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Vertical Transmission of Dengue

Joon K. Chye, Chin T. Lim, Kwee B. Ng,
Jason M. H. Lim, Rebecca George, and Sai K. Lam

From the Departments of Pediatrics, Obstetrics and Gynecology, and

Medical Microbiology, Faculty of Medicine, University of Malaya,
Kuala Lumpur, Malaysia

Dengue is endemic in Malaysia [1] and is also prevalent in

many tropical and subtropical countries. Its effects on pregnant
mothers and their fetuses and on newborns are unclear. The
possible adverse effects of maternal dengue fever on fetuses
have been suggested by some investigators [2] but refuted by
others [3]. Similarly, except for a few reported cases [4, 5],
data on the incidence and effects of perinatal transmission of
maternal dengue to newborn infants is scant.
We report our recent experience with the first two laboratoryconfirmed cases of neonatal dengue that we believe were the
results of vertical transmission. These cases occurred during
the Malaysian dengue epidemic in 1996.

Case Reports
Case 1

A 25-year-old pregnant Malay woman (gravida 2, para 0)

who had no history of major medical illness was admitted to
the hospital at 36 weeks gestation in June 1996 for stabilization
of proteinuric pregnancy-induced hypertension (blood pressure,
160/100 mm Hg). Two days after her admission, she developed
an acute fever (temperature, 39.47C) with no obvious clinical
focus. The fever gradually abated over the next 72 hours with
paracetamol treatment. She had generalized edema and an enlarged liver (2 cm) but no petechiae. Transient mild bleeding
of the gums and easy bruising at venipuncture sites were noted
on day 5 of illness.

Received 26 March 1997; revised 11 July 1997.

Reprints or correspondence: Dr. Joon Kin Chye, Department of Pediatrics,
Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
Clinical Infectious Diseases 1997;25:13747
q 1997 by The University of Chicago. All rights reserved.
10584838/97/25060014$03.00

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The complete blood count (CBC) on the second day of illness

revealed a hemoglobin level of 103 g/L, a hematocrit of 30%,
a platelet count of 0.0 1 109/L, and a WBC count of 6.9 1
109/L. The platelet counts over the next 2 days ranged from 8
to 12 1 109/L. Coagulation analysis revealed slightly abnormal
results, with a prothrombin time (PT) ratio of 1.1, an activated
partial thromboplastin time (APTT) of 74 seconds (normal
range, 30.5 40.5 seconds), but normal levels of fibrinogen
degradation product. Daily transfusions with therapeutic doses
of platelets and fresh frozen plasma were given from days 4
to 8 because of persistent thrombocytopenia and coagulopathy.
In view of the rise in liver enzyme levels (aspartate aminotransferase [AST] level, 739 U/L; alanine aminotransferase
[ALT] level, 301 U/L), persistent hypertension, worsening proteinuria, generalized edema, the presence of ascites, and oligohydramnios (detected by ultrasonography), a provisional diagnosis of severe preeclampsia was made; labor was induced on
day 5 by artificial rupture of the membranes and by oxytocin
infusion. A male infant weighing 2.2 kg was delivered vaginally. In the postpartum period, she became anemic (hemoglobin level, 7.1 g/L; hematocrit, 20%) and was given a whole
blood transfusion. Urinalysis was negative for hemoglobin.
The diagnosis of dengue was confirmed on day 7 of illness,
when IgM antibody specific to dengue virus was detected in
the mothers blood. By day 11, her platelet count began to
increase (27 1 109/L) and eventually normalized on day 16.
The APTT (49 seconds) similarly increased by day 9. The
abnormal results of liver function tests peaked on day 7 (AST
level, 5,523 U/L; ALT level, 689 U/L; alkaline phosphatase
level, 189 U/L; serum bilirubin level, 149 mmol/L; and albumin
level, 21 g/L) before recovery started to occur. She was discharged to home after 18 days of hospitalization.
Blood samples taken on days 4 and 10 of illness were positive for IgM antibody specific to dengue virus by an ELISA
performed in the laboratory at our hospital [6]. Virus was not

