Since the 2016 Zika outbreak and the understanding of the teratogenic effect of this infection, there has been a newfound interest in arbovirus infections and their effects on pregnancy, resulting in numerous publications in the last 5 years. However, limited literature focuses on arbovirus infection in different stages of pregnancy and their effect on the neonate. There is currently no consensus management of perinatal acquisition of arboviruses, and current evidence is largely anecdotal observational reports. Teratogens can have different effects on the developing fetus depending on the time of infection, so infections during pregnancy should be analyzed by trimester. A better understanding of arbovirus infection in the perinatal period is required to assist obstetric, neonatal, and pediatric clinicians in making decisions about the management of mother and neonate. Our objective was to assess the evidence of adverse neonatal outcomes for several arboviral infections when contracted during the perinatal period to guide clinicians in managing these patients. There are 8 arboviruses for which neonatal outcomes from maternal acquisition in the perinatal period have been reported, with the most data for dengue and Chikungunya virus infections. The evidence reviewed in this article supports the adoption of preventive strategies to avoid ticks and mosquitoes close to the date of delivery. For the other arbovirus infections, further community-based cohort studies during outbreaks are required to evaluate whether these infections have a similar teratogenic impact.

Arboviruses are viruses transmitted by >100 species of arthropods.1,2  The 2016 Zika outbreak and its association with congenital Zika virus (ZIKV)–associated syndrome stimulated research into the effects of arboviruses in pregnancy, with researchers in some publications stratifying changes by trimester.1,35 

The third trimester, and as an extension the perinatal period, is a vulnerable period for newborns, with ∼1 million newborn deaths attributed to maternal infections around childbirth annually.6  The International Classification of Diseases, 10th Revision, Clinical Modification, defines the perinatal period as the period starting at 22 completed weeks' gestation and lasting until 7 days after birth.7  Transmission of infection during this period can occur during the last trimester of pregnancy, delivery, and breastfeeding. The routes of vertical transmission include direct fetal infection, placental infection leading to reduced delivery of nutrients and oxygen to the fetus, and maternal illness, with increased production of cytokines and chemokines leading to adverse neonatal outcomes.8  In this review, we aim to assist clinicians in managing these pregnancies by evaluating the neonatal outcomes from perinatal acquisition of arboviruses.

Dengue virus (DENV) is a mosquito-borne flavivirus causing ∼390 million infections globally per year9  and is endemic in >100 countries worldwide.10  DENV has 4 distinct serotypes, and symptoms can range from asymptomatic to severe dengue (or dengue hemorrhagic fever).10  There has been a surge in reports in which researchers look at the impact of dengue during pregnancy (Fig 1), consistent with the dramatic eightfold increase in reported adult dengue cases in the last 2 decades. This has largely been attributed to increased recognition and reporting practices.10 

FIGURE 1

The number of publications on dengue during pregnancy over time. Publications (case reports, studies, and review articles) included after literature review on “dengue in pregnancy” and analysis for this review article. Only English language reports with full texts available were included in the analysis.

FIGURE 1

The number of publications on dengue during pregnancy over time. Publications (case reports, studies, and review articles) included after literature review on “dengue in pregnancy” and analysis for this review article. Only English language reports with full texts available were included in the analysis.

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DENV has been shown to increase the production of proinflammatory cytokines that can stimulate the uterus, potentially initiating preterm labor, and increase vascular permeability, predisposing one to plasma leakage.11,12  Compromised vascular permeability resulting in barrier dysfunction can facilitate virus entry through to the placenta.13,14  Demonstrated pathologic changes in the placenta include villous stromal edema, syncytial knots, and chorangiosis, which can result in fetal hypoxia.12,15 

Some publications describe an increased risk of preterm birth, stillbirth, and low birth weight,11,12,1620  but for others findings were conflicting.2124  A 2016 meta-analysis revealed a significant association with preterm birth and low birth weight only with the inclusion of studies reporting symptomatic disease.12  In an updated 2017 meta-analysis, in which the researchers claimed to include 2 more studies and a superior analytic method, no increased risk of premature delivery, low birth weight, stillbirth, or miscarriage was found.24 

An increased risk of preterm delivery and low birth weight has been described in a few publications focused on the perinatal period.18,20  From 336 Brazilian pregnant women with dengue, 35 births occurred within 15 days from the onset of maternal symptoms.20  A statistically significant increase in preterm births (14.6% vs 4.7%) and low birth weight neonates (22.0% vs 4.4%) was reported, compared with those born outside of this time period.20  In a 2019 report, researchers evaluated 17 673 live births of mothers diagnosed with dengue; the risk of preterm birth and low birth weight was doubled in those mothers who displayed symptoms within 10 days of delivery as well as those who had severe dengue.18  There was no statistically significant association between small-for-gestational-age infants and infection in this period, so it was inferred that low birth weight was likely related to prematurity rather than pathology related to virus infection.

