Updated CDC Recommendations for Using Artemether-Lumefantrine for the Treatment of Uncomplicated Malaria in Pregnant Women in the United States

Sarah-Blythe Ballard, MD, PhD; Allison Salinger, MPHc; Paul M. Arguin, MD; Meghna Desai, PhD; Kathrine R. Tan, MD

Morbidity and Mortality Weekly Report. 2018;67(14):424-431.

Abstract and Introduction

Abstract

Malaria infection during pregnancy is associated with an increased risk for maternal and fetal complications. In the United States, treatment options for uncomplicated, chloroquine-resistant Plasmodium falciparum and P. vivax malaria in pregnant women are limited to mefloquine or quinine plus clindamycin.^[1] However, limited availability of quinine and increasing resistance to mefloquine restrict these options. Strong evidence now demonstrates that artemether-lumefantrine (AL) (Coartem) is effective and safe in the treatment of malaria in pregnancy. The World Health Organization (WHO) has endorsed artemisinin-based combination therapies (ACTs), such as AL, for treatment of uncomplicated malaria during the second and third trimesters of pregnancy and is currently considering whether to add ACTs, including AL, as an option for malaria treatment during the first trimester.^[2,3] This policy note reviews the evidence and updates CDC recommendations to include AL as a treatment option for uncomplicated malaria during the second and third trimesters of pregnancy and during the first trimester of pregnancy when other treatment options are unavailable. These updated recommendations reflect current evidence and are consistent with WHO treatment guidelines.

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Table 1. Findings of randomized trials of artemisinin-based regimens for treatment of malaria in pregnancy
Author, publication year	Country	Indication for treatment	Drug regimen	No. of participants	Follow-up time (days)	Treatment outcome, % (95% CI)
McGready, et al., 2000*	Thailand	Uncomplicated P. falciparum, second and third trimesters	1. MQ 25 mg/kg x 1 and As 4 mg/kg/d x 3d	66	63	Cure 98.2 (94.7–100)^†
McGready, et al., 2000*	Thailand	Uncomplicated P. falciparum, second and third trimesters	2. Q 10 mg/kg q8hr x 7d	42	63	Cure 67.0 (43.3–90.8)^†
McGready, et al., 2001^§	Thailand	Uncomplicated P. falciparum, second and third trimesters	1. As 2 mg/kg/d x 7d	64	42	Cure 100
McGready, et al., 2001^§	Thailand	Uncomplicated P. falciparum, second and third trimesters	2. Q 10 mg/kg q8hr x7d and CL 5 mg/kg q8hr x7d	65	42	Cure 100
McGready, et al., 2005^¶	Thailand	Uncomplicated P. falciparum, second and third trimesters	As 4 mg/kg/d x 3d and A 20 mg/kg/d x 3d and P 8 mg/kg/d x 3d	39	63	Cure 94.9 (81.37–99.11)^†,**
McGready, et al., 2005^¶	Thailand	Uncomplicated P. falciparum, second and third trimesters	Q 10 mg/kg q8hr x 7d	42	63	Cure 63.4 (46.9–77.4)^†,††
Piola, et al., 2010^§§	Uganda	Uncomplicated P. falciparum	1. AL 20/120 mg 4 tabs at 0 and 8hr x 1d, then BID x 2d	152	42	Cure 99.3 (96.0–99.9)^†,¶¶
Piola, et al., 2010^§§	Uganda	Uncomplicated P. falciparum	2. Q 10 mg/kg q8hr x 7d	152	42	Cure 97.6 (93.1–99.5)^†,***
Kaye, et al., 2008^†††	Uganda	Uncomplicated P. falciparum, second and third trimesters	1. AL 20/120 mg 4 tabs at 0 and 8hr x1d, then BID x 2d	57	28	Cure 100
Kaye, et al., 2008^†††	Uganda	Uncomplicated P. falciparum, second and third trimesters	2. LapDap x 3d	57	28	Cure 100

Abbreviations: A = atovaquone; AL = artemether-lumefantrine; AQ = amodiaquine; As = artesunate; BID = twice daily; CI = confidence interval; d = days; hr = hour(s); kg = kilogram; LapDap = chlorproguanil-dapsone; mg = milligram; MQ = mefloquine; P = proguanil; PCR = polymerase chain reaction; Q = quinine; qd = once daily; q8hr = every 8 hours.
