J Med Sci, Volume 50, No.

2, 2018 April: 180-190

Mohammad Juffrie, 1

Enny Kenangalem , Faustina Helena Burdam , Leily Triyanti ,

Rintis Noviyanti , Din 5

Syafruddin , Rukhsana Ahmed , Feiko ter Kuile , Jeanne Rini

Poespoprojo 7

1 Department of Pediatrics, Faculty of Medicine, Public Health and Nursing / Dr. Sardjito General
Hospital, Department of Parasitology, Faculty of Medicine, Public
2

Health and Nursing, Departments 3

of Obstetric and Genecology, Faculty of Medicine, Public Health and

Health Development
Foundation, Jayapura, Eijkman Institute for Molecular Biology,
5

Jakarta, Liverpool School of

Tropical Medicine, UK, Mimika District Hospital, Timika, Papua

DOI: http://dx.doi.org/10.19106/JMedSci005002201807
ABSTRACT
Malaria infection during pregnancy is a significant global health problem
with substantial
risks for pregnant women, her father, and the newborn child. Infant
malaria is a major
public health concern in Timika, Papua. The aim of the study was to
study the impact
of malaria during pregnancy on infant's susceptibility to malaria
infections, the timing of
its occurrence, the number of malaria infections during pregnancy. This
was a cohort
prospective study conducted in Timika, Papua from October 2013 to
September 2016.
Malaria investigation was done by microscopic and PCR
methods. Demographic data and
malaria status of mother-infant pairs were collected and analyzed by
SPSS 22.0 version.
One hundred seventy-eight infants consisting of 95 (53.37%) infants
born to mothers
with malaria and 83 (46.63%) without malaria 91 (51.12%) boys and 87
(48.88%) girls
were involved in the study. The mean of mothers' ages were 25.35 ± 6.30
vs. 26.0 ±
5.69 years. At the ages of 6 and 12 months, infants born to malaria
positive mothers
were more susceptible to malaria infections compared to negative infants
born to malaria
mothers with RR = 3.49; 95% CI: 1.02-11.96; p = 0.03 and RR =
8.74; 95% CI: 1.14-
66.81; p = 0.01, respectively. Independent risk factors of infant
susceptibility to malaria
infection during the first year of life were malaria in pregnancy (MiP) in
2 trimester (RR
nd

= 4.50; 95% CI: 1.5-13.49; p = 0.07), pregnant women who only got
malaria infection
1 time during pregnancy (RR = 2.95; 95% CI: 1.04-8.33; p = 0.04), and
Papuan ethnicity
(RR = 3.58; 95% CI: 1.22-10.59; p = 0.02). In conclusion, infant
susceptibility to malaria
is associated with maternal malaria status during pregnancy. MiP in
second trimester,
pregnant women who only had malaria once and Papuan ethnicity were
independent risk
factors for infant's increased susceptibility to malaria infection.
ABSTRACT
Malaria infection during pregnancy is a significant global health problem
with great risk for pregnant women, fetuses, and babies born. Malaria in
infants
is a major public health problem in Timika, Papua. The purpose of this
research
to assess the impact of malaria during pregnancy on a baby's
vulnerability to infection
malaria, the time of occurrence of malaria infection in the mother, the
number of malaria infections during pregnancy.
This study is a prospective cohort study conducted in Timika, Papua
from October 2013 to September 2016. Examination of malaria in
pregnant women
and infants performed by microscopic and PCR methods. Demographic
and status data