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Dengue, an important mosquito-borne flavivirus infection, is endemic in Southeast Asia. We

describe two mothers who had acute dengue 4 and 8 days before the births of their infants. One
mother had worsening of her proteinuric pregnancy-induced hypertension, liver dysfunction, and
coagulopathy and required multiple transfusions of whole blood, platelets, and fresh frozen plasma.
Her male infant was ill at birth, developed respiratory distress and a large uncontrollable left
intracerebral hemorrhage, and died of multiorgan failure on day 6 of life. Dengue virus type 2 was
isolated from the infants blood, and IgM antibody specific to dengue virus was detected in the
mothers blood. The second mother had a milder clinical course; she gave birth to a female infant
who was thrombocytopenic at birth and had an uneventful hospitalization. Dengue virus type 2
was recovered from the mothers blood, and IgM antibody specific to dengue virus was detected in
the infants blood. This report highlights not only the apparently rare occurrence of vertical transmission of dengue virus in humans but also the potential risk of death for infected neonates.

CID 1997;25 (December)

Vertical Transmission of Dengue

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Table 1. Summary of data from two cases of vertical transmission of dengue.

Case, patient
Case 1
Mother
Infant
Case 2
Mother
Infant

HI titer (days of paired serum sampling)

IgM antibody

Virus isolated

RT PCR analysis

1:80 to 1:160 (4 and 10)*

1:10 to 1:10 (2 and 6)

Positive
Negative

None
Dengue virus type 2

Negative
Positive

1:10 to 1:2,560 (2 and 6)*

1:160 to 1:320 (1 and 11)

Positive
Positive

Dengue virus type 2

None

Positive
Negative

NOTE. HI hemagglutination inhibition test; RT reverse transcription.

* Days of illness.

Days of life.

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developed more respiratory difficulties, and ventilatory support

was started again because of frequent desaturations. Another
chest radiograph showed bilateral, generalized, patchy perihilar
opacities. Intravenous cloxacillin therapy was stopped, and intravenous imipenem and cefotaxime were added to the therapeutic regimen because the possibility of meningitis was entertained. A posttransfusion CBC disclosed a hemoglobin level
of 127 g/L, a hematocrit of 37%, a WBC count of 7.7 1 109/L,
and a platelet count of 12 1 109/L; these findings necessitated
a further platelet transfusion. Another lumbar puncture again
yielded heavily blood-stained CSF. A second cranial ultrasonographic scan obtained at 90 hours of life demonstrated a massive left intracerebral hemorrhage with a midline shift that was
causing obliteration of the left lateral ventricle and dilatation
of the right lateral ventricle.
Over the next 2 days, the infant developed severe acute renal
failure, hypotension, seizures, hypoglycemia, abnormal liver
function, and coagulopathy. Despite the maximal intensive support given, the infants condition continued to deteriorate rapidly, and he finally died on day 6 of life. A postmortem examination was declined by the family. Both sets of blood cultures
and the CSF cultures were negative for bacterial growth. Dengue virus type 2 was isolated from a blood specimen obtained
on day 2 of life; this isolation was confirmed by RT PCR
analysis. However, IgM antibody specific to dengue virus was
not detected in blood specimens obtained on days 2 and 6 of
life. Similarly, the HI tests did not show any change in the low
titers of antibody to dengue virus.
Case 2

A 31-year-old pregnant Malay woman (gravida 5, para 4)

was admitted to the hospital at 38 weeks gestation in August
1996 because of fever and mild dysuria. Her husband had been
admitted to another hospital because of dengue fever 2 months
previously. Her temperature had peaked at 39.47C on the day
of admission, and the fever gradually subsided over the subsequent 48 hours. A urine culture was negative for bacterial
growth. Treatment with intravenous ampicillin and oral nitrofurantoin was stopped after 10 days. The initial CBC showed a
hemoglobin level of 123 g/L, a WBC count of 10.8 1 109/L,

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isolated from the first sample when mosquito larva inoculation

