DRUG DEVELOPMENT RESEARCH 71:56–68 (2010)

Research Overview

Which Drug is Effective and Safe for Acute Malariain Pregnancy? Reviewing the Evidence

Rose McGready1– 3� and Franc-ois Nosten1– 3

1Shoklo Malaria Research Unit, Mae Sot, Thailand2Mahidol-Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine,

Mahidol University, Bangkok, Thailand3Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford,

Oxford, United Kingdom

Strategy, Management and Health Policy

Enabling

Technology,

Genomics,

Proteomics

Preclinical

Research

Preclinical Development

Toxicology, Formulation

Drug Delivery,

Pharmacokinetics

Clinical Development

Phases I-III

Regulatory, Quality,

Manufacturing

Postmarketing

Phase IV

ABSTRACT During pregnancy, a woman living or travelling in a malaria endemic area is more at riskof contracting the disease and developing a severe infection and dying than a non-pregnant woman.Despite this increased morbidity and mortality in pregnancy, there are almost no studies on which to baserecommendations on the use of antimalarial drugs in this vulnerable group. This is because, paradoxically,the emphasis is often put on the safety of the unborn child rather than that of the infested mother. As aresult of this neglect, tens of thousands of pregnant women (and their fetuses) are dying every year of a verypreventable and treatable infection. In recent years, some trials have been conducted, especially in areasof high resistance in Plasmodium falciparum in South East Asia. The results show that quinine plusclindamycin is the treatment of choice in the first trimester, while artemisinin treatment should be used inthe second and third trimesters in the treatment of uncomplicated malaria. For severe malaria, parenteralartesunate is the treatment of choice. However these studies have also shown that the pharmacokineticproperties of most antimalarials are altered during gestation and that the doses used in non-pregnant adultsare often not adapted to pregnancy. Urgent efforts are required to optimize the treatment of malaria inpregnancy. Drug Dev Res 71:56–68, 2010. r 2009 Wiley-Liss, Inc.

Key words: malaria; P. falciparum; pregnancy

INTRODUCTION

The aim of this review is to provide up-to-dateinformation on the efficacy and safety of antimalarialsused for treatment (not prophylaxis) of malaria inpregnancy (MIP), based on published evidence. Thereare few or no studies for most of the drugs used for thetreatment of tropical infections in pregnancy, and onlyfew or no evidence-based recommendations [White et al.,2008]. While prompt and effective treatment is nowrecognized as essential and far outweighs the risk ofhaving malaria parasites in a pregnant woman’s body,there are remarkably few studies of antimalarial drugs inpregnancy [Nosten et al., 2007]. Of over 500 antimalarial

drug trials conducted between 1966 and December 2006,only 31 evaluated antimalarial treatments (includingintermittent preventive treatments) in pregnant women,and 14 of these were from a single centre [Myint et al.,2004]. Most of what is know about chloroquine usein pregnancy comes from research on autoimmunedisease in pregnancy [Costedoat-Chalumeau et al.,

DDR

Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ddr.20348

�Correspondence to: Rose McGready, Shoklo MalariaResearch Unit, PO Box 46, Mae Sot, Tak, Thailand, 63110.E-mail: rose@shoklo-unit.com

�c 2009 Wiley-Liss, Inc.

2003; Ostesen, 1994; Parke, 1988; Parke and West, 1996]and for quinine from its historical use [Dilling andGemmell, 1929; Maxwell, 1908]. Sulphadoxine-pyri-methamine has been widely advocated in pregnancywithout ever knowing the efficacy or until recently thepharmacokinetic properties of this drug in pregnantwomen [Green et al., 2007; Nyunt et al., 2009].

Measuring the efficacy of antimalarial drugs inpregnancy differs in a very important way from non-pregnant studies in that Plasmodium falciparum has theability to sequester in the placenta. In a recentlyconducted randomized controlled trial with artemisininsin pregnancy on the Thai-Burmese border, one third ofPCR-confirmed drug failures occurred after day 42 offollow-up, and as late as day 98. This has been reportedpreviously in Asia [Brockman et al., 1999; McGready et al.,2000] and Africa [Kalilani et al., 2007]. Treatment trials inpregnancy require a longer period of follow-up and abroader approach than treatment trials in non-pregnantpatients as two hosts are essentially under study. Thesample size of randomized controlled treatment trials ofmalaria are usually determined by the difference betweenthe expected efficacy of the trial drug and that of thecomparator. However, these trials are often underpoweredto describe safety in the mothers and their infants.