Congenital malformations are a rare complication associated with maternal dengue infections, with a prevalence of <1% across all trimesters.17  Two studies describe a possible relationship between maternal DENV in early pregnancy and congenital neurologic malformations,25,26  but confounding factors, including maternal fever in early pregnancy, had not been considered.27 

Laboratory-confirmed vertical transmission of DENV has been well documented, with a predominance of cases in the peripartum period. A vertical transmission rate between 18.5% and 22.7% was reported in a population of 54 DENV-infected pregnant women in French Guiana, which increased to 56.2% when the infection occurred close to delivery.21  A systematic review also supported these findings and demonstrated an average time of 7 days between maternal and neonatal fever, which may be insufficient time to confer maternal immunity via transplacental antibody transfer to the fetus.28 

Many cases of vertical transmission have been reported since the first in 199329  and have provided further clarity on the natural history of neonatal infection. Symptoms develop in the first week of life, with the most common presentation being fever and thrombocytopenia.28  Other frequently reported clinical features include irritability, lethargy, and hepatomegaly. The severity of disease ranges from asymptomatic to severe dengue with pleural effusions, intracranial hemorrhage and circulatory collapse.3032  Only 3 neonatal deaths have been reported.3032 

In the adult population, secondary dengue infection with a different serotype is the basis of severe dengue. Nonneutralizing antibodies from the initial infection theoretically aids uptake of the virus into target cells after subsequent exposure, leading to increased viral load and more severe disease.33  Infants display severe disease even in a primary infection, likely because of transplacentally acquired maternal antibodies.34,35  Maternally-acquired DENV-specific antibodies at birth provide protection to the neonate but, as they decline to lower levels, increase the risk of severe disease through an antibody-dependent enhancement similar to that seen in adult secondary infections.3335 

Detection of DENV RNA in breast milk has been reported, and breast milk transmission appears possible.36,37  An infant delivered 2 days after the onset of maternal symptoms developed a fever on day 4 of life.37  Breastfeeding had been ceased on the same day because of significant DENV-viral loads detected in a breast milk sample. The neonate’s cord blood sample and serum sample from day 2 were both DENV-negative but were DENV-positive on day 4. Acquisition through the placenta or delivery cannot be excluded, but readily detectable virus in breast milk is of concern and requires further evaluation.

Tocolytic agents, used to suppress labor, have been proposed to reduce adverse fetal events in DENV infection, but there is limited evidence for this practice.5,3840  In a Colombian study of 47 DENV-infected pregnant women, 6 received tocolytic drugs to prolong their pregnancy.39  A total of 5 of the 6 newborns still required hospitalization, but there were no cases of perinatal transmission. Theoretically, allowing transplacental transfer of maternal antibodies to the neonate would be beneficial, but further prospective studies are needed. Currently, tocolysis should only be performed for transfer to a tertiary center or for premature labor in which delaying delivery is beneficial and other differential diagnoses are excluded.5  After delivery, the neonate should be observed in the hospital for at least the first week of life.

Chikungunya virus (CHIKV) is spread through bites from Aedes species mosquitoes and is endemic in parts of Asia, Africa, Europe, and the Americas. One of the most documented outbreaks occurred on the Réunion Island in 2005 and was the first in which vertical transmission of CHIKV was documented.41 

In a 2018 meta-analysis, researchers calculated an overall risk of mother-to-child transmission during pregnancy at 15.5%, which increased to 50% during the intrapartum period.42  Symptomatic neonatal infections, which was the outcome primarily reported in these cohorts, presented in the first week of life.42 

Although largely a self-limiting condition, neonatal Chikungunya infection has a case fatality rate between 0.8% and 37.5%.43  The disease also claims high medical costs, with an estimated cost of US$375.1 per CHIKV-infected neonate in Colombia.44 

