MALARIA IN PREGNANCY

Elita Ismi, Nastiti Bekti, Shofi Iqda, and Sastika Herdiyanti

Faculty of Medicine, Jember University, Jember - Indonesia

1. Background
Malaria, a parasitic infection transmitted by mosquitoes, is one of the most
devastating infectious diseases, killing more than 1 million people annually.
Pregnant women, children, and immunocompromised individuals have the highest
morbidity and mortality, and Africa bears the heaviest burden. The World Health
Organization defines malaria as a disease of poverty caused by poverty. Pregnant
women infected with malaria usually have more severe symptoms and outcomes,
with higher rates of miscarriage, intrauterine demise, premature delivery, lowbirth-weight neonates, and neonatal death. They are also at a higher risk for severe
anemia and maternal death. Malaria can be prevented with appropriate drugs, bed
nets treated with insecticide, and effective educational outreach programs.
Malaria is the second most common cause of infectious disease-related
death in the world, after tuberculosis. It is estimated to affect between 350 to 500
million people annually and accounts for 1 to 3 million deaths per year.1,2 SubSaharan Africa has the largest burden of malarial disease, with over 90% of the
worlds malaria-related deaths occurring in this region. Twenty-five million
pregnant women are currently at risk for malaria, and, according to the World
Health Organization (WHO), malaria accounts for over 10,000 maternal and
200,000 neonatal deaths per year.
These figures may underestimate the impact malaria has in maternal
morbidity and mortality. A recent study from Mozambique that assigned cause of
maternal death via autopsy examination found that up to 10% of maternal deaths
were directly attributed to malarial infection and 13% were secondary to human
immunodeficiency virus (HIV)/AIDS, which can be exacerbated by coexisting
malarial infection. This suggests that in parts of the world where malaria is
endemic, it may directly contribute to almost 25% of all maternal deaths.

Malaria in pregnancy also contributes to significant perinatal morbidity

and mortality. Infection is known to cause higher rates of miscarriage, intrauterine
demise, premature delivery, low-birth-weight neonates, and neonatal death. As
funding increases to combat both malaria and maternal mortality, understanding
how malaria specifically affects pregnant women is crucial in our efforts to
improve maternal and perinatal health and curb the spread of this preventable
infectious disease.
2. Epidemiology
Malaria is a parasitic infection caused by the 4 species of Plasmodium that
infect humans: vivax, ovale, malariae, and falciparum. Of these, Plasmodium
falciparum is the most deadly. The infection is transmitted by the female
anopheline mosquito; therefore factors that influence mosquito breeding, such as
temperature, humidity, and rainfall, affect malaria incidence. In the United States,
malaria

was

eradicated

in

the

1940s

after

widespread

spraying

of

dichlorodiphenyltrichloroethane (DDT) in the South. Other areas of the world,

including Europe and parts of Central and South America, have also had success
in eradicating malaria, whereas Sub-Saharan Africa continues to bear the burden
of disease.
3. Classification
3.1 Severe and complicated malaria
The severe signs of malaria are non-specific and other causes must be
excluded before assigning the signs and symptoms to malaria (Box 1). The
parasitaemia of severe malaria can be less than 2%. Pregnant women with
2% or more parasitised red blood cells are at higher risk of developing
severe malaria and should be treated with the severe malaria protocol.
3.2 Uncomplicated malaria
Uncomplicated malaria in the UK is defined as fewer than 2% parasitised
red blood cells in a woman with no signs of severity and no complicating
features.

3.3 Congenital malaria

Congenital malaria in the very young infant or newborn results from the
passage of parasites or infected red blood cells from the mother to the
newborn while in utero or during delivery and not by the bite of the female
anopheline mosquito.
3.4 Artemisinin combination therapy
Artemisinin combination therapy is a combination of artemisinin or one of
its derivatives with an antimalarial or antimalarials of a different class.
3.5 Resistance
Resistance is defined as the ability of a parasite strain to survive and
multiply despite the administration and absorption of a medicine given in
doses equal to or higher than those usually recommended but within the

