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New estimates show higher rates of Zika-related brain abnormalities in infants
Results from two recent studies indicate that microcephaly and other brain abnormalities in fetuses and infants exposed to Zika virus during pregnancy occurred more frequently than previous estimates. However, the proportion of infants with birth defects vastly differed between the studies.
“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,” Lyle R. Petersen, MD, MPH, director of the CDC’s Division of Vector-Borne Diseases and Infectious Disease News Editorial Board member, and colleagues wrote in JAMA. “More complete clinical evaluation of infants including neuroimaging and audiological, ophthalmological, neurological and developmental assessments will be needed to fully describe the extent of brain abnormalities and other adverse outcomes in affected fetuses and infants.”
Preliminary estimates reveal higher rates of microcephaly
Preliminary data on completed pregnancies in the United States showed that 6% of fetuses or infants with congenital Zika exposure had one or more birth defects potentially linked to the virus. In addition, researchers found that cases exposed to Zika virus during the first trimester were disproportionately affected by the infection.
The JAMA report included data from the U.S. Zika Pregnancy Registry (USZPR) on completed pregnancies with evidence of Zika virus infection that were reported in the continental United States and Hawaii from Jan. 15 to Sept. 22, 2016. All infections were developed during travel to areas with active transmission, including Barbados, Belize, Brazil, Columbia, Dominican Republic, El Salvador, Guatemala, Haiti, Honduras, Mexico, Republic of Marshall Islands and Venezuela. Peterson and colleagues examined the data to estimate the proportion of fetuses and infants with abnormalities possibly linked to Zika and to determine whether the incidence of birth defects varied by trimester and maternal symptoms.
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The researchers identified 442 completed pregnancies, including 395 live births and 47 pregnancy losses. Overall, 26 (6%; 95% CI, 4%-8%) fetuses or infants had birth defects possibly caused by Zika virus. The proportion of fetuses and infants with birth defects was similar among symptomatic (6%; 95% CI, 4%-9%) and asymptomatic women (6%; 95% CI, 3%-11%), underscoring the importance of screening all pregnant women for exposure to Zika virus and testing patients in accordance with CDC recommendations, the researchers wrote.
Eleven percent (95% CI, 6%-19%) of fetuses exposed during the first trimester had birth defects, which is consistent with previous reports, according to the CDC. There were no birth defects among cases exposed to Zika during the second or third trimesters.
However, the proportion of infants with microcephaly represented 4% of completed pregnancies. According to the researchers, this estimate is substantially higher than the background prevalence of microcephaly in the U.S., which is approximately 0.07% of live births.
Of the 26 fetuses and infants with birth defects, four had microcephaly and no reported neuroimaging, 14 had microcephaly and other brain abnormalities — including intracranial calcifications, corpus callosum abnormalities, abnormal cortical formation, cerebral atrophy, ventriculomegaly, hydrocephaly and cerebellar abnormalities — and four had microcephaly without brain abnormalities.
In a related editorial, William J. Muller, MD, PhD, of the department of pediatrics, and Emily S. Miller, MD, MPH, of the department of obstetrics-gynecology at Northwestern University Feinberg School of Medicine in Chicago, Illinois, addressed several limitations of the study. They noted that USZPR data on pregnant women tested for Zika likely represents an underestimation of asymptomatic cases, and that many infants were not assessed for disorders after delivery. According to Peterson and colleagues, 12% of infants with birth defects and 41% of all fetuses and infants lacked testing results.
Muller and Miller also added that there was potential Zika exposure in more than one trimester for many of the affected pregnancies, and longer-term outcomes of infants are not yet available.
“Thus, for congenital Zika infection, based on these data it remains unclear whether the increased risk of congenital abnormalities observed with periconceptional or first-trimester exposure is a result of an increased propensity toward overall fetal infection or, rather, a reflection of an increased severity of adverse fetal effects when infection occurs earlier in gestation,” they wrote.