In a mouse model, CHIKV tropism was reported for muscle, joint, and skin fibroblasts and, in severe infections, dissemination into the central nervous system.45  In mice, infected cells were not detected in the placentas, so it was surmised that, rather than a placental infection, viremic maternal blood may leak into the fetal circulation through breaches in the placenta barrier from labor contractions.45 

Common clinical features of neonatal Chikungunya infection are fever, rash, and thrombocytopenia (Fig 2). The rash has been described in many forms, including maculopapular, bullous, desquamation, petechial, and hyperpigmentation.42 

FIGURE 2

Reported clinical features of Chikungunya infection in neonates. Symptomatic neonatal infections, which was the outcome primarily reported in these cohorts, present in the first week of life.42 

FIGURE 2

Reported clinical features of Chikungunya infection in neonates. Symptomatic neonatal infections, which was the outcome primarily reported in these cohorts, present in the first week of life.42 

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Severe features of complicated infection include meningoencephalitis, myocarditis, disseminated intravascular coagulation (DIC), and circulatory collapse.4648 

CHIKV infection from perinatal transmission can cause lifelong disabilities, with 1 study revealing 51% of infected children showing a global neurodevelopmental delay, when compared with 15% of an uninfected cohort.49  Interestingly, it was noted that maternal exposure to CHIKV during pregnancy, with no subsequent neonatal infection, had no impact on the child’s development at 2 years of age.49 

Strategies for management of maternal CHIKV in late pregnancy remain uncertain. Cesarean delivery appears to have no influence on transmission, with 48.7% of these deliveries leading to an infected neonate, compared with 52.9% with uninfected neonates.50  Tocolysis has been considered as a method of preventing perinatal transmission. An investigation into the Réunion Island outbreak found that 118 out of 151 CHIKV-infected pregnant women were not viremic at the time of delivery and did not transmit infection to their baby51 ; the only affected neonates were those born to mothers with polymerase chain reaction–evidence of viremia at time of delivery. There is anecdotal evidence that tocolysis, resulting in an average interval of 6 days between maternal symptoms and delivery, may allow for transplacental transfer of protective maternal antibodies.52  Tocolysis, used only when there are no obstetric complications, could be a valuable strategy, but further systematic investigations are needed.

ZIKV is primarily a mosquito-borne flavivirus that was declared a Public Health Emergency of International Concern in February 2016 by the World Health Organization.53  It is known to have other routes of transmission (eg, sexual, mother-to-child, or blood transfusion) and has been deemed a teratogen in pregnancy.54 

By the end of the 2014 outbreak in French Polynesia, 66% of the population had been infected with ZIKV.55  In a study on their pregnant population, researchers attempted to describe the prevalence of microcephaly in each trimester.55  A statistically significant risk was identified during the first trimester, but no models that excluded the first trimester were supported by the data. Brazilian data on reports of suspected microcephaly were best correlated with ZIKV incidence around week 17 of pregnancy.56  In a Columbian study, researchers looking at a group of 1850 women found that >90% of the women infected in the third trimester delivered healthy infants with no sign of microcephaly.57  Fetal deaths in the last trimester have also been reported, but the frequency was not statistically different to that of the general population.58 

Although microcephaly has not been found to be associated with ZIKV in the third trimester, there have been reports of other neurologic abnormalities. Two such examples were from Brazilian women infected with ZIKV in their 36th week of gestation with normal prenatal ultrasounds, who delivered infants at term with normal head circumferences.59  The infants were found on cranial ultrasound to have subependymal cysts and lenticulostriate vasculopathy, which were confirmed on MRI. These neonates were asymptomatic and noted to have normal development during the limited follow-up period. Studies have also reported other neuroimaging findings during the third trimester, including parenchymal hemorrhages and cerebral calcifications.58 

These cerebral abnormalities are thought to result from the neurotropism of ZIKV.60  Laboratory studies have revealed the highest ZIKV viral loads in the fetal brain of an affected neonate, with lower amounts in other organs, suggesting the brain is the main target organ for viral replication.60,61  To gain access to the fetal vessels and central nervous system, the placenta has been reported as the main route of vertical transmission.62  The most prevalent abnormalities detected in placentas infected with ZIKV in the third trimester were delayed villous maturation and hyperplasia of Hofbauer cells. Hofbauer cells are macrophages that are physically located close to the umbilical vessels and are able to migrate through to the fetal circulation and act as a “Trojan horse” to spread infection.63 