tolerance of the subject, with the caveat that the form of the drug active
against the parasite must be able to gain access to the parasite or the
infected red blood cell for the duration of time necessary for its normal
action.
4. Pathophysiology
Malaria is transmitted when an infected mosquito takes a human blood
meal and the Plasmodium sporozoites are transferred from the saliva of the
mosquito into the capillary bed of the host. Within hours, the parasite will
migrate to the liver, where it undergoes further cycling and replication before
being released back into the hosts bloodstream.
The incubation period, from the time of mosquito bite until clinical
symptoms appear, is typically 7 to 30 days. Symptoms include fever,
headache, nausea, vomiting, and myalgias. Due to the cycling parasitemia in
the bloodstream, patients will often experience symptoms every 2 to 3 days,
depending on the type of Plasmodium with which they are infected.
In the human, plasmodial infection is a complicated reproductive life cycle
involving hepatic and erythrocytic infection. Once the sporozoite enters the
liver, it multiplies and exits into the bloodstream in the merozoite form. The
merozoite then invades erythrocytes, leading to phagocytosis of infected
blood cells by the spleen. Malarial symptoms are caused mainly by the red
blood cell invasion and the bodys inflammatory response. Malarial infection
causes marked immunoglobulin synthesis and, in the case of P falciparum,
creates immunoglobulin complexes and increased production of tumor
necrosis factor. The ability of P falciparum to cause cytoadherence of
erythrocytes to vascular walls leads to sequestration of infected cells in small
blood vessels, causing end organ damage via hemorrhage or infarct.
Phagocytosis of infected blood cells in the spleen helps clear infection, but
also contributes to profound anemia and folic acid deficiency.
It has been established that repeated malarial infections lead to some
immunity. In fact, in areas where malaria incidence is episodic rather than
endemic, patients will present with more severe forms of the disease, as their

previously learned immunity appears to fade over time. It is not surprising,

therefore, that malaria-naive and immunocompromised patients are prone to
more severe infection. This puts pregnant women, children, travelers to
endemic regions, and persons with coexisting HIV infection at highest risk
for morbidity and mortality secondary to malarial infection.
4. 1
Incubation period
95% of cases develop symptoms within one month. Incubation period
depends on the species
P. falciparum 9-14 days
P. vivax and P. ovale 12-18 days
P. malariae 18-40 days
P. knowlesi 9-12 days
4. 2
Route of transmission
Malaria is caused by the bite of the female Anopheles mosquito, which
results in infection of the red blood cell.
4. 3
Plasmodiums Life Cycle
The malaria parasite life cycle involves two hosts. During a blood
meal,

malaria-infected

female Anopheles mosquito

sporozoites into the human host

mature into schizonts

inoculates

. Sporozoites infect liver cells

and

, which rupture and release merozoites

. (Of

note, in P. vivax and P. ovale a dormant stage [hypnozoites] can persist in

the liver and cause relapses by invading the bloodstream weeks, or even
years later.) After this initial replication in the liver (exo-erythrocytic
schizogony

), the parasites undergo asexual multiplication in the

erythrocytes (erythrocytic schizogony

cells

). Merozoites infect red blood

. The ring stage trophozoites mature into schizonts, which rupture

releasing merozoites . Some parasites differentiate into sexual

erythrocytic

stages

(gametocytes)

. Blood

stage parasites

responsible for the clinical manifestations of the disease.

The gametocytes, male (microgametocytes)

and

are

female

(macrogametocytes), are ingested by an Anopheles mosquito during a

blood meal

. The parasites multiplication in the mosquito is known as

the sporogonic cycle

. While in the mosquito's stomach, the

microgametes penetrate the macrogametes generating zygotes

. The

zygotes in turn become motile and elongated (ookinetes)

which invade

the midgut wall of the mosquito where they develop into oocysts
oocysts grow, rupture, and release sporozoites

. The

, which make their way

to the mosquito's salivary glands. Inoculation of the sporozoites

into a

new human host perpetuates the malaria life cycle.

5. Diagnosis
Suspicion of malaria requires prompt confirmation by malaria blood film,
as there are no clinical algorithms that permit accurate diagnosis by signs and
symptoms. In its early stages, the symptoms and signs of malaria can mimic
influenza and other common viral infections.

