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Treatment and prevention of malaria in pregnancy and newborn

Article in Journal of Perinatal Medicine · February 2008

DOI: 10.1515/JPM.2008.002 · Source: PubMed

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J. Perinat. Med. 36 (2008) 15–29 • Copyright by Walter de Gruyter • Berlin • New York. DOI 10.1515/JPM.2008.002

Treatment and prevention of malaria in pregnancy and

newborn*
 , Hospital h
Oriol Coll1,**, 9
Service de Gyne´
o
Clara Clinic, r cologie Obste´
Menendez2, Universitat de : trique, Centre
Francesc Botet3, Barcelona,
O
Hospitalier
Rajeshwar Spain r Intercommunal de
Dayal4, and the 4
Department of i Poissy-St
o
WAPM Perinatal Pediatrics, S.N.
l
Germain, Poissy,
Infections Medical College, France
Working Group: Agra, India C
o
Xavier 5
Professor of
l A
Carbonell- Pediatrics, Baylor l b
Estrany3, College of Medicine, , s
Leonard E. and Director of the M t
Weisman5, Perinatal Center at D r
Mauricio M. Texas Children’s Dep a
artm c
Anceschi6, Anne Hospital, Houston, ent
Greenough7, TX, USA of t
Ronald S. 6
Department of Mat
erna Pregnant women are at
Gibss8 and Yves Gynecology and
Obstetrics, University
l increased risk for malaria
Ville9 Feta infection. Although
‘‘La Sapienza’’, Rome, l
Italy Med important advances have
1
Department of icine been made in the last
7
King’s College
Maternal Fetal Insti years, the mechanisms
London School of tut
Medicine, Institut that explain the increased
Medicine Regional Clini
Clinic de Ginecologia, c de susceptibility are not
Neonatal Intensive yet fully under- stood.
Obstetricia i Gin
Care Center ecol Malaria infection in
Neonatologia, Institut supported by ogia pregnancy is associated
d’Investigacions WellChild 4th Floor
Obs
tetri with maternal and fetal
Biomediques August Golden Jubilee Wing, cia i morbidity and mortality.
Pi i Sunyer (IDIBAPS), King’s College Neo The severity of the
Hospital Clinic de nato
Hospital, Denmark disease depends on the
logi
Barcelona, Hill, London, UK level of pre-pregnancy
a
B 8
E. Stewart Taylor Institut d’Investigacions acquired immunity
a Biomediques August Pi i against malaria, and the
Professor and Sunyer
r conse- quences of
c Chairman, (IDIBAPS)
Hospital Clinic de Barcelona infection are more
e Department of
C/Sabino de Arana 1 severe in non-immune
l Obstetrics and Barcelona 08034
o women. In highly
Gynecology University Spain
n Tel.: q34 932275600 endemic areas, the
of Colorado School of
a Fax: q34 932275605 frequency and severity
Medicine, Denver, E-mail: ocoll@clinic.ub.es of the infection is
,
USA higher in primigravida
S and decreases with
p *This paper was worked out increasing parity. In
a under the auspices of the non-immune women, the
i WAPM to achieve
risk is similar across the
consensus on issues in
n perinatal practice. Coordi- parity and malaria may
2
Barcelona Center nator of the working group: be an important direct
for International Oriol Coll. cause of maternal
*
Health Research mortality. Malaria
(CRESIB), Institut * infection during
d’Investigacions C pregnancy has important
o nega- tive effects on
Biomediques r
August Pi i Sunyer r infant’s health, causing
(IDIBAPS), e intrauterine growth
s retardation and
Universitat de p prematurity or directly
Barcelona, Spain o
n through congenital
3
Neonatal
d infection. In this paper,
Unit, Institut i we review the pathology,
Clinic de n diag- nosis, and current
Ginecologia, g
recommendations for
Obstetricia i a treatment and prevention
Neonatologia u of malaria in the
t
pregnant woman and her
infant.
Keywords: Malaria;
mother-to-child
transmission; preg-
nancy; prevention;
treatment.