Although there is an abundance of literature on ZIKV transmission in pregnancy, most studies are generalized, not trimester-specific.64  There have been only 2 cases of suspected neonatal infection from maternal ZIKV in the perinatal period, with French-Polynesian mothers thought to be viremic around the time of delivery.65  Both infants had positive serology results within a few days; 1 infant was completely asymptomatic, and the other displayed a transient rash, jaundice, and thrombocytopenia. Neither suffered from long-term developmental problems.66 

Transmission of ZIKV through vaginal secretions during delivery is unlikely because viral shedding in these secretions is scarce,67  but transmission via breast milk has been reported. A breastfeeding mother in Venezuela became unwell with Zika-like symptoms in 2016 and 4 days later, her breast milk, serum, and urine tested positive for ZIKV by reverse-transcription polymerase chain reaction (RT-PCR). On that same day, the urine for her 5-month-old child also tested positive for ZIKV. The child remained asymptomatic during the observation period. The 2 ZIKV genomes were sequenced and demonstrated 99% similarity.68,69  There have been 6 other cases of ZIKV-infected mothers with virus detected in breast milk but no evidence of transmission.7072  These findings imply that, although there may be evidence of viral shedding in breast milk, it may not cause a clinically significant infection in the neonate. On the basis of current evidence, the benefits of breastfeeding outweigh any possible risk of breast milk transmission, and mothers should be encouraged to breastfeed even if infected.73 

Unlike DENV and CHIKV, there are limited data on the management of ZIKV-infected pregnancies. Current guidelines only support close ultrasound surveillance and, after delivery, close monitoring and testing of the newborn.5 

West Nile virus (WNV) is spread by the Culex species mosquitoes and is commonly found in Africa, Europe, the Middle East, North America, and West Asia. WNV is also known to be transmitted through blood transfusions and organ transplants.74  There have been reports of possible intrauterine transmission, but they appear to be infrequent.75 

One American study reported 3 infants with possible infection from the perinatal period.76  One mother had a fever 3 weeks before delivery but was not tested for WNV at the time and delivered an infant who developed seizures at 7 days of age and died a few weeks later. Anti-WNV immunoglobulin M (IgM) was detected in both the neonate’s cerebrospinal fluid at 17 days of age and mother’s serum 1 month after delivery. Another mother had symptoms 6 days before delivery, and her infant developed WNV meningitis at 10 days of age and was anti-WNV IgM–positive in cerebrospinal fluid. This is toward the upper limit of the incubation period of 2 to 14 days, but WNV has been known to be transmitted even after 21 days.74  In the third case, the mother became unwell on the day of delivery, and her infant had a transient rash. Testing was not performed on the infant’s cord blood or serum immediately postpartum, but at 1 month of age the child’s serum was anti-WNV IgM–positive. For the last 2 infants, normal growth and development was observed up to 12 months of age, consistent with another study.77 

The rarity of perinatal transmission is reflected in a larger prospective study of 566 pregnant women in North America during a local outbreak.78  A total of 4% percent of the infants had anti-WNV immunoglobulin G detected in cord blood samples, and no anti-WNV IgM was detected in any case.

Transmission through breast milk has been reported, but this appears to be rare, with 1 probable case noted in 2002.7981  A new mother received a transfusion of WNV-contaminated red blood cells and developed WNV encephalitis, with her serum and breast milk both positive for anti-WNV IgM. Her infant remained asymptomatic but was also serologically positive for anti-WNV IgM.79 

Studies have also revealed no difference in growth parameters and the rate of congenital malformations between pregnant women infected with WNV in various trimesters and those uninfected.82 

Yellow fever virus (YFV) is a mosquito-borne flavivirus that mainly occurs in tropical areas of Africa and South America.83  Two cases of perinatal transmission of YFV have been reported. The first was described in 2009, when a pregnant woman was infected with yellow fever late in the pregnancy.84  She delivered a healthy neonate 3 days later, but the infant developed a fever at 3 days of age and went on to develop DIC and seizures and died on day 12. The neonate’s sample from day 8 had serological evidence of yellow fever; a positive RT-PCR result and sequencing of the isolate revealed a wild-type YFV.84 

