Tag Archive for: Mulkey

borrelia bacteria

First-of-its-kind study on impacts of Lyme disease in pregnancy and infant development

borrelia bacteria

Lyme disease is caused by the bacterium Borrelia burgdorferi.

Understanding the effects of Lyme disease on the developing fetal brain is essential to ensure timely prenatal and postnatal treatments to protect the fetus and newborn. In response to this need, Children’s National Hospital is leading a pilot study to establish the groundwork needed for a larger study to determine the effect of in utero exposure to Lyme disease on pregnancy and early childhood neurodevelopmental outcomes.

Why it’s important

“Insect-borne illnesses have more than doubled during the last twenty years as a result of multiple factors including environmental changes,” says Sarah Mulkey, M.D., Ph.D., principal investigator of the study and prenatal-neonatal neurologist at Children’s National Hospital. Dr. Mulkey is the Co-Director of the Congenital Infection Program at Children’s National Hospital and has led a long-term child outcome study of the mosquito-borne Zika virus infection in pregnancy and impacts on child neurodevelopment. She is now adding Lyme disease to her work on pregnancy and child outcomes. Lyme disease is transmitted to humans via an infected tick and can be acquired throughout much of the United States. “Very little is known about Lyme disease in pregnancy and if and how it may affect the fetus and impact child neurodevelopment,” said Dr. Mulkey.

This pilot study is funded by the Clinical Trials Network for Lyme and other Tickborne Diseases (CTN), supported by the Steven and Alexandra Cohen Foundation. Roberta DeBiasi, M.D., M.S., division chief of infectious diseases at Children’s National, is a CTN Node Principal Investigator. The study team at Children’s National works closely with members of the CTN as well as other Lyme disease-focused organizations and nonprofits to make sure that the pilot study addresses Lyme disease advocates’ research priorities in a scientifically rigorous way. “This is an important opportunity for us to engage with advocacy groups and others who have been stressing the need for this type of research for decades,” says Meagan Williams, M.S.P.H., C.C.R.C., the senior research coordinator for the study. “We know how important it is to maintain a patient-centered and trauma-sensitive lens in our work with families impacted by Lyme disease during pregnancy. We’ve been working hard to build this study in a way that centers our participants’ lived experiences and focuses on the topics they find important. We’re very grateful to have the support of Lyme disease focused organizations and advocates as we embark on this study because they know and have expressed exactly where the gaps are in the literature. It’s our job to do the work to fill those gaps.”

The big picture

This pilot study aims to build upon existing research, case studies and advocacy to assess developmental and other family impacts of Lyme disease exposure during pregnancy.

Especially as tick season begins in Washington, D.C., and surrounding regions, the investigators are determined to make sure that all eligible people diagnosed with Lyme disease during their pregnancy are aware of the study and have the opportunity to participate. Pregnant volunteers can sign up for participation in the study here. Volunteers may be eligible to join if they are currently pregnant, live in the U.S. or Canada and were diagnosed with Lyme disease during pregnancy or have post-treatment Lyme disease syndrome (PTLDS).

Anyone interested in sharing information about the study with their clients or colleagues may email mewilliams@childrensnational.org for access to the team’s recruitment toolkit that includes flyers, FAQs and other resources. “We have resources available for clinicians, public health professionals, friends and family members and anyone else who may be able to help us identify participants and spread the word about this important study,” Williams says.

The study is registered on ClinicalTrials.gov (NCT06026969). If you have questions about the study, please reach out to Meagan at mewilliams@childrensnational.org or email cnhlymestudy@gmail.com.

Members of the Columbia Zika virus research team

School entry neurodevelopmental outcomes of Zika-exposed Colombian children

Members of the Columbia Zika virus research team

The Children’s National Hospital Zika Research Team and collaborators from Biomelab, in Barranquilla, Colombia take a picture after a study visit in Sabanalarga, Colombia following the neurodevelopmental outcomes of children who had in utero exposure to Zika virus. Pictured from Children’s National Hospital: Dr. Sarah Mulkey, Regan Andringa-Seed, Margarita Arroyave-Wessel, and Dr. Madison Berl.

The long-term neurodevelopmental effects of antenatal Zika virus (ZIKV) exposure in children without congenital Zika syndrome (CZS) remain unclear, as few children have been followed to the age of starting primary school.

In a new study published in Pathogens, researchers found children with in utero ZIKV exposure appear to have an overall positive developmental trajectory at 4 to 5 years of age but may experience risks to neurodevelopment in areas of emotional regulation and adaptive mobility.

The hold up in the field

Children who were born during the ZIKV epidemic and who had in utero exposure to ZIKV are only now at the age to start school. Child neurodevelopmental outcome data has not been reported at the age of school entry for children with antenatal ZIKV exposure who do not have the severe birth defects of CZS.

“As these children approach the early school-age years, we aim to examine whether there are neurodevelopmental differences in executive function, motor ability, language development or scholastic skills as compared to a group of unexposed control participants from the same communities in Colombia,” says Sarah Mulkey, M.D., Ph.D., prenatal-neonatal neurologist in The Zickler Family Prenatal Pediatrics Institute at Children’s National Hospital and lead author of the study.

Moving the field forward

Building on previous findings, this study presents the longitudinal outcomes of a well-characterized Colombian cohort of ZIKV-exposed children without CZS at ages 4 to 5 years. These children have been seen for neurodevelopmental follow-up as infants and toddlers at approximately 6 months, 18 months and 3 years of age as part of an international collaboration between researchers in Barranquilla, Colombia and at Children’s National beginning in 2016. The objective of this study was to assess the multi-domain neurodevelopmental outcomes in 4 to 5-year-old children with antenatal ZIKV exposure without CZS compared to unexposed controls in Colombia.

Why we’re excited

Many of the children who had antenatal ZIKV exposure are making good progress in multiple areas of their neurodevelopment. However, the researchers found that children with antenatal ZIKV exposure have differences in areas of emotional regulation, executive function, mood and behavior which may relate to virus exposure during their early brain development.

“These areas of brain function are important for future academic achievement, employment, mental health and social relationships,” says Dr. Mulkey. “So, it will be important to continue to follow these children at older ages when they start school.”

Children’s National leads the way

Children’s National is a leader in conducting outcome studies of children born following antenatal ZIKV exposure. This study follows children in Colombia who are now 5 years old who were first studied while they were in the womb. These children have contributed unique longitudinal understanding to early child neurodevelopment following in utero exposure to ZIKV.

Dr. Mulkey is committed to studying the long-term neurodevelopmental impacts that viruses like Zika and SARS-CoV-2 have on infants born to mothers who were infected during pregnancy through research with the Congenital Infection Program at Children’s National and in collaboration with colleagues in Colombia.

Additional Children’s National authors include Meagan Williams M.S.P.H., C.C.R.C., senior research coordinator; Regan Andringa-Seed, clinical research coordinator, Margarita Arroyave-Wessel, clinical research coordinator; L. Gilbert Vezina, M.D., director, Neuroradiology Program; Dorothy Bulas, M.D., chief, Diagnostic Imaging and Radiology; Robert Podolsky, biostatistician.

Researchers showing paintings of zika virus

Dr. Sarah Mulkey and Children’s National clinical research coordinators in the Prenatal Pediatrics Institute and the Division of Pediatric Infectious Diseases display their paintings of the Zika virus. Pictured from left to right: Manuela Iglesias, Elizabeth Corn, Dr. Sarah Mulkey, Emily Ansusinha and Meagan Williams.

A blue background showcases a brain made of gears, symbolizing the intricate workings of the mind.A blue background showcases a brain made of gears, symbolizing the intricate workings of the mind.

Measuring preschoolers’ cognitive development in Latin America

A blue background showcases a brain made of gears, symbolizing the intricate workings of the mind.A blue background showcases a brain made of gears, symbolizing the intricate workings of the mind.

Neurodevelopment occurs at a rapid pace during the preschool years, research shows.

Measuring and tracking development in early childhood is important for understanding how to best support long-term positive health outcomes for children. However, the art of selecting measurement tools that are appropriate for a given study sample is complex; variations in language, cultural relevance and adaptations, availability of normative data, and more can impact the administration and interpretation of study findings.

In a recent study published in the Journal of Pediatric Psychology, the authors systematically review the standardized neurodevelopmental assessments used to study preschool-aged children’s cognitive development in Spanish-speaking Latin America.

“Thinking critically about the ways we measure these outcomes is an important first step in conducting ethical and accurate global research,” said Meagan Williams, M.S.P.H., C.C.R.C., senior clinical research coordinator for the division of Infectious Diseases and the Zickler Family Prenatal Pediatrics Institute at Children’s National Hospital and corresponding author of the study.

The hold-up in the field

The field of child development research is complicated by the presence and use of many different neurodevelopmental assessment tools, only some of which are standardized and use norms to allow researchers to compare their cohorts’ performance with population-level data.

“Many cognitive assessments, including some of the most commonly used assessments identified in our review of research conducted in Spanish-speaking Latin America, have only been officially normed in the United States,” Williams added. “Others have been translated into Spanish and normed in large countries such as Mexico or Spain, but Latin America is a large and culturally diverse region, and it is unclear whether these normative samples are generalizable and culturally relevant to other regions of Spanish-speaking Latin America.”