I
n
t
r
o
d
u
c
t
i
o
n

Malaria is caused by
infection with one or
more of four species of
Plasmodium (i.e., P.
falciparum, P. vivax, P.
ovale, and P. malariae)
and is a devastating
health prob- lem. Malaria
has its greatest impact in
sub-Saharan Afri- ca, but
the burden of the
disease is increasing in
Asia and Oceania w91x. It
is transmitted by the bite
of an infec- tive female
Anopheles sp. mosquito
although it can be also
transmitted through
transfusion of infected
blood, and from the
mother to the fetus.
Nearly half of the
world’s population lives
in endemic areas w113x
and it is estimated that
more than 500 million
episodes of clinical
disease occur each year
w91x. The estimated
death toll is
2.7 million w64x, of which
75% occur in children
younger than five years
of age in Sub-Saharan
Africa w88x. In non-
endemic areas, the
majority of reported
cases are import- ed
from endemic regions
although other sources
can be found such as
congenital infections,
infections second-
16 Coll et al., Treatment and prevention of malaria in pregnancy and newborn
 Coll et al., Treatment and prevention of malaria in pregnancy and newborn 17
ary to blood or blood cause of maternal 93, 103x (Table 1). The Tabl
derivatives transfusion mortality in this region. estimated number of e 1
annual deaths due to Preg
and except- ionally after Pregnant women are nant
a local mosquito bite particularly susceptible to malaria related LBW is wom
w63x. In endemic anoph- eles w50x and it is 7 en
countries, this burden well known that they are 5 and
, mala
is concentrated largely at higher risk to become ria.
0
among young children infected w26, 59x.
0
and pregnant women. Furthermore, during 0 1.
preg- nancy the Pregnant
– women
likelihood of microscopic 2 are at
M parasitemia increas- es 0 higher risk
a several fold w12, 33x. 0 due to:
l This susceptibility exists ,
0 Pregnancy-specific
a throughout pregnancy immunological
r but especially in the 0
factors that make
0
i second tri- mester, and them more
a to some extent into the susceptible to
puerperium w23x. During w malaria infection w50x
pregnancy, malaria is 9 Adhesion receptors
a 3 in the placenta that
n more likely to result in lead to placen- tal
x
d severe disease among . parasite
non-immune women w71x. sequestration w26x
The risk of pregnancy A particular attraction to
p anopheles
malaria is highest in a P
r
first pregnancy and a
e 2. Although signs and
among HIV infected t
g symptoms of malaria in
pregnant women w98x. h pregnancy are similar to
n
Recent data support o the non-pregnant adult,
a
that parasitemic pregnant l pregnant women have
n higher risk to develop
women in sub-Saharan
c o hypoglycemia, and
Africa do not frequently
y g complications such as
present clinical signs and,
y pulmonary edema and
therefore, it is difficult to cerebral malaria
Although all four
detect and cure early P. falciparum can be
Plasmodium species can
infections in pregnancy found in the intervillous 3. Malaria infection has
infect preg- nant women,
w14x. been associated with
only susceptibility to P. spaces of the maternal
Placental infection is pregnancy
vivax and P. falci- parum circulation of the complications
very variable and
is known to increase placenta w74, 104x espe- (miscarriage,
ranges from
during pregnancy. maternal anemia,
3.5% to 75% depending premature delivery
Around 50 million on the malaria infant low
pregnant women live in epidemiology in the area, birthweight,
endemic areas (half in seasonality of infection intrauterine demise,
sub-Saharan Africa), and etc. w61x. The only spe- maternal and infant
most of them in areas of cies that was shown to mortality) w 107x
intense P. falciparum colonize the human
transmission. Malaria placenta is P. falciparum,
infection during preg- cially in primigravid
and there is no evidence
nancy poses substantial women. Inflammatory
that other species such
risk to the mother, her response and maternal
as P. vivax can do it.
fetus (and the neonate). anemia may be
The fetus might be
It is a major cause of responsible for LBW
adversely affected as
severe maternal ane- mia through the production
well w27, 59x. Maternal
and responsible for an of inflammatory
malaria infection has
estimated 30–35% of cytokines w61, 74x. P.
been associated with
low birth weight (LBW) vivax has been
mis- carriage, maternal
babies and for 75,000– associated as well with
anemia, infant low
200,000 infant deaths LBW w70x, although it
birthweight (LBW)
each year w93x. Recent does not seem to
secondary to fetal growth
evidence suggests that sequester in the placenta
restriction, premature
the impact of malaria w57x. Information about
delivery, intrauterine
on the mother in sub- other species or
demise w107x and
Saharan Africa has been interspecies interactions
maternal and infant mor-
underestimated and that during pregnancy is
tality w7, 10, 17, 25, 35,
it may be an important scant w55x.
 18 Coll et al., Treatment and prevention of malaria in pregnancy and newborn
n
i
S t
i a
g l
n
s i
n
a f
n e
d c
t
s i
y o
m n
p
t D
o e
f
m
i
s n
i
Malaria symptoms t
usually occur between i
seven and fifteen days o
after a mosquito n
inoculation. Signs and
symptoms related to There is no clear
malaria infection are consensus on the
varied, but the majority of definition of congen- ital
patients have fever. It is malaria. Congenital
generally character- ized malaria is generally
by recurrent attacks with defined as malaria
moderate to severe acquired by the fetus or
shak- ing chills, high- newborn directly from
fever, profuse sweating the mother, either in
during the fall of body utero or during delivery.
temperature, general In endemic areas,
feeling of unease and demonstration of
discom- fort (malaise). parasites in the newborn
Other signs and within
symptoms are headache, 24 h of birth has been
nausea, vomiting and used as a diagnostic
diarrhea. Malaria should criterion. Around 40–
be sus- pected in every 50% of newborns with
febrile patient who lives malaria parasitemia
or has traveled to an
endemic area and in the
differential diagnosis of
patients who have
fever of unknown
origin, malaria should
also be considered. Any
patient with an untreated
P. falciparum infection
can rapidly progress to
coma, renal failure,
pulmonary edema, and
death w63x.

