Perinatal and Neonatal Chikungunya Virus Transmission: A Case Series

Abstract

Background

Large-scale epidemics in countries with high birth rates can create a concerning scenario where pregnant people are more likely to transmit the virus. In addition, increased international mobility has made arboviruses a growing problem for travelers. The increased risk of vertical transmission has been related to maternal viremia near delivery. Such transmission leads to severe infection of newborns and may be associated with subsequent neurological impairment including cerebral palsy. This case series provides an overview of clinical and laboratory findings in pregnant individuals with confirmed chikungunya virus (CHIKV) infection as well as the clinical effects on their newborn emphasizing the severity of neonatal chikungunya.

Methods

An ambispective case series enrolled newborns with confirmed exposure to CHIKV in utero or in the neonatal period.

Results

During the delivery period, the transmission rate among viremic individuals was approximately 62% (18/29). Fever, irritability, rash, and poor feeding in the first week of life were critical signs of neonatal chikungunya, highlighting its severity.

Conclusion

Close monitoring of healthy newborns during the first week of life is essential in areas affected by CHIKV epidemics, and in offspring of pregnant travelers who visited the outbreaks zones. This case series is intended to increase neonatologists’ awareness of the possibility of mother-to-child transmission of CHIKV among newborns with a sepsis-like presentation. Prioritizing CHIKV vaccination for women of childbearing age should also be considered.

1. INTRODUCTION

In recent decades, the triad of urbanization, globalization, and international mobility have contributed to increased worldwide incidence of arboviruses. Salient examples include dengue, yellow fever, Zika, and chikungunya virus (CHIKV). CHIKV is an alphavirus belonging to the family Togaviridae that is believed to have originated in Africa. However, CHIKV has now spread globally and diversified into three major genotypes: West African, East/Central/South African (ECSA), and Asian [1, 2]. Due to this range expansion, the burden of chikungunya (CHIK) is no longer limited to tropical regions. Currently, CHIK disease is a growing concern for travelers: from 2005 to 2020, the GeoSentinel network recorded 1202 CHIK cases in travelers returning from nearly 100 destinations, with a hospitalization rate of 10.3% [3].

Unlike other arboviruses, such as dengue, the majority of cases are symptomatic, especially in individuals infected with the ECSA lineage [4, 5]. Although children with CHIK typically experience a sudden onset of fever and other symptoms, and their illnesses tend to be shorter than those of adults, severe disease is not exclusive to adults and can occur in newborns. In severe forms of CHIKV infection, particularly during the neonatal period, both human infants and neonatal mice have been shown to mount a robust type I interferon response. However, this strong immune response appears to be insufficient for completely controlling the infection [6].

Vertical transmission of CHIKV was first reported during a large epidemic on Reunion Island in June 2005 [7]. Although fetal infection appears to be extremely rare, the infection rate of newborns from viremic mothers can reach 50%. This is of greatest concern during large epidemics in countries with high natality. In such settings, up to half of cases experience severe disease and encephalopathy/encephalitis possibly followed by neurological sequelae [7]. In the neonate, the most common clinical manifestations are the triad of fever, irritability, and prostration. Other symptoms in order of frequency are peripheral edema, rubeoliform, petechial, and roseoliform rash. Thrombocytopenia, lymphopenia, and hemolysis have also been observed [8]. Hyperpigmentation and fine peeling at the extremities were described in newborns at the end of rash [9].

Little is known about the effects of CHIKV in the perinatal period on neurocognitive development. Encephalopathy/encephalitis is the most common complication in infants with CHIKV infection by vertical transmission [10, 11]. During the large outbreak on Reunion Island, CHIKV was a significant cause of central nervous system disease. During that epidemic, the case-fatality rate of CHIKV-associated encephalopathy/encephalitis was 16.6% and the proportion of children discharged with persistent disabilities was estimated between 30% and 45% [10]. Beyond the neonatal period, the clinical presentation and outcomes were less severe in infants than in adults [10].

To complement important studies conducted on Reunion Island, it is also valuable to characterize maternal–neonatal CHIK infection in other geographic regions. Therefore, this case series examines the clinical and laboratory presentation of CHIKV-exposed neonates in Brazil. Investigating this population has the potential to broaden the available data about CHIKV infection in mother–infant dyads. It is hoped that this will contribute to a more robust evidence base on which neonatologists, including those practicing in nonendemic areas, can draw to diagnose and treat these infections.