*McGready R, Brockman A, Cho T, et al. Randomized comparison of mefloquine-artesunate versus quinine in the treatment of multidrug-resistant falciparum malaria in pregnancy. Trans R Soc Trop Med Hyg 2000;94:689–93.
^†PCR-adjusted.
^§McGready R, Cho T, Keo NK, et al. Artemisinin antimalarials in pregnancy: a prospective treatment study of 539 episodes of multidrug-resistant Plasmodium falciparum. Clin Infect Dis 2001;33:2009–16.
^¶McGready R, Ashley EA, Moo E, et al. A randomized comparison of artesunate-atovaquone-proguanil versus quinine in treatment for uncomplicated falciparum malaria during pregnancy. J Infect Dis 2005;192:846–53.
**37 of 39 participants.
^††26 of 41 participants.
^§§Piola P, Nabasumba C, Turyakira E, et al. Efficacy and safety of artemether-lumefantrine compared with quinine in pregnant women with uncomplicated Plasmodium falciparum malaria: an open-label, randomised, non-inferiority trial. Lancet Infect Dis 2010;10:762–9.
^¶¶137 of 139 participants.
***122 of 125 participants.
^†††Kaye DK, Nshemerirwe R, Mutyaba TS, Ndeezi G. A randomized clinical trial comparing safety, clinical and parasitological response to artemether-lumefantrine and chlorproguanil-dapsone in treatment of uncomplicated malaria in pregnancy in Mulago hospital, Uganda. J Infect Dev Ctries 2008;2:135–9.

Table 2. Summary of studies using artemisinin-based treatment for malaria in second and third trimesters of pregnancy and safety outcomes
Author, publication year	Indication (country)	Drug(s)	No. of participants	Pregnancy outcomes, n/N (%)*	Congenital anomalies, n/N (%)	Maternal adverse events, n/N (%)
Randomized trials (all open label) using nonartemisinin drug in comparison group
McGready, et al., 2000^†	Uncomplicated P. falciparum (Thailand)	MQ 25 mg/kg x 1 and As 4 mg/kg/d x 3d	66	Miscarriage, 2 (3)	0 (0)	Anemia day 7, 32/48 (67)^§
				Stillbirth, 0 (0)		Dizziness, (45)^§
				Low birth weight, 9/53 (17)		Tinnitus, (17)^§
		Q 10 mg/kg q8hr x 7d	42	Miscarriage, 0 (0)	0 (0)	Anemia day 7, 14/33 (42)^§
				Stillbirths, 0 (0)		Dizziness, (87)^§
				Low birth weight, 6/33 (18)		Tinnitus, (66)^§
McGready, et al., 2001^¶	Uncomplicated P. falciparum (Thailand)	As 2 mg/kg/d x 7d	64	Stillbirth, 1 (2)**	Minor, 1 (2)	Tinnitus, (9)^§
McGready, et al., 2001^¶	Uncomplicated P. falciparum (Thailand)	Q 10 mg/kg q8hr x 7d and CL 5 mg/kg q8hr x 7d	65	Stillbirth, 1 (2)**	Major, 1(2)	Tinnitus, (45)^§
McGready, et al., 2005^††,§§	Uncomplicated P. falciparum (Thailand)	As 4 mg/kg/d x 3d and A 20 mg/kg/d x 3d and P 8 mg/kg/d x 3d	39	Preterm, 4/34 (12)	Polythelia and cleft lip and palate, 2/34 (6)**	Tinnitus, (24)^§
			39	Low birth weight, 6/23 (26)	Polythelia and cleft lip and palate, 2/34 (6)**	Tinnitus, (24)^§
		Q 10 mg/kg q8hr x 7d	42	Stillbirth, 1 (2)	Left aural atresia, 1/38 (3)**	Tinnitus, (79)^§
				Preterm, 6/38 (16)
				Low birth weight, 4/30 (13)