C
o
n
g
e
Coll et al., Treatment and prevention of malaria in pregnancy and newborn 19
 20 Coll et al., Treatment and prevention of malaria in pregnancy and newborn
have different genotypes presence of neonatal the placenta is more More recent
to those of the mother infection w14x. Placental severe following infec- epidemiological studies
and have no confirmed colonization is vari- able tion with P. falciparum suggest that the
placental infection. In and oscillates between w6, 74x. Parasites in the frequency of congenital
endemic areas, con- 3–75% according to the umbilical cord blood or malaria could be
genital malaria is epi- demiology of the fetal blood may be underestimated w3, 28,
considered only in the zone and seasonality w31, cleared spontaneously, 72x and may be
first week after birth, and 74x. The low frequency of resulting in no disease increasing.
thereafter it is considered vertical transmission was manifestation or may Transplacental trans-
as acquired. Outside attributed to the effective proliferate, with mission of P. falciparum
endemic areas, where barrier served by the development of clinical is not an uncommon
postnatal transmission placenta to the passage signs of the disease. event even in partially
can be reasonably of the parasite as well as Trans- mission of malaria immune women. This
excluded, it is evident to the protective effect of by breast-feeding does increase could be due to
that clinical onset of trans- placentally not occur. several factors such as
disease in congenital acquired maternal increased resistance of
malaria is usually antibodies in the fetus P. falciparum to
delayed several weeks. and newborn. It is antimalarial drugs
Many cases of congenital postulated that resulting in increased
malaria in endemic are- congenital malaria is maternal parasitemia w2,
as are, therefore, likely to more common in infants 16, 29x an increased
be misclassified as being of non-immune virulence w3x, and
post- natally acquired. In population and the previously many
addition, parasitemia incidence increases congenitally infected
detected shortly after during epidemics newborns were though to
birth may not always (www.malariasite. com). It be infected after birth w41,
evolve into clinically is more common among 49, 79x. More- over,
significant disease w94x. infants of women who newborns have
There is a need for a emigrate from areas in frequently low parasite
standard definition to which malaria is endemic densities that may be
facilitate the to areas that are free of undetected w39, 53x. The
comparability between malaria, presumably as a use of more sen- sitive
different epidemi- result of waning immunity PCR suggests that
ological and intervention from lack of continued congenital malaria may
studies of malaria in exposure. Pregnant be more frequent (10–
pregnancy. women are presumably 32%) w1, 45, 46, 52, 100,
at greater risk when they 115x, although it is
return to the endemic unclear if a positive PCR
Epi
area. The risk of represents an active
de
mio transmission decreases infection w85x.
log with increase in parity In non-endemic
y due to increase in countries, vertically
and acquired anti- bodies. acquired cases are
nat Women in their first or exceptional. In 2004 in
ural the US, a total of 1324
second pregnancy who
hist malaria cases were
ory live in endemic areas who
have a certain degree of reported of which only
immu- nity are at higher three were vertically
The prevalence of acquired w63x, and in
congenital malaria in risk of placental
Germany from a total of
non-immune mothers has colonization and, there-
9248 cases from 1993 to
been reported to be fore, to infect the
2003, no vertical
about 10% w79x and it offspring. In non-immune
transmission was identi-
occurs in -5% of women (travelers etc.),
fied w85x.
affected pregnancies. there seems to be no
A mother with
Malaria in preg- nancy is relationship between
asymptomatic
detrimental to the fetus. parity and risk of
parasitemia episodes in
Transplacental spread of congenital infection.
either endemic and non-
infection to the fetus can Although congenital
endemic areas, may
result in congenital malaria can be observed
transmit the infection to
malaria. There is a clear- with any of the human
the fetus. Clinical signs
cut relationship between malaria species,
and symptoms start
the intensity of the congenital infection is
between 2–6 weeks of
placenta/umbilical cord more severe with P.
life with failure to thrive,
parasitation and the falciparum. The
jaundice, fever,
inflammatory response in
 Coll et al., Treatment and prevention of malaria in pregnancy and newborn 21
hepatomegaly, anemia s
and low platelet count. i
t
e
s
D
i To assess the presence
a of parasites in adults or
g children, peripheral blood
n should be examined for
o parasites by a Giemsa-
s stained thick or thin film.
i Thick and thin blood films
s must be prepared
correctly to achieve an
Diagnosis of malaria can adequate accuracy and
be difficult. The clinical should be done by
diag- nosis is based on experienced laboratory
patient’s symptoms, personnel. This technique
physical findings, and remains the gold
epidemiological history. standard for laboratory
Malaria should be confirmation of malaria.
suspected in any febrile However, it depends
patient who lives in or
has traveled to an
endemic area.
In rural endemic
areas, the frequent
prevalence of
asymptomatic infections
and the lack of
resources has led
peripheral health facilities
to use presumptive treat-
ment to manage
malaria infection.
Patients with fever
without any obvious
cause are presumed to
have malaria and are
treated without laboratory
confirmation. This
practical policy allows
the treatment of a
potentially fatal disease,
even though it also
frequently leads to
incorrect diagnoses and
unnecessary use of
antimalarial drugs. This
results in additional
expenses and increases
the risk of selecting drug-
resistant parasites.

M
a
l
a
r
i
a

p
a
r
a
22 Coll et al., Treatment and prevention of malaria in pregnancy and newborn
 Coll et al., Treatment and prevention of malaria in pregnancy and newborn 23
on the quality of the r pregnancy: (i) treatment the women are non-
reagents, of the o of the infected women immune. Drugs proven to
microscope, and on the l and (ii) prevention of be safe should be used
experience of the o the exposed-uninfected unless no alternatives of
laboratory technician. g women. proven efficacy are
y Treatment options of available w111x.
A malaria during pregnancy Nevertheless, for many of
Serology detects
n should be according to the new drugs available
antibodies against
t the severity of maternal or under development,
malaria parasites but only
i disease. Preg- nant information is scarce or
detects a past and not a
g patients with severe worrisome w81, 105x.
e current infection. It may
malaria disease, Risks and benefits should
n be useful to detect the
including coma or be carefully assessed
level of exposure and is
respiratory distress, since maternal malaria
d an interesting tool in
should be treated with may have a great impact
e seroepidemiological
the best available on both mother and
t studies.
treatment regardless of newborn.
e
reproductive safety of the
c D
t r drug w81, 82x. Treatment of
i u In pregnant women uncomplicated
o g with symptomatic or malaria in pregnancy
n asymptomat-
ic parasitemia, severe The decision on the drug
r
Various rapid test kits disease may develop, or combinations of drugs
e
are available to detect especially if to be used during
s
antigens derived from i pregnancy will depend
malaria parasites and s on the severity of
may offer a useful t maternal disease, drug
alternative to microscopy a efficacy, maternal and
in situations where n fetal tox- icity, pregnancy
reliable microscopic c pharmacokinetics and
diagnosis is not e the level of drug
available. It is especially resistance in the area.
The development of
useful in the diagnosis of Unfortunately, the
resistance to drugs poses
malaria infection in non- disease may be very
one of the greatest
immune patients due to severe during pregnancy
threats to malaria control.
the frequently low but information on
Drug resistance has been
parasite density and low toxicity and
described for P.
reliability of microscopy. pharmacokinetics may be
falciparum and P. vivax.
The World Health very limited. The frequent
The prob- lem is
Organization provides emergence of resistant
especially with P.
technical information, strains in different areas
falciparum, which has
including a list of of the world and the
also devel- oped
commercially available need to use drugs with
resistance to nearly all
malaria RDTs an unknown fetal safety
other currently available
(http://www.wpro.who.int or even with proven
antimalarial drugs and
/rdt/.) toxicity are a great
varies considerably
challenge for clinicians.
depending on the area of
P Many of the older
the world. Several
C drugs are no longer
protocols exist for testing
R effective in preventing or
drug resistance in
treating malaria in many
In selected cases, if malaria and these have
parts of the world and
blood-film diagnosis or been devel- oped by the
little information is
species determination is WHO w110x.
available on the new
inadequate, a PCR can
ones. Many studies are
be performed. It is also
currently under way. Data
used for research Malaria
on out- comes of
purposes. This technique treatment
exposed women and
is more accurate than during
their babies after a com-
microscopy, but it is pregnanc
plete follow-up should be
expensive and requires a y
collected.
specialized laboratory.
Not all drugs or
Several scenarios must
combinations are
S be considered regarding
licensed in all coun- tries.
e malaria treatment during
Thus, first and second
 24 Coll et al., Treatment and prevention of malaria in pregnancy and newborn
line treatments may differ Chloroquine Although
between countries chloroquine currently
according to level of remains effective against
resistance, costs and most species, resistant
availability of the drugs. strains are very
The current WHO
recommendation for the
treatment of
uncomplicated malaria in
pregnancy relies on
artemisi- nin-
combinations in the
second and third
trimester as the first
choice, whereas oral
quinine for seven days is
the first choice in the first
trimester of gestation
w114x.