BACKGROUND

Malaria is the most important parasitic infectionin humans and in pregnancy is detrimental to both themother and fetus. The protozoan parasites, Plasmo-dium falciparum, P. vivax, P. malariae, P. ovale andrarely P. knowlesi are transmitted by the bite of asporozoite-bearing female anopheline mosquito.P. falciparum causes greater morbidity (maternal andfetal), principally low birth weight and anaemia, andmortality than non-falciparum infections [Desai et al.,2007]. After a period of pre-erythrocytic developmentin the liver, the blood-stage infection, which causes thedisease, begins. Parasitic invasion of the erythrocyteconsumes hemoglobin and alters the red cell mem-brane allowing it to cytoadhere (or stick) inside thesmall blood vessels of brain, kidneys, and other affectedorgans. P. falciparum–infected red cells may alsoadhere to uninfected red cells to form rosettes.Cytoadherence and rosetting of falciparum malariainterfere with microcirculatory flow and metabolism ofvital organs. The hallmark of malaria in pregnancy isparasites sequestered in the placenta. Sequesteredparasites evade the host defence mechanisms of splenicprocessing and filtration. Sequestration is not knownto occur in the benign malarias due to P. ovale andP. Malariae but is suspected in P. vivax.

In pregnancy the adverse effects of malariainfection arise from two main processes. The first is

from systemic infection, comparable to the effects ofany severe febrile illness in pregnancy, which causesmaternal/fetal mortality, abortion, stillbirth, and pre-mature delivery. The second is the parasitisation itself,which results in fetal growth restriction and low birthweight, maternal/fetal anemia, interaction with HIV,and susceptibility of the infant to malaria.

Lack of premunition, i.e., the degree of naturalacquired host immunity to malaria, or malaria-specificimmunity, results in the accumulation of parasites andinflammatory cells in the placenta, leading to pooroutcomes for both mother and baby, and in the case ofnon-immune women, pregnancy increases the risk ofsevere disease and death. A recent review of the burdenof MIP estimates that about 1 in 4 women in Sub-Saharan Africa in areas of stable transmission havemalaria at the time of delivery [Desai et al., 2007].Ideally, malarial infection (parasitation) during preg-nancy should be prevented but failing this (an increasingproblem due to drug resistance) prompt diagnosis andeffective treatment will prevent potentially fatal out-comes and reduce morbidity in mothers and infants.

METHODS

A literature search was performed using Medline(1983–2009). The keywords used were ‘‘malaria,’’‘‘severe malaria,’’ ‘‘P. falciparum,’’ ‘‘P. vivax,’’ ‘‘chloro-quine-resistant P. vivax,’’ ‘‘pregnancy,’’ ‘‘treatment,’’‘‘antimalarials,’’ ‘‘amodiquine,’’ ‘‘quinine,’’ ‘‘artemisi-nins,’’ ‘‘artesunate,’’ ‘‘mefloquine,’’ ‘‘chloroquine,’’ ‘‘ma-larone,’’ ‘‘clindamycin,’’ ‘‘artemether-lumefantrine,’’‘‘dihyroartemisinin-piperaquine,’’ ‘‘atovaquone-progua-nil,’’ ‘‘suphodoxine-pyrimethamine,’’ ‘‘malaria mortal-ity,’’ and ‘‘maternal mortality.’’ Nearly all of thepreceding words were used in combinations with thekeyword ‘‘pregnancy,’’ e.g., ‘‘P. falciparum’’ and ‘‘preg-nancy.’’ Reference lists of the articles identified werehand-searched for additional articles. Other sourcesincluded: malaria treatment guidelines from the UK,Centre for Disease Control (CDC), World HealthOrganisation (WHO), and Shoklo Malaria ResearchUnit (SMRU), as well as websites for malaria,travellers, and pregnancy. Where possible, recommen-dations are based on, and explicitly linked to, theevidence that supports them. Overall, there were 10randomized controlled trials (RCT) on the treatment ofP. falciparum in pregnancy [Bounyasong, 2001; Keuteret al., 1990; McGready et al., 2000, 2001b, 2005, 2008;Naing et al., 1988; Nosten et al., 1993; Sowunmi et al.,1998; Tagbor et al., 2006] and one on severe malariathat did not exclude pregnant women [Dondorp et al.,2005], 13 pharmacokinetic studies [Abdelrahim et al.,2007; Green et al., 2007; Massele et al., 1997;McGready et al., 2003b,c, 2006a,b; Na-Bangchang

57MALARIA TREATMENT IN PREGNANCY

Drug Dev. Res.

et al., 1994, 2005; Nosten et al., 1990; Nyunt et al.,2009; Phillips et al., 1986; Wangboonskul et al., 1993],and treatment and prevention trials that were observa-tional or descriptive.

