Malaria in Pregnancy

Dr. dr. Loeki Enggar Fitri, MKes, SpParK

Department Of Parasitology
Faculty of Medicine, Brawijaya University

Scope of the Malaria

Problem:
Malaria is the most common
life-threatening infection
1 million deaths/yr
300-500 million infections/yr

~90% of these deaths occur

in sub-Saharan Africa
most victims are children <5
yrs
Pregnant women are also
especially vulnerable.

Why Is the Issue of Malaria

During Pregnancy
Important?
Each year, more than 30 million women
in become pregnant in malaria-endemic
areas.
Malaria during pregnancy in malariaendemic settings may account for:
2-15% of maternal anemia
5-14% of low birth weight newborns

3-8% of infant mortality

(Steketee et al., Am. J. Trop. Med. Hyg, 2001)

Outline
The global burden of malaria
Importance of malaria in reproductive health
>50 million pregnant women exposed to malaria each
year
~3.5 million pregnant women infected
Poor birth outcomes
Poor maternal outcomes
Responsible for 0.5 23% of maternal deaths in Africa
Malaria causes severe anemia and platelets can
predispose to death from hemorrhage (www.premaeu.org)

MALARIA
Human Malaria is caused by one of 4 protozoan parasites:

Plasmodium falciparum
Plasmodium vivax
Plasmodium ovale
Plasmodium malariae
Plasmodium knowlesi ?

Plasmodium
falciparum
Most common
Multi-drug resistant
Most dangerous

Transmission intensity
Stable malaria
Prevalence persistently
high
Transmission can
continue with few
vectors
Collective immunity is
high
P. falciparum
Young children and
pregnant women at
greatest risk
Type: sub-Saharan
Africa

Unstable malaria
Variability in space and
time
Disease fluctuates (inc.
epidemics)
Collective immunity is
low
P. vivax, also P.
falciparum
All ages at risk
Type: S.E. Asia

MALARIA clinical syndromes

Chronic Disease

Acute Disease

Non-severe Chronic or Recurrent

Asymptomatic
Acute Febrile
Infection
disease
Cerebral
Malaria

Anemia
Developmental
Disorders
Transfusions

Death

Death

Infection
During
Pregnancy
Placental
Malaria
& Anemia
Low
Birth weight
Increased
Infant
Mortality

Effect of Malaria on Pregnancy in

Unstable Transmission Areas
Acquired Immunity Low

Clinical Illness

Severe Disease

Risk to Mother
Source: WHO 2002.

Risk to Fetus

Pregnancy-associated malaria
(PAM)
In areas of high Plasmodium falciparum
transmission, immunity to malaria is acquired
during childhood, so that adults in general are
clinically immune. One exception is that first-time
pregnant women are susceptible to pregnancyassociated malaria (PMA) caused by
accumulation of parasites in the placenta.

Effects on the Pregnant Woman

Effects
High fever
Placental infection
Puerperal sepsis
Complicated malaria
Severe anemia
Cerebral malaria
Hypoglycemia
Pulmonary edema
Acute renal failure

Increased maternal
mortality

Primigravidae
in Stable
malaria areas

All parities in
Unstable malaria
areas

+
+++
++

+++
+
++

+++
+

+++
++
++
++
++
++

( +++ =Very Common, ++ =Common, + =Infrequent, -- =Rare)

Rogerson et al. 2003

Consequences of Pregnancy
Associated Malaria (PAM) on the
Fetus and Newborn
Effects

Primigravidae in
Stable malaria
areas

All parities in
Unstable
malaria areas

+++

++

++

++

++

Low birth weight

IUGR
Prematurity

Abortion
Stillbirth
Congenital malaria
Fetal anemia
Infant mortality

( +++=Very Common, ++=Common, +=Infrequent, -- =Rare)

Rogerson et al. 2003

Low birth weight

The first theory

SEQUESTRATION
Central to the pathogenesis of P falciparum
infection in pregnancy is the observation that
infected erythrocytes accumulate in the maternal
vascular area of the placenta, the intervillous
space.