In 2019, a term pregnant woman infected with YFV delivered an infant via an emergency cesarean 3 days after the onset of symptoms.85  The neonate remained asymptomatic until day 6, when she developed jaundice and then seizures and DIC. Unfortunately, the neonate did not recover, and laboratory tests revealed a YFV-positive RT-PCR.85 

In terms of the YFV vaccine, the current guideline is to avoid administration in pregnant and lactating women, unless they are in endemic areas.86  Noting that the vaccine is a live vaccine, a Brazilian article found no indication that in utero exposure to the immunization carried an increased risk of major neonatal malformations.87  However, there have been reports of breast milk transmission after vaccine administration.8890  The neonates in these cases presented with fever, seizures, and encephalitis up to 3 weeks after maternal immunization, but all recovered and had adequate development at the time of follow-up.8890  Interestingly, the YFV vaccine is noted to have an increased neurovirulence in the developing nervous system for unknown reasons and is contraindicated in infants <6 months of age.91 

Endemic to North America, the Western equine encephalitis virus (WEEV) is spread primarily through the mosquito species Culex tarsalis.92  There has been a marked reduction in cases over the last 30 years after a peak during the mid-20th century and, although different social and ecological changes have been proposed as the cause of the decline, there have been no proven theories.93  Reports in the 1950s revealed an association between maternal WEEV in late pregnancy and neonatal encephalitis, but only 3 cases have been reported.94,95  In 1 report, twin girls presented at 5 days of age with fever and seizure-like movements.95  Mosquitoes likely infected their mother 3 days before delivery. Serum samples from the mother and neonates revealed a relative increase in titers for anti-WEEV antibodies during their illness.95  No other cases have been reported in the last 70 years.

Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne infection, endemic to Africa, Asia, and the Middle East, that classically presents with fever, thrombocytopenia, and hemorrhagic signs.96  For CCHFV in the perinatal period, some studies have reported linkage to prematurity, stillbirth, and neonatal infection,9698  whereas in other reports no transmission to neonates was found.99101 

Ribavirin, an antiviral, is contraindicated in pregnancy because of teratogenic effects, but 2 studies have postulated that, in maternal CCHFV infections, ribavirin in the last trimester may have a protective effect on the neonate.96,100  In 1 study, researchers discussed 8 pregnant women infected with CCHFV, including 4 who were infected in the peripartum period.96  One infected woman in her 38th week of gestation was treated with ribavirin and other supportive treatments on day 2 and delivered a healthy infant on day 11. The other 3 pregnant women were not treated with ribavirin and their pregnancies resulted in fetal and neonatal deaths.96  The sample size was too small to achieve statistical significance. Regardless, in a Cochrane review in 2018, researchers found insufficient evidence supporting the use of ribavirin for the treatment of CCHFV, even in nonpregnant individuals.102 

There have been 2 other documented cases of suspected perinatal transmission, both leading to neonatal death. In 2005, a 38-week pregnant woman from Turkey was found to have contracted CCHFV and delivered an infant that was initially well but, by the fifth day of life, had developed thrombocytopenia and deranged liver function tests.98  The infant suffered devastating cerebral bleeding and died. Serological tests only revealed anti-CCHFV immunoglobulin G, but the viral PCR was positive for CCHFV. The other case was a Russian woman who was infected by a tick late in pregnancy and delivered an infant 2 days after her initial symptoms.97  Her infant developed respiratory failure within a few hours of life and died of DIC and circulatory collapse a few days later. CCHFV was confirmed on RT-PCR on a serum sample, and the complete genome of the CCHFV isolate, a strain belonging to lineage V of CCHFV and found in southern European Russia, had a high identity to that obtained from the mother.97 

Rift Valley fever virus (RVFV) occurs mainly in Africa and the Middle East and is a mosquito-borne virus, with several different species of mosquitoes able to act as vectors.103 

There have been 2 documented cases of vertical transmission of RVFV. A woman in Saudi Arabia became unwell with RVFV 4 days before delivery, and her infant developed a fever at 2 days of life, with subsequent positive serum results for anti-RVFV IgM. The neonate became coagulopathic and, despite active resuscitation, died of DIC at 6 days of life.104  The other case was in Sudan, where a term woman became unwell with fever and then delivered within 2 weeks. Samples from both the mother and infant were positive for anti-RVFV IgM. The neonate had a generalized rash, jaundice, and hepatosplenomegaly but was discharged by the family against medical advice, so follow-up was not possible.105  There is no information available in the literature on breast milk transmission.