PITFALLS IN TREATMENT OF UNCOMPLICATED MIP

Accidental exposure in the first trimester toantimalarials can be minimized by practising basic(essential) prescription procedures. Woman of child-bearing age should be asked if they could be pregnantbecause most of the commonly used antimalarialsshould not be prescribed in the first trimester. Thisshould be clearly explained. Where there is doubt,confirmation by urine pregnancy testing is helpful.Similar enquiries should be made to every patientregarding allergy. The diagnosis of malaria in pregnancy,as in non-pregnant patients, relies on microscopic (thecurrent gold standard) examination of thick and thinblood films for parasites, or the use of rapid diagnostictests that detect specific parasite antigens. An experi-enced microscopist can detect 15 parasites/mL of bloodin a thick film (well below the pyrogenic densitythreshold of symptoms in non-pregnant patients) usingsimple Field’s stain or Giemsa stain [Nosten et al., 2007].However, malaria in pregnancy is associated withdeleterious effects even at parasite densities below thelimit of detection of microscopy or rapid diagnostic tests.A negative test by microscopy is still compatible with atotal parasite biomass of 108 parasites that will bedeleterious to the mother and the fetus. In immunewomen, peripheral thick films can be negative whenthere are parasites in the placenta but these are onlydetectable at delivery when it is far too late to doanything about it. This means that the diagnosis ofmalaria in pregnancy is more difficult than in non-pregnant patients. In a febrile patient, 3 negative malariasmears (smear interval of 12–24 h) almost certainly rulesout malaria as the cause of fever but patients who mayhave taken prophylaxis that can suppress the parasitae-mia below the level of microscopic detection (totalbiomass 108 parasites) need to be taken into account.

Treatment response in the presence of resistanceto antimalarial drugs depends on the grade ofresistance and the immune response of the patient.At low levels of resistance, the patient may appear to bebetter for some weeks before symptoms recur. When adrug fails to suppress circulating parasitaemia, thepatient symptoms will fail to be resolved by treatmentand the risk of morbidity and mortality is high [Priceet al., 2004; Roper et al., 2003; Wernsdorfer, 1994;White, 1999]. Logically, this means that a woman with abreakthrough episode of malaria whilst on prophylaxisshould not be treated with the same drug, wherealternative treatment is available. Similarly, a woman

with parasite reappearance following treatment is bestnot treated with the same antimalarial again. Evidencesupporting this was documented while treating womenin an area with high levels of multidrug-resistant strainsof P. falciparum (MDR-Pf) in descriptive studiespublished 10 years ago [McGready and Nosten,1999]. In the early years of artemisinin use inpregnancy on the Thai-Burmese border, artesunatewas reserved for women with multiple treatmentfailures. The standard treatments of quinine andmefloquine were favoured as first- and second-linetreatment under the assumption that more was knownabout their safety in pregnancy than on the effects ofartemisinin. Women with a third reappearance weretreated with an artemisinin derivative as a last resort.Retreatment, compared to primary treatment inpregnancy, with quinine and mefloquine, resulted in anear doubling of the failure rates (Table 1).

This evidence has been further verified inpregnancy with PCR genotyping data in a recentlypublished trial of artemisinin-based combination therapy[McGready et al., 2008]. The PCR confirmed failurerates of women who entered the study with a PCRconfirmed failure of a previous episode rather than asnovel or primary infections, were significantly higherwith the use of 3 days of artemether-lumefantrine: 26.1(12–40.8; 95% CI)% compared to 7 days of artesunatemonotherapy: 8.9 (0–21.2)%, P 5 0.034.

The following drugs should not be given inpregnancy: primaquine, which is associated withneonatal hemolysis and methemoglobinaemia; tetracy-cline/doxycycline, which can cause dental discolourationand maternal hepatoxicity with large parenteral doses;and halofantrine, which should not be used because ofsignificant and potentially fatal cardiotoxicity.

In any case of MIP, treatment with antimalarialsshould not be delayed regardless of whether thewoman has symptoms or not. Even asymptomatictreated episodes (even a single episode) are associatedwith a reduction of birth weight and anemia. This istrue for falciparum [Nosten et al., 1991] and vivax[Nosten et al., 1999a].

