2018.

  PMID: 30071004 BACKGROUND

• Unwin VT, Ahmed R, Noviyanti R, Puspitasari AM, Utami RAS, Trianty L, Lukito T, Syafruddin D, Poespoprodjo JR, Santana-Morales MA, Ter Kuile FO, Adams ER. Use of a highly-sensitive rapid diagnostic test to screen for malaria in pregnancy in Indonesia. Malar J. 2020 Jan 16;19(1):28. doi: 10.1186/s12936-020-3110-6.

  PMID: 31948448 BACKGROUND

• Burger RJ, van Eijk AM, Bussink M, Hill J, Ter Kuile FO. Artemisinin-Based Combination Therapy Versus Quinine or Other Combinations for Treatment of Uncomplicated Plasmodium falciparum Malaria in the Second and Third Trimester of Pregnancy: A Systematic Review and Meta-Analysis. Open Forum Infect Dis. 2015 Nov 12;3(1):ofv170. doi: 10.1093/ofid/ofv170. eCollection 2016 Jan.

  PMID: 26788543 BACKGROUND

• PREGACT Study Group; Pekyi D, Ampromfi AA, Tinto H, Traore-Coulibaly M, Tahita MC, Valea I, Mwapasa V, Kalilani-Phiri L, Kalanda G, Madanitsa M, Ravinetto R, Mutabingwa T, Gbekor P, Tagbor H, Antwi G, Menten J, De Crop M, Claeys Y, Schurmans C, Van Overmeir C, Thriemer K, Van Geertruyden JP, D'Alessandro U, Nambozi M, Mulenga M, Hachizovu S, Kabuya JB, Mulenga J. Four Artemisinin-Based Treatments in African Pregnant Women with Malaria. N Engl J Med. 2016 Mar 10;374(10):913-27. doi: 10.1056/NEJMoa1508606.

  PMID: 26962727 BACKGROUND

• Kovacs SD, van Eijk AM, Sevene E, Dellicour S, Weiss NS, Emerson S, Steketee R, Ter Kuile FO, Stergachis A. The Safety of Artemisinin Derivatives for the Treatment of Malaria in the 2nd or 3rd Trimester of Pregnancy: A Systematic Review and Meta-Analysis. PLoS One. 2016 Nov 8;11(11):e0164963. doi: 10.1371/journal.pone.0164963. eCollection 2016.

  PMID: 27824884 BACKGROUND

• Clark RL, White TE, A Clode S, Gaunt I, Winstanley P, Ward SA. Developmental toxicity of artesunate and an artesunate combination in the rat and rabbit. Birth Defects Res B Dev Reprod Toxicol. 2004 Dec;71(6):380-94. doi: 10.1002/bdrb.20027.

  PMID: 15617018 BACKGROUND

• Clark RL, Lerman SA, Cox EM, Gristwood WE, White TE. Developmental toxicity of artesunate in the rat: comparison to other artemisinins, comparison of embryotoxicity and kinetics by oral and intravenous routes, and relationship to maternal reticulocyte count. Birth Defects Res B Dev Reprod Toxicol. 2008 Aug;83(4):397-406. doi: 10.1002/bdrb.20165.

  PMID: 18702118 BACKGROUND

• Clark RL. Animal Embryotoxicity Studies of Key Non-Artemisinin Antimalarials and Use in Women in the First Trimester. Birth Defects Res. 2017 Aug 15;109(14):1075-1126. doi: 10.1002/bdr2.1035. Epub 2017 Jun 24.

  PMID: 28646540 BACKGROUND

• Dellicour S, Sevene E, McGready R, Tinto H, Mosha D, Manyando C, Rulisa S, Desai M, Ouma P, Oneko M, Vala A, Ruperez M, Macete E, Menendez C, Nakanabo-Diallo S, Kazienga A, Valea I, Calip G, Augusto O, Genton B, Njunju EM, Moore KA, d'Alessandro U, Nosten F, Ter Kuile F, Stergachis A. First-trimester artemisinin derivatives and quinine treatments and the risk of adverse pregnancy outcomes in Africa and Asia: A meta-analysis of observational studies. PLoS Med. 2017 May 2;14(5):e1002290. doi: 10.1371/journal.pmed.1002290. eCollection 2017 May.

  PMID: 28463996 BACKGROUND

• Ballard SB, Salinger A; MPHc; Arguin PM, Desai M, Tan KR. Updated CDC Recommendations for Using Artemether-Lumefantrine for the Treatment of Uncomplicated Malaria in Pregnant Women in the United States. MMWR Morb Mortal Wkly Rep. 2018 Apr 13;67(14):424-431. doi: 10.15585/mmwr.mm6714a4.