Sulfadoxine-
pyrimethamine (SP)
The components target
different enzymes in the
parasite’s folic acid path-
way. In recent years
alone, or in combination
with others, this was the
first line treatment for
uncomplicated malaria in
many African countries.
In more than 20 African
coun- tries, it is presently
recommended for
malaria treatment.
Several mutations were
recently identified that
may render SP
therapeutically useless.
Adverse events are
common with repeated
use w87x (Stevens-
Johnson syn- drome can
follow SP treatment w37x),
but its incidence is not
increased by pregnancy.
Although SP has shown
to be embryotoxic in rats
w20x, and although
pregnant wom- en should
not use SP during the
first trimester of preg-
nancy (theoretical risk
of causing neural tube
defects secondary to
maternal folate
deficiency), no increase
in spontaneous abortion
or congenital defects
has been reported w67x.
No information is
available on SP phar-
macodynamics in
pregnancy.
Coll et al., Treatment and prevention of malaria in pregnancy and newborn 25
 26 Coll et al., Treatment and prevention of malaria in pregnancy and newborn
common and it is seldom indicated to treat P.
falciparum. Emerging resistance is appearing in many
areas of the world w8x. Chloroquine has been used
extensively in pregnancy for malaria treatment and
prevention and appears to be safe during pregnancy and
lactation. Over- dose of chloroquine, however, is
common and may have severe effects. The theoretical
appearance of resistant strains is currently limiting its
use although this problem has to be properly evaluated
before excluding this drug from most treatment
protocols.
Mefloquine Mefloquine is effective for treatment of
malaria and has shown to be as well very effective in
prophylaxis in travelers in the second and third trimesters
of pregnancy. It can be administered weekly as it has a
very long half-life and it could replace SP for malaria
prevention. Current data support that mefloquine is safe
during pregnancy, including in the first trimester w77x.
Amodiaquine Aminoquinoline is similar to chloroquine
and is increasingly being used as part of first line therapy
where chloroquine is not effective. Amodiaquine
chemoprophylaxis was associated with severe toxicities
such as agranulocytosis and hepatic failure w36, 66x, but
these appear to be rare with treatment courses. No data
on animal toxicity have been published and very limited
information is available on safety and tolerability of
amodiaquine in pregnancy w99x.
Artesunate, artemether and artemisinins Treatment
with artemisinins should be continued for more than sev-
en days if given as single drug treatment and, therefore,
are usually used in combination with other drugs. Com-
binations with an artimisinin are quickly becoming very
common and are the current recommendation by the
WHO for malaria endemic areas w114x. No resistances
have yet been demonstrated to these drugs. Available
information, especially from East Asia, shows that arte-
misinins are at least as effective as alternative treatments
and maybe even better w11x. All these drugs may cause
similar adverse effects. Studies in rats and rabbits have
shown fetal resorption and skeletal abnormalities even at
relatively low doses.
Data from artesunate treatment in more than 600 preg-
nancies, in the second and third trimesters have not
revealed maternal or fetal toxicity w69x. It appears to be
safe as well if the mother is breast-feeding her infant.
Studies on its use during pregnancy are currently under
way. While such information is not available, artemisinins
should not be used for malaria treatment during preg-
nancy unless no other treatment is available.
Regarding artemether-lumefantrine, no data on its use
in pregnancy are available, but there is a trial in progress
in Thailand. Studies on reproductive toxicity and phar-
macokinetics of dihydroartemisinin and piperaquine have
yet to be carried out. Its use in pregnancy has been
reported in China w22x, without adverse events.
Chlorproguanil/Dapsone, or LapDap Research in
progress in Tanzania and Mali will provide data on phar-
macokinetics, safety, tolerability and efficacy in treating
infected pregnant women. Animal studies do not show
that LapDap has reproductive toxicity w19x.
Chlorproguanil-dapsone-artesunate (CDA) Research
involving pregnant women is currently underway. The low
cost of this treatment is an important advantage for inter-
mittent preventive treatment. It has the same problems
with regard to reproductive toxicity as other artemisinin-
based combination therapies.
Atovaquone-proguanil (Malarone ) In non-pregnant
individuals, this drug is increasingly being used for treat-
ment and prophylaxis in travelers. A low incidence of
adverse effects w96x and the fact that it needs to be taken
for seven days at the end of exposure are of great advan-
tages. Its high cost is a disadvantage for use in endemic
countries. When used in a small number of pregnant
women in combination with artesunate, it appeared to
be safe and highly effective against multi-drug resistant
malaria w56, 58x.
Treatment of severe or complicated malaria in
pregnancy
Quinine Quinine is still the treatment of choice for
parenteral treatment of severe malaria in pregnancy
w109x. Nevertheless, compliance is usually poor due to
the need of prolonged treatment (seven days), low
tolerability (gastrointestinal and ear symptoms) and very
bitter taste.
Quinine is a category C drug for the US Food and Drug
Administration. The increase in the rate of miscarriage or
stillbirth, however, is associated to malaria and not to
quinine w76x. Quinine-induced hypoglycemia is more
common in pregnant women w106x and requires moni-
toring of blood glucose and parenteral dextrose supple-
mentation if necessary.
Artesunate It has recently been described that parent-
eral artesunate is superior to quinine in the treatment of
severe malaria w24x and thus it is likely that intravenous
artesunate will become the treatment of choice in severe
cases for pregnant women especially in Asia where qui-
nine has a lower efficacy. However, given the concerns
regarding reproductive safety, studies are needed in
African pregnant women to confirm the superiority of
artemisinin derivatives over quinine, before a general rec-
ommendation for pregnancy is made.
An international consortium of experienced scientists
in the field of malaria in pregnancy is being developed to
answer the main questions regarding the control of
Table 2 Malaria treatment during pregnancy.
Severe disease
Treat with the best (more efficacious) available treatment
regardless of reproductive toxicity of the drug
Uncomplicated symptomatic malaria or with an asymptomatic
parasitemia
Risk of developing severe disease. Treat with drugs of well
established safety profile in pregnancy
Chemoprophylaxis
Use drugs with of well established safety profile in
pregnancy
Drugs to be used will depend on:
Severity of maternal disease
level of maternal immunity against malaria
Drug efficacy
Maternal and fetal toxicity
Pregnancy pharmacokinetics (not well established)
Emergence of resistant strains in the area
malaria in pregnancy. This will include the careful evalu-
ation of drug alternatives to the current ones in different
endemic settings.
Tables 2–4 summarize the various malaria treatments
during pregnancy.
Malaria prevention in pregnancy
Drug based prevention
Chemoprophylaxis Chemoprophylaxis in pregnancy
has shown to reduce maternal anemia and low birth
weight, particularly in first and second pregnancies w32x.
Chloroquine chemoprophylaxis was until recently
widely recommended during pregnancy in African wom-
en for malaria prevention due to its low cost, availability,
and good safety profile during all trimesters. The emer-
gence of resistant parasites has currently made its use
unpractical in many parts of the world, a poor compli-
ance to weekly chemoprophylaxis was already a problem
w84x. It is currently being only used in some countries in
West Africa, Latin America and India. At present, chlo-
roquine has almost no role except against P. vivax, which
is usually resistant to SP. In Latin America no chemopro-
phylaxis is presently used, although it is recommended
as policy in some countries.
A different approach to prevent pregnancy malaria
complications was investigated to overcome the low
compliance of weekly chemoprophylaxis: Intermittent
Preventive Treatment in Pregnancy (IPTp). The mode of
action of this strategy is not fully understood. It may act
through the reduction of parasitemia, clearing of placen-
tal infection or through a prophylactic effect against new
infections w82x.
Intermittent preventive treatment during pregnancy
(IPTp) IPT is currently the recommended approach to
prevent malaria in pregnancy in areas of stable malaria
transmission such as most of sub-Saharan Africa. IPT
consists of a full course of an anti-malarial treatment to
a population at risk at specified time points regardless of
whether or not they are known to be infected. IPT is also
being explored as a potential way of preventing malaria
in infants but its effect on this subgroup of patients has
not yet been demonstrated. Several issues need to be
addressed before intermittent preventive treatment in
children can be advocated for use in malaria control pro-
grammes. Several trials are currently being conducted to
address this issue.
Sulfadoxine-pyrimethamine (Fansidar, or SP): An
African study showed that two treatment doses during
pregnancy of SP was more effective than chloroquine
treatment doses or prophylaxis w86x. Furthermore, other
studies have shown an increase in birth weight and
maternal hemoglobin w47, 89, 102x with a low morbidity