THE OBJECTIVES OF TREATMENT

The objective of treatment of uncomplicatedmalaria is to cure the infection to prevent diseaseprogression and reduce morbidity [WHO, 2006]. Inendemic areas, there is the public health goal ofreducing the transmission of infection to others andpreventing the emergence and spread of resistance toantimalarials. The prophylactic effect of antimalarials isan important consideration in pregnancy as preventioncan reduce the number of parasitemic episodes and,

58 MCGREADY AND NOSTEN

Drug Dev. Res.

hence, the detrimental effects of MIP. In severemalaria, the aim is only to prevent death and reducethe risk of severe complications in the mother. Inpregnancy, there is the additional objective of avoidingharm to the fetus but the life of the mother always takespriority. In severe (or cerebral) malaria in pregnantwomen, the death of the fetus is almost alwaysinevitable. Table 2 provides a summary of treatmentsaccording to species, severity, trimester, and evidence.

TREATMENT OF UNCOMPLICATED MALARIA IN THE1ST TRIMESTER OF PREGNANCY

The risk of teratogenicity from quinine, chlor-oquine, or proguanil is low [Levy et al., 1991;McGready et al., 2002; Nosten et al., 2007; Phillips-Howard et al., 1998]. Of these, quinine remains themost effective and clindamycin augments its efficacy[McGready et al., 2001b] and is safe in the firsttrimester. Inadvertent exposure to antimalarials is notan indication for termination of pregnancy.

WHO has held two informal consultations todiscuss the role of artemisinin derivatives in pregnancy[WHO, 2003]. At that time, there were only 124women exposed in the first trimester with documentedoutcome and these were normal. The conclusions werethat there was insufficient evidence to support the useof artemisinin derivatives in the first trimester butthese should not be withheld if the life of the motherwas endangered and other antimalarials were consid-ered unsuitable. Published data now totals 183 women[Adam et al., 2004, 2009; McGready et al., 2001a;Poespoprodjo et al., 2008] indicating the (low) speed atwhich reliable data can be accumulated. In terms ofsevere malaria where the only aim is to preventmaternal death, iv artesunate is clearly superior to ivquinine and should be used [Dondorp et al., 2005].

TREATMENT OF UNCOMPLICATED MALARIA IN THE2ND AND 3RD TRIMESTERS OF PREGNANCY

If quinine must be used, efficacy can be improvedby combination with clindamycin [McGready et al.,2001b]. Quinine and clindamycin are best giventogether tid for 7 days. Given the disadvantages ofquinine, which include long treatment, high risk of sideeffects, and increased risk of hypoglycaemia, artemisi-nin combination therapies are considered preferablefor these trimesters. The evidence in support of the useof artemisinin combination therapy rather than mono-therapy results from studies in non-pregnant patientsand documented in systematic review and meta-analysis of individual data from 16 randomizedcontrolled trials (RCT) (total of 5,948 people) [Adjuiket al., 2004]. The current assessment of benefitscompared with potential risks suggests that theT

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59MALARIA TREATMENT IN PREGNANCY

Drug Dev. Res.

artemisinin deriviatives should be used to treatuncomplicated falciparum malaria in the 2nd and 3rdtrimesters [Dellicour et al., 2007; Nosten et al., 2006,2007; WHO, 2006] with experience in more than 1,500documented pregnancies [Adam et al., 2004, 2006;

Bounyasong, 2001; Deen et al., 2001; McGready et al.,1998, 2000, 2001a,b, 2003a, 2006a,b, 2008; Rijkenet al., 2008; Sowunmi et al., 1998; Wang, 1989]. Therehave been no documented adverse effects attributableto the artemisinins on the mother or fetus (Table 3).

TABLE 2. Treatment of MIP Based on Species, Trimester and Severity�

Species and trimester Severity Treatment Evidence

P. vivax, P ovale andP. malariaeRegardless oftrimester

Not usually severe Ifsevere, seeP. falciparum (severe)

Chloroquine phosphate (one tablet contains250 mg salt equivalent to 155.3 mg base).Doses 10 mg/kg base once a day for 2 daysfollowed by 5 mg/kg base on the 3rd day.For chloroquine 5 resistant P. vivax,amodiaquine, quinine, or artemisininderivatives can be used

[McGready et al., 2002; Nostenet al., 1999a]

1st trimesterP. falciparum ormixed species

Uncomplicated Primary episode: quinine 10 mg/kg 3 timesdaily for 7 days, preferably withclindamycin 5 mg/kg 3 times daily for 7daysa

