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Safety, efcacy and determinants of effectiveness of

antimalarial drugs during pregnancy: implications for


prevention programmes in Plasmodium falciparum-endemic
sub-Saharan Africa
Robert D. Newman
1,2
, Monica E. Parise
1
, Laurence Slutsker
1
, Bernard Nahlen
1,3
and Richard W. Steketee
1
1 Malaria Epidemiology Branch, Division of Parasitic Diseases, CDC, Atlanta, GA, USA
2 Epidemic Intelligence Service, Division of Applied Public Health Training, CDC, Atlanta, GA, USA
3 Roll Back Malaria, World Health Organization, Geneva, Switzerland
Summary Plasmodium falciparum malaria in pregnancy poses substantial risk to a pregnant woman and her
neonate through anaemia and low birth weight (LBW), respectively, and is responsible for up to 35% of
preventable LBW in malaria-endemic areas. Chemoprophylaxis or intermittent preventive treatment
(IPT) with an effective antimalarial can ameliorate the adverse effects of malaria during pregnancy.
Current guidelines from the WHO recommend that women in highly malarious areas receive IPT with
an effective antimalarial. Two central considerations in evaluating drugs for use during pregnancy are
safety for the mother and her foetus and effectiveness, which is determined by efcacy, cost, availability,
deliverability and acceptability of the drug. These factors may be scored and potential drugs or drug
combinations ranked in order of potential effectiveness for use in prevention programmes. The seven
most promising regimens are all IPT, primarily because they are more easily delivered and less expensive
than chemoprophylaxis. Currently, IPT with sulphadoxinepyrimethamine (SP) is more likely to have
the best overall effectiveness in preventing adverse outcomes associated with malaria in pregnancy. Its
low cost, wide availability, easy deliverability and acceptability make it the clear choice in countries
where efcacy of the drug remains good. For countries where resistance to SP is rising or already high,
amodiaquine (alone or in combination with SP or artesunate) artesunate + SP, chlorproguanildapsone
(with and without artesunate) and artemetherlumefantrine require urgent evaluation for use in
pregnancy.
keywords malaria, drug therapy, antimalarials, drug safety, pregnancy, primary prevention
Introduction
Malaria is an enormous global health problem and most of
the disease burden affects young children and pregnant
women. The adverse impact of malaria in pregnant women
is largely caused by Plasmodium falciparum; approxi-
mately 90% of P. falciparum clinical cases globally occur
in sub-Saharan Africa. This year, there will be approxi-
mately 50 million pregnancies in women living in malar-
ious areas, of which approximately half will occur in sub-
Saharan Africa (Steketee et al. 2001).
Malarial infection during pregnancy poses substantial
risk to the mother, her foetus and the neonate. In areas of
low transmission of P. falciparum, women do not acquire
substantial antimalarial immunity and are susceptible to
episodes of severe malaria, which may result in stillbirths,
spontaneous abortions, or maternal death. In areas of high
transmission of P. falciparum, where adult women have
considerable acquired immunity, women may have
asymptomatic infections or be minimally symptomatic, but
such infections can contribute to maternal anaemia and
cause placental parasitaemia, both of which may subse-
quently lead to low birth weight (LBW) (Steketee et al.
1996c). Prevalence of parasitaemia is greatest in the second
trimester (Brabin 1983), and susceptibility to clinical
malaria appears higher in both second and third trimesters
(Diagne et al. 2000). Although there are fewer data about
the role of P. vivax, there is evidence that it may also lead
to anaemia and LBW (Nosten et al. 1999a). LBW is an
important contributor to neonatal mortality (McCormick
1985; McDermott et al. 1996). It is estimated that malaria
in pregnancy is responsible for 512% of all LBW, 35% of
Tropical Medicine and International Health
volume 8 no 6 pp 488506 june 2003
488 2003 Blackwell Publishing Ltd
LBW that is preventable during pregnancy (Steketee et al.
1996a), and contributes to 75,000200,000 infant deaths
each year (Steketee et al. 2001).
Current guidelines from the WHO Expert Committee on
Malaria suggest a package of interventions for pregnant
women to combat malaria during pregnancy (WHO2000a).
Those interventions include intermittent preventive treat-
ment (IPT), insecticide-treated nets, malaria case manage-
ment and treatment of anaemia. Two of these
interventions, IPT and case management, require the use of
antimalarial drugs. In this paper, we review antimalarial
drugs and their potential for programmatic use to prevent
the consequences of malaria in pregnancy.
The two major issues for considering antimalarial drug
use in a programme for prevention or management of
malaria in pregnant women are safety and effectiveness.
First, is the drug toxic to the woman or foetus during
pregnancy, or to the infant during lactation? Safety is, of
course, a central tenet of malaria prevention. Secondly, is
the drug use strategy and its implementation likely to have
its desired effect reduce the burden of malaria in
pregnancy? Programme effectiveness is determined by the
efcacy of the drug against the parasite and the charac-
teristics of the drug when used programmatically. These
characteristics include: affordability and availability of the
drug; deliverability (dosing requirements and ease of
incorporation into existing antenatal care delivery sys-
tems); and acceptability to the population. Although a drug
may be safe and efcacious, it may prove a poor choice for
prevention programmes because of high cost, poor avail-
ability, unfavourable dosing scheme, or unacceptable side
effects; such a drug will fail in the transition from efcacy
to effectiveness.
Methods
We searched the medical literature from 1966 to the
present using both Pubmed and Ovid by several strategies:
(1) each drug name as a keyword, (2) antimalarials and
pregnancy, and (3) malaria and pregnancy. Relevant
articles were then reviewed for inclusion. Where appro-
priate, articles prior to 1966 and chapters in textbooks
were also reviewed. A scale for estimating the programme
effectiveness potential for each drug was developed a priori
(as outlined below).
Safety
For an antimalarial to be considered for use in pregnancy,
it must be safe for the mother, the foetus and later for the
breast-feeding infant. However, safety is a relative term
and it is difcult to unequivocally prove safety. There are
inherent limitations in these drug safety data in pregnancy.
For some drugs, there are years of programmatic experi-
ence to suggest that a drug is generally safe for use during
pregnancy. Sometimes there are no data at all from use in
pregnant women. At other times, a drug may be a new
combination of component drugs where the individual
drugs are considered to be safe in pregnancy, but for which
there are no data on the combination. Ultimately, we have
widely varying amounts of information on antimalarial
drugs that allow us to broadly categorize them as (1) useful
for a pregnant woman, as there are extensive data from
programmatic use during pregnancy, (2) possibly useful for
a pregnant woman, but more data are needed, or (3) not
useful for a pregnant woman because they have known
adverse events associated with their use in pregnancy, and
safe and efcacious alternatives exist. Drugs in this third
category are not considered further in the paper, as efcacy
and effectiveness are irrelevant in the face of poor or
questionable safety. Finally, at the end of this section, we
briey review safety concerning antimalarial use during
lactation.
Drugs generally considered safe in pregnancy
A number of antimalarial compounds have received
widespread programmatic use during pregnancy, and are
thought to be safe, although overdoses and idiosyncratic
reactions could lead to detrimental effects on the mother
and/or the foetus.
Chloroquine (CQ), perhaps the most widely used anti-
malarial, is generally considered safe in all trimesters of
pregnancy (Phillips-Howard & Wood 1996; WHO 1979).
Children born to a cohort of 169 non-immune women who
took CQ chemoprophylaxis throughout pregnancy had no
more birth defects than 454 births to women who had not
received CQ (Wolfe & Cordero 1985). Among >2500
women who received CQ (as IPT or weekly chemoproph-
ylaxis), there was no reported increase in abortions,
stillbirths, or congenital abnormalities, although there were
frequent non-severe side effects such as itching, dizziness
and gastrointestinal complaints (Steketee et al. 1996d).
There are reports of increased spontaneous abortions,
particularly in patients with systemic lupus erythematosus
treated with high doses of CQ over prolonged periods
(Levy et al. 1991), and in some settings, CQ has gained a
reputation as an abortifacient at higher doses. CQ over-
doses have been responsible for numerous deaths (Weniger
1979), but its abortifacient effects appear to be limited to
these very high doses that are life-threatening to the
mother.