RVFV is known to induce mass abortions in livestock during outbreaks and, in 2016, an association was found in Sudan between RVFV in pregnancy and late miscarriages.106  These authors did acknowledge that there may be many other factors in play, including limited access to health care as well as lack of appropriate health records.

A 2018 study on healthy placental tissue from elective terminations during the second trimester revealed that the RVFV infected the placental chorionic villi directly, and the virus had a tropism for human placental tissue and could replicate in syncytiotrophoblasts.107 

Publications in relation to arbovirus infection in the perinatal period are sparse and further research is required to clarify the natural history of these viruses in this context. Only English language reports with full texts available were included in this review. The major limitation was publication bias, with only symptomatic and largely hospital-based cases being reported. For example, a study on asymptomatic West Nile fever virus–viremic blood donors revealed only 38% sought medical care and 2% were hospitalized for their symptoms.108 

An important factor to also include when evaluating the impact of congenitally acquired arboviruses is the potential for acquisition postnatally directly from an infected arthropod. The short incubation period in the described cases favors perinatal transmission but direct acquisition from the vector should still be considered.

Moreover, this review is focused on the only 8 arboviruses that have reported perinatal transmission (Table 1; Fig 3). There have been cases of other arboviruses in the perinatal period that can be considered as a differential for clinicians, but these have led to inconclusive results on transmission (Table 2; Supplemental Table 3).

TABLE 1

Arboviruses With an Association With Human Perinatal Transmission

VirusPrincipal VectorGeographical AreaPerinatal TransmissionConsequences of Perinatal TransmissionCommon Clinical Features of Neonatal InfectionUncommon Clinical Features of Neonatal Infection
CHIKV Mosquito (Aedes spp.) United States, Africa, Asia, Australian, and Indian Ocean Up to 50% risk of transmission during intrapartum period Neonatal infection Fever Neurologic manifestations (including seizures and/or encephalopathy) 
     Lethargy and/or irritability Cardiac manifestations (including myocarditis, coronary dilatation) 
     Rash Hemorrhagic manifestations (including DIC, NEC, hemorrhagic fever) 
     Thrombocytopenia Developmental delays 
     Acrocyanosis  
     Hyperpigmentation  
     Petechia  
     Peripheral edema  
CCHFV Tick (>30 species; mainly Hyalomma genus) Middle East, Africa, Asia, and Southeast Europe Rare Uncertain; reports of prematurity, stillbirths, and neonatal infection with hemorrhagic disease N/A N/A 
DENV Mosquito (Aedes spp.) Tropical and subtropical areas worldwide Up to 56.2% risk of transmission during the intrapartum period; possible breast milk transmission Prematurity Fever Severe dengue (pleural effusion, intracranial hemorrhage, circulatory collapse) 
    Neonatal infection Thrombocytopenia  
     Petechia  
     Deranged liver function tests  
     Hepatomegaly  
RVFV Mosquito (Aedes spp.) Africa and Middle East Rare Uncertain; reports of fever, jaundice, hepatic dysfunction, and DIC N/A N/A 
WEEV Mosquito (Culex spp.) North America Rare Uncertain; reports of encephalitis N/A N/A 
WNV Mosquito (Culex spp.) Worldwide: mainly Africa, Europe, Middle East, North America, and West Asia Rare; breast milk transmission also reported Uncertain; reports of transient rashes and meningitis N/A N/A 
YFV Mosquito (Aedes spp. and Haemagogus spp.) South America, Africa Rare; breast milk transmission also reported Neonatal infection Fever DIC 
     Irritability Seizures and/or encephalitis 
     Jaundice  
ZIKV Mosquito (Aedes spp.) Americas, Africa, and Southeast Asia Rare; breast milk transmission also reported Uncertain: most cases appear to be asymptomatic but reports of brain lesions (eg, subependymal cysts) N/A N/A 
VirusPrincipal VectorGeographical AreaPerinatal TransmissionConsequences of Perinatal TransmissionCommon Clinical Features of Neonatal InfectionUncommon Clinical Features of Neonatal Infection
CHIKV Mosquito (Aedes spp.) United States, Africa, Asia, Australian, and Indian Ocean Up to 50% risk of transmission during intrapartum period Neonatal infection Fever Neurologic manifestations (including seizures and/or encephalopathy) 
     Lethargy and/or irritability Cardiac manifestations (including myocarditis, coronary dilatation) 
     Rash Hemorrhagic manifestations (including DIC, NEC, hemorrhagic fever) 
     Thrombocytopenia Developmental delays 
     Acrocyanosis  
     Hyperpigmentation  
     Petechia  
     Peripheral edema  
CCHFV Tick (>30 species; mainly Hyalomma genus) Middle East, Africa, Asia, and Southeast Europe Rare Uncertain; reports of prematurity, stillbirths, and neonatal infection with hemorrhagic disease N/A N/A 
DENV Mosquito (Aedes spp.) Tropical and subtropical areas worldwide Up to 56.2% risk of transmission during the intrapartum period; possible breast milk transmission Prematurity Fever Severe dengue (pleural effusion, intracranial hemorrhage, circulatory collapse) 
    Neonatal infection Thrombocytopenia  
     Petechia  
     Deranged liver function tests  
     Hepatomegaly  
RVFV Mosquito (Aedes spp.) Africa and Middle East Rare Uncertain; reports of fever, jaundice, hepatic dysfunction, and DIC N/A N/A 
WEEV Mosquito (Culex spp.) North America Rare Uncertain; reports of encephalitis N/A N/A 
WNV Mosquito (Culex spp.) Worldwide: mainly Africa, Europe, Middle East, North America, and West Asia Rare; breast milk transmission also reported Uncertain; reports of transient rashes and meningitis N/A N/A 
YFV Mosquito (Aedes spp. and Haemagogus spp.) South America, Africa Rare; breast milk transmission also reported Neonatal infection Fever DIC 
     Irritability Seizures and/or encephalitis 
     Jaundice  
ZIKV Mosquito (Aedes spp.) Americas, Africa, and Southeast Asia Rare; breast milk transmission also reported Uncertain: most cases appear to be asymptomatic but reports of brain lesions (eg, subependymal cysts) N/A N/A 

