LONDON,(Reuters) - Evidence is building for the theory that Zika can cause newborn brain defects and the World Health Organization is promising more answers in weeks, but nailing a definitive link will be neither simple nor swift.

Picking apart numerous potential connections between mothers who show evidence of infection with the mosquito-borne virus and babies born with microcephaly, in which the head is abnormally small, will require precision and patience, specialists say.

In the case of rubella, another similar virus that is now known to cause congenital defects, it was a decade before the matter was finally settled.

Anthony Fauci, director of the U.S. National Institute of Allergy and Infectious Disease (NIAID), says the timing of any conclusion "depends on how definitive you want to be".

"The absolute definitive proof will come from case-controlled studies, and those usually take months," he said.

The current outbreak of Zika started in 2015 in Brazil and has since spread to over 20 countries in the Americas, leading the WHO to declare the virus and its suspected links to birth defects and neurological problems a global emergency.

Brazil has confirmed more than 500 microcephaly cases in the last few months and officials believe most are Zika-related. Authorities are investigating another 3,900 suspected cases.

Ian MacKay, a virus specialist at Australia's University of Queensland, has no doubts that proving or disproving a causative Zika-microcephaly link will take "a long time".

"Even then there may not be any single 'smoking gun'," he told Reuters.

Among criteria used by experts seeking to prove whether or not a pathogen is causing disease are a group of tests known as "Koch's postulates". Developed in the 19th century, they were used in 1984 to show that human immunodeficiency virus (HIV) causes AIDS.

Albert Ko, a tropical disease expert at Yale University and at Brazil's Oswaldo Cruz Foundation, a government research institute, said these criteria would take some time to fulfill.

"We need to do rigorous science, and doing rigorous science helps us understand better how to treat the disease," he said.


Part of the challenge is the difficulty of ruling other things out.

Microcephaly is known to be linked to some parasitic and bacterial diseases, as well as rubella, herpes, HIV, exposure to chemicals such as arsenic, mercury and alcohol, and radiation.

To be certain that Zika is also a culprit, scientists must test for links with these known suspects, and also be sure not to ignore unknown possibilities.

"It's a huge amount of work, but a powerful study would be one lasting a year or more that enlists a cohort of mums-to-be months before becoming pregnant and intensively monitors them until the delivery of their baby," said MacKay.

Which is exactly what scientists in Brazil are aiming to do. Various research projects are in the works already, including a retrospective study in the northeastern state of Paraiba, and studies led by Ko's team in Salvador, on Brazil's east coast.

In Recife in Pernambuco State on the eastern tip of Brazil, a team led by Laura Rodrigues, a professor of infectious disease epidemiology at the London School of Hygiene and Tropical Medicine, plans three studies.

In the first, researchers will interview mothers of babies born with microcephaly about Zika exposure during pregnancy, collect blood samples, measure head circumferences and conduct infant CT scans. They will also do the same with a comparative group of mothers and babies with no microcephaly.

For a second study, pregnant women who get the kind of rash associated with Zika will be recruited and tested for Zika, as well as dengue and chikungunya, two other mosquito-borne viruses.

"Then we follow them to establish what proportion will have a miscarriage or a stillbirth, and what proportion have a baby with microcephaly or other malformations," Rodrigues said. "That will tell us how common microcephaly really is and how it is affected by the trimester in which the mother becomes infected."

The third study will track potential developmental delays by looking at factors such as whether babies have convulsions, and how they interact and make eye contact.

Rodrigues, whose team is working with closely with local hospitals and with the Pernambuco state health department, says there is "a sense of urgency", but full answers will take some months to emerge.


Researchers have found the Zika virus in the brain tissue and amniotic fluid of babies and stillborn fetuses with microcephaly whose mothers had Zika during pregnancy.

This still falls short of causative proof, but as NIAID'S Fauci believes "the evidence is increasingly mounting that there is a direct connection".

Preliminary results of two case control studies could come in May, according to U.S. officials.

The WHO, which in its Feb. 1 emergency declaration cited a "strongly suspected" link between Zika and microcephaly, says it hopes to see some new data within weeks, but it will likely be six months "before we can say with some certainty".

In the case of rubella, also known as German measles, the process of establishing proof of a link with congenital defects started in 1940, when Norman Gregg, an ophthalmologist from Sydney, noticed a spike in cases of babies with congenital cataracts after an epidemic of German measles in Australia.

He concluded in a paper published in 1941 that the disease was responsible.

The Lancet medical journal weighed in three years later, by which time rubella had also been linked to deafness and heart defects, to say Gregg still needed better data and "he cannot yet be said to have proved his case".

Definitive verification of the link only came in a 1951 paper by Australian statistician Oliver Lancaster, who showed that peaks in the age distribution of deaf people dating back decades coincided with past rubella epidemics.

Today, the connection is taken as proven and rubella vaccination is routine.

(Additional reporting by Julie Steenhuysen in Chicago and Ben Hirschler in London; Editing by Sonya Hepinstall)