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Southeast D

Asian J Tinrop
engue Med Public Health
Pregnancy

DENGUE INFECTION IN PREGNANCY


Kriangsak Khamim1, Boonluck Khamim2 and Krisana Pengsaa3

1Department of Obstetrics and Gynecology, Ban Pong Hospital, Ratchaburi;


2Department of Pediatrics, Makarak Hospital, Kanchanaburi; 3Department of Tropical
Pediatrics, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand

Abstract. While dengue infection is still on the increase in adults in Thailand, it also
affects pregnant women, especially pregnant teenagers. This study was designed
to investigate dengue infection during pregnancy. Seven cases of dengue infection
in pregnant women were admitted to Ban Pong Hospital, Ratchaburi, Thailand,
between 2008 and 2012. Dengue infection presented in all pregnancy trimesters.
There were two severe cases: one was dengue hemorrhagic fever in the first trimes-
ter, and the second was at a critical stage of the infection during labor. There were
three cases of abortion. These three cases included one complete, one incomplete,
and one threatened abortion, with rising hematocrits of 22.8%, 17.1%, and 14.7%,
respectively. Two out of the three teenage pregnancies experienced complete and
threatened abortions, while the third abortion case was a threatened abortion preg-
nancy at the critical stage of infection during intrapartum. Leukopenia was identified
in six out of seven women. Low baseline hematocrit and low maximum hematocrit
were laboratory findings. Clinical management involved administration of intrave-
nous fluids and antipyretics. Favorable outcomes can be obtained through early
diagnosis and supportive treatment. The morbidity profile can be more serious in
teenage pregnancies. Additional studies should be conducted to establish whether
low baseline hematocrit, low percentages of rising hematocrit in pregnant women
with dengue infection, and abortions (with a high degree of increasing hematocrit
during the critical stage of the disease) are typical clinical signs.
Keywords: dengue infection, HELLP, pregnancy, teenage, Thailand

INTRODUCTION about 500,000 develop dengue hemor-


rhagic fever (DHF), and 22,000 die of the
Dengue infection is a major public
disease (Thisyakorn and Pengsaa, 2012).
health problem in tropical and subtropi-
Dengue infection severity is variable, rang-
cal countries. This mosquito-borne viral
ing from mild, non-specific febrile illnesses
disease is a potential threat to 50-100 mil-
to classic dengue fever (DF) or DHF and
lion people each year. Of those infected,
dengue shock syndrome (DSS), which are
more severe forms of the disease. DF, an
Correspondence: Kriangsak Khamim MD, De- acute febrile disease, frequently presents
partment of Obstetrics and Gynecology, Ban
with headache, bone, joint and muscle
Pong Hospital, 12 Sangchuto Road, Ratchaburi
70110, Thailand. pain, rash, and leukopenia. In contrast,
Tel: +66 (0) 32 222845; Fax: +66 (0) 32 211766 DHF is characterized by four major clinical
E-mail: ksak6@hotmail.com manifestations: high fever, hemorrhagic

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phenomena (often with hepatomegaly), Furthermore, because of the presence of