Piola, et al., 2010^¶¶	Uncomplicated P. falciparum (Uganda)	AL 20/120 mg 4 tabs at 0 and 8hr x 1d, then BID x 2d	152	Miscarriage, 2/144 (1)	Polydactyly, 2 (1)**	Tinnitus, 0 (0)^§
				Intrauterine fetal death, 1/144 (1)	Acyanotic heart disease, 1 (1)	Headache, 26 (17)^§
				Stillbirth, 2/144 (1)		Nausea, 8 (5)^§
				Preterm, 12/143 (1)		Vomiting, 6 (4)^§
				Low birth weight, 12/120 (10)		Anorexia, 6 (4)^§
		Q 10 mg/kg q8hr x 7d	152	Miscarriage, 2/137 (2)	Polydactyly, 2 (1)**	Tinnitus, 111 (73)^§
				Intrauterine fetal death, 2/137 (2)		Headache, 9 (6)^§
				Stillbirth, 3/137 (2)		Nausea, 26 (17)^§
				Preterm, 17/137 (3)		Vomiting, 28 (18)^§
				Low birth weight, 16/137 (13)		Anorexia, 16 (11)^§
Kaye, et al., 2008***	Uncomplicated P. falciparum (Uganda)	AL 20/120 mg 4 tabs at 0 and 8hr x 1d, then BID x 2d	57	Not assessed	Not assessed	Palpitations, 4 (7)
						Dizziness, 1 (2)
						Drowsiness, 1 (2)
						Rash, 1 (2)
		LapDap x 3d	57	Not assessed	Not assessed	Vomiting, 1 (2)
						Diarrhea, 1 (2)
						Palpitations, 1 (2)
Randomized trials (open label unless otherwise noted) using artemisinin in comparison group
Sowunmi, et al., 1998^†††	Failed CQ, SP or CQ-SP treatment for P. falciparum (Nigeria)	Ar 3.2 mg/kg IM x 1 then 1.6 mg/kg IM qd x 4d	23	IUGR, 1	None	None
		Ar 3.2 mg/kg IM x 1 then MQ 7.5 mg/kg qd x 2d	22	None	None	Abdominal discomfort, 2 (9)
		Ar 3.2 mg/kg IM x 1 then MQ 7.5 mg/kg qd x 2d	22	None	None	Dizziness, 2 (9)
McGready, et al., 2008^§§§	Uncomplicated P. falciparum (Thailand)	AL 20/120 mg 4 tabs BID x 3d	124	Miscarriage, 0 (0)	None	Vomiting, 2 (2)
		AL 20/120 mg 4 tabs BID x 3d	124	Stillbirth, 1/119 (1)	None	Vomiting, 2 (2)
		As 2 mg/kg qd x 7d	125	Miscarriage, 1/122 (1)**	None	Vomiting, 1 (1)
		As 2 mg/kg qd x 7d	125	Stillbirth, 1/119 (1)	None	Rash, 1 (1)
Ukah, et al., 2015^¶¶¶	Uncomplicated P. falciparum (Nigeria, double-blind)	AL (80 mg/480 mg) BID x 3d	75	Miscarriage, 1/71 (1)	Not assessed	Body weakness 2 (3)
		AL (80 mg/480 mg) BID x 3d	75	Stillbirth, 2/71 (3)	Not assessed	Pruritis 0 (0)
		Ar-AQ (100 mg/270 mg) BID x 3d	75	Miscarriage, 1/65 (2)	Not assessed	Body weakness, 26 (35)
		Ar-AQ (100 mg/270 mg) BID x 3d	75	Stillbirth, 1/65 (2)	Not assessed	Pruritis, 4 (5)
PREGACT, 2016****	P. falciparum (four African countries)	AL	880	Miscarriage, 1	Any defect, 17/832 (2)
				Stillbirth, 16/856 (2)
				Preterm, (10)
		AQ-As	842	Miscarriage, 4 (<1)	Any defect, 8/776 (1)	Anemia, 2 (<1
				Stillbirth, 17/815 (2)		Abdominal pain, 1 (<1)
				Preterm, (3)		Malaise, 2 (<1)
		MQ-As	848	Miscarriage, 4	Any defect, 13/780 (2)	Abdominal pain, 1 (<1)
				Stillbirth, 23/821 (3)		Vomiting, 2 (<1)
				Preterm, (8)		Malaise, 1 (<1)
		DHA-PIP	853	Miscarriage, 4 (<1)	Any defect, 6/767 (1)	Headache/weakness, 1 (<1)
				Stillbirth, 22/818 (3)
				Preterm, (10)
Cohort study
Manyando, et al., 2010^{††††,§§§§}	Uncomplicated P. falciparum (Zambia)	AL 20 mg/120 mg 4 tabs BID x 3d	495	Miscarriage, 7/504 (1) (all first trimester exposures)	Any defect, 29/449 (7)	Not reported