This systematic review outlined 41 different neurodevelopmental assessments used in 97 studies, including information about each study’s sample, use of each measurement tool and findings related to child cognitive development. The review goes into detail about the most widely used assessments, including background information of each assessment and trends in how authors of the studies in this review reported their methods and results.

Moving the field forward

When researchers use similar methods and valid outcome measures across studies, it becomes possible to combine data between cohorts and draw stronger conclusions about child outcomes. For example, The Wechsler Preschool and Primary Scale of Intelligence (WPPSI) was identified as the most used tool to measure intelligence of young children ages 2-6 in the systematic review. The WPPSI is also one of many assessments that Williams’s research team, led by Sarah Mulkey, M.D., is using to measure neurodevelopment among children exposed to Zika virus in utero.

“If researchers studying longitudinal outcomes after Zika virus exposure also use the WPPSI for their study samples – and if they openly report on their methods, adaptations, and sample characteristics – then it may be possible to harmonize data from multiple cohorts and draw stronger conclusions across studies,” Williams said.

But even the most popular and widespread assessments such as the WPPSI are not without their limitations. While norms exist for regions such as the United States and Mexico, additional work needs to be done to appropriately adapt and validate these tools for use in other populations.

Benefiting patients

Neurodevelopment occurs at a rapid pace during the preschool years. The earlier neurodevelopmental delays can be identified, the earlier experts can administer interventions to respond to these delays and help children get back on track with their peers.

This is particularly salient for research conducted in low- and middle-income countries, where socioeconomic, environmental and other exposures that are known to impact child development differ from those in higher-resource settings. Internationally, there appears to be significant variability in not only the assessment tools which are selected for use, but also in the methods reported across studies to conduct and interpret these assessments.

“By coming together as a field and prioritizing the use and validation of common and culturally appropriate assessments, we can better understand child outcome data on both an individual study level as well as on a broader population level, which will lead to a better understanding of the unique needs and strengths of the children we serve,” Williams said.

The team at Children’s National has been studying the neurodevelopment of children exposed to the Zika virus in Colombia since the beginning of the Zika epidemic.

“As our study on Zika virus has overlapped with the COVID-19 pandemic, we have had the opportunity to collect child outcome data at a very interesting time in history. We are excited that this review revealed that we chose a popular and well-studied assessment for our data collection in this region and we look forward to publishing our 5-year outcome data (which will include WPPSI data) in the coming year,” Williams and Mulkey concluded.

Dr. Mulkey is committed to studying the long-term neurodevelopmental impacts that viruses like Zika and SARS-CoV-2 have on infants born to mothers who were infected during pregnancy through research with the Congenital Infection Program at Children’s National and in collaboration with colleagues in Colombia.

Additional Children’s National authors include Madison Berl, Ph.D.

mother and baby doing a telehealth call

Using telehealth to study babies born to mothers infected with SARS-CoV-2

mother and baby doing a telehealth call

Continued advancements in telehealth methods to follow child neurodevelopment will help ensure robust child follow-up and inclusion of diverse cohorts.

Multiple studies have shown that SARS-CoV-2 infection can impact pregnant mothers and their fetuses but more research is needed to understand the long-term impact on the neurodevelopment of these children as they get older. Child neurodevelopmental evaluations are typically performed in-person. Since the COVID-19 pandemic began, the transition to telehealth methods was needed.

Continued advancements in telehealth methods to follow child neurodevelopment will help ensure robust child follow-up and inclusion of diverse cohorts, says a commentary in JAMA Network Open.

Why it matters

Commentary author Sarah Mulkey, M.D., prenatal-neonatal neurologist at Children’s National Hospital, highlights a new study that used a novel telehealth method to look for neurodevelopmental differences in infants ages 6-12 months born to mothers with SARS-CoV-2 infection compared to nonexposed infants of the same age and found no differences in neurodevelopment among the two cohorts. The study adapted a standardized assessment to a telehealth method.

“The results of this study provide needed reassurance to the many mothers who have experienced SARS-CoV-2 infection during pregnancy,” says Dr. Mulkey.

What’s been the hold up in the field?

“Developmental assessments that rely on observation of infants’ developmental skills can naturally make the transition to a telehealth platform,” says Sarah Mulkey, M.D., prenatal-neonatal neurologist at Children’s National Hospital and commentary author. “General movement assessment is an observation-based assessment of infants that can be captured by a parent or caregiver on video, and it has been used in neurodevelopmental outcomes studies of children after antenatal SARS-CoV-2 exposure.”

Moving the field forward

Child outcomes research can have improved enrollment and continuity of participant follow-up due to the availability of remote assessments. Neurodevelopmental tools are being developed that can be used on a telehealth platform or by parent recorded videos.

Researchers from the Children’s National Congenital Zika Virus Program have also developed telehealth-based methods for child outcome research that has been utilized in international Zika outcome studies funded by the Thrasher Research Fund and the NIH.

Read the full commentary, Use of Telehealth Methods to Track Infant Neurodevelopment After In Utero SARS-CoV-2 Exposure, in JAMA Network Open.

coronavirus and DNA

Will SARS-CoV-2 during pregnancy impact child’s neurodevelopment?

coronavirus and DNA

Sarah Mulkey, M.D., prenatal-neonatal neurologist at Children’s National, will lead the neurodevelopmental evaluations of the infants born to mothers with SARS-CoV-2 infection during pregnancy to understand any long-term neurological effects in offspring.

Scientists led by the Lieber Institute for Brain Development are studying how a mother’s SARS-CoV-2 infection during pregnancy affects the biology of the placenta and the corresponding trajectory of the child’s brain development, including the risk for neurodevelopmental disorders such as schizophrenia and autism. The work is made possible by a $3 million, five-year grant from the Eunice Kennedy Shriver National Institute of Child Health & Human Development, part of the National Institutes of Health.

The project stems from a collaboration between the Lieber Institute for Brain Development on the Johns Hopkins medical campus in Baltimore, Children’s National Hospital in Washington, D.C., and the Women’s Health Integrated Research Center at Inova Health System in Virginia.

The big picture

The group aims for a clearer picture of how a mother’s SARS-CoV-2 infection during pregnancy affects neurodevelopment in utero, the effects of which may manifest early in a child’s life. The researchers hope to understand how the infection interacts with other factors relevant to brain development, including genomic risk for neurodevelopmental disorders, maternal stress and social determinants of health.

The team will study whether the relationship between maternal SARS-CoV-2 infection and offspring brain development is mediated by changes in the biology of the placenta and the activation of the mother’s immune system. They will also gauge any differences in the effects of SARS-CoV-2 between female and male children and in the offspring of vaccinated and unvaccinated mothers.

Why it matters

Preliminary data show that pregnant people with symptomatic SARS-CoV-2 infections are more likely to have a preterm delivery, abnormalities in the placenta and prenatal and perinatal complications such as preeclampsia and fetal growth restriction. All these complications have been found to increase a child’s risk of neurodevelopmental disorders later in life.

What we hope to discover

Sarah Mulkey, M.D., prenatal-neonatal neurologist at Children’s National, will lead the neurodevelopmental evaluations of the infants born to mothers with SARS-CoV-2 infection during pregnancy to understand any long-term neurological effects in offspring. The researchers will evaluate the children’s neurodevelopment at both 24 and 36 months of age. This work builds upon Dr. Mulkey’s longitudinal neurodevelopmental evaluations in children exposed to Zika virus in utero.

“What we’ve learned is that even when babies don’t have Zika-virus-related birth defects, we still find differences in early child development compared to children who weren’t exposed to Zika virus,” said Dr. Mulkey. “With SARS-CoV-2, there is still so much we don’t know. But by better understanding the long-term impact of COVID exposure during pregnancy, we can ultimately find ways to prevent adverse outcomes.”

pregnant woman

Early SARS-CoV-2 exposure may impact infant development

pregnant woman

The study found that some infants with in utero or early-life exposure to SARS-CoV-2 had borderline to low developmental screening scores.

Early SARS-CoV-2 exposure may impact neurodevelopment, especially among infants exposed in utero to symptomatic parents. This is according to a new study led by Sarah Mulkey, M.D., Ph.D., prenatal-neonatal neurologist in the Prenatal Pediatrics Institute at Children’s National Hospital. Dr. Mulkey and team conclude that vaccination and other precautions to reduce early-in-life infection may protect against neurodevelopmental delays. Children with early SARS-CoV-2 exposure should have additional long-term screening for neurodevelopmental delays.

Children’s National Hospital leads the way

The developing brain is vulnerable to both direct and indirect effects of infection during pregnancy and in the early neonatal period. To chart the impact of this exposure, the team created a clinical follow-up protocol in the Congenital Infection Program at Children’s National to chart the development of 34 infants exposed to SARS-CoV-2 in utero or in the neonatal period.

