ARTICLE IN PRESS

Travel Medicine and Infectious Disease (2007) 5, 183188

Available at www.sciencedirect.com

journal homepage: www.elsevierhealth.com/journals/tmid

Dengue fever and pregnancyA review and comment

I. Dale Carrolla,, Stephen Tooveyb,c,d, Alfons Van Gompele
a

The Pregnant Traveler, 4475 Wilson Ave., SW, Suite 8, Grandville, MI 49418, USA
Royal free and University College Medical School, London, UK
c
Travel Clinic, Cape Town, South Africa
d
Burggartenstrasse 32, CH-4103 Bottmingen, Switzerland
e
Institute of Tropical Medicine, Kronenburgstraat 43/3, 2000 Antwerp, Belgium
b

Received 9 November 2006; accepted 9 November 2006

Available online 5 January 2007

KEYWORDS
Dengue;
Dengue hemorrhagic
fever;
Arbovirus;
Pregnant;
Parturient;
Neonate

Summary
Background: The increasing incidence of dengue with the concomitant rise in travel
during pregnancy makes it likely that a pregnant woman will plan travel to or present after
travel to endemic areas.
Method: Literature search and communication with researchers.
Results: Case reports of dengue during pregnancy, the peripartum period and neonatal
dengue were found. There is little systematic research.
Conclusions: Pregnancy appears not to increase the incidence or severity of dengue, but
some case reports suggest that dengue may predispose to certain pregnancy complications. Transplacental infection occurs, but protective antibodies pass transplacentally and
fetal effects may be minimal given sufficient immune response. In near-term disease,
severe fetal or neonatal illness and death may occur. Such illness may also predispose the
newborn to subsequent dengue hemorrhagic fever. Clinicians should be aware that
presentation in either maternal or neonatal disease may be atypical and confound
diagnosis. Women in late pregnancy should avoid travel to areas of ongoing disease, and
those earlier in pregnancy should consider dengue a serious hazard. If travel is
unavoidable, mosquito avoidance measures are mandated. If a woman acquires dengue
fever while pregnant, conservative medical and obstetrical management are the
treatments of choice. Further research is required.
& 2006 Elsevier Ltd. All rights reserved.

Introduction
Denguethe disease
Corresponding author. Tel.:+1 616 988 0980; fax: +1 616 988 0982.

E-mail addresses: travdoc@travdoc.com (I. Dale Carroll),

malaria@freesurf.ch (S. Toovey), fvgompel@itg.be (A.V. Gompel).
1477-8939/$ - see front matter & 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tmaid.2006.11.002

Dengue fever has in recent years seen a great resurgence in

tropical climates and appears to be spreading to new areas.

ARTICLE IN PRESS
184
It is now estimated that over 100 million infections with this
virus occur annually throughout the world, 250,000 of these
progressing to dengue hemorrhagic fever (DHF) and 25,000
resulting in death.1
Dengue viruses are members of the Flaviviridae genus,
which includes the causative organisms of yellow fever, West
Nile fever and Japanese encephalitis. It is spread through
the bite of the Aedes mosquito. There are four serologic
types of dengue virus. Infection with one type does not
appear to confer immunity to the others. In fact, the first
attack of dengue fever (primary dengue) may predispose to
much more severe illness following infection with other
serotypes (secondary dengue).2
The incubation period of the disease is normally 38 days.
The virus is detectable in human subjects 618 h before
the onset of symptoms and viremia ends as the fever
abates.3
The disease can present with a wide range of symptoms,
from essentially asymptomatic to a life-threatening hemorrhagic diathesis (DHF) or dengue shock syndrome (DSS).4
Generally, the severe forms of the disease are thought to
occur more commonly after prior sensitization with a
different serotype. They may occur, however, even with a
primary infection, perhaps depending on the infecting
serotype.5
Typically the disease presents with acute fever, headache, retro-orbital pain and severe muscle and joint pains.
In some patients, the predominant symptoms are respiratory
and gastrointestinal. Commonly, there is also a fine,
petechial rash. Fever typically lasts 57 days but the disease
may be followed by a prolonged period of physical and
emotional fatigue.6

Pregnancy questions
Pregnant women represent a particularly worrisome subgroup of travelers to dengue-prone areas. One study of
women living in a highly endemic area has estimated the risk
of exposure to be almost 1% during a given pregnancy in a
highly endemic area. It behooves us, therefore, to be aware
of how the disease and pregnancy may interact and thus how
to advise the pregnant traveler.7
Questions that arise include the effect of pregnancy on
the disease process, the effect of the disease on the
pregnancy, what might be the effects on the fetus and
neonate, and how the pregnant woman and the newborn
might best be managed.