				Stillbirth, 9/504 (2)
				Preterm, 71/504 (14)
		SP (1500 mg/75 mg)	506	Miscarriage, 8/516 (2) (in 5 women, including one with twins and one with triplets)	Any defect, 18/444 (4)	Not reported
				Stillbirth, 13/516 (3)
				Preterm, 90/516 (17)
Descriptive studies (includes pharmacokinetic studies and case series)
McGready, et al., 2001^¶ (includes data published 1998)^¶¶¶¶	P. falciparum or mixed, primary and recrudescent, uncomplicated and severe (Thailand)	As given 2–4 mg/kg up to 7 days (varies by indication) or As 4 mg/kg qd x 3d and AP or As 4 mg/kg qd x 3d and MQ	461	Miscarriage, 20/414 (5)	Any defect, 3/386 (1) Major 1/386 (0)	No serious adverse events
			461	Stillbirth, 7/386 (2)	Any defect, 3/386 (1) Major 1/386 (0)	No serious adverse events
		Community (no treatment)		Miscarriage, 1003/8154 (12)	Any defect, 866/6418 (14)
				Stillbirth, 114/7058 (2)
				Low birth weight, 866/6418 (14)
Mosha, et al., 2014*****	Uncomplicated P. falciparum (Tanzania)	AL 20/120 mg 4 tabs at 0 and 8hr x1d, then BID x 2d	35	Not assessed, (follow-up to 42 days only)	Not assessed	No serious adverse events
Nyunt, et al., 2015^{†††††}	Uncomplicated P. falciparum (Uganda)	AL 20/120 mg 4 tabs at 0 and 8hr x 1d, then BID x 2d	30	Not assessed, (follow-up to 42 days only)	Not assessed	No serious adverse events
Adam, et al., 2004^{§§§§§,¶¶¶¶¶}	P. falciparum (Sudan)	Ar 80 mg IM BID x1d then qd x 2d	28	Miscarriage, 0 (0)	Not assessed	Not assessed
				Stillbirth, 0 (0)
				Premature, 1 (4)**
Adam, et al., 2009******^,¶¶¶¶¶	P. falciparum (Sudan)	Ar IM As and SP AL	62	Miscarriage, 2 (3)** (both had received artemether injections early in pregnancy and miscarried while receiving quinine infusions for a second malaria infection)	Not assessed	Not assessed
Wang, 1981^{††††††}	"Plasmodium" (China)	Ar in oil 500–900 mg IM qd x 3d or Ar 600 mg IM qd x 3d	6	Miscarriage, 0 (0)	Any defect, 0 (0)	Not assessed
				Stillbirth, 0 (0)
				Premature, 0 (0)

Abbreviations: A = atovaquone; AL = artemether-lumefantrine; AQ = amodiaquine; Ar = artemether; As = artesunate; BID = twice daily; CL = clindamycin; CQ = chloroquine; d = day(s); DHA-PIP = dihydroartemisinin-piperaquine; hr = hour(s); IM = intramuscular; IUGR = intrauterine growth retardation; kg = kilogram; LapDap = chlorproguanil-dapsone; mg = milligram; MQ = mefloquine; P = proguanil; Q = quinine; qd = once daily; q8hr = every 8 hours; SP = sulfadoxine pyrimethamine.
*In studies with incomplete outcome data, denominators are provided.
^†McGready R, Brockman A, Cho T, et al. Randomized comparison of mefloquine-artesunate versus quinine in the treatment of multidrug-resistant falciparum malaria in pregnancy. Trans R Soc Trop Med Hyg 2000;94:689–93.
^§Significant difference between comparison groups.
^¶McGready R, Cho T, Keo NK, et al. Artemisinin antimalarials in pregnancy: a prospective treatment study of 539 episodes of multidrug-resistant Plasmodium falciparum. Clin Infect Dis 2001;33:2009–16.
