In 2020, “the virus” has come to mean one thing: SARS-CoV-2. But just a few years ago, Zika had the world’s attention, as one news report after another described children with microcephaly born to women who’d been infected while pregnant.
It can be difficult for physicians to determine whether a birth defect is the result of Zika. Most infections have few or no symptoms, and mothers may not know if they’ve been exposed. Karin Nielsen, MD, remembers one child in particular, a 9-month-old boy born with microcephaly whose parents brought the infant to her in 2018 because he had started having seizures.
The child was born in Mexico in 2017, when the Zika virus was still known to be circulating in the Americas, says Nielsen, a pediatric infectious disease specialist at the David Geffen School of Medicine at University of California, Los Angeles. Brain imaging revealed calcifications and other signs in the boy’s brain that were consistent with exposure. But his mother said she was never sick during pregnancy.
Because Zika is transmitted not just via mosquito and from mother to fetus but also sexually, Nielsen thinks the mother probably contracted an asymptomatic infection from her husband, who recalled having a rash when she was 4 months pregnant. When they participated in a research study, both parents tested positive for Zika antibodies.
“The child had the classic symptoms of congenital Zika syndrome,” Nielsen said. “He was 9 months old, he had microcephaly, and he was having mal seizures.”
Researchers have since learned that children with such classic symptoms represent only a small proportion of those affected by prenatal Zika exposure — about 3% to 5%. The virus was at its height during the 2016-2016 epidemic and is not currently causing outbreaks. But as researchers have followed cohorts of children exposed to Zika in utero, they have found many subtler effects physicians will need to monitor as the children grow up.
“When we’re seeing hundreds of kids with microcephaly, we had a lot of people infected,” Nielsen said. “Microcephaly is only the tip of the iceberg.”
Microcephaly may be the most identifiable symptom of fetal Zika infection, but researchers tracking cohorts of exposed children have begun to build a more complete picture of what long-term effects might look like. “Congenital Zika syndrome” refers specifically to the most severe effects from prenatal exposure: microcephaly, seizures, cerebral palsy, hearing and vision problems, feeding difficulties, and other disabilities. But hundreds, if not thousands, of children have been exposed to Zika in the womb — it’s not clear how many, Nielsen said — and many show a range of effects that don’t officially qualify as congenital Zika syndrome.
Current estimates suggest about one third of exposed children have some type of neurologic or neurodevelopmental problem, even though prevalence of visible effects is much lower. Over time, the incidence of these effects has fluctuated; some developmental delays and sensory deficits began manifesting later in childhood whereas others, at least in a few children, have resolved.
“We’re just beginning to have some of the data that we need to think about the full spectrum of outcomes,” said Cindy Moore, MD, chief medical officer in the Division of Congenital and Developmental Disorders in the Centers for Disease Control and Prevention’s National Center on Birth Defects and Developmental Disabilities.
“As we’re learning more and more, we’re learning the spectrum is expanding to less severe forms,” Moore said. “We do know that with some infections, there are later onset of problems.”
Clinical features of infants with congenital Zika infection include microcephaly, arthrogryposis, redundant scalp, clenched fist, knee fovea, retinal lesion, posterior fossa alterations, ventricular dilatation, and loss of brain tissue on MRI scan.
Studies published in 2018 described cohorts of children whose mothers had confirmed or suspected Zika infections during pregnancy in the French Territories of America (Guadalupe, Martinique, and French Guiana) and in Salvador, Brazil. The research provided valuable early data on the incidence of microcephaly and other severe effects in newborns, but noted the need for long-term follow up.
The U.S. Zika Pregnancy and Infant Registry is one of the largest such cohorts. In August 2018, researchers made their first report on data from the registry They looked at 1450 children age 1 or older who had undergone neuroimaging or screenings (developmental, vision, hearing) or both. In 6%, at least one birth defect was linked to Zika, and 9% had at least one neurodevelopmental abnormality.
As these children age past developmental milestones, more effects will likely manifest — even in those children whose appearance and imaging presented as healthy at birth.
Nielsen at UCLA and M. Elisabeth Lopes Moreira, MD, of the Oswaldo Cruz Foundation in Rio de Janeiro, are following a cohort of more than 100 children born in Rio de Janeiro during Brazil’s 2015-2016 epidemic to mothers with symptomatic, PCR-confirmed Zika infections during pregnancy. In December 2018, their team reported that rates of severe neurodevelopmental delay and sensory dysfunction — 14% of 131 children aged 12-18 months — were higher than those found in earlier studies.
In August 2019, the team described neurodevelopmental, vision, and hearing outcomes in 216 Zika-exposed children 2 years after birth. They used the Bayley-III Scales of Infant and Toddler Development to assess cognitive, language and motor skills in 146 of the children. Forty percent of them were below or very below average in development, more than one third (35%) had language delays, 12% percent had hearing loss, and 7% had abnormal eye anatomy, such as underdeveloped retinas.
In 2 of the 8 children in the cohort with microcephaly, the abnormality unexpectedly resolved. Although that finding received a lot of press, Nielsen points out that “not all microcephalies are created equal.”
