Dengue y Embarazo

• 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.

• 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.

• las manifestaciones hemorrágicas aparecen• desde el primer día de evolución. Las imágenes• de la ecografía abdominal pueden presentar• edema perivesical, más las alteraciones• por hepatomegalia, esplenomegalia, y serositis• en el hemorrágico.• Fueron hallazgos frecuentes la presencia de• hepatomegalia, epigastralgia y vómito, que en• la población general se da solo en las formas• graves de dengue. El mayor porcentaje de los casos de dengue• ocurrió en el primero y segundo trimestre• del embarazo.

• 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

• Las mujeres gestantes que sufren de dengue• tienen un riesgo mayor de hemorragia vaginal,• y tendencia a las hemorragias durante• procedimientos quirúrgicos, en heridas quirúrgicas,• y sangrado posquirúrgico. Las embarazadas con

dengue clásico por lo• general presentan un parto y puerperio normales.• La muerte materna por dengue es un evento• poco frecuente.

fetal• 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 Chye’s 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

• 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

• 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.

• Los recién nacidos cursan con trombocitopenia,

• fiebre, hepatomegalia y grados variables• de insuficiencia circulatoria, y que suele

diagnosticarse• como sepsis neonatal. Se pueden• presentar trastornos neurológicos.

• Dengue at parturition• Although conservative obstetrical management is usually• advocated,21 of the 17 patients in Sirinavin’s 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.

• 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• 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.5,13,25–27 Thus, a• Cesarean would increase maternal risk without being of any• particular benefit to the infant.

• 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 1–5 days. There did not appear to be any• significant difference in this whether the mother’s 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

• 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

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

• 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

• 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

• 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.

• 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.

• 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.• References

• Discussion• This study suggests that dengue during pregnancy can increase• maternal mortality, as previously reported [11]. It also suggests• that pregnancy is associated with DHF/DSS and that the• susceptibility to severe disease increases with pregnancy age.• Severe dengue has been associated with maternal deaths, with• fatality rates ranging from 2.9%–22% [5–6,11–13]. The maternal• dengue fatality in this study was 7.4%. The differences in dengue• fatality in pregnant women likely result from differences in the• designs and in the heterogeneity of the studies sample sizes.• Additionally, it may represent different regional management of• dengue in pregnant women.

• More than half of pregnant women were hospitalized and it• was twice the rate of hospitalization for non-pregnant women,• since it was a recommendation of Rio de Janeiro’s healthcare• authorities to prevent dengue complications in this group.• Moreover, the proportion of DHF could still be underestimated• as the identification of plasma leakage syndrome through the• hemoconcentration or hypoproteinemia may be compromised• from the seventh to the 32rd week of gestation, by the• physiological increase of intravascular volume of this period• [14].• The reasons for the association of DHF/DSS with pregnancy• were not assessed in this study. The amount of vascular leakage• during early versus late pregnancy may have different effects on• the clinical presentation and on the perceived severity level. The• higher risk for developing severe disease in the 2nd and 3rd• trimesters should be confirmed by prospective studies as the• selection bias related to admission because of risk of preterm• delivery cannot be excluded.• The non-laboratory confirmed dengue cases were not analyzed• to avoid a detection bias, and the confusion of dengue with• pregnancy complications, such as HELLP syndrome.

• CONCLUSION• El dengue durante el embarazo, es un padecimiento• que debe investigarse en toda paciente con fiebre, mialgias, artralgias, ataque

al• estado general en zonas endémicas, ya que• las complicaciones para la madre y su hijo• pueden ser fatales si no se tratan oportunamente;• por ello es importante el diagnóstico• materno temprano, fundamentado en la sospecha• clínica y epidemiológica hasta la confirmación• mediante pruebas de laboratorio para lograr• un tratamiento adecuado y oportuno, buscando• la mejoría clínica de la madre y disminuir• riesgos para los productos de la concepción

• La presentación clínica del dengue en embarazadas• es semejante a la población general;• las manifestaciones hemorrágicas aparecen• desde el primer día de evolución. Las imágenes• de la ecografía abdominal pueden presentar• edema perivesical, más las alteraciones• por hepatomegalia, esplenomegalia, y serositis• en el hemorrágico.• Fueron hallazgos frecuentes la presencia de• hepatomegalia, epigastralgia y vómito, que en• la población general se da solo en las formas• graves de dengue. El mayor porcentaje de los casos de dengue• ocurrió en el primero y segundo trimestre• del embarazo.

• Estas pacientes presentan con mayor frecuencia• actividad uterina desencadenada por• la infección en cualquier trimestre del embarazo• (amenaza de aborto, aborto, amenaza de• parto prematuro y parto prematuro), y desencadenamiento• del trabajo de parto en embarazos• a términos simultáneamente con la infección.• Se informó ruptura prematura de membranas;• hipertensión inducida por el embarazo y• empeoramiento de los casos de hipertensión• inducida por el embarazo, preeclampsia,• eclampsia; retardo en el crecimiento intrauterino,partos distócicos, todos con

mayor frecuencia• que en la población general.

• Hay mucha controversia sobre si el virus del• dengue es o no de transmisión vertical. Su confirmación• requiere la presencia de IgG e IgM• específica tanto en la madre como en el RN.• La transmisión perinatal del dengue es bastante• rara. Al igual que se presentan dudas sobre• si es causante o no de efectos teratogénicos,• de sufrimiento fetal, de bajo peso al nacer• y de muerte fetal.• La evaluación del crecimiento y el desarrollo• de los niños fueron adecuada.

• Es difícil explicar el porque de las discrepancias• en cuanto a los efectos del virus del• dengue en el embarazo y en el recién nacido• que existen en los estudios, pero podría plantearse• que la diferencia en los efectos puede• ser reflejo de la severidad variable de las formas• clínicas de la enfermedad, determinadas a• su vez por factores como la infección secuencial,• la virulencia de la cepa, las características• individuales de las personas y otros factores• epidemiológicos, que pueden tener influencia• en la presentación y la severidad de los efectos• mórbidos durante la gestación.