N/A, not applicable; NEC, necrotizing enterocolitis.

FIGURE 3

Reported stages and possible outcomes of perinatal transmission of key arboviruses.

FIGURE 3

Reported stages and possible outcomes of perinatal transmission of key arboviruses.

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TABLE 2

Arboviruses With Limited Data on Perinatal Transmission

VirusGeographical AreaGenus; FamilyCurrent Evidence on Perinatal TransmissionRef No(s).
Colorado tick fever virus United States, Canada Coltivirus; Reoviridae One reported case in 1959: a neonate born 6 d after onset of maternal symptoms developed fever and leucopenia, which subsequently resolved. 109  
JEV Southeast Asia, Western Pacific Flaviviridae; Flaviviridae During the 1978 and 1980 outbreaks in India, 9 pregnant women were infected with JEV. Five of them were infected in the third trimester, with 1 infected the day before delivery. One woman infected at 28 wk gestation was lost to follow-up; the rest delivered healthy infants with no signs of infection. There was no routine test for infants, so there was no definitive evidence of the lack of transplacental infection. 110,111  
Sindbis virus Africa, Australia, Asia, Europe Alphavirus; Togaviridae A cohort study in Finland: 2 infected pregnant women delivered stillborn children, including 1 in the 32nd week of pregnancy. There was no statistically significant association between stillbirths and SIMV infection in pregnancy. 112  
Tick-borne encephalitis virus Central and Eastern Europe, Northern Asia Flavivirus; Flaviviridae One reported case in Slovakia: A woman with an infant 37 wk’ gestational age, infected in the peripartum period, gave birth 3 wk later to a healthy newborn. There was no neurologic impairment and there were negative serology results for the infant. 113  
VEEV Central and South America Alphavirus; Togaviridae In 1977, Dr Wenger performed autopsies on 4 infants born to mothers who were infected with VEEV in the third trimester (1 was 2 wk before delivery, and 3 were not as close to delivery). Findings: massive necrosis and hemorrhage of the brain for all 4 infants and signs of resorption of the necrotic tissue for the last 3 infants. No infant survived longer than a week and died of severe respiratory distress syndrome. There was no mention of testing on neonatal samples to confirm perinatal transmission. 114  
VirusGeographical AreaGenus; FamilyCurrent Evidence on Perinatal TransmissionRef No(s).
Colorado tick fever virus United States, Canada Coltivirus; Reoviridae One reported case in 1959: a neonate born 6 d after onset of maternal symptoms developed fever and leucopenia, which subsequently resolved. 109  
JEV Southeast Asia, Western Pacific Flaviviridae; Flaviviridae During the 1978 and 1980 outbreaks in India, 9 pregnant women were infected with JEV. Five of them were infected in the third trimester, with 1 infected the day before delivery. One woman infected at 28 wk gestation was lost to follow-up; the rest delivered healthy infants with no signs of infection. There was no routine test for infants, so there was no definitive evidence of the lack of transplacental infection. 110,111  
Sindbis virus Africa, Australia, Asia, Europe Alphavirus; Togaviridae A cohort study in Finland: 2 infected pregnant women delivered stillborn children, including 1 in the 32nd week of pregnancy. There was no statistically significant association between stillbirths and SIMV infection in pregnancy. 112  
Tick-borne encephalitis virus Central and Eastern Europe, Northern Asia Flavivirus; Flaviviridae One reported case in Slovakia: A woman with an infant 37 wk’ gestational age, infected in the peripartum period, gave birth 3 wk later to a healthy newborn. There was no neurologic impairment and there were negative serology results for the infant. 113  
VEEV Central and South America Alphavirus; Togaviridae In 1977, Dr Wenger performed autopsies on 4 infants born to mothers who were infected with VEEV in the third trimester (1 was 2 wk before delivery, and 3 were not as close to delivery). Findings: massive necrosis and hemorrhage of the brain for all 4 infants and signs of resorption of the necrotic tissue for the last 3 infants. No infant survived longer than a week and died of severe respiratory distress syndrome. There was no mention of testing on neonatal samples to confirm perinatal transmission. 114  