In many countries, quinine remains the principal treat-
ment for severe malaria. It has been associated with
Tropical Medicine and International Health volume 8 no 6 pp 488506 june 2003
R. D. Newman et al. Antimalarials during pregnancy
2003 Blackwell Publishing Ltd 489
teratogenic effects and damage to foetal optic and auditory
nerves when taken at very high (abortifacient) doses (West
1938; McKinna 1966; Dannenberg et al. 1983; Briggs
et al. 1998), but should be considered safe in pregnancy
when taken at normal therapeutic doses (Looareesuwan
et al. 1985; Phillips-Howard & Wood 1996). There is,
however, a risk of hyperinsulinaemia and subsequent
hypoglycaemia in women who take quinine (Looareesu-
wan et al. 1985). The related compound, quinidine, is also
considered safe in pregnancy (Briggs et al. 1998). There are
no reports of congenital abnormalities associated with its
use during pregnancy, although there have been reports of
neonatal thrombocytopenia after maternal use (Briggs
et al. 1998).
Proguanil is generally considered safe during pregnancy.
A cohort of pregnant travellers who took proguanil in
combination with CQ had no higher rates of spontaneous
abortions or congenital anomalies than the expected
background rate (Phillips-Howard et al. 1998). A study in
Nigeria found no increase in adverse outcomes among
pregnant women receiving daily proguanil (100 mg) in
addition to weekly CQ (Fleming et al. 1986). Another
study in Tanzania found no increase in adverse outcomes
among women receiving proguanil alone or in combination
with weekly CQ compared with those receiving CQ alone
(Mutabingwa et al. 1993).
Sulphonamides are also generally considered safe in the
second and third trimesters of pregnancy. Although there is
very limited evidence that sulpha drugs may be associated
with kernicterus when given to premature neonates (Silv-
erman et al. 1956), this problem has not been noted in
studies of IPT where sulphadoxinepyrimethamine (SP)
was administered to the mother (Parise et al. 1998;
Verhoeff et al. 1998; Shulman et al. 1999). Studies exam-
ining the risk to the foetus from in utero exposure to SP
combination have generally not found any increased risk in
spontaneous abortions or congenital defects (Anonymous
1983; Parise et al. 1998; Verhoeff et al. 1998). A retro-
spective study of antifolate drugs given before and during
pregnancy found that there was an increased risk of birth
defects when such drugs were taken during the rst
trimester, but not during the second or third trimester
(Hernandez-Diaz et al. 2000). When given weekly as
prophylaxis, SP has been associated with rare and severe
cutaneous reactions such as toxic epidermal necrolysis and
StevensJohnson syndrome (Miller et al. 1986); there is no
evidence that this risk is any greater in pregnant women.
In summary, these drugs are considered safe in the second
and third trimesters of pregnancy.
Pyrimethamine is usually given in combination with
sulphadoxine (see section above). However, studies in
which pyrimethamine has been given alone have also found
no increase in adverse pregnancy outcomes (Morley et al.
1964).
Dapsone has been used extensively in pregnant women
with leprosy, without reported adverse effects (Kahn
1985). Studies in which dapsone was given in combination
with pyrimethamine (Maloprim
1
) for malaria chemo-
prophylaxis during pregnancy had no increase in adverse
pregnancy outcomes (Greenwood et al. 1989, 1994;
Menendez et al. 1994). However, a severe hypersensitivity
syndrome has been described in a non-pregnant woman
receiving weekly Maloprim (Grayson et al. 1988). Addi-
tionally, occasional reports have been received of non-
pregnant patients developing agranulocytosis following
Maloprim chemoprophylaxis, although usually after twice-
weekly dosing, which is no longer recommended (Bruce-
Chwatt & Hutchinson 1983). A study using dapsone in
combination with SP in children found no serious adverse
effects (Mutabingwa et al. 2001b). Dapsone is most often
used currently with chlorproguanil (as Lapdap, see below).
Clindamycin has been used routinely as an antibiotic
in pregnancy without any evidence of adverse effects
(Dinsmoor & Gibbs 1988; Zambrano 1991; Briggs et al.
1998). Although the drug does cross the placenta and does
accumulate in foetal tissues perhaps to the point of
therapeutic levels (Philipson et al. 1973), there is no
evidence that this accumulation is harmful. A recent trial in
quinine comparing quinineclindamycin with artesunate
for the treatment of falciparum malaria during pregnancy
found no serious adverse events, no increase in stillbirths or
congenital anomalies above expected levels, and no
negative impact on infant development (McGready et al.
2001b).
Drugs with questionable safety during pregnancy
or with insufcient data
For a number of other drugs there are some concerns of
safety in pregnancy, or there are limited data about their
use during pregnancy.
Amodiaquine (AQ), a 4-aminoquinoline related to CQ,
falls under the category of antimalarials about which there
are insufcient data to be certain about their use in
pregnancy. In non-pregnant women taking AQ for chemo-
prophylaxis, there have been reports of agranulocytosis
and granulocytopenia (Hatton et al. 1986; Neftel et al.
1986), hepatitis (Larrey et al. 1986; Bernuau et al. 1988),
and increases in serum aspartate aminotransferase (AST)
levels (Sturchler et al. 1987). A study comparing AQ with
1
Use of trade names is for identication only and does not
imply endorsement by the Public Health Service or by the
US Department of Health and Human Service.
Tropical Medicine and International Health volume 8 no 6 pp 488506 june 2003
R. D. Newman et al. Antimalarials during pregnancy
490 2003 Blackwell Publishing Ltd
atovaquone + proguanil found no serious adverse events,
but found that pruritis, weakness, insomnia and dizziness
were more common in the AQ group (Radloff et al. 1996).
However, a recent systematic review of studies of AQ for
the treatment of malaria found no increase in adverse
events when compared with CQ or SP, and found that all
adverse events were minor or moderate, and not life-
threatening (Olliaro & Mussano 2000). A recently
completed three-country trial in Africa found no cases of
clinical hepatitis among children >10 years receiving either
AQ or AQ + artesunate, but did nd that 6% of children
developed neutropenia (neutrophil count <1000/ll) and
that 60% of children experienced a decline in serial
neutrophil counts (Adjuik et al. 2002). In a smaller study
involving younger (659 month) Tanzanian children, no
serious adverse effects of AQ were noted, and no increase
in neutropenia was noted when compared with children
receiving SP (Schellenberg et al. 2002). In Burma, AQ and
quinine were compared for treatment of malaria in
pregnant women. A high overall rate of spontaneous
abortion was noted, but was not stratied by treatment
type (Thet et al. 1988).
Chlorproguanil (Lapudrine), in combination with dap-
sone (in development as a xed combination: Lapdap), has
only been evaluated in a single published trial among
pregnant women (Keuter et al. 1990). However, the study
did not specically address whether any adverse foetal
outcomes were observed. There are two studies in children
that have demonstrated good safety of Lapdap (Muta-
bingwa et al. 2001a; Sulo et al. 2002), although one trial
did nd a higher rate of severe anaemia among children
treated with Lapdap than among those treated with SP
(Sulo et al. 2002). Given that the component drugs are
both considered safe in pregnancy, it is expected that the
combination will also be safe for use in pregnancy.
Meoquine (MQ) is a quinolinemethanol compound
(Bruce-Chwatt et al. 1986) that has been used extensively,
particularly in Asia for the treatment of P. falciparum. It
has also been used extensively for malaria chemoprophyl-
axis among travellers to areas with CQ-resistant
P. falciparum malaria (Croft & Garner 1997).
Safety of MQ during pregnancy has been evaluated
through postmarketing surveillance, retrospective and
prospective studies. An early dose-nding study in Thai-
land found no increase in adverse pregnancy outcomes
among women who took either 125 or 250 mg/week for
prophylaxis during the third trimester (Nosten et al. 1990).
Post-marketing data collected by the manufacturers of MQ
showed that among 1627 women exposed to the drug
during pregnancy (95% for chemoprophylaxis), there
was no increase in congenital malformations over the
expected background rate (Vanhauwere et al. 1998). In
one prospective study of pregnant women, MQ chemo-
prophylaxis was more frequently associated with stillbirths
than SP chemoprophylaxis, (9.1% vs. 2.6%), but this rate
did not differ from the background rate of stillbirths
among the population studied (710%) (Phillips-Howard
et al. 1998). Among 451 women in Malawi who took MQ
treatment (750 mg) followed by weekly MQ chemo-
prophylaxis (250 mg), no increase in the incidence of
stillbirths or spontaneous abortions was observed (Steketee
et al. 1996d). Among US soldiers in Somalia, 72 women
used MQ for chemoprophylaxis before learning of their
pregnancies, and a greater expected percentage (16.7%)
had spontaneous abortions (Smoak et al. 1997). Data from
two studies in Thailand have showed no difference in
infant development between infants born to mothers given
MQ chemoprophylaxis during pregnancy and those given
placebo (Nosten et al. 1994), or between women treated
with MQ + artesunate and those treated with quinine
(McGready et al. 2000).