What we hoped to discover

“We conducted this study because we know that infants, when exposed to maternal COVID-19 infection in utero can be exposed to inflammation, fever and an abnormal intrauterine environment. SARS-CoV-2 can also affect the placenta, and in turn, the developing brain,” Dr. Mulkey shared with Healio.

This study aimed to determine if infants with early SARS-CoV-2 exposure developed abnormal neurodevelopment in infancy and the factors that may impact neurodevelopment differences. The study found that some infants with in utero or early-life exposure to SARS-CoV-2 had borderline to low developmental screening scores, most common among babies born to mothers with symptomatic COVID-19. Researchers followed the infants in their first months of life, gauging how the exposure affected their neurologic development. Results were demonstrated using a screening test called the Ages & Stages Questionnaires (ASQ), and those whose scores were borderline or low were most often born to mothers with symptomatic COVID-19.

Why it matters

In conducting this study, the team found that babies born during the pandemic, specifically under these conditions, do, in fact, require additional follow-up in the early stages of life. We may also see more differences in developmental outcomes as children get older.

“Any measure we can take to help prevent infections for mothers in their pregnancy can improve long-term developmental outcomes for children,” says Dr. Mulkey.

Other members of the Children’s National team that contributed to this work include Roberta L. DeBiasi, M.D., M.S.; Meagan E. Williams, M.S.P.H.; Nadia Jadeed, R.N.C.; Anqing Zhang, Ph.D.; and Smitha Israel, B.S.N.

Dr. Mulkey also published a recent article in the American Journal of Obstetrics & Gynecology that found the COVID-19 vaccine may protect pregnant women from SARS-CoV-2 placentitis and stillbirth. This work builds upon Dr. Mulkey’s longitudinal studies on Zika virus infection in pregnancy and long-term impacts on the child, funded by the Thrasher Research Fund and the National Institutes of Health.

Sarah Mulkey

Exposure to Zika in utero may produce neurodevelopmental differences

Sarah Mulkey

“There are still many unanswered questions about the long-term impacts of Zika on children exposed in utero,” says Sarah Mulkey, M.D., Ph.D., a prenatal-neonatal neurologist in the Prenatal Pediatrics Institute at Children’s National Hospital.

Children who are exposed to the Zika virus while in the womb, but who are not subsequently diagnosed with Zika-related birth defects and congenital Zika syndrome (CZS), may still display differences in some aspects of cognitive development, mood and mobility compared to unexposed children, reports a study published in Pediatric Research. These findings suggest that Zika-exposed children may need some additional support and monitoring as they get older.

“There are still many unanswered questions about the long-term impacts of Zika on children exposed in utero,” says Sarah Mulkey, M.D., Ph.D., a prenatal-neonatal neurologist in the Prenatal Pediatrics Institute at Children’s National Hospital and the study’s first author. “These findings are another piece of the puzzle that provides insight into the long-term neurodevelopment of children with prenatal Zika virus exposure. Further evaluation is needed as these children get older.”

It has not been clear how children who were exposed to the Zika virus in the womb during the 2015–2017 epidemic, but who did not develop CZS and serious neurological complications, will develop as they get older.

Dr. Mulkey and colleagues examined the neurodevelopment of 55 children aged 3-5 years who were exposed to Zika in the womb in Sabanalarga, Colombia, and compared them to 70 control children aged 4-5 years who had not been exposed to Zika. Assessments occurred between December 2020 and February 2021. Health professionals tested the children’s motor skills (such as manual dexterity, aiming and catching, and balance) and their readiness for school (including knowledge of colors, letters, numbers and shapes). Parents completed three questionnaires providing information about their child’s cognitive function (such as memory and emotional control), behavioral and physical conditions (such as responsibility and mobility), and their parenting experience (including whether they felt distress).

Parents of Zika-exposed children reported significantly lower levels of mobility and responsibility compared to control children, although differences in cognitive function scores were not significant. Additionally, parents of 6 (11%) Zika-exposed children reported mood problems compared to 1 (1%) of control children, and Zika-exposed parents were significantly more likely to report parental distress.

Professional testing revealed no significant differences in the Zika-exposed children’s manual dexterity, such as their ability to catch an object or post a coin through a slot, compared to the control children. Both Zika-exposed and control children also scored lowly on readiness for school.

The authors highlight that parental responses may have been influenced by the Zika-exposed children’s parents’ perceptions or increased worry about the development of their child. Some differences in results may also have been caused by the age – and therefore developmental – differences between the groups of children.

The authors conclude that while these Zika-exposed children are making progress as they develop, they may need additional support as they prepare to start school.

Dr. Mulkey is committed to studying the long-term neurodevelopmental impacts that viruses like Zika and SARS-CoV-2 have on infants born to mothers who were infected during pregnancy through research with the Congenital Infection Program at Children’s National and in collaboration with colleagues in Colombia.

pregnant woman getting vaccinated

COVID-19 vaccine may protect pregnant women from SARS-CoV-2 placentitis and stillbirth

pregnant woman getting vaccinated

In a new article published in the American Journal of Obstetrics & Gynecology, researchers conclude that the vaccine not only protects pregnant women but may also be lifesaving for their unborn children.

Stillbirth is a recognized complication of COVID-19 in pregnant women caused by harmful changes to the placenta induced by the virus. Termed SARS-CoV-2 placentitis, it can render the placenta incapable of providing oxygen to the fetus, leading to stillbirth and neonatal death. Researchers now suggest that pregnant women who get the COVID-19 vaccine may be protected from SARS-CoV-2 placentitis and stillbirth. In a new article published in the American Journal of Obstetrics & Gynecology, researchers conclude that the vaccine not only protects pregnant women but may also be lifesaving for their unborn children.

The extensive examination of published literature involved reviewing nearly 100 papers looking at COVID-19’s impacts on pregnant women and the effects on the placenta and pregnancy outcome. Sarah Mulkey, M.D., Ph.D., a prenatal-neonatal neurologist in the Division of Prenatal Pediatrics at Children’s National Hospital and co-author of the article, says the findings make a strong case for vaccination.

“The COVID-19 virus fortunately does not cause birth defects like other viruses such Zika, but it can cause severe injury to the placenta that can result in stillbirth and other pregnancy complications,” says Dr. Mulkey. “I hope patients who are pregnant or planning to become pregnant can learn how the COVID vaccine may help keep them and their baby healthy throughout pregnancy from some of the worst effects of this virus.”

While stillbirths can have many causes, the data analyzed supports that the COVID-19 vaccine is beneficial for pregnancies and for reducing the risk of stillbirth by reducing the risk of the virus impacting the placenta.

“In the multiple reports of SARS-CoV-2 placentitis that have been associated with stillbirths and neonatal deaths, none of the mothers had received COVID-19 vaccinations,” says David Schwartz, M.D., lead author, epidemiologist and perinatal pathologist. “And although not constituting proof, we’re not aware, either personally, via collegial networks, or in the published literature, of any cases of SARS-CoV-2 placentitis causing stillbirths among pregnant women having received the COVID-19 vaccine.”

Earlier in 2022, Dr. Schwartz led a team from 12 countries that found SARS-CoV-2 placentitis destroyed an average of 77.7% of placental tissue, resulting in placental insufficiency and fetal death, all occurring in unvaccinated mothers.

Fortunately, the large majority of pregnancies affected by a COVID-19 infection do not result in stillbirth. The development of SARS-CoV-2 placentitis is complex and likely involves both viral and immunological factors. The characteristics of a SARS-CoV-2 variant may also affect risk.

“Placental pathology is an important component in understanding the pathophysiology of SARS-CoV-2 infection during pregnancy,” says Dr. Mulkey.

As part of the Congenital Infection Program at Children’s National, Dr. Mulkey has been following infants born to mothers who had SARS-CoV-2 infection during pregnancy since the beginning of the pandemic. She will present the results of the early neurodevelopment of these infants at ID Week in Washington, D.C., on Oct. 22, 2022. Dr. Mulkey will also lead the neurodevelopmental follow-up of a large cohort of infants born to mothers with SARS-CoV-2 infection during pregnancy to better understand any long-term neurological effects to offspring.

The study builds upon Dr. Mulkey’s longitudinal studies on Zika virus infection in pregnancy and long-term impacts on the child that is funded by the Thrasher Research Fund.

zika virus

The importance of following the Zika population long-term

zika virus

Invited commentary by Sarah Mulkey, M.D., Ph.D., prenatal-neonatal neurologist in the Division of Prenatal Pediatrics at Children’s National Hospital, emphasizes importance of studying the Zika population long term.

A simple measuring tape could be the key to identifying which children could develop neurological and developmental abnormalities from Zika virus exposure during gestation. This is according to an invited commentary published July 7, 2020 in JAMA Network Open and written by Sarah Mulkey, M.D., Ph.D., prenatal-neonatal neurologist in the Division of Prenatal Pediatrics at Children’s National Hospital.

Zika virus (ZIKV), first isolated in 1947 in the Zika Forest in Uganda, made headlines in 2015-2016 for causing a widespread epidemic that spread through parts of North and South America, several islands in the Pacific and parts of Southeast Asia. Although previously linked with no or mild symptoms, researchers discovered during this epidemic that Zika can cross from a pregnant woman to her gestating fetus, leading to a syndrome marked by microcephaly (decreased brain growth), abnormal neurologic tone, vision and hearing abnormalities and joint contractures.

