Keywords Zika virus - prenatal ultrasound - fetal arthritis - Dandy–Walker malformation - single
umbilical artery - congenital Zika virus syndrome - neonatal demise - prolonged maternal
Zika virus seropositivity - perinatal universal precautions
Zika virus (ZIKV) presents an unprecedented public health challenge as the first mosquito-borne
and sexually transmitted virus that has been associated with human birth defects and
fetal losses.[1 ] The first cases of this public health emergency of international concern were reported
from South America in 2015, although retrospective studies have since confirmed that
ZIKV was responsible for the outbreak in Micronesia in 2007 and epidemics in various
Pacific islands in 2013 and 2014. Brazil has been most affected thus far with over
2,100 cases of ZIKV-attributed neonatal microcephaly, but severe birth defects linked
to ZIKV infection have been reported in almost 30 countries. As of February 15, 2017,
ZIKV has been linked to 5,040 reported cases of travel-associated infections, including
1,455 pregnant women, in the United States; Puerto Rico is experiencing explosive
spread of this epidemic with approximately 37,000 locally acquired cases, while Florida
has 214 cases of locally acquired mosquito-borne ZIKV infections in Miami, and Texas
6 cases in Brownsville.[2 ]
[3 ] Forty-three liveborn infants with birth defects and five pregnancy losses with birth
defects have been documented in the United States thus far. Sexual transmission of
ZIKV can occur from both male and female partners; the virus may be able to persist
in vaginal secretions for 2 weeks after infection, and in semen for up to 6 months.
ZIKV has clinical manifestations in adults that overlap with chikungunya and dengue
viruses—namely, fever, malaise, rash, arthralgia, and conjunctivitis—but is self-limited
in the vast majority of adult cases, causing the Centers for Disease Control and Prevention
(CDC) to call this a silent epidemic.[1 ] It has been associated with the rare Guillain–Barre syndrome in affected adults,
but its most worrisome effects are on the human fetus when the pregnant woman is infected,
particularly in the first half of gestation. Prior studies have confirmed the association
between ZIKV infection during pregnancy and serious birth defects, including microcephaly.
The risk of microcephaly after ZIKV infection early in pregnancy may be between 1
and 13%.[4 ] Ongoing studies are exploring the full spectrum of the congenital ZIKV syndrome.
We present the first case of neonatal demise with travel-associated ZIKV infection
in the United States, including a novel fetal ultrasound finding and pathological
analyses.
Case Presentation
In March 2016, a young Latina primigravida presented to our health care system in
Southeast Texas to initiate prenatal care at 23 weeks of gestation. The routine evaluation
was only remarkable for body mass index of 35 kg/m2 . She had an initial screening prenatal ultrasound examination at 26 weeks, which
was remarkable for ([Fig. 1 ]).
Fig. 1 Prenatal ultrasound findings at 26 weeks: (A ) Dandy–Walker malformation, ventriculomegaly, (B ) hypoechoic right knee, and (C ) dorsal right foot edema.
Fetal Dandy–Walker malformation
Asymmetrical fetal cerebral ventriculomegaly without microcephaly
Hypoechoic right fetal knee
Dorsal right fetal foot edema
Single umbilical artery
Mild polyhydramnios (amniotic fluid index: 24.3 cm)
Syndromic etiology was suspected, and genetic counseling recommended amniocentesis,
referral to the Fetal Center for multidisciplinary evaluation and fetal magnetic resonance
imaging (MRI)—which were all declined. Cell-free placental DNA in the maternal circulation
was negative for major aneuploidies. The pregnancy continued with sporadic care (gravida
missed several appointments, but desired full resuscitation of the infant at birth).
In June 2016, the parturient presented to our institution at 36 weeks with an 11-hour
history of vaginal leaking of amniotic fluid and painful contractions. Nonreassuring
fetal heart tones, rupture of membranes with thick meconium and frank breech presentation
were noted upon emergency obstetrical evaluation, and an urgent cesarean delivery
was performed. A growth-restricted, microcephalic, and arthrogrypotic female infant
was delivered alive and immediately resuscitated by neonatologists. Despite advanced
resuscitation, adequate ventilation could not be obtained. The Apgar score was 2/10
at 1 minute, 1/10 at 5 minutes, 1/10 at 10 minutes, 1/10 at 15 minutes, and 0/10 at
20 minutes; the neonate was pronounced dead 31 minutes after delivery.
The placenta had no gross abnormality; the umbilical cord had a single umbilical artery.
