A new study of toddlers exposed to the Zika virus during their mothers' pregnancies found that nearly a third suffered developmental delays and other problems — even if they were born without the abnormally small heads and underdeveloped brains often associated with the virus.
The study of more than 200 babies, published Monday in the journal Nature Medicine, also shows that a very small number of children born with the congenital condition known as microcephaly had their symptoms improve. Conversely, a very small number of the children born without symptoms of microcephaly went on to develop it.
The research further also noted a higher rate of autism among children exposed to the virus than among those in the general population.
Infectious disease expert Albert Ko, a professor of epidemiology and medicine at the Yale School of Public Health, who was not involved in the study, said that during the 2015-2016 Zika epidemic, public health professionals were focused on the most severe birth defects, such as microcephaly, but "we always suspected that was the tip of the iceberg."
The study, Ko said, shows "there are more subtle, but very significant, defects associated with Zika infection, such as below-average neurodevelopmental performance." These deficits can affect language, learning and social interactions, among other things, he said.
During the outbreak in Brazil, which spread through North and South America, Zika spurred widespread concern that scores of babies exposed to the virus in utero would be born with devastating and long-lasting birth defects. Indeed, Ko said, research has shown that about 4 to 6% of those studied developed microcephaly, many with abnormally small heads and partly collapsed skulls, eye problems, hearing problems, issues with joints and muscles, and severe developmental issues.
But experts say the new research shows the issue may be more complex. Because a large number of children without microcephaly are nevertheless still suffering neurosensory and developmental problems, children who were exposed to the virus before birth should be monitored throughout their formative years for potential problems in school and in life.
"You can't just look at them when they're born and say they don't have microcephaly and they look normal and they're fine, because there are repercussions for the developing brain," said lead author Karin Nielsen-Saines, a pediatric infectious disease specialist at the University of California, Los Angeles.
She noted these children should be watched for developmental problems because "if you see that these children are at risk for bad neurodevelopmental outcomes, you can implement measures" to help them.
"That, I think, is the major message," Nielsen-Saines said, "that you should follow these children and that this may allow for interventions that can give them a better future."
Researchers from UCLA, with help from those in Brazil, Austria and Germany, monitored the children up to age 3 to determine how the virus would affect their development.
The researchers found that eight of those children had microcephaly — four developed it at birth and remained affected by it, two were born without it but fit the diagnostic criteria within the first year, and two were born with it but grew out of it, according to the study.
Nielsen-Saines said one of the children who overcame the disorder also had a birth defect in which the bones in the skull fuse too early, affecting both appearance and brain development.
Before surgery to repair the baby boy's skull at about 6 months of age, he had several Zika-related symptoms — an issue with the retina, calcifications in the brain and significant developmental deficits, Nielsen-Saines said. After surgery, the child began to improve, though she noted that his developmental scores remained below average.
The other child who improved, Nielsen-Saines said, was born with a moderate case of microcephaly and experienced developmental delays early on. But by the time he was about a year old, Nielsen-Saines said, the microcephaly had resolved — his head shape and size were within the normal range and he had no developmental issues.
Nielsen-Saines noted that the child who improved spontaneously was not as severely affected as the other child and did not have eye or hearing problems. Nielsen-Saines also said that his parents used developmental stimulation early on to try to help him.
Nielsen-Saines said the researchers never expected to see a reversal of microcephaly in the study, but it did "not come as a complete surprise" because children with other developmental disorders, such as cerebral palsy, can improve with stimulation. This type of stimulation uses intensive playing, learning and interacting with others, for example, to help develop babies' brains.
Nielsen-Saines, who has been studying Zika and its effects on children since the epidemic, said that three other children who were exposed to the virus were diagnosed with autism at age 2. She said the children were developing normally but stopped talking and started showing other symptoms of the disorder at that age. Since the study, she said, two more have been diagnosed.
Ko, an epidemiologist, said that given the small number of children who went on to develop microcephaly as well as the small number who recovered from it, it would be difficult to estimate how often these situations occur. In the same vein, he said that although the number of children who developed autism is "quite concerning," there's no way to determine the extent of the risk at this point.
Still, Ko agreed with the study's authors that these children should be monitored for potential problems, especially as they are entering school.
"As we are following these babies longer, we're learning more and more about the potential harms that were caused during gestation," Ko said.