Placental malaria
Parasites accumulate
and thrive in the
placenta
Only affects
primigravidae in
areas of high
transmission

Gravidity and malaria

Primigravidae have no pre-existing
immunity to placental parasites and are
highly susceptible
In high transmission areas, primigravidae
develop immunity to placental parasites and
are protected in subsequent pregnancies
In low transmission areas, multigravidae are
unexposed and unprotected

Infected erythrocytes are able to

adhere
to the placenta

Smith and Deitsch, 2004. J Exp Med

Classification of placental pathology

Description
Not infected

No evidence of parasites or malaria

pigment (haemozoin)

Active-acute

Parasites present, with absent or

minimal pigment deposition within
fibrin

Active-chronic

Parasites, with substantial amounts of

pigment in fibrin or in cells

Past

Presence of pigment with no parasites

Rogerson et al. 2003

Effect of Malaria Sequestration

on Pregnancy in
Stable Transmission Areas
Plasmodium falciparum malaria
Asymptomatic Infection
Placental Sequestration
Altered Placental Integrity
Reduced Nutrient and Oxygen Transport
Anemia

Low Birth Weight (IUGR)

Risk of Newborn Mortality
Source: WHO 2002.

The second theory

Immunopathology

Other findings associated with pregnancy

associated malaria include increased numbers
of maternal phagocytic cells especially
monocytes in the intervillous space, and
deposition of haemozoin or malaria pigment,
in phagocytic leucocytes and within fibrin
deposits in the intervillous space.

Figure 1: Placental tissue from (A) normal and (B) malaria-infected women
Sections were stained with monoclonal antibody to CD68, specifi c to monocytes and macrophages,
and developed with diaminobenzidine (brown colour). Asterisks indicate CD68 staining of
monocytes/macrophages in the intervillous space. Arrows indicate parasitised erythrocytes. The lines
indicate the outline of the trophoblast layer. Original magnifi cation (oil immersion) 1000. NRBC=non-parasitised red blood cells. Adapted Suguitan and colleagues.10 Copyright, Infectious
Diseases Society of America. Published by University of Chicago Press.

Immunopathogenesis of
malaria in pregnancy
During normal pregnancy, the cellular immune
response (Th1) is suppressed to prevent fetal
rejection
Malaria stimulates the Th1 response intrauterine
growth retardation
Strong Th1 responses during pregnancy are also
associated with maternal anemia, spontaneous
abortions, and premature deliveries.
Moormann et al., JID, 1999; Tkachuk et al., JID 2001; Abrams
et al., Am. J. Reprod. Immunol., 2004

Immunopathogenesis of
malaria in pregnancy
In studies that have related placental cytokine
changes to adverse pregnancy outcomes, the
clearest finding has been an association between
raised levels of TNF and babies of low birthweight, including low birth-weight caused by fetal
growth restriction and preterm delivery
Up-regulation of interleukin 10 has been reported in
the intervillous space, and could help prevent the
pathological effects of the pro-inflammatory
cytokines

CONGENITAL MALARIA
Adapted from Steve Meshnick, M.D., Ph.D.
Seminars in Fetal & Neonatal Medicine (2007),12, 207-213

Definition of congenital
malaria
Malaria parasites cross the placenta either
during pregnancy or at the time of delivery.
The presence of asexual forms of malaria
parasites in the peripheral blood within the
first 7 days of life, or later.

Prevalence of congenital
malaria
In non-immune mothers has been reported to
be around 10%.
Infants born in non-endemic countries whose
mothers have a travel history or origin in
malaria endemic areas.
Present clinical manifestations several days
or weeks after delivery.
Seminars in Fetal & Neonatal Medicine (2007),12, 207-213

The variability in
prevalence
1. Differences in the definition of congenital
malaria
2. Levels of maternal immunity
3. The type of blood sample examined
( peripheral blood of neonates or cord blood)

Seminars in Fetal & Neonatal Medicine (2007),12, 207-213

Mechanisms of congenital
malaria
Maternal transfusion into the fetal circulation
either during pregnancy or at the time of
delivery, direct penetration through the
chorionic villi, or through premature
separation of the placenta.
Malaria infection of the placenta may be
accompanied by intervillous infiltrates of
mononuclear cells (and other APC)
Seminars in Fetal & Neonatal Medicine (2007),12, 207-213

Mechanisms of congenital
malaria
Intervillous mononuclear inflammation (IVMI)
is especially severe in the first pregnancy and
it is associated with maternal anaemia and
LBW.
IVMI induces an alteration in the cytokine
balance and may cause pathological changes
in trophoblasts that can damage the
syncytiotrophoblastic membrane.
Seminars in Fetal & Neonatal Medicine (2007),12, 207-213

Clinical manifestations
Fever, irritability, hepatosplenomegaly, anorexia,
progressive haemolytic anaemia,
thrombocytopaenia, jaundice, regurgitation,
loose stools, poor feeding, restlessness and
cyanosis.
Asymptomatic at birth but clinical manifestations
frequently appear within 10-30 days of birth.
Seminars in Fetal & Neonatal Medicine (2007),12, 207-213

Clinical manifestations

1.
2.
3.
4.