Literature review
Seeking the answers to these and related questions, the
authors performed a literature search of the National
Library of Medical Publications database and of the Ovid
database, using the search terms dengue AND pregnancy.
This was supplemented by reading the references within
these articles as well as by personal communication with
some of the authors.
We offer here a review of the available information
followed by a discussion of how this information might be
used in patient management and identification of those
areas where further research is needed.

I. Dale Carroll et al.

Dengue during pregnancy

First, one must identify how often this type of infection is
apt to occur in a pregnant population. Perret et al. studying
parturients in a highly endemic area, found a seropositivity
rate of 94.7%. Only 0.8% of the study population, however,
showed evidence of having acquired the infection during
pregnancy, and in those cases, the disease occurred early in
the pregnancy. The seropositivity rate increased with
advancing maternal age, indicating that younger women
were more at risk to contract the disease during pregnancy
while the older patients were more likely to have preexisting protective immunity.7
It should be remembered, however, that the study group
was a native population living in a highly endemic area.
These authors believe that the disease risk for immunologically nave travelers to such areas would be higher
because of their lack of pre-existing protective antibodies.
The next question is if the disease presents during
pregnancy, does it have a different presentation and clinical
course than in the non-pregnant patient? The available data,
although quite sparse, would seem to indicate not. In these
studies, pregnant patients with dengue fever still were
mostly diagnosed clinically with the diagnosis later being
confirmed by laboratory tests. In a review by Sirinavin et al.
13/14 (93%) cases for which presentation was recorded had
a typical presentation of abrupt fever accompanied by
headache, retro-orbital pain, muscle aches and thrombocytopenia, in some cases accompanied by hemoconcentration,
pleural effusion and shock. Similarly, a case reported by
Phuphong followed a typical course.810 The question arises,
however, whether a patient with an atypical presentation
would be recognized as having dengue fever and the
appropriate laboratory studies initiated.
Next is the question of how the disease process might
affect the pregnant woman.
Data from two authors showed an increase in the rate of
prematurity. Carles et al.11,12 in their review of 38 cases in
French Guiana indicate a significant increase in prematurity
and fetal death. In these cases the timing of the fetal death
led the investigators to assume that death was due to the
dengue, but one patient was also co-infected with malaria.
But this group studied only severely ill, hospitalized
patients. They point out that had they included patients
with milder disease the incidence of fetal death and
prematurity would have been less, more in line with an
earlier study by Mirovsky in Vietnam.13 Ismail et al. in a
recent review also noted a 50% prematurity rate and
reported three maternal deaths out of 16 cases.14
In the Perret study, there appeared to be no fetal effects
from the maternal dengue infection. But only two patients in
the study showed antibody evidence of having had dengue
during the pregnancy. Also, the study was done at the time of
delivery. It is possible that women who get dengue early in
pregnancy miscarry and thus would not present for delivery.
Other reports by Chyes group in 1997 and Restrepo et al.
in 2003 do not indicate a propensity toward premature labor,
fetal death, or other complications of pregnancy, but do
indicate that the signs and symptoms of dengue fever might
easily be confused with those of other pregnancy complications such as toxemia or its variant, HELLP syndrome
(hemolysis, elevated liver enzymes, low platelets).15,16