Data from a recent retrospective study in Thailand
suggest a signicantly increased risk of stillbirth among
women exposed to treatment doses of MQ during preg-
nancy compared with those exposed to quinine [odds ratio
(OR) 4.72], other treatments (OR 5.10) or women who
had no malaria (OR 3.50) (Nosten et al. 1999b). However,
no general patterns of physical abnormalities or specic
defects were observed in the stillbirths from MQ-using
women.
Although most of the data from a variety of sources
suggest that MQ is safe for use in pregnancy, these recent
data from Thailand highlight the need for continued
vigilance in monitoring adverse events of women treated
with MQ in pregnancy.
Artemisinins, a group of related compounds (sesquiter-
pene lactones) also known by their Chinese name, Qi-
nghaosu, are derived from the medicinal herb Artemisia
annua (L.), which is also known as annual or sweet
wormwood (Hien & White 1993). Its antimalarial
properties appear to have been known in ancient times, but
were rediscovered in China in the early 1970s (Hien &
White 1993). Artemisinins are available in a variety of oral
(artemisinin, artesunate, artemether and dihydroartemisi-
nin), parenteral (artemether, arteether and artesunate), and
rectal (artesunate and dihydroartemisinin) formulations
WHO (1998). These compounds have received widespread
attention in recent years in the treatment of severe malaria,
and in the treatment of multidrug-resistant falciparum
malaria, particularly in Southeast Asia.
There are limited data on the use of artemisinins
during pregnancy. A small case series from China found
that among six pregnant women treated for malaria
(P. falciparum or P. vivax) at a mean of 21.7 weeks of
Tropical Medicine and International Health volume 8 no 6 pp 488506 june 2003
R. D. Newman et al. Antimalarials during pregnancy
2003 Blackwell Publishing Ltd 491
gestation, none had adverse outcomes (Wang 1989). In
another trial from China, seven children exposed in utero
between 17 and 27 weeks of gestation were tracked after
birth from 3 to 10 years; no adverse outcomes were found
(Li 1990). In another clinical trial in China, 21 pregnant
women were included and were given a variety of
artemisinins; no adverse outcomes were recorded (Li et al.
1994). A study in 83 women in Thailand treated with
either artesunate or artemether found no increase in
adverse outcomes (4% spontaneous abortion and 3%
stillbirth all of which were explainable by other events).
Sixteen of the women in this study were accidentally
exposed to artemisinins during the rst trimester. Follow-
up of the live born children from this cohort found no
developmental delay (McGready et al. 1998). Further
work in Thailand has shown that women treated with
MQ + artesunate (n 66) (McGready et al. 2000) or
7 days of artesunate alone (McGready et al. 2001b) had no
increase in adverse effects or adverse birth outcomes, and
no negative developmental impact when compared with
women treated with quinine. A further 461 women in
Thailand treated with either artesunate (n 528 treatment
courses) or artemether (n 11 treatment courses) for
P. falciparum malaria had no increase in rates of abortion,
stillbirth, congenital abnormality, or mean gestation at
delivery (McGready et al. 2001a). A total of 287 pregnant
women in the Gambia were exposed to artesunate in
combination with SP during a mass drug administration;
no difference was noted in the rates of abortions,
stillbirths, or infant deaths among those exposed or not
exposed to the drugs (Deen et al. 2001).
A recent consultation held at WHO has recommended
that: (1) because of the limited experience with the
artemisinins in pregnancy they should only be used when
other treatments are considered unsuitable, (2) presently,
they cannot be recommended for treatment of malaria in
the rst trimester. They should not, however, be withheld if
they are considered lifesaving for the mother, (3) to further
document the safety of artemisinin compounds in preg-
nancy, careful follow-up is required, with documentation
of pregnancy outcome and the subsequent development of
the child whenever possible, and (4) to guide further
development of policies on the use of artemisinin deriva-
tives during pregnancy, alone or in combination, there is an
urgent need for further research/documentation of their
efcacy and safety for use as therapy for malaria and for
IPT (B. Nahlen, personal communication).
Malarone, a xed combination of atovaquone (250 mg)
and proguanil (100 mg), is currently being evaluated
in pregnant women. (See earlier section on proguanil).
In clinical trials among non-pregnant persons, Malarone
appears to have an excellent safety prole when used at the
dosage recommended for prophylaxis of P. falciparum.
The most commonly reported adverse effects include
gastrointestinal disturbances (Shanks et al. 1998; Sukwa
et al. 1999; van der Berg et al. 1999; Hogh et al. 2000;
Overbosch et al. 2001) and headache (Sukwa et al. 1999;
van der Berg et al. 1999; Overbosch et al. 2001). There
were no signicant differences in moderate to severe
adverse effects in the randomized, placebo-controlled,
double-blind studies (Lell et al. 1998; Shanks et al. 1998;
Sukwa et al. 1999).
Generally, atovaquone/proguanil is as well or better
tolerated than most drugs at doses necessary for treatment
of malaria (Radloff et al. 1996; de Alencar et al. 1997;
Anabwani et al. 1999; Bustos et al. 1999; Looareesuwan
et al. 1999b; Mulenga et al. 1999), although there are not
yet any published data on the use of Malarone for
treatment of pregnant women with malaria. Treatment
limiting adverse events occur in <1% of patients receiving
treatment doses, and serious adverse effects attributable to
treatment doses are rare (Looareesuwan et al. 1999a). The
most common adverse effects at treatment doses include
vomiting, nausea and abdominal pain (Radloff et al. 1996;
Sabchareon et al. 1998; Anabwani et al. 1999; Bustos
et al. 1999; Looareesuwan et al. 1999b,c; Mulenga et al.
1999; Bouchaud et al. 2000). Elevated alanine amino-
transferase (ALT) and AST occurred in patients treated
with atovaquone-proguanil and at a greater frequency than
patients treated with MQ; however, the differences were
not signicant and values returned to normal by day 28 in
most patients (Looareesuwan et al. 1999b). Although the
clinical signicance of these elevations is unknown, studies
have not shown liver enzyme elevations to be treatment-
limiting (Looareesuwan et al. 1999b).
Azithromycin is another compound for which there are
limited data about safety in pregnancy. There are several
trials in which azithromycin was used in the treatment of
sexually transmitted diseases and other genital infections
during pregnancy; no adverse neonatal outcomes were
noted (Adair et al. 1998; Ogasawara & Goodwin 1999).
Azithromycin does not readily cross the placenta (Heikki-
nen et al. 2000), and the drug appears to be generally safe
for use in pregnancy (Duff 1997; Donders 2000). There are
no published data evaluating the safety of azithromycin for
the treatment or prevention of malaria during pregnancy.
Lumefantrine, formerly known as benumetol, is a novel
aryl amino alcohol antimalarial related to quinine,
meoquine and halofantrine. For clinical use, it has been
combined with artemether in a xed combination pill of
120 mg lumefantrine and 20 mg of artemether (Riamet,
Coartem). Although an early trial in African children
suggested a possible prolongation of the QT interval after
therapy (von Seidlein et al. 1997), other evaluations have
Tropical Medicine and International Health volume 8 no 6 pp 488506 june 2003
R. D. Newman et al. Antimalarials during pregnancy
492 2003 Blackwell Publishing Ltd
found no evidence of QT prolongation or other cardio-
toxicity (van Vugt et al. 1999a; Bindschedler et al. 2002).
Administration of quinine following co-artemether (Ria-
met) resulted in a greater risk of QTc prolongation than
among patients administered only quinine (Lefevre et al.
2002). In general, the safety of artemetherlumefantrine
has been good in both children (von Seidlein et al. 1997)
and adults (van Vugt et al. 1999b), but the drug has not
been evaluated in pregnant women.
Drugs generally considered contraindicated
during pregnancy
Certain antimalarials are generally considered contrain-
dicated in pregnancy because of their effects on the
foetus. Two antibacterials, tetracycline and doxycycline,
fall into this category. Tetracycline easily crosses the
placenta, and can lead to disturbances of skeletal
growth, permanent discoloration of teeth, corneas and
lenses (Cohlan et al. 1961, 1963). Additionally, tetra-
cycline has been associated with an increased hepato-
toxicity among pregnant women, especially in the last
trimester (Dowling & Lepper 1964; Whalley et al. 1964;
Kunelis et al. 1965). Doxycycline, a closely related
compound, has been presumed to be capable of causing
similar tooth discoloration, although recent data suggest
that perhaps because of its lower binding afnity for
calcium than tetracycline, doxycycline does not cause
clinically signicant staining of permanent teeth follow-
ing use in childhood (Lochary et al. 1998; Purvis &
Edwards 2000).