[McGready et al., 2001b, 2002]2nd ref RCT, but not in1st trimester

Subsequent episodes: repeat treatment withquinine and clindamycin (as above); ACTthat is locally effective or artesunate2 mg/kg per day for 7 days withclindamycin (as above)a

[Deen et al., 2001; McGreadyet al., 2001a]

2nd and 3rd trimestersP. falciparum ormixed species

Primary episode: artemisinin basedcombination that is locally effective, orartesunate plus clindamycin as above.Malarone (atovaquone-proguanil) alonecan be used for treatment in pregnancy butit is highly recommended to use it withartesunate to maximize fever and parasiteclearance times and ensure cure andreduce resistance emergingb,c

15 studies 5 RCT [Bounyasong,2001; Keuter et al., 1990;McGready et al., 2000,2001b, 2005, 2008; Sowunmiet al., 1998] and 8 descriptive[Adam et al., 2004, 2006;Deen et al., 2001; McGreadyet al., 2001a, 2003a, 2006a,b;Wang, 1989]

Subsequent episodes: artesunate plusclindamycin as above.a Artesunate-atovaquone-proguanil anddihyrartemisinin piperaquine can be usedfor P. falciparum recurrence in the samepregnancy

[McGready et al., 2003a; Rijkenet al., 2008]

Regardless of trimester UncomplicatedHyperparasitaemia

Artesunate oral: start with 4 mg/kg loadingdose then 2 mg/kg every 24 h for 7 dayswith clindamycin as abovea OR IV quinine(see below)

Regardless of trimester Severe Artesunate 2.4 mg/kg IV at h 0, 12 and 24 hthen every 24 h until the patient cantolerate oral artesunate 2 mg/kg per dose,for a total of 7 days, and clindamycin5mg/kg 3 times daily for 7 daysa OR QuinineIV: loading dose 20 mg/kg given over 4hthen 10mg/kg 8h after the loading dose wasstarted, followed by 10mg/kg every 8h for 7days. Once the patient has recoveredsufficiently to tolerate oral medicationboth quinine 10mg/kg and clindamycin5mg/kg, three times daily should becontinued for/until 7 days

Ib [Dondorp et al., 2005] andpregnant women notspecifically excluded

aWhen clindamycin is not available, give artesunate monotherapy [McGready et al., 2001a, 2008].bMalarone use in pregnancy [McGready et al., 2003a,b, 2005; Na-Bangchang et al., 2005].cPrescribe artemether-lumefantrine, and dihydroartemisinin-piperaquine with fat, e.g., 200 mL of milk [Ashley et al., 2007; Sim et al., 2005].�Any clinical deterioration in a patient on oral treatment should be regarded as a signal to change to parenteral treatment [WHO, 2006]. Thehigher biomass of parasites in hyperparasitaemia requires a longer treatment course, usually of 7 days.

60 MCGREADY AND NOSTEN

Drug Dev. Res.

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14

58

(90.6

)0

57

(98.3

)2840-

1(1

.7)

01

(1.8

)12

mth

50

(87.7

)

[McG

read

yet

al.,

2001a]

,TB

Bf

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57.5

^A

S1

/�oth

er(2

49)

N.A

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mg/

kg(3

–7d)

12–1

4214

(85.9

)15

(7.0

)195

(91.1

)2782

4(1

.9)

3(1

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N.A

.N

.A.

[Sow

unm

iet

al.,

1998],

Nig

eria

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3)

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stat

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mg/

kg(5

d)

or

3.2

(1d)

4–1

245

(100)

045

(100)

3100-

3200

00

06–1

2m

th21

(46.7

)

[Adam

etal

.,2004],

Sudan

DES

^A

MIM

(28)

N.A

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mg

6dose

s(5

d)

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28

(100)

028

(100)

3190

00

1(3

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N.A

.

[McG

read

yet

al.,

2003a]

,TB

B

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^A

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P(2

7)

N.A

.4

mg/

kg(3

d)

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27

(100)

027

(100)

2670

00

1(3

.7)

1m

th27

(100)

[McG

read

yet

al.,

2003b],

TB

B

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(27)

N.A

.4

mg/

kg(3

d)

12

24

(88.8

)0

24

(100)

2850

00

0N

.A.

61MALARIA TREATMENT IN PREGNANCY

Drug Dev. Res.

TA

BLE

3.