  PMID: 29649190 BACKGROUND

• Kayentao K, Doumbo OK, Penali LK, Offianan AT, Bhatt KM, Kimani J, Tshefu AK, Kokolomami JH, Ramharter M, de Salazar PM, Tiono AB, Ouedraogo A, Bustos MD, Quicho F, Borghini-Fuhrer I, Duparc S, Shin CS, Fleckenstein L. Pyronaridine-artesunate granules versus artemether-lumefantrine crushed tablets in children with Plasmodium falciparum malaria: a randomized controlled trial. Malar J. 2012 Oct 31;11:364. doi: 10.1186/1475-2875-11-364.

  PMID: 23113947 BACKGROUND

• Longo M, Pace S, Messina M, Ferraris L, Brughera M, Ubben D, Mazue G. Piperaquine phosphate: reproduction studies. Reprod Toxicol. 2012 Dec;34(4):584-97. doi: 10.1016/j.reprotox.2012.09.001. Epub 2012 Sep 19.

  PMID: 23000234 BACKGROUND

• Batty KT, Moore BR, Stirling V, Ilett KF, Page-Sharp M, Shilkin KB, Mueller I, Karunajeewa HA, Davis TM. Toxicology and pharmacokinetics of piperaquine in mice. Toxicology. 2008 Jul 10;249(1):55-61. doi: 10.1016/j.tox.2008.04.004. Epub 2008 Apr 16.

  PMID: 18502018 BACKGROUND

• Bretscher MT, Dahal P, Griffin J, Stepniewska K, Bassat Q, Baudin E, D'Alessandro U, Djimde AA, Dorsey G, Espie E, Fofana B, Gonzalez R, Juma E, Karema C, Lasry E, Lell B, Lima N, Menendez C, Mombo-Ngoma G, Moreira C, Nikiema F, Ouedraogo JB, Staedke SG, Tinto H, Valea I, Yeka A, Ghani AC, Guerin PJ, Okell LC. The duration of chemoprophylaxis against malaria after treatment with artesunate-amodiaquine and artemether-lumefantrine and the effects of pfmdr1 86Y and pfcrt 76T: a meta-analysis of individual patient data. BMC Med. 2020 Feb 25;18(1):47. doi: 10.1186/s12916-020-1494-3.

  PMID: 32098634 BACKGROUND

• Clark RL, Youreneff M, DeLise AM. Developmental toxicity studies of lumefantrine and artemether in rats and rabbits. Birth Defects Res B Dev Reprod Toxicol. 2016 Dec;107(6):243-257. doi: 10.1002/bdrb.21189.

  PMID: 28032463 BACKGROUND

• Manyando C, Mkandawire R, Puma L, Sinkala M, Mpabalwani E, Njunju E, Gomes M, Ribeiro I, Walter V, Virtanen M, Schlienger R, Cousin M, Chipimo M, Sullivan FM. Safety of artemether-lumefantrine in pregnant women with malaria: results of a prospective cohort study in Zambia. Malar J. 2010 Sep 1;9:249. doi: 10.1186/1475-2875-9-249.

  PMID: 20809964 BACKGROUND

• Rulisa S, Kaligirwa N, Agaba S, Karema C, Mens PF, de Vries PJ. Pharmacovigilance of artemether-lumefantrine in pregnant women followed until delivery in Rwanda. Malar J. 2012 Jul 6;11:225. doi: 10.1186/1475-2875-11-225.

  PMID: 22770264 BACKGROUND

• Mosha D, Mazuguni F, Mrema S, Sevene E, Abdulla S, Genton B. Safety of artemether-lumefantrine exposure in first trimester of pregnancy: an observational cohort. Malar J. 2014 May 27;13:197. doi: 10.1186/1475-2875-13-197.

  PMID: 24884890 BACKGROUND

• Dellicour S, Desai M, Aol G, Oneko M, Ouma P, Bigogo G, Burton DC, Breiman RF, Hamel MJ, Slutsker L, Feikin D, Kariuki S, Odhiambo F, Pandit J, Laserson KF, Calip G, Stergachis A, ter Kuile FO. Risks of miscarriage and inadvertent exposure to artemisinin derivatives in the first trimester of pregnancy: a prospective cohort study in western Kenya. Malar J. 2015 Nov 18;14:461. doi: 10.1186/s12936-015-0950-6.

