Complicated Malaria and Dengue

During Pregnancy 10
Haresh U. Doshi

Complicated Malaria degrades intracellular proteins especially hemo-

globin and also alters the permeability of red cell
Malaria continues to be a major global health membrane.
problem with over 40 % of the world population
at risk for malaria. As reported by the National Table 10.1 Chemotherapy of severe and complicated
Vector Borne Disease Control Programme malaria
(NVBDCP) director in 2013, around 1.5 million Initial parenteral treatment Follow-up
laboratory-confirmed cases are annually reported for at least 48 h: choose one of treatment, when
in India. Complicated malaria also known as following four options patient can take oral
severe malaria is defined by clinical or labora- medication
following parenteral
tory evidence of vital organ dysfunction.
treatment
Malaria is caused by a malarial parasite, a pro- Quinine: 20 mg quinine salt/ Quinine 10 mg/kg
tozoal parasite of genus Plasmodium. Five spe- kg body weight on admission three times a day
cies can infect human beings. Severe malaria is (IV infusion or divided IM with:
most commonly caused by infection with injection) followed by clindamycin
maintenance dose of 10 mg/kg 10 mg/kg 12 hourly
Plasmodium falciparum although P. vivax and P. 8 hourly; infusion rate should to complete 7 days
knowlesi [1] can also cause severe disease. not exceed 5 mg/kg per h. of treatment
Malaria is transmitted by bite of infected female Loading dose of 20 mg/kg
Anopheles mosquito which is a definite host for should not be given, if the
patient has already received
the parasite while a human being is an intermedi- quinine
ate host. Artesunate: 2.4 mg/kg IV or Full oral course of
Malaria produces hemolytic anemia by (1) IM given on admission area-specific ACT:
rupture of infected RBCs, (2) increased removal (time = 0), then at 12 h and In northeastern
of parasitized cells by the spleen, and (3) infected 24 h, and then once a day states: age-specific
or ACTAL for 3 days
RBCs that become antigenic and produce autoan- Artemether: 3.2 mg/kg bw IM In other states: treat
tibodies which can cause hemolysis. Parasite given on admission and then with ACT-SP for
1.6 mg/kg per day 3 days
or
Arteether: 150 mg daily IM
H.U. Doshi, MD, PhD for 3 days
Department of ObGyn, GCS Medical College, ACTAL artemisinin-based combination therapy (arte-
Hospital and Research centre, Ahmedabad, India mether + lumefantrine), ACT-SP artemisinin-based combi-
e-mail: doshiharesh@hotmail.com nation therapy (artesunate + sulfadoxine + pyrimethamine)

Springer India 2016 81

A. Gandhi et al. (eds.), Principles of Critical Care in Obstetrics: Volume II,
DOI 10.1007/978-81-322-2686-4_10
10 Complicated Malaria and Dengue During Pregnancy 82