Table 3 Treatment of uncomplicated malaria in pregnancy.

Area/Plasmodium Resistance Adverse events Pregnancy 18 trimester use

strains lactation safety

SP Africa Increasing Well tolerated Safe No (theoretical risk)

Chloroquine No P. falciparum Increasing Common risk of Safe Yes
overdose
Mefloquine* All No Frequent Safe Yes
Quinine ? No Safe Recommended drug
Artesunate All No Well tolerated Safe† No
Artemether
Artemisinins
New drugs: ? ? ? Safe†
Chlorproguanil/Dapsone, or LapDap , Chlorproguanil-dapsone-artesunate
Atovaquone-proguanil). To be evaluated during pregnancy
SPsSulfadoxine-pyrimethamine.
*Could replace SP for malaria prevention.
†
Very limited information. To be used only if no other treatment is available.
Table 4 Treatment of severe or complicated malaria in pregnancy.

Parenteral treatment Side effects Complications

Quinine Treatment of choice Common Few (hypoglycemia)
Artesunate Likely future ? Risk of fetal toxicity
similar to treatment. It is recommended that in areas with
stable transmission, IPTp with SP at least twice a week
should be used. HIV infected women may require more
frequent doses w75x. SP is today the only option for ITPp
and, therefore, due to the appearance of resistant para-
sites, alternatives to SP should urgently be investigated
w75x. WHO recommends IPTp in at least two treatment
courses of SP, at least one month apart, administered
from the second trimester onwards w112x. Unfortunately
such regimens do not seem to overcome compliance lim-
itations of chemoprophylaxis and implementation of a
second dose is surprisingly poor w38, 80, 101x. Although
this strategy is promising, more research on other strat-
egies is needed.
Although more costly, monthly administration may
have an advantage over two dose and should be encour-
aged. However, studies are needed to assess the safety
and cost-effectiveness of the monthly administration
before it is widely recommended.
Alternatives to SP for IPTp: No IPTp studies with oth-
er drugs have been performed, and further exploration
on the role in prophylaxis and efficacy of IPT in pregnan-
cy is needed. Although mefloquine may cause some side
effects, a single study with a treatment dose (750 mg)
followed by weekly prophylaxis (250 mg) resulted in
improved birth weights due to decreased placental
malaria w92x. IPTp studies with chlorproguanil-dapsone
(LapDap) are under way and others with drugs combi-
nations will follow. The combination of SP and
artesunate is potentially promising for use in West Africa
and other areas where SP resistance is still uncommon.
SP plus azithromycin is also being investigated.
Azithromycin is safe during pregnancy and has a broad
spectrum of anti- bacterial and antimalarial activity and
may be especially useful in HIV-infected pregnant
women.
Dapsone has extensively been used to treat leprosy.
Its role in pregnancy was recently reviewed w13x and has
not been associated with reported adverse effects w44x.
Table 5 Malaria drug based prevention in pregnancy.
Cost/availability/safety
Chemoprophylaxis
Chloroquine Good
IPTp
SP Only option for IPT
Alternatives None properly evaluated
SPsSulfadoxine-pyrimethamine.
IPTpsIntermittent preventive treatment during pregnancy.
A bi-weekly prophylaxis in combination with pyrimetha-
mine (Maloprim ) proved successful in pregnant Gam-
bian women w34, 60x, but more studies are needed.
Potential toxicities include methhemoglobinemia and
hemolysis in G6PD deficient individuals. The appearance
of pyrimethamine resistance in Africa may limit its future
use.
The international consortium on malaria in pregnancy
will be also evaluating alternative drugs to SP as IPTp as
one of its main objectives. Table 5 summarizes malaria
drug based prevention in pregnancy.
Non-pharmacological interventions
Several strategies have been developed to reduce the
risk of mosquito bite and patient susceptibility to infec-
tion. A reduction in human-vector contact by use of
insecticide treated nets (ITN) has proven to be effective
in Africa in reducing mortality due to malaria in children
under five years of age. Vector controls effort such as
indoor residual spraying and source reduction (larval con-
trol) can be envisaged but several factors limit its use
including: cost, insecticide resistance and ecologic bar-
riers. Certain malaria vaccines such as RTSS/AS02A
combination protected young children from infection and
several other vaccines are currently being developed w4,
9x (see Table
6).
Mosquito bite protection Mosquitoes usually bite
between dusk and dawn. To avoid being bitten, women
should remain indoors in a screened or air-conditioned
area during the peak biting period and if outdoors, they
should cover their exposed skin with insect repellent.
Three recent independent studies in East Africa
showed that ITN use during pregnancy results in signifi-
cant health benefits for both the mother and her infant
w54, 68, 97x. WHO is currently recommending its use in
sub-Saharan Africa. The recommendation is that ITNs
Resistant strains Compliance
Increasing Poor
? 28 dose poor
Promising
Table 6 l b malaria outweigh those
Non- l associated with
pharmacol e prophylaxis. Safe
c
ogical
l chemoprophylaxis
interventio
i 6 regimens are available
ns.
n .
i (http://www.cdc.gov/trave
Reduction of risk of c l/mal_preg_pub.htm).
mosquito bite and . Despite the risk, most
patient susceptibility to
infection
S travelers can avoid
Insecticide treated nets p contracting malaria by
should be offered to all
(ITN): e taking several
pregnant women
Effective during c precautions.
pregnancy. attending ante- natal
i General measures: If
