The toll that Zika virus takes on pregnancies appears to be even higher than was previously estimated, with a newly updated study from Brazil suggesting that 42 percent of infants infected in the womb may have significant birth defects.
When the authors factored in stillbirths and miscarriages suffered by women who had been infected with Zika, 46 percent of pregnancies were affected. Microcephaly — a condition in which babies are born with smaller than normal heads — was seen in only about 3 percent of babies in the study.
“Microcephaly is just the tip of the iceberg. It’s definitely not where the focus should be,” said Dr. Karin Nielsen-Saines, the paper’s senior author. “For every case of microcephaly you’re probably going to have 10 cases of other problems that haven’t been recognized.”
Nielsen-Saines is a professor in the division of pediatric infectious diseases at the University of California, Los Angeles. Her co-authors are from Brazil and the US.
The group reported adverse outcomes — pregnancy losses or birth defects — in 55 percent of pregnancies in which infection occurred in the first trimester, 52 percent of pregnancies in which infection occurred in the second trimester, and 29 percent in which infection occurred in the third trimester.
Nielsen-Saines told STAT on Tuesday that she’d been surprised by the 29 percent figure and is more surprised still by the updated estimates. But on the issue of the danger the virus poses to developing fetuses, she is now clear.
“I actually don’t think there’s anything more harmful to a fetus than Zika,” she said. “It’s probably the most teratogenic virus that exists.”
The March study and the update are published in the New England Journal of Medicine.
An unrelated study, from scientists at the Centers for Disease Control and Prevention, may shed some light on why Zika is so harmful to developing brains. That study, published in the journal Emerging Infectious Diseases, found levels of virus in the brains of infected infants (who died after birth) were 1,000 times higher than the viral levels in women’s placentas.
“Our findings show that Zika virus can continue to replicate in infants’ brains even after birth, and that the virus can persist in placentas for months – much longer than we expected,” said Julu Bhatnagar, head of the molecular pathology team at CDC’s Infectious Diseases Pathology Branch and the study’s lead author.
“We don’t know how long the virus can persist, but its persistence could have implications for babies born with microcephaly and for apparently healthy infants whose mothers had Zika during their pregnancies.”
The research group that conducted the Brazilian study has been tracking dengue virus infections in Rio de Janiero for years. When the Zika outbreak started, they quickly adapted the study to investigate what happens when pregnant women become infected with the virus.
Women who developed a fever and a rash were enrolled in the study and tested to see if they had Zika. The study, which is ongoing, follows both women who tested positive for the virus and women who didn’t. The latter group is used as a comparator.
Several scientists not involved in the study noted that the effect it recorded might be artificially high, because all women who had Zika had a symptomatic infection. It’s known that most people who contract Zika don’t have symptoms, and women with those milder infections may not give birth to babies with birth defects at the same rate, suggested Dave O’Connor, a professor of pathology and laboratory medicine at the University of Wisconsin-Madison who has been studying Zika in non-human primates.
“Asymptomatic infections certainly carry risk too, but symptomatic infections may have disproportionately high risk. This is still speculative, but an important caveat on their results,” O’Connor said in an email.
It is known that women who have asymptomatic Zika infections do sometimes give birth to babies with microcephaly. Scientists from Colombia and the Centers for Disease Control and Prevention reported on four such cases in June.
In the Brazilian study, researchers reported on 125 pregnant women who were infected with Zika and had given birth or lost their pregnancy between Jan. 1 and July 31. They compared them to 61 women who were not infected with Zika during their pregnancies.
Cases of microcephaly were actually rare in the study. Four babies born to Zika-infected mothers had microcephaly, but two of those babies were small and their heads were proportionate to their bodies.
There would have been at least one more case. But a woman whose ultrasound showed a profoundly affected fetus dropped out of the study; Nielsen-Saines said multiple attempts to find her failed.
The range of other birth defects was substantial, including seizure activity, visual and hearing impairment, spasticity, contracted limbs, and difficulty swallowing and feeding. All these are signs of brain damage, Nielson-Saines said, adding she expects with time that more developmental problems will become apparent.
“The newborns may appear to be normal, but they may not be normal at six months, and there’s a whole gradient of problems,” she said.
The researchers plan to track these babies for two years — if their mothers will allow it. Nielsen-Saines admitted some mothers are reluctant to bring the babies back for medical assessment. “They don’t want to know.”
While infection early in pregnancy appeared to carry the highest risk, infection as late as 39 weeks was associated with problems in some cases. This is unlike rubella — another virus infamous for causing birth defects — where the danger period for infection is in the first 20 weeks of pregnancy, the authors noted.
The women who were not infected with Zika also had an unusually high percentage of problems — 11.5 percent. But 42 percent of them were infected during their pregnancy with chikungunya, another virus that has also been associated with pregnancy losses — stillbirths and miscarriages.
Two of the leaders of the Zika response team at the Centers for Disease Control and Prevention said the findings suggest the Zika virus — written as ZIKV in scientific shorthand — will have a large effect where it spreads.
“The scope of the ZIKV outbreak in the Americas suggests that ZIKV infections will have a profound impact on the cohort of infants delivered in the nine months after the outbreak peak in each country,” Margaret Honein and Dr. Denise Jamieson wrote in an editorial published by the journal.
Brain defects may not be all that serious. Dr. John Lorber (a neurologist) had studied hundreds of hydrocephalic patients who had severely reduced brain tissue. During his investigations, he had noted that even some of the most severely affected individuals (where the ventricle expansion fills 95 percent of the cranium) had IQ’s greater than 100 [see reference: Lorber, J. (1981). Is your brain really necessary? Nursing Mirror, 152(18):29-30].
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