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Neurodevelopmental Delays Appear in Children Exposed to Zika Virus Who Appeared Normal at Birth

Article In Brief

Children who were exposed to Zika in utero but who appeared normal at birth still develop neurodevelopmental abnormalities up to 18 months later.

Children exposed to the Zika virus in the womb who showed no abnormalities on fetal MRI and ultrasound and appeared normal at birth can still have neurodevelopmental delays, a study published January 6 in JAMA Pediatrics found.

Scientists at Children's National Hospital in Washington, DC, and in Barranquilla, Colombia, have been evaluating pregnant women exposed to the Zika virus and their babies since 2016. They used prenatal ultrasound and MRI to look for abnormalities in the fetus caused by Zika virus. They wanted to understand how imaging would help in identifying sick babies.

They enrolled 82 pregnant women: 79 from Colombia and three from the US. The pregnant women had the classic signs of infection: rash, red eyes, and fever; lab tests came back positive for the virus. They identified severe fetal or postnatal brain abnormalities in five babies born to these women. Only two of these severely affected babies are still alive. The rest had normal imaging scans and had normal head circumference at birth.

Some infants who had normal imaging before birth had mild findings only on head ultrasound that are non-specific, meaning they can be seen in normal babies or in babies with different types of medical conditions or other congenital infections, but not necessarily Zika.

Study Design, Findings

The scientists conducted neurodevelopmental exams of 70 children at two time periods, between four and eight months and then again at nine to 18 months, when the developmental abnormalities emerged. Thirty percent of the children showed delays in milestones such as crawling, walking, and social cognition.

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Will they continue to deviate from the norm or will they normalize? We just dont know.”—DR. SARAH B. MULKEY

“These infants had no evidence of Zika brain abnormalities at birth,” said Sarah B. Mulkey, MD, PhD, a fetal/neonatal neurologist at Children's National and first author of the paper. Infants who had the mild findings on head ultrasound seemed to show a lower developmental trajectory compared with those infants whose imaging was completely normal.

Dr. Mulkey said this is the first hint that these nonspecific subtle brain injuries found via imaging may be driving these developmental delays, at least for some of the children. The scans showed calcification or mineralization of small brain vessels in the basal ganglia and thalamus, and some of the scans also showed small cysts near the ventricles. (These nonspecific findings may be seen in about 2 to 5 percent of newborns normally, and it is not clear whether they are caused by exposure to the Zika virus in these infants or due to a different reason.)

“It will be important to understand whether these changes have anything to do with the long-term neurodevelopmental outcomes in these children,” Dr. Mulkey added. The investigators do not know whether the children have or had circulating Zika virus in their systems. There is not a good blood test to identify Zika virus in babies as they get older because the tests cross-react with related flaviviruses and children may have additional exposure to these viruses after birth. The team has received another grant to follow the children until they are 5-years-old.

“Will they continue to deviate from the norm or will they normalize?” asked Dr. Mulkey. “We just don't know.”

Dr. Mulkey and her colleagues have provided clinical consultation to 92 other pregnant women in the US exposed to Zika through the Children's National Congenital Zika Virus Program. She said that this is just a fraction of pregnant women who could have been exposed as 80 percent of women can be asymptomatic.

It is estimated that 5 to 10 percent of babies exposed in utero will have serious life-threatening consequences: microcephaly and global brain damage. The greatest risk occurs when fetuses are exposed during the first trimester. The three children from the original cohort who were born in the US had severe outcomes and were not part of the longitudinal outcome study reported in JAMA Pediatrics.

The US Centers for Disease Control and Prevention (CDC) has been tracking reports from doctors throughout the country who had suspicions of Zika infection in their pregnant patients. Since 2016, the CDC has collected medical information on more than 7,400 pregnancies with laboratory evidence of a possible or confirmed Zika infection.

This represents only those women whose infection was identified by laboratory testing; many infections go undetected due to the lack of symptoms, Dr. Mulkey noted. Between 5 to 10 percent of the babies born to these women have birth defects that could be attributed to the virus, mainly brain defects, microcephaly, and eye defects.