“For the 90% to 95% of ZIKV-exposed infants who fortunately were not born with severe abnormalities at birth and were normocephalic, our hope was that these children would have normal neurodevelopmental outcomes,” Dr. Mulkey writes in the commentary. “Unfortunately, this has not been the case.”

Her commentary expands on a study in the same issue entitled “Association between exposure to antenatal Zika virus and anatomic and neurodevelopmental abnormalities in children” by Cranston et al. In this study, the researchers find that head circumference — a simple measure taken regularly at postnatal appointments in the U.S. — can provide insight into which children were most likely to develop neurologic abnormalities. Their findings show that 68% of those whose head circumference was in the “normal” range at birth developed neurologic problems. Those whose head circumference was at the upper end of this range were significantly less likely to have abnormalities than those at the lower end.

Just this single measurement offers considerable insight into the risk of developing neurologic problems after Zika exposure. However, notes Dr. Mulkey, head circumference growth trajectory is also key. Of the 162 infants whose heads were initially in the normocephalic range at birth, about 10.5% went on to develop microcephaly in the months after birth.

“Because early head growth trajectory is associated with cognitive outcomes in early childhood,” Dr. Mulkey writes, “following the head circumference percentile over time can enable recognition of a child with increased risk for poor outcome who could benefit from early intervention therapies.”

This simple assessment could be significantly augmented with neuroimaging, she adds. The study by Cranston et al., as well as others in the field, have shown that brain imaging often reveals problems in ZIKV-exposed children, such as calcifications and cerebral atrophy, even in those with normal head circumferences. This imaging doesn’t necessarily need to take place at birth, Dr. Mulkey says. Postnatal development of microcephaly, failure to thrive or developmental delay can all be triggers for imaging later on.

Together, Dr. Mulkey says, the study by Cranston et al. and others that focus on ZIKV-exposed children support the need for following these patients long term. Children exposed to ZIKV in the epidemic nearly five years ago are now approaching school age, a time fraught with more complicated cognitive and social demands. Through her own research at Children’s National’s Congenital Zika Virus Program and collaboration with colleagues in Colombia, Dr. Mulkey is following multiple cohorts of ZIKV exposed children as they grow. She recently published a study on neurological abnormalities in one of these cohorts in JAMA Pediatrics in January 2020.

“It’s really important to follow these children as long as possible so we’ll really know the outcomes of this virus,” Dr. Mulkey says.

Vittorio Gallo and Mark Batshaw

Children’s National Research Institute releases annual report

Vittorio Gallo and Marc Batshaw

Children’s National Research Institute directors Vittorio Gallo, Ph.D., and Mark Batshaw, M.D.

The Children’s National Research Institute recently released its 2019-2020 academic annual report, titled 150 Years Stronger Through Discovery and Care to mark the hospital’s 150th birthday. Not only does the annual report give an overview of the institute’s research and education efforts, but it also gives a peek in to how the institute has mobilized to address the coronavirus pandemic.

“Our inaugural research program in 1947 began with a budget of less than $10,000 for the study of polio — a pressing health problem for Washington’s children at the time and a pandemic that many of us remember from our own childhoods,” says Vittorio Gallo, Ph.D., chief research officer at Children’s National Hospital and scientific director at Children’s National Research Institute. “Today, our research portfolio has grown to more than $75 million, and our 314 research faculty and their staff are dedicated to finding answers to many of the health challenges in childhood.”

Highlights from the Children’s National Research Institute annual report

  • In 2018, Children’s National began construction of its new Research & Innovation Campus (CNRIC) on 12 acres of land transferred by the U.S. Army as part of the decommissioning of the former Walter Reed Army Medical Center campus. In 2020, construction on the CNRIC will be complete, and in 2012, the Children’s National Research Institute will begin to transition to the campus.
  • In late 2019, a team of scientists led by Eric Vilain, M.D., Ph.D., director of the Center for Genetic Medicine Research, traveled to the Democratic Republic of Congo to collect samples from 60 individuals that will form the basis of a new reference genome data set. The researchers hope their project will generate better reference genome data for diverse populations, starting with those of Central African descent.
  • A gift of $5.7 million received by the Center for Translational Research’s director, Lisa Guay-Woodford, M.D., will reinforce close collaboration between research and clinical care to improve the care and treatment of children with polycystic kidney disease and other inherited renal disorders.
  • The Center for Neuroscience Research’s integration into the infrastructure of Children’s National Hospital has created a unique set of opportunities for scientists and clinicians to work together on pressing problems in children’s health.
  • Children’s National and the National Institute of Allergy and Infectious Diseases are tackling pediatric research across three main areas of mutual interest: primary immune deficiencies, food allergies and post-Lyme disease syndrome. Their shared goal is to conduct clinical and translational research that improves what we know about those conditions and how we care for children who have them.
  • An immunotherapy trial has allowed a little boy to be a kid again. In the two years since he received cellular immunotherapy, Matthew has shown no signs of a returning tumor — the longest span of time he’s been tumor-free since age 3.
  • In the past 6 years, the 104 device projects that came through the National Capital Consortium for Pediatric Device Innovation accelerator program raised $148,680,256 in follow-on funding.
  • Even though he’s watched more than 500 aspiring physicians pass through the Children’s National pediatric residency program, program director Dewesh Agrawal, M.D., still gets teary at every graduation.

Understanding and treating the novel coronavirus (COVID-19)

In a short period of time, Children’s National Research Institute has mobilized its scientists to address COVID-19, focusing on understanding the virus and advancing solutions to ameliorate the impact today and for future generations. Children’s National Research Institute Director Mark Batshaw, M.D., highlighted some of these efforts in the annual report:

  • Eric Vilain, M.D., Ph.D., director of the Center for Genetic Medicine Research, is looking at whether or not the microbiome of bacteria in the human nasal tract acts as a defensive shield against COVID-19.
  • Catherine Bollard, M.D., MBChB, director of the Center for Cancer and Immunology Research, and her team are seeing if they can “train” T cells to attack the invading coronavirus.
  • Sarah Mulkey, M.D., Ph.D., an investigator in the Center for Neuroscience Research and the Fetal Medicine Institute, is studying the effects of, and possible interventions for, coronavirus on the developing brain.

You can view the entire Children’s National Research Institute academic annual report online.

sleeping baby

False negatives: Delayed Zika effects in babies who appeared normal at birth

sleeping baby

Colombian infants exposed to Zika virus in the womb showed neurodevelopmental delays as toddlers, despite having “normal” brain imaging and head circumference at birth, a finding that underscores the importance of long-term neurodevelopmental follow-up for Zika-exposed infants.

Colombian infants exposed to Zika virus in the womb showed neurodevelopmental delays as toddlers, despite having “normal” brain imaging and head circumference at birth, a finding that underscores the importance of long-term neurodevelopmental follow-up for Zika-exposed infants, according to a cohort study published online Jan. 6, 2020, in JAMA Pediatrics.

“These infants had no evidence of Zika deficits or microcephaly at birth. Neurodevelopmental deficits, including declines in mobility and social cognition, emerged in their first year of life even as their head circumference remained normal,” says Sarah B. Mulkey, M.D. Ph.D., a fetal/neonatal neurologist at Children’s National Hospital and the study’s first author. “About one-third of these newborns who underwent postnatal head ultrasound had nonspecific imaging results, which we believe are the first published results finding a link between subtle brain injuries and impaired neuromotor development in Zika-exposed children.”

The multi-institutional research group led by Children’s National enrolled pregnant women in Atlántico Department, which hugs the Caribbean coast of Colombia, who had been exposed to Zika, and performed a series of fetal magnetic resonance images (MRI) and ultrasounds as their pregnancies progressed.

Even though their mothers had laboratory-confirmed Zika infections, 77 out of 82 of their offspring were born with no sign of congenital Zika syndrome, a constellation of birth defects that includes severe brain abnormalities, eye problems and congenital contractures, and 70 underwent additional testing of neurodevelopment during infancy. These apparently normal newborns were born between Aug. 1, 2016, and Nov. 30, 2017, at the height of the Zika epidemic, and had normal head circumference.

When they were 4 to 8 months or 9 to 18 months of age, the infants’ neurodevelopment was evaluated using two validated tools, the Warner Initial Developmental Evaluation of Adaptive and Functional Skills (a 50-item test of such skills as self-care, mobility, communication and social cognition) and the Alberta Infant Motor Scale (a motor examination of infants in prone, supine, sitting and standing positions). Some infants were assessed during each time point.

Women participating in the study were highly motivated, with 91% following up with appointments, even if it meant traveling hours by bus. In addition to Children’s National faculty traveling to Colombia to train staff how to administer the screening instruments, videotaped assessments, MRIs and ultrasounds were read, analyzed and scored at Children’s National. According to the study team, the U.S. scoring of Alberta Infant Motor Scale tests administered in Colombia is also unprecedented for a research study and offers the potential of remote scoring of infants’ motor skill maturity in regions of the world where pediatric specialists, like child neurologists, are lacking.

