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Contents lists available at ScienceDirect

Pediatric Infectious Disease

journal homepage: www.elsevier.com/locate/pid

Congenital Dengue Infection: Are we missing the Diagnosis? Case report with review of literature

Congenital dengue infection: Are we missing the diagnosis?

Ramani Ranjan a,*, Kishore Kumar b,c, Nandini Nagar d
a
Consultant Neonatologist and Pediatrician Adiyta Birla Hospital, Veraval, Gujarat, India
b
Consultant Neonatologist & Paediatrician Chairman - Cloudnine Hospitals, India
c
Adjunct Professor of Neonatology & Paediatrics, Notre Dame University, Australia
d
Consultant Neontalogist and Paediatrician Cloudnine Hospital, Bangalore

A R T I C L E I N F O A B S T R A C T

Article history: Neonatal dengue is now being increasingly reported for changing epidemiology and improved rapid
Received 2 May 2016 detection methods. Vertical transmission with dengue virus is concordant with rules of nanomedicine
Accepted 13 July 2016 and may present differently in newborns from what we normally see in older children. It may have
Available online xxx
prolonged symptomatology and protracted thrombocytopenia. There are no specic guidelines for
neonatal dengue management. There is dearth of standard literature about neonatal dengue per se and
Keywords: most recommendations are based on experiences with older children and adults. The unique pathogen
Neonatal dengue
host interaction complicates dengue vaccine development and creates provocative questions in vaccine
Vertical transmission
development. We present a case report of neonatal dengue with review of literature. A day 8 old
newborn with maternally acquired dengue was admitted in our NICU and had an eventful course. This
congenital dengue infection case gives us good learning experiences in a not so well understood entity.
2016 Published by Elsevier B.V. on behalf of Indian Academy of Pediatrics, Infectious Disease Chapter.

1. Introduction
Dengue is the most important tropical mosquito-borne infec-
tious disease caused by an arbovirus, the dengue virus. After being
bitten by a vector mosquito, human beings will obtain the dengue
virus, which can result in infection. The dengue virus is a single-
stranded RNA virus in the genus Flavivirus and family Flaviviridae.
This virus is approximately 4060 nm. There are four distinct
serotypes of dengue virus that can cause disease. A high fever,
accompanied by hemo-concentration and thrombocytopenia, is
the hallmark of severe dengue disease.1,2
Concern regarding women who are pregnant becoming infected
with dengue has been heightened in recent years due to an
increase in adolescent and adult infections3 Women of child-
bearing age are now increasingly at risk of acquiring dengue
infection while pregnant and may be more likely to develop severe
disease as second infections occur later in life. DHF during
Abbreviations: CRP, C reactive protein; CPAP, continuous positive airway pressure;
I.V., intravenous; LFT, liver function test; RFT, renal function test; DSS, dengue shock
syndrome; DHF, dengue hemorrhagic fever; ADE, antibody dependant enhance-
ment; NS1, non-structural antigen 1; RT-PCR, reverse transcriptase polymerase
chain reaction.
* Corresponding author at: Consultant Neonatologist and Pediatrician Adiyta
Birla Hospital, Veraval, Gujarat, India.
E-mail address: dr.r.ranjan@gmail.com (R. Ranjan).
pregnancy has not been shown to cause any congenital abnormal-
ities however transmission from mother to fetus can cause
perinatal mortality and morbidity.4 In one study recent dengue
infection was demonstrated in 2.5% of parturients, with a vertical
transmission rate of 1.6%.5
DHF in the newborn may begin as a severe, non-specic illness
and symptoms may not be present immediately after birth.
Because symptoms in the newborn may be non-specic, a high
degree of suspicion is needed.6 We present a case report of
newborn with congenital dengue which presented to us on day 8 of
life with maternal positive dengue report.
2. Case report
A term male baby born to 29 year old Primi mother (out born)
by normal vaginal delivery with birth weight 3.05 kg was admitted
in our NICU on day 8 of life with history of fever for 1 day after
being referred by a local pediatrician. Antenatal history was
unremarkable. Apgars were normal at birth but baby developed
tachypnea at 2 hour of birth and was treated at transient
tachypnea of newborn. Baby was discharged to home on 3rd
post-natal day with mother. Mother was readmitted in same
hospital on 4th post-natal day with high grade fever and was
diagnosed to have dengue fever by positive IgM Elisa test. She had
severe thrombocytopenia (lowest platelet being 16,000/cmm) and
recovered without any hemorrhagic manifestations.

http://dx.doi.org/10.1016/j.pid.2016.07.003
2212-8328/ 2016 Published by Elsevier B.V. on behalf of Indian Academy of Pediatrics, Infectious Disease Chapter.