2. PATIENTS AND METHODS

This ambispective (prospective and retrospective) case series was conducted at the Maternal Fetal Medicine Department of a public hospital, the Hospital Universitário Gaffrée e Guinle (HUGG) affiliated with the Universidade Federal do Estado do Rio de Janeiro (UNIRIO). We enrolled newborns with confirmed exposure to CHIKV in utero or in the neonatal period between March 2016 and August 2020.

Pregnant people were monitored during prenatal care, at the time of delivery, and postpartum during hospitalization in the maternity ward. If they had fever and/or arthralgia and/or rash, they were tested by reverse transcriptase polymerase chain reaction (RT-PCR) and/or CHIKV monoclonal antibody IgM capture ELISA testing. Clinical signs and symptoms of CHIKV infection in newborns up to 28 days of age such as fever, neurological manifestations (seizure, irritability, and hypoactivity), and rash were monitored and RT-PCR or IgM serology for CHIKV was done.

The study protocol was approved by the Ethics Committee of Fiocruz (IRB number 62557316.3.0000.5248) and the Gaffree and Guinle University Hospital (IRB number 62557316.3.3001.5258). Written informed consent was obtained from all participants. Patient-specific information has been de-identified.

The diagnosis of neonatal CHIKV infection was based on RT-PCR detection of the viral genome in the neonate’s serum, cerebrospinal fluid (CSF), and urine and/or anti-CHIKV IgM in serum and CSF during the first 28 days of life. The diagnosis of maternal CHIKV infection was based on RT-PCR detection of the viral genome in maternal serum, or urine, or placenta; or anti-CHIKV IgM in serum. Cases of mother-to-child transmission of CHIKV infection were defined as neonates with CHIKV infection in the first week of life, whose mothers tested positive by RT-PCR or anti-CHIKV IgM within 7 days before or 2 days after delivery.

For each mother–infant dyad, we report demographic and clinical data (maternal age, neonatal sex, gestational age at delivery, birth weight, and 1- and 5-min Apgar scores), mode of delivery, laboratory and imaging anomalies, adverse perinatal and neonatal outcomes (spontaneous abortion (< 20 weeks of gestation), still birth (≥ 20 weeks of gestation), maternal death, fetal heart rate abnormalities, low birth weight, preterm delivery, and congenital malformations), and the timing and severity of CHIK symptoms.

This study was structured according to the CARE case report guidelines.

3. RESULTS

Between March 2016 and August 2020, this study included 58 pregnant people and their 58 newborns. Of the 58 infected pregnant people, 39 experienced symptoms during the third trimester, with 27 experiencing symptoms within a week before or 3 days after delivery. Of the 39 pregnant people infected during the third trimester and 2 asymptomatic pregnant people, 18 newborns subsequently tested positive for CHIKV, resulting in a vertical transmission rate of 46%. In the subgroup of pregnant people who were viremic near delivery, the vertical transmission rate was 62% (18/29) (Figure 1). Two cases of neonatal CHIKV infection were characterized as postnatal and confirmed as mosquito-borne transmission. Only one case of neonatal CHIKV infection by vertical transmission was asymptomatic. The others were severe cases that required admission to the Neonatal Intensive Care Unit (NICU). Among newborns who had intrauterine CHIKV exposure but did not test positive for CHIKV during the first week of life, 9 (21.9%) developed severe illness and were admitted to the NICU (Figures 1 and 2).

Figure 1.

Study population: 58 pregnant people positive for CHIKV: RT-PCR positive and/or IgM positive; infants symptomatic confirmed: RT-PCR and/or IgM positive (n = 17); infants symptomatic not confirmed: RT-PCR and/or IgM negative (n = 9); and infants asymptomatic: RT-PCR and/or IgM negative (n = 29) and RT-PCR and/or IgM positive (n = 1).

Figure 2.

Flowchart of newborns exposed to CHIKV.