The umbilical arterial blood gas had a pH of 7.25 and base deficit of 2 mmol/L. The
birth weight was 1,885 g (1st percentile), the crown to heel length was 46.5 cm (50th
percentile), and the fronto-occipital circumference was 28.5 cm (< 1st percentile).[5 ]
[6 ]
[7 ]
Breaking fetal imaging data from Brazil[8 ] were combined with the prenatal sonographic and neonatal findings triggering clinical
suspicion. Therefore the puerpera was approached on the first postoperative day with
direct questions regarding possible ZIKV exposure. Upon revisiting her travel history,
she disclosed for the first time that she had reached Texas via bus from El Salvador
in January 2016, during the first half of pregnancy; her husband remained in El Salvador,
and she denied physical contact with him or other sexual activity since her arrival
in Texas. She denied ZIKV infection symptoms but consented to serologic screening
and the infant's autopsy with appropriate genetic and virologic testing. The puerpera
grieved her loss, but recovered well physically from her abdominal delivery and was
discharged from the hospital on the third postoperative day. She provided written
consent for the publication of this report.
Cytogenetic analysis of cultured fibroblasts obtained from the left neonatal patellar
tendon demonstrated normal female karyotype, 46XX [Table 1 ], [Fig. 2 ].
Table 1
Pathology findings
Autopsy
External findings
Microcephaly, arthrogryposis
Misshapen/collapsed auricular tragi bilaterally ([Fig. 2A ])
Hyperflexed wrists, extended arms; decreased musculature
Shortened forearms and forelegs
Fingers elongated bilaterally; shortened thumbs
Bilateral hands without identifiable palmar creases ([Fig. 2C ])
Legs extended at knees, flexed at hips; decreased musculature
Bilateral foot edema ([Fig. 2B ])
Hypertrichosis of fine downy hair on extremities and back
Internal findings
Heart, outlet ventricular septal defect (5 × 5 mm)
Pulmonary hypoplasia; the lung-to-body weight ratio was low: 0.012
Well-formed kidneys; duplicate right renal artery
Bicornuate uterus
Neuropathology
Immature brain, 175 g with microcephaly
Asymmetry, with smaller right cerebrum, malformation of cerebral cortical development
with agyria/pachygyria of bilateral temporal and right frontoparietal lobe ([Fig. 2D ]), and subarachnoid glioneuronal heterotopia
Asymmetric ventriculomegaly ([Fig. 2E ])
Dandy–Walker malformation with large posterior fossa fourth ventricular cyst, and
near-complete agenesis of the cerebellar vermis ([Fig. 2F ])
Bilateral cerebellar cortical dysplasia, extensive, lateral parts of the hemispheres;
focal cerebellar cortical heterotopia in the white matter
Dystrophic calcification, multifocal: cerebral periventricular, thalamus, and midbrain
Diffuse reactive astrocytosis, cerebral/cerebellar white matter
Placental pathology
Placenta weight: 306 g, 16 × 16 × 3 cm
Membranes: Meconium-laden macrophages, minimal acute inflammation
Umbilical cord: single vessel vasculitis, focal acute funisitis, moderately coiled,
22 cm long
Villi: Accelerated maturation, increased karyorrhexis
Fig. 2 Neonatal phenotype and pathology. (A ) Lateral view of newborn demise, showing microcephaly, arthrogryposis, and collapsed
auricular tragus. (B ) Close-up view of the right hand showing elongated fingers, shortened thumb, and
absent palmar creases. (C ) The lateral view is showing arthrogryposis, decreased musculature, shortened forelegs,
and redundant dorsal foot skin. (D ) Basilar view of the neonatal brain at autopsy showing asymmetry, with smaller right
cerebrum and disruption of cerebral cortical development with agyria/pachygyria of
bilateral temporal and right frontoparietal lobes. (E ) Coronal section of the neonatal brain showing asymmetric ventriculomegaly. (F ) Dorsal view of the neonatal cerebellum showing Dandy–Walker malformation with near-complete
agenesis of the vermis.
The Texas Department of State Health Services was alerted to the maternal travel history.
Maternal blood was collected for flavivirus IgM antibody testing with enzyme-linked
immunosorbent assay. Umbilical and neonatal brain tissue specimens were also collected
and formalin-fixed. Maternal serology was positive for flavivirus IgM. The CDC was
contacted to process the specimens from the neonatal autopsy by real-time reverse-transcriptase
polymerase chain reaction (rRT-PCR). The ZIKV NS-5 gene was identified by rRT-PCR
in the umbilical cord, near its placental origin, and in the neonatal brain[9 ] in August 2016. The young Latina could no longer be reached for viremic testing
at that point.