and signs of circulatory failure in severe various obstetrical indicators, eight (10.2%)
cases. DHF patients may develop hypovo- patients were delivered by Caesarean sec-
lemic shock (known as DSS) resulting from tion (Ishag et al, 2010).
plasma leakage; this can be fatal (WHO, During normal pregnancy, physiologi-
1997; CDC, 2013). Currently, neither a cal changes to the cardiovascular system
vaccine nor specific antiviral therapy exists. and blood increase the cardiac output,
Dengue infection is most often en- heart rate, and stroke volume while slightly
countered in children. However, more decreasing the diastolic blood pressure
recently, dengue infection in Thailand has (Ouzounian and Elkayam, 2012). These
started to affect people over 10 years of normal signs could be misinterpreted as
age as well as adults. In Thailand, the plasma leakage and hypotensive shock
modal age group affected by dengue has caused by dengue infection. Some of
shifted from <10 years of age to 10-34 the overlapping clinical and/or laboratory
years of age. In 2012, 79,593 cases of features of dengue infection in pregnancy
dengue infection were reported in 76 Thai can be confused with a diagnosis of pre-
provinces. The highest proportion of cases eclampsia, eclampsia, or HELLP syndrome
by age group was found in 15-24 year olds (hemolysis, elevated liver enzymes, and
(23.79%, n=18,923), followed by 10-14 low platelet count).
year olds (21.59%, n=17,182), 7-9 year Despite the high prevalence of dengue
olds (11.85%, n=9,432), and 25-34 year infection in Thailand, there have been few
olds (9.86%, n=7,853) (Department of reported cases of this infection in pregnant
Disease Control, 2012). women. This study was conducted to inves-
Dengue infection can appear in preg- tigate pregnancy-related dengue infection
nant women at any time as well as in the in an area of high prevalence.
immediate post-partum period (Waduge
et al, 2006). These infections can have MATERIALS AND METHODS
various complications, including maternal
mortality, preterm delivery, fetal death, This descriptive retrospective study
low birth weight, neonatal admissions, was conducted at Ban Pong Hospital,
fetal anomalies, and spontaneous abor- Ratchaburi, Thailand, which is a dengue
tion. In East Sudan, dengue infection endemic area. All hospitalized pregnant
during pregnancy has poor maternal and women with dengue infection were in-
prenatal outcomes (Ishag et al, 2010). In cluded in the study, which took place from
this Sudanese region (2008-2009), 17 2008 Jan 1 to 2012 Dec 30. Diagnoses
(21.7%) maternal deaths, 14 (17.9%) of and classification of dengue infection as
the 78 women with preterm deliveries, DF, DHF, and DSS were made according
and 19 (24.3%) admissions of neonates to WHO (1997) criteria. Maternal clini-
to neonatal intensive care units were re- cal signs, laboratory findings, pregnancy
ported. Additionally, 19 (24.3%) women outcomes, and information concerning
gave birth to low birth weight babies, and complications in mothers and fetuses were
there were seven (8.9%) perinatal deaths. examined. The study was approved by

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Dengue in Pregnancy

the Ethics Committee for research involv- blood. Hematocrits were low baseline (35%,
ing human subjects at Ban Pong Hospital 35%, 29%, 35%, 30%, 35%, and 34%) and
(Registered No R 2014-001). The patients low maximum (43%, 41%, 33%, 37%, 32%,
provided written informed consent. 37%, and 39%). The maximal percentages
of rising hematocrit during the critical stage
RESULTS of the disease were 22.8%, 17.1%, 13.8%,
5.7%, 6.7%, 5.7%, and 14.7%. The first
There were 11,690 deliveries and and the seventh cases had dengue virus-
2,829 dengue infections at Ban Pong positive IgM rapid test results; the other
Hospital during the five-year study period. cases were not tested.
The seven pregnancy-related dengue Of the pregnancy outcomes of the four
infection cases had no associated mortal- women who carried infants of 20 weeks or
ity. Three cases of dengue infection were less gestation, two out of four had complete
teenagers (14, 16, and 19 years old), and and incomplete spontaneous abortions,
four were adult pregnant women (27, 32, while one had a threatened abortion. All
33, and 34 years old). The women’s ages, three abortion cases had high maximal
gestational ages, clinical manifestations, rising hematocrit percentages during the
laboratory data and pregnancy outcomes critical stage of the disease: 22.8% (for
for expectant mothers with dengue infec- the complete abortion), 17.1% (for the
tion are shown in Table 1. Infection oc- incomplete abortion), and 14.7% (for the
curred in three women in the first trimester threatened abortion). The times from on-
at 5, 10, and 12 weeks of gestational age, set of fever to abortion in the three cases
two women in the second trimester at 14 were 8 weeks (for the complete abortion),
and 26 weeks, and two women in the third 3 weeks (for the incomplete abortion) and 1
trimester at 33 and 38 weeks. There were day (for the threatened abortion). Four out
two severe dengue cases: the first was of seven cases, including the threatened
DHF in the first trimester, and the second abortion, progressed to normal deliveries
was when labor occurred at the critical with healthy full-term neonates.
stage of the infection. Both cases were Two of the three teenaged pregnant
teenaged women. women with dengue infections had com-
The clinical manifestations in all cases plete and threatened abortions; whereas,
were fever (duration 3-5 days) and myal- the other infection was intrapartum at the
gia whereas bleeding episodes such as critical stage of infection, so a referral to a
epistaxis and petechia were less common. tertiary care hospital was necessary.
Tourniquet tests were done in four cases, The clinical management of the
of which three cases were positive.   pregnant women with dengue infection
Complete blood counts in all seven included supportive care, rest, intravenous
cases revealed low white blood cell counts fluids, and antipyretic medication. None of
of 2,100, 4,900, 3,110, 6,700, 4,980, 1,680, patients required platelets or other blood
and 3,500/µl of blood while the thrombocyto- components except for one patient whose
penia values were 74,100, 84,400, 95,800, critical stage of infection occurred during in-
73,200, 26,100, 83,200, and 39,000 / µl of trapartum. Because she may have needed