Primaquine (PQ), an 8-aminoquinolone used primarily
for the radical cure of P. vivax and P. ovale infections, but
also used as chemoprophylaxis against P. falciparum, is
also generally considered contraindicated in pregnancy.
Persons who have a deciency of glucose-6-phosphate
dehydrogenase (G6PD) are at increased risk of acute
hemolytic events associated with the administration of PQ
(Beutler 1991). There is a theoretical increased risk of
haemolysis and subsequent jaundice among G6PD deci-
ent infants whose mothers have received PQ. This risk
would be greatest in Africa, where the gene responsible for
G6PD deciency is most common. Because of the theor-
etical risk, the recommendation for laboratory screening
for G6PD deciency, the ability to delay radical cure with
PQ until after pregnancy, and the availability of other
antimalarials, PQ is not recommended for use in
pregnancy.
Tafenoquine (also known as WR 238605) is, like PQ, an
8-aminoquinolone. It has been shown to be effective
prophylaxis against P. falciparum infections in semi-
immune teenagers and young adults (Lell et al. 2000;
Shanks et al. 2001), and effective in preventing relapse
with P. vivax (Walsh et al. 1999). There are currently no
published data about its safety in pregnancy, as trials to
date have specically excluded pregnant or lactating
women. However, it is more likely to have properties
similar to other 8-aminoquinolone, and therefore pose a
theoretical risk to women and neonates with G6PD
deciency, and therefore be inappropriate for use during
pregnancy.
Other antimalarials have been associated with serious
side effects in non-pregnant adults and should therefore
also be used with caution in pregnant women. Halofan-
trine has been associated with lengthening of the QT
interval, and with fatal arrhythmias in some persons
(Nosten et al. 1993; Monlun et al. 1995; Touze et al.
1996). Current recommendations suggest that this drug be
used for treatment only in those who have a documented
normal electrocardiogram, which makes its use in many
developing world settings impractical (Monlun et al. 1995;
Anonymous 1997).
The questionable safety of these drugs (tetracycline,
doxycycline, PQ, tafenoquine and halofantrine) in preg-
nant women does not imply that they are completely
contraindicated. In the face of serious illness and in settings
where a limited number of drugs are available, it is
necessary to balance the risk to the life of the mother
(whose death could also lead to foetal demise), with
hypothetical risks to the foetus.
Antimalarial safety during lactation
A number of antimalarials are considered safe during
lactation, including: CQ, quinine, SP, pyrimethamine,
dapsone, clindamycin, meoquine, doxycycline and tetra-
cycline (American Academy of Pediatrics (AAP) Commit-
tee on Drugs 1994; Briggs et al. 1998). Six of these (CQ,
quinine, pyrimethamine, dapsone, clindamycin and tetra-
cycline) are specically mentioned as compatible with
breastfeeding by the AAP (American Academy of Pediatrics
(AAP) Committee on Drugs 1994). There is some evidence
that caution should be exercised when using sulphona-
mides in infants who are sick, premature, or have G6PD
deciency; because these drugs are present in breast milk,
lactation under these conditions should take place with
caution (American Academy of Pediatrics (AAP) Commit-
tee on Drugs 1994). For other drugs, there are no data
about secretion into breast milk or use during lactation.
However, as proguanil is considered safe for use in
pregnancy, and AQ, Lapdap, azithromycin and Coartem
are considered safe for use in infancy, it is more likely that
these drugs would not pose serious harm to the infant
through lactation.
Tropical Medicine and International Health volume 8 no 6 pp 488506 june 2003
R. D. Newman et al. Antimalarials during pregnancy
2003 Blackwell Publishing Ltd 493
Efcacy
The efcacy of individual or combination antimalarials
varies widely by region and changes over time. There are
often few data about the efcacy of a specic antimalarial
in pregnancy; in the absence of these data, data on efcacy
in older children and adolescents (age 514 years) may be
indicative of likely efcacy in pregnant women. Thera-
peutic efcacy testing in Malawi has demonstrated that
resistance rates of P. falciparum to CQ are similar between
pregnant women and children 510 years of age, and that
these levels are approximately half of resistance levels
identied in children <5 years of age (CDC 1995). In
addition to achieving clinical cure, an antimalarial in
pregnancy should also clear placental parasitaemia, which
has been associated with LBW (Steketee et al. 1988,
1996b; Parise et al. 1998). We have therefore elected to
review the overall efcacy of antimalarials that might be
used programmatically in pregnancy, with a focus on
pregnancy-specic data where available.
The most widely used drug for the treatment of malaria
worldwide is CQ. Resistance to CQ is widespread and has
been described in all countries with P. falciparum malaria
except for the island of Hispaniola (Haiti and the
Dominican Republic), countries in Central America north-
west of the Panama Canal and a few areas of the Middle
East (Bloland & Ettling 1999). However, CQ may still be
relatively efcacious in many countries in West Africa with
P. falciparum transmission.
Many studies have examined the use of CQ chemo-
prophylaxis during pregnancy and effect on placental para-
sitaemia, anaemia, and LBW. A randomized controlled
trial in Cameroon found that in spite of moderate
resistance of P. falciparum to CQ, directly observed
chemoprophylaxis of primigravidae with weekly CQ
(300 mg) was associated with a decrease in placental
parasitaemia and LBW, and an increase in mean birth
weight (Cot et al. 1995). In Cameroon and Burkina Faso,
women who received CQ chemoprophylaxis during preg-
nancy had signicantly higher haematocrit values than
women who had not received chemoprophylaxis (Cot et al.
1998). Women in Zaire who reported having received CQ
chemoprophylaxis during pregnancy (duration unknown)
were only 39% as likely as women who reported no CQ
chemoprophylaxis to deliver a LBW neonate (Nyirjesy
et al. 1993). An evaluation of weekly CQ (directly
observed), in combination with daily proguanil (self-dosed
at home) in Mali, showed a 55% reduction in moderate-
to-severe anaemia (Bouvier et al. 1997b), and an increase
of 429 g in the birth weight of neonates born to
primigravidae and secundigravidae (when taken for
20 weeks or more) (Bouvier et al. 1997a).
Although there are data regarding the use of AQ for
treatment during pregnancy (Thet et al. 1988), there are no
completed studies (McDermott et al. 1988) regarding its
use for malaria prevention during pregnancy. In some
settings with CQ resistance, AQ has been found to be more
efcacious than CQ among non-pregnant individuals
(Olliaro et al. 1996; Brasseur et al. 1999). Given these
ndings, it is more likely that AQ would perform similarly
to CQ, with perhaps slightly better efcacy in areas with
increasing CQ-resistant P. falciparum.
Given rising rates of SP resistance, there has been recent
interest in using AQ in combination with SP (McIntosh &
Greenwood 1998), in part as an inexpensive way to delay
the generation of resistance and to improve treatment
efcacy. This combination has not been tried in pregnancy,
but a recent trial in young children conducted in Tanzania
demonstrated better efcacy (fewer treatment failures) in
children treated with AQ + SP than in children treated
with AQ or SP alone (Schellenberg et al. 2002).
Sulphadoxinepyrimethamine has had broad use in the
treatment of P. falciparum malaria in both pregnant and
non-pregnant women worldwide. A trial in Malawi
showed that placental parasitaemia rates were lower in
women who received IPT as two courses of SP (once in the
second and once in the third trimester) (9%), than in
women who received SP treatment followed by weekly CQ
chemoprophylaxis (26%), or women who received CQ
treatment followed by weekly CQ chemoprophylaxis
(32%) (Schultz et al. 1994b). Among women in Kenya
who received an IPT regimen of two courses of SP, the rate
of placental parasitaemia was lower among women who
were treated with SP for febrile episodes (case manage-
ment) (12% vs. 27%) (Parise et al. 1998). A signicant
reduction in severe anaemia (39% protective efcacy) was
observed among a different group of Kenyan women
treated with IPT (one to three treatment courses of SP)
when compared with controls, as was a reduction,
although not statistically signicant, in neonatal deaths
among those in the SP group (Shulman et al. 1999). Among
Malawian babies born to primigravidae treated with SP
during pregnancy, a signicant reduction in LBW was
found when compared with those not treated with SP
(Verhoeff et al. 1998). Two or three courses were more
efcacious than one course in reducing the incidence of
LBW. Anaemia reduction was more pronounced among
multigravidae treated with SP than among primigravidae,
although this may have been due in part to micronutrient
supplementation (Verhoeff et al. 1998). In Malawi, where
two-course IPT with SP has been national policy since
1993, prescription of SP was associated with a decrease in
placental parasitaemia (33% no prescription vs. 23% 2
courses SP), and a decrease in LBW (23% no prescription
Tropical Medicine and International Health volume 8 no 6 pp 488506 june 2003
R. D. Newman et al. Antimalarials during pregnancy
494 2003 Blackwell Publishing Ltd
vs. 10% 2 courses SP), among women delivering at a large
urban hospital (Rogerson et al. 2000).