Conti

nued

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mg/

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n(%

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n(%

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n(%

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P(3

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ine(

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38

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34

(89.5

)2763

02

(5.2

)1

(2.9

)12

mth

17

(50.0

)

[Adam

etal

.,2006],

Sudan

DES

^A

S1SP

(32)

N.A

.4

mg/

kg(3

d)

12

32

(100)

032

(100)

3270

00

1(3

.1)

1m

th30

(96.8

)[K

alil

ani

etal

.,2007]

RC

TA

S1SP

(47)

SP1

AZ

(47)

SP(4

7)

200

mg/

day

(3d)

12

38

(80.9

)0

34

(72.3

)2836-

4(8

.5)

03

(8.8

)1

mth

31

(91.2

)[D

ondorp

etal

.,2005],

SEA

sia

RC

TA

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(23)

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(26)

2.4

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l(7

d)

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.A.

N.A

.N

.A.

N.A

.N

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N.A

.N

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N.A

.

[Rijke

net

al.,

2008],

TB

BD

ES^

DH

A1

PPQ

(50)

N.A

.4

mg/

kg(3

d)

12

45

(90)

045

(90)

2816

02

(4.4

)1

(2.2

)1

mth

44

(97.8

)[P

oes

popro

djo

etal

.,2008],

Wes

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ua

DES

DH

A1

PPQ

or

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DH

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PPQ

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94)

2.2

mg/

kg(7

d)

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0111

(100)

N.A

N.A

N.A

.N

.AN

.AN

.A.

N.A

.

[McG

read

yet

al.,

2008],

TB

B

RC

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M-L

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25)

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N.A

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mg/

kgB

ID(3

d)

AS

2m

g/kg

(7d)

12–1

4122

(97.6

)123

(96.0

)

01

(0.8

)120

(98.4

)117

(95.1

)

2861-

2805

1(0

.2)

1(0

.2)

2(1

.7)

4(3

.3)

1(0

.8)

5(5

.1)

12

mth

93

(77.5

)85

(72.6

)

[Muta

bin

gwa

etal

.,2009]

Tan

zania

RC

TA

Q1

AS

(83)

SP(2

8)

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AS

4m

g/kg

(3d)

12

79

(95.2

)0

76

(96.2

)3200-

3(3

.8)

3(3

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3(3

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6w

k(9

6.0

)

[Adam

etal

.,2009],

Sudan

DES

AM

IM(4

8)

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SP(1

1)

AL-

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)

N.A

.N

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12–1

462

(100)

2(3

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60

(96.8

)3021

00

012

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[Pio

la,

2008,

Uga

nda

RC

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M-L

F(1

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AM

1.6

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kgB

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114

(83.2

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(1.8

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(95.6

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3(2

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4(3

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12

mth

N.A

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group.

62 MCGREADY AND NOSTEN

Drug Dev. Res.

The choice of the partner drug for an artemisininderivative relies on it being independently effective andhaving a different mode of action to artemisinin[Chawira et al., 1987; Curtis and Otoo, 1986; Peters,1969, 1987, 1990; White et al., 1999]. Artemisinin and itsderivatives are rapidly eliminated. When given incombination with rapidly eliminated and slow-actingcompounds (e.g., clindamycin), a 7-day treatment courseis required; but when given in combination with a slowlyeliminated antimalarial (e.g., piperaquine or meflo-quine), shorter courses (3 days) of treatment areeffective. In pregnancy, the choice of combinationpartner is difficult. Mefloquine has been associated withan increased risk of stillbirth in Thailand [Nosten et al.,1999b] but not in Malawi [Steketee et al., 1996a,b], thesafety of pyronaridine is unknown, and the othercandidates are lost to resistance: sulphadoxine-pyri-methamine and amodiaquine. The data on fixed andnon-fixed ACT remain sparse for the moment but trialsare in progress. Artemether-lumefantrine, dihyroartemi-sinin-piperaquine [Poespoprodjo et al., 2008; Rijkenet al., 2008], and artesunate-atovaquone-proguanil[McGready et al., 2003a,b, 2005] are better toleratedthan quinine and result in faster fever and parasiteclearance times but they must be given with fat [Ashleyet al., 2007; Sim et al., 2005]. The sub-optimal efficacy[McGready et al., 2008] and lower drug concentration[McGready et al., 2006a] of artemether-lumefantrine inpregnancy suggest it is not suitable for use in areascomplicated by a high level of MDR P. falciparum.Pharmacokinetic modelling suggests higher dosing willlead to improved cure rates [Tarning et al., 2009] but nostudies have examined this yet. What does this mean inpractice? If artemether-lumefantrine is the only anti-malarial available in the hospital, then it can beprescribed but higher cure rates are likely to be achievedwith 7 days of artesunate (or quinine) and clindamycin.