**Considered not related to drug.
^††McGready R, Ashley EA, Moo E, et al. A randomized comparison of artesunate-atovaquone-proguanil versus quinine in treatment for uncomplicated falciparum malaria during pregnancy. J Infect Dis 2005;192:846–53.
^§§1-year follow-up of infants indicated no differences in development.
^¶¶Piola P, Nabasumba C, Turyakira E, et al. Efficacy and safety of artemether-lumefantrine compared with quinine in pregnant women with uncomplicated Plasmodium falciparum malaria: an open-label, randomised, non-inferiority trial. Lancet Infect Dis 2010;10:762–9.
***Kaye DK, Nshemerirwe R, Mutyaba TS, Ndeezi G. A randomized clinical trial comparing safety, clinical and parasitological response to artemether-lumefantrine and chlorproguanil-dapsone in treatment of uncomplicated malaria in pregnancy in Mulago hospital, Uganda. J Infect Dev Ctries 2008;2:135–9.
^†††Sowunmi A, Oduola AMJ, Ogundahunsi OAT, et al. Randomised trial of artemether versus artemether and mefloquine for the treatment of chloroquine/sufadoxine-pyrimethamine-resistant falciparum malaria during pregnancy. J Obstet Gynaecol 1998;18:322–7.
^§§§McGready R, Tan SO, Ashley EA, et al. A randomised controlled trial of artemether-lumefantrine versus artesunate for uncomplicated Plasmodium falciparum treatment in pregnancy. Rogerson S, editor. PLoS Med 2008; 5:e253.
^¶¶¶Ukah M, Badejoko O, Ogunniyi S, Loto O, Aboderin O, Fatusi A. A randomized trial of artesunate-amodiaquine versus artemether-lumefantrine for the treatment of acute uncomplicated malaria in pregnancy. Int J Gynaecol Obstet 2015;131:41–4.
****PREGACT Study Group. Four artemisinin-based treatments in African pregnant women with malaria. N Engl J Med 2016;374:913–27.
^††††Manyando C, Njunju EM, Virtanen M, Hamed K, Gomes M, Van Geertruyden JP. Exposure to artemether-lumefantrine (Coartem) in first trimester pregnancy in an observational study in Zambia. Malar J 2015;14:77.
^§§§§Included women at all trimesters.
^¶¶¶¶McGready R, Cho T, Cho JJ, et al. Artemisinin derivatives in the treatment of falciparum malaria in pregnancy. Trans R Soc Trop Med Hyg 1998;92:430–3.
*****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;13:197.
^{†††††}Nyunt MM, Nguyen VK, Kajubi R, et al. Artemether-lumefantrine pharmacokinetics and clinical response are minimally altered in pregnant Ugandan women treated for uncomplicated falciparum malaria. Antimicrob Agents Chemother 2016;60:1274–82.
^§§§§§Adam I, Elwasila E, Mohammed Ali DA, Elansari E, Elbashir MI. Artemether in the treatment of falciparum malaria during pregnancy in eastern Sudan. Trans R Soc Trop Med Hyg 2004;98:509–13.
^¶¶¶¶¶Included women in first and second trimesters.
******Adam I, Elhassan EM, Omer EM, Abdulla MA, Mahgoub HM, Adam GK. Safety of artemisinins during early pregnancy, assessed in 62 Sudanese women. Ann Trop Med Parasitol 2009;103:205–10.
^{††††††}Wang TY. Follow-up observation on the therapeutic effects and remote reactions of artemisinin (Qinghaosu) and artemether in treating malaria in pregnant woman. J Tradit Chin Med 1989;9:28–30.