In most settings with CQ-resistant P. falciparum, MQ
continues to be an effective drug for both treatment and
chemoprophylaxis. Among pregnant women, studies have
also found that the drug has excellent efcacy in clearance
of parasitaemia and reduction of malaria-associated ad-
verse outcomes. Among Thai women treated with 500 mg
of MQ, followed by chemoprophylaxis with 250 mg of
MQ weekly for 4 weeks, and then 125 mg weekly until
term, there was 86% protection against P. falciparum
infection, but no effect on birth weight or the incidence
of LBW among delivered infants (Nosten et al. 1994).
Malawian women who received a treatment dose of MQ
(750 mg) followed by weekly MQ chemoprophylaxis
(250 mg) were less likely to have persistent or break-
through parasitaemia than those women treated with any
of three CQ regimens in comparison groups (Steketee et al.
1996e). That same study also found that women in the MQ
group had signicantly fewer LBW infants than women
treated with CQ-containing regimens (Steketee et al.
1996b). Although there is evidence that pregnant women
need larger doses of MQ to achieve comparable blood
levels (Na Bangchang et al. 1994), there is also evidence
that pregnant women living in areas with little or no MQ
resistance can clear P. falciparum parasitaemia with a
single reduced dose (12.5 mg/kg) of MQ (Okoyeh et al.
1996).
Maloprim, a xed combination of pyrimethamine
12.5 mg and dapsone 100 mg, has also been evaluated as a
potential chemoprophylaxis drug for use during preg-
nancy. One study in the Gambia found that primigravidae
who received fortnightly Maloprim given by traditional
birth attendants (TBAs) had higher mean packed cell
volume (30.1 vs. 26.6), delivered infants with higher mean
birth weights (mean: 159 g), and fewer LBW infants (6%
vs. 22%) than those not receiving Maloprim (Greenwood
et al. 1989). Among Gambian women treated with weekly
Maloprim by TBAs starting at an average of 24 weeks
gestation there was a signicant decrease in placental
parasitaemia, and a signicant increase in the birth weight
of their infants (mean 153 g increase); however, there was
no correlation between placental infection and birth weight
(Menendez et al. 1994). When several of the studies in the
Gambia were evaluated together, it was estimated that the
chemoprophylaxis programme might be expected to reduce
infant mortality by up to 18% (Greenwood et al. 1992).
Another potential drug for use in pregnant women is
chlorproguanildapsone (Lapdap). This combination has
been shown to be efcacious in treating non-pregnant
persons in a small study in Kenya (100% cure on day 7)
(Watkins et al. 1988), but less efcacious in the treatment
of acute uncomplicated falciparum malaria in Thailand
(10% cure rate). Another study in Kenya found that
although clearance of parasitaemia was good following
both one- and three-course chlorproguanildapsone treat-
ment (93.4% and 98.0%), reinfection rates were just as
rapid as those seen in community surveillance (Amukoye
et al. 1997). In Kenya and Malawi, research has shown
that children treated with chlorproguanildapsone did not
have higher retreatment rates than children treated with
SP, and that treatment failures were less common (Sulo
et al. 2002). In Tanzania, chlorproguanildapsone was
more efcacious than SP at treating drug-resistant falcipa-
rum malaria in children <5 years of age (Mutabingwa et al.
2001a). A trial in pregnant women in Kenya comparing a
single treatment course with SP, CQ, or chlorproguanil
(1.2 mg/kg) and dapsone (2.4 mg/kg) given as a single dose
found that chlorproguanildapsone was as effective as SP
in clearing initial parasitaemia by day 7, but less effective
in maintaining parasite clearance by day 28 (67% parasi-
temic for chlorproguanildapsone vs. 19% for SP) (Keuter
et al. 1990). A rise in haemoglobin concentrations was
observed in all the three groups, but was sustained until
day 42 only among those women who remained free of
malaria parasites. The study did not examine placental
parasitaemia or birth weight. The short half-life of
chlorproguanildapsone, compared with SP, appears to
result in poorer long-term freedom from peripheral
parasitaemia, which one might hypothesize would result
in poorer prevention of placental parasitaemia.
However, there is evidence that the shorter half-life of
chlorproguanildapsone may exert less selective pressure
for drug resistance than longer-acting drugs like SP (Nzila
et al. 2000).
There are very few studies that show the efcacy of
monotherapy with artemisinins for the treatment of mal-
aria in pregnant women. In a descriptive, non-randomized
study along the ThaiBurmese border, only 16% of
pregnant women failed treatment with 12 mg/kg of oral
artesunate over 7 days (recrudescence within 42 days),
which compared favourably with quinine and MQ in that
setting (McGready et al. 1998). However, this study did
not examine maternal anaemia, placental parasitaemia, or
birth weight. Among 287 pregnant women in the Gambia
exposed to artesunate in combination with SP during a
mass drug administration, the mean birth weight was
0.48 kg higher among the exposed than among the
unexposed group (Deen et al. 2001). To date, no studies
evaluating artemisinins for IPT during pregnancy have
been undertaken, although an evaluation of combination
therapy with an artemisinin and SP during pregnancy is
planned for Tanzania (Peter Bloland, CDC, personal
communication).
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R. D. Newman et al. Antimalarials during pregnancy
2003 Blackwell Publishing Ltd 495
Amodiaquine + artesunate is another possible combina-
tion for use in pregnant women, although no trials have yet
been conducted. However, a recent multicenter African
trial in children found improved efcacy in treating
falciparum malaria in two of three countries among those
treated with AQ + artesunate when compared with AQ
alone (Adjuik et al. 2002).
There are no published studies evaluating the efcacy of
Malarone in treating or preventing malaria in pregnant
women. However, early studies with this drug indicate that
it is highly efcacious in the treatment of P. falciparum
malaria in men and non-pregnant women (Radloff et al.
1996; Bustos et al. 1999; Bouchaud et al. 2000). Multiple
studies have demonstrated high efcacy of Malarone when
used as chemoprophylaxis in both non-immune travelers
(Hogh et al. 2000; Overbosch et al. 2001), semi-immune
adults (Shanks et al. 1998; Sukwa et al. 1999) and semi-
immune children (Lell et al. 1998).
There are no studies evaluating artemetherlumefantrine
in pregnant women. However, 100% of Gambian children
with uncomplicated P. falciparum malaria treated with
3 days of artemetherlumefantrine cleared asexual para-
sites within 72 h (von Seidlein et al. 1998). Second episodes
of malaria by 4 weeks were more common in those treated
with artemetherlumefantrine than SP in this trial, al-
though most of these were determined by genotyping to be
new infections (von Seidlein et al. 1998). Efcacy in the
treatment of adults with multidrug-resistant P. falciparum
has also been good; six doses over 5 days appears more
effective than four doses over 3 days (van Vugt et al.
1999b; Lefevre et al. 2000). A Cochrane review of artem-
etherlumefantrine concluded that the combination was
more effective than CQ, but less effective than meoquine
or meoquineartesunate in treating uncomplicated falci-
parum malaria, and that no conclusion could be reached
regarding comparison with SP (Omari et al. 2002).
There are no studies that have evaluated the efcacy of
azithromycin in treating or preventing malaria in pregnant
women. A trial conducted among semi-immune non-
pregnant adults in Kenya found a protective efcacy
against P. falciparum infection of 83% for daily azithro-
mycin (250 mg) and 64% for weekly azithromycin
(1000 mg), as compared with 93% for daily doxycycline
(Andersen et al. 1998). A trial in Indonesia among adults
with limited immunity taking daily azithromycin (250 mg)
found fair protection against P. falciparum (72%), and
excellent protection against P. vivax (99%) (Taylor et al.
