Keywords
cytomegalovirus - intraventricular hemorrhage - fetal ultrasound - prenatal diagnosis
- congenital infection
Cytomegalovirus (CMV) infection is one of the most common antepartum viral infections,
complicating 0.2 to 2.2% of all pregnancies.[1] Risk of vertical transmission is estimated to be 35 to 40% and can be associated
with significant fetal and neonatal sequelae.[1] Common fetal findings include growth restriction, echogenic bowel, ventriculomegaly,
periventricular calcifications, microcephaly, and hydrops.[2]
[3] Although the risk of vertical transmission after maternal primary CMV infection
increases with advancing gestational age, earlier infection increases the risk of
symptomatic neonates at birth.[1]
Intraventricular hemorrhage (IVH) is a significant cause of neonatal neurologic injury
seen in the setting of preterm birth.[4] The pathogenesis of IVH is attributed to the fragility of the germinal matrix and
instability of cerebral blood flow seen in prematurity.[5] IVH affects approximately 3 to 25% of infants born prior to 32 weeks.[4] Outside of preterm birth, antenatally diagnosed IVH is very uncommon, with only
240 identified cases in published literature from 1980 to 2019.[5] More specifically, prenatal diagnosis of IVH has rarely been reported in the setting
of congenital CMV infection. This report presents a case of fetal CMV-associated IVH,
including the antenatal presentation, diagnostic challenges, management strategies,
and subsequent outcomes. We aim to enhance the understanding of this rare condition,
highlighting the complexities and intricacies associated with precise prenatal diagnosis
and management.
Case Description
Thirty-three-year-old G2P1001 presented with preterm labor and vaginal bleeding at
27 weeks gestation. She reported a low-grade fever for several days prior to presentation
with an otherwise negative review of systems. This pregnancy was conceived by in vitro
fertilization (IVF) with a donor embryo and assessment of fetal anatomy at 20 weeks
did not identify any abnormalities. Her prior pregnancy, also conceived with IVF,
was uncomplicated and resulted in a full-term delivery. That child, now 2 years old,
was healthy and in daycare. On the initial exam, she was well-appearing with mild
discomfort with contractions. A sterile vaginal exam noted the cervix to be 3 cm dilated
and 50% effaced with the head at −3 station, and she was noted to have frequent contractions
and a reassuring fetal heart rate tracing. She was admitted to the antepartum unit
and administered magnesium sulfate for neuroprotection, indomethacin for tocolysis,
betamethasone for fetal lung maturity, and ampicillin for group B Streptococcus prophylaxis.
She continued to have vaginal bleeding and contractions over the next 24 hours with
progression of her cervical dilation to 5 cm after which time her contractions decreased
and her cervical exam remained stable. Initial ultrasound showed normal fetal growth,
normal fluid, and no evidence of abruption. Heterogeneous echogenic material was seen
in the lateral ventricles suspicious for IVH (left greater than right). Echogenic
material was also seen in the third ventricle. There was no ventriculomegaly or dilation
of the third ventricle, midline shift, mass effect, or parenchymal abnormalities.
Middle cerebral artery peak systolic velocity was elevated at 1.99 multiple of the
median (MoM) suggesting moderate to severe fetal anemia Initial evaluation included
an infectious workup for CMV, parvovirus, toxoplasmosis, herpes simplex virus, and
a platelet antibody screen. Due to suspected fetal anemia, plans were made to perform
percutaneous umbilical cord blood sampling (PUBS) the following day with intrauterine
transfusion (red blood cells and/or platelets) if indicated. However, overnight the
patient's contractions increased in frequency and she developed a persistent category
II fetal heart rate tracing with recurrent variable decelerations, so the decision
was made to proceed with a cesarean delivery. The cesarean delivery was uncomplicated,
and she delivered a liveborn male weighing 1,235 g with 1 and 5 minutes APGAR scores
of 2 and 8, respectively. Cord blood analysis confirmed fetal anemia (hemoglobin:
9.1 g/dL) and thrombocytopenia (platelets: 67,000/cmm). Significant leukocytosis was
also noted (WBC: 63,000/cmm). The neonate required critical care admission due to
prematurity with acute respiratory distress requiring intubation and ventilation;
transfusion of red cells and platelets was also performed. Approximately 8 hours after
delivery maternal serology results returned consistent with an acute primary CMV infection.
Additional findings consistent with CMV infection included positive placental CMV
immunostain and neonatal saliva CMV polymerase chain reaction (PCR) positive. The
neonate was treated with valganciclovir 16 mg/kg twice daily and therapy is planned
for 6 months. Initial neonatal head ultrasound on the day of delivery found nonacute
bilateral grade 3 germinal matrix hemorrhages and mild ventriculomegaly (left more
than right) with concurrent chemical epididymitis. Subsequent exams over the next
9 weeks showed the development of posthemorrhagic hydrocephalus which later returned
to mild ventriculomegaly, no evidence of additional bleeding, and no parenchymal abnormalities.
