ANNAPOLIS, MD. (FRONTLINE MEDICAL NEWS) – The scramble to learn exactly how and when after infection the Zika virus affects the developing fetus, has put pregnant women at the center of an unprecedented infectious disease emergency response.

“It’s the most complicated infectious disease response we’ve ever done,” Dana Meaney-Delman, MD, of the Centers for Disease Control and Prevention, told an audience at the annual scientific meeting of the Infectious Diseases Society for Obstetrics and Gynecology. “It’s also the first time an emergency response team has included an ob.gyn.”

Although research into Zika virus is happening at breakneck speed, every finding seems to lead to still more questions. “It’s hard to keep up,” said Dr. Meaney-Delman, who is a Clinical Deputy on the Pregnancy and Birth Defects Task Force, part of the CDC’s Zika virus response.

What is known

What is known is that Zika virus is primarily vector-borne, either manifesting as a mild illness or remaining subclinical. The virus is also communicable through male-to-female sex, female-to-female sex, blood donation, and organ transplantation. Once infected, one is immune; if symptomatic, the presentation clears within a couple of weeks. If a woman is infected during pregnancy, it can be transmitted to the developing fetus, including at the time of birth, according to Dr. Meaney-Delman.

“We know transmission can occur in any trimester. We’ve seen it in the placenta, in amniotic fluid, in the brain, as well as in the brains of infants who have died,” she said.

Whether the virus poses a risk to the fetus around the time of conception is not clear, but Dr. Meaney-Delman said that since other infections such as rubella and cytomegalovirus do pose a risk, the CDC is issuing Zika guidance accordingly.

Despite an initial theory that pregnant women were more susceptible to Zika infection, there is no evidence to date confirming this, but “the combination of mosquitoes and sexual transmission really puts a woman of reproductive age at risk,” said Catherine Y. Spong, MD , who also spoke during the meeting. Dr. Spong is acting director of the National Institute of Child Health and Human Development, part of the National Institutes of Health.

Based on data derived from other flaviviruses, the “good news” is that infected nonpregnant women who later want to conceive do not have a higher risk of bearing a child with Zika-related complications, according to Dr. Meaney-Delman.

Abnormalities seen and unseen

During the initial stages of the Zika outbreak in Brazil, the spiking rate of babies born with microcephaly attracted the most attention; yet it is now apparent that children were also born with a growing list of other Zika-associated pregnancy outcomes that likely were missed at the time, according to Dr. Spong.

“That’s not to say that a child that doesn’t have microcephaly does or doesn’t have some of these other complications. We don’t know; they weren’t studied because they didn’t have the microcephaly,” Dr Spong said. “To get the data right, you need to follow all the children.”

Brain abnormalities such as ventriculomegaly and intracranial calcifications, as well as a range of growth abnormalities, miscarriage, and stillbirth are increasingly associated with infants born to infected women. Data is also beginning to link Zika virus to limb abnormalities, hypertonia, hearing loss, damage to the eyes and central nervous system, and seizures.

The World Health Organization has also noted the involvement of the cardiac, genitourinary, and digestive systems in babies born to infected mothers in Panama and Colombia. “The caveat [to these data], is that all these women were symptomatic,” Dr. Spong said, noting that in Brazil, where the outbreak was first documented, 80% of the infected pregnant women were asymptomatic during the pregnancy.

“Just because the mother has no symptoms, she’s fine? That doesn’t make any sense to me,” Dr. Spong said. “We know that infections in pregnancy can result in long-term outcomes in kids that you don’t have the ability to diagnose at birth. We need to be cognizant of this and we need to study it.”

Although initial theories were that viremia in symptomatic women was likely higher, thus imparting a higher risk of infection in their fetus, Dr. Meaney-Delman said the number of asymptomatic women whose fetuses are affected has debunked this line of thinking.

Risk of infection during pregnancy

As to what the actual risk of Zika virus infection is during pregnancy, “honestly we don’t know,” said Dr. Spong. “There are modeling estimates that [it’s] between 1% and 13% in a first trimester infection, but we don’t have the hard and fast data.”

The Zika in Infants and Pregnancy (ZIP) study , recently launched by the NIH, will provide a prospective look at birth outcomes in 10,000 women aged 15 years and older who will be followed throughout their pregnancies to determine if they become infected with Zika virus, and if so, how infection impacts birth outcomes.

The international, multi-site study will help clarify the timing of risk, Dr. Spong said, and is intended to elucidate pregnancy risks in symptomatic vs. asymptomatic women. The study will also help indicate whether nutritional, socioeconomic status, and other cofactors such as Dengue infection are implicated. Once born, all children in the study will be observed for a year. “Even if they have no abnormalities, after birth there could be developmental delays, or more subtle consequences later on in the child’s life,” Dr. Meaney-Delman said.

Meanwhile, researchers are attempting to map how varying levels of viremia affect transmission. Zika virus has been found in semen after 90 days in at least two studies, “and we don’t know if Zika can be transmitted through other bodily fluids,” Dr. Spong said.

Surveillance data from the CDC’s Zika Pregnancy Registry has shown viremia in symptomatic women can last up to 46 days after onset of symptoms. In at least one asymptomatic pregnant woman, viremia was detected 53 days after exposure. Another study found prolonged viremia – 10 weeks – in a patient who had Zika infection in her first trimester; imaging showed the fetus was developing normally until week 20, when signs of severe brain abnormalities were detected.

The emerging picture of Zika’s potential for prolonged viremia has prompted the CDC to recommend clinicians use reverse transcription–polymerase chain reaction (RT-PCR) testing rather than serologic testing, as it is more sensitive and helps rule out other flavivirus infections, which require different management, Dr. Meaney-Delman said.

Potential mechanisms of action

“It’s clear that the virus does directly infect human cortical neural progenitor cells with very high efficiency, and in doing so, stunts their growth, dysregulates transcription, and causes cell death,” Dr. Spong said.

Researchers have also found that Zika replicates in subgroups of trophoblasts and endothelial cells, and in primary human placental macrophages, resulting in vascular damage and growth restriction. Other research suggests the virus spreads from basal and parietal decidua to chorionic villi and amniochorionic membranes, leading to the theory that uterine-placental suppression of the viral entry cofactor TIM1 could stop transmission to the fetus.

Prevention and management

CDC officials expect the current outbreak to mimic past flavivirus outbreaks which were contained locally in portions of the South and U.S. territories, Dr. Meaney-Delman said. Still, she emphasized that clinicians should screen patients, regardless of location. “Each pregnant women should be assessed for [vector] exposure, travel, and sexual exposure and asked about symptoms consistent with Zika virus,” Dr. Meaney-Delman said.

She also emphasized the importance of patients consistently using insect repellent and using condoms during pregnancy, as Zika has been detected in semen for as long as 6 months. “It’s been very hard to invoke this behavioral change in women, but it’s very effective.”

The CDC continues to update guidance , including how to evaluate newborns for Zika-related defects.

As for what resources might be needed in future to help affected families, in an interview Dr. Meaney-Delman said that depends on information still unknown. “Zika is a public health concern that we should be factoring in long term, but what we do about it will depend upon the outcomes,” she said. “If there are children that are born normal but who have lab evidence of Zika, then we will probably not do much. I don’t think we have a projection yet.”

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