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Symptomatic dengue infection during pregnancy associated with adverse fetal outcomes
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Women infected with dengue during pregnancy, particularly those who experienced clinical symptoms, were more likely to have a miscarriage, stillbirth or an infant born preterm and/or with low birth weight, according to a systematic review and meta-analysis recently published in The Lancet Infectious Diseases.
“To our knowledge, our study is the first to show an association between dengue infection during pregnancy and adverse fetal outcomes,” Enny S. Paixão, MSc, of the department of infectious disease epidemiology at the London School of Hygiene & Tropical Medicine, and colleagues wrote. “Since women of reproductive age in endemic areas are at risk of dengue infection, whether dengue infection during pregnancy is associated with adverse fetal outcomes needs to be established.”
Dengue is prevalent in more than 100 countries, mostly in South America and Southeast Asia, and infects an estimated 390 million people annually, according to the researchers. About 96 million patients develop clinical symptoms of dengue, including fever, headache, retro-ocular pain, muscle and joint pain, nausea, vomiting and a rash. An even smaller proportion of cases develop severe illnesses involving capillary leakage, bleeding, thrombocytopenia and liver injury.
There is limited data on the effects of dengue infection during pregnancy; however, it is “biologically plausible” that dengue could cause adverse fetal outcomes, Paixão and colleagues wrote. Dengue infection may increase the production of pro-inflammatory cytokines, which can impact the production of uterine activation proteins and stimulate contractions, leading to preterm delivery. Moreover, clinical symptoms of dengue may cause damage to the placental circulation, and severe illness capable of endothelial damage and increased vascular permeability may result in vertical transmission.
“Once the virus reaches the placental tissue, pathological changes might occur such as villous stromal edema, increased formation of syncytial knots and chorangiosis, all of which can result in hypoxia,” the researchers wrote. “The hypoxia itself could cause stillbirth, restrict fetal nutrition or initiate trophoblast apoptosis leading to fetal growth restriction.”
To investigate whether these adverse fetal outcomes are associated with dengue infection during pregnancy, Paixão and colleagues evaluated data from 16 studies published from 1994 to 2014, including five cohort studies, one case-control study, one cross-sectional study and nine case series. They performed a systematic review on all studies, which were conducted in Brazil, Colombia, Cuba, French Guiana, India, Malaysia, Mexico, Sri Lanka, Sudan and Venezuela. In addition, meta-analyses of eight studies that included 6,071 pregnant women, 292 of whom exposed to dengue, were performed to further assess the risk for miscarriages, preterm birth, low birth weight or intrauterine growth restriction.
The prevalence of miscarriages possibly linked to dengue infection during pregnancy ranged from 3.8% (95% CI, 0-21) to 16% (95% CI, 4.3-41), according to the researchers. A meta-analysis of two studies revealed that the occurrence of a miscarriage was more likely to occur in women infected with dengue vs. noninfected women (crude overall OR = 3.51; 95% CI, 1.15-10.77).
For stillbirth, the incidence rate ranged from 4.7% (95% CI, 0.1-26) to 13% (95% CI, 1.6-48). The researchers calculated the risk for stillbirth based on data from one cohort study conducted in French Guiana and predicted that stillbirth also was more likely to occur in symptomatic women infected with dengue during pregnancy vs. noninfected women (crude RR = 6.7; 95% CI, 2.1-21.3).
The most common adverse pregnancy outcomes associated with dengue infection during pregnancy were preterm birth (crude overall OR = 1.71; 95% CI, 1.06-2.76) and low birth weight or intrauterine growth restriction (crude overall OR = 1.41; 95% CI, 0.9-2.21), though the relationships were not significant, Paixão and colleagues wrote. However, post-hoc sensitivity analyses excluding two studies where the majority of women (89% and 63%, respectively) did not have clinical symptoms of dengue demonstrated a significant association for both preterm birth and low birth weight, indicating that the presence of clinical symptoms and disease severity are associated with an increased risk for adverse outcomes.
“The occurrence of stillbirth mainly in women who had severe dengue also supports this hypothesis,” Paixão and colleagues wrote. “Consequently, we think that the presence of clinical symptoms is an important factor in the increased risk of adverse birth outcomes for women who have dengue infection during pregnancy.”
The researchers concluded that additional epidemiological studies with larger samples sizes should be carried out to confirm their findings.
“If an association between dengue infection during pregnancy and adverse fetal outcomes can be confirmed, recommendations should be made for the close monitoring of pregnancies during which dengue is diagnosed and for strategies for dengue control to include pregnant women as an at-risk population," they wrote.
In a related editorial, Gabriel Carles, MD, of the Hospital West Guyanese Franck Joly in French Guiana, wrote that in addition to asymptomatic forms, minor forms of dengue infection during pregnancy also appear to have a small effect on fetal outcomes. Meanwhile, severe forms, which are more likely to occur in pregnant women vs. the general population, may have more of an impact.
“My experience in French Guiana supports these conclusions about the risk of miscarriage, preterm birth, low birth weight and stillbirth essentially being associated with symptomatic forms of dengue infection,” Carles wrote. – by Stephanie Viguers
Disclosure: The researchers report no relevant financial disclosures.
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