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Ratni Indrawanti et al., The impact of malaria in pregnancy on infant
susceptibility to malaria infection
Mother-baby partner malaria was collected and analyzed with SPSS
version 22.0. As much
178 babies consisting of 95 (53.37%) babies born to mothers with
malaria and 83
(46.63%) without malaria and 91 (51.12%) baby boys and 87 (48.88%)
baby girls
involved in research. The mean age of the mother was 25.35 ± 6.30 vs
26.0 ± 5.69 years.
At ages 6 and 12 months, babies born to malaria positive mothers are
more susceptible to
malaria infections compared with infants of malaria-negative mothers
(RR = 3.49; 95% CI:
1.02-11.96; p = 0.03 and RR = 8.74; 95% IK: 1.14-66.81; p = 0.01). Risk
factor
independent of infant susceptibility to malaria infection during the first
year is
malaria in pregnancy during the second trimester (RR = 4.50; 95% CI:
1.5-13.49; p =
0.07), pregnant women who were only infected with malaria 1 time
during pregnancy (RR = 2.95;
95% IK: 1.04-8.33; p = 0.04), and ethnic Papuans (RR = 3.58; 95% CI:
1.22-10.59; p =
0.02). It can be concluded, the susceptibility of infants to malaria is
related to status
maternal malaria during pregnancy. Malaria in the second trimester of
pregnancy, pregnant women
who have only been infected with malaria once during pregnancy and
ethnic Papuans are a factor
independent risk associated with increasing infants susceptibility to
malaria infection
Keywords : Malaria - pregnancy - infant susceptibility - Timika Papua -
risk factors -
INTRODUCTION
Malaria is a mosquito-borne infectious
disease caused by the parasite Plasmodium.
The predominant species are Plasmodium
falciparum and P. vivax with an estimated
182.2 million clinical cases of P. falciparum
malaria, 15.8 million clinical cases of P. vivax
malaria and 584,000 deaths attributable to
malaria every year. 1 The greatest burden of
disease is reported in young children and
pregnant women. 2 Annually, 88.2 (70%) of
125.2 million pregnancies in endemic malaria
regions occur in the Asia-Pacific area. 3
Malaria in pregnancy (MiP) or pregancy-
associated malaria, is defined as peripheral
or placental infection by Plasmodium. The
MiP presents as a major public health concern
due to significant adverse health effects on
both the mother and the fetus. 4 The effects of
MiP on infants include intra-uterine growth
retardation (IUGR) and pre-term delivery, low
birth weight (LBW), abortion and stillbirth,
congenital malaria and foetal anemia. 5
The risk of IUGR is associated with malaria
was greatest after three or more cumulative
infections (RR 3.3; 95% CI: 1.3–8.2) and was
two to eight-fold higher among women with
evidence of undernutrition. 6 Submicroscopic
malaria infections in pregnant women were
associated with significantly increased risk
of low birth weight in primigravidae and
premature births in multigravidae. 7
According to Poespoprojo 8 infant malaria
is a major public health issue in Timika, Papua
(Indonesia) and the risk starts at birth with the
majority of malaria cases going undiagnosed,
being mostly asymptomatic. Newborns and
young infants (less than 6 months of age)
are thought to be relatively protected from
symptomatic malaria. 9 This protection has been
considered to be primarily mediated by maternal
antimalarial IgG antibodies transferred to the
foetus in the last trimester of pregnancy. 10
Antimalarial IgG antibodies may have
three roles: first blocking sporozoite invasion
of hepatocytes and merozoite invasion of
erythrocytes; second, opsonize merozoites
and infected erythrocytes expressing variant
surface antigens (VSA) on their surface for
phagocytosis; and third, fixing and activating
complements on the merozoite surface with
resultant parasite lysis. 11 Primarily in the third
trimester, transplacental transfer of maternal
IgG antibodies to the foetus occurs and is