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a blood transfusion, she was referred to a partum period (Waduge et al, 2006). In the
tertiary care hospital. present study, the dengue infections oc-
curred mainly during the first trimester. The
DISCUSSION clinical signs and symptoms experienced
by the seven pregnant women with den-
From 2008 to 2012, dengue infection gue infection (fever of 3-5 days duration,
was present in both teenaged and adult myalgia, nausea and vomiting, epistaxis,
pregnant women admitted to Ban Pong and petechiae) were similar to those of
Hospital, Thailand. Three out of seven non-pregnant women with this infection.
cases were teenaged pregnant women. Leukopenia was identified in all the
Over the last decade, dengue infection cases except for Case 4, who was 38
has started to affect people over 10 years weeks pregnant and had a normal white
of age (Department of Disease Control, blood cell count during the intrapartum
2012). Concurrently, the number of teen- period (Table 1). During the febrile phase
age pregnancies in Thailand has increased of dengue fever in non-pregnant women,
(Prohmmo, 2007). At delivery, 94.7% of a leukopenia (white blood cell count below
the Thai pregnant women had dengue 5,000/µl) indicates that the fever will likely
HAI antibodies, and a mother’s age was dissipate within the next 24 hours and that
the only risk factor associated with dengue the patient is entering into the critical stage
infection, because older mothers were of the disease (CDC, 2013); however, in
significantly more likely to be seropositive normal pregnancy, a modest leukocytosis
than younger ones (Perret et al, 2005). is observed. The normal white blood cell
The seropositivity rate for dengue infection count ranges during the first, second, and
increases with advancing maternal age, third pregnancy trimesters and in non-
indicating that younger women are more pregnant adults were 5.7-13.6, 5.6-14.8,
at risk of contracting dengue infection dur- 5.9-16.9, and 3.5-9.1 (×103/µl), respec-
ing pregnancy. These three factors (older tively (Abbassi-Ghanavati et al, 2009).
susceptible age group, higher numbers of Therefore, pregnant women presenting
teenage pregnancies, and low antibody with febrile illness after travelling to or living
seropositivity in younger women) are likely within a dengue-endemic area who have
to have increased the numbers of pregnant significantly decreased white blood cell
women with dengue infection although counts (leukopenia) compared with those
teenagers tend to experience more severe of normal pregnancies warrant further in-
effects than older women do. vestigation. Careful monitoring of infection
Dengue infection can appear at any indicators in pregnant women suspected
time during pregnancy and the intrapar- of having dengue infections is essential.
tum period. In Sri Lanka (2000-2004), Thrombocytopenia was present in all
26 patients were reported with dengue- the case studies. Assuming that the earli-
associated pregnancies. One (3.8%), 2 est abnormality found in a complete blood
(7.7%), and 20 (77%) presented in the first, count is a progressive decrease in the total
second, and third trimesters, respectively, white cell count followed by progressive
as well as 3 (11.5%) in the immediate post- thrombocytopenia, an obstetrician should

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Table 1
Dengue infection in pregnant women.
Case number 1 2 3 4 5 6 7

Diagnosis (WHO, 1997) DHF DF DF DF DF DF DF


Age (years) 14 32 33 16 34 27 19
Gestational age (weeks) 12 14 33 38 26 5 10
Fever Yes Yes Yes Yes Yes Yes Yes