Some degree of resistance in newborns to

multiplication of malaria parasites because
of :
Fetal hemoglobin
Failure of the parasites to grow in cord blood
Persistence of maternal IgG in the
newborns blood
Fast elimination of parasites from the fetal
circulation
Seminars in Fetal & Neonatal Medicine (2007),12, 207-213

Diagnosis
If untreated, congenital malaria caused by P.
falciparum is potentially rapidly lethal, (babies
born to non-immune women).
Suggested that babies born to mothers with a
history of febrile illness within the last 2
weeks of pregnancy should have a blood
smear taken for malaria parasite examination.
Seminars in Fetal & Neonatal Medicine (2007),12, 207-213

Treatment of congenital
malaria
Congenital falciparum malaria, whether
symptomatic or not, should be treated with
Quinine (10 mg/kg orally every 8 hr, or IV)
Effective regimen for susceptible P. vivax is
oral Chloroquine, 10 mg/kg as the base,
followed by three doses of 5 mg/kg at 6, 24
and 48 hr after the first dose.
Seminars in Fetal & Neonatal Medicine (2007),12, 207-213

Prevention of congenital
malaria
Prevention of malaria in non-immune
pregnant women travelling to endemic areas
is difficult.
Use vector control measures : insect
repellents and insecticide treated nets
(ITNs), receive malaria
chemoprophylaxis.
Seminars in Fetal & Neonatal Medicine (2007),12, 207-213

Prevention of congenital
malaria
WHO recommends that pregnant women
living in stable (high) malaria endemic areas
should be :
1. Protected against the infection by using
ITNs.
2. Receiving intermittent preventative
treatment (IPT) with Sulphadoxinepyrimethamine (IPTp).
Seminars in Fetal & Neonatal Medicine (2007),12, 207-213

IPT
Malawi first to introduce (1993)
Two therapeutic doses of SP to all
pregnant women at quickening and at 2834 wks Inexpensive (~$0.20)
2-dose coverage is still low (<25%)
New recommendations include 4-doses or
monthly SP
Prevents 23-86% of severe maternal anemia

Intermittent Preventive
Therapy (IPT)
Areas of high transmission
Therapeutic doses of SP given periodically to
all pregnant women or infants at risk
Takes advantage of
High utilization by pregnant women of
antenatal clinics
High coverage of infants for EPI
vaccination visits (2, 3, 9 mos)

ITNs
Cost ~$4.00
Reduce malaria, severe anemia and LBW by
30-50%
Socially marketed nets (~$1.00)
Low uptake
Freely distributed nets
High uptake and well utilized
Less sustainable

Insecticide Treated
Nets
Bednets impregnated with
permethrin insecticide
Need retreatment every 6
months
New permanets do not
need retreatment
Act as human-baited
mosquito traps and are better
with high coverage
Should they be socially
marketed or freely
distributed?

Malaria is the most common

and easily preventable cause
of poor birth outcomes in the
world

Programmatic priorities
Integration of malaria prevention into
Reproductive health programs
Programs to prevent mother-to-child
transmission of HIV

Increase uptake of IPT and ITNs

Make programs sustainable

Malaria and HIV coinfections during pregnancy

Up to 10% of pregnant women may be co-infected
with both HIV and malaria
HIV-infected pregnant women have more frequent
and severe malaria
Malaria infection might increase mother-to-child
transmission of HIV
Infant mortality rate for offspring of co-infected
mothers is 3-8 fold higher than singly infected
mothers

Summary
Malaria is an enormous reproductive health
problem, especially in sub-Saharan Africa
IPT and ITNs are inexpensive and effective
interventions
Investment in malaria control can do the
most good for the least amount of money