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J Med Sci, Volume 50, No. 2, 2018 April: 180-190
182
mediated by the neonatal Fc receptor. 12 After
birth, all isotypes of maternal antibodies, except
for IgA, are transferred to infants in breast milk,
despite the fact that these are not systemically
absorbed and act primarily in the gut. The 13th
waning of maternal antimalarial IgG antibodies
by 6–9 months of age had been reported
previously, which coincides with the period of
time in which the risk for malaria infection and
clinical disease in infants begins to increase. 14
Beside transplacental transfer of protective
antibodies from mother to foetus, several factors
that allegedly contributed to the susceptibility
of infants to malaria are innate mechanisms
including hemoglobin foetus (HbF), 15 para
amino benzoic acid (PABA) -deficiency and
transforming growth factor (TGF) in breast
milk, exclusive breast feeding, 16 neonatal
responses to priming by transplacental transfer
of parasites or products, 17 placental malaria, 18
infant nutritional status, high exposure to
Plasmodium, 19
and proper implementation
of insecticide-treated nets and intermittent
preventive treatment. 20
In placental intervillous spaces the
parasite specific adhesion may contribute
to placental insufficiency which may relate,
either directly or indirectly, to increase growth
restriction and premature birth. Susceptibility
of women to placental malaria is attributed
to increased parasites sequestered in the
placenta mediated by chondroitin sulfate A
binding to the trophoblast 21 and pregnancy-
associated suppression of inflammatory
responses caused by hormonal changes. 22
Pregnant women experience immunological
and hormonal changes, particularly estrogen
and progesterone which are partly driven by
increased levels of pregnancy-associated
hormones. 23 A recent study found the role of
soluble human leukocyte antigen G (sHLA-G)
in infant susceptibility to malaria during
pregnancy. 24
There were some evidences of the effect
of placental malaria on infants, which also
includes greater susceptibility to malaria
and anemia in those born to mothers with
a parasitized placenta. 17, 25 All these studies
have focused on placental infection at
delivery, with no exploration of the mother’s
history of infection earlier during pregnancy.
Our study aimed to investigate the impact
of MiP on infant susceptibility to malaria
infection, taking into account the timing of its
occurrence, the number of MiP infections and
demographic data during the first year of life.
MATERIALS AND METHODS
Subjects
The study was conducted from October
2013 to September 2016 in lowland Timika,
Papua Indonesia, an area where P. falciparum
and P. vivax malaria are similarly prevalent. This
was a nested study from a randomized cluster
trial of maternal malaria prevention and
treatment. Pregnant women with gestational
age <24 weeks were enrolled at their first
antenatal visit at Posyandu (community health
center) after giving written informed consent.
The subjects of this study were the infants
born to these mothers who were enrolled
consecutively until the number of sample size
was sufficient. Inclusion criteria were healthy
term newborns and consenting mothers living
in the study areas for the duration of follow-
up. The babies would be excluded if preterm
(<37 weeks gestation), sick newborns
requiring hospitalization, withdrawal by the
parent / mother, and loss to follow-up for more
than 6 months.
Sample size of infants was based on the
cohort prospective method 26 with RR = 2.13
assumed as significant, where the prevalence
of malaria in infants in groups without risk
factor was (P2) = 0.123 27 with α = 0.05; power

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Ratni Indrawanti et al., The impact of malaria in pregnancy on infant
susceptibility to malaria infection
80%; zα = 1.96; and zβ = 0.842, then the project
required a sample size of 162 infants (81 per
arm). Ethics approval was obtained from the
Medical and Health Research Ethics Committee
at the Faculty of Medicine, Gadjah University
Mada, Yogyakarta, Indonesia.
Protocol
Pregnant women were followed-up 3 or 4
times (3 if enrolled after 24 weeks and 4 times
if enrolled between 16-23 weeks) and again
at delivery. At those times blood samples
were taken from the finger prick for malaria
investigation. Infants born to a mother with
either MiP or no MiP would be followed for
1 year and we performed malaria laboratory
diagnosis at 6 and 12 months.
The diagnosis of malaria both in mothers
and infants were based on PCR examination.
Demographic data from the mother included:
age, gravidity, ethnicity and bed net utilization
while from the baby data included: gender, birth
weight, birth length and head circumference.
Gestational age at birth were assessed from
neuromuscular and physical maturity score
of the newborn according to Ballard methods.
The procedures were performed by a trained
research nurse.
Statistical analysis
Statistical analysis using SPSS version
22.0 (UGM online license). Numerical data
with normal distribution were analyzed
using student t test or one way analysis of
variance (Anova). If there was an abnormal
distribution then it would be analyzed using
Mann-Whitney U test. Categorical data were
analyzed using chi square test with Yates
correction or Fisher exact test. Statistical
significance was considered if p <0.05. To
control confounding variables and look for
independent risk factors from malaria in
infants, bivariates and multivariate tests were
be performed.
RESULTS
One hundred and ninety three mother–
infant pairs were enrolled between October
2013 and September 2016. There were 4
parental refusals. Among 193 infants, 9
infants did not complete the 12 months follow
up (4 infants from mother without MiP and 5
infants from mother with MiP), and 2 infants
edited from mothers with MiP due to sepsis and
watery diarrhea (FIGURE 1).
193 pregnant woman and infant pairs
4 parents refusal
189 infants
followed up for 12 months
87
infants born to
mother without MiP
102
infants born to mother
with MiP 128
4 lost to follow up
95 infants
-5 lost to follow up
-2 death (1 sepsis, 1 severe
dehydration caused by diarrhea)
83 infants
analysis
analysis
FIGURE 1. Flowchart of subject selection.