3.1 Clinical and Perinatal Characteristics of Pregnant People

Among 58 pregnant people enrolled in the study, 98% (n = 57) had clinical signs and symptoms of CHIKV as well as laboratory-confirmed CHIKV infection, 29% (17/58) of whom were positive by RT-PCR and 68% (40/59) by ELISA. Two (3.5%) participants were asymptomatic and did not have confirmed CHIKV infection. However, their newborns were symptomatic, and their laboratory tests confirmed CHIKV infection. Three pregnant people in the postnatal period experienced symptom onset within 48–72 h after childbirth. They remained hospitalized in the maternity ward for continued hypertension management. The mean age of the pregnant people was 23 years, 74.5% were non-white, and none had private insurance.

There were no cases of spontaneous abortion, stillbirth, congenital birth defects, or maternal death. C-section was indicated by fetal distress (15%; n = 9/58). In 33% (n = 20/60) of cases, newborns presented clinical and laboratory findings of CHIK fever. Most births (n = 53/58; 88%) were full-term (GA > 37 weeks), with birth weight > 2,500 g (n = 55/58; 95%) and the most frequent mode of delivery was by C-section (n = 31; 53%). Infections occurred in the first trimester in 15.5% (n = 9/58) of women exposed to CHIKV, in the second trimester in 14% (n = 8/58), and in the third trimester 67% (n = 39/58). Approximately 5% (n = 3/58) of women showed clinical signs compatible with CHIKV fever (48–72 h postpartum). The main maternal signs and symptoms observed were arthralgia (n = 48, 81%), rash (n = 46, 78%), fever (n = 45, 76%), and arthritis (n = 16, 27%) (Tables 1 and 2).

Table 1.

Demographics of Pregnant Participants Infected with CHIKV at a University Hospital During an Epidemic in Rio de Janeiro, Brazil, 2016–2020 (n = 58)

Maternal Demographics (N = 58)
Maternal age, median (range)	23.2 (16–41)
Maternal Race
Black or mixed race	43 (74%)
White	15 (25.5%)
Highest Maternal Educational Level
Primary school	18 (30.5%)
Secondary school	29 (51%)
Higher education	11 (18.5%)
Timing of Onset of Maternal CHIKV Symptoms
First trimester	9 (15.5%)
Second trimester	8 (14%)
Third trimester	39 (67%)
Clinical Signs and Symptoms
Any symptoms	57 (96.5%)
Arthralgia (non-inflammatory joint pain)	48 (81%)
Rash	46 (78%)
Fever	45 (76%)
Arthritis (inflammatory joint pain)	16 (27%)
Myalgia	8 (13.5%)
Pruritus	4 (7%)
Cholestasis	3 (5%)
Asymptomatic	2 (3.5%)
Comorbidities
Any comorbidity	18 (30.5%)
Preeclampsia	6 (10%)
Hypertension	3 (5%)
Urinary tract infection	4 (7%)
Diabetes	2 (3%)
Hashimoto’s disease	2 (3%)
Epilepsy	1 (1.5%)
Placenta previa	1 (1.5%)
Rheumatic arthritis	1 (1.5%)
Urinary sepsis	1 (1.5%)

CHIKV—chikungunya virus.

Table 2.

Perinatal and Neonatal Outcomes Among Pregnant People Infected with CHIKV at a University Hospital During an Epidemic in Rio de Janeiro, Brazil, 2016–2020 (n = 58)

Median Gestational Age at Delivery (Range)	38 (34–42)
Preterm < 37 weeks (N = 58)	7 (12%)
Sex assigned at birth female (N = 58)	32 (53%)
Mode of Delivery (N = 58)
Cesarean	31 (53.5%)
Spontaneous vaginal delivery	27 (46.5%)
Spontaneous abortion, stillbirth	0
Maternal death	0

CHIKV—Chikungunya virus.