Misdiagnosis has been reported to occur when the leading symptoms are
jaundice or respiratory3840 and possibly gastrointestinal (certainly in
children) in nature. Misdiagnosis and delay of treatment are the most
common reasons cited for death from malaria in Europe and the USA. For the
non-falciparum malarias, the history of travel may be more than 1 year before
the onset of symptoms and, for any woman who has taken prophylaxis,
compliance does not rule out the diagnosis of malaria. In the only case series
of imported malaria in pregnant women in Europe (Marseille, France), the
majority (14 of 18) had fever and the four women who did not, had
thrombocytopenia or anaemia associated with splenomegaly.

A history of travel to the tropics and the non-specific nature of the

symptoms and signs will lead clinicians to consider investigating other travelrelated diagnoses, according to the region visited; for example, influenzalike
illnesses including H1N1, severe acute respiratory syndrome, avian influenza,
HIV, meningitis/encephalitis and viral haemorrhagic fevers, hepatitis, dengue
fever, scrub and murine typhus and leptospirosis. However, for malaria
diagnosis a blood film is vital.
Malaria should be considered in pregnant women with a fever who have
travelled to malaria-endemic areas
Laboratory diagnosis
Collect blood in an EDTA tube for thick and thin films to detect

malarial parasites.
In a febrile patient, 3 negative malaria smears 12 to 24 hours apart

rules out the diagnosis of malaria

Rapid diagnostic tests for malaria antigens should also be requested

(a negative antigen test does not exclude malaria)

Other tests should include complete blood examination, urea,
creatinine, electrolytes, liver function tests, serum glucose, venous

pH, serum lactate and coagulation studies

Antepartum
Regular antenatal care including assessment

of

maternal

haemoglobin, platelets, glucose and fetal growth scans is advised

following recovery from an episode of malaria

If growth restriction is identified, follow management as per Fetal

growth restriction
Intrapartum
Uncomplicated malaria in pregnancy is not a reason for induction of

labour
Vertical transmission to the fetus can occur particularly when there is
infection at the time of birth and the placenta and cord are blood film

positive for malaria

Send placenta for histopathology
Send additional cord and infant blood films to detect congenital
malaria

6. Complication
Malaria in pregnancy adversely affects the mother and fetus. The main
complications are:
Miscarriage
Stillbirth
Preterm birth
Low infant birthweight
Severe maternal and neonatal anaemia
7. Treatment
7. 1
Treatment based on South Australian Perinatal Guidelines
Antimalarial Treatment
Early treatment of malaria in the woman reduces the systemic effects of
parasitaemia and reduces the adverse effects on the fetus. Advice should be
sought from an Infectious Diseases specialist or experienced Travel medicine
doctor before prescribing antimalarials for prophylaxis or treatment. The
choice of agent depends on many factors including the area to which the
woman has or is travelling and reported antimalarial drug resistance patterns.
Severe malaria in pregnancy
Treat as complicated malaria if one or more of the following:
Unable to tolerate oral medication
Parasitaemia >2% of red blood cells
Any signs of severe malaria:

altered mental state

jaundice
renal impairment
oliguria
unable to sit unaided
respiratory distress
severe anaemia
hypoglycaemia
acidosis

First trimester

Expert advice should be obtained from an Infectious Diseases

specialist for management of severe malaria

Artesunate 2.4 mg / kg IV, on admission and repeat at 12 hours and
24 hours, then once daily until oral therapy is tolerated

OR (if parenteral artesunate is not immediately available) Quinine

dihydrochloride 20 mg / kg IV over 4 hours as a loading dose, then
10 mg / kg IV over 4 hours (starting 4 hours after the loading dose is

completed), 8-hourly until oral therapy is tolerated

The IV loading dose of quinine is not required if the patient has
received:
- 3 or more doses of quinine or quinidine in the last 48 hours
- Mefloquine prophylaxis in the last 24 hours or a treatment dose
-

of mefloquine in the last 3 days

For patients receiving IV quinine, measure blood pressure and
blood glucose concentration frequently (because quinine
stimulates insulin secretion and can cause hypoglycaemia).
Cardiac monitoring is also necessary. If treatment with IV
quinine continues for longer than 48 hours, dose adjustment may
be necessary, especially in patients with renal impairment