[7] and AP-61 mosquito cell cultures were performed [8]. Viral
nucleic acid was not detected in the serum by reverse transcription (RT) PCR analysis with dengue virus specific primers
[9]. Hemagglutination inhibition (HI) tests [10] performed on
paired serum samples showed only a twofold rise in titers from
1:80 to 1:160 (table 1).
The Apgar scores for the infant were 6/10 and 7/10 at 1
and 5 minutes, respectively. No resuscitation was required.
However, he appeared pale and was grunting soon after birth;
he was promptly admitted to the special care nursery after a
routine intramuscular dose of vitamin K was administered. At
12 hours of life, he was intubated and received ventilatory
support because of increasing oxygen requirement and respiratory distress. The ventilatory support needed was minimal, and
he was extubated 24 hours later and received oxygen in a head
box. Mild, nonspecific, generalized streaky changes were noted
on his chest radiograph. His initial CBC count showed a hemoglobin level of 189 g/L, a hematocrit of 58%, a WBC count
of 41.8 1 109/L, and a platelet count of 165 1 109/L. Since
sepsis was suspected, a blood specimen for culture was obtained, and intravenous penicillin and gentamicin therapy was
started.
A transient generalized blanchable red rash was noted at the
end of the first day. At 36 hours of life, he started to have
episodes of low grade fever (temperature, 387C), irritability,
and opisthotonus. A lumbar puncture was performed, and a
second blood specimen for culture was obtained. CSF analysis
revealed heavily blood-stained fluid, for which a traumatic tap
was considered the most likely cause. A WBC count in the
CSF could not be determined, but the sugar and protein levels
in the CSF were normal. At this stage, intravenous penicillin
and gentamicin therapy was changed to intravenous cloxacillin
and amikacin therapy. Another CBC count revealed a hemoglobin level of 116 g/L, a hematocrit of 34%, a WBC count of
7.3 1 109/L, and a platelet count of 16 1 109/L. Coagulation
analysis showed a marginally prolonged PT ratio of 1.3 and
an APTT of 54 seconds. Whole blood and platelet transfusions
were then administered.
Findings on a cranial ultrasonographic scan obtained at 50
hours of life were unremarkable. At 60 hours of life, the infant

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Chye et al.

Discussion
Perinatal transmission of dengue is evidently rare. Worldwide, only six newborn infants with infections due to dengue

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virus types 1 and 2 have been described in Tahiti and Thailand

[4, 5]. All these infants had common clinical features of thrombocytopenia, fever, hepatomegaly, and varying degrees of circulatory insufficiency, which were also found in our two cases.
However, case 1 deviates from the benign course reported for
these six infants and our second case.
In retrospect, our first infant, who had signs of cerebral
irritation on day 2 of life, may have had meningoencephalitis.
There are increasing reports implicating the direct involvement
of this virus in patients with neurological manifestations [11].
Unfortunately, the lack of a postmortem examination and the
blood-contaminated CSF precluded the confirmation of this
postulation. Alternatively, the marked irritability of the infant
could have resulted from subarachnoid hemorrhages, as evidenced by blood in the CSF (the amount of which was not
sufficiently large to be detected by the first cranial ultrasonographic scan). Subarachnoid hemorrhages, uncommon compared with hemorrhages in the gastrointestinal tract and skin,
have been reported at autopsy for infants and children with
acute dengue [12]. The severe intracerebral hemorrhage, which
led to the later multiorgan dysfunction, was unexpected. The
mildly prolonged coagulopathy (within the normal range for
neonates), severe thrombocytopenia, and the underlying vasculopathy of this disease [13] may have initiated and caused the
progression of the hemorrhage in this infant.
It is uncertain whether the early administration of platelets
and fresh frozen plasma had any true protective value for our
second infant because all six other reported cases had favorable
outcomes without any intervention [4, 5]. The severity of the
maternal dengue virus infection, a probable primary dengue
virus infection in the mother, a delay in the laboratory confirmation of dengue in both the mother and the infant, and the
poor condition of the infant at birth (case 1) were the main
distinguishing features between our two cases; these factors
may have been important contributors to the death of the first
infant because the strain of the viruses in both cases was the
same (type 2).
The serological features of these two cases are also interesting (table 1). In the first case, when the possibility of maternal
dengue virus infection was raised on day 4 of illness, the mother
had become afebrile. The failure to detect virus in her serum
was thus a reflection of the short period of viremia that had
passed, and seroconversion with IgM antibody to dengue virus
had happened. The poor results of HI tests suggest that this
infection was most likely primary dengue. In comparison, the
dengue virus was recovered from her infant on day 2 of life
and 6 days after the onset of the maternal fever (i.e., when the
platelet count dropped and he became symptomatic). His lack
of an IgM antibody response as well as the negative HI tests,
probably reflects the short duration of his illness before his
death.
In contrast, dengue virus infection was suspected early in
the second mother; the blood tests were performed early in the
mothers febrile illness, thus accounting for the initial detection

