Zika and Microcephaly: How Doctors Made the Link

Sonya Collins and Brenda Goodman

February 04, 2016

The first ultrasound scans were devastating.

In grainy black and white, doctors peeking into the wombs of pregnant women in Brazil could see trouble.

The brains of their tiny patients weren’t keeping pace with the rest of their growth. And something was badly wrong. The brain’s inner chambers seemed enlarged and deformed, and other key structures were altered -- a condition known as microcephaly.

Most puzzling to Adriana Melo, MD, PhD, an obstetrician and fetal medicine specialist in Campina Grande, Brazil, were the bright spots called calcifications that dotted the brain tissue.

“Since the first exams, when I started to see a strange pattern, I thought that this was something different, something new in Brazil,” Melo says. She says when the brain’s inner chambers are enlarged, it usually points to a genetic problem, but “...calcification suggests infection. So the combination of these findings was confusing.”

In an average year, a doctor in Brazil might see one or two pregnancies with birth defects like these. But by October, Melo had heard about more than 60 of these babies.

Fear took hold.

“There was a terrible rumor that vaccines were the cause,” Melo says. “And that was very hard for us, because people would talk about microcephaly and then someone would say, ‘Oh, just don’t get any vaccines,’” she says. “People started to believe that it was related.”

But Melo knew it had to be something else, and she raced to find it.

“We couldn’t just sit here,” she says. “I knew what I was seeing was something different, something new that we hadn’t seen before.”

Her first patient was a 34-year-old first-time mom. Melo had been her doctor from the beginning of her pregnancy. The woman had no risk factors for microcephaly. She didn’t smoke, didn’t drink, didn’t use drugs, and had no family history of genetic problems that might cause the condition.

What she did have was a rash and achy joints when she was about 8 weeks pregnant. Her symptoms had faded and she had seemingly recovered without a problem.

Source: Courtesy of Adriana Melo, MD

Nobody suspected Zika virus.

“We’ve had dengue here for years, and we just haven’t been that worried about that virus, and we thought this was going to be same,” Melo says.

Doing Detective Work

The virus was first discovered in a monkey in Uganda in 1947. It was only reported in humans about a dozen times for the next 50 years. Then in 2007, Zika infected about three-quarters of the population on the tiny island of Yap, between the Philippines and Papua New Guinea in the western Pacific Ocean. In 2013 the virus skipped east, where it caused another major outbreak on the islands of French Polynesia.

The virus seemed mild. About 80% of people who are infected never even know it. Those who do have mild symptoms, like a rash, joint pain, fever and red eyes, and they tend to recover quickly.

Melo says she first started hearing about Zika infections in Campina Grande in July. She and other doctors shrugged. It was a nuisance, but hardly unexpected in a tropical climate.

But as she tried to figure out what was affecting so many pregnant women at the same time, she remembered her patient’s rash and achy joints. Could it be Zika?

She read as much as she could about the virus. She learned it was neurotropic, meaning it likes to infect the nervous system. She also found two scientific reports that showed the same kind of brain damage in fetal cows and sheep after their mothers had been experimentally infected with viruses in the same family as Zika.

Melo knew she was on to something.

On Nov. 10, she used a long needle to draw samples of the pale amniotic fluid from two of her patients whose babies were showing signs of microcephaly. She sent them off for analysis.

On Thursday, as luck would have it, she had registered to attend a medical meeting in Sao Paulo --about 1,600 miles south of Campina Grande -- on the development of the fetal brain.

She took her patients’ medical records and their ultrasound scans so other doctors could see them and weigh in.

There she met Gustavo Malinger, MD, director of the obstetrical ultrasound unit at the Tel Aviv Sourasky Medical Center in Israel. She knew Malinger to be “one of the greatest fetal brain experts in the world.”

He was interested, but he expressed doubts.

“He thought it was virtually impossible that this could be caused by a virus,” she says. “But I insisted we were seeing a pattern. That made an impression on him.”

He asked her if she could bring the patients to him so he could repeat the scans. She told him that no, the patients lived thousands of miles to the north, and it wouldn’t be possible.