1999).
Finally, although quinine is generally a safe antimalarial
for use in pregnancy and is effective in clearing parasitae-
mia among infected women in most settings, its short half-
life, bitter taste and frequent side effects make it generally
unsuitable for consideration as a drug for prevention
programmes for malaria in pregnancy. It is usually reserved
for the treatment of severe malaria or drug-resistant
uncomplicated malaria in both pregnant and non-pregnant
persons (WHO 2000b).
Determinants of effectiveness
For a drug to be programmatically effective in the
prevention of malaria during pregnancy, in addition to
being locally efcacious, it must also be available, afford-
able, deliverable and acceptable to the population of
women who will be taking the drug. Unless a drug is
sufciently available for distribution to pregnant women in
rural settings, a prevention programme cannot be success-
ful. Affordability is another key component of effectiveness
because an expensive drug may not be purchased by many
countries, or may be purchased in insufcient quantities to
supply all needs. In addition, some countries have adopted
cost-recovery schemes that pass at least some of the
treatment cost onto the consumer. In these settings,
prescriptions for more expensive drugs may be more likely
to go unlled if the consumer must pay, and therefore
contribute to poor compliance (WHO 1994). Even if the
drug is free to pregnant women, a more expensive drug
may have a greater likelihood of being resold than a less
expensive one. Deliverability measures the frequency of
required drug dosing, and whether all treatment doses can
be given under direct observation during antenatal care
(ANC), or must be taken partly unsupervised. Drugs that
require more frequent dosing, and more unsupervised
doses, are more likely to result in poorer compliance, and
thus be less effective. Finally, acceptability is also an
important consideration. A bitter drug (in some cultures
bitterness is associated with abortifacients) that has com-
mon side effects is more likely to be associated with poorer
compliance and a consequent decrease in effectiveness.
Measuring and comparing effectiveness
An attempt to compare the potential effectiveness of
antimalarial drugs in prevention programmes for malaria
in pregnancy is presented in Table 1. Drugs that are
currently considered unsafe during pregnancy are not
included in the table. We present a scoring system to
summarize the evaluation of effectiveness and to provide a
means of comparing alternative drugs and drug strategies
for malaria prevention in pregnant women. A lower score
is better for each of the individual categories, and therefore
also for the overall score. Each drug has been scored on
efcacy (15) and on four determinants of effectiveness:
cost (15), local availability (13), deliverability (15) and
Tropical Medicine and International Health volume 8 no 6 pp 488506 june 2003
R. D. Newman et al. Antimalarials during pregnancy
496 2003 Blackwell Publishing Ltd
acceptability (13). A specic summary number can be
determined for each drug and regimen, however, the values
may vary among countries depending on specic situations.
One possible scoring system for drug efcacy would be
based on the latest WHO recommendations for monitoring
antimalarial drug-resistance (WHO 2001a), and would be
based on adequate clinical and parasitological response
(ACPR), dened as the absence of parasitaemia on day 14
irrespective of axillary temperature without previously
meeting any of the criteria of early treatment failure or late
parasitological failure. The proposed ve-point scoring
system is: 1 >95% ACPR; 2 8594% ACPR; 3 75
84% ACPR; 4 6074% ACPR; 5 <60% ACPR. In
Table 1, there are two summary scores, one assuming ideal
efcacy (ACPR >95%, score 1), and one assuming poor
efcacy (ACPR 6074%, score 4). Drugs with an ACPR
<60% (score 5) should not be considered for program-
matic use, and a summary score should not be assigned.
One limitation of this approach is that drug efcacy in
children with clinical malaria is not equivalent to the
clinical efcacy in clearing placental parasitaemia in
asymptomatic pregnant women. It is possible that efcacy
in asymptomatic women with low levels of parasitaemia
may be better than in highly parasitemic sick infants (see
discussion at beginning of efcacy section). Unfortunately,
there is no standardized methodology for determining true
antimalarial efcacy for pregnant women, and relatively
few published data are available. In light of this constraint,
Table 1 Comparison of effectiveness of antimalarial drug regimens for use in malaria prevention in pregnant women
Drug name Regimen*
Efcacy
(15)
Cost
(15)
Local
availability
(13)
Deliverability
(15)
Acceptability
(13)
Total score
(ideal
efcacy 1)
Total score
(poor
efcacy 4)
Sulfadoxinepyrimethamine (SP) IPT 15 1 1 1 1 5 8
Chloroquine IPT 15 1 1 2 3 8 11
Amodiaquine IPT 15 2 2 2 2 9 12
Amodiaquine + SP IPT 15 2 2 2 2 9 12
Chlorproguanildapsone
(Lapdap)
IPT 15 2 3 2 1 9 12
Sulfadoxinepyrimethamine +
artesunate
IPT 15 4 2 2 1 10 13
Artemetherlumefantrine
(Riamet; Coartem)
IPT 15 4 2 2 1 10 13
Pyrimethaminedapsone (Maloprim) Cpx 15 3 2 3 1 10 13
Amodiaquine + artesunate IPT 15 4 2 2 2 11 14
Chlorproguanildapsone + artesunate IPT 15 4 3 2 1 11 14
Chloroquine Cpx 15 2 1 4 3 11 14
Atovaquoneproguanil (Malarone) IPT 15 5 3 2 1 12 15
Meoquine IPT 15 4 3 2 3 13 16
Meoquine + artesunate IPT 15 5 3 2 3 14 17
Atovaquoneproguanil (Malarone) Cpx 15 5 3 5 1 15 18
Azithromycin Cpx 15 5 3 5 1 15 18
Proguanil + chloroquine Cpx 15 4 2 5 3 15 18
Meoquine Cpx 15 5 3 4 3 16 19
* Regimen: IPT, intermittent preventive treatment; Cpx, chemoprophylaxis.
See text for methods of scoring for categories of efcacy, cost, availability, deliverability and acceptability.
A low overall score is indicative of good overall effectiveness for the regimen.
Scoring system is as follows: Efcacy: 1, >95% ACPR; 2, 8594% ACPR; 3, 7584% ACPR; 4, 6074% ACPR; 5, <60% ACPR;
cost: 1, $0.01$0.25; 2, $0.260.50; 3, $0.51$1.50; 4, $1.51$5.00; 5, >$5.00; local availability: 1, on national formulary, widely
available; 2, on national formulary, not widely available; 3, not on national formulary; deliverability: one, two- or three-course IPT with
a single treatment dose that can be given under observation; 2, two- or three-course IPT with multiple treatment doses, some of which
must be taken unsupervised; 3, monthly or biweekly dosing for IPT/chemoprophylaxis; 4, weekly chemoprophylaxis; 5, daily
chemoprophylaxis; acceptability: 1, generally acceptable; one point can then be added for each of the following categories, bitter
taste/pregnancy-related taboos, other adverse reactions (such as itching or dizziness), up to a maximum of three points. Scores are best used
for comparative purposes between drugs and regimens. Note that drugs which scores 5 for efcacy [<60% adequate clinical and
parasitilogical response (ACPR)] should not be given an overall score and should be excluded from programmatic consideration.
Worst-case efcacy for scoring purposes is therefore efcacy, 4 (6074% ACPR).
Lapdap is currently in commercial development, but its components (chlorproguanil and dapsone) are available.
Tropical Medicine and International Health volume 8 no 6 pp 488506 june 2003
R. D. Newman et al. Antimalarials during pregnancy
2003 Blackwell Publishing Ltd 497
we suggest using WHO standardized methodology for
determining drug efcacy in infants as a substitute until
other tools are developed and available.
To score cost, we calculated the average cost of a
regimen that would cover the second and third trimesters
of pregnancy, assuming that all women began taking
medication at the start of the second trimester. Therefore,
if the regimen were weekly CQ at 300 mg, then the total
cost would be 26 weeks multiplied by the unit cost of a
300 mg dose. If the regimen were two-course SP, then the
cost is twice the unit cost of a treatment course of SP.
We divided the possible costs of regimens into quintiles,
and then assigned scores as follows (1 $0.010.25;
2 $0.260.50; 3 $0.511.50; 4 $1.515; 5 >$5).
Drug costs were derived in general from the recent
consultation on antimalarial drugs at WHO (2001b), or
other sources if needed (McFayden 1999). Where cost is
not yet established, (as is the case with Lapdap), we chose
estimates based on component costs. As with efcacy, these
costs may vary by region or country depending upon
various factors such as tariffs, shipping costs and the
availability of local production.