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184
During the pregnancy, 46 women were
infected during the 1 st trimester, 54 during the
2 nd trimester, and 14 during the 3 rd trimester.
There were 48 (27%) pregnant women that
had at least one malaria infection, 29 (16.3%)
had two infections, 14 (7.98%) had 3 or more
infections and 87 (48.9%) had no infection.
During delivery there were 44 mothers who
had malaria infection, where 42 mothers had
positive placental infection and 22 mothers had
peripheral parasitemia. The mean of mother age
was 25.35 ± 6.30 vs 26.0 ± 5.69 years, and the
youngest was 12 years old and the oldest was 42
years old (TABLE 1). There were no significant
differences in baseline characteristics between
mothers with MiP and without MiP.
TABLE 1. Mother baseline characteristics
Characteristic
Malaria in pregnancy (+)
n = 95
Malaria in pregnancy (-)
n = 83
p*
Age (years ± SD)
25.35 ± 6.30
26.0 ± 5.69
0.14
Gravidity, n (%)
• Primigravidae
• Secundigravidae
• Multigravidae
31 (17.4)
25 (14.0)
39 (21.9)
17 (9.6)
34 (19.2)
32 (17.9)
0.69
Ethnic Group, n (%)
• Papuan
• Non Papuan
48 (27.0)
47 (26.4)
38 (21.3)
45 (25.3)
0.53
Bed net utilization
• Yes
• No.
28 (15.7)
67 (37.6)
24 (13.5)
59 (33.2)
0.94
* Fisher exact test, significant if p <0.05
TABLE 2 shows that there were 91
(51.12%) boys and 87 (48.88%) girls. Birth
weight, head circumference and low birth
weight were more likely to occur in infants
from mothers with MiP positive compared
with MiP negative mothers, but these results
were not significant (p> 0.05).
TABLE 2. Characteristics of infant
Characteristics
Malaria in Pregnancy (+)
n = 95
Malaria in Pregnancy (-)
n = 83
p*
Gender, n (%)
• Boy
• Girl
50 (28.1)
45 (25.3)
41 (23.0)
42 (23.6)
0.67
Birth weight (mean ± SD)
3028.95 ± 450.87
3051.21 ± 388.13
0.32
Birth length (mean ± SD)
49.13 ± 2.08
49.02 ± 2.06
0.68
Head circumference (mean ± SD)
32.73 ± 1.56
33.02 ± 1.62
0.54
Gestational age (mean ± SD)
37.76 ± 1.07
37.53 ± 0.89
0.45
Low birth weight, n (%)
• Yes
• No.
11 (6.2)
84 (47.2)
3 (1.7)
80 (44.9)
0.55
* Fisher exact test, significant if p <0.05