3.2 Clinical Characteristics of Newborns

Of the 60 newborns recruited, 58 had confirmed exposure to CHIKV in utero. Two newborns, recruited at 21 and 28 days of age, exhibited clinical and laboratory evidence of viral infection. Without confirmed maternal infection, these cases were classified as postnatal, likely resulting from mosquito-borne transmission. The main clinical manifestations of newborns exposed to CHIKV were hypoactivity and weak suction (n = 15; 25%), followed by fever (n = 13; n = 22%), seizure and encephalitis (n = 9; 15%), rash (n = 11; 18%), respiratory distress (n = 11; 18%), irritability (n = 7; 12%), hyperchromia (n = 7; 12%), vesicobullous lesions (n = 7; 12%), apnea (n = 5; 8%), and low weight gain (n = 3; 5%). Some of the cutaneous features were observed during the acute stage and others during convalescence. Pigmentary changes including “CHIK sign” (hyperpigmentation in the nose), were found to be the most common cutaneous finding and it is more evident during convalescence, followed by maculopapular eruption and vesiculobullous lesions, which are more characteristic in the acute phase of the disease (Figure 3). The clinical manifestations observed in newborns who had laboratory-confirmed CHIKV infection are shown in Table 3. In 15.5% (n = 9/58) of the newborns exposed to the virus, but not infected, clinical manifestations were due to prematurity, suspected neonatal sepsis, and respiratory distress at birth, however, we cannot rule out perinatal transmission of CHIKV because it may have occurred a false negative on diagnostic tests. Fully 59% (n = 34/58) of the newborns were asymptomatic. The most common laboratory findings were thrombocytopenia and lymphopenia. Approximately one-third (n = 22) of neonates with intrauterine CHIKV exposure exhibited clinical signs and symptoms of CHIKV in the first week of life, and 91% of these neonates (n = 20) were admitted to the NICU due to neonatal sepsis.

Figure 3.

Clinical manifestations of CHIKV infection in neonates. (A) Post chikungunya pigmentary disorder, (B) chik sign, (C) scaled skin syndrome like presentation, (D) irritability and crusty perioral lesions, (E) roseoliform rash and respiratory distress, and (F) vesicolobullous lesions.

Table 3.

Clinical Manifestations Among CHIKV-Infected Newborns (n = 20) at a University Hospital During Epidemics in the Period of 2016–2020 in Rio de Janeiro

	Clinical Manifestations	N (%)
Neurological	Hypoactivity Irritability Weak suction Seizure Encephalitis	14 (70)
Fever		11 (55)
Dermatological	Rash Hyperpigmentation Vesicobullous lesions	10 (50)
Respiratory	Apnea Respiratory failure	9 (45)
Hematological	Thrombocytopenia Disseminated intravascular coagulation	8 (40)
Muscular	Hyperalgesia	5 (25)
Cardiovascular	Hemodynamic instability	1 (5)
Total number of children with CHIKV infection		20 (33)

CHIKV—Chikungunya virus.

Radiological exams were performed to evaluate the central nervous system using transfontanelle ultrasound with Doppler (88.3%; n = 53), which showed changes in 5.6% of the exams with indirect signs of hypoxic-ischemic encephalopathy.

Cerebral magnetic resonance imaging (MRI) was performed for 65% (n = 13) of symptomatic newborns and was altered in 38.4% (n = 5) of the cases. The five neonates were diagnosed with encephalopathy based on International Encephalitis Consortium criteria [12]: hypoactivity lasting more than 24 h; fever ≥ 38°C within 72 h after hospitalization; seizures; abnormalities in brain MRI scans; and abnormalities in electroencephalograms. The CSF analysis revealed no pleocytosis or elevated protein levels, but the CHIKV genome was identified (ECSA). The changes observed were compatible with areas of restricted diffusion in the subcortical white matter of both hemispheres and in the corpus callosum in exams performed in the acute phase of the disease (up to 2 weeks after infection) and the presence of areas of cystic cavitation with perivascular distribution in the subacute phase or in chronic disease (after 2 weeks of infection). In three children retained in follow-up, a reduction was observed in the volume of cavitations, and areas of restricted diffusion were resolved [13] (Table 4, Figure 4).

Table 4.