Table 3. Summary of safety outcomes in studies using artemisinin-based treatment for malaria in first trimester of pregnancy
Author, publication year	Description or indication (country)	Drug or regimen (no.)	Pregnancy outcomes, no. (%) (unless otherwise indicated)*	Congenital anomalies, no. (%) (unless otherwise indicated)	Maternal adverse events, no. (%) (unless otherwise indicated)
Meta-analysis
Dellicour, et al., 2017^†	Included five observational studies (individual participant data from six sub-Saharan African countries, and aggregate data from Thailand)	Areg (717)	Miscarriage:	As 1.5% (95% CI = 0.6–3.5); Q 1.2% (95% CI = 0.6–2.4)	Not assessed
			Areg versus Q: aHR = 0.73 (95% CI = 0.44–1.21)
			Areg versus none: aHR = 1.16 (95% CI = 0.81–1.66)
		Q (947)	Stillbirth:
			Areg versus Q: aHR = 0.29 (95% CI = 0.08–1.02)
			Areg versus none: aHR = 0.65 (95% CI = 0.34–1.23)
		No antimalarials (28,954)	Stillbirth and miscarriage:
		No antimalarials (28,954)	Areg versus Q: aHR = 0.58 (95% CI = 0.36–1.02)
Observational studies
Any anomaly, 1 (1) Any anomaly, 1 (1) Any anomaly, 2 (3)	Identified women with inadvertent use of AL, other antimalarials, or none, then followed to birth outcome (Tanzania)	AL (164)	Miscarriage, 5 (3) and stillbirth, 6 (3.7);		Not assessed
			aOR = 1.4 (95% CI = 0.8–2.5, p = 0.295)
			Low birth weight, 8 (5.2);
			aOR = 1.2 (95% CI = 0.6–2.5, p = 0.573)
			Preterm, 8 (5.2);
			aOR = 0.9 (95% CI = 0.5–1.8, p = 0.865)
		Q (70)	Miscarriage, 3(4.3) and stillbirth, 5 (7.1);		Not assessed
			aOR = 2.5 (95% CI = 1.3–5.1, p = 0.009)
			Low birth weight, 1 (1.6);
			aOR = 0.6 (0.1–2.4, p = 0.461)
			Preterm, aOR = 2.6 (95% CI = 1.3– 5.3, p = 0.007)
		SP (66)	Miscarriage, 0 and stillbirth, 2 (3.0);		Not assessed
			aOR = 0.5 (95% CI = 0.1–2.0, p = 0.312)
			Low birth weight, 2 (3.1);
			aOR = 0.7 (95% CI = 0.2–3.0, p = 0.639)
			Preterm, 7 (10.9);
			aOR = 1.8 (95% CI = 0.8–4.1, p = 0.160)
		AQ (11)	Miscarriage, 0 and stillbirth, 0	Any anomaly, 0 (0)	Not assessed
			Low birth weight, 0
			Preterm, 0
		No antimalarials (1,464)	Miscarriage, 34 (2.3) and stillbirth, 49 (3.3);	Any anomaly, 19 (1)	Not assessed
			aOR = 0.8 (95% CI = 0.5–1.2, p = 0.260)
			Low birth weight, 69 (5.0);
			aOR = 1.2 (95% CI = 0.6–2.3, p = 0.564)
			Preterm, 88 (6.4);
			aOR = 0.7 (95% CI = 0.5–1.1, p = 0.168)
Dellicour, et al., 2015**^,¶	Identified women with inadvertent use of AL, other antimalarials, or none, then followed to birth outcome (Kenya)	Confirmed ACT (77)	Miscarriage:	Not assessed	Not assessed
		Unconfirmed ACT (222) Q (13)	Confirmed ACT exposure only:
			ACT 6/77 versus no antimalarial 57/793
			aHR = 1.72 (95% CI = 0.66–4.45, p = 0.266)
		No ACT exposure (835)	Q 0/3 versus no antimalarial 57/793
			ACT 5/72 versus Q 1/13;
			aHR = 0.48 (95% CI = 0.12–1.89, p = 0.297)
			Confirmed and unconfirmed ACT: ACT 29/299 versus no antimalarial 57/793;
			aHR = 1.66 (95% CI = 1.04–2.67, p = 0.034)
			Q 1/13 versus no antimalarial 57/793;
			aHR = 4.27 (95% CI = 0.53–34.33, p = 0.172)
			ACT 28/286 versus Q 1/13;
			aHR = 0.64 (95% CI = 0.08–4.91, p = 0.665)
Moore, et al., 2016^††,¶	Data from antenatal clinics analyzed (Thai-Myanmar border)	Areg (183)	Miscarriage: when compared with Q or Q and CL, Areg, 92 (11): aHR = 0.78 (95% CI = 0.45–1.34, p = 0.3645)	Any malformation: Uncomplicated Pf treated with Areg, 2/109 (2), Q, 9/641 (1), Severe Pf treated with: Areg, 2/22 (9); Q, 0/8 (0)	Not assessed