Operational research clinics where issues such
a they live in an endemic
needed. Issues of as IPTp are discussed.
distribution very The goal of achieving a
l area they should ensure
relevant (through mosquito bite protection
target of 60% of pregnant
ANC) s by use of DEET-
women sleeping under
Mosquito repellent i
(DEET): an ITN by 2005 is far
Safe in pregnancy. from being reached and t
Clinical benefit not yet other operational u
demonstrated strategies should be a
assessed. The value of t
V i
adding both interventions
a
c in Africa is currently o
c being assessed. n
i Mosquito repellents s
n
such as N, N-diethyl-m-
e
s toluamide (DEET) are T
safe to use in pregnancy h
but clinical benefit e
f
o remains to be
r demonstrated. Efficacy p
and safety of resid- ual r
m indoor spraying (RIS) has e
a g
not yet been evaluated in
l n
a the settings where it is a
r used. Pregnant women n
i should use insect t
a repellent as
recommended for other t
i adults and wash it off with
n r
soap and water after a
coming indoors. v
p
e
r
e Vaccines for malaria in l
g pregnancy Effective e
n r
vaccines might reduce
a
n the impact of malaria Prevention of malaria
c during pregnancy, There is no easy
y especially in areas where strategy to prevent
When available, need to immunity may be
be evaluated in pregnant malaria in naı¨ve
incomplete prior to the pregnant women
women
Likely to reduce the first pregnancy w80, 81, traveling to endemic
impact of malaria during 95x. It is theoretically areas. These are the
pregnancy feasible to develop patients at greatest risk
A vaccines specific to to develop a severe
N pregnancy through disease. Pregnant
C blocking of adhesion of
s travelers should be
A parasites to placental counseled to avoid
n CSA w26x. traveling to risk areas. If
t Non-pharmacological deferral of travel is
e interventions are
n impossible, pregnant
summarized in
a women should be
t T
informed that the risks for
a a
containing repellents that serious general or preg- increased risk to develop
are not toxic, use of nancy complications. severe disease and
appropri- ate protective Pregnant women should combine
clothing, and avoiding originally from areas insecticide treated nets
exposure to vectors at where malaria is endemic and IPT.
night. but live in non-endemic
Chemoprophylaxis: areas may be only par- H
There is extensive tially immune. When I
experience with traveling to their V
chloroquine, alone or with countries of origin, they
proguanil, for prophylaxis should be considered as i
in pregnancy, and this non-immune and receive n
policy is recommended the same f
for trav- eling to areas recommendations as the e
with chloroquine- general non-immune c
t
sensitive malaria (www/ women.
e
who.int/publications/2005. d
International travel and Treatment of clinical
health). However, these disease in non-immune p
areas are very limited pregnant women Non- r
and the current immune pregnant women e
recommendation is the are at great risk of g
combination of chloro- developing severe n
quine once or twice disease. Quinine is a
weekly plus daily generally rec- ommended n
proguanil. This for treatment of P. t
combination can be falciparum in pregnant w
safely administered women who are not o
during all tri- mesters. m
immune. The risk of
e
Mefloquine is the induced hypo- glycemia n
treatment of choice in has to be considered
second and third w51x. In high quinine resis- The severity of malaria in
trimesters and the tance areas, the HIV infected pregnant
Centers for Disease treatment of choice women may be due to
Control also recommend when available should the lack of specific
this protocol during the be artemisinins. immunity. This group
first trimester (CDC Nevertheless, problems may require more
website). Currently, there such as safety and lack frequent doses of IPTp
is no evidence on the of registration in most w75x and more
safety of other endemic areas, have to
antimalarials in be taken into
pregnancy. It has been consideration.
shown that doxycycline
can cause toxic effects M
to the fetus, and no i
information during g
pregnancy is available on r
atovaquone-proguanil a
(Malarone ). Travelers n
should be aware that: t
s
missing or delaying
doses increases the risk
of acquiring malaria, a
n
chemoprophylaxis should
d
be continued after
leaving the malaria-risk
r
area and that overdose
e
can be fatal. Most
f
antimalarial drugs are u
well- tolerated; and most g
travelers do not need to e
stop taking their drug e
because of side effects. If s
infection occurs, delaying
treatment can lead to These women are at
adverse events to chloroquine, proguanil, c d
e
several drugs are amodiaquine or meflo- )
expected w43, 73x. quine by the mother. w
o
Cotrimoxazole is Chloroquine and o m
recommended for mefloquine are found in r e
prophylaxis of oppor- breast milk but only in n
tunistic infection in HIV such small amounts that w Higher risk of
except during the first they are not i severe disease
t and adverse
trimester. This drug is contraindicated during events
h
also effective in treating breast-feeding. These Cotrimoxazole and
malaria in non-preg- nant levels are insufficient to protease might be
p
adults and children w5, protect the newborn. r
useful for both
62x, but its efficacy in Atovaquone/proguanil o infections, but
preg- nant women is should not be taken by g need to be
u evaluated. Not yet
unknown. Protease women breastfeeding
a specific
inhibitors have shown to children under 11 kg, and n recommendation
have direct and indirect primaquine is i other than vector
effects on malaria in vitro contraindicated in those l control measures