“Normally, neurodevelopment in infants and toddlers continues for years, building a sturdy neural network that they later use to carry out complex neurologic and cognitive functions as children enter school,” Dr. Mulkey adds. “Our findings underscore the recommendations by the Centers for Disease Control and Prevention (CDC) that all infants exposed to Zika in the womb undergo long-term follow-up, providing an opportunity to intervene earlier.”

An accompanying editorial by CDC staffers concurs, saying the study reported “intriguing data” that add “to the growing evidence of the need for long-term follow-up for all children with Zika virus exposure in utero to ensure they receive the recommended clinical evaluations even when no structural defects are identified at birth.”

In addition to Dr. Mulkey, study co-authors include Margarita Arroyave-Wessel, MPH, Dorothy I. Bulas, M.D., chief of Diagnostic Imaging and Radiology, JiJi Jiang, MS, Stephanie Russo, BS, Robert McCarter, ScD, research section head, design and biostatistics,  Adré J. du Plessis, M.B.Ch.B., MPH, chief of the Division of Fetal and Transitional Medicine, and co-Senior Author, Roberta L. DeBiasi, MD, MS, chief of the Division of Pediatric Infectious Diseases, all of Children’s National; Colleen Peyton, PT, DPT, of Northwestern University; Yamil Fourzali, M.D., of Sabbag Radiologos, Barranquilla, Colombia; Michael E. Msall, M.D., of University of Chicago Comer Children’s Hospital; and co-Senior Author, Carlos Cure, M.D., BIOMELab, Barranquilla, Colombia.

Funding for the research described in this post was provided by the Thrasher Research Fund, the National Institutes of Health under award Nos. UL1TR001876 and KL2TR001877, and the Leadership Education in Neurodevelopmental and Related Disorders Training Program under grant HRSA/MCHB T73 MC11047.

Paradoxical outcomes for Zika-exposed tots

In the midst of an unprecedented Zika crisis in Brazil, there were a few flickers of hope: Some babies appeared to be normal at birth, free of devastating birth defects that affected other Brazilian children exposed to the virus in utero.

In the midst of an unprecedented Zika crisis in Brazil, there were a few flickers of hope: Some babies appeared to be normal at birth, free of devastating birth defects that affected other Brazilian children exposed to the virus in utero. But according to a study published online July 8, 2019, in Nature Medicine and an accompanying commentary co-written by a Children’s National clinician-researcher, the reality for Zika-exposed infants is much more complicated.

Study authors led by Karin Nielsen-Saines at David Geffen UCLA School of Medicine followed 216 infants in Rio de Janeiro who had been exposed to the Zika virus during pregnancy, performing neurodevelopmental testing when the babies ranged in age from 7 to 32 months. These infants’ mothers had had Zika-related symptoms themselves, including rash.

Although many children had normal assessments, 29% scored below average in at least one domain of neurological development, including cognitive performance, fine and gross motor skills and expressive language, Sarah B. Mulkey, M.D., Ph.D., and a colleague write in a companion commentary published online by Nature Medicine July 29, 2019.

The study authors found progressively higher risks for developmental, hearing and eye abnormality depending on how early the pregnancy was at the time the infants were exposed. Because Zika virus has an affinity for immature neurons, even babies who were not born with microcephaly remained at continued risk for suffering abnormalities.

Of note, 24 of 49 (49%) infants who had abnormalities at birth went on to have normal test results in the second or third year of life. By contrast, 17 of 68 infants (25%) who had normal assessments at birth had below-average developmental testing or had abnormalities in hearing or vision by age 32 months.

“This work follows babies who were born in 2015 and 2016. It’s heartening that some babies born with abnormalities tested in the normal range later in life, though it’s unclear whether any specific interventions help to deliver these positive findings,” says Dr. Mulkey, a fetal–neonatal neurologist in the Division of Fetal and Transitional Medicine at Children’s National in Washington, D.C. “And it’s quite sobering that babies who appeared normal at birth went on to develop abnormalities due to that early Zika exposure.”

It’s unclear how closely the findings apply to the vast majority of U.S. women whose Zika infections were asymptomatic.

“This study adds to the growing body of research that argues in favor of ongoing follow-up for Zika-exposed children, even if their neurologic exams were reassuring at birth,” Dr. Mulkey adds. “As Zika-exposed children approach school age, it’s critical to better characterize the potential implications for the education system and public health.”

In addition to Dr. Mulkey, the perspective’s senior author, William J. Muller, Northwestern University, was the commentary’s lead author.

zika virus

Neuroimaging essential for Zika cases

zika virus

About three years ago, Zika virus emerged as a newly recognized congenital infection, and a growing body of research indicates the damage it causes differs from other infections that occur in utero.

Seventy-one of 110 Brazilian infants at the highest risk for experiencing problems due to exposure to the Zika virus in the womb experienced a wide spectrum of brain abnormalities, including calcifications and malformations in cortical development, according to a study published July 31, 2019 in JAMA Network Open.

The infants were born at the height of Brazil’s Zika epidemic, a few months after the nation declared a national public health emergency. Already, many of the infants had been classified as having the severe form of congenital Zika syndrome, and many had microcephaly, fetal brain disruption sequence, arthrogryposis and abnormal neurologic exams at birth.

These 110 infants “represented a group of ZIKV-exposed infants who would be expected to have a high burden of neuroimaging abnormalities, which is a difference from other reported cohorts,” Sarah B. Mulkey, M.D., Ph.D., writes in an invited commentary published in JAMA Network Open that accompanies the Rio de Janeiro study. “Fortunately, many ZIKV-exposed infants do not have abnormal brain findings or a clinical phenotype associated with congenital Zika syndrome,” adds Dr. Mulkey, a fetal–neonatal neurologist in the Division of Fetal and Transitional Medicine at Children’s National in Washington, D.C.

Indeed, a retrospective cohort of 82 women exposed to Zika during their pregnancies led by a research team at Children’s National found only three pregnancies were complicated by severe fetal brain abnormalities. Compared with the 65% abnormal computed tomography (CT) or magnetic resonance imaging (MRI) findings in the new Brazilian study, about 1 in 10 (10%) of babies born to women living in the continental U.S. with confirmed Zika infections during pregnancy had Zika-associated birth defects, according to the Centers for Disease Control and Prevention.

“There appears to be a spectrum of brain imaging abnormalities in ZIKV-exposed infants, including mild, nonspecific changes seen at cranial US [ultrasound], such as lenticulostriate vasculopathy and germinolytic cysts, to more significant brain abnormalities, such as subcortical calcifications, ventriculomegaly and, in its most severe form, thin cortical mantle and fetal brain disruption sequence,” Dr. Mulkey writes.

About three years ago, Zika virus emerged as a newly recognized congenital infection, and a growing body of research indicates the damage it causes differs from other infections that occur in utero. Unlike congenital cytomegalovirus infection, cerebral calcifications associated with Zika are typically subcortical, Dr. Mulkey indicates. What’s more, fetal brain disruption sequence seen in Zika-exposed infants is unusual for other infections that can cause microcephaly.

“Centered on the findings of Pool, et al, and others, early neuroimaging remains one of the most valuable investigations of the Zika-exposed infant,” Dr. Mulkey writes, including infants who are not diagnosed with congenital Zika syndrome.  She recommends:

  • Cranial ultrasound as the first-line imaging option for infants, if available, combined with neurologic and ophthalmologic exams, and brainstem auditory evoked potentials
  • Zika-exposed infants with normal cranial ultrasounds do not need additional imaging unless they experience a developmental disturbance
  • Zika-exposed infants with abnormal cranial ultrasounds should undergo further neuroimaging with low-dose cranial CT or brain MRI.

Autonomic nervous system appears to function well regardless of mode of childbirth

Late in pregnancy, the human body carefully prepares fetuses for the rigors of life outside the protection of the womb. Levels of cortisol, a stress hormone, ramp up and spike during labor. Catecholamines, another stress hormone, also rise at birth, helping to kick start the necessary functions that the baby will need to regulate breathing, heartbeat, blood pressure and energy metabolism levels at delivery. Oxytocin surges, promoting contractions for the mother during labor and stimulating milk production after the infant is born.

These processes also can play a role in preparing the fetal brain during the transition to life outside the womb by readying the autonomic nervous system and adapting its cerebral connections. The autonomic nervous system acts like the body’s autopilot, taking in information it needs to ensure that internal organs run steadily without willful action, such as ensuring the heart beats and eyelids blink at steady intervals. Its yin, the sympathetic division, stimulates body processes while its yang, the parasympathetic division, inhibits them.

Infants born preterm have reduced autonomic function compared with their full-term peers and also face possible serious neurodevelopmental impairment later in life. But is there a difference in autonomic nervous system function for full-term babies after undergoing labor compared with infants delivered via cesarean section (C-section)?