Second and third trimester

IV artesunate as above
IV quinine should be avoided in the second and third trimesters as it

is associated with recurrent hypoglycemia

Uncomplicated malaria in pregnancy
Refers to mild cases and excludes criteria listed above in severe malaria
First trimester

Quinine sulfate 600 mg (adult less than 50 kg: 450 mg) orally, 8hourly for 7 days, PLUS clindamycin 300 mg orally, 8-hourly for 7
days

Second and third trimester

artemether+lumefantrine tablets 20+120 mg. 4 tablets per dose orally

with fatty food or full-fat milk (to ensure adequate absorption of
lumefantrine), at 0, 8, 24, 36, 48 and 60 hours, making a total adult

dose of 24 tablets in 6 doses

If unable to tolerate oral therapy, treat as for severe malaria as above
Adverse effects of uncomplicated malaria
Anaemia is one of the principal adverse effects of uncomplicated malaria
in pregnancy and all women with malaria should be screened for anaemia.

If anaemia is detected, iron and folic acid supplementation should be

considered after completion of a course of antimalarial.
Resistance
Artemisinin resistance has been reported in some areas of the
Greater Mekong Sub region (Thailand, Vietnam, Cambodia, Laos
and Myanmar [Burma]), resulting in reduced efficacy of artemisininbased combination therapy against P. falciparum (but not other

malaria species)
For patients with malaria caused by P. falciparum (either alone or
with other species) acquired from this region and who respond
slowly to artemether+lumefantrine (i.e. persisting parasitaemia after
72 hours of therapy), switch to oral quinine sulfate 600 mg (adult
less than 50 kg: 450 mg) orally, 8-hourly for 7 days PLUS

clindamycin 300 mg orally,8-hourly for 7 days.

Eradication treatment for dormant parasites in the liver
P. vivax and P. ovale can exist as dormant parasites (hypnozoites) in
the liver, which can reactivate to cause relapsed malaria. The
regimens above for the blood-stage of malaria (see above) do not
eliminate hypnozoites, so continued treatment with chloroquine

throughout pregnancy is required for both P.vivax and P.ovale

Primaquine for the treatment of hypnozoites should not be given

during pregnancy
Pregnant women with these species should be maintained on

chloroquine prophylaxis for the duration of their pregnancy

The dose of chloroquine phosphate 500mg orally once per week
(available via the Special Access Scheme) equivalent to 400mg of
hydroxychloroquine sulphate

Postpartum

After delivery, patients with P. vivax or P. ovale infections may be

treated

with

primaquine

providing

glucose-6-phosphate

dehydrogenase (G6PD) deficiency has been excluded in both the

mother and her breastfed infant

For P. vivax infection, once G6PD deficiency has been excluded for
mother and breastfed infant, use: Primaquine 30 mg orally, daily, or
if nausea occurs 15 mg orally, 12-hourly. Treat for a minimum of 14
days or, in adults more than 70 kg, until a total cumulative dose of 6

mg/kg is reached
For P. ovale infection, once G6PD deficiency has been excluded, for
mother and breastfed infant, use: Primaquine 15 mg orally, daily for

14 days
Primaquine can cause severe haemolysis in patients who are glucose6-phosphate dehydrogenase (G6PD) deficient. If the patient is G6PD
deficient, seek expert advice. For persons with borderline G6PD
deficiency or as an alternate to the above regimen, primaquine may
be given at the dose of 45 mg (base) orally one time per week for 8
weeks, seek Infectious Diseases specialist advice. See reference

below
Antimalarial medications
Chloroquine*/ Hydroxychloroquine
There has been no evidence of harmful effects on the fetus when
chloroquine /hydroxychloroquine is used in the recommended doses

for the prevention or treatment of malaria in pregnancy

There have been cases reports describing an association with fetal
effects including neurological disturbances and interference with
hearing, balance and vision when chloroquine is used in high doses
and long term therapy for other indications. However, causation has