The majority of these children being tracked in the United States, now between 18 months and 4 years old, have not had all of the recommended evaluations, and it is just not known how many of the other children were exposed in utero and may have been left with less obvious brain and eye problems. There are now several ongoing studies that are beginning to report neurodevelopmental effects in children born to mothers exposed to the Zika virus during pregnancy.

Expert Commentary

“The findings from this new study are concerning and it highlights the need for follow-up with these children,” said Margaret A. Honein, PhD, MPH, director of the division of birth defects and infant disorders at the CDC National Center on Birth Defects and Developmental Disabilities. Dr. Honein was one of the authors of an editorial accompanying the current study in JAMA Pediatrics.

“The CDC recommends that these children be seen by physicians and receive all recommended evaluations to identify any disabilities, so that they can get the services they need,” she said. “We want to understand the full range of problems and figure out what it takes to care for these children and what we need to do in the event of another outbreak.”

“This is an important study,” added James F. Bale, MD, emeritus professor of pediatrics at the University of Utah. “We still don't know what effects Zika is having on the human brain, especially the developing brain. We know that other viruses have caused long-term developmental problems in some children.”

Dr. Bale added that while it is great that the scientists will follow these children until they are 5, “it will be important to follow them into the teenage years to understand the full impact of this virus on the brain.”

He said the study also raises questions about the subtle changes identified on cranial ultrasound, and how these changes correlate with the developmental outcome. Karin Nielsen-Saines, MD, MPH, professor of clinical pediatrics in the division of infectious diseases at the David Geffen School of Medicine at UCLA, published a study in 2019 with similar findings—one-third of the 216 children in their cohort, all from Brazil, had some degree of neurodevelopmental delay.

“Confirmation of study results across different research groups is always good,” she said. “They used different assessment tools and a slightly different study design in the present study but in the end independent studies identified a very vulnerable population of children at risk for developmental problems.”

“There is still this idea that if a child exposed to Zika in utero is apparently normal at birth and has no microcephaly then things will be fine,” said Dr. Nielsen-Saines. “But we now know this is not necessarily the case. Children with subtle developmental problems can fall through the cracks.

“There has to be awareness that Zika can cause later repercussions in children exposed during their mother's pregnancy. For this reason they should be followed prospectively and that includes hearing and eye assessments and developmental testing. These cohorts are invaluable and can provide us with information to guide management of future outbreaks.”

Disclosures

Drs. Mulkey, Honein, Bale, and Nielsen-Saines reported no competing interests.

Link Up for More Information

• Mulkey SB, Arroyave-Wessel M, Peyton C, et al. Neurodevelopmental abnormalities in children with in utero Zika virus exposure without congenital Zika syndrome https://jamanetwork.com/journals/jamapediatrics/article-abstract/2758105. JAMA Pediatr 2020; Epub 2020 Jan 6.
    • Mulkey SB, Bulas DI, Vezina G, et al. Sequential neuroimaging of the fetus and newborn with in utero Zika virus exposure https://jamanetwork.com/journals/jamapediatrics/fullarticle/2716801. JAMA Pediatr 2019;173(1):52–59.
      • Honein MS, Woodworth KR, Gregory CJ. Neurodevelopmental abnormalities associated with in utero Zika virus infection in infants and children–The unfolding story https://jamanetwork.com/journals/jamapediatrics/article-abstract/2758100. JAMA Pediatr 2020; Epub 2020 Jan 6.
        • Rice ME, Galang RR, Roth NM, et al. Vital signs: Zika-associated birth defects and neurodevelopmental abnormalities possibly associated with congenital Zika virus infection https://www.cdc.gov/mmwr/volumes/67/wr/mm6731e1.htm. MMWR Morb Mortal Wkly Rep 2018;67(31):858–867.
        • Nielsen-Saines K, Brasil P, Kerin T, et al. Delayed childhood neurodevelopment and neurosensory alterations in the second year of life in a prospective cohort of ZIKV-exposed children https://www.nature.com/articles/s41591-019-0496-1. Nat Med 2019;25(8):1213–1217.