Investigators have added more evidence to the link between congenital Zika virus infection and fetal brain damage, and the data offer insight into how the virus affects brain development at different stages, according to a case study published online ahead of print March 30 in the New England Journal of Medicine.
“Our study highlights the possible importance of [Zika virus] RNA testing of serum obtained from pregnant women beyond the first week after symptom onset, as well as a more detailed evaluation of the fetal intracranial anatomy by means of serial fetal ultrasonography or fetal brain MRI,” said Rita W. Driggers, MD, of Johns Hopkins University in Baltimore, and her associates.
Rita W. Driggers, MD
The study also helps to fill gaps in research that were highlighted by Lyle R. Petersen, MD, MPH, and his associates at the CDC in an overview of the virus. “These [gaps] include a complete understanding of the frequency and full spectrum of clinical outcomes resulting from fetal Zika virus infection and of the environmental factors that influence emergence, as well as the development of discriminating diagnostic tools for flavivruses, animal models for fetal developmental effects due to viral infection, new vector control products and strategies, effective therapeutics, and vaccines to protect humans against the disease,” said Dr. Petersen.
MRI Found Fetal Brain Abnormalities
In the case study, a 33-year-old Finnish woman developed an infection from Zika virus in her 11th week of pregnancy while on vacation in Mexico, Guatemala, and Belize. She had the following common Zika virus symptoms: mild fever, eye pain, rash, and muscle pain for five days. The woman also had evidence of Zika virus RNA in her blood between 16 and 21 weeks’ gestation.
Although the fetal head size remained within the normal range during the 16th and 17th weeks of pregnancy, fetal head circumference decreased from the 47th percentile at 16 weeks’ gestation to the 24th percentile at 20 weeks’ gestation. Ultrasound and MRI imagery found fetal brain abnormalities, including a thin cerebral mantle and potential agenesis of the corpus callosum at 19 and 20 weeks’ gestation. Neither microcephaly nor calcifications in the brain were seen, however.
“We suspect these reductions in brain growth would have eventually met the criteria for microcephaly,” said the researchers. “As this case shows, the latency period between Zika virus infection of the fetal brain and the detection of microcephaly and intracranial calcifications on ultrasonography is likely to be prolonged.”
Negative findings could be “falsely reassuring and might delay critical time-sensitive decision making,” they added.The woman chose to terminate the pregnancy at 21 weeks. High viral loads of Zika were found in the fetal brain during a postmortem exam. The fetus also had lower amounts of Zika RNA in the muscle, liver, lung, and spleen, as did the mother’s amniotic fluid.
Diagnosis Remains Challenging
“Although the evidence of the association between the presence of Zika virus in pregnant women and fetal brain abnormalities continues to grow, the timing of infection during fetal development and other factors that may have an effect on viral pathogenesis and their effects on the appearance of the brain abnormalities are poorly understood,” said the researchers.
In addition, differentiating Zika virus infections from dengue or other flavivirus infections is challenging, said Dr. Petersen. “Reliable testing regimens for the diagnosis of prenatal and antenatal Zika virus infection have not been established.”
The CDC predicts the identification of millions more Zika cases in the Americas, given the previous incidence of dengue and chikungunya cases, but the burden of long-term effects is harder to predict. “The long-term outlook with regard to the current Zika outbreak in the Americas is uncertain,” said Dr. Petersen. “Herd immunity sufficient to slow further transmission will undoubtedly occur, although this will not obviate the need for immediate and long-term prevention and control strategies.”
A Call for Cooperation
“We need research to clarify the best way to provide protection and to prevent serious consequences of Zika virus and other flaviviruses that were previously unknown,” said Charlotte J. Haug, MD, PhD, international correspondent for the New England Journal of Medicine; Marie-Paule Kieny, PhD, Assistant Director-General for Health Systems and Innovation at the World Health Organization (WHO); and Bernadette Murgue, MD, PhD, Project Manager of WHO’s R&D Blueprint; in an accompanying editorial. “Until recently, Zika virus was believed to cause only mild disease, which it still does in the majority of cases. The main concern today is the growing body of evidence that Zika virus infection results in severe neurologic complications—Guillain-Barré syndrome in infected patients and microcephaly in unborn babies—combined with the very rapid spread of the virus.