Clinical and MRI Follow-Up Characteristics of Three Newborns with CHIKV Encephalitis at a University Hospital During Epidemics in the Period of 2016–2020 in Rio de Janeiro

	Case 1	Case 2	Case 3
Neonate sex	Female	Female	Female
Gestational age at the onset of maternal symptoms	36 weeks	37 weeks	38 weeks
Clinical and laboratory diagnosis of maternal CHIKV	Fever and rash Positive IgM	Fever and arthralgia Positive RT-PCR	Fever and rash Positive IgM
Delivery	Caesarean	Caesarean	Vaginal
Gestational age at birth	36 weeks	38 weeks	38 weeks
Onset of neonatal symptoms	4 days	5 days	6 days
Neonatal age at first brain MRI	17 days	30 days	25 days
First MRI findings	Subcortical cavitations in the frontal and parietal lobes and areas of restricted diffusion throughout the corpus callosum	Subcortical cavitations in the frontal and parietal lobes with perivascular distribution, without areas of restricted diffusion with thinning of the corpus callosum	Discreet focus of hemorrhage in the right parietal lobe with normal myelination for age
Follow-up brain MRI (interval between MRI)	Normal corpus callosum, regression of subcortical cavitations (2.5 months)	Regression of subcortical cavitations (1 year and 4 months)	Persistence of cerebral hemorrhage focus with normal evolution of myelination (10 months)

Neuroradiol J. 2020 Dec; 33(6):532–7 [14].

CHIKV—Chikungunya virus; MRI—Magnetic resonance imaging; RT-PCR—Real-time polymerase chain reaction.

Figure 4.

Brain magnetic resonance imaging (MRI) showing restricted diffusion in the corpus callosum (arrows in (A)), associated with subcortical vasogenic edema (arrows in (B)), and cavitations in the frontal and parietal lobes, suggesting a perivascular distribution (arrows in (C)). Follow-up brain MRI, in the third month of life demonstrated thinning of the corpus callosum (arrow in (D)), without restricted diffusion (E) and that the cavitation had shrunk and the subcortical lesions had improved (arrows in (F)) [1, 13].

4. DISCUSSION

We report the clinical, laboratory, and radiological features of perinatal and neonatal CHIKV infection. Among the 60 newborns recruited, 97% (n = 58) exhibited evidence of in utero CHIKV exposure. Fully 31% (n = 18) developed laboratory-confirmed CHIKV infection, reflecting a perinatal transmission rate of 62%, which surpasses the reported range of 28–50% [7, 14–16]. The role of the placenta in CHIKV transmission is not fully understood. It is believed that vertical transmission can occur via the direct infection of trophoblasts or syncytiotrophoblasts, as well as from breaches of the trophoblast layer or via paracellular transport from maternal blood to fetal capillaries [17]. We observed that vertical transmission occurred regardless of the mode of delivery, almost always occurring during maternal viremia in the peripartum period, as shown in studies from Reunion Island [7].

In this study, 12% of neonates with CHIKV were born preterm, which is higher than a study in India (7.3%), but lower than a study in Sudan [18, 19] (14%). Studies from Reunion Island [20, 21] reported that CHIKV is not associated with an increased risk of perinatal complications, like prematurity, stillbirth, congenital anomalies, and low birth weight [15, 20], which is compatible with our results.

In this population, almost all infected neonates were born to mothers with peripartum viremia, and most newborns exposed to CHIKV were healthy at birth, but developed clinical manifestations in the first week of life. We can conjecture that this was attributable to peripartum transmission. This means that all children exposed to antepartum in the first and second trimesters should have been protected against mother-to-child perinatal transmission and postnatal transmission of CHIKV because a strong IgG maternal antibody response transfers protective neutralizing antibody to the fetus still in utero [22].

In this case series, the severity of neonatal illness ranged from asymptomatic infection to life-threatening disease affecting multiple organ systems. Given that there were only nine maternal infections during the first trimester, and the natural prevalence of congenital defects is close to 3%, our study did not allow us to detect any birth defect [23].

The predominant clinical manifestations were related to neonatal sepsis: hypoactivity, irritability, difficulty nursing, apnea, and respiratory failure. Most newborns exhibited fever, rash, vesicobullous lesions, hyperpigmentation, and neurological manifestations. Seizures were the main neurological manifestations found in these newborns and may have been due to encephalitis and intracranial hemorrhage, as reported elsewhere [15]. Some neonates presented with severe vesicobullous lesions highly suggestive of CHIKV infection [24]. While staphylococcal scalded skin syndrome was initially considered, the absence of Staphylococcus aureus in cultures confirmed a primary association with CHIKV.