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and a platelet count of 187 1 109/L. The platelet count had

dropped to 81 1 109/L on day 3 of her illness. On day 8,
platelets were transfused because she developed generalized
petechiae with severe thrombocytopenia (platelet count, 11 1
109/L).
Although the platelet count increased the next day to 42 1
109/L, she had epistaxis, which was controlled with further
platelet transfusions. She also went into spontaneous labor; a
live female infant weighing 3.0 kg was delivered vaginally on
day 9 without any complications. The postpartum period was
uneventful. Results of liver function tests and coagulation analysis were normal. She was discharged after 13 days of hospitalization.
Dengue virus type 2 was detected in the blood sample obtained on day 2 of her illness; this isolation was confirmed by
RT PCR analysis. Only the second blood sample, obtained on
day 6, was positive for IgM antibody specific to dengue virus.
The HI tests on paired serum samples showed a large rise in
titers from 1:10 to 1:2,560.
Given the confirmed diagnosis of maternal dengue fever and
the death of the infant in the previous case, the infant was
admitted to the special care nursery immediately after birth for
close observation, even though her condition at birth was good
(Apgar scores were 9/10 and 10/10 at 1 and 5 minutes, respectively). She had a palpable 1-cm liver edge at the time of
admission, flushed skin at 24 hours of age, and slightly diminished peripheral perfusion on day 3. A low-grade fever (maximum temperature, 38.47C), which lasted for 24 hours, was
noted on day 4. Intravenous penicillin and gentamicin therapy
for presumed sepsis was started, but this therapy was stopped
when the blood cultures yielded no organisms. The infant remained clinically well.
The CBC on day 1 showed a hemoglobin level of 229 g/L,
a WBC count of 30 1 109/L, and a platelet count of 50 1
109/L. Coagulation analysis was unremarkable: PT ratio, 1.0;
APTT, 49.5 seconds. Transfusions with platelets and fresh frozen plasma were given. The platelet count rose transiently to
109 1 109/L the next day and then stayed at 60 63 1 109/L
for 2 days before gradually rising to 148 1 109/L on day 8.
Liver function tests revealed the following: AST level, 108
U/L; ALT level, 32 U/L; alkaline phosphatase level, 183 U/L;
and albumin level, 26 g/L. Serial cranial ultrasonographic scans
obtained on days 1, 7, and 11, subsequent liver function tests,
and a coagulation profile were unremarkable. The infant was
discharged to home on day 11 of life.
IgM antibody specific to dengue virus was detected in blood
samples obtained on days 6 and 11 of life but not in the two
samples of blood (cord and peripheral venous blood) obtained
on the day of birth. The HI tests showed a low rise in titers
from 1:160 to 1:320. No virus was isolated from the acutephase serum sample, and RT PCR analysis was negative.

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dengue fever may be absent, and the occurrence of subclinical

