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ARTICLE IN PRESS

Travel Medicine and Infectious Disease (2007) 5, 183–188

Available at www.sciencedirect.com

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

Dengue fever and pregnancy—A 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
b
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

Received 9 November 2006; accepted 9 November 2006


Available online 5 January 2007

KEYWORDS Summary
Dengue; Background: The increasing incidence of dengue with the concomitant rise in travel
Dengue hemorrhagic during pregnancy makes it likely that a pregnant woman will plan travel to or present after
fever; travel to endemic areas.
Arbovirus; Method: Literature search and communication with researchers.
Pregnant; Results: Case reports of dengue during pregnancy, the peripartum period and neonatal
Parturient; dengue were found. There is little systematic research.
Neonate Conclusions: Pregnancy appears not to increase the incidence or severity of dengue, but
some case reports suggest that dengue may predispose to certain pregnancy complica-
tions. 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

Dengue—the disease
Corresponding author. Tel.:+1 616 988 0980; fax: +1 616 988 0982.
E-mail addresses: travdoc@travdoc.com (I. Dale Carroll), Dengue fever has in recent years seen a great resurgence in
malaria@freesurf.ch (S. Toovey), fvgompel@itg.be (A.V. Gompel). tropical climates and appears to be spreading to new areas.

1477-8939/$ - see front matter & 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tmaid.2006.11.002
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184 I. Dale Carroll et al.

It is now estimated that over 100 million infections with this Dengue during pregnancy
virus occur annually throughout the world, 250,000 of these
progressing to dengue hemorrhagic fever (DHF) and 25,000 First, one must identify how often this type of infection is
resulting in death.1 apt to occur in a pregnant population. Perret et al. studying
Dengue viruses are members of the Flaviviridae genus, parturients in a highly endemic area, found a seropositivity
which includes the causative organisms of yellow fever, West rate of 94.7%. Only 0.8% of the study population, however,
Nile fever and Japanese encephalitis. It is spread through showed evidence of having acquired the infection during
the bite of the Aedes mosquito. There are four serologic pregnancy, and in those cases, the disease occurred early in
types of dengue virus. Infection with one type does not the pregnancy. The seropositivity rate increased with
appear to confer immunity to the others. In fact, the first advancing maternal age, indicating that younger women
attack of dengue fever (primary dengue) may predispose to were more at risk to contract the disease during pregnancy
much more severe illness following infection with other while the older patients were more likely to have pre-
serotypes (secondary dengue).2 existing protective immunity.7
The incubation period of the disease is normally 3–8 days. It should be remembered, however, that the study group
The virus is detectable in human subjects 6–18 h before was a native population living in a highly endemic area.
the onset of symptoms and viremia ends as the fever These authors believe that the disease risk for immunolo-
abates.3 gically naı̈ve travelers to such areas would be higher
The disease can present with a wide range of symptoms, because of their lack of pre-existing protective antibodies.
from essentially asymptomatic to a life-threatening hemor- The next question is if the disease presents during
rhagic diathesis (DHF) or dengue shock syndrome (DSS).4 pregnancy, does it have a different presentation and clinical
Generally, the severe forms of the disease are thought to course than in the non-pregnant patient? The available data,
occur more commonly after prior sensitization with a although quite sparse, would seem to indicate not. In these
