What we need to find out about Zika and pregnancy

Researchers across the world are urgently studying the virus to understand more about its effects on unborn babies.

Until a few months ago, Zika virus had done little to attract attention since it first emerged in Uganda in 1947. Now, it is the centre of an international health emergency and has highlighted the weaknesses in the infrastructure we have to respond to epidemics.

Since it reached South America, Zika has spread rapidly. For almost everyone infected, the effects are short-lived. But among the babies born to infected women, there has been a surge in microcephaly, a condition where they have unusually small heads and sometimes associated brain abnormalities.

So what do – and don't – we know about Zika and pregnancy? And what are scientists doing to find out more?

In many ways, says Professor Laura Rodrigues from the London School of Hygiene & Tropical Medicine, we are starting from scratch. "We don't have a vaccine, we don't have a treatment, and we have very little immunological knowledge."

Because Zika was such a mild disease and microcephaly was so uncommon, little effort was made to monitor them. Zika is so short-lived and often so mild that some people do not even realise they are infected, and there is no reliable test for past infection. As for microcephaly, there isn't even a standardised definition (the World Health Organization is currently convening experts to come up with one).

This is why Rodrigues, who leads collaborations between the London School and her native Brazil, has flown to Pernambuco, the Brazilian state at the centre of the epidemic, to help carry out three studies.

Scientists are also trying to unpick Zika on a molecular level, and to discover what other effects it might have. It is possible, for example, that these include Guillain–Barré syndrome, a disease caused by damage to the nervous system. Researchers are also investigating Zika's pattern of transmission – primarily by the Aedes mosquito – as well as mapping its geographical spread and investigating whether previous infection provides immunity (which would suggest a vaccine should work).

Already many theories have been advanced – for example, that microcephaly might be triggered not by Zika alone, but by some interaction with pre-existing antibodies to dengue. A key question, according to Professor Tom Solomon, director of the Institute of Infection and Global Health at the University of Liverpool, is whether Zika manifests in the same way wherever it occurs, or whether its effects differ between places: "Does [microcephaly] in some way relate to the population, to the high levels of dengue antibodies [in Brazil], or yellow fever vaccinations? Or is this just what this virus does?"

In answering such questions, scientists have useful road maps to guide them. Zika, like dengue and yellow fever, is a flavivirus, a group of well-studied viruses. "Although Zika is newly emerged, there's a whole range of other flaviviruses which cause various degrees of neurological disease, so we do have some approaches to follow," says Solomon. For example, he predicts, based on previous experience, that Zika may also cause encephalitis.

The virus can also be compared with a group of others that affect unborn babies, including toxoplasmosis, rubella, cytomegalovirus and herpes. Zika seems to share some of their properties, but not all: for example, Zika is the only one to be transmitted by mosquito.

Several studies have now found Zika virus in the brains of fetuses or newborns with microcephaly, including one whose mother is thought to have been infected with Zika at the end of her first trimester. Something we don't know, according to Rodrigues, is why some viruses that cross the placenta and cause malformations at birth but others don't.

"We know that once Zika crosses the placenta it multiplies in the brain of the fetus," says Rodrigues. "It’s certainly the cortical function of the brain that's affected: attention, reasoning, language. But what we don't understand is how the virus has these effects on the cortex (the folded outer layers of the brain). For example, does it cause direct damage, or does it make other cells migrate there?"

The Zika research seeks to understand how the virus spreads and causes disease, to control the mosquito that carries it, and, ideally, to develop a vaccine. Yet there is an ethical stumbling block. Pregnant women, or those planning to be pregnant, have traditionally been excluded from medical trials, because of the risks to the baby and the fact that pregnant bodies work differently from other women's. But this means that, in an emergency, we have little idea of which drugs or vaccines pregnant women can safely use.

This situation is changing.

"Normally the default would be that pregnant women shouldn't be included [in research] and you'd have to justify including them," says Dr Annette Rid, a senior lecturer in bioethics at King's College London. "Now it's increasingly recognised that you need to give a reason to exclude them."

But even though the Council for International Organizations of Medical Sciences is updating its guidelines to reverse the presumption that "groups in need of special protection" should be excluded from clinical studies, the ethical concerns remain. "If someone has a bright idea for treating a woman who gets Zika in very early pregnancy, and there's an intervention they want to try to treat her or prevent malformation, it's at that stage that the tricky questions would come up," says Rid.

This isn't the only ethical issue with Zika. In the absence of a vaccine, health authorities are focusing on prevention. This includes targeting the mosquitoes that carry the virus and educating people on how to avoid becoming infected, especially while pregnant.

Some have argued that this should include promoting contraception and abortion. Yet Brazil is a Catholic country; while the former is legal, the latter is not. Creating an exemption for microcephaly is a decision for politicians, not doctors – as is how to divide funding between preventing Zika infection, researching cures and vaccines, and supporting the victims.

Today, the most urgent task for researchers is to get a clearer idea of the relationship between Zika and microcephaly: what the infection does, when the risks are highest and, ultimately, what we need to do to stop its spread within the Americas and across the rest of the world.

This is a massive challenge," says Rodrigues. "The scientific community has only had four months to start studying and thinking. There are so many questions – and findings. There are new things happening all the time."