Brian Dang, MD
Brian Dang, MD
Pediatrics · San Francisco, CA

Outcomes in Children Exposed to Maternal Zika

May 30th

Project Description

Zika virus (ZIKV) gained international attention in 2015, when several countries experienced an outbreak of an exanthematous condition, along with an increased number of infants with microcephaly. It was then that ZIKV was identified for the first time in Brazil and hypothesized to be a causative agent in this increased rates in birth defects. Now, we better understand the effects of ZIKV in-utero, where vertical transmission of the virus can lead to fetal loss, intrauterine growth restriction (IUGR) and neurologic abnormalities. In its most severe manifestation, infants may suffer from Congenital Zika Syndrome (CZS), which can manifest as microcephaly, seizures, developmental delay, and auditory/visual deficits. Further, a previous study in Brazil reported an increased incidence of non-severe congenital heart defects (CHDs) in infants with diagnosis of CZS.

For this project, we hope to better understand the diverse longitudinal impact of maternal ZIKV exposure. We will evaluate neurodevelopment and intellectual functioning using WISC-III (Weschler Intelligence Scale for Children III). We will evaluate records of school performance to assess the presence of any potential learning disabilities. We will perform audiometric assessments via brainstem evoked response audiometry (BERA) to evaluate for hearing deficits. A pediatric ophthalmologist will perform complete eye exams to evaluate for progression or development of eye disease. A pediatric cardiologist will perform repeat transthoracic echocardiograms, which will be instrumental in assessing the rates of persistent or resolved non-severe congenital heart defects.

ZIKV may resurge, as we have recently learned from heightened pandemic awareness; thus, knowledge gained by this cohort will be instrumental in the management of future outbreaks. Further, this project will help identify at-risk populations that require early intervention to optimize long-term outcomes.

Population Served

Zika virus (ZIKV) is an arbovirus in the Flavivirus genus, similar to Dengue virus and Yellow Fever virus. Rio de Janeiro has served as the site for multiple outbreaks of arboviruses, and this is attributed to a variety of ecological and economic factors, including poor sanitation infrastructure and pools of standing water that serve as mosquito breeding sites. Thus, Brazil plays a pivotal role in many clinical trials and studies to better understand the pathophysiology and outcomes in a variety of infectious diseases that thrive in warm, wet tropical climates.

The beneficiaries of this project include the pediatric patients in Rio de Janeiro who were exposed to maternal ZIKV in utero. After the 2015 ZIKV epidemic in Brazil, recognition of the associated neurologic findings in infants with vertical exposure to ZIKV generated many questions in this very vulnerable population. There has been continued desire to better identify the, 1) proportion of infants that have normal neurologic outcomes after prenatal exposure to maternal Zika infection, 2) age at which families be reassured that their child will develop normally, 3) methods to anticipate neurologic sequelae, and 4) age at which early interventions should start.

We will perform a variety of assessments in our ZIKV exposed cohort of infants (maternal positive ZIKV PCR during pregnancy) who are now 6-8 years of age at the Fernandes Figueira Institute in Rio de Janeiro, Brazil. These children were asymptomatic at birth without clinical features of microcephaly or CZS. In comparison, we have been following an ongoing cohort of 140 control children whose mothers had no serologic or clinical evidence of ZIKV infection during pregnancy.

Expected Impact

We have two aims and expected impacts in this study.

Specific aim #1
Children with CZS, especially those who are microcephalic, often have neurodevelopmental delay. However, the neurodevelopment in non-microcephalic children with confirmed antenatal ZIKV exposure, without the overt stigmata of ZIKV infection, has not been well characterized. Therefore, we aim to characterize clinical and neurodevelopmental outcomes in school-aged children who were exposed to ZIKV in-utero in comparison to healthy control children. The outcomes measured include intellectual functioning, the presence of learning disabilities, as well as audiological and ophthalmic examinations.

Specific aim #2
A previous study in Brazil reported an increased incidence of non-severe congenital heart defects (CHDs) in infants with diagnosis of CZS, predominantly in the form of atrial septal defect, ventricular septal defect, and/or patent ductus arteriosus, compared with the general population. We aim to characterize the incidence of non-severe CHDs in school-aged children who were exposed to ZIKV in-utero in comparison to healthy control children. This will help us better understand the longitudinal impact of this increased trend in CHDs.

Our findings will help answer the following questions. At 6-8 years of age, what proportion of infants will have normal neurologic outcomes after prenatal exposure to maternal Zika infection? Can we reassure families that their child will develop normally? Can we predict neurologic sequelae and at what age should early interventions start? What is the clinical significance of these non-severe cardiac defects? Now that these children are school-aged, it is imperative to connect these patients with services since early-interventions will optimize long-term outcomes. Further, these findings will also help us determine the next steps in neurodevelopment and cardiac monitoring in this population.

Trip Photos & Recap

I was able to work with the incredible medical team at the Instituto Fernandes Figueira (IFF), many of whom were frontline providers during the surge of the zika infection. They have been working tirelessly over the years to better understand the long term consequences of this infection. Overall, I had an incredible experience working with this phenomenal team. I was able to take part in the follow up of children exposed to zika virus, where they received extremely comprehensive evaluations to monitor their general health, school performance, vision, and hearing. As a budding cardiologist, I was especially interested in measuring their cardiovascular health.

It is difficult to describe in words the joy I felt during this month. Cariocas (what Rio locals call themselves) are some of the most friendly, compassionate, and fun people that I have ever met. Their joy for life is immediately obvious in their amazing music, food, culture, etc. Further, Rio is perhaps, the most beautiful city I have ever been to, with skyscrapers and thriving neighborhoods carved between the stunning mountains and beaches.

Overall, I hope to return during the next chapter in these patients’ lives, since this work is vital to better understand the long term consequences of zika exposure in-utero.