In one case, a child born small for gestational age had proportional microcephaly: the baby’s head circumference met the criteria for microcephaly, but the infant’s head was proportional to the body so, as the child grew, the apparent microcephaly disappeared.
In the other case, the child was born with craniosynostosis, in which the skull sutures fuse too early — another effect seen with prenatal Zika exposure, Nielsen said. After corrective surgery, the child’s head circumference no longer met the definition of microcephaly, but the child still had symptoms related to congenital Zika: a developmental delay and calcifications in the brain. Meanwhile, two other children in the Rio cohort developed secondary microcephaly.
Physicians examine the eyes of a child with congenital Zika infection.
In another follow-up study of children up to age 4, Nielsen and colleagues found that both clinicians and family may think that Zika-exposed infants without microcephaly are developing normally, but that may not be true. Nearly 70% of children without microcephaly had neurologic abnormalities on physical examination, and more than half had failure to thrive because of poor feeding related to neurologic abnormalities.
Initially, some children may be able to mask subtle problems. A study published in January from Sarah B. Mulkey, MD, PhD, of Children’s National Hospital in Washington, DC, and colleagues described neurodevelopmental outcomes in 70 Colombian children up to 18 months old who had been exposed to Zika in utero. The children had a normal head circumference at birth and a normal fetal MRI, but — compared with typically developing peers — their communication, social cognition, and mobility scores on standardized assessments tended to decline as they got older.
“Especially in a very young child, there’s always going to be a possibility that you can compensate for a deficit, and it appears that at least some of these children are doing so,” William J. Muller, MD, PhD, an associate professor of pediatrics at Northwestern Feinberg School of Medicine, Chicago, Illinois, said. When the children are older, certain behavioral effects will become easier to assess.
“With these children now approaching school age, understanding the full spectrum of neurodevelopmental abnormalities has important public health and educational system implications,” Muller and Mulkey write in a commentary about one of Nielsen’s studies.
Zika-exposed infants wearing corrective lenses to improve visual tracking.
Researchers face multiple barriers to understanding the long-term effects of fetal Zika infection. Many infants known to have been exposed in utero never received the recommended early assessments and haven’t been followed long-term. Particularly in Brazil, poverty, poor access to healthcare, and overcrowding all complicate surveillance efforts, Muller said. Stigma related to children’s neurodevelopmental problems also can potentially reduce a mother’s willingness to attend all follow-ups and assessments.
Some children may have been exposed but were never recognized as such, making it difficult for researchers to track their development and assemble a complete picture of prenatal Zika infection outcomes. Asymptomatic infection occurs in about 80% of Zika infections, though it’s not clear if that number holds for infections during pregnancy as well, according to Muller and Mulkey. Because nearly all the current research involves children whose mothers had symptomatic infections, the studies’ generalizability may be limited.
Those likely asymptomatic infections are also a major reason none of the cohorts have comparison groups.
“There are literally hundreds of things that can contribute to or cause developmental problems,” said Moore of the CDC, who noted that it would be nice to have a comparison group so as to know what Zika may not be responsible for. That said, it would be difficult-to-impossible to create a control group with similar geographic and demographic characteristics as the exposed children, a group who researchers can be certain weren’t exposed.
Neurodevelopmental disabilities occur in about 15% of the general population, making it difficult to determine whether Zika causes any or all long-term, less severe developmental findings in exposed children. The difficulty only compounds with time: the older a child is when a developmental problem is recognized, the harder it is to go back and say the problem is a result of something that occurred before birth, Moore said. “It’s a challenging field to say, this is what caused that outcome.”
Interpreting the clinical implications of available studies is also challenging. It can be difficult to distinguish between central nervous system damage and peripheral damage, leaving the true etiology of poor vision or hearing elusive. The Zika virus can attack both the optic nerve and the part of the brain that interprets what a person sees: “Are you not seeing well because that part of your brain is not developed, or is it just a problem with the eye?” Nielsen said.
When problems can’t be precisely identified, successful interventions are harder. If the cochlea is normal, for instance, but the part of the brain that interprets sound or language has deficits, a hearing aid won’t help.
The services and interventions that children need depend on their specific developmental or cognitive deficits, regardless of the cause. But if clinicians know the cause is likely Zika exposure, they also know to look for other deficits.
Children showing likely effects of congenital Zika infection should be further evaluated for other possible birth defects and referred to a developmental specialist, early intervention services, and family support services. Depending on the child, primary care providers might consider referrals to an infectious disease specialist, clinical geneticist, neurologist, or other specialists.
Even with no confirmed infection or visible signs at birth, clinicians should remain vigilant with children who had possible exposure. A recently published study of 120 children conceived during the Zika outbreak in Paraíba, Brazil, assessed as infants and then again at 2 years old, exemplifies why. Researchers identified adverse neurologic outcomes and developmental delays in several children who had no physical evidence of birth defects as newborns, but whose antibody tests showed possible infection.
“In this post-epidemic period, with decreased Zika transmission and less public awareness,” write Mulkey and a colleague, “follow-up of these children is now more important than ever.”
Tara Haelle is an independent health and science journalist and book author. She specializes in reporting on vaccines, pediatrics, women’s health, mental health, and medical research.