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Ratni Indrawanti et al., The impact of malaria in pregnancy on infant
susceptibility to malaria infection
TABLE 3 shows a bivariate analysis of
the effects of MiP on infant malaria infections
at age 6 and 12 months in which infants born
to mother with MiP were more susceptible to
malaria infection than infants born to mother
without MiP (p = 0.03; RR = 3.49; 95% CI
1.02-11.96) and (p = 0.01; RR = 8.74; 95% CI
1.14-66.81) respectively.
TABLE 3. Malaria infant in 6 and 12 months old
Variable
Malaria Infant, n (%)
p*
RR
95% CI
(+)
(-)
6 months old
MiP (+)
12 (12.63)
83 (87.37)
0.03
3.49
1.02-11.96
MiP (-)
3 (3.61)
80 (96.39)
12 months old
MiP (+)
MiP (-)
10 (10.53)
1 (1.21)
85 (89.47)
82 (98.79)
0.01
8.74
1.14-66.81
* Fisher exact test, significant if p <0.05
We performed a multivariate analysis
between all malaria infections over a period of
12 months with malaria-infected timings and
maternal demographics (TABLE 4). In this
study we found that MiP occurred in
second trimester, pregnant women who only
had malaria infection 1 time before delivery
and Papuan ethnicity were independent
factors related to the infant susceptibility to
malaria infection.
TABLE 4. Factors related to infant susceptibility to malaria
infection at 6 and 12 months old
Characteristics
Infant Parasitemia
Crude
Logistics Regression
(+)
(-)
RR
95% CI
p
RR
95% CI
p
Malaria during pregnancy
1st Trimester
• Yes
• No.
2 (20.0)
19 (11.3)
8 (80.0)
149 (88.7)
1.77
0.48-6.55
0.41 2.76 0.41-18.43 0.29
2nd Trimester
• Yes
• No.
12 (25.0)
9 (6.9)
36 (75.0)
121 (93.1)
3.61
1.63-8.02
0.00 4.21 1.36-13.60 0.01
3rd Trimester
• Yes
• No.
5 (13.5)
16 (11.3)
32 (86.5)
125 (88.7)
1.19
0.47-3.04
0.72 0.99
0.27-3.74
0.99
Malaria infection 1 time
• Yes
• No.
9 (18.8)
12 (9.2)
39 (81.2)
118 (90.8)
2.03
0.91-4.51
0.81 3.39 1.09-10.57 0.03
Parasitemia at Delivery
Peripheral
• Yes
• No.
4 (16.7)
17 (11.0)
20 (83.3)
137 (89.0)
1.51
0.56-4.11
0.43 2.43 0.18-33.64 0.51
Placental
• Yes
• No.
6 (14.6)
15 (10.9)
35 (85.4)
122 (89.1)
1.34
0.55-3.22
0.51 2.99 0.41-22.12 0.28

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186
Primigravidae
• Yes
• No.
6 (12.5)
15 (11.5)
42 (87.5)
115 (88.5)
1.08
0.45-2.63
0.86 1.63
0.47-5.69
0.44
Mother Age
• <18 years
•> 18 years
2 (11.1)
19 (11.9)
16 (88.9)
141 (88.1)
0.94
0.24-3.19
0.48 0.53
0.09-3.09
0.48
Ethnicity
• Papuan
• Non Papuan
15 (17.4)
6 (6.5)
71 (82.6)
86 (93.5)
2.67
1.09-6.58
0.03 3.35 1.09-10.28 0.03
Bednet Utilization
• Yes
• No.
8 (14.4)
13 (10.3)
44 (84.6)
113 (89.7)
1.49
0.66-3.38
0.34 2.53
0.78-8.19
0.12
DISCUSSION
We found that at 6 and 12 months old, MiP
was related to malaria infection in infants. This
study is consistent with previous studies that
found a significant relationship between MiP
and infant susceptibility to malaria infection 27
and it also correlates with the increasing of
malaria episodes during infancy. 28 Infants born
to positive MiP mothers are more susceptible
to malaria, presumably because it is placental
malaria causes the transfer of maternal
antibody decrease 29 leading to increase of
infant susceptibility to malaria infection.
Our study found that after logistics
regression analysis, MiP occurrence in the
second trimester was independently associated
with infant susceptibility to malaria infection
in the first year of life (RR = 4.21; 95% CI 1.36-
13.60; p = 0.01) (TABLE 4). This finding is in
contrast with the results of a previous study 18
that found MiP in the third trimester increased
the risk of malaria infection during the first
year of life. The association between MiP in
the second trimester and infant susceptibility
to malaria infection was thought to be related
to the duration of malaria exposures in the
mother. 22 Malhotra et al. 17 reported a tolerant
immune process that depends
on the type of malaria antigen in contact
with the foetus, the number of parasites and
the duration of exposure and timing during
pregnancy. This finding supports the premise
that although the mother was exposed to
malaria but the foetus has not been sensitized,
so the infants are more susceptible to malaria
infection. 17 Boudova et al. 18 reported that
only placental infection during pregnancy is
associated with increased risk of malaria in
infancy, but in this study we found there was
no significant correlation between placental
malaria and infant susceptibility to malaria.
Another study reported that primigravidae
are at greater risk of MiP compared to
multigravidae 30 and their offspring are also
more susceptible to malaria infection mainly
as a result of reduced antibody transfer. 31
Yet in this study we did not find support for
this conclusion. However, this study found
that pregnant women who lived from
malaria as much as 1 time before delivery
were associated with infant susceptibility to
malaria infection. Among 26 cases of malaria
in infants at 6 and 12 months of age, there
were 4 infants who had malaria twice. The
remaining of 21 cases consisting of 5 infants
born to mothers without MiP, 7 infants born
to mothers with MiP who had a different
plasmodium species as their mothers and
9 infants born to mothers with MiP had the
same plasmodium species as their mothers.