A team from the Children’s National Inova Collaborative Research Program (CNICA) – a research collaboration between Children’s National in Washington, D.C., and Inova Women’s and Children’s Hospital in Virginia – set out to answer that question in a paper published online July 30, 2019, in Scientific Reports.

They enrolled newborns who had experienced normal, full-term pregnancies and recorded their brain function and heart performance when they were about 2 days old. Infants whose conditions were fragile enough to require observation in the neonatal intensive care unit were excluded from the study. Of 167 infants recruited for the prospective cohort study, 118 newborns had sufficiently robust data to include them in the research.  Of these newborns:

  • 62 (52.5%) were born by vaginal delivery
  • 22 (18.6%) started out with vaginal delivery but ultimately switched to C-section based on failure to progress, failed labor induction or fetal intolerance to labor
  • And 34 (28.8%) were born by elective C-section.

The CNICA research team swaddled infants for comfort and slipped electrode nets over their tiny heads to simultaneously measure heart rate variability and electrocortical function through non-invasive techniques. The team hypothesized that infants who had been exposed to labor would have enhanced autonomic tone and higher cortical electroencephalogram (EEG) power than babies born via C-section.

“In a low-risk group of babies born full-term, the autonomic nervous system and cortical systems appear to function well regardless of whether infants were exposed to labor prior to birth,” says Sarah B. Mulkey, M.D., Ph.D., a fetal–neonatal neurologist in the Division of Fetal and Transitional Medicine at Children’s National and the study’s lead author.

However, infants born by C-section following a period of labor had significantly increased accelerations in their heart rates. And the infants born by C-section during labor had significantly lower relative gamma frequency EEG at 25.2 hours old compared with the other two groups studied.

“Together these findings point to a possible increased stress response and arousal difference in infants who started with vaginal delivery and finished delivery with C-section,” Dr. Mulkey says. “There is so little published research about the neurologic impacts of the mode of delivery, so our work helps to provide a normal reference point for future studies looking at high-risk infants, including babies born preterm.”

Because the research team saw little differences in autonomic tone or other EEG frequencies when the infants were 1 day old, future research will explore these measures at different points in the newborns’ early life as well as the role of the sleep-wake cycle on heart rate variability.

In addition to Dr. Mulkey, study co-authors include Srinivas Kota, Ph.D., Rathinaswamy B. Govindan, Ph.D., Tareq Al-Shargabi, MSc, Christopher B. Swisher, BS, Laura Hitchings, BScM, Stephanie Russo, BS, Nicole Herrera, MPH, Robert McCarter, ScD, and Senior Author Adré  J. du Plessis, M.B.Ch.B., MPH, all of Children’s National; and Augustine Eze Jr., MS, G. Larry Maxwell, M.D., and Robin Baker, M.D., all of Inova Women’s and Children’s Hospital.

Financial support for research described in this post was provided by the National Institutes of Health National Center for Advancing Translational Sciences under award numbers UL1TR001876 and KL2TR001877.

Sarah Mulkey

MRI and ultrasound imaging detect the spectrum of Zika’s impact

Sarah Mulkey

“A combination of prenatal MRI and US was able to detect Zika-related brain abnormalities during pregnancy, giving families timely information to prepare for the potential complex care needs of these infants,” says Sarah B. Mulkey, M.D., Ph.D.

Worldwide, thousands of babies have been born to mothers who were infected during pregnancy with Zika, a virus associated with neurological deficits, impaired vision and neurodevelopmental disabilities, among other birth defects. These birth defects are sometimes severe, causing lifelong disability. But they’re also relatively rare compared with the overall rates of infection.

Predicting how many Zika-exposed babies would experience neurological birth defects has been challenging.

However, an international study led by Children’s faculty suggests that ultrasound (US) imaging performed during pregnancy and after childbirth revealed most Zika-related brain abnormalities experienced by infants exposed to the Zika virus during pregnancy, according to a prospective cohort study published online Nov. 26, 2018, in JAMA Pediatrics. Some Zika-exposed infants whose imaging had been normal during pregnancy had mild brain abnormalities detected by US and magnetic resonance imaging (MRI) after they were born.

“A combination of prenatal MRI and US was able to detect Zika-related brain abnormalities during pregnancy, giving families timely information to prepare for the potential complex care needs of these infants,” says Sarah B. Mulkey, M.D., Ph.D., a fetal-neonatal neurologist at Children’s National Health System and the study’s lead author. “In our study, we detected mild brain abnormalities on postnatal neuroimaging for babies whose imaging was normal during pregnancy. Therefore, it is important for clinicians to continue to monitor brain development for Zika-exposed infants after birth.”

As of Nov. 20 2018, nearly 2,500 pregnant women in the U.S. had laboratory confirmed Zika infection, and about 2,400 of them had given birth, according to the Centers for Disease Control and Prevention (CDC). While more than 100 U.S. infants were born with Zika-associated birth defects, the vast majority of Zika-exposed U.S. infants were apparently normal at birth. The sequential neuroimaging study Dr. Mulkey leads seeks to determine the spectrum of brain findings in infants exposed to Zika in the womb using both US and MRI before and after birth.

The international research team enrolled 82 women in the study from June 15, 2016, through June 27, 2017. All of the women had been exposed to Zika during pregnancy; all but one experienced clinical symptoms by a mean gestational age of 8.2 weeks. Eighty of those women lived in or near Barranquilla, Colombia, and were exposed to Zika there. Two U.S. study participants were exposed to the primarily mosquito-borne illness during travel to Zika hot zones.

All women received fetal MRIs and US during the second and/or third trimester of pregnancy. After their infants were born, the children received brain MRI and cranial US. Blood samples from both mothers and babies were tested for Zika using polymerase chain reaction and serology.

Fetal MRI was able to discern Zika-related brain damage as early as 18 weeks gestation and picked up significant fetal brain abnormalities not fully appreciated in US imaging. In one case, the US remained normal while fetal MRI alone detected brain abnormalities. Three fetuses (4 percent) had severe fetal brain abnormalities consistent with Zika infection, including:

Seventy-five infants were born at term. One pregnancy was terminated at 23 weeks gestation due to the gravity of the fetal brain abnormalities. One fetus with normal imaging died during pregnancy. One newborn who was born with significant fetal brain abnormalities died at age 3 days.

Cranial US and brain MRI was performed on the majority of infants whose prenatal imaging had been normal.  Seven of 53 (13 percent) Zika-exposed infants had mild brain abnormalities detected by MRI after birth. In contrast, postnatal cranial US was better at detecting changes of lenticulostriate vasculopathy, cysts within the brain’s choroid plexus (cells that produce cerebrospinal fluid), germinolytic/subependymal cysts and/or calcifications, which were seen in 21 of 57 (37 percent) infants.

“Sequential neuroimaging revealed that the majority of Zika-exposed fetuses had normal brain development. Tragically, in a small number of pregnancies, Zika-related brain abnormalities were quite severe,” Dr. Mulkey adds. “Our data support the CDC’s recommendation that cranial US be performed after Zika-exposed babies are born. In addition, there is clearly a need to follow these babies over time to gauge whether the brain anomalies we see in imaging affects language, motor and social skills.”

Companion editorial: Revealing the effects of Zika

In addition to Dr. Mulkey, study co-authors include Dorothy I. Bulas, M.D., Gilbert Vezina, M.D., Margarita Arroyave-Wessel, MPH,  Stephanie Russo, B.S, Youssef A. Kousa, D.O, Ph.D., Roberta L. DeBiasi, M.D., MS, Senior Author Adré J. du Plessis, M.B.Ch.B., MPH, all of Children’s National; Christopher Swisher, BS, Georgetown University and Caitlin Cristante, BS, Loyola University, both of  whose contributions included research performed at Children’s National; Yamil Fourzali, M.D., Armando Morales, M.D., both of Sabbag Radiologos; Liliana Encinales, M.D., Allied Research Society; Nelly Pacheco, Bacteriologa, Bio-Nep; Robert S. Lanciotti, Ph.D., Arbovirus Diseases Branch, Centers for Disease Control and Prevention; and Carlos Cure, M.D., BIOMELAB.

Research reported in this news release was supported by the IKARIA fund.

Sarah Mulkey

MRI finds novel brain defects in Zika-exposed newborns

Sarah Mulkey

“Imaging is constantly helping us make new discoveries with this virus, and in these two cases we found things that had not been previously described,” says Sarah Mulkey, M.D., Ph.D.

Magnetic resonance imaging (MRI) has identified two brain abnormalities never before reported in newborns with prenatal exposure to the Zika virus. Children’s National Health System researchers reported these findings from a study of more than 70 fetuses or newborns with Zika exposure in utero. The study was published in the January 2018 edition of Pediatric Neurology.

The two novel defects – cranial nerve enhancement and cerebral infarction – may join the growing list of neurological findings associated with congenital Zika infection.

“Imaging is constantly helping us make new discoveries with this virus, and in these two cases we found things that had not been previously described,” says Sarah Mulkey, M.D., Ph.D., the study’s lead author and a fetal-neonatal neurologist at Children’s National. Dr. Mulkey works in Children’s Congenital Zika Virus Program, one of the nation’s first comprehensive, dedicated Zika programs.

