By Hal B. Jenson, MD, FAAP

Professor of Pediatric and Adolescent Medicine, and Dean, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, MI

Dr. Jenson reports no financial relationships relevant to this field of study.

SYNOPSIS: Two recent studies clarify the substantial risk of congenital abnormalities following maternal Zika virus infection. The risk is highest in the first trimester of pregnancy, and appears similar following symptomatic and asymptomatic maternal infection.

SOURCES: Honein MA, Dawson AL, Petersen EE, et al. Birth defects among fetuses and infants of U.S. women with evidence of possible Zika virus infection during pregnancy. JAMA 2017;317:59-68.

Brasil P, Pereira JP Jr, Moreira ME, et al. Zika virus infection in pregnant women in Rio de Janeiro. N Engl J Med 2016;375:2321-2334.

The United States Zika Pregnancy Registry, established by the Centers for Disease Control and Prevention (CDC), monitors pregnancy and fetal or infant outcomes among pregnant women or their offspring with laboratory evidence of Zika virus infection. Since February 2016, the CDC has recommended Zika virus testing for all pregnant women following possible exposure to Zika virus through travel, sexual contact, or mosquito transmission, regardless of symptoms. Laboratory evidence of Zika virus infection includes a positive test result by RT-PCR or other nucleic acid amplification test, maternal IgM antibody, seroconversion, or immunohistochemical staining of tissues such as placenta.

A total of 442 pregnant women (median age, 28 years; range, 15-50 years) with possible Zika virus infection in the registry had completed pregnancies, with 271 (61%) asymptomatic mothers, 167 (38%) symptomatic mothers, and 4 (1%) with insufficient information. All pregnant women had travel-associated Zika virus infections, with four cases resulting from sexual transmission from a traveler to a non-traveler.

There were 26 offspring (6%; 95% confidence interval [CI], 4-8%) with birth defects, including 21 infants with birth defects among 395 live births, and five fetuses with birth defects among 47 pregnancy losses. Twenty-two (85%) of these fetuses or infants had microcephaly (4), brain abnormalities only (4) (e.g., intracranial calcifications, corpus callosum abnormalities, abnormal cortical formation, cerebral atrophy, ventriculomegaly, hydrocephalus, and cerebellar abnormalities), or both (14). Infants with microcephaly represented 4% (18/442) of the completed pregnancies.

The proportion of infants and fetuses with birth defects was 6% for both symptomatic women (95% CI, 3-11%) and asymptomatic women (95% CI, 4-9%). No birth defects were reported among pregnancies with maternal exposure or symptoms during only the second or third trimesters.

In Rio de Janeiro from September 2015 through May 2016, a total of 345 pregnant women who tested positive for Zika virus by RT-PCR and had a rash within the previous five days were enrolled in a prospective cohort to follow pregnancy outcomes. The timing of Zika virus infection ranged from 6-39 weeks of gestation, and the predominant maternal symptoms included a descending macular/maculopapular rash, pruritus (90%), arthralgia (62%), conjunctival injection (50%), headache, and short-term, low-grade fever (27%). Zika-negative women were more likely to have nausea, vomiting, anorexia, fatigue or malaise, myalgia, respiratory symptoms, and fever than Zika-infected women, who typically had a pruritic maculopapular rash and conjunctival injection.

There were 125 completed evaluable pregnancies among Zika-infected women, and 61 evaluable completed pregnancies among Zika-negative women. Fetal death rates were 7% in both groups. Small size for gestational age was seen in 9% of Zika-exposed newborns and in 5.3% of offspring of uninfected mothers. Central nervous system abnormalities on physical examination, imaging, or both were observed in 49 newborns (42%) among Zika-infected mothers, and in three newborns (5.3%) among uninfected mothers. Microcephaly was seen in four (3.4%) of the Zika-exposed newborns, and none of the offspring of uninfected mothers. A total of 31 of the 49 infants (63%) among Zika-infected mothers had grossly abnormal neurologic examinations, including hypertonicity, clonus, hyperreflexia, spasticity, contractures, and seizures.

Adverse outcomes occurred among Zika-infected mothers throughout pregnancy, affecting 55% (11 of 20) infected in the first trimester, 52% (37 of 71) in the second trimester, and 29% (10 of 34) in the third trimester.

One of the first-trimester miscarriages occurred in a Zika-infected mother who was also coinfected with chikungunya virus. Three of the seven adverse outcomes among the Zika-uninfected mothers were among mothers who were diagnosed with chikungunya virus.

COMMENTARY

The significant impact of Zika virus as a cause of central nervous system congenital abnormalities is becoming more clear, and is substantial. Microcephaly is an extreme finding, occurring in 3-4% of pregnancies following maternal infection, with central nervous system imaging and clinical abnormalities also occurring. These studies likely underestimate the complete risk of abnormalities with Zika virus infection. Entry criteria for both studies included having a positive test for Zika virus infection, which likely was performed because of the finding of maternal symptoms, and the Brazilian study also specifically included a maternal rash within five days. The U.S. study showed that the risk of congenital abnormalities was similar (6%) among both symptomatic and asymptomatic mothers. Outcomes in both studies were the immediate and severe sequelae in fetuses and newborns, and not the subtler potential long-term effects, such as learning deficits, which may not be seen until late childhood.

The Brazilian study found that the risk of congenital abnormalities was present throughout pregnancy, though with higher risk in early pregnancy. Microcephaly was found in four infants of mothers infected at 8, 12, 30, and 38 weeks of gestation, although disproportionate microcephaly was seen only in infants of mothers infected in the first trimester of pregnancy. These outcomes are perhaps analogous to other congenital infections, such as rubella, where the risk is significantly higher during the first 20 weeks of gestation and minimal later in pregnancy.

The best steps currently to manage Zika virus infection are preventive: counseling pregnant women to wear long-sleeves and use repellants to minimize exposure to mosquitos, including voluntarily limiting travel to Zika-endemic areas, and delaying conception after potential Zika virus exposure, for eight weeks for women and six months for men, and using barrier protection with sexual partners who potentially have been exposed.