Sulphadoxine-pyrimethamine and atovaquone-proguanil are not recommended for treatment inpregnancy if they have been given for prophylaxis.Although chloroquine and sulphadoxine-pyrimetha-mine are recognized as failing treatments, they stillappear in randomized controlled treatment trials. Inthe Gambia, chloroquine, sulphadoxine-pyrimethamine(SP), amodiaquine, or amodiaquine plus sulphadoxine-pyrimethamine were used in randomized trials to treatparasitaemic pregnant women in the 2nd and 3rdtrimester. Chloroquine and SP failed to reach the 95%cure rates recommended by WHO to accept a drug asefficacious [WHO, 2006]. PCR-corrected parasitologi-cal failure by day 28 was 14, 11, 3, and 0% in thewomen assigned chloroquine, sulphadoxine-pyrimetha-mine, amodiaquine, and amodiaquine plus sulpha-doxine-pyrimethamine, respectively (Po0.0001). The

unacceptably low 28-day cure rate with SP was notmentioned in the discussion. There were no major toxicside effects although minor side-effects were moreoften reported on day 3 by those women treated withamodiaquine (86%) or amodiaquine plus sulphadoxine-pyrimethamine (90%) than those receiving sulphadox-ine-pyrimethamine (48%). In Tanzania, 1,433 womenwere screened and 272 were randomized to one offour study arms: sulfadoxine-pyrimethamine, chlorpro-guanil-dapsone, SP1amodiaquine, or amodiaquine1

artesunate. The day-28 PCR confirmed failure rateswere 18% for CD, 1% for SP1AQ, and 4.5% forAQ1AS. The high failure rates for monotherapy wereacknowledged. Chlorproguanil-dapsone is no longer indevelopment because of the risk of severe hemolysis.

THE PROBLEM WITH QUININE

Quinine is almost universally relied upon as thefall-back treatment for malaria in pregnancy. However,quinine has significant side-effects, principally cinch-onism and hypoglycaemia [Nosten et al., 2007] and thisfrequently leads to failure of the 7-day treatmentcourse due to non-compliance [Bunnag et al., 1996;Denis, 1998; Fungladda et al., 1998; Lasserre, 1989;White, 1998]. For this reason, directly observedtherapy for each dose of quinine [Abdel-Hameed,2001; Fungladda et al., 1998] is advisable.

VOMITING ANTIMALARIALS AND PREGNANCY

Vomiting is a known side-effect of quinine [Bolandet al., 1985; Phillips-Howard and Wood, 1996; Whiteet al., 1982] and mefloquine [Palmer et al., 1993; terKuile et al., 1995] and is associated with antimalarialtreatment failure [White, 1998]. If the woman vomitsrepeatedly within the first hour after treatment,consideration should be given to the use of parenteraltreatment. Antipyretics can control the fever and anantimetic can control nausea and vomiting [Matok et al.,2009] although there are no studies of their efficacy inmalaria in pregnancy [WHO, 2006]. Vomiting in the firsthalf hour after requires readministration of the fulltreatment dose. Further vomiting is a definite indicationfor parenteral treatment.

TREATMENT OF SEVERE MALARIA IN PREGNANCY

Treatment of severe malaria in pregnancy is amedical emergency and ideally patients should beadmitted to an intensive care facility without delay.Antimalarial drugs recommended to treat severemalaria in pregnancy are artesunate iv, artemetherim, and parenteral quinine. Artesunate and artemetherare faster acting and do not cause hypoglycaemia. In arandomised trial, where pregnant women were not

63MALARIA TREATMENT IN PREGNANCY

Drug Dev. Res.

excluded, iv artesunate (2.4 mg/kg initial dose and at12 h, followed by 2.4 mg/kg qd) reduced mortality inAsian adults by 35% compared with iv quinine[Dondorp et al., 2005]. Artemether im can also beused to treat severe malaria but absorption is lesspredictable than that of artesunate, especially inpatients with cardiovascular collapse. When artemetherand artesunate are not available, parenteral quininewith a loading dose (20 mg/kg) is recommended.Quinine frequently causes hyperinsulinemia and hy-poglycemia in pregnant women that can be profoundand intractable [Davis et al., 1994; Looareesuwan et al.,1985; White et al., 1983]. Artesunate has not achievedGMP certification, but it has received the OrphanMedicinal Drug Designation from the EuropeanMedicines Agency (www.emea.europa.eu/pdfs/human/comp/opinion/48693207en.pdf) and may be obtainedfrom IDIS Pharma (www.idispharma.com). Treatmentshould commence with parenteral quinine if there willbe a delay in acquiring injectable artesunate. Compli-cations of severe malaria should be managed accordingto WHO malaria treatment guidelines [WHO, 2006].