Brazil reports even higher incidence of birth defects
In a separate study published in The New England Journal of Medicine, researchers found that adverse outcomes for infants in Rio de Janeiro occurred at a much higher rate when exposed to Zika during any trimester.
For the trial, Patrícia Brasil, MD, PhD, and colleagues from Rio de Janeiro, Brazil, examined data on 134 completed pregnancies with evidence of Zika virus infection, and 73 pregnancies with no evidence of the infection. All pregnant women included in the analysis developed a rash within 5 days of enrollment from Sept. 2015 through May 2016. Among the participants, 42% without Zika virus infection tested positive for chikungunya, and 3% were coinfected with both viruses (P < .001).
Based on available information, fetal death rates were 7% in both groups. However, 46% of fetuses and infants exposed to Zika had birth defects vs. 11.5% of fetuses and infants with no evidence of Zika virus infection (P < .001) Forty-two percent of 117 live infants exposed to Zika had abnormal clinical or brain imaging findings, or both, including four infants with microcephaly. These adverse events occurred in 55% of infants exposed during the first trimester, 52% exposed during the second trimester, and 29% exposed during the third trimester.
“Although microcephaly has been widely discussed in relation to [Zika virus] infection, it is important to note that other findings such as cerebral calcifications and fetal growth restriction were present more frequently,” Brasil and colleagues wrote. “We observed a variety of neurologic findings, including visual and hearing deficits, seizure activity, hypertonicity, spasticity, hyperreflexia, contractures, dysphagia and feeding difficulties.”
The researchers added that a “troubling aspect” of the study was that cases were assessed early in infancy when subtle neurologic manifestations are difficult to identify; however, the infants will continue to be monitored.
A CDC report released last month showed that infants born without microcephaly can develop the condition and other neurologic disorders later in life. The MMWR report described 13 infants in Brazil who did not have microcephaly at birth but tested positive for Zika virus-specific IgM and later developed brain abnormalities related to congenital Zika syndrome, including decreased brain volume, cortical malformations, ventriculomegaly and subcortical calcifications. Their head growth began to decelerate as early as 5 months after birth, and 11 of the infants developed microcephaly. Based on this information, CDC stated in a news release that the proportion of infants with Zika-related birth defects could increase within the first year of life.
Meanwhile, a more recent CDC study revealed that Zika virus replicates and persists in placentas and fetal brains, strengthening the link between congenital Zika virus infection and microcephaly. The researchers tested samples from eight infants with microcephaly who died and 44 women with suspected Zika virus infection during pregnancy. Through in situ hybridization, they identified replicative Zika RNA in tissues from seven fetal brains and placentas of nine women who had a pregnancy loss during the first or second trimester.
Despite this accumulation of new evidence, Margaret A. Honein, PhD, MPH, epidemiologist and chief of the Birth Defects Branch at CDC, and Denise J. Jamieson, MD, MPH, chief of the CDC’s Women’s Health and Fertility Branch, suggested that more research is needed to determine risks associated with Zika virus infection during specific gestational periods and to identify the role of other factors, including coinfections with dengue, chikungunya or toxoplasmosis.
“Although in this past year we have learned rapidly about the effects of [Zika virus] infection during pregnancy, many questions remain,” they wrote in an editorial. “Most notably, we need to develop an effective vaccine and promote a vaccination strategy to protect pregnant women and their infants.” – by Stephanie Viguers
References:
Bhatnagar J, et al. Emerg Infect Dis. 2016;doi:10.3201/eid2303.161499.
Brasil P, et al. N Engl J Med. 2016;doi:10.1056/NEJMoa1602412.
Honein MA, et al. JAMA. 2016;doi:10.1001/jama.2016.19006.
Honein MA and Jamieson DJ. N Engl J Med. 2016;doi:10.1056/NEJMe1613368.
Muller WJ and Miller ES. JAMA. 2016;doi:10.1056/NEJMoa1602412.
van der Linden V, et al. MMWR. 2016:doi:10.15585/mmwr.mm6547e2.
Disclosures: One researcher affiliated with the JAMA study received grant support from the Bill and Melinda Gates Foundation.