not been established

*Chloroquine is not registered in Australia but is available via the

Special Access Scheme

Mefloquine
Melfoquine registries and surveillance data have recorded thousands
of exposures (mainly in the first trimester of pregnancy) with no

increase rate of malformations or spontaneous abortions

Mefloquine may be used throughout pregnancy for the prophylaxis

and treatment of malaria if there is no resistance

Primaquine

Primaquine should not be used during pregnancy because of the

potential risk of haemolytic effects in the fetus

Primaquine may be used during breastfeeding but should be avoided
in breastfed infants who have glucose-6-phosphate dehydrogenase
(G6PD) deficiency, are less than one month old or have

hyperbilirubinaemia, as there is a risk of haemolysis in these infants

Quinine
Quinine has not been associated with an increased risk of birth
defects when used in doses for the treatment of malaria, however
when used in the last part of pregnancy severe maternal

hypoglycaemia has been reported

A small number of case reports have suggested that eye, ear, CNS
and limb defects may be associated with quinine use, however these

results have not been replicated in a larger surveillance study

Quinine may be used in pregnancy
Clindamycin
Clindamycin is used in combination with oral quinine for the
treatment of uncomplicated P. falciparum infection. It has not been
associated with an increased risk of malformations or complications
when used in pregnancy
Artermether+Lumefantrine(Riamet)

or

Atovaquone+Proguanil

(Malarone)
Artermether+Lumefantrine (Riamet) or Atovaquone+Proguanil
(Malarone) may be usedon advice from an Infectious Diseases
Specialist if other treatment options are not available or are not being

tolerated
Experience regarding the use of artemisinin based therapy in
pregnancy is limited to less than 1,000 reported cases (250 exposures
to artermether+lumefantrine) and the majority of exposures have
been in the second and third trimesters. No difference in the
incidence of birth defects or birth outcomes has been observed when
compared to controls18

There have been a limited number of pregnancies exposed to

atovaquone+proguanil and there has been no significant association
with increased risk of birth defects

7. 2

Treatment guideline based on Royal College of Obstetricians &

Gynaecologists UK

Table 1. UK treatment guidelines in pregnancy3

Severity

Indication

Drug and dosage

Severe or complicated
Malaria

Any species (for specific cases

expert consultation; see Table 2)

Artesunate IV 2.4 mg/kg at 0, 12 and 24 hours, then daily

When the patient is well enough to take oral medication she
can be to oral artesunate 2 mg/kg (or IM artesunate 2.4
switched
mg/kg)
once daily, plus clindamycin. If oral artesunate is not
available,
useof
a Riamet (GSK) or atovaquone-proguanil
3-day
course
(Malarone,
Novartis) or a 7-day course of quinine and clindamycin at 450
mg
3 times a day 7 days.
ALTERNATIVELY

Any species

Quinine IV 20 mg/kg loading dose (no loading dose if patient

already
taking quinine or mefloquine) in 5% dextrose over 4 hours
andmg/kg
then IV over 4 hours every 8 hours plus clindamycin IV
10
450
mg
every
8 hours (max. dose quinine 1.4 g). When the patient is
well
enough to take oral medication she can be switched to oral
quinine
600 mg 3 times a day to complete 57 days and oral
clindamycin
450 mg 3 times a day 7 days (an alternative rapid quinineloading
regimen is 7 mg/kg quinine dihyrochloride IV over 30 minutes
using an pump followed by 10 mg/kg over 4 hours).
infusion
Note: quinine dosing should be reduced to 12-hourly dosing if
IV
therapy extends more than 48 hours or if the patient has renal
or hepatic dysfunction.56 Quinine is associated with severe
and recurrent hypoglycaemia in late pregnancy.57

Uncomplicated
malariab

Non-falciparum
malariac

P. falciparum

Oral quinine 600 mg 8 hourly and oral clindamycin 450 mg 8

hourly
for 7 days (can be given together)
or Riamet 4 tablets/dose for weight 35 kg, twice daily for
(with
3 daysfat)
or atovaquone-proguanil (Malarone) 4 standard tablets daily
3 days.
for

Vomiting but no signs of severe or

complicated malaria

Quinine 10 mg/kg dose IV in 5% dextrose over 4 hours every

8 hours
plus
IV clindamycin 450 mg every 8 hours. When the patient
is well to take oral medication she can be switched to oral
enough
quinine
600 mg 3 times a day to complete 57 days and oral
clindamycin
can
if
needed be switched
to 450 mg 3 times a day 7 days.