different serotype. They may occur, however, even with a studies, pregnant patients with dengue fever still were
primary infection, perhaps depending on the infecting mostly diagnosed clinically with the diagnosis later being
serotype.5 confirmed by laboratory tests. In a review by Sirinavin et al.
Typically the disease presents with acute fever, head- 13/14 (93%) cases for which presentation was recorded had
ache, retro-orbital pain and severe muscle and joint pains. a typical presentation of abrupt fever accompanied by
In some patients, the predominant symptoms are respiratory headache, retro-orbital pain, muscle aches and thrombocy-
and gastrointestinal. Commonly, there is also a fine, topenia, in some cases accompanied by hemoconcentration,
petechial rash. Fever typically lasts 5–7 days but the disease pleural effusion and shock. Similarly, a case reported by
may be followed by a prolonged period of physical and Phuphong followed a typical course.8–10 The question arises,
emotional fatigue.6 however, whether a patient with an atypical presentation
would be recognized as having dengue fever and the
Pregnancy questions appropriate laboratory studies initiated.
Next is the question of how the disease process might
affect the pregnant woman.
Pregnant women represent a particularly worrisome sub-
Data from two authors showed an increase in the rate of
group of travelers to dengue-prone areas. One study of
prematurity. Carles et al.11,12 in their review of 38 cases in
women living in a highly endemic area has estimated the risk
French Guiana indicate a significant increase in prematurity
of exposure to be almost 1% during a given pregnancy in a
and fetal death. In these cases the timing of the fetal death
highly endemic area. It behooves us, therefore, to be aware
led the investigators to assume that death was due to the
of how the disease and pregnancy may interact and thus how
dengue, but one patient was also co-infected with malaria.
to advise the pregnant traveler.7
But this group studied only severely ill, hospitalized
Questions that arise include the effect of pregnancy on
patients. They point out that had they included patients
the disease process, the effect of the disease on the
with milder disease the incidence of fetal death and
pregnancy, what might be the effects on the fetus and
prematurity would have been less, more in line with an
neonate, and how the pregnant woman and the newborn
earlier study by Mirovsky in Vietnam.13 Ismail et al. in a
might best be managed.
recent review also noted a 50% prematurity rate and
reported three maternal deaths out of 16 cases.14
Literature review In the Perret study, there appeared to be no fetal effects
from the maternal dengue infection. But only two patients in
Seeking the answers to these and related questions, the the study showed antibody evidence of having had dengue
authors performed a literature search of the National during the pregnancy. Also, the study was done at the time of
Library of Medical Publications database and of the Ovid delivery. It is possible that women who get dengue early in
database, using the search terms ‘‘dengue AND pregnancy.’’ pregnancy miscarry and thus would not present for delivery.
This was supplemented by reading the references within Other reports by Chye’s group in 1997 and Restrepo et al.
these articles as well as by personal communication with in 2003 do not indicate a propensity toward premature labor,
some of the authors. fetal death, or other complications of pregnancy, but do
We offer here a review of the available information indicate that the signs and symptoms of dengue fever might
followed by a discussion of how this information might be easily be confused with those of other pregnancy complica-
used in patient management and identification of those tions such as toxemia or its variant, HELLP syndrome
areas where further research is needed. (hemolysis, elevated liver enzymes, low platelets).15,16
ARTICLE IN PRESS
Dengue fever and pregnancy 185