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Duration of fever (days) 5 3 3 3 3 3 5
Tourniquet test No data Positive Positive No data No data Positive Negative
Petechiae No No No Yes Yes Yes No
Epistaxis No No Yes No Yes No No
Nausea/Vomiting Yes No Yes Yes No Yes Yes
Myalgia Yes Yes Yes Yes Yes Yes Yes
White blood cell (/µl) min 2,100 4,900 3,110 6,700 4,980 1,680 3,500
Platelet count (/µl) min 74,100 84,400 95,800 73,200 26,100 83,200 39,000
Hematocrit (%)
max 43 41 33 37 32 37 39
Dengue in Pregnancy

min (baseline) 35 35 29 35 30 35 34
Rising hematocrit (%) 22.8 17.1 13.8 5.7 6.7 5.7 14.7
Serological IgM rapid test Positive No data No data No data No data No data Positive
Blood component transfusion None None None No data None None None
Outcome of pregnancy Complete Incomplete Normal labor: Referral Normal labor: Normal Labor: Threatened
abortion abortion healthy baby healthy baby healthy baby abortion/
Normal labor:
healthy baby
Duration from diagnosis to 8 3 7 Referral 12 35 1 day/
outcome of pregnancy (weeks) 30 weeks

DF, Dengue fever; DHF, Dengue hemorrhagic fever.

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be alert to the likelihood of dengue infection. All cases in the present study except
Among the seven reported cases, low the one who was intrapartum and at the
baseline hematocrit and low maximum critical stage of the disease were managed
hematocrit were present. Three out of four by supportive care, rest, intravenous fluids
cases with pregnancies of 20 weeks or and antipyretic medication similar to recent
less had complete (n=1), incomplete (n=1) reports in which good clinical outcomes
spontaneous abortions, and a threatened were obtained (Malhotra et al, 2006; Carroll
abortion (n=1); these cases had high et al, 2007; Ishag et al, 2010). Three cases
maximal rising hematocrit values during the of teenaged pregnant women with dengue
critical stage of the disease (22.8%, 17.1%, infection had poor outcomes; two experi-
and 14.7%, respectively). By comparison, enced spontaneous abortions, and one full-
the other cases (with no abortion) all had term pregnancy experienced labor during
low maximal rising hematocrit percentages the critical stage of the disease. While the
during the critical stage of the infection. four pregnant women (>20 years old) with
However, access to a larger data set is nec- dengue infection had three normal deliver-
essary to confirm whether these findings ies and full term healthy neonates, there
are generally applicable to pregnancies of was only one case of incomplete abortion.
20 weeks or less. This is not the first report of dengue infec-
Low baseline hematocrit and rising tion associated with spontaneous abortion,
hematocrits during pregnancy may be af- or of the increased risk of such abortions
fected by plasma leakage or normal physi- occurring during the first trimester (Waduge
ological changes in the cardiovascular et al, 2006; Tan et al, 2012).
system. For example, an increase of 40%- Fever with thrombocytopenia during
50% in plasma volume, which is relatively pregnancy, especially during the intrapar-
greater than the accompanying 20%-30% tum period, can cause massive bleeding;
increase in red blood cell mass, results in therefore, obstetricians have to be ex-
hemodilution and decreased hematocrit tremely careful with cases presenting with
(Ouzounian and Elkayam, 2012). Hence, these clinical signs. DHF and DSS are
the criterion for a diagnosis of anemia in associated with fatality rates ranging from
pregnancy is a hematocrit of <30%, 33%, 2.9%-22% (Morta et al, 2012; Marchado
and 30% in the first, second, and third et al, 2013). These fatality rate differences
trimester, respectively; these values are probably result from differences in the ways
lower than those of normal adult females these diseases are managed (Ishag et al,
(Abbassi-Ghanavati et al, 2009). 2010; Pouliot et al, 2010). Hence, accurate
Having an enlarged gravid uterus and rapid diagnosis of DF, DHF, and DSS
makes it difficult to evaluate the clinical in pregnant women is very important; how-
signs of plasma leakage such as pleural ever, hemodilution in normal pregnancy
effusion and ascites. Therefore, routine can conceal the classical features of hemo-
abdominal and chest ultrasound examina- concentration associated plasma leakage
tions to detect free fluid in abdominal or in DHF. Ultrasound detection of free fluid in
thoracic cavities should be considered for the chest or abdomen may precede clinical
pregnant women with dengue infection. detection of DHF.