ARTICLE IN PRESS
Dengue fever and pregnancy
The patients in these studies were women with severe
disease who presented for medical care. The authors question
whether milder cases of disease occurring earlier in pregnancy
might have presented instead as miscarriage and have been
suspected of having a septic abortion. Or would a preponderance of milder cases have more firmly demonstrated the
absence of significant effects on pregnancy by dengue?
Sharma et al. reported an increased incidence of neural
tube defects following dengue infection,17 but as this defect
has been demonstrated following other febrile illnesses, it
may well have been due to the fever rather than to any
teratogenic effect of the dengue virus per se.18
Regarding dengue fever in the newborn infant, Perrett et al.
come to the conclusion that serious dengue disease occurs only
when the mother is at or near term and there is insufficient
time for the maternal production of protective antibodies.7
There is some evidence that in many viral infections the
placenta is protective to the fetus, but this is not consistent
or complete.19,20 There have been case reports of transplacental infection of the neonate with dengue virus, the data
being summarized by Sirinavin et al. in their review article.8
Seventeen cases of vertical transmission of dengue were
reviewed. Sixteen of 17 (94%) infants survived without
sequelae, with one (6%) neonatal death from intracerebral
hemorrhage that may have been coincidental to the dengue
infection.
In these studies, when maternal dengue fever was
encountered prior to term it was managed conservatively
without attempting premature delivery of the infant.

Dengue at parturition
Although conservative obstetrical management is usually
advocated,21 of the 17 patients in Sirinavins review in whom
there was vertical transmission of dengue fever, 6/17 (35%)
were delivered by Cesarean section, 4/36 (24%) of whom
required blood transfusions, with 1/36 (3%) suffering a
massive maternal hemorrhage. Of the 11/17 (65%) who were
delivered vaginally, 4/11 (36%) of these also required
transfusions. Post-partum course was not reported for 5/17
(29%) of the patients in this review.
Newborn management was complicated by the fact that it
was often initially impossible to tell whether the newborns
symptoms were due to infection with dengue virus, or other
types of infection. Thus, many of these infants underwent a
series of diagnostic studies and treatment with antibiotics
while the diagnosis was being established. Nonetheless, all
of the infants did well except one. The one neonatal death
may have been from causes other than dengue fever.8
Thus, Fatimil in a report from Bangladesh states, A
pregnant woman with fever, myalgia and/or bleeding
manifestations should raise a high suspicion that the baby
may develop the disease, and both the mother and baby
should be closely followed-up.22
Regarding the transfer of maternal antibodies to the
fetus, the following observations were made in these
studies. First, that maternal antibodies are transferred to
the fetus. Regarding the protective efficacy of these
antibodies, one author reports that antibodies with increased cross-reactivity to other dengue serotypes preferentially cross the placenta and are protective to the infant

185
after birth.23 Two other authors conclude that although
these may initially be protective, as their level wanes they
may instead predispose the infant to DHF or DSS.5,24
Secondly, babies of low birth weight were found to have
lower levels of transferred antibodies.7 It is impossible to
tell from the available data whether pre-existing placental
pathology prevented the passage of these antibodies or if
the presence of dengue fever itself caused placental
damage resulting in low birth weight.

Neonatal dengue
If the dengue virus was transferred to the infant via the
vaginal mucosa at parturition, such as with genital herpes
infection, some fetal advantage might be gained by Cesarean
delivery.19 However, studies showing the presence of dengue
virus in fetal and cord blood samples, seem to indicate
intrauterine infection of the neonate.5,13,2527 Thus, a
Cesarean would increase maternal risk without being of any
particular benefit to the infant. In fact, Bunyavejchevin et al.
in their discussion advocate conservative management.28
Perret et al. in their paper point out that yall reported
cases of symptomatic congenital dengue infection have
occurred in neonates born to mothers infected very late in
pregnancyymaternal infections occurring close to the time
of delivery would have insufficient protective antibodies to
be transferred and consequently direct viremia into the
fetal blood stream may result.7 They also warn that the
congenital dengue infection rate would be expected to be
higher in any group of patients with less prior infection and
thus a greater susceptibility to the disease near term.
The course of congenital infection in these studies
indicated that often the diagnosis could eventually be
suspected on clinical grounds and then confirmed in the
laboratory, but initial presentation was often confusing.
In the review by Sirinavin, the onset of fever in the
newborn varied from 1 to 11 days after birth with an average
of 4 days and lasted 15 days. There did not appear to be any
significant difference in this whether the mothers dengue
infection was primary or secondary.
All of the infants developed fever and thrombocytopenia,
and 14/17 (82%) were found to have an enlarged liver.
Eleven of 17 (65%) had at least some evidence of bleeding,
but none required transfusion despite some very low
platelet counts. Four of the 17 infants (24%) developed
pleural effusion but only 2/17 (12%) manifested a rash.29,30
Transplacental maternal antibodies are felt to be protective to the newborn while the titers remain high, typically
for about 6 months. After that, however, the lower titers
may in fact result in immunological enhancement and
predispose the infant to DHF or DSS.31 Breast feeding might
be somewhat protective as neutralizing activity against
dengue virus was observed in some patients. The degree of
this protection, however, has not been studied.32