Clinical Features diagnosis which is particularly important in low-

density malarial parasitemia of P. falciparum.
Malaria and pregnancy are mutually aggravat- Thin smear is important for knowing the species
ing conditions. The physiological changes of and degree of parasitemia.
pregnancy and the pathological changes due to Rapid diagnostic tests (RDTs) provide diag-
malaria have a synergistic effect on the course nosis of malaria where reliable microscopy is not
of each other. Malaria is more common in preg- reliable or practical. RDTs detect antigen pro-
nancy as compared to the general population. duced by malarial parasite. The most widely used
Immunosuppression and loss of acquired immu- RDTs for detecting P. falciparum target the
nity could be the causes [2]. A case of uncompli- HRP2 antigen. RDTs are less sensitive than blood
cated malaria usually presents with fever, rigors, films [7] and cannot diagnose the species or
headache, body ache, fatigue, anorexia, and nau- quantify the number of RBCs infected.
sea. In pregnancy, malaria tends to be more PCR: Parasite nucleic acid detection by PCR
atypical in presentation. This could be due to the is more sensitive and specific than microscopy
hormonal, immunological, and hematological but available in sophisticated laboratories only.
changes of pregnancy. Pregnant mothers are three PCR is a very useful tool for confirmation of spe-
times more likely to develop severe disease than cies and detecting of drug resistance mutations.
nonpregnant women acquiring infection from the Laboratory diagnosis of complicated malaria
same area. Primigravida and nonimmune pregnant is as follows:
women are at increased risk for severe falciparum
malaria [3]. The parasitemia tends to be ten times Hypoglycemia (<40 mg/dl)
higher, and as a result, all the complications of fal- Metabolic acidosis (plasma bicarbonate
ciparum malaria are more common in pregnancy <15 mmol/l)
compared to the nonpregnant population. Apart Severe normocytic anemia (Hb <5 g/dl, PCV
from severe anemia and severe recurrent hypogly- <20 %)
cemia, other clinical features of severe malaria are Hemoglobinuria
impaired consciousness, prostration, convulsions, Hyperlactatemia (lactate >5 mmol/l)
deep breathing and respiratory distress, acute pul- Hyperparasitemia (>2 % parasitized red blood
monary edema, circulatory collapse, acute kidney cells)
injury, clinical jaundice, and abnormal bleeding. Renal impairment
Severe malaria increases the maternal and peri- Pulmonary edema confirmed radiologically
natal morbidity as well as mortality. Severe falci-
parum malaria is associated with substantially high
mortality in pregnancy (50 %) than in nonpregnant Management
women (1520 %) [4]. Perinatal complications of
malaria include abortion, preterm labor, IUGR, Severe malaria is a medical emergency and treat-
fetal distress and IUFD, and congenital malaria [5].
ment should be given as per severity and associated
The newborn with congenital malaria may not complications which can be best decided by a treat-
present with typical symptoms of malaria such as ing physician. Patients of severe malaria should be
fever but have other clinical manifestations likeadmitted in the ICU. Prompt diagnosis and aggres-
jaundice and hemolytic anemia [6]. sive antimalarial treatment are crucial to prevent
mortality in case of severe malaria. Parenteral arte-
misinin derivatives or quinine should be used irre-
Diagnosis spective of chloroquine resistance status of the area
and irrespective of the species of malaria seen on
Microscopic examination of the peripheral blood the blood smear. Oral antimalarial drugs are not rec-
smears is the gold standard for diagnosis. Thick ommended for the initial treatment of severe
smears are more sensitive than thin smears for malaria. Treatment advised by the directorate of
10 Complicated Malaria and Dengue During Pregnancy 83