But she knew this was a critical piece of evidence. She left Malinger and quickly called Brazil’s Ministry of Health -- an agency that’s a bit like the Department of Health and Human Services in the U.S. -- and convinced them to pay for plane tickets for the women to travel to Sao Paulo the next day.

“I performed the examinations in Sao Paulo,” Malinger says, after the doctors found a private hospital that allowed them to do ultrasounds and MRIs.

“The findings were very surprising,” he says. “Most of the brain structures were destroyed. Also the eyes were destroyed.” They were, he says, “without hope.”

Malinger did the exams on the Nov. 14. By the following Monday, Melo had her lab results back. The amniotic fluid around the babies was teeming with Zika virus.

“On Monday, when I gave him the results, he was truly taken aback. This was something,” Melo says. “It was the first time in the world that we had been able to detect Zika virus in amniotic fluid. And we had documented just how aggressive the virus was.”

The two later published their findings as a “Physician Alert” in the journal Ultrasound in Obstetrics and Gynecology.

'We Needed to Say Something to Women'

Though local doctors had suspected Zika might be causing microcephaly since September, “every time we tried to broach the subject, we were criticized because we didn’t have any evidence,” Melo says.

Evidence in hand, Melo alerted the Ministry of Health. After laboratory tests found Zika virus in the amniotic fluid around a third baby, stillborn in the neighboring state of Ceara, the agency sounded the alarm.

A week later, the European Centre for Disease Prevention and Control put out the first international alert that the microcephaly cases in Brazil might be linked to Zika.

The Brazilian doctors were criticized for the warning. Even with Zika in the amniotic fluid, the virus has still never been found in the blood from a baby’s umbilical cord. And right now, there’s no biological theory to explain how the virus might be doing its dirty work.

“For this, you need long-term studies,” Melo says. “We all know that. But my concern was -- why I wanted to get clarification of these cases -- is because we needed to say something to women who are pregnant now,” she says.

“This is very serious. They have to have a chance.”

For many of her patients, the discovery was simply too late. After learning of the microcephaly, many women wanted to abort their pregnancies, but abortion is against the law in Brazil.

But at least the government started to advise pregnant women to protect themselves with long pants, long sleeves, and socks, and to put screens on their windows -- something that’s rarely done in Brazil. Health officials have also started a campaign called “Sabado da Faxina,” or “Cleaning Saturday,” to get people to walk around their houses to check for trash and small pools of still water, even water that might collect in sidewalk cracks.

“There’s no such thing as enough protection,” Melo says.

Besides the infants who are obviously affected, Malinger predicts something worse.

“First they will diagnose the children who are most severely affected. In time, after 2 or 3 years, they will find other children who are sick -- they will be blind, they will have hearing problems, they will have cardiac problems. It won’t only affect the brain. It will be a multi-organ disease.” Melo stays in touch with mothers who have given birth to babies with microcephaly, privately, on social media.

“These mothers’ situations are very hard right now,” she says. “It’s the uncertainty. Because there’s nothing we can tell them about the prognosis of these children, so it’s very difficult for a mother who doesn’t know if her child is going to sit up, if her child is going to walk.”

The Brazilian Ministry of Health has pledged to follow the microcephaly babies. They are offering families physical therapy and other programs to help the children and try to minimize the consequences.

“These services are going to be overloaded. And this isn’t [just] a problem with Brazil. Nobody can say ‘Oh, Brazil isn’t prepared for this.’ No country is prepared for this,” Melo says.

SOURCES:

Adriana Melo, MD, PhD, President, Professor Joaquim Amorim Neto Research Institute, Campina Grande, Paraiba, Brazil.

Gustavo Malinger, MD, director of the obstetrical ultrasound unit at the Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.

Ultrasound in Obstetrics and Gynecology, January, 2016.

Morbidity and Mortality Weekly Report, January 22, 2016.

European Center for Disease Prevention and Control, November 24, 2015.

Emerging Infectious Diseases, September 15, 2009.

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