Please cite this article in press as: Ranjan R, et al. Congenital dengue infection: Are we missing the diagnosis? Pediatr Infect Dis. (2016),
http://dx.doi.org/10.1016/j.pid.2016.07.003
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The baby on admission to NICU had moderate fever (100.2 8F)
and other normal vitals. Liver was 2.5 cm palpable under RCM
and spleen tip just palpable. Lab tests revealed NS1 antigen
positive and negative IgM/IgG Elisa. Platelet count was 1.1 lacs/
cmm and CRP mildly positive (CRP-7 mg/L; normal range 0
6 mg/L) on admission. Baby was started on rst line I.V
antibiotics after drawing blood C/S and put full feeds with plan
to repeat PCV and Platelet next day. Baby became afebrile next
day and clinical examination was other unremarkable except for
hepatosplenomegaly. Over next few days platelet count fell
(minimum being 10,000/cmm on 11th day of life) and multiple
platelet transfusions were given during this period (total
9 transfusion during hospital stay). In view of baby not
completing feeds completely I.V. uid was started on D3 of
admission and platelets/PCV checked at regular intervals. On D4
of admission (11th post-natal day) baby developed respiratory
distress and was started on bubble CPAP. Bedside USG revealed
mild ascites and pleural effusion B/L and there was RDS type of
picture on chest X-ray. The baby was kept nil per oral and uids
were hiked. Considering mild rise in CRP value the antibiotics
were further upgraded too and blood C/S was repeated. The child
improved next day and CPAP was removed and over next 4 days
remained clinically stable. On D8 of admission the baby had
features of shock and was managed with uid boluses and
ionotropes. There was reappearance of fever (maximum recorded
100.6 8F). USG showed increased third space loss and chest X-ray
was suggestive of right collapse consolidation. Dengue serology
was sent and IgM dengue came positive. Baby started to have
hemorrhagic manifestations, coagulation prole was abnormal
(APTT 90, INR 1.73) and CRP shot up to 110 mg/L. Along with
platelet, FFP transfusion was given and considering downhill
course baby was put on mechanical ventilator. LFT on day
13 post-natal life showed elevated liver enzymes (SGOT 356/
SGPT 565) and both blood culture reports were sterile. Echo was
done twice to see myocardial function and was reported normal
on both occasions. USG brain on day 16 of life showed diffuse
brain edema. Inspite of using 3 ionotropes in moderate to high
dosage (dopamine, dobutamine and noradrenaline) the mean BP
was persistently below 40 mmHg. Inspite of all efforts baby sadly
expired on day 16 of life.
3. Discussion/review of literature
DHF/DSS is uncommon in children below 1 year who are
usually exposed to infection by dengue virus for the rst time.
However infection-enhancing antibodies acquired by the
mother from previous Flavivirus infections are passively trans-
mitted to the baby and this results in serious manifestations in the
newborn.7
Maternal age was the only risk factor associated with dengue
infection as older mothers (>20 years) were signicantly more
likely to be sero-positive than younger women. Cord antibody
titers varied with maternal age and antibody titer were signi-
cantly higher in babies born to younger mothers (<20 years) and
were signicantly correlated with maternal titer. Low birth weight
babies had Lower transfer ratios for antibody compared to heavier
babies.8 In our case mothers age was 29 years and possibly it was a
secondary infection considering the severity in mother and the
baby.
Although many arboviruses are known to cause fetal death,
premature birth and teratogenic changes in humans and animals,
the few reports of fetal malformation or wastage from dengue
infection are poorly documented6 and the evidence is contradic-
tory. In case of early pregnancy, there is no evidence for vertical
transmission2 although there are reports of prematurity and low
birth weight.5
Please cite this article in press as: Ranjan R, et al. Congenital dengue infection: Are we missing the diagnosis? Pediatr Infect Dis. (2016),
http://dx.doi.org/10.1016/j.pid.2016.07.003
The longer the time interval between the onset of maternal
fever and delivery the sooner is the appearance of fever in the
infant which is consistent with the incubation period of dengue
infection of 57 days. The incubation period for dengue
infection in infants or the duration between fever in mothers