National Vector Borne Disease Control Programme Manifestation or

in India recently is as follows (Table 10.1): complication Management
WHO recommends that IV artesunate is the Spontaneous Transfuse fresh whole blood
preferred first-line drug for all severe malaria cases bleeding and and blood products; give
coagulopathy vitamin K injection
in adults including pregnant women [8]. As com-
Metabolic acidosis Prevent by careful fluid
pared to quinine, artesunate is associated with balance; exclude or treat
35 % reduction in mortality [9]. Although there is hypoglycemia, hypovolemia,
insufficient evidence to support the use of artemis- and septicemia; if severe add
hemofiltration or hemodialysis
inin in the first trimester, the drug should not be
Shock Suspect septicemia, take blood
withheld if the life of the woman is endangered
culture, give broad-spectrum
[10]. One of the reasons of high mortality in the antibiotics, correct
past was the delay in institution of proper antima- hemodynamic disturbances
larial drugs [11]. Artesunate is well tolerated with
no attributable local or systemic adverse effects.
As quinine stimulates insulin secretion, treatment Provide good nursing care. This is vital espe-
with quinine in pregnancy is associated with cially if the patient is unconscious. Avoid
severe and recurrent hypoglycemia [12]. Quinine NSAIDs which increase the risk of gastrointesti-
does not induce abortion or labor. Mild side effects nal bleeding. For fluid balance urine output
known as cinchonism are common with quinine should be aimed at >1 ml/kg/h. Give packed cell
including tinnitus, hearing loss, dizziness, nausea, volume (PCV) transfusion if there is severe ane-
uneasiness, restlessness, and blurring of vision. mia. Exchange transfusion to treat severe parasit-
emia is not proved by evidence.
Supportive care in severe malaria [8] Role of early cesarean section in severe malaria
Manifestation or is unproven. For patients in labor, second stage
complication Management should be shortened by instrumental delivery.
Coma (cerebral Monitor using Glasgow Coma For prevention of malaria, personal protective
malaria) Scale. Maintain airway, place measures like long protective clothing, mosquito
patient on her side, and coils and body repellants (sprays and lotion), and
exclude treatable causes of
coma (e.g., hypoglycemia,
wire screening on windows should be practiced.
meningitis) Treated bed nets (ITN)/long-lasting insecticidal
Hyperpyrexia Administer tepid sponging, nets (LLIN) should be encouraged for pregnant
fanning, and antipyretic drugs women. Meta-analysis of intervention trials sug-
Convulsions Maintain airway, treat promptly gests that successful prevention of these infec-
with intravenous diazepam tions reduces the risk of severe maternal anemia
Hypoglycemia Check blood glucose regularly, by 38 %, low birth weight by 43 %, and perinatal
correct hypoglycemia, and
maintain with (blood glucose mortality by 27 % among primigravidae [13].
<40 mg/dl) glucose-containing RTS,S is the most recently developed recombi-
infusion nant vaccine for malaria. Phase III clinical trials
Severe anemia Transfuse with packed red have shown modest protection against malaria. It
cells might be available for clinical use soon.
Acute pulmonary Treat by propping patient up at
edema an angle of 45, give oxygen,
give a diuretic, stop IV fluids,
intubate, and add PEEP/CPAP Dengue
if required
Renal failure Exclude prerenal causes; check Dengue infection is a mosquito-borne viral infec-
fluid balance and urinary
tion causing a flu-like febrile illness and some-
sodium; if in established renal
failure, add hemofiltration or times causing a potentially lethal complication
hemodialysis called severe dengue. Dengue infection is
10 Complicated Malaria and Dengue During Pregnancy
endemic in tropical and subtropical countries
including India. The incidence of dengue has
increased 30-fold over the past 50 years. This
increase is due to many factors like urbanization,
population growth, increased international travel,
and global warming. About half of the worlds
population is now at risk [14]. Indias National
Vector Borne Disease Control Programme
reported in 2013 that the country had experienced
an annual average of 20,474 dengue cases and
132 dengue-related deaths since 2007 [15]. As
dengue is more common in children and young
adults, pregnant patients are at increased risk.
Also the infection in pregnant mothers is reported
to be more severe as compared to nonpregnant
females and with higher mortality rates [16].
Dengue virus is an RNA virus of the family
Flaviviridae, genus Flavivirus. Originally there
were four strains of the virus called serotypes
DENV-1, DENV-2, DENV-3, and DENV-4.
Recently, the fifth type is discovered in 2013. The
Aedes aegypti mosquito is the primary vector of
dengue. The virus is transmitted to humans
through the bites of infected female mosquitoes.
Aedes aegypti is a daytime feeder biting mainly
early in the morning and in the evening before
dusk. Infected humans are the main carriers and
multipliers of virus serving as a source for unin-
fected mosquitoes.
Recovery from infection by one serotype pro-
vides lifelong immunity against that particular
serotype but only partial and temporary immu-
nity to the other serotypes. Subsequent infections
by other serotypes increase the risk of developing
severe dengue.
Dengue can also be transmitted via infected
blood products and through organ donation.
Vertical transmission during pregnancy is also
reported [17]. Otherwise infection does not occur
directly from human to human.
Original WHO classification (1997), still in
use, divides dengue into undifferentiated fever,
dengue fever, and dengue hemorrhagic fever
(DHF). Dengue hemorrhagic fever was subdi-
vided into grades IIV. Grade I is the presence
only of easy bruising or a positive tourniquet test
in someone with fever, grade II is the presence of
spontaneous bleeding into the skin and else-