The research team recommends that postnatal brain MRI be considered in addition to ultrasound for newborns exposed to Zika in utero. “Brain MRI can be performed in the newborn often without sedation and provides an opportunity to look for brain abnormalities we might not catch otherwise – or might not detect until much later,” says Dr. Mulkey.

Birth defects are seen in 6 to 11 percent of pregnancies affected by Zika, and some of the neurological complications in infants are not apparent until well after birth.

Of the two infants in which the new abnormalities were observed, both had normal head size at birth. Neither had smaller-than-normal head size (microcephaly), one of the more severe effects associated with congenital Zika syndrome.

One infant had a normal neurological evaluation at 2 days of age. However, a brain MRI conducted the following day, using gadolinium contrast due to concern of infection, showed enhancement of multiple cranial nerves. “Nerve root enhancement is very rare in a newborn and had not been described with Zika before,” Dr. Mulkey says. “Yet, there was no neurological deficit that we could identify by physical exam.”

The research team acknowledges that the clinical significance of this finding is not yet known.

In the second patient, brain MRI conducted without contrast at 16 days of age revealed a small area consistent with chronic infarction (ischemic stroke) that likely occurred during the third trimester.

“We followed the mother throughout her pregnancy, and both MRI and ultrasound imaging were normal at 28 weeks gestation,” Dr. Mulkey says. “A postnatal ultrasound was also normal, but the postnatal MRI showed a stroke that had occurred at least one month prior to the MRI and after the last fetal study.”

She adds: “This is the first published report of fetal stroke associated with Zika infection, and it may add to our knowledge of what can occur with congenital Zika infection.”

Unlike most congenital infections, Zika virus does not appear to cause viral-induced placental inflammation, which can lead to fetal stroke. So, the authors say they cannot be sure that congenital Zika contributed to the infarct in this case. However, they write, “Given the relatively low incidence of perinatal ischemic infarct and the lack of other maternal- or birth-related risk factors for this patient, Zika infection is considered a possible etiology.”

In both patients, neonatal brain MRI identified subclinical findings that had not previously been described as part of congenital Zika syndrome. As the body of evidence about the Zika virus has grown, the spectrum of associated brain abnormalities has expanded to include considerably more findings than isolated microcephaly.

Data gathered in 2017 from the Centers for Disease Control and Prevention’s Zika pregnancy and infant registry indicates that 25 percent of eligible U.S. infants receive recommended postnatal imaging. Dr. Mulkey said this represents many possible missed opportunities for earlier identification of brain abnormalities.

“Brain MRI should be considered in all newborns exposed to Zika virus in utero, even in the presence of normal birth head circumference, normal cranial ultrasound and normal fetal imaging,” she says. “In both of these patients, the changes we observed were not evident on cranial ultrasound or on fetal MRI and fetal ultrasound.”

In addition to Dr. Mulkey, Children’s co-authors include L. Gilbert Vezina, M.D., Neuroradiology Program director; Dorothy I. Bulas, M.D., chief of Diagnostic Imaging and Radiology; Zarir Khademian, M.D., radiologist; Anna Blask, M.D., radiologist; Youssef A. Kousa, M.S., D.O., Ph.D., child neurology fellow; Lindsay Pesacreta, FNP; Adré  J. du Plessis, M.B.Ch.B., M.P.H., Fetal Medicine Institute director; and Roberta L. DeBiasi, M.D., M.S., senior author and Pediatric Infectious Disease division chief; and Caitlin Cristante, B.S.

Financial support for this research was provided by the Thrasher Research Fund.

Neonatal baby

Multidisciplinary experts help CDC’s Zika research

“We are very excited about this next phase in our Zika research,” says Roberta L. DeBiasi, M.D., M.S. “It is a natural extension of our earlier participation as subject matter experts assisting as the CDC developed and published guidelines to inform the care of Zika-exposed and Zika-infected infants across the nation and U.S. territories.”

The Centers for Disease Control and Prevention (CDC) is funding three multidisciplinary experts from the Congenital Zika Virus Program at Children’s National Health System to collaborate on two of the CDC’s longitudinal Zika research projects in Colombia, South America.

“Zika en embarazadas y niños en Colombia” (ZEN) is a research study jointly designed by Colombia’s Instituto Nacional de Salud (INS) and the CDC to evaluate the association between Zika virus infection and adverse maternal, fetal and infant health outcomes. The study is following a large cohort of Colombian women from the first trimester of pregnancy, their male partners and their infants.

Under the six-month contract, Roberta L. DeBiasi, M.D., M.S., Sarah B. Mulkey, M.D., Ph.D., and Cara Biddle, M.D., M.P.H., will serve as consultants for the ZEN study providing expertise in pediatric infectious diseases, neurology, neurodevelopment and coordination of the complex care needs of Zika-affected infants.

The federal funding will underwrite the consultants’ work effort, as well as travel to the CDC’s headquarters in Atlanta and to research sites in Colombia. To that end, Drs. DeBiasi, Mulkey and Biddle participated in a December 2017 kickoff meeting, joining ZEN team leaders based in the U.S. at the CDC, as well as the INS in Colombia, with whom they will conduct research and collaborate academically.

Cara-Biddle-and-Sarah-Mulkey

Cara Biddle, M.D., M.P.H., and Sarah B. Mulkey, M.D., Ph.D., also will serve as consultants for the ZEN study.

“We are very excited about this next phase in our Zika research,” says Dr. DeBiasi, chief of the Division of Pediatric Infectious Diseases and co-director of the Children’s Zika program. “It is a natural extension of our earlier participation as subject matter experts assisting as the CDC developed and published guidelines to inform the care of Zika-exposed and Zika-infected infants across the nation and U.S. territories.”

Children’s National is leading its own longitudinal studies in Colombia that explore such questions as whether Zika-exposed infants whose neuroimaging appears normal when they are born experience any longer-term neurological issues and the role of genetics in neurologic injury following congenital Zika virus exposure and infection.

Roberta DeBiasi and Sarah Mulkey

Children’s National experts contribute to new Zika guidelines

Roberta DeBiasi and Sarah Mulkey

Roberta DeBiasi, M.D., M. S., and Sarah B. Mulkey, M.D., Ph.D., members of Children’s multidisciplinary Congenital Zika Virus Program, were among the experts invited to participate in a forum held in Atlanta at CDC headquarters in late August to formulate new Zika recommendations.

The Centers for Disease Control and Prevention (CDC) on Oct. 19, 2017 updated guidelines for evaluation of women, fetuses and infants exposed to the Zika virus during pregnancy. Although only women with symptoms will now be routinely tested, asymptomatic and symptomatic infants born to these women will still be tested for the Zika virus using blood and urine tests.

Infants who appear normal, whose mothers either had negative Zika results or who had not undergone testing, will not undergo Zika testing. These infants still will undergo a standard evaluation, including a detailed physical exam, hearing screen and routine developmental assessments. The revised Zika guidance includes input from practitioners on the front lines of the Zika epidemic, including Children’s National Health System clinicians.

“These changes in the recommendations for Zika testing should not be interpreted as Zika infection risks subsiding for pregnant women and their infants in the United States. It’s simply an acknowledgement of the limitations of current testing methods – which must occur within a narrow window after Zika exposure – and the poor predictive value of Zika testing right now,” says Roberta L. DeBiasi, M.D., M.S., chief of Children’s Division of Pediatric Infectious Diseases. Dr. DeBiasi and Sarah B. Mulkey, M.D., Ph.D., members of Children’s multidisciplinary Congenital Zika Virus Program, were among the experts invited to participate in the Zika forum held in Atlanta at CDC headquarters in late August to formulate the recommendations.

While all infants will receive a standard evaluation, expanded evaluations that include an ophthalmologic assessment, more detailed hearing evaluation and ultrasound of the newborn’s head will be reserved for infants born to mothers confirmed to be Zika positive or Zika probable, or for infants born with abnormalities potentially consistent with congenital Zika syndrome, regardless of maternal status.

The majority of U.S. infants who have been exposed to Zika in the womb appeared normal at birth, according to CDC registries. Now, the next wave of these normal-appearing babies will receive standard evaluations when they are born, including a newborn hearing screening. At each well-child visit, these infants will receive:

  • A comprehensive physical examination
  • An age-appropriate vision screening
  • Developmental monitoring and screening using validated tools

“This is a natural evolution in the diagnosis and screening strategy now that the peak of the first wave of Zika transmission appears to be over,” Dr. DeBiasi says. “While we continue to evaluate new possible cases of Zika infection among pregnant women in our practice, a sizable proportion of Children’s cases are Zika-exposed infants whose physical exam and neuroimaging appeared normal at birth. Through ongoing monitoring, we hope to learn more about these children’s long-term neurodevelopment outcomes.”

Sarah Mulkey

Fetal MRI plus ultrasound assess Zika-related brain changes

Sarah Mulkey

Magnetic resonance imaging and ultrasound provide complementary data needed to assess ongoing changes to the brains of fetuses exposed to Zika in utero, says Sarah B. Mulkey, M.D., Ph.D.