Discussion
We report the first case of neonatal demise related to travel-associated ZIKV infection
in United States.[10 ] This case is remarkable for atypical fetal/neonatal neuropathology, growth restriction,
late-onset microcephaly, funisitis of a two-vessel umbilical cord, and arthrogryposis
with pulmonary hypoplasia—as well as the previously unseen prenatal sonographic finding
of the hypoechoic fetal knee. We speculate that this case resulted from asymptomatic
maternal ZIKV infection in El Salvador, during the first half of gestation (late 2015).
The timing of this woman's presentation (soon after the first reported clinical description
of ZIKV embryopathy, before the implementation of systematic screening for travel
history in our health care system), her decision to forego fetal MRI and amniocentesis
despite counseling, her sporadic prenatal care and the atypical prenatal sonographic
findings all contributed to the absence of clinical suspicion for ZIKV infection until
postnatally. In fact, if it were not for the serendipitous review by one of the authors
(N.Z.) of the May 2016 webinar[8 ] wherein Dr. Pedro Piris' breaking fetal imaging data from Recife, Brazil, were presented
regarding the association of ZIKV with Dandy–Walker malformation and ventriculomegaly
without microcephaly, this case may well have gone undiagnosed. Two seminal articles
published since this case, provide an atlas of neuroimaging findings in ZIKV embryopathy—including
a single case with comparable presentation[10 ]—and a more crystallized delineation of the congenital ZIKV syndrome.[11 ]
To our knowledge, this is the first reported case of hypoechoic fetal knee, thought
to represent inflamed epiphyseal cartilage and/or synovium with joint effusion, in
general—and in association with ZIKV embryopathy, in particular. One may speculate
as to the association of this novel prenatal sonographic finding with this fetal viral
pathogen—however, the unprecedented nature of both conditions makes random coincidence
extremely unlikely. ZIKV shares clinical characteristics and tropisms with other flaviviruses,
such as chikungunya, and is known to cause arthralgia in adults, therefore, at least
transient fetal arthritis/effusion is not only biologically plausible, but also likely
in the pathogenesis of ZIKV embryopathy and (along with neuromuscular pathology) may
contribute to the end-result of fetal arthrogryposis—increasingly recognized as a
hallmark of the congenital ZIKV syndrome. The pathogenesis of arthrogryposis associated
with ZIKV embryopathy is thought to be due to a neurogenic or vascular insult. Tropism
of ZIKV for fetal mesenchymal cells with an affinity for perichondrium has recently
been reported[12 ]; we speculate that this viral affinity may underlie the collapsed auricular cartilage
and the novel sonographic marker of hypoechoic fetal knee noted in this case.
The edema of the fetal dorsal foot (“Oedipus sign”—Greek for swollen foot) has been
previously described in association with fetal Turner, Neu–Laxova, and Pena–Shokeir
syndromes. Neonatal karyotype and physical examination excluded these fetal syndromes;
arthrogryposis was confirmed at delivery, likely resulting in pulmonary hypoplasia
in this perinatally lethal case of congenital ZIKV syndrome.
The funisitis with ZIKV-positive focus near the placental origin of the umbilical
cord is noteworthy and indicates ongoing Zika viremia in the fetoplacental circulation
at delivery. This is in accord with recent evidence that the fetus may act as a reservoir
of ZIKV causing repetitive maternal reinfection throughout gestation[13 ]—and could explain the persistent maternal flavivirus IgM seropositivity, in this
case, over 5 months after the estimated time of maternal ZIKV infection.
In summary, this first perinatally lethal case of congenital ZIKV syndrome in United
States presented with atypical and novel prenatal sonographic findings, which may
prove useful in tracking and diagnosing new cases of this global epidemic—and could
have remained undiagnosed, if travel history and correlation with emerging data from
Brazil had not been clinically combined to trigger pathological examination of the
placenta and neonatal tissues. As a result of this case, our hospital has instituted
a policy of storing all placentas for 72 hours, to allow for their pathological examination
should any indications arise. Our perinatal staff (mostly women of reproductive age)
have been alerted to this case, and urged to meticulously observe universal precautions
around pregnant women under our care (most are Latinas, many with unclear ZIKV exposure
status due to personal and/or partner travel history), to minimize the risk of viral
transmission by body fluids. Physician and health care system vigilance are required
to address this significant and enduring global health threat optimally.