For local availability, scores were assigned as follows:
1, on national formulary, widely available; 2, on national
formulary, not widely available; 3, not on national
formulary. For the example table, we took the following
approach. For certain drugs, such as CQ, we assigned 1, as
it is nearly universally available. For drugs that are still in
development, and for drugs that have almost no distribu-
tion outside of private pharmacies in large cities, we
assigned 3, as they are not likely to be on national
formularies. For all other drugs we assigned 2.
Deliverability was scored as follows: 1, two- or three-
course IPT with a single treatment dose that can be given
under observation; 2, two- or three-course IPT with
multiple treatment doses, some of which must be taken
unsupervised; 3, monthly or biweekly dosing for IPT/
chemoprophylaxis; 4, weekly chemoprophylaxis; 5, daily
chemoprophylaxis. Likely dosing regimens for each of the
drugs or drug combinations are outlined in Table 2.
Acceptability was scored in the following manner: 1,
generally acceptable; one point can then be added for each
of the following categories, bitter taste/pregnancy-related
taboos, other adverse reactions (such as itching or dizzi-
ness), up to a maximum of three points. Pregnancy-related
taboos may differ from country-to-country; we have
elected to summarize available information across coun-
tries for the purposes of this example table.
It should be recognized the values assigned in this table
should not be viewed as xed. As new information
becomes available, the overall effectiveness score in a
specic setting may change. For example, at the moment in
west Africa, SP is inexpensive, widely available and
generally has good efcacy whereas artemetherlumefan-
trine is not widely available, and is far more expensive than
SP (total score: SP, 5; artemetherlumefantrine, 10).
However, if SP efcacy were to fall to 70% ACPR,
artemetherlumefantrine were to become widely available
(from 2 to 1), and its price were to drop (from 4 to 2), then
the relative score of artemetherlumefantrine becomes
better than SP (SP, 8; artemether-lumefantrine, 7).
As can be noted in the table, SP generally has the most
favourable effectiveness prole (score range: 58) of
currently and soon to be available antimalarials. SP is very
inexpensive ($0.16 for a 2-course IPT regimen), widely
available, easily delivered (it can be given as directly
observed treatment as a single dose during an ANC visit),
and has a good acceptability prole. Some of these were
factors identied in a Malawi study that projected that
two-course IPT with SP would be more cost-effective than
CQ-containing prophylactic regimens in preventing infant
deaths (Schultz et al. 1996). SP also retains fair-to-good
efcacy across much of Africa, although there is increasing
resistance in east Africa. In settings with increasing
resistance, SP may not be the best choice.
Chloroquine, if given as two-course IPT regimen (for
which there are not yet any published data), also has an
attractive effectiveness prole (score: 811). CQ is very
inexpensive ($0.14 for a 2-course regimen), nearly univer-
sally available and relatively easy to deliver, although not
as easy as SP because some of the IPT treatment doses must
be taken at home. However, CQ has a number of factors
that limit its acceptability. Its bitter taste is unacceptable to
some people (MacCormick & Lwihula 1983), although
new formulations are available in capsule form that mask
its bitter taste (Ndesendo et al. 1996), and have been found
to increase compliance compared with uncoated formula-
tions (Helitzer-Allen et al. 1993). It is likely, however, that
this formulation would be more expensive. Some women
believe that CQ, as a bitter medicine, is dangerous in
pregnancy (Kaseje et al. 1987; Schultz et al. 1994a). For
other women, one of the mild adverse reactions
associated with CQ, pruritis, is an impediment to usage,
and has been reported as a frequent reason for not taking
CQ chemoprophylaxis in Kenya (Kaseje et al. 1987) and
Tanzania (MacCormick & Lwihula 1983). The principal
problem with CQ is that it is not an efcacious antimalarial
in most of sub-Saharan Africa. The spreading
CQ-resistance will continue to diminish its efcacy and
therefore its effectiveness as an antimalarial for pregnant
women.
If CQ is given as weekly chemoprophylaxis in regions
where the resistance to the drug is low enough to make it a
viable option, the overall effectiveness score of CQ drops
Tropical Medicine and International Health volume 8 no 6 pp 488506 june 2003
R. D. Newman et al. Antimalarials during pregnancy
498 2003 Blackwell Publishing Ltd
(score: 1114) because of a slight increase in price and a
large drop in deliverability. While weekly chemoprophyl-
axis dosing may be reasonable under research conditions, it
is more difcult to implement at a programmatic level.
Amodiaquine has a summary effectiveness score that is
similar to CQ (score range: 912), although the individual
scores differ in several important ways. AQ is more
expensive than CQ ($0.30) for a 2-course IPT regimen. Its
availability is patchy, as it has been taken off the formulary
of some countries because of concerns over its safety. Its
deliverability as a two-course IPT regimen is fairly good
(3 days for each course), and its acceptability is fairly good
(not as bitter as CQ, but some patients experience
dizziness). Chemoprophylaxis with AQ has been associated
with more serious adverse reactions than treatment
(Olliaro et al. 1996) and we have therefore not included
chemoprophylaxis with AQ as an acceptable regimen.
Amodiaquine in combination with SP is a potentially
attractive combination therapy for use as IPT if safety and
efcacy can be demonstrated. The cost of this combination
($0.46 for two-dose IPT) is moderate and its combined
effectiveness score would be good (912).
Although Lapdap is not yet available commercially, it is
a potentially attractive option for use in pregnancy (score:
912). Given the low cost of its components, which are
both available, the cost of Lapdap is likely to be fairly low.
It is estimated that the cost of Lapdap will be <$0.50 per
3-day treatment course, for an adult, in the public sector
(Peter Winstanley, University of Liverpool, personal
communication). As with all new drugs, its availability
will initially be poor, but could be expected to improve
over time. As a two-course IPT regimen it has good
deliverability (although it requires a 3-day treatment
regimen) and should be fairly acceptable. The efcacy of a
chlorproguanildapsone combination in pregnant women
has yet to be conclusively shown, but general efcacy
appears promising. The required frequency of the IPT
regimen for chlorproguanildapsone will need to be
established because of the short half-life of the component
drugs.
Table 2 Possible regimens for treatment and prophylaxis for antimalarial drugs for use in pregnancy
Drug name
Intermittent preventive
treatment (IPT) regimen* Chemoprophylaxis regimen
Sulfadoxine (25 mg)pyrimethamine
(500 mg) (SP)
Three tablets as a single dose Not recommended
Chloroquine 25 mg base/kg total in divided
doses over 3 days
300 mg base weekly
Amodiaquine 30 mg base/kg total in divided
doses over 3 days
Not recommended
Amodiaquine + SP Amodiaquine as above + SP as above Not recommended
Chlorproguanil (80 mg) + dapsone
(100 mg) (Lapdap)
Chlorproguanil 2 mg/kg daily for 3 days +
dapsone 2.5 mg/kg daily for 3 days
No available data
SP + artesunate SP as above + artesunate 4 mg/kg daily
for 3 days total in divided doses over
3 days (safety in pregnancy debated)
Not recommended
Artemether (20 mg)lumefantrine (120 mg)
(Riamet, Coartem)
Four tablets at 0, 8, 24 and 48 h or
four tablets at 0, 8, 24, 36, 48 and 60 h
Not recommended
Chlorproguanil + dapsone + artesunate Dose not yet determined Not recommended
Amodiaquine + artesunate Amodiaquine as above + artesunate as above Not recommended
Pyrimethamine (12.5 mg)dapsone
(100 mg) (Maloprim)
Not recommended One tablet weekly
Atovaquone (250 mg)proguanil
(100 mg) (Malarone)
Four tablets daily for 3 days
(safety in pregnancy not established)
One tablet daily (safety in pregnancy
not established)
Meoquine 15 mg base/kg as a single dose, or
25 mg/kg divided as two doses 68 h apart
5 mg base/kg weekly (usually 250 mg
or one tablet)
Meoquine + artesunate Meoquine as above + artesunate as
above (safety in pregnancy debated)
Not recommended
Azithromycin Not recommended 250 mg daily (safety for this use
not established)
Proguanil + chloroquine Not recommended Proguanil 200 mg daily + chloroquine
prophylaxis as above
* Frequency of repeating the regimen during pregnancy may vary.