In our study, CHIKV neonatal infection was frequently associated with neurological complications. This finding is compatible with a recent systematic review that analyzed 94 publications with cases of neurological complications due to CHIKV. According to the review, disorders of the nervous system appeared to be the most common severe complication [25]. They found 856 cases of CHIKV-associated neurological disease: including 60 cases of vertical transmission [25]. In another systematic review, 42 pregnancies with vertical transmission due to neurological complications of CHIKV were analyzed and neurological findings were the most common complication reported in 57% of studies [11]. Fourteen (70%) of our infected newborns had seizures, hypoactivity, and irritability. In this study, we tested CSF from five newborns. Although the specimens were all positive for CHIKV by RT-PCR, white blood cell counts and biochemistries were normal. Similarly, in a study on Reunion Island, nine neonates with encephalitis/encephalopathy had normal biochemistry and white cell counts, and the virus was detected in five of the babies [26]. Among the newborns exposed in utero to CHIKV, 10% (n = 4/40) had neurological manifestations including irritability and hypoactivity, but the presence of CHIKV could not be confirmed because CSF was not tested. Our imaging studies suggested that perinatal CHIKV infection was associated with encephalitis/encephalopathy. Severe white matter injury is well characterized in a three-stage pattern comprising ischemia, reperfusion, and demyelination [26]. In our study, MRI was indicated for children with positive RT-PCR and/or IgM or in cases with neurodevelopmental delay during follow-up.

The first case of this series had prolonged neurological involvement of CHIKV infection, detected by RT-PCR in the infant’s CSF 2 months after birth. We describe an atypical and severe case of laboratory-confirmed CHIKV infection with cutaneous and neurological manifestations in infants from the sixth day to the second month of life. The nature of CHIKV persistence and how it is related to chronic disease are not known [27]. The mechanism by which the virus affects the nervous system has not been fully elucidated. Many questions are still unanswered, such as: how certain patients develop neurological disease after CHIKV infection and others do not, whether the virus acts directly or indirectly toward neurons and if the process differs in the central nervous system and peripheral nervous system; and the significance of the phylogenetic strain and factors driving placental transmission [25].

There is no specific treatment for CHIK. Supportive management includes close monitoring of vital signs and maintenance of adequate intravascular volume.

A limitation of this study is the potential underdiagnosis of CHIKV infection in neonates due to challenges in sample collection and viremia detection. This is particularly relevant during epidemic periods when newborns with symptoms resembling neonatal sepsis may be overlooked. Despite the small sample, our case series provides valuable insights into the clinical and laboratory features of maternal and neonatal CHIK. The findings underscore the potential severity of CHIKV neonatal infection, emphasizing the need for vigilant monitoring of healthy newborns during the first week of life, especially in resource-constrained environments with limited diagnostic capabilities. In addition, this study expands the limited knowledge base on the clinical presentation of confirmed CHIKV infection in newborns, providing pediatricians with a more comprehensive understanding of maternal-neonatal CHIK, which is crucial for effective disease management and prevention of complications.

A key strength of this study includes its unique setting in a country with a high birth rate and its conduct during epidemic outbreaks. Prioritizing vaccination for women of childbearing age before pregnancy in this scenario is a critical step toward optimal protection for mothers and newborns. Vaccination should be a key focus once a vaccine is approved in endemic countries.

In addition, enhanced surveillance of CHIKV infection including IgM testing and real-time PCR of pregnant people and newborns during the peripartum period allowed for accurate estimation of perinatal transmission rate during epidemics. Given the limited available research, we believe this study makes a significant contribution to the field.

5. CONCLUSION

During the delivery period, the rate of transmission for people who are viremic found in our study was close to 62%, the highest ever described. Despite appearing healthy at birth, in the first week of life, neonates with CHIKV often develop sepsis-like conditions leading to NICU admission. In light of early signs of CNS involvement, neonates with suspected CHIKV infection should be followed up for at least 2 years for evidence of neurodevelopmental delay. Future work should aim to elucidate the pathophysiology mechanisms of neurological complications to improve supportive management strategies.

Financial support. This work was supported by grants from the Fundação Carlos Chagas de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ (CNE) E-26/200.935/2022); FAPERJ (Emergentes) E-26/010.002424/2019—Grant 101137283; and Centro Nacional de Pesquisa (CNPQ-311562/2021-3).

Potential conflicts of interest. The authors have no conflicts of interest to disclose.