A pregnant woman is examined for dengue.

Zika is the topical tropical disease on everyone’s lips due to the devastating consequences of the latest outbreak; namely, the microcephaly suffered by offspring of women who have become infected during pregnancy.

Zika virus is a flavivirus that is primarily transmitted by infected Aedes mosquitoes. This vector also transmits the dengue virus and is commonly found in tropical and sub-tropical environments in Africa, the Americas, Asia and the Pacific.

The recent outbreak of Zika virus has been accompanied by an unprecedented rise in the number of children being born with microcephaly, or an unusually small head. In addition, several countries, including Brazil, reported a steep increase in the neurological condition Guillain-Barré syndrome, which can cause paralysis and is often fatal. The epidemic of birth defects caused by the Zika virus has led researchers to look more closely at the potential consequences of other viruses during pregnancy.

Dengue during pregnancy and associated fetal adverse outcomes

Although Zika and dengue viruses are closely related, there is limited data on the possible adverse effects of dengue infection during pregnancy on fetal outcomes. Yet, just like Zika, dengue virus is spreading fast across Brazil and other South American countries.A recently published systematic review and meta-analysis aimed to estimate the increase in the risk of four adverse fetal outcomes in women who had dengue infection during pregnancy; namely, stillbirth, miscarriage, preterm birth, and low birthweight.

A recently published systematic review and meta-analysis aimed to estimate the increase in the risk of four adverse fetal outcomes in women who had dengue infection during pregnancy; namely, stillbirth, miscarriage, preterm birth, and low birthweight.

Researchers at the London School of Hygiene & Tropical Medicine engaged in a systematic review and meta-analysis, searching the available literature for any relevant studies.

The review included any original studies that reported any fetal outcomes for pregnant women who had dengue infection during the gestational period. They excluded case reports, ecological studies, reviews, in-vitro studies, and studies without data for pregnancy outcomes, but case-control, cohort, and cross-sectional studies and unselected case series were eligible for inclusion.

They identified 16 studies that were eligible for inclusion in the systematic review and eight that were eligible for the meta-analyses; these included over 6,000 pregnant women, with almost 300 of these having been exposed to dengue during pregnancy.

The results were nothing sort of significant; evidence emerged that dengue infection alone, in the absence of clinical symptoms, does not affect the outcome of pregnancy, but suggested clinical dengue during pregnancy seems to increase the frequency of stillbirth, prematurity, and low birth weight.

For example, with miscarriage, the researchers determined women with dengue infection during pregnancy were three and a half times more likely to experience a miscarriage compared with those without.

In addition, the risk of stillbirth was estimated to be up to seven times as high for a woman with dengue infection versus those without; although a meta-analysis for stillbirth could not be carried out because that outcome was investigated in just one study, the researchers calculated the crude relative risk to be 6.7 in women with symptomatic dengue compared with women without dengue. Preterm birth and low birth weight were the most common adverse pregnancy outcomes.

The authors concluded that the evidence suggests symptomatic dengue during pregnancy might be associated with fetal adverse outcomes.

“If confirmed, it would be important to monitor pregnancies during which dengue is diagnosed and to consider pregnant women in dengue control policies,” they said.

Mrs. Enny Paixão, of the LSHTM, was the lead author on the study. Dengue during pregnancy is the topic of her PhD at the School, and she is also part of a research group on dengue and other arboviruses at the Federal University of Bahia in Brazil.

She explains that this group is one of the most important in Brazil in the field of epidemiology of infectious diseases and has been conducting investigations on dengue and latterly Zika and chikungunya, as well as other infectious diseases of interest to public health.

In terms of what instigated the recent meta-analysis, Mrs. Paixao says that while there a broad understanding that dengue fever is potentially dangerous in pregnancy, exact data was not known. The recent emergence of severe antenatal side effects of Zika virus was another factor.

Zika and dengue risks to expecting mothers

Zika is from the same family of diseases as dengue fever, yet has been receiving far more attention in the past few months – are people unaware of how common and potentially dangerous dengue infection is?

“Zika is an emerging disease, and there is a lack of information about the effects of the disease in the general population and in pregnant women. So it is important to investigate the potential effects of both diseases. There is evidence that other infections can be harmful during pregnancy so it was pertinent to produce information about the effects of dengue during pregnancy. Another systematic review published in 2010, had concluded that vertical transmission is possible and that the virus could potentially be dangerous in pregnancy,” she explains.

It is estimated that each year, 390 million people are infected with dengue and 96 million develop clinical symptoms. The results of the meta-analysis and review provide further evidence of a link between symptomatic dengue virus and adverse outcomes in pregnancy.
“Most cases of dengue are asymptomatic or self-limiting, however, some cases progress to severe illness. Infections without any clinical symptoms do not appear to be harmful to the fetus, but also that clinical dengue during pregnancy seems to increase the frequency of stillbirth, prematurity, and low birth weight,” says Mrs. Paixão.

The results are extremely interesting but not conclusive, she stresses; further insights must be gained into how, why, and when dengue virus impacts fetal development.

“The results of this study are key to attract attention to this important topic but there are many questions that remain without an answer. These should be better investigated, such as the relevance of clinical symptoms and the gestational age at which the disease occurs.”
The research team at LSHTM have recommended the development of further epidemiological studies on this theme, with larger sample sizes, adequate comparison groups, as well as control groups to avoid confounding.

Right now, the implications of these findings for clinicians treating people in areas where dengue fever is rampant are unclear but Paixao says that there are a plethora of strategies that could be employed if these findings are confirmed in the future.

“If this association is confirmed, recommendations should be made for the close monitoring of pregnancies during which dengue is diagnosed and also strategies for dengue control to include pregnant women as an at-risk population.”

The LSHTM team call for original research into this issue to be carried out; but while there are scientists interested in the topic, developing an appropriate methodology to carry out these studies is not an easy task, admits Paixao.

“Acquiring dengue during the nine months of pregnancy is relatively rare in a population where dengue has already been circulating for a long time. Yet we need a large number of individuals in order to be able to observe if there is a relationship between dengue and adverse fetal outcomes. Also, it is difficult to establish a direct relation with a fetal outcome that sometimes occurs seven to eight months after the disease onset,” she explains.

According to Paixao, people are already aware of the potential dangers of Zika can cause, and a similar level of awareness must be raised in relation to dengue fever.

“Dengue and Zika are both vector-borne disease so the way to be protected is the same, avoiding a bite from the mosquito. But it is also important to warn of the potential risk of dengue harmful outcomes when acquired during pregnancy because the risk of dengue infection will be continued in the areas where arboviruses are circulating until the development of a vaccine.”

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