As the Zika virus spreads, hitting 52 countries to date according to the World Health Organization’s Friday update, health authorities are increasingly worried about microcephaly. At the same time, new research is tightening the connection between the virus and this potentially devastating birth defect.

So far, only Brazil and French Polynesia have experienced sustained outbreaks of microcephaly, but that could potentially change quickly. Zika has reached the Americas, the Caribbean, Europe and and the Pacific, according to the WHO. (On Friday, researchers in Colombia reported they had found infants with microcephaly there too.) The WHO says that just two pregnancies exhibiting the defect have been confirmed in women who were infected while pregnant and traveling in the Zika zone: one in Slovenia, and one in Hawaii.

As the epidemic advances, investigations are moving in two directions: attempting to pin down just what is causing microcephaly, and whether countries have the detection and financial resources they will need to prevent or assist affected pregnancies.

In Brazil, 641 cases of microcephaly have been confirmed since the virus arrived in the country last year, according to the Ministry of Health; there have been 139 miscarriages and infant deaths from complications of microcephaly. Another 4,222 are being investigated, and 1,046 suspected cases have been rejected for not meeting the case definition of microcephaly.

View Images At the AACD Rehabilitation Hospital in Recife, Brazil, a physiotherapist examines children with Zika-related microcephaly and counsels their mothers. Photograph by Tomás Munita, National Geographic

Such a large outbreak “is extraordinarily unusual,” Dr. Thomas Frieden, director of the U.S. Centers for Disease Control and Prevention, said last week during the private Milken Institute Public Health Summit in Washington, DC. He pointed out that until now only two infections, rubella and cytomegalovirus, were known to cause microcephaly, adding: “In more than 50 years, no other pathogenic cause of severe fetal malformation has been identified—and as far as I know, never before has there been the possibility that you could be bitten by a mosquito, and end up with an infant with a devastating birth defect.”

The CDC, which is anticipating more U.S. cases beyond the single known affected birth (plus two miscarriages and two elective abortions), is struggling to better understand how the virus affects infants’ brains.

“Microcephaly is just a very crude estimate of the size of the head, but really what we are seeing is a pattern of severe brain abnormalities—destruction of brain tissue, and then basically the skull collapses,” said Dr. Denise Jamieson, an obstetrician who is co-leader of the pregnancy and birth defects group in the CDC’s Zika Virus Response Team. As a result, she says, researchers are starting to think of microcephaly as a suite of defects.

As for pinning down Zika as the cause, a recent study found Zika virus in brain tissue of microcephalic infants. “We’re not saying currently that Zika causes adverse pregnancy outcomes such as microcephaly, but we are gathering more evidence every day suggesting there is a link,” Jamieson said.

The lack of brain development in microcephaly has been seen in rare cases before, she said. In the medical literature, it is called “fetal brain disruption sequence,” and while not common, it is associated with the pregnant women being traumatically injured or contracting other viral illnesses. Overall, Jamieson said, the current rate of microcephaly in the United States is six cases per 10,000 births.

To detect an increase—which could happen if women residing in the U.S. were infected while pregnant and traveling, or were made pregnant by infected sexual partners, or if Zika began to spread on the U.S. mainland—the CDC has made Zika a “nationally notifiable” disease, which requires physicians to report diagnoses to state health departments, who forward the information to the CDC. The agency has also set up a birth registry, expected to go live this week on its website, that will collect the information gathered by health departments and sift it for clues. (To reach the registry or ask questions about Zika in pregnancy, doctors can also call the CDC at (770) 488-7100 and ask for the CDC Zika Pregnancy Hotline, or email ZikaMCH@cdc.gov.)

Latest Science

Two scientific papers published Friday help illuminate the puzzle of how Zika affects pregnancy and how it causes brain damage. An examination of the pregnancies of 88 women in Rio de Janeiro, published in the New England Journal of Medicine, revealed “serious and frequent problems in fetal and central nervous system development” in 29 percent of the pregnancies in which women who had experienced Zika symptoms and were pregnant allowed prenatal imaging. (Some declined or could not obtain it.)

View Images Arthur Ferreira Da Conceicao, who is 4 months old, was born with microcephaly after his mother contracted Zika while pregnant. He and his family live in Ibura, Recife, Brazil. Photograph by Tomás Munita, National Geographic

The women were infected not just in their first trimester but across the durations of their pregnancies. Not all of the pregnancies have come to term yet, but so far, the researchers said, there have been two miscarriages and six live births. Both the live infants and those yet to be born show a range of birth defects: not just microcephaly but calcifications in brain tissue, abnormalities of brain structure, eye disorders, clubfoot, and several children small for their gestational age.

Also Friday, researchers from Florida State University, Johns Hopkins University, and Emory University published in the journal Cell Stem Cell a description of an experiment in which they infected a range of human cells with Zika virus in the lab. The virus showed a preference for developing in and destroying cells similar to those that form the cortex, the grey matter, of the brain during fetal development: infecting up to 90 percent of them, destroying a third, and retarding the development of the rest. The cells did not appear to mount an immune response to the virus. The researchers cautioned that their work was very preliminary, but said it might provide the first steps in understanding why Zika appears to destroy infants’ brain tissue.

A day earlier, CDC researchers published an analysis and data tool that could help areas experiencing Zika anticipate the highest-risk times for the occurrence of birth defects. Using data from the Brazilian state of Bahia, the researchers mathematically derived the time in pregnancy when risk is highest: the first trimester and early in the second trimester. The researchers said this could help jurisdictions prepare for the extensive, expensive public services that microcephalic babies and their families are likely to need.

Back in the United States, experts in birth defects worry about how rapidly Zika infection will appear in children here.

“We’re very concerned,” said Dr. Edward R.B. McCabe, who is executive vice president and chief medical officer at the March of Dimes, which has launched a Zika rapid-response team and an information bank in English and Spanish. “We really need to figure out much more real-time detection. You want to find that baby right now, and look at them in their family and their community, so you can link the community to prevention, contact tracing, (mosquito) management.”

What Will Happen to These Babies?

Registries are funded by states, and state support for public health is very variable. McCabe said birth defect experts are already tense about how much funding will be available for services and support as affected children grow up.

View Images In slums, mosquitoes find prime conditions to breed and spread disease. In a favela in Pilar, Recife, Brasil, Maria de Fatima dos Santos, 20, holds her three-month-old baby Eduarda Vitoria Santos, who was born with microcephaly. Older daughter Vittoria is not affected. Photograph by Tomás Munita, National Geographic

“We really need to invest in the follow-up of babies exposed to Zika, to detect later-onset problems, which might be behavioral or school problems,” he said. “We may see a spectrum from the severe microcephaly we are seeing in Brazil to milder neurological [conditions].”

If the disease burgeons in the U.S., McCabe said—a possibility, given the presence of the mosquitoes that carry it, the lack of any vaccine and the disorganized state of U.S. mosquito control—the cost could be enormous. “If we find Zika-associated microcephaly becomes a big problem in the United States,” he warned, “this is going to be a huge blow to the public health system.”