TREATMENT OF P. vivax: CHLOROQUINE-SENSITIVEAND -RESISTANT

At least for P. vivax, the adverse effects ofinfection, maternal anaemia, and low-birth weight aresimilar but not as severe as infection with P. falciparum[Nosten et al., 1999a; Poespoprodjo et al., 2008; Singhet al., 1998]. It is not unreasonable to assume P. ovaleand P. malariae would have similar adverse effects asP. vivax in pregnancy but there are no data to supportthis. The fever of P. vivax is associated with prematurelabour and as for P. falciparum requires prompttreatment and effective antimalarials.

Evidence from non-pregnant patients has demon-strated that chloroquine-resistant P. vivax should betreated in the same way as chloroquine-resistantP. falciparum. [Baird et al., 1991; Poespoprodjo et al.,2008; Pukrittayakamee et al., 2001; Ratcliff et al.,2007a,b]. Artemisinin-based combination therapies(except artesunate-sulphadoxine pyrimethamine) are,therefore, indicated [WHO, 2006]. Women in the firsttrimester of pregnancy should be treated with quinine.Severe P. vivax malaria can be treated with parenteralquinine or artesunate [Tjitra et al., 2008]. Primaquineused to treat liver stages of P. vivax crosses the placentaand is absolutely contraindicated in pregnancy.

PHARMACOKINETIC STUDIES OF ANTIMALARIALSIN PREGNANCY

An essential determinant of drug efficacy is thepresence of the drug in the blood circulation (or itsmetabolites) for a duration and at a concentration

sufficient to eliminate all parasites. There are very fewstudies of the pharmacokinetics of antimalarials duringpregnancy [Ward et al., 2007]. Most of those publishedare from Karen pregnant women on the Thai-Burmeseborder. These studies have shown that the disposition ofmost antimalarials is altered during pregnancy[McGready et al., 2003b,c, 2006a,b; Nosten et al.,1990]. This is explained either by the physiologicalchanges induced by gestation (increase in the volume ofdistribution, and in the glomerular filtration, reduction ofthe intestinal transit and the gastric emptying), orhormonal changes that impact on the functions of theliver cytochromes. Artesunate (and its metabolite DHA),artemether, lumefantrine, and atovaquone all have lowerplasma concentrations during pregnancy as comparedwith non-pregnant patients. Proguanil bio-transformationinto the active cycloguanil is impaired by pregnancy.These changes translate into lower parasitologicalefficacy of the drugs when given to pregnant women.Recently, the kinetics of SP were reported and it appearsthat this drug has been used and recommended for manyyears at a suboptimal dose [Green et al., 2007; Nyuntet al., 2009]. There is an urgent need for information inthe kinetics of mefloquine, quinine, and other drugsin different populations as genetic factors could result indifferences in the dispositions of these drugs. It is criticalthat information be obtained on the relationship betweenday-7 blood levels and efficacy in treatment (and forIPTp) for mefloquine, piperaquine, and lumefantrineand between venous and capillary sampling, as it may notbe the same as in non-pregnant patients due to alteredphysiology. Interactions with ARVs must also be studiedas the two infections often coexist [Nosten et al., 2006].

CONCLUSIONS

What is the Best Drug for Treatment of Malariain Pregnancy?

This question has no single correct answer.Efficacy depends upon the country of origin of thewoman, the use of antimalarial prophylaxis, theinfecting species and country of origin where malariawas acquired, whether the patient is under treatmentfor a primary or recrudescent infection, the severity ofmalaria, the gestational age of the pregnancy, and thehistory of drug allergies in the patient. In mostresource-poor settings, the final choice is likely to relyon drug availability and cost. Progress in antimalarialdrug trials in pregnancy is slow because the emphasis isoften on the safety for the fetus and this translates intoa long period of follow-up in the first year of life. Inparts of the world where women are infected withmultidrug-resistant strains of P. falciparum, the choiceof antimalarials is severely restricted. Until now, there

64 MCGREADY AND NOSTEN

Drug Dev. Res.

is no safe, efficacious, and affordable 3-day treatmentfor pregnant women. Compliance with 7-day regimensis poor. The fixed ACTs including dihyroartemisinin-piperaquine and mefloquine-artesunate are the mostlikely candidate drugs for this indication assumingartesunate does not also fall to resistance.

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