Discussion
Summary of findings
These reports demonstrate that although pregnancy does
not seem to increase the risk of contracting dengue fever,

ARTICLE IN PRESS
186
the disease can be severe in pregnancy, with devastating
consequences. Even with what is believed to be primary
disease, it can progress to manifestations typical of DHF.33
Furthermore, those familiar with pregnancy will recognize
that diagnosis and treatment may be hampered by confusion
of dengue fever with other disease processes such as
toxemia and HELLP syndrome or certain forms of sepsis.
In the studies cited, however, the diagnosis of dengue
fever was made on clinical grounds based on a typical
presentation of the disease. The question arises whether in
usual practice a patient with an atypical presentation would
be recognized as having dengue fever and the appropriate
laboratory studies initiated. Teichmann et al. in a German
study of 71 cases cite the diagnostic difficulties encountered
because of the atypical clinical presentation in many of
these patients.34
Effects on the fetus or newborn seem to be variable, with
apparently less fetal harm occurring earlier in pregnancy
when there is time for protective maternal antibodies to the
formed and passed to the infant. When maternal infection
occurs closer to the time of delivery, there is more chance
for the infant to become ill.
Published reports do indicate several fetal and newborn
deaths, but clearer evidence is needed in order to attribute
the deaths to the dengue infection per se. In only one case is
the clinical course of the infant discussed, and there is
reason to believe that the causes of neonatal death in that
case were other than the dengue fever. In the other cases,
the fetal deaths were assumed to be from dengue but no
actual laboratory evaluation was undertaken to establish
this.

Pertinent pregnancy facts

From these data we are reassured that the dengue virus,
unlike for example those of rubella and varicella, poses no
specific threat of fetal malformation or disease-specific
fetal harm. Also it would appear that pregnancy does not
predispose to more severe disease as in the case, for
instance, of malaria.
But misdiagnosis or delay in diagnosis remains a significant
hazard, especially to the busy obstetrician who may be
unfamiliar with dengue fever.
There are several pregnancy-related issues that might
confuse the unsuspecting obstetrician. These include common alterations in the immune, coagulation and cardiovascular systems as well as hepatic enzymes and the febrile
response to illness during pregnancy.35
During pregnancy the white blood cell count is typically
elevated and manifests a shift to the left. Thus, such a minor
change due to dengue fever might be overlooked.
Similarly, pregnancy results in an increased tendency
toward coagulability while at the same time the platelet
count is normally low. How these factors might interact with
the course and laboratory findings in a case of DHF is
unclear. And would the hemoconcentration that occurs with
DHF be masked by the normal hemodilution of pregnancy?
Both dengue fever and pregnancy typically manifest mild
elevations of liver enzymes. Would this lend itself toward a
delayed diagnosis of dengue fever?36 And finally, pregnancy
sometimes blunts the normal febrile response to illness.

I. Dale Carroll et al.

While this might be protective to the fetus, would it also
cause a delay in the diagnosis?
In addition to all this, it would be interesting to know if
Aedes mosquitoes have a special attraction to pregnant
women as has been demonstrated in the case of the
Anopheline mosquitoes that transmit malaria. But such a
study has not yet been undertaken.37
Regarding fetal and neonatal effects, placental passage of
antibodies does occur and may initially be protective to the
infant. But if the infant stays in the endemic area he or she
is eventually at increased risk for DHF and DSS.38
Thus the fact remains that pregnant patients, especially
those without pre-existing immunity, traveling to areas
where dengue fever is prevalent are at significant risk of
contracting the disease. If this occurs, the maternal and
fetal effects include all those of any other severe febrile
illness, plus the potential for hemorrhage and shock. And
there are no specific preventive measures to use, such as
vaccination or prophylactic medication.

