Pinning down the likelihood of birth defects in pregnant women with Zika virus has been an urgent research need, and two new cohort studies—one from Brazil and one from the United States—reported initial findings that show different rates for the two groups but shed more light on the connection between pregnancy exposure and birth defects.

In another key development, researchers have shown for the first time that Zika virus can replicate and persist not only in fetal brains—and even in babies after birth—but also in the placentas of pregnant women.

The Brazil-based study, published yesterday in the New England Journal of Medicine (NEJM), updates a preliminary report from March that compared outcomes in Brazilian pregnant women who did and didn't have Zika. The final report found that 42% of babies who contract the virus from symptomatic mothers during pregnancy may have birth defects.

Today researchers from the US Centers for Disease Control and Prevention (CDC) reported their first findings from the US Zika Pregnancy Registry. The data reveal that, of 442 completed pregnancies, 6% of babies had Zika-related birth defects, with the number a little higher (11%) in babies who were likely infected during the first pregnancy trimester.

The team published its findings in an early online edition of the Journal of the American Medical Association (JAMA).

Brazilian team found problems from exposure in all trimesters

In the Brazilian study, researchers enrolled 345 pregnant women from Rio de Janeiro from September 2015 through May 2016 who had a rashlike illness during pregnancy for clinical evaluation and to monitor the impact on babies. Zika virus infection was confirmed in 182 (53%) of the women, with chikungunya—another mosquito-borne illness—found in 42% of women without Zika infections.

Looking at known pregnancy outcomes as of July, the researchers saw birth defects in 46% of 125 Zika-affected pregnancies, compared with similar problems in 11.5% of babies born to women who tested negative for Zika virus. The fetal death rate of 7% was similar for both Zika-positive and Zika-negative mothers.

Of the 117 babies born live to Zika-infected mothers, 42% had abnormalities on clinical exam, brain imaging, or both, and four had microcephaly. Alongside evidence of growth restriction and cerebral calcification, clinicians also saw a range of neurologic problems, including vision and hearing defects, seizures, and difficulties with swallowing and feeding.

Birth defects were noted in babies exposed to the virus in all pregnancy trimesters, even as late as 39 weeks. Birth defects were more common, however, when mothers were sick with Zika during the first and second trimesters.

In an editorial in the same issue of NEJM, two CDC experts said the findings provide new evidence on the range of Zika-related birth defects and the risk of problems at any point during pregnancy. The experts are Margaret Honein, PhD, MPH, chief of the CDC's birth defects branch, and Denise Jamieson, MD, MPH, chief of the CDC's women's health and fertility branch.

Though the clinical significance of the imaging findings is still murky, the Brazilian group's findings make it clear that the devastating effects of Zika virus aren't limited to early pregnancy and that fetal brain damage can occur even with infections during the second and third trimesters, the experts said.

"These findings are sobering and emphasize the public health urgency of planning for the needs of children and families affected by the congenital Zika syndrome," they wrote, warning that longer-term follow-up is needed to detect problems that appear later in babies with normal postnatal exams.

US study: Similar birth defect levels for women with, without symptoms

In the second cohort study, CDC investigators looked at 442 completed pregnancies in which mothers, fetuses, or babies had lab-confirmed evidence of possible Zika infection. The cases reflect exposure that occurred in countries or locations abroad with local Zika activity. The pregnancies were reported from US states from January 15 through September 22.

Zika-related birth defects were identified in 26 (6%) of the completed pregnancies: 21 were live births and 5 involved pregnancy losses. The level of birth defects was the same in pregnant women who did and didn't have symptoms. The birth defects were somewhat more common when infants' exposure to Zika occurred only during the first trimester, though the investigators said the infection timing wasn't known for several of the pregnancies.

Of the 26 Zika-affected babies or fetuses, 22 had brain abnormalities with or without microcephaly. Four had microcephaly.

The researchers said their preliminary findings are within the range of the 1% to 13% risk of microcephaly estimated from a Zika outbreak in Bahia, Brazil. "Although much of the attention has focused on microcephaly, the underlying brain abnormalities, particularly those not easily detectable on clinical assessment of the newborn, are of paramount concern," the researchers said. They added that more complete evaluation of affected babies is needed to describe the full extent of the abnormalities in affected infants.

The findings support the importance of screening pregnant women for exposure to Zika virus, the team concluded.

In a related editorial, two experts from Northwestern Feinberg School of Medicine in Chicago said though the data have some limitations, they shed light on the question of whether asymptomatic and symptomatic infections are equally likely to lead to birth defects. The authors are William Muller,MD, PhD, with the department of pediatrics, and Emily Miller, MD, MPH, with the department of obstetrics and gynecology.

They said the study notes that only 41% of babies born to women with lab evidence of Zika virus didn't have Zika virus testing completed, suggesting a significant practice gap, given that serologic and polymerase chain reaction testing is recommended.

The early findings from the CDC registry underscores the importance of its recommendations, including urging pregnant women to avoid active transmission areas, avoid mosquito bites, and practice safe sex, the two wrote.

New tests reveal Zika persistence in fetal brains, placenta

The new Zika replication findings, meanwhile, may help explain why the virus causes such serious birth defects and pregnancy losses. Investigators from the CDC and Colombia published their findings yesterday in an early online edition of Emerging Infectious Diseases.

They examined tissues samples from 52 patients—8 babies with microcephaly who died and 44 women—that were submitted to CDC labs for testing. The patients were from the United States and its territories, Brazil, and Colombia. The team developed new tests to detect Zika in tissue samples that can show evidence of virus in tissues long after it would be seen in blood samples, which is only 12 weeks after infection.

Brain tissue from all eight of the infants were positive for Zika virus, which was also found in placental samples of 16 of 22 women. Mothers of babies who died and women who tested positive for Zika virus had been sick during their first pregnancy trimester. Zika virus RNA, however, was also found in one third of the women who delivered apparently healthy babies.

Julu Bhatnagar, PhD, a molecular pathologist from the CDC's Infectious Diseases Pathology Branch and lead author of the study, said in a CDC press release yesterday, "Our findings show that Zika virus can continue to replicate in infants' brains even after birth, and that the virus can persist in placentas for months—much longer than we expected."

She said it's not known how long the virus can persist, but lingering Zika could have an impact on babies with microcephaly and apparently healthy infants whose mothers contracted the virus during pregnancy.

The new molecular tests could help provide answers to women who were sick with Zika during early pregnancy but were never diagnosed, Bhatnagar said. "These tests could help determine whether Zika virus may have caused their miscarriage, pregnancy loss, or adverse birth outcome."

See also:

Dec 13 NEJM abstract

Dec 13 NEJM editorial

Dec 14 JAMA abstract

Dec 14 JAMA editorial

Dec 13 Emerg Infect Dis report

Dec 13 CDC press release