Tag Archive for: du Plessis

Baby on ventilator

Autonomic markers of extubation readiness in premature infants

Baby on ventilator

Premature infants often require a breathing tube and mechanical ventilation as a mainstay in their therapy. It can be difficult to predict when these patients are ready to come off the ventilator (extubate).

Premature infants often require a breathing tube and mechanical ventilation as a mainstay in their therapy. It can be difficult to predict when these patients are ready to come off the ventilator (extubate). In a study from Pediatric Research, experts from Children’s National Hospital describe a model to predict the success of extubation using markers of autonomic tone (rest and digest versus fight or flight response). This study was led by Suma Hoffman, M.D., neonatologist and co-authored by Adré J. du Plessis, M.B.Ch.B., M.P.H., division chief of Prenatal Pediatrics Institute, Sarah Schlatterer, M.D., prenatal and neonatal neurologist, and Rathinaswamy B. Govindan, Ph.D.

The team deployed a study of 89 infants less than 28 weeks. Heart rate variability (HRV) metrics 24 hours prior to extubation were compared for those with and without extubation success within 72 hours. Receiver-operating curve analysis was conducted to determine the predictive ability of each metric and a predictive model was created.

Conclusions show that extubation success is associated with HRV. The authors demonstrate an autonomic imbalance with low sympathetic and elevated parasympathetic tone in those who failed. α1, a marker of sympathetic tone, was noted to be the best predictor of extubation success especially when incorporated into a clinical model.

Learn more about the study in Pediatric Research.

doctor examining pregnant woman

Low parental socioeconomic status alters brain development in unborn babies

doctor examining pregnant woman

A first-of-its-kind study with 144 pregnant women finds that socioeconomic status (SES) has an impact in the womb, altering several key regions in the developing fetal brain as well as cortical features.

Maternal socioeconomic status impacts babies even before birth, emphasizing the need for policy interventions to support the wellbeing of pregnant women, according to newly published research from Children’s National Hospital.

A first-of-its-kind study with 144 pregnant women finds that socioeconomic status (SES) has an impact in the womb, altering several key regions in the developing fetal