Tropical Medicine and International Health volume 8 no 6 pp 488506 june 2003
R. D. Newman et al. Antimalarials during pregnancy
2003 Blackwell Publishing Ltd 499
The short half-life of artemisinin compounds diminishes
their suitability as single agents for IPT; their role as a
component of a combination drug IPT regimen remains to
be determined (both in terms of safety and efcacy). For
settings where the efcacy of SP as a single agent is
diminishing, the use of artemisinins in combination with
other drugs could prove useful. Artesunate combined with
SP (score range: 1013) would be more costly than SP
alone ($4.48 for two-course IPT), would be easily avail-
able, would be slightly less easily delivered (requires
multiple treatment doses that could not be given as directly
observed therapy in the ANC clinic), and should have
similar acceptability. Artesunate combined with AQ has an
effectiveness score range (1114) that is not as good as AQ
alone (912), because it would be much more expensive
($4.62 for two-dose IPT). Clearly, the advantage of this
regimen over AQ would be that in areas with AQ
resistance, the addition of artesunate to the regimen would
likely result in a highly efcacious regimen. Artesunate
combined with MQ (score range: 1417) would be more
costly than MQ ($10.76 for two-course IPT), less easily
available, similarly deliverable, and no more acceptable
(since the acceptability prole of MQ is already poor).
Artesunate combined with chlorproguanildapsone would
have a moderate cost (not currently known, although
slightly greater than artesunateSP) and other scores
comparable with an artesunateSP combination.
The effectiveness of artemetherlumefantrine appears to
be fairly good (score 1013). The drug does not currently
have wide availability outside of Southeast Asia, although
it is registered for use in many countries. It is more likely to
have a moderately high cost if used programmatically
(approximately $5), have good deliverability and good
acceptability.
The effectiveness prole of Maloprim appears to be
fairly good (score range: 1013). It has a moderate cost
and patchy availability, but is generally well tolerated
and acceptable. Deliverability is somewhat problematic
as the drug has typically been given as biweekly
chemoprophylaxis.
Malarone is another potential candidate for use in
malaria prevention (IPT score: 1215, chemoprophylaxis
score: 1518) although its safety and efcacy have yet to be
determined in pregnant women. The primary limiting
factor for its use in pregnant women is the cost, estimated
at $84 for a two-course IPT regimen, nearly 10 times more
expensive than the most expensive alternative regimen.
Availability is also currently very limited, although deliv-
erability and acceptability should be good. As a chemo-
prophylaxis regimen, the cost would become even more
prohibitive, and the deliverability, as a daily drug, would
be poor.
The long half-life of MQ and its efcacy in clearing
parasitaemia make MQ and MQ-containing combination
therapy theoretically attractive options for chemoprophy-
laxis or IPT (IPT score range: 1316, chemoprophylaxis
score range: 1619). However, MQ has several serious
limitations. The cost of MQ, estimated at $2.14 per
treatment course, is high. MQ is also not widely available
in most countries in sub-Saharan Africa. MQ as a drug for
IPT has good deliverability, as 25 mg/kg could be given
over 2 days. A regimen of weekly chemoprophylaxis would
make the regimen less deliverable. MQ has also been
associated with a range of side effects that could diminish
compliance and therefore effectiveness. A trial in Thailand
found increased incidence of dizziness among women after
the rst prophylactic dose of MQ, although this difference
was not seen during the larger second phase of the trial
(Nosten et al. 1994). Like CQ, MQ is a bitter medicine,
which may lead to diminished acceptability among women
in cultures where bitter foods and medicines are proscribed
during pregnancy. Finally, the experience in South-east
Asia with the rapid rise of MQ-resistance may make the
use of MQ as a single agent for pregnant women a poor
choice in Africa. The addition of artesunate to MQ for IPT
(score: 1519) would improve efcacy in regions with MQ
resistance, but would raise the overall cost of the regimen.
Proguanil, when combined with CQ, also has less ideal
effectiveness as an antimalarial for use in pregnancy (score
range: 1518). Although the unit cost of both proguanil
and CQ is low, the daily dose of proguanil combined with
the cost of weekly CQ would result in a high cost over
many weeks of chemoprophylaxis. Availability of progua-
nil is patchy and its bitterness may limit its acceptability to
pregnant women in some countries. The main constraint
for use of proguanil, even in an area where it is efcacious,
is the need for daily dosing, which gives it a very poor score
for deliverability.
Azithromycin could prove to be an effective agent in the
prevention of malaria during pregnancy in semi-immune
women, as it is generally well tolerated by pregnant women
who are being treated for other infections (score: 1518)
(Bush & Rosa 1994; Adair et al. 1998). However, it has a
high cost, limited availability and poor deliverability as a
daily chemoprophylactic. These features combine to give
azithromycin a poor summary score for effectiveness, even
assuming ideal efcacy.
Summary recommendations
In summary, optimal antimalarial regimens for the pre-
vention of malaria in pregnancy do exist, but there are few.
By examining a variety of determinants of effectiveness, we
found that the seven most promising regimens were all IPT
Tropical Medicine and International Health volume 8 no 6 pp 488506 june 2003
R. D. Newman et al. Antimalarials during pregnancy
500 2003 Blackwell Publishing Ltd
as opposed to chemoprophylaxis. Given the enormous
logistic complexity and added cost of chemoprophylaxis,
this is not surprising.
Presently, IPT with SP is likely to have the best overall
effectiveness in preventing the adverse outcomes associated
with malaria in pregnancy in countries where resistance
remains relatively low. Its low cost, wide availability, easy
deliverability and good acceptability make it the clear
choice in countries where efcacy of the drug remains
good. For the increasing number of countries where
resistance to SP is rising or already high, the choice
becomes more complicated. In no country should it be
acceptable to promote an inefcacious drug, regardless of
what its other attractive properties might be. In most of
these settings, CQ is not efcacious and therefore its
overall effectiveness will be severely reduced. Also, CQ
only receives a good score for effectiveness if two-course
IPT with CQ proves efcacious in the settings with
CQ-sensitive P. falciparum. As a chemoprophylactic regi-
men, the poor deliverability of CQ makes it and all other
chemoprophylactic regimens less effective options.
Lapdap, AQ, AQ + SP, SP + artesunate, AQ + artesu-
nate and artemetherlumefantrine are other options that
appear promising for use in control programmes in
pregnancy. However, currently there are limited data
about the use of these regimens in pregnancy. There is,
therefore, a pressing need to evaluate the efcacy and
safety of these drugs and drug combinations for IPT during
pregnancy.
Many of the other choices for IPT are sharply limited by
their high cost. Malarone, MQ and MQ in combination
with artesunate would be reasonable options, but only with
a drastic reduction in their market price.
Ultimately, drug efcacy is the most important factor in
determining antimalarial selection for programmatic use
(among drugs that are considered safe for use in preg-
nancy). Therefore, there is an urgent need to develop a
standardized way of assessing antimalarial drug efcacy in
semi-immune pregnant women, as drug efcacy in this
population likely remains far greater than in young
children, in whom the majority of therapeutic efcacy
monitoring is undertaken.
For now, SP must be seen as the antimalarial with the
best overall effectiveness for prevention of malaria in
pregnancy in areas of the world where substantial SP
resistance has not yet developed. In areas of the world
where resistance to SP may be developing, AQ (alone or in
combination with SP or artesunate) and artesunate in
combination with SP may be promising alternatives,
pending further data about safety of AQ and artemisinins
for use during pregnancy. In areas where resistance to SP is
already high, alternatives to SP alone or in combination
with artemisinin compounds, such as Lapdap and artem-
etherlumefantrine, because of their favourable effective-
ness proles, require urgent evaluation for use in
pregnancy. Given that formal trials of the safety of these
drugs in pregnancy may be difcult to conduct, it is
essential that post-marketing surveillance of pregnant
women who are exposed to new drugs be as vigilant and
complete as possible.
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Authors
Robert D. Newman (corresponding author), Dr Monica E. Parise, Laurence Slutsker and Richard W. Steketee, Malaria Epidemiology
Branch, Division of Parasitic Diseases, NCID, Centers for Disease Control and Prevention, 4770 Buford Highway NE, MS F-22,
Atlanta, GA 30341, USA. Tel.: +1 770 488 7559; Fax: +1 770 488 4206; E-mail: rnewman@cdc.gov
Dr Bernard Nahlen, Roll Back Malaria, World Health Organization, 20 Avenue Appia. CH-1211 Geneva 27, Switzerland.
E-mail: nahlenb@who.int
Tropical Medicine and International Health volume 8 no 6 pp 488506 june 2003
R. D. Newman et al. Antimalarials during pregnancy
506 2003 Blackwell Publishing Ltd