and infants, was shorter in mothers with secondary infection.
Severe dengue occurs only when the clinical picture in the
mother happens near term or the birth itself, and no time to
maternal production of protective antibodies. In our case the
fever in baby appeared on 8th post-natal day while mother had
symptoms starting 5th post-natal day so it is quite probable that
mother was infected quite close to the delivery day although
infective period ranges 14 days before to 14 days after delivery.
Theoretically horizontal transmission in our case report baby
cannot be ruled out but considering the care in hospital it looks
improbable.
Dengue serotypes may play a role in the severity of disease.
Symptoms seemed to be more severe with secondary dengue type
2 infection.
The mode of delivery did not change the course of disease or
reduce the rate of bleeding in infants.9
The dengue virus, an RNA virus, has a small molecular size
(about 4060 nm) and is concordant with the basic rule of vertical
transmission in nanomedicine. Immunopathogenesis is proposed
to be the main possible pathogenesis leading to congenital dengue
infection. In the neonate with congenital dengue infection, the
passed dengue virus from the mother might stimulate the antibody
response and further induce thrombocytopenia via possible
autoimmune mechanisms.
Three mechanisms of dengue-related illness in the fetus can be
postulated6:
1. Maternal infection during pregnancy may result in hematoge-
nous spread of the virus to the placenta and subsequent passage
to the fetus.
2. Maternal viremia during labor could result in viral transmission
and infection of the fetus or the newborn because of blood
exchange during the delivery process.
3. Severe maternal illness during pregnancy or labor could alter
placental function and injure the fetus in the absence of actual
fetal infection.
Fever is the most common Clinical feature in congenital
dengue infection. The age at presentation ranges from 16 h to
11 days after birth and lasts 26 days with body temperatures
between 38.0 and 38.8 8C.6 Biphasic fever was seen our case
(fever reappeared on D 15 of life) and it has been reported once
in newborns10 but it is not a common feature. Fever in longer in
children experiencing primary infections rather than secondary
infection. Newborn infants often do not mount a febrile
response to an infection, and consequently cases of perinatal
dengue virus transmission may be missed if the mother is not
identied as having dengue.11 Similarly late appearance of fever
may mimic late onset neonatal sepsis and confound the clinical
picture. It is not uncommon to have raised CRP values as the
disease advances as was seen in our case and reported in
literature12,13 Strong suspicion in an endemic zone is needed to
diagnose congenital dengue infection. Non-specic signs such as
poor sucking, irritability, diarrhea, and pallor may be present.
Acrocyanosis or cyanosis of the perioral and periorbital area may
be present for long duration. Hepatosplenomegaly with elevated
enzymes (AST or ALT >1000) may herald onset of shock
syndrome and should be interpreted as disease advancement
and severe dengue.14 Maculo papular Rash may be present on
day 1 starting on face and spreading to involve the trunks and
limbs later.
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It has been established that DHF is caused by a Cytokine
Tsunami but despite extensive studies for over four decades, its
genesis is still not fully understood. The mechanisms that have
been considered to cause DHF include antibody-dependent
enhancement (ADE), T cell response, and a shift from Th-1 to
Th-2 response.15 DSS/DHF in newborn presents as hypotonia,
mottled skin, tachypnea and bradycardia. Third space losses
(Pleural effusion/ascites) are usually seen on post-natal day 45
but may be prolonged. In our reported case B/L pleural effusion and
moderate ascites was rst seen on day 12 of life and gradually
increased during the last phase of illness. Circulatory insufciency/
hypotension may develop in short span of time. In neonatal cases
of DHF, muco-cutaneous or subcutaneous bleeding is the most
common hemorrhagic manifestation.6
Unusual presentations of congenital dengue infection such as
prolonged neonatal cholestasis and myocarditis have been
reported.16,17
Laboratory investigations include serial CBCs, Liver function
tests, blood chemistries, urine analysis (Urinalysis is needed to
assess the presence of gross or microscopic hematuria) and