As of April 6, 2020, there were no data on perinatal transmission on the following arboviruses known to infect humans: Barmah Forest disease virus, Chandipura virus, Kyasanur Forest disease virus, La Crosse virus, Mayaro virus, Murray Valley encephalitis virus, O’Nyong-nyong virus, Oropouche virus, Powassan virus, Ross River virus, Santi Louise encephalitis virus, severe fever with thrombocytopenia syndrome virus, Tahyna virus, and Toscana virus. JEV, Japanese encephalitis virus; VEEV, Venezuelan equine encephalomyelitis virus.

With globalization and climate instability increasing the frequency of outbreaks of arbovirus infections, clinicians need to be aware of the clinical features of these infections and the current evidence for management of these pregnancies. Our State-of-the-Art Review is the first to stratify neonatal outcomes from arboviruses in pregnancy into stages, looking specifically at the perinatal period. It has highlighted this time as a risk period because of the barriers between mother and infant becoming more permissive. As such, maternal arbovirus infections during the perinatal period can lead to a range of adverse neonatal outcomes.

To meaningfully improve newborn and maternal health, the most cost-effective strategy is preventive management with avoidance of mosquito and tick bites close to the expected time of delivery. This involves the removal of mosquito breeding sites, wearing of long-sleeved clothing, and use of repellents and mosquito nets. Other recommendations include administration of available immunizations before pregnancy and before travel to endemic areas and close observation of neonates when risk factors have been identified. Systematic studies are required to evaluate the use of tocolytics in these situations, and community-based cohort studies during outbreaks are required to determine the frequency of perinatal transmission of other arboviruses, for which there are no current reports.

Australian governments fund the Australian Red Cross Lifeblood to provide blood, blood products, and services to the Australian community. We thank Dr Joseph Tauro for his review of the article and insightful feedback.

Drs Ginige and Viennet conceptualized the study; Dr Ginige performed the literature review and drafted the initial manuscript; Drs Viennet and Flower critically reviewed and revised the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

FUNDING: No external funding.

     
  • CCHFV

    Crimean-Congo hemorrhagic fever virus

  •  
  • CHIKV

    Chikungunya virus

  •  
  • DENV

    dengue virus

  •  
  • DIC

    disseminated intravascular coagulation

  •  
  • IgM

    immunoglobulin M

  •  
  • RT-PCR

    reverse-transcription polymerase chain reaction

  •  
  • RVFV

    Rift Valley fever virus

  •  
  • WEEV

    Western equine encephalitis virus

  •  
  • WNV

    West Nile virus

  •  
  • YFV

    yellow fever virus

  •  
  • ZIKV

    Zika virus

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

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