infections lends further confusion to the problem. A high index
of suspicion is therefore required for the diagnosis, especially
in areas of endemicity and during epidemic outbreaks. Thus,
a proper epidemiological study is necessary to help understand
and to delineate the extent of this potentially fatal disease.
In conclusion, vertical transmission of dengue virus may
lead to a full-blown illness in the neonate similar to that seen
in children and adult patients. An awareness, and hence early
diagnosis and management, of this potentially lethal condition
is necessary to reduce perinatal morbidity and mortality, especially in communities where dengue is endemic.
References
1. George R. Current status of the knowledge of dengue/DHF/DSS in Malaysia: clinical aspects. Malaysian Journal of Child Health 1994; 6:3 8.
2. Sharma JB, Gulati N. Potential relationship between dengue fever and
neural tube defects in a northern district of India. Int J Gynecol Obstet
1992; 39:291 5.
3. Chong KY, Lin KC. A preliminary report of the fetal effects of dengue
infection in pregnancy. Kao Hsiung I Hsueh Ko Hsueh Tsa Chih 1989;
5:31 4.
4. Thaithumyanon P, Thisyakorn U, Deerojnawong J, Innis BL. Dengue
infection complicated by severe hemorrhage and vertical transmission
in a parturient woman. Clin Infect Dis 1994; 18:248 9.
5. Poli L, Chungue E, Soulignac O, Gestas P, Kuo P, Papouin-Rauzy M.
Dengue materno-foetale. Bull Soc Pathol Exot 1991; 84:513 21.
6. Lam SK, Devi S, Pang T. Detection of specific IgM in dengue infections.
Southeast Asian J Trop Med Public Health 1987; 18:532 8.
7. Lam SK, Chew CB, Poon GK, Ramalingam S, Seow SC, Pang T. Isolation
of dengue viruses by intracerebral inoculation of mosquito larvae. J
Virol Methods 1986; 14:133 40.
8. Tesh RB. A method for the isolation and identification of dengue viruses,
using mosquito cell cultures. Am J Trop Med Hyg 1979; 28:1053 9.
9. Chan SY, Kautner IM, Lam SK. The influence of antibody levels in dengue
diagnosis by polymerase chain reaction. J Virol Methods 1994; 49:
315 22.
10. Clarke DH, Casals J. Techniques for hemagglutination and hemagglutination-inhibition with arthropod-borne viruses. Am J Trop Med Hyg 1958;
7:561 73.
11. Lam SK. Dengue infections with central nervous system manifestations.
Neurological Journal of Southeast Asia 1996; 1:3 6.
12. Bhamarapravati N, Tuchinda P, Boonyapaknavik V. Pathology of Thailand
haemorrhagic fever: a study of 100 autopsy cases. Ann Trop Med Parasitol 1967; 61:500 11.
13. Halstead SB. Dengue: hematological aspects. Semin Hematol 1982; 19:
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of virus and the later appearance of IgM antibodies on day 6.

The dramatic and rapid rise in the titers of IgM antibody to
dengue virus that were measured by the HI tests indicates that
this infection was most probably secondary dengue. Her infant,
who was born 8 days after the start of the maternal fever,
was thrombocytopenic at birth. Since both the virus and IgM
antibody were not detected at birth, we postulate that the brief
period of viremia had occurred while in utero and that the
window period for seroconversion had included the day of
birth. IgM antibody became detectable 6 days later. The mildly
elevated titer of antibody to dengue virus that was detected
at birth was probably due to maternal IgG antibody acquired
transplacentally.
Except for the lack of rise in the hematocrit (20%) and
the absence of pleural effusions (as demonstrated on a chest
radiograph), the first mother had all the other features that
fulfill the criteria of the World Health Organization [14] for
classic adult dengue hemorrhagic fever. She had acute dengue
virus hepatitis, bleeding tendencies, and clinical evidence of
increased vascular permeability, as manifested by generalized
edema, hypoalbuminemia (albumin level, 21 g/L), and ascites.
The large volume of blood products and intravenous fluids that
she received during the acute phase of her illness would have
prevented the development of any hemoconcentration and possible circulatory shock. A chest radiograph was not obtained
because of the absence of clinical indications, but normal respiratory status does not exclude asymptomatic pleural effusions
(which are highly likely in the context of her clinical illness).
It is unclear whether the existing criteria of the World Health
Organization for dengue hemorrhagic fever is applicable to
nonclassic cases, such as infected neonates, pregnant
women (with or without complications of pregnancy), and individuals being monitored and treated early in the course of their
illnesses.
Even though dengue virus infection is common in Malaysia,
to date, there have not been any reported cases of vertical
transmission of dengue to neonates in this country. It is anticipated that such cases would be underappreciated and underdiagnosed. Obstetric conditions, such as HELLP syndrome (hemolysis, elevated liver enzyme levels, and low platelet counts),
may confuse or mask the clinical manifestations of dengue
virus infection namely, deranged liver functions and thrombocytopenia. In neonates, other infections (bacterial, viral, or
fungal) can cause clinical features and hematologic changes
similar to those of dengue virus infection. The typical rash of

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