coagulation prole (prothrombin time and partial thromboplastin
time). Coagulation abnormalities can be present in DHF but are not
common in dengue fever. Ancillary tests, e.g. chest X-ray and USG
scan are required to look for third space losses. In various case
reports thrombocytopenia is universal marker of dengue infection
and may be severe and protracted even up to 2 months. A
continuous, marked decline in platelet level and increase in
hematocrit to >20% of the base value could be the rst sign of the
development of DHF.6 In our case the thrombocytopenia persisted
till last inspite of regular platelet transfusions (minimum platelet
recorded was 10,000/cmm on D5 of admission).
Laboratory investigations include virus isolation and RNA
detection which are considered conrmatory evidence of dengue
infection. Serological diagnosis depends on the presence of
antidengue IgM antibody or a rise in IgG antibody titer in paired
(acute and convalescent phase) sera. Currently, the most widely
used IgM assay is the IgM capture enzyme-linked immunosor-
bent assay. Almost 90% of infected babies are IgM positive by the
6th day after the onset of symptoms. Specimens collected less
than 6 days after the onset of symptoms have a variable
percentage of samples without IgM antibodies (dengue virus-
specic IgM rst appears at about day 3 and is prominent from
day 5 onward).18
The rapid detection of the dengue virus genomic sequence by
real-time one-step RT-PCR has become a trend in most European
countries. NS1 Ag assay holds promise in early diagnosis of
dengue infection. When used in combination with MAC-ELISA
on a single sample it signicantly improves the diagnostic
algorithm without the requirement of paired sera.19 Further
studies are needed to evaluate its usefulness and to compare it
with real-time one-step RT-PCR with respect to its sensitivity
and specicity.
Treatment wise currently there are no guidelines for manage-
ment of neonatal dengue and most experiences are based on
treatment protocols implemented for older children. The manage-
ment of dengue virus infection is essentially supportive and
symptomatic. No specic treatment is available. However, there
are Indian studies which have contributed in terms of better
management of DHF/DSS. A rapid response to platelet and fresh
frozen plasma (FFP) transfusion is reported in a study.20 Anti-D has
been used in children with DHF and severe refractory thrombocy-
topenia.21
Prevention of dengue mainly rests on vector control measures
and development of vaccine which has been long due although a
tetravalent vaccine which simultaneously provides long-term
protection against all DV serotypes is round the corner.22
Please cite this article in press as: Ranjan R, et al. Congenital dengue infection: Are we missing the diagnosis? Pediatr Infect Dis. (2016),
http://dx.doi.org/10.1016/j.pid.2016.07.003
3
4. Conclusion
Neonatal dengue infection is reported more often now for
changing epidemiology of dengue virus and improved rapid
diagnostic techniques nevertheless high index of suspicion with
appropriate maternal history is cornerstone to its diagnosis.
Presentation in newborn may be quite subtle and non-specic and
also there is variation from pediatric dengue in terms of extended
symptoms and thrombocytopenia therefore giving a false
impression of septicemia. We found biphasic fever as an
important nding and in our case it coincided with acute
deterioration in babys condition so reappearance of fever should
be regarded as disease advancement. Persisting thrombocytope-
nia inspite of platelet transfusion is a poor prognostic marker as is
increasing evidence of third space loss. We maintain that newborn
with dengue should be managed in hospital set up for at least
2 weeks from diagnosis or rst symptom lest baby deteriorates at
home after getting discharged even in otherwise apparently
normal looking newborn.
Authors contribution
RR: Planned the review and prepared the initial draft of the
manuscript. KK: Conceived the idea and provided the resource
literature. NN: Diagnosed the case and helped in preparing
manuscript.
All authors approved the nal manuscript for publication.
Funding
None.
Conicts of interest
The authors have none to declare.
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Please cite this article in press as: Ranjan R, et al. Congenital dengue infection: Are we missing the diagnosis? Pediatr Infect Dis. (2016),
http://dx.doi.org/10.1016/j.pid.2016.07.003