The patients in these studies were women with severe after birth.23 Two other authors conclude that although
disease who presented for medical care. The authors question these may initially be protective, as their level wanes they
whether milder cases of disease occurring earlier in pregnancy may instead predispose the infant to DHF or DSS.5,24
might have presented instead as miscarriage and have been Secondly, babies of low birth weight were found to have
suspected of having a septic abortion. Or would a preponder- lower levels of transferred antibodies.7 It is impossible to
ance of milder cases have more firmly demonstrated the tell from the available data whether pre-existing placental
absence of significant effects on pregnancy by dengue? pathology prevented the passage of these antibodies or if
Sharma et al. reported an increased incidence of neural the presence of dengue fever itself caused placental
tube defects following dengue infection,17 but as this defect damage resulting in low birth weight.
has been demonstrated following other febrile illnesses, it
may well have been due to the fever rather than to any Neonatal dengue
teratogenic effect of the dengue virus per se.18
Regarding dengue fever in the newborn infant, Perrett et al. If the dengue virus was transferred to the infant via the
come to the conclusion that serious dengue disease occurs only vaginal mucosa at parturition, such as with genital herpes
when the mother is at or near term and there is insufficient infection, some fetal advantage might be gained by Cesarean
time for the maternal production of protective antibodies.7 delivery.19 However, studies showing the presence of dengue
There is some evidence that in many viral infections the virus in fetal and cord blood samples, seem to indicate
placenta is protective to the fetus, but this is not consistent intrauterine infection of the neonate.5,13,25–27 Thus, a
or complete.19,20 There have been case reports of transpla- Cesarean would increase maternal risk without being of any
cental infection of the neonate with dengue virus, the data particular benefit to the infant. In fact, Bunyavejchevin et al.
being summarized by Sirinavin et al. in their review article.8 in their discussion advocate conservative management.28
Seventeen cases of vertical transmission of dengue were Perret et al. in their paper point out that ‘‘yall reported
reviewed. Sixteen of 17 (94%) infants survived without cases of symptomatic congenital dengue infection have
sequelae, with one (6%) neonatal death from intracerebral occurred in neonates born to mothers infected very late in
hemorrhage that may have been coincidental to the dengue pregnancyymaternal infections occurring close to the time
infection. of delivery would have insufficient protective antibodies to
In these studies, when maternal dengue fever was be transferred and consequently direct viremia into the
encountered prior to term it was managed conservatively fetal blood stream may result.’’7 They also warn that the
without attempting premature delivery of the infant. 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.
Dengue at parturition The course of congenital infection in these studies
indicated that often the diagnosis could eventually be
Although conservative obstetrical management is usually suspected on clinical grounds and then confirmed in the
advocated,21 of the 17 patients in Sirinavin’s review in whom laboratory, but initial presentation was often confusing.
there was vertical transmission of dengue fever, 6/17 (35%) In the review by Sirinavin, the onset of fever in the
were delivered by Cesarean section, 4/36 (24%) of whom newborn varied from 1 to 11 days after birth with an average
required blood transfusions, with 1/36 (3%) suffering a of 4 days and lasted 1–5 days. There did not appear to be any
massive maternal hemorrhage. Of the 11/17 (65%) who were significant difference in this whether the mother’s dengue
delivered vaginally, 4/11 (36%) of these also required infection was primary or secondary.
transfusions. Post-partum course was not reported for 5/17 All of the infants developed fever and thrombocytopenia,
(29%) of the patients in this review. and 14/17 (82%) were found to have an enlarged liver.
Newborn management was complicated by the fact that it Eleven of 17 (65%) had at least some evidence of bleeding,
was often initially impossible to tell whether the newborn’s but none required transfusion despite some very low
symptoms were due to infection with dengue virus, or other platelet counts. Four of the 17 infants (24%) developed
types of infection. Thus, many of these infants underwent a pleural effusion but only 2/17 (12%) manifested a rash.29,30
series of diagnostic studies and treatment with antibiotics Transplacental maternal antibodies are felt to be protec-
while the diagnosis was being established. Nonetheless, all tive to the newborn while the titers remain high, typically
of the infants did well except one. The one neonatal death for about 6 months. After that, however, the lower titers
may have been from causes other than dengue fever.8 may in fact result in immunological enhancement and
Thus, Fatimil in a report from Bangladesh states, ‘‘A predispose the infant to DHF or DSS.31 Breast feeding might
pregnant woman with fever, myalgia and/or bleeding be somewhat protective as neutralizing activity against
manifestations should raise a high suspicion that the baby dengue virus was observed in some patients. The degree of
may develop the disease, and both the mother and baby this protection, however, has not been studied.32
should be closely followed-up.’’22
Regarding the transfer of maternal antibodies to the
fetus, the following observations were made in these Discussion
studies. First, that maternal antibodies are transferred to
the fetus. Regarding the protective efficacy of these Summary of findings
antibodies, one author reports that antibodies with in-
creased cross-reactivity to other dengue serotypes prefer- These reports demonstrate that although pregnancy does
entially cross the placenta and are protective to the infant not seem to increase the risk of contracting dengue fever,
ARTICLE IN PRESS
186 I. Dale Carroll et al.