w65, with G6PD deficiency. First trimester, (ITNs and mosquito
90x. When widely used Scant information is also repellents)
chloroquine
in Africa, these drugs available on doxycycline,
and proguanil.
might be useful for both but it seems to be safe In chloroquine-
infections, but this needs during breast-feeding. resistant
to be evaluated. Table 7 areas
summarizes aspects for (frequent):
Table 7
specific groups at mefloquine in
all trimesters
i Specific
n
groups Treatment of clinical
c disease
r Quinine is generally
e at
recommended for
a P. falciparum High
increase
s quinine resistance
e d risk. areas: artemisinins
d are recom- mended
Pregnan (if available)
r
i t women M
i
s
traveler g
k r
. (non- a
n
immune) t
s
Prevention
B A pregnant woman a
r should not travel to a n
e Malaria d
Risk-area
a
If travel is unavoidable
s or living in an r
t e
endemic area:
f
- General measures:
u
f sleep under g
e insecticide treated e
net, use of mosquito e
e repellent (DEET) and s
d protective clothing Combine ITNs and IPTp
i Chemoprophylaxis:
n Chloroquine, H
g alone (only if I
known non- P. V
falciparum
There is no information r
e i
on adverse events in n
s
breast-fed infants f
i
associated with the s e
intake of antimalarial t c
a t
drugs such as e
n
Considerations for and have a key role in during pregnancy.
future strategies for improving malarial Unless the patient has
malaria prevention control in pregnancy a complicated disease
and treatment during including: access to and a safer alternative is
pregnancy drugs and availability of not avail- able:
antenatal care. Different doxycycline, primaquine,
N strategies have to be put or atovaquone/proguanil
e in place in each different or artemisinins’
w setting to overcome local derivatives should not be
problems. Each dif- used in the first trimester.
d ferent setting will
r encounter very different
u problems. New strategies M
g have to adapt to such a
s specific problems. l
a
o Other specific new r
r aspects: dosing, i
adverse effects and a
c cost-effectiveness of
o different strategies
m i
b As with many other drugs n
i in pregnancy, dosages
n c
rec- ommended for both
a h
treatment and prevention
t
in preg- nancy are the i
i
o same as in non-pregnant l
n adults. Nevertheless, d
s dosing during pregnancy r
may have to be e
In the very near future reevaluated. Studies on n
several drugs will have pharmacokinetics during
to be replaced. About 20 preg- nancy are S
new drugs are at required. Any drug i
different stages of prophylaxis or treatment g
development n
will be used on a large
(www.mmv.org) and s
scale. Therefore, adverse
some are very prom- effects have to be closely
ising alone or in monitored. a
combination. If efficacy is n
Pharmacovigilance, espe-
proven in the general d
cially post marketing
population, these drugs surveillance, to detect
should be evaluated dur- s
serious adverse events
ing pregnancy. Safety y
during pregnancy is m
during pregnancy and needed. p
during all trimesters and The proper t
lactation should also be assessment of cost- o
evaluated. effectiveness of the m
different prevention s
N strategies is especially
e important in limited The majority of neonates
w resources settings. The with a congenital
new drugs for preventing infection are
s malaria are more asymptomatic. Onset
t expensive and the impact may be as early as 14 h
r of age to as late as 8
on health has to be
a weeks but on an
t determined in a cost-
effectiveness average onset is
e between
g assessment.
Some drugs are 10 to 28 days of life.
i
Fever, irritability, feeding
e contraindicated because
problems,
s they are not safe or there
is insufficient information
Several other factors available about their use
have to be considered
anemia, and Rhesus alloimmuni- ion of (f) Only very small
thrombocytopenia, zation. treat concentrations of
reticulocytosis, loose ment antimalarial drugs
is
stools, failure to thrive, T are detected in
seve
jaundice, r breast milk, the
n
hepatosplenomegaly and e amount is neither
days.
res- piratory distress may a harmful nor
t Add clindamycin:
occur w108x. The 20–40 mg/kg/day protective against
m
incidence of infant every 8 h for five malaria.
e
mortality secondary to n days.
congenital malaria in t (d) Quinine resistant
endemic are- as is cases: Halofantrine Pre
unknown. Among the Currently, information ven
based thera- pies
cases of congenital available regarding the tion
may be used w40x.
malaria reported outside clinical management of (e) Exchange of
malaria areas, short-term congenital malaria is transfusion may be mal
outcome was generally scant. required when para- aria
favorable. All newborns with sitaemia exceeds in
The delay in positive hematological 10%. Supportive chil
presentation of examination or with risk dre
management for
factors (malarial parasite n
congenital malaria could fever; fluids, calories
be attributed to some demonstrated in mother and electrolytes. Prevention of malaria in
degree of resistance of during pregnancy) and
children traveling to
newborns to neonates with suggestive
endemic areas As with
multiplication of malaria disturbances need
adults, keystones of
parasites because of treatment.
malaria prevention are
fetal hemoglobin, failure
(a) Mild infections or assessment of risk of
of parasites to grow in
parasitaemia by P. infection based on travel
cord blood, persistence
vivax, P. ovale, P. itin- erary, person
of maternal IgG in the
malariae or protection measures
newborn’s blood, and
chloroquine (reducing risk of mos-
fast elimination of
sensitive P. quito bites), appropriate
parasites from the fetal
falciparum: chemoprophylaxis and