  PMID: 26581434 BACKGROUND

• Augusto O, Stergachis A, Dellicour S, Tinto H, Vala A, Ruperez M, Macete E, Nakanabo-Diallo S, Kazienga A, Valea I, d'Alessandro U, Ter Kuile FO, Calip GS, Ouma P, Desai M, Sevene E. First trimester use of artemisinin-based combination therapy and the risk of low birth weight and small for gestational age. Malar J. 2020 Apr 8;19(1):144. doi: 10.1186/s12936-020-03210-y.

  PMID: 32268901 BACKGROUND

• Walker PG, ter Kuile FO, Garske T, Menendez C, Ghani AC. Estimated risk of placental infection and low birthweight attributable to Plasmodium falciparum malaria in Africa in 2010: a modelling study. Lancet Glob Health. 2014 Aug;2(8):e460-7. doi: 10.1016/S2214-109X(14)70256-6. Epub 2014 Jul 23.

  PMID: 25103519 BACKGROUND

• Kapito-Tembo A, Meshnick SR, van Hensbroek MB, Phiri K, Fitzgerald M, Mwapasa V. Marked reduction in prevalence of malaria parasitemia and anemia in HIV-infected pregnant women taking cotrimoxazole with or without sulfadoxine-pyrimethamine intermittent preventive therapy during pregnancy in Malawi. J Infect Dis. 2011 Feb 15;203(4):464-72. doi: 10.1093/infdis/jiq072. Epub 2011 Jan 7.

  PMID: 21216867 BACKGROUND

• ACOG committee opinion no. 561: Nonmedically indicated early-term deliveries. Obstet Gynecol. 2013 Apr;121(4):911-915. doi: 10.1097/01.AOG.0000428649.57622.a7.

  PMID: 23635710 BACKGROUND

• Hoffman MK, Goudar SS, Kodkany BS, Metgud M, Somannavar M, Okitawutshu J, Lokangaka A, Tshefu A, Bose CL, Mwapule A, Mwenechanya M, Chomba E, Carlo WA, Chicuy J, Figueroa L, Garces A, Krebs NF, Jessani S, Zehra F, Saleem S, Goldenberg RL, Kurhe K, Das P, Patel A, Hibberd PL, Achieng E, Nyongesa P, Esamai F, Liechty EA, Goco N, Hemingway-Foday J, Moore J, Nolen TL, McClure EM, Koso-Thomas M, Miodovnik M, Silver R, Derman RJ; ASPIRIN Study Group. Low-dose aspirin for the prevention of preterm delivery in nulliparous women with a singleton pregnancy (ASPIRIN): a randomised, double-blind, placebo-controlled trial. Lancet. 2020 Jan 25;395(10220):285-293. doi: 10.1016/S0140-6736(19)32973-3.

  PMID: 31982074 BACKGROUND

• Landis SH, Lokomba V, Ananth CV, Atibu J, Ryder RW, Hartmann KE, Thorp JM, Tshefu A, Meshnick SR. Impact of maternal malaria and under-nutrition on intrauterine growth restriction: a prospective ultrasound study in Democratic Republic of Congo. Epidemiol Infect. 2009 Feb;137(2):294-304. doi: 10.1017/S0950268808000915. Epub 2008 Jun 30.

  PMID: 18588723 BACKGROUND

Related Links

• Organization WH. Every Newborn: an action plan to end preventable deaths.
• WHO. Recommendations on intermittent screening and treatment in pregnancy and the safety of ACTs in the first trimester.

MeSH Terms

Conditions

Malaria, Falciparum; Stillbirth; Premature Birth

Interventions

Artemether, Lumefantrine Drug Combination

Condition Hierarchy (Ancestors)

Malaria; Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases; Fetal Death; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Death; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Obstetric Labor, Premature; Obstetric Labor Complications

Intervention Hierarchy (Ancestors)

Artemether; Artemisinins; Reactive Oxygen Species; Free Radicals; Inorganic Chemicals; Organic Chemicals; Lumefantrine; Fluorenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sesquiterpenes; Terpenes; Polycyclic Compounds; Drug Combinations; Pharmaceutical Preparations

Study Officials

• Steve M Taylor, MD, MPH

  Duke University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Stephen James, MPH

CONTACT

919-668-0420; stephen.james@duke.edu

Irene Okumu

CONTACT

919-660-6321; irene.okumu@duke.edu

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: SCREENING
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Random assignment to either a) usual antenatal care or b) testing for malaria with a high-sensitivity rapid diagnostic test followed by treatment with artemether-lumefantrine if tested positive

Study Record Dates

• First Submitted: February 24, 2023
• First Posted: March 7, 2023
• Study Start: November 6, 2023
• Primary Completion (Estimated): February 1, 2027
• Study Completion (Estimated): February 1, 2027
• Last Updated: January 20, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

KE (1); DE (1)