the disease can be severe in pregnancy, with devastating While this might be protective to the fetus, would it also
consequences. Even with what is believed to be primary cause a delay in the diagnosis?
disease, it can progress to manifestations typical of DHF.33 In addition to all this, it would be interesting to know if
Furthermore, those familiar with pregnancy will recognize Aedes mosquitoes have a special attraction to pregnant
that diagnosis and treatment may be hampered by confusion women as has been demonstrated in the case of the
of dengue fever with other disease processes such as Anopheline mosquitoes that transmit malaria. But such a
toxemia and HELLP syndrome or certain forms of sepsis. study has not yet been undertaken.37
In the studies cited, however, the diagnosis of dengue Regarding fetal and neonatal effects, placental passage of
fever was made on clinical grounds based on a typical antibodies does occur and may initially be protective to the
presentation of the disease. The question arises whether in infant. But if the infant stays in the endemic area he or she
usual practice a patient with an atypical presentation would is eventually at increased risk for DHF and DSS.38
be recognized as having dengue fever and the appropriate Thus the fact remains that pregnant patients, especially
laboratory studies initiated. Teichmann et al. in a German those without pre-existing immunity, traveling to areas
study of 71 cases cite the diagnostic difficulties encountered where dengue fever is prevalent are at significant risk of
because of the atypical clinical presentation in many of contracting the disease. If this occurs, the maternal and
these patients.34 fetal effects include all those of any other severe febrile
Effects on the fetus or newborn seem to be variable, with illness, plus the potential for hemorrhage and shock. And
apparently less fetal harm occurring earlier in pregnancy there are no specific preventive measures to use, such as
when there is time for protective maternal antibodies to the vaccination or prophylactic medication.
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. Recommendations
Published reports do indicate several fetal and newborn
deaths, but clearer evidence is needed in order to attribute Pregnant patients should be advised of these risks and, if
the deaths to the dengue infection per se. In only one case is practical, the trip postponed, especially in late pregnancy.
the clinical course of the infant discussed, and there is This may be more important for the non-immune pregnant
reason to believe that the causes of neonatal death in that traveler, or younger pregnant travelers returning to endemic
case were other than the dengue fever. In the other cases, areas. For pregnant travelers with pre-existing immunity
the fetal deaths were assumed to be from dengue but no returning to dengue endemic areas, as may be the case with
actual laboratory evaluation was undertaken to establish emigrants visiting their countries of origin, there will
this. 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
Pertinent pregnancy facts application of bite-preventive measures is advised, includ-
ing the use of an effective insect repellent. Although there
From these data we are reassured that the dengue virus, is a report of mental retardation in a child whose mother
unlike for example those of rubella and varicella, poses no used DEET throughout pregnancy,39 more recent work has
specific threat of fetal malformation or disease-specific demonstrated the safety of DEET during the second and
fetal harm. Also it would appear that pregnancy does not third trimesters.40
predispose to more severe disease as in the case, for When such a patient develops a fever or rash a high index
instance, of malaria. of suspicion for dengue fever is warranted. The early signs
But misdiagnosis or delay in diagnosis remains a significant and symptoms of dengue are not unique. Those signs that
hazard, especially to the busy obstetrician who may be might be more helpful might include conjunctival injection,
unfamiliar with dengue fever. pharyngeal erythema, lymphadenopathy, and hepatome-
There are several pregnancy-related issues that might galy.1 Leukopenia occurs with dengue fever and is a useful
confuse the unsuspecting obstetrician. These include com- diagnostic feature, as is thrombocytopenia. Mild elevations
mon alterations in the immune, coagulation and cardiovas- of hepatic enzymes might also aid in the diagnosis.41
cular systems as well as hepatic enzymes and the febrile Laboratory diagnosis is typically not available in developing
response to illness during pregnancy.35 countries and the diagnosis must be suspected and responded
During pregnancy the white blood cell count is typically to clinically. The differential diagnosis in such cases would
elevated and manifests a shift to the left. Thus, such a minor include influenza, enteroviral infection, other viral ex-
change due to dengue fever might be overlooked. anthems, malaria, leptospirosis and typhoid fever.42,43
Similarly, pregnancy results in an increased tendency Where appropriate laboratory facilities are available, the
toward coagulability while at the same time the platelet most frequently used serologic tests are the hemagglutina-
count is normally low. How these factors might interact with tion inhibition (HI) assay and IgG or IgM enzyme immunoas-
the course and laboratory findings in a case of DHF is says. The IgM immunoassay (MAC-ELISA or equivalent) is the
unclear. And would the hemoconcentration that occurs with most commonly used for rapid confirmation of the diag-
DHF be masked by the normal hemodilution of pregnancy? nosis.44 Dengue viruses can be isolated in mosquitoes or
Both dengue fever and pregnancy typically manifest mild tissue culture if such facilities are available.
elevations of liver enzymes. Would this lend itself toward a Acute and convalescent specimens should be analyzed
delayed diagnosis of dengue fever?36 And finally, pregnancy together by HI assay or IgG immunoassay to provide a
sometimes blunts the normal febrile response to illness. definitive serologic diagnosis.
ARTICLE IN PRESS
Dengue fever and pregnancy 187

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