circulation.
Chloroquine orally seeking early medical
10 mg/kg initially, care of fever within two
D
followed by months after travel. It is
i
a 5 mg/kg after 6 h not recommended that
g and then once a day an infant -6 weeks old
n for the next two should travel to an
o days. Primaquine is endemic area. If strictly
s not required for necessary,
i treatment as the chemoprophylaxis with
s tissue phase is chloroquine and proguanil
absent in congenital can be given while the
If congenital malaria P.
malaria. (CDC, infant (even -6-weeks-
falciparum is untreated, it
www.cdc.gov). old) is under malaria
can be rapidly lethal,
(b) Severe infection: exposure and continuing
especially in babies born
Quinine initially 20 four weeks after the
to non-immune women
mg/kg IV in 5% infant has returned from
w21, 39, 83x. Therefore, a
dextrose over 4 h the endemic area.
diagnosis is crucial in
followed by 10 Personal protection
treating the disease. The
mg/kg/8 h IV until measures: All protective
diagnosis is by the
oral treatment is person- al measures
examination of peripheral
possible, for a total previously described for
blood for malarial
duration of seven the adult, apply for
parasite taken from cord
days. (CDC. children (stay indoors at
blood, heel prick or
www.cdc.gov). night, wear appropriate
Buffy-coat test. PCR of
(c) Chloroquine resistant clothing, use insecticide
the DNA and the
cases (most frequent treated nets with DEET,
antigenic quick tests are
with P. falciparum): etc.). Permethrin treated
also useful. Several
Quinine is given
other infections have to clothing may be helpful
parenterally until oral
be ruled out such as w15, 18, 30x. When
treatment is
CMV, herpes, rubella, outdoors, insect
possible.
toxoplasmosis, syphilis repellent containing
Durat
G30% DEET on (www.cdc.goc/travel/dise
exposed skin is ases.htm malaria), the
recommended for CDC Health Information
children G2 months of for International travel
age. Insect repellent 2005–2006 and the
should not be applied to malaria Case
eye, mouth and wounds Management Hotline
or broken skin. Several (
non-DEET repellents are 7
promising. Picardin (a 7
0
piperidine derivative) has
-
been used in several 4
areas and no serious 8
adverse events have 8
been reported; duration -
of protection, however, 7
may be less than with 7
DEET. Oil of lemon euca- 8
lyptus formulations 8
)
appear to be safe, but is
.
only rec- ommended in
children three years of
age w15, 48, 78x.
Chemoprophylaxis:
As with adults, the choice
of che- moprophylaxis
will depend on the travel
destination including the
risk of acquiring malaria,
risk of drug resis- tant
parasites in that area,
drug availability, risk of
adverse events and costs
of treatment. In all cases,
par- ents should be
aware that no
chemoprophylaxis is
100% protective. It is
generally recommended
that daily pro- guanil and
weekly chloroquine
should be administered.
No data on the safety of
other drugs on newborns
are available (malarone,
amodiaquin, mefloquin,
artemisinin derivatives).
Dosages are
determined by weight
and should never exceed
adult dosage.
Chemoprophylaxis
should begin
1–7 days prior to arrival
and end 1–4 weeks after
depar- ture depending on
the drug used. As with
adults, drugs are
generally well tolerated
but they may cause
adverse effects.
Clinical information is
available on the CDC
malaria website
Prevention of malaria in l Proguanil
children resident in o m
Same instructions as
endemic areas To q g
with Chloroquine.
protect infants, the u /
It is currently
preventive measures i w
recommended that
n e
described by the WHO in Proguanil and Chlo-
e e
the ‘‘Roll Back Malaria’’ roquine are used in
k
cam- paign could be combination.
Adult dosage: 250 .
used including prevention mg/week (full stomach )
of mosquito bites through with a full glass of liquid). Side effects: nausea
use of ITNs and early First dose 1 week and vomiting, headache, Appendix 2.
detection and treat- ment before arrival. dizzi- ness, blurred Hotlines for
of symptomatic cases. Last dose 4 weeks vision, and itching. Most
pregnant women if
IPT is the currently after leaving risk area. travelers do not have
Side effects seldom side effects serious
complications occur
recommended approach
serious enough to stop enough to stop taking the
to prevent malaria in
prophy- laxis. Most drug. Center for International
pregnancy and is being common side effects: Contraindicated in Health, Hospital
explored as a potential headache, nausea, patients allergic. Clinic/Barce- lona
way of preventing dizziness, difficulty University, Barcelona,
malaria in infants. sleeping, anxiety, vivid Spain.
Several issues need to dreams, and visual Centers for Disease
be addressed before disturbances. Serious Control Malaria Hotline
intermittent preventive side effects: very rare. at 770-
treatment in children can Not to be used if: 488-7788.
be advocated for use in depression, psychosis or
malaria control generalized anxiety
disorder, history of Web pages on malaria
programmes. Several
seizures, allergy or if
trials are currently being cardiac conduction http://www.cdc.gov/m
conducted to address abnormalities. alaria/diagnosis_treat
this issue ment/ clinicians1.htm
(http://www.ipti- http://www.mayoclini
C
malaria.org). c.com/health/malaria/
h
DS00475/
Recent advances in l
DSECTIONs2
molecular pathogenesis o
http://www.planetwire
of the disease have r
.org/files.fcgi/3438_B
contributed to the o
Pmal- Ma02e.pdf
development of can- q
http://www.ipti-malaria.org
u
didate vaccines. As
i
previously mentioned, the
n
RTS S/AS02A malaria e
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