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Dengue in Pregnancy

Pregnant women with severe dengue be helpful for arriving at a provisional diag-
infection must be differentiated from those nosis while the definite diagnosis of dengue
with HELLP syndrome, preeclampsia or infection should be confirmed serologically.
eclampsia. Laboratory findings for severe In the cases described herein, the
dengue infection and HELLP syndrome dengue infections in the pregnant women
overlap with thrombocytopenia and el- were managed by supportive care, rest,
evated liver enzymes whereas laboratory administration of intravenous fluids, and
findings supporting a diagnosis of HELLP antipyretic medication. None of the patients
syndrome include hemolysis of peripheral required platelets or other blood compo-
blood smears, serum lactate dehydroge- nents except one patient who had the criti-
nase ≥ 600 IU/l and proteinuria. However, cal stage of the infection during intrapartum
in pregnancy, proteinuria is the only one and was, therefore, referred to a tertiary
criterion used to diagnose preeclampsia. care hospital because of the possibility of
In 2013, the American College of Obste- needing a blood transfusion. The handbook
tricians and Gynecologists’ Task Force for clinical management of dengue (WHO
on Hypertension in Pregnancy modified and TDR, 2012) advises that clinicians
(in recognition of the syndromic nature need to maintain a high index of suspicion
of preeclampsia) the dependence of the when dealing with pregnant women who
diagnosis on proteinuria. In the absence present with febrile illness after travelling
of proteinuria, preeclampsia should be to or living in dengue-endemic areas. Early
diagnosed as hypertension in association admission to hospital for close monitoring is
with thrombocytopenia (platelet count less desirable, particularly for pregnant women
than 100,000/µl), impaired liver function close to full-term and labor while the treat-
(elevated blood levels of liver transami- ment of choice is medically conservative
nases to twice the normal concentration), with obstetrical management of dengue
the new development of renal insufficiency disease (WHO and TDR, 2012).
(elevated serum creatinine greater than 1.1 Dengue infection occurs during all
mg/dl or a doubling of serum creatinine in trimesters and the morbidity levels as-
the absence of other renal disease), pul- sociated with it can be more serious in
monary edema, or new-onset cerebral or teenage pregnancies. Favorable outcomes
visual disturbances (American College of can be obtained by early diagnosis and
Obstetricians and Gynecologists, 2013). supportive treatment. Leukopenia was
In cases where proteinuria is absent, observed in most of the pregnant women
similar clinical and laboratory findings of with dengue infection. Further studies
thrombocytopenia, impaired liver function, should be conducted to determine whether
renal insufficiency, pulmonary edema, and the low baseline hematocrits and low rising
new-onset cerebral or visual disturbances hematocrits (or abortions associated with
in severe preeclampsia and severe den- increasing hematocrits during the critical
gue infection in pregnant women may be stage of the disease) that we observed in
found. Therefore, a history of fever and pregnant women with dengue infection are
hypertension that predates pregnancy may typical clinical signs.

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ACKNOWLEDGEMENTS surveillance information system. PLOS


Negl Trop Dis 2013 May 9; 7: e2217.
The authors would like to thank the Morta AK, Miranda Filtio AL, Saraceni V, Korif-
Medical Records Unit at Ban Pong Hospital man S. Maternal mortality and impact of
for providing the data used for this study dengue in Southeast Brazil: an ecological
and the hospital staff for their assistance study, 2001-2005. Cad Saude Publica
with data collection. We give special thanks 2012; 28: 1057-66.
to Dr Dulwit Tapaneeyakorn, the Director Ouzounian JG, Elkayam U. Physiologic chang-
es during normal pregnancy and delivery.
of Ban Pong Hospital, for supporting this
Cardiol Clin 2012; 30: 317-29.
study.
Perret C, Chanthavanich P, Pengsaa K, et al.
Dengue infection during pregnancy and
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