Zika Virus Infection in Pregnancy Linked to Severe Outcomes Including Fetal Death, CNS Injury

Laurie Barclay, MD

March 04, 2016

Zika virus (ZIKV) infection in pregnancy is linked to severe fetal outcomes including death, central nervous system (CNS) injury, growth restriction, and placental insufficiency, according to a preliminary report of a surveillance case series from Rio de Janeiro, Brazil, published online March 4 in the New England Journal of Medicine.

"[O]ur findings provide further support for a link between maternal ZIKV infection and fetal and placental abnormalities that is not unlike that of other viruses that are known to cause congenital infections characterized by intrauterine growth restriction and placental insufficiency," write Patrícia Brasil, MD, from Fundação Oswaldo Cruz, Rio de Janeiro, and colleagues.

Maternal ZIKV infection has previously been associated with neonatal microcephaly. From September 2015 through February 2016, the investigators enrolled 88 pregnant women with rash, of whom 72 (82%) tested positive for ZIKV in blood and/or urine by reverse-transcriptase polymerase chain reaction assays. The researchers followed the women prospectively with clinical examinations and serial ultrasound.

Despite relatively mild symptoms in the mothers, the infants experienced grave outcomes. These included two deaths at 36 and 38 weeks of gestation, in utero growth restriction with or without microcephaly, ventricular calcifications or other CNS lesions, and abnormal amniotic fluid volume or cerebral or umbilical artery flow.

"Women with suspected or confirmed ZIKV infection should be monitored closely, with serial ultrasonography to evaluate for signs of placental insufficiency, given the risks of fetal death and intrauterine growth restriction," the study authors write. "The establishment of a scientifically credible link between ZIKV and abnormal congenital findings is of utmost importance for the effective and successful management of this epidemic in Brazil and worldwide."

Maternal Symptoms Relatively Mild, but Fetal Outcomes Severe

Women presented with suspected acute ZIKV infection at 5 to 38 gestational weeks. Characteristic symptoms were descending macular or maculopapular rash, which was pruritic in 94%; joint pain; conjunctival injection; and headache. Fever was not a prominent finding, occurring in less than one third of the patients (28%), and was mostly short-term and low-grade when present.

Compared with women who were negative for ZIKV, those who were positive were more likely to have maculopapular rash (44% vs 12%; P = .02), conjunctival involvement (58% vs 13%; P = .002), and lymphadenopathy (41% vs 6%; P = .02). Joint pain occurred in 65% of ZIKV-positive women and in 41% of ZIKV-negative women, which was not a statistically significant difference (P = .16).

"As compared with women who tested negative for acute ZIKV infection, women who tested positive for the virus had distinctive clinical features of ZIKV infection that included conjunctival injection, lymphadenopathy, and absence of respiratory symptoms," the study authors write. "These clinical features, in addition to a macular or maculopapular rash with pruritus, should raise the suspicion for ZIKV infection. Low-grade fever was found in only 28% of the women; therefore a case definition that is based on the presence of fever would miss more than 70% of cases."

All ZIKV-negative women had fetal ultrasound, as did 42 ZIKV-positive women (58%). Doppler ultrasound showed fetal abnormalities in 12 (29%) of the 42 ZIKV-positive women compared with none of the 16 ZIKV-negative women. Two ZIKV-positive women miscarried during the first trimester, yielding a fetal death rate of 4.8%.

The authors describe these findings as "worrisome," because the patients were all healthy women with no other risk factors for adverse pregnancy outcomes. Adverse ultrasound findings included the following:

  • in utero growth restriction with or without microcephaly (n = 5),

  • abnormal cerebral or umbilical artery flow (n = 4),

  • cerebral calcifications (n = 4),

  • other CNS alterations (n = 2),

  • oligohydramnios and anhydramnios (n = 2), and

  • additional malformations (n = 1): agenesis of the vermis, Blake's pouch cyst, and potentially a club foot in a fetus with cerebral calcifications, intrauterine growth restriction, microcephaly, and negative genetic findings.

Eight of the 42 ZIKV-positive women undergoing fetal ultrasonography delivered their babies (six live births and two stillbirths), with confirmation of abnormalities detected on ultrasound.

Abnormalities were noted in the fetuses of women who were infected at any week of gestation. Although fetuses infected in the first trimester had findings suggestive of pathologic change during embryogenesis, CNS abnormalities also occurred in fetuses infected as late as 27 weeks.

Similarities to Rubella, but Without Population Immunity

The investigators note that many aspects of ZIKV infection resemble those of rubella, notably maternal rash, joint pain, pruritus, and lymphadenopathy without high fever, as well as intrauterine growth restriction, seen in approximately 85% of babies with congenital rubella in the 1959 to 1965 US pandemic.

"A major difference of concern between ZIKV infections in Brazil in 2015–2016 and rubella virus infections in the U.S. pandemic of 1959–1965 is the level of population immunity," the study authors conclude. "In Brazil in 2015–2016, none of the population has antibodies to ZIKV. In contrast, in the United States during the rubella epidemic, there were 20,000 cases of the congenital rubella syndrome, but in 1959 only 17.5% of women of childbearing age lacked rubella antibodies."

This study was not supported by any research funds. The authors have disclosed no relevant financial relationships.

N Engl J Med. Published online March 4, 2016. Full text