Early Ultrasounds May Miss Zika-Induced Microcephaly

Janis C. Kelly

April 15, 2016

A case of Zika virus infection (ZIKV) with prolonged viremia in the mother and fast-moving but hard-to-detect brain damage in the fetus may point to new changes in how clinicians should care for pregnant women who have contracted this disease, according to a brief report published online March 30 in the New England Journal of Medicine.

The researchers found that the latency period between fetal ZIKV infection and the development of changes visible with ultrasound (US) may be prolonged, and that a fetal brain magnetic resonance imaging (MRI) scan might be needed to detect those changes. In addition, ZIKV RNA testing in pregnant women might be advisable for longer than currently recommended, Rita W. Driggers, MD, from the Department of Gynecology and Obstetrics, Division of Fetal Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, and colleagues write. Persistent ZIKV viremia in a pregnant woman might signal ongoing placental or fetal infection.

The 33-year-old mother in the report apparently contracted ZIKV during the 11th week of gestation while on holiday in Mexico, Guatemala, and Belize. She and her husband both became ill with eye pain, myalgia, mild fever, and a rash. Symptoms resolved within 1 week.

Serologic analysis of the mother 4 weeks later was positive for anti-ZIKV immunoglobulin G and immunoglobulin M, indicating acute or recent ZIKV infection. Serologic analysis also ruled out chikungunya virus, and the patient had previously been vaccinated against tick-borne encephalitis and yellow fever.

At 16 weeks of gestation, nested reverse transcriptase polymerase chain reaction (RT-PCR) and confirmatory specific ZIKV quantitative RT-PCR identified the Central American epidemic strains of ZIKA. The Centers for Disease Control and Prevention's Division of Vector-Borne Diseases confirmed active infection at 17 weeks of gestation.

Fetal ultrasonography at 13, 16, and 17 weeks showed no microcephaly (occipitofrontal circumference below the third percentile for gestational age and sex) or intracranial calcifications. After the confirmation of maternal ZIKV, additional assessment of the fetus was performed.

US at 19 weeks showed abnormal intracranial anatomy. The authors write, "The cerebral mantle appeared to be thin with increased extra-axial spaces. Both frontal horns were enlarged with heterogeneous, predominantly echogenic material present in the frontal horn and body of the left lateral ventricle, a finding that raised concern about intraventricular hemorrhage. Dilation and upward displacement of the third ventricle, dilation of the frontal horns of the lateral ventricles, concave medial borders of the lateral ventricles, and the absence of the cavum septum pellucidum suggested agenesis of the corpus callosum. No parenchymal calcifications were seen." Thickness of the cortical mantle in frontal regions was 1.4 mm in the fetus with ZIKV compared with 8 mm in a normal fetus with gestational age of 20 weeks.

Between week 16 and week 20, the fetal head circumference on US decreased from the 47th percentile to the 24th percentile in the ZIKV-infected fetus.

Fetal MRI at week 20 added more to this bleak picture, including diffuse cerebral atrophy, most severely in the frontal and parietal lobes; absence of the normal pattern of cerebral mantle lamination; a shortened corpus callosum; diminished cavum septum pellucidum; enlarged lateral ventricles and third ventricle; and a prominent choroid plexus without hemorrhage.

The mother elected to terminate the pregnancy at 21 weeks of gestation. Postmortem microscopic analysis showed apoptosis of intermediately differentiated postmigratory neurons in the neocortex and early mineralization focally associated with the apoptotic neurons. Well-differentiated neurons in other areas of the brain were relatively unaffected.

Atrophy in the subventricular zone and white matter, with extensive axonal loss and macrophage infiltration, correlated with the atrophy seen on prenatal imaging.

ZIKV viral load was highest in fetal brain but was also high in the placenta, fetal membranes, and umbilical cord. Low levels of ZIKV RNA were found in fetal muscle, liver, lung, and spleen, as well as (with low viral counts) in amniotic fluid taken at the time of termination. ZIKV RNA with low viral count was also found in maternal serum taken the day before termination. ZIKA viremia had cleared from maternal serum, monocytes, saliva, and urine by 11 days after pregnancy termination.

Fetal brain samples were able to transmit ZIKV in vitro to cells from a human neuroblastoma cell line, as demonstrated by an increase in ZIKV RNA on quantitative RT-PCR. Supernatant from that experiment yielded a complete ZIKV genome, sequenced on day 5 after inoculation.

The authors note that ZIKV viremia typically lasts for less than 1 week after infection, which is why ZIKV RNA testing in pregnant women is not recommended beyond the first week after symptom onset. They suspect that the persistent ZIKV viremia in this patient was actually a result of viral replication in the fetus or placenta.

"Therefore, in addition to current ZIKV diagnostics, the use of quantitative RT-PCR methods may be a potential diagnostic approach for ongoing placental or fetal infections in pregnant women. Notably, in this patient, the ZIKV RNA levels were slightly higher in the maternal serum than in the amniotic fluid," they write.

The reduction in fetal head circumference from 47th percentile to 24th percentile in sequential US images taken between 16 and 20 weeks' gestation suggests a dramatic reduction in the rate of brain growth during that period, after apparent infection during week 11. The authors suspect this would eventually meet the criteria for microcephaly.

The delay between fetal brain infection and US-detectable microcephaly means clinicians should be wary of relying on US studies to rule out fetal damage in the pregnancies of women who have tested positive for ZIKV.

"Negative ultrasonographic studies during this period would be falsely reassuring and might delay critical time-sensitive decision making," the authors warn.

Dr Driggers and colleagues advised clinicians to consider serial US measurements of fetal head circumference and fetal brain MRI for better soft tissue resolution to help detect evolving fetal brain anomalies.

In a review of Zika virus also published online March 30 in the New England Journal of Medicine, Lyle R. Petersen, MD, and colleagues from the Centers for Disease Control and Prevention write, "Microcephaly can occur as a result of fetal brain disruption sequence, a process in which, after relatively normal brain development in early pregnancy, collapse of the fetal skull follows the destruction of fetal brain tissue. Although previous case reports of maternal infection leading to fetal brain disruption sequence do not include information on the timing of maternal infection, some evidence indicates that this damage can occur late during the second trimester or even early in the third trimester."

Dr Petersen and colleagues comment that US is not a highly sensitive method for detecting microcephaly, but that US findings associated with ZIKV infection include "an absent corpus callosum, hydranencephaly, cerebral calcifications, ventricular dilatation, brain atrophy, abnormal gyration, hydrops fetalis, anhydramnios, and intrauterine growth retardation."

The researchers also predict, on the basis of recent experience with the chikungunya virus in the Americas, clinicians should expect millions of ZIKV infections in the coming months, as well as "substantial numbers of infants with microcephaly and other adverse pregnancy outcomes."

The authors have disclosed no relevant financial relationships.

N Engl J Med. Published online March 30, 2016. Brief report full text, Review full text

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