P. vivax, P. ovale, P. malariae

Oral chloroquine (base) 600 mg followed by 300 mg 68 hours

later.
Then 300 mg on day 2 and again on day 3.

Resistant P. vivax

As for uncomplicated malaria P. falciparum

Preventing relapse DURING

pregnancy
Preventing relapse AFTER delivery

Chloroquine oral 300 mg weekly until delivery

P. ovale

Oral primaquine 15 mg single daily dose for 14 days

P. vivax

Oral primaquine 30 mg single daily dose for 14 days

Postpone until 3 months after delivery and G6PD testing

G6PD (mild) for P. vivax or P. ovale

Primaquine oral 4560 mg once a week for 8 weeks

Severe and complicated malaria published evidence, see Appendix 3.1;

Uncomplicated malaria published evidence, see Appendix 3.2;
c
Non-falciparum malaria published evidence, see Appendix 3.3; IM = intramuscular, IV = intravenous
b

8. Prevention
Minimise exposure to mosquitoes in malarial risk areas
Avoid outdoor night time activities
Use mosquito nets preferably impregnated with Permethrin-emulsifiable
concentrate. Permethrin is an insecticide but not a repellent (not

recommended for skin application)

Wear clothing that covers the arms and legs
Use a mosquito repellent (a solution of 20 to 50% DEET has been in
widespread use with no apparent effects, however, there is no specific data

on the safety of DEET in the first trimester of pregnancy)

There is no 100 % effective malaria chemoprophylaxis regimen for
women

planning

pregnancy

or

during

pregnancy.

Malaria

chemoprophylaxis should only be prescribed in consultation with an

Infectious Diseases specialist or experienced Travel medicine doctor
9. Prognosis

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Geneva:

World

Health

Organization;

2010

[www.who.int/malaria/publications/atoz/9789241547925/en/index.html].
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Compounds in Pregnancy. Report of two joint informal consultations
convened in 2006 by the Special Programme for Research and Training in
Tropical Diseases (TDR) sponsored by UNICEF/UNDP/World bank/WHO
and The global Malaria Programme of the World Health Organization.
Geneva: WHO; 2007
[http://apps.who.int/tdr/svc/publications/tdrresearchpublications/artemisini
n-compounds-pregnancy].
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prevention of malaria in pregnancy. Green top guideline 54A; April 2010.
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diagnosis and treatment of malaria in pregnancy. Green top guideline 54B;
April

2010.

[https://www.rcog.org.uk/globalassets/documents/guidelines/gtg_54b.pdf]
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of severe malaria, CDC [online] 2015 cited 2015 Mar 03. Available from
URL http://www.cdc.gov/malaria/diagnosis_treatment/clinicians3.html 21.
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uncomplicated malaria. CDC [online] 2015 cited 2015 Mar 03. Available
from

URL:

http://www.cdc.gov/malaria/diagnosis_treatment/clinicians2.html
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Diseases Unit, Royal Darwin Hospital. 6th ed. Department of Health,
Northern

Territory

2012.

Epublication

available

from

URL:

http://health.nt.gov.au/Centre_for_Disease_Control/Publications/CDC_Pro
tocols/index. Aspx
8. South Australian Perinatal Practice Guidelines malaria in pregnancy

Department for Health and Ageing, Government of South Australia.

https://www.sahealth.sa.gov.au/wps/wcm/connect/d9ba0b004ee4f7c0966c
9fd150ce4f37/Malaria+in+Pregnancy_July2015.pdf?
MOD=AJPERES&CACHEID=d9ba0b004ee4f7c0966c9fd150ce4f37