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Ratni Indrawanti et al., The impact of malaria in pregnancy on infant
susceptibility to malaria infection
In all of the 9 infants who have the same
species as their mothers, malaria infection of
the mother occurred 1 time during the second
trimester. This phenomenon corresponds to
the theory that naturally acquired immunity
develops over time after repeated infections 10
and the development of antimalarial
antimalarial antibodies as well as maternal
antibodies transferred to the photo in the last
trimester are thought to play a crucial role. 28
In malaria endemic areas like in Timika
Papua, individuals develop naturally acquired
immunity to both P. falciparum and P. vivax
after repeated infections. 2 This immunity does
not generally protect against infection per se,
but protects against the development of high
parasite densities and clinical symptoms. 32
HLA-G might play an important role in infant
susceptibility to infection. A high level of
soluble HLA-G (sHLA-G), a non-classical
HLA class Ib antigen, with important immune-
regulatory functions 33
was significantly
associated with a higher incidence ratio of
malaria in children. 34 It was consistent with the
fact that the inhibition of immune responses
by HLA-G expression could lead to greater
susceptibility to malaria. 24 In this study infant
susceptibility to malaria infection besides
being associated to MiP was also significantly
correlated to ethnic Papuan (RR = 3.35; 95% CI
1.09-10.28; p = 0.03) (TABLE 4). This finding
is consistent with previous research that found
an association between Papuan ethnicity and
the risk of parasitemia in pregnant women. 8
Although a complete explanation
of the pathophysiology of MiP has not
yet been developed, exposure to malaria
intrauterine probably correlates with placental
sequestration of erythrocytes. The immune
tolerance process then depends on the
type of malaria antigen in contact with the
foetus, the amount and the duration of the
exposure, and the timing of exposure during
pregnancy. The timing of malaria episodes
during pregnancy results in different effects
on both the mother and the foetus, where
parasitaemia appears to be higher during the
first and second trimesters, although follow-
up on P. falciparum parasitaemia during the
first trimester has seldom been complete. 35
CONCLUSIONS
Infant susceptibility to malaria is
associated with maternal malaria status during
pregnancy. MiP in the second trimester,
pregnant women who only had malaria once
and Papuan ethnicity are independent risk
factors for infant's increased susceptibility to
malaria infection.
ACKNOWLEDGMENTS
We are grateful to Amungme and Kamoro
Community Development Foundation,
Mimika, Papua. We would also like to thank
the study participants for their significant
contribution to the study, the research
assistants, field and laboratory staff of the
Papua Health and Community Development
Foundation. This study was supported by The
National Institute of Health Research and
Development – Menzies School and Wellcome
National Health and Medical Research Trust
Council (NHMRC).
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