Recommendations
Pregnant patients should be advised of these risks and, if
practical, the trip postponed, especially in late pregnancy.
This may be more important for the non-immune pregnant
traveler, or younger pregnant travelers returning to endemic
areas. For pregnant travelers with pre-existing immunity
returning to dengue endemic areas, as may be the case with
emigrants visiting their countries of origin, there will
probably be an increased risk of suffering either DHF or
DSS, which may translate into an increased risk to the fetus.
If such travel cannot be avoided, then the conscientious
application of bite-preventive measures is advised, including the use of an effective insect repellent. Although there
is a report of mental retardation in a child whose mother
used DEET throughout pregnancy,39 more recent work has
demonstrated the safety of DEET during the second and
third trimesters.40
When such a patient develops a fever or rash a high index
of suspicion for dengue fever is warranted. The early signs
and symptoms of dengue are not unique. Those signs that
might be more helpful might include conjunctival injection,
pharyngeal erythema, lymphadenopathy, and hepatomegaly.1 Leukopenia occurs with dengue fever and is a useful
diagnostic feature, as is thrombocytopenia. Mild elevations
of hepatic enzymes might also aid in the diagnosis.41
Laboratory diagnosis is typically not available in developing
countries and the diagnosis must be suspected and responded
to clinically. The differential diagnosis in such cases would
include influenza, enteroviral infection, other viral exanthems, malaria, leptospirosis and typhoid fever.42,43
Where appropriate laboratory facilities are available, the
most frequently used serologic tests are the hemagglutination inhibition (HI) assay and IgG or IgM enzyme immunoassays. The IgM immunoassay (MAC-ELISA or equivalent) is the
most commonly used for rapid confirmation of the diagnosis.44 Dengue viruses can be isolated in mosquitoes or
tissue culture if such facilities are available.
Acute and convalescent specimens should be analyzed
together by HI assay or IgG immunoassay to provide a
definitive serologic diagnosis.

ARTICLE IN PRESS
Dengue fever and pregnancy
Treatment is supportive with fever reduction measures,
analgesics and careful maintenance of fluid and electrolyte
balance. Added to this would be careful monitoring of
hematologic status and serum albumin and, when necessary,
replacement of blood components. These measures will
hopefully reduce progression to more severe illness and
reduce the risk of pregnancy-specific effects such as neural
tube defects and premature labor.
Prior to term, there seems to be little indication for
induction of labor or other obstetrical intervention. The
fetus while in utero will benefit from the transfer of
maternal antibodies as well as from those treatment
measures instituted for the mother.
At term, there may be some indication for induction of
labor in order to allow for better management of mother
and infant. This is countered, however, by the risk of
precipitating a Cesarean section in an otherwise unstable
patient. This is fraught with anesthetic risks (such as
performing spinal anesthetic in a patient with a bleeding
tendency) as well as the risk of excessive blood loss from the
surgery. Thus, the majority opinion would be for conservative management unless there is some other obstetrical
reason to intervene.
Care of the neonate under these circumstances would
primarily be a matter of careful observation with a high
index of suspicion, remembering that some neonates have
become ill as long as 11 days after birth. Diagnosis and
treatment can be further complicated in these cases by
confusion with bacterial sepsis, birth trauma and other
causes of neonatal illness.

Conclusion
The spread of dengue fever to new geographic areas
combined with an increase in international travel add this
disease to the list of infectious disease risks regarding which
travelers, especially pregnant travelers, need to be warned.
Early diagnosis of this disease is made difficult by the nonspecificity of findings, a broad differential diagnosis, and
physiologic changes of pregnancy that may confuse the
clinician.
Whenever practical therefore, pregnant women should be
advised to avoid travel to dengue endemic areas. When the
disease does occur in pregnancy, keys to successful management include a high index of suspicion, prompt diagnosis,
and a team approach to the management of both mother
and infant. In the absence of other complications the
disease does not appear to be of itself an indication for
obstetrical intervention.

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