The initial hearing screen was negative. Newborn was eventually discharged in stable
condition and followed closely as an outpatient.
Discussion
While IVH is more commonly diagnosed postnatally following a traumatic or preterm
birth, this case of congenital CMV represents a rare complication of IVH identified
antenatally. The incidence of fetal IVH is estimated to occur between 1 and 5 per
10,000 pregnancies.[6] The paucity of existing literature regarding germinal matrix or IVH is limited to
descriptive or observational studies. As a result, very little is understood regarding
risk factors when IVH occurs antepartum. Reported associations of fetal IVH include
pregnancies affected by multifetal gestation, fetal growth restriction, congenital
anomalies, maternal infection, hypertensive disorders, and abnormal amniotic fluid
volume.[6] Causative mechanisms of IVH are hypothesized to result from altered fetal hemodynamics,
clotting, or cerebral autoregulation.[6] Severe complications such as twin-to-twin transfusion syndrome and neonatal alloimmune
thrombocytopenia (NAIT) are conditions that are better understood to be risk factors
for fetal neurologic injury and intracranial bleeding, respectively.[6]
Ultrasound diagnosis of IVH can be a challenging endeavor. Acute hemorrhage appears
as an echogenic and homogenous lesion. With time, the appearance becomes less echogenic
but more heterogenous. Additionally, IVH can be associated with ventriculomegaly or
periventricular calcifications from obstruction of cerebrospinal fluid and intracranial
vasculature. Identification of intracranial lesions after a normal mid-gestation anatomy
ultrasound requires additional or subsequent antenatal imaging. In the setting of
pregnancy complications or co-morbidities, indicated ultrasound surveillance allows
for additional opportunities for detecting IVH. ([Fig. 1])
Fig. 1 Fetal head ultrasound in grayscale of left lateral ventricle demonstrating heterogeneous
and echogenic portions of choroid plexus suspicious for intraventricular hemorrhage
(white arrow). LT, left; RT, right.
In this case report, the integration of diagnostic ultrasound as a part of the patient's
clinical workup helped identify fetal IVH in the setting of her preterm labor. The
ultrasound finding of IVH prompted the utilization of middle cerebral artery Doppler
to assess the risk of fetal anemia. Middle cerebral artery peak systolic velocity
greater than 1.5 MoM suggests moderate to severe fetal anemia. These sonographic markers
led to a broad clinical differential, which included the possibility of congenital
infection, NAIT, other genetic thrombocytopenia, germinal matrix hemorrhage, and abnormal
vasculature. ([Fig. 2])
Fig. 2 Fetal middle cerebral artery peak systolic velocity by pulse wave color Doppler ultrasound.
Peak systolic velocity is 72.45 cm/second, correlating with 1.99 MoM, indicating risk
for fetal anemia.
Prenatal diagnosis of congenital CMV infection solely by ultrasound imaging alone
is generally not able to consistently diagnose intrauterine infection.[7] However, the presence of intracranial and/or multiple abnormalities such as growth
restriction, echogenic bowel, microcephaly, hepatosplenomegaly, hepatic calcifications,
and hydrops can be more supportive.[7] When CMV infection is suspected, serology testing with CMV-specific IgG, IgM, and
IgG avidity should be offered.[8] Diagnosis of maternal primary CMV infection should be on the basis of the detection
of both CMV IgM and low-to-moderate avidity of CMV IgG antibodies.[8] Our patient reported a several-day history of low-grade fever with an otherwise
negative review of systems. Primary infection during pregnancy is asymptomatic in
approximately 75 to 95% of women.[9] When symptomatic, CMV infection may involve mild febrile illness with associated
fatigue, myalgia, headache, or rhinitis.[9]
Prenatal diagnosis of fetal CMV infection can be made by nucleic acid test assays
such as PCR after 20 weeks gestation, once fetal urination is well established, and
at least 6 to 8 weeks from the time of maternal CMV infection.[10] In congenital infection, the sensitivity of CMV PCR from fetal urine excreted into
the amniotic fluid is roughly 70%.[10] Amniocentesis for CMV is recommended when there is maternal CMV infection during
pregnancy or when there are abnormalities on ultrasound consistent with fetal infection.
Postnatal diagnosis of congenital CMV in affected neonates should include PCR of saliva
or urine within the first 21 days of life, with saliva as the preferred method.[10] In this case report, CMV testing by maternal serology and newborn saliva PCR were
consistent with primary maternal infection that resulted in congenital infection.
Intended amniocentesis with PUBS was planned but unable to be completed due to indicated
cesarean delivery.
Recent literature has reported the utilization of antenatal cord blood testing by
PUBS or cordocentesis to supplement fetal assessment in CMV congenital infection.
In one study, prenatal diagnosis of congenital CMV by fetal blood had a similar sensitivity
of 75.6% compared with 72.7% by amniotic fluid.[7] However, due to the higher complication rate associated with PUBS sampling, amniocentesis
is still considered the method of choice for diagnosis of fetal CMV infection. In
addition to virologic testing, fetal blood can provide other laboratory information
such as platelet count, β-2 microglobulin, and liver enzymes.[7] Fetuses affected by CMV can present with thrombocytopenia, elevated β-2 microglobulin,
and transaminitis compared with noninfected fetuses.[7] Reported thresholds such as β-2 microglobulin >14 mg/L or platelet counts <120,000/cmm
were associated with severe ultrasound abnormalities.[7] A separate recursive analysis completed on a case-control study described that the
presence of moderate thrombocytopenia <120,000/cmm, CMV DNA load >5 log10 IU/mL, or
β-2 microglobulin >12 mg/L in cases with severe brain abnormalities on prenatal imaging
achieved a positive predictive value (PPV) of 100%.[11] Even in cases without severe intracranial abnormalities at prenatal imaging, moderate
thrombocytopenia had a PPV of 83% for symptoms at birth.[11] Conversely, the contribution of PUBS could be particularly useful for fetuses without
any ultrasound or laboratory abnormalities as the negative predictive value is close
to 100% for moderate to severe symptomatic infections.[11] Although these studies are observational, the results allude to the possible prognostic
value of antenatal imaging and PUBS as helpful supplemental tools for identifying
fetuses at increased risk for severe disease. Information obtained antenatally can
change ongoing fetal surveillance and is informative for the neonatal management of
the newborn.
Pathology examination of the placenta also demonstrated CMV-positive cells by immunoperoxidase
stain. Congenital infection occurs through placental-mediated vertical transmission.[1] As the first organ exposed to the CMV virus, the placenta initially serves as a
barrier before succumbing as a reservoir for viral replication.[1] The CMV virus crosses the placenta and replicates in the tubular epithelium of the
kidneys, with a trophism for the reticuloendothelial and central nervous system.[1] CMV-infected placentas demonstrate histopathological changes that affect cellular
morphology. The classic histopathologic finding associated with СMV infection is villitis,
but may also include plasma cell deciduitis, sclerosis of the villous capillaries,
chorionic vessel thromboses, necrotizing villitis and hemosiderin deposition in the
villous stroma.[12]
[13] As demonstrated by the obstetric outcome in this case report, congenital CMV infection
with placental pathology is associated with an increased risk for preterm delivery.[12] ([Fig. 3])
Fig. 3 Positive immunoperoxidase stain for CMV on placental pathology (positive stain colored
brown).
While the relationship between infection severity and newborn outcomes of antenatally
diagnosed IVH is not fully understood, maternal CMV infection in the first trimester
is well established as a risk factor for the most severe fetal symptoms.[1]
[6] An estimated 19 to 29% of fetuses infected in the first trimester are likely to
have neurologic lesions, with an increased risk of late-onset sequelae such as cognitive,
motor, and sensory impairments.[11] Infection in the second trimester may also lead to symptoms in the fetus or the
newborn.[1] Following delivery, the newborn was admitted to the neonatal intensive care unit
due to complications of prematurity and CMV infection. Initial head ultrasound demonstrated
grade 3 IVH, meaning the hemorrhage occupied >50% of the lateral ventricle area with
acute ventricular dilation. The infant's posthemorrhagic hydrocephalus improved to
mild ventriculomegaly without any evidence of parenchymal abnormalities prior to discharge
home. He was treated with valganciclovir for 6 months of total therapy. Long-term
sequelae of congenital CMV infection in symptomatic neonates can include sensorineural
hearing loss and neurodevelopmental delay.[9] His initial hospital and subsequent outpatient hearing evaluations were normal.
He was seen at 9 months of age (corrected age 6 months) at our institution's newborn
specialty center for outpatient surveillance. Bayley Scales of Infant and Toddler
Development (BSID) was utilized for developmental assessment. BSID provides a comprehensive
evaluation of an infant's motor, speech, and cognitive milestones.[14] For his adjusted age, our infant was meeting his cognitive and motor milestones
but demonstrated delays in his speech and expressive language. Plan of care recommendations
involved referral to speech therapy through the Early Intervention program.
IVH is an uncommon manifestation of congenital CMV infection. In this case, our patient
in preterm labor had imaging suggesting IVH and fetal anemia which was subsequently
diagnosed with primary CMV infection. The inflammatory process of the viral infection
likely led to the development of preterm labor. The IVH may have occurred due to CMV-associated
thrombocytopenia; alternatively, the IVH may have been the primary event (perhaps
due to inflammation) leading to anemia and thrombocytopenia. Suspicion for congenital
CMV infection, especially in the cases of asymptomatic mothers relies on fetal ultrasonographic
findings to initiate workup. Our case indicates the need for detailed sonographic
imaging in pregnancies complicated by preterm labor, as ultrasound findings can significantly
impact management.