		MQ (25)	MQ 2 (8): aHR = 0.54 (95% CI = 0.13–2.31, p = 0.4082)
		Q or Q and CL (971)	When comparing malaria with no malaria in first trimester, miscarriage: aHR = 1.61 (95% CI = 1.32–1.97, p<0.0001)
Manyando, et al., 2015^§§,¶	Data analyzed from previous prospective cohort, women with inadvertent first trimester exposure (Zambia)	AL (135)	Miscarriage not assessed	Any malformation, 9 (7)	Not assessed
			Stillbirth, 2 (1.5) (95% CI = 0.4–5.2)
			Low birth weight, 13 (10.2)
		AL and SP (7)	Miscarriage not assessed	Any malformation, 8/121 (7)	Not assessed
			Stillbirth, 0 (0) (95% CI = 0–39.0)
			Low birth weight, 1 (14.3)
		SP and/or Q (129)	Miscarriage not assessed		Not assessed
			Stillbirth, 3 (2.3) (95% CI = 0.8–6.6)
			Low birth weight, 8 (6.7)
		No antimalarial (644)	Miscarriage not assessed	Not assessed	Not assessed
			Stillbirth, 17 (2.6) (95% CI = 1.7–4.2)
			Low birth weight, 52 (8.7)
Descriptive studies
McGready, et al., 2001^¶¶ (includes data from McGready et al., 1998)***	P for mixed infection, both primary and recrudescent, uncomplicated and severe (Thailand)	Areg (19 primary treatment, 25 for retreatment)	Miscarriage, 7 (18.9)^†††	Any malformation, 0	Not assessed
		Community (no treatment)	Miscarriage, 1,003/8,154 (12.3)	Any malformation, 56/3,707 (2)	Not assessed

Abbreviations: A = atovaquone; aHR = adjusted hazard ratio; AL = artemether-lumefantrine; aOR = adjusted odds ratio; AQ = amodiaquine; Ar = artemether; Areg = artemisinin regimen; As = artesunate; BID = twice daily; CI = confidence interval; CL = clindamycin; CQ = chloroquine; DHA-PIP = dihydroartemisinin-piperaquine; LapDap = chlorproguanil-dapsone; MQ = mefloquine; P = proguanil; Pf = Plasmodium falciparum; Q = quinine; SP = sulfadoxine pyrimethamine. *In studies with incomplete outcome data, denominators are provided.
^†Dellicour S, Sevene E, McGready R, et al. First-trimester artemisinin derivatives and quinine treatments and the risk of adverse pregnancy outcomes in Africa and Asia: a meta-analysis of observational studies. Krishna S, editor. PLOS Med 2017;14:e1002290.
^§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;13:197.
^¶Study included in Dellicour 2017 meta-analysis.
**Dellicour S, Sevene E, McGready R, et al. First-trimester artemisinin derivatives and quinine treatments and the risk of adverse pregnancy outcomes in Africa and Asia: a meta-analysis of observational studies. Krishna S, editor. PLOS Med 2017;14:e1002290.
^††Moore KA, Simpson JA, Paw MK, et al. Safety of artemisinins in first trimester of prospectively followed pregnancies: an observational study. Lancet Infect Dis 2016;16:576–83.
^§§Manyando C, Njunju EM, Virtanen M, Hamed K, Gomes M, Van Geertruyden JP. Exposure to artemether-lumefantrine (Coartem) in first trimester pregnancy in an observational study in Zambia. Malar J 2015;14:77.
^¶¶McGready R, Cho T, Keo NK, et al. Artemisinin antimalarials in pregnancy: a prospective treatment study of 539 episodes of multidrug-resistant Plasmodium falciparum.
***McGready R, Cho T, Cho JJ, et al. Artemisinin derivatives in the treatment of falciparum malaria in pregnancy. Trans R Soc Trop Med Hyg 1998;92:430–3.
^†††Not different from overall community rate p = 0.211.