For Zika-affected pregnancies, fetal magnetic resonance imaging (MRI) used in addition to standard ultrasound (US) imaging can better assess potential brain abnormalities in utero, according to research presented by Children’s National Health System during IDWeek 2017. In cases of abnormal brain structure, fetal MRI can reveal more extensive areas of damage to the developing brain than is seen with US.

“MRI and US provide complementary data needed to assess ongoing changes to the brains of fetuses exposed to Zika in utero,” says Sarah B. Mulkey, M.D., Ph.D., a fetal/neonatal neurologist at Children’s National Health System and lead author of the research paper. “In addition, our study found that relying on ultrasound alone would have given one mother the false assurance that her fetus’ brain was developing normally while the sharper MRI clearly pointed to brain abnormalities.”

As of Sept. 13, the Centers for Disease Control and Prevention (CDC) reported that 1,901 U.S. women were exposed to Zika at some point during their pregnancies but their infants appeared normal at birth. Another 98 U.S. women, however, gave birth to infants with Zika-related birth defects.  And eight more women had pregnancy losses with Zika-related birth defects, according to CDC registries.

The longitudinal neuroimaging study led by Children’s National enrolled 48 pregnant women exposed to the Zika virus in the first or second trimester whose infection was confirmed by reverse transcription polymerase chain reaction, which detects Zika viral fragments shortly after exposure, and/or Immunoglobulin M testing, which reveals antibodies the body produces to neutralize the virus. Forty-six of the study volunteers live in Barranquilla, Colombia, where Zika infection is endemic. Two women live in the Washington region and were exposed to Zika during travel elsewhere.

All of the women underwent at least one diagnostic imaging session while pregnant, receiving an initial MRI or US at 25.1 weeks’ gestational age. Thirty-six women underwent a second MRI/US imaging pair at roughly 31 weeks’ gestation. Children’s National radiologists read every image.

Three of 48 pregnancies, or 6 percent, were marked by abnormal fetal MRIs:

  • One fetus had heterotopias (clumps of grey matter located at the wrong place) and abnormal cortical indent (a deformation at the outer layer of the cerebrum, a brain region involved in consciousness). The US taken at the same gestational age for this fetus showed its brain was developing normally.
  • Another fetus had parietal encephalocele (an uncommon skull defect) and Chiari malformation Type II (a life-threatening structural defect at the base of the skull and the cerebellum, the part of the brain that controls balance). The US for this fetus also detected these brain abnormalities.
  • The third fetus had a thin corpus callosum (bundle of nerves that connects the brain’s left and right hemispheres), an abnormally developed brain stem, temporal cysts, subependymal heterotopias and general cerebral/cerebellar atrophy. This fetal US showed significant ventriculomegaly (fluid-filled structures in the brain that are too large) and a fetal head circumference that decreased sharply from the 32nd to 36th gestational week, a hallmark of microcephaly.

After they were born, infants underwent a follow-up MRI without sedation and US. For nine infants, these ultrasounds revealed cysts in the choroid plexus (cells that produce cerebrospinal fluid) or germinal matrix (the source for neurons and glial cells that migrate during brain development). And one infant’s US after birth showed lenticulostriate vasculopathy (brain lesions).

“Because a number of factors can trigger brain abnormalities, further studies are needed to determine whether the cystic changes to these infants’ brains are attributable to Zika exposure in the womb or whether some other insult caused these troubling results,” Dr. Mulkey says.

Sarah Mulkey Columbia Zika Study

Damage may lurk in “normal” Zika-exposed brains

Sarah Mulkey Columbia Zika Study

An international study that includes Sarah B. Mulkey, M.D., Ph.D., aims to answer one of the most vexing questions about Zika: If babies’ brains appear “normal” at birth, have they survived Zika exposure in the womb with few neurological repercussions? Dr. Mulkey presented preliminary findings at PAS2017.

It has been well established by researchers, including scientists at Children’s National Health System, that the Zika virus is responsible for a slew of birth defects – such as microcephaly, other brain malformations and retinal damage – in babies of infected mothers. But how the virus causes these often devastating effects, and who exactly is affected, has not been explained fully.

Also unknown is whether exposed babies that appear normal at birth are truly unaffected by the virus or have hidden problems that might surface later. The majority of babies born to Zika-infected mothers in the United States appear to have no evidence of Zika-caused birth defects, but that’s no guarantee that the virus has not caused lingering damage.

Recently, Sarah B. Mulkey, M.D., Ph.D., made a trip to Colombia, where Children’s National researchers are collaborating on a clinical study. There, she tested Zika-affected babies’ motor skills as they sat, stood and lay facing upward and downward. The international study aims to answer one of the most vexing questions about Zika: If babies’ brains appear “normal” at birth, have they survived Zika exposure in the womb with few neurological repercussions?

“We don’t know the long-term neurological consequences of having Zika if your brain looks normal,” says Dr. Mulkey, a fetal-neonatal neurologist who is a member of Children’s Congenital Zika Virus Program. “That is what’s so scary, the uncertainty about long-term outcomes.”

According to the Centers for Disease Control and Prevention (CDC), one in 10 pregnancies across the United States with laboratory-confirmed Zika virus infection results in birth defects in the fetus or infant. For the lion’s share of Zika-affected pregnancies, then, babies’ long-term prospects remain a mystery.

“This is a huge number of children to be impacted and the impact, as we understand, has the potential to be pretty significant,” Dr. Mulkey adds.

Dr. Mulkey, the lead author, presented the research group’s preliminary findings during the 2017 annual meeting of the Pediatric Academic Societies (PAS). The presentation was one of several that focused on the Zika virus. Roberta L. DeBiasi, M.D., M.S., chief of the Division of Pediatric Infectious Diseases at Children’s National, organized two invited symposia devoted to the topic of Zika: Clinical perspectives and knowledge gaps; and the science of Zika, including experimental models of disease and vaccines. Dr. DeBiasi’s presentation included an overview of the 68 Zika-exposed or infected women and infants seen thus far by Children’s multidisciplinary Congenital Zika Virus Program.

“As the world’s largest pediatric research meeting, PAS2017 is an ideal setting for panelists to provide comprehensive epidemiologic and clinical updates about the emergence of Congenital Zika Syndrome and to review the pathogenesis of infection as it relates to the fetal brain,” Dr. DeBiasi says. “With temperatures already rising to levels that support spread of the Aedes mosquito, it is imperative for pediatricians around the world to share the latest research findings to identify the most effective interventions.”

As one example, Dr. Mulkey’s research sought to evaluate the utility of using magnetic resonance imaging (MRI) to evaluate fetal brain abnormalities in 48 babies whose mothers had confirmed Zika infection during pregnancy. Forty-six of the women/infant pairs enrolled in the prospective study are Colombian, and two are Washington, D.C. women who were exposed during travel to a Zika hot zone.

The women were infected with Zika during all three trimesters and experienced symptoms at a mean gestational age of 8.4 weeks. The first fetal MRIs were performed as early as 18 weeks’ gestation. Depending upon the gestational age when they were enrolled in the study, the participants had at least one fetal MRI as well as serial ultrasounds. Thirty-six fetuses had a second fetal MRI at about 31.1 gestational weeks. An experienced pediatric neuroradiologist evaluated the images.

Among the 48 study participants, 45 had “normal” fetal MRIs.

Three fetuses exposed to Zika in the first or second trimester had abnormal fetal MRIs:

  • One had heterotopia and an early, abnormal fold on the surface of the brain, indications that neurons did not migrate to their anticipated destination during brain development. This pregnancy was terminated at 23.9 gestational weeks.
  • One had parietal encephalocele, a rare birth defect that results in a sac-like protrusion of the brain through an opening in the skull. According to the CDC, this defect affects one in 12,200 births, or 340 babies, per year. It is not known if this rare finding is related to Zika infection.
  • One had a thin corpus callosum, dysplastic brainstem, heterotopias, significant ventriculomegaly and generalized cerebral/cerebellar atrophy.

“Fetal brain MRI detected early structural brain changes in fetuses exposed to the Zika virus in the first and second trimester,” Dr. Mulkey says. “The vast majority of fetuses exposed to Zika in our study had normal fetal MRI, however. Our ongoing study, underwritten by the Thrasher Research Fund, will evaluate their long-term neurodevelopment.”

Adré J. du Plessis, MB.Ch.B., M.P.H., director of the Fetal Medicine Institute and senior author of the paper, notes that this group “is a very important cohort to follow as long as Dr. Mulkey’s funding permits. We know that microcephaly is among the more devastating side effects caused by Zika exposure in utero. Unanswered questions remain about Zika’s impact on hearing, vision and cognition for a larger group of infants. Definitive answers only will come with long-term follow-up.”

Many of the Colombian families live in Sabanalarga, a relatively rural, impoverished area with frequent rain, leaving pockets of fresh water puddles that the mosquito that spreads Zika prefers, Dr. Mulkey adds. Families rode buses for hours for access to fetal MRI technology, which is not common in Colombia.

“The mothers are worried about their babies. They want to know if their babies are doing OK,” she says.