84
where, grade III is the clinical evidence of shock,
and grade IV is shock so severe that BP and pulse
cannot be recorded. Grades III and IV are referred
to as dengue shock syndrome (DSS).
The latest WHO 2009 classification [14]
divides dengue fever into two groups: uncompli-
cated and severe. Severe dengue is defined as that
associated with severe bleeding, severe organ
dysfunction, or severe plasma leakage, while all
other cases are classified as uncomplicated.
Clinical Features
Symptoms usually begin 46 days after infection
and last for up to 10 days. Symptoms include sud-
den, high fever, severe headaches, retro-orbital
pain, arthralgia, and myalgia. Nausea and vomit-
ing may also occur. Skin rash appears initially as
flushed skin and after 34 days as measles like
rash. Mild bleeding from mucous membranes of
the mouth or nose may occur. In some people the
disease proceeds to a critical phase as fever
resolves. There is leakage of plasma from the
blood vessels which typically last 12 days. This
may result in fluid accumulation in the chest, i.e.,
pleural effusion, and in the abdominal cavity, i.e.,
ascites. Depletion of platelets leads to severe
bleeding typically from gastrointestinal tract. This
is called dengue hemorrhagic fever (DHF).
Depletion of fluid from circulation and hem-
orrhage leads to profound hypotension and shock.
This is called dengue shock syndrome (DSS)
which can cause mortality. Patients with weak-
ened immune system as well as those with a sec-
ond or subsequent dengue infection are at greater
risk for developing dengue hemorrhagic fever.
With improved diagnosis and treatment, the pro-
portion of DHF cases in dengue fever is decreas-
ing from 20 to <10 % in the last 5 years.
Apart from preterm labor, if pregnant woman
delivers at the height of viremia, there is a risk of
severe postpartum hemorrhage [18]. Carles et al.
reported significant increase in prematurity and
fetal death in dengue fever during pregnancy [19].
This may be related to hyperpyrexia. Vertical
transmission of 10.5 % was reported in their
study. Vertical transmission rate might be
10 Complicated Malaria and Dengue During Pregnancy
dependent on the severity of maternal dengue.
Severe dengue affects the newborn only when
dengue develops close to term or delivery time,
and the mother has no time to produce protective
antibodies. Most neonates develop fever within
45 days of life and consequently develop throm-
bocytopenia requiring platelet transfusions [20].
In a study by Fernandes et al., 5-year follow-up of
newborns after vertical dengue infection showed
no long-term sequelae [21].
Dengue hemorrhagic fever may be confused
with HELLP syndrome in a case of preeclampsia in
pregnancy, but in HELLP constitutional symptoms
are absent and serological tests are negative [22].
Diagnosis
High index of suspicion is the key for diagnosis
when the pregnant patient with fever is from an
endemic area or when there are epidemics. A
definite diagnosis of dengue can be done by sero-
logical tests. IgM capture ELISA is a rapid, sim-
ple, and most widely used method. Both IgM and
IgG positive suggest secondary infection. Serum
sample should be taken 510 days after the onset
of the disease. Virus isolation in cell cultures and
nucleic acid detection by PCR although more
accurate are not widely available due to high
cost. Viral antigen detection (NS1) is 90 % sensi-
tive in primary infection but less in subsequent
infection.
Treatment
Dengue fever is usually self-limited. There is no
specific antiviral treatment available for dengue
fever. Most cases only require conservative treat-
ment [23]. Supportive care with antipyretics, bed
rest, adequate fluid replacement, and mainte-
nance of electrolyte balance forms are the main-
stay of treatment. Paracetamol is preferred.
NSAIDs are avoided due to risk of bleeding.
Normal saline is preferred to Ringers lactate for
intravenous hydration.
Patients with dengue hemorrhagic fever and
dengue shock syndrome are kept in the ICU with
85
monitoring of hematological status and serum
albumin levels at timely intervals. The physi-
ological hemodilution of normal pregnancy can
mask the criteria of hemoconcentration in DHF.
Prophylactic transfusion of platelets or FFP is
not recommended. Platelets are given in patients
with severe thrombocytopenia who went in labor
or who require surgery [24]. PCV and FFPs
are required in a dengue patient who has active
bleeding. Therapeutic benefit of gamma globu-
lin is reported in nonpregnant patient of DHF,
but it is not evaluated in pregnant women [25].
Corticosteroids have no role in treatment.
In the absence of associated fetomaternal
complications, infection by itself does not appear
to be an indication for obstetric interference.
Prevention: Prevention of dengue fever is by
controlling the vector mosquito and avoiding
mosquito bites. Controlling the vector can be
done by environmental modification. Using of
personal household protection measures men-
tioned under malaria is recommended.
Research: Currently research is under way for
(1) development of vaccine against dengue, (2)
for antiviral drugs against dengue virus, and (3)
finding new methods of vector control.
Key Points
1. High index of suspicion in endemic
areas and during epidemics helps in the
early diagnosis of both malaria and den-
gue fever.
2. Severe malaria and severe dengue are
medical emergencies and patients
should be treated in the ICU.
3. For severe malaria parenteral artemis-
inin derivatives or quinine should be
used without delay.
4. There is no specific antiviral treatment
for dengue. Supportive therapy with an
aim to maintain normothermia and fluid
and electrolyte imbalance is the corner-
stone of therapy.
5. Pregnant women should be counseled
about preventive strategies to avoid
mosquito bites.
10 Complicated Malaria and Dengue During Pregnancy 86
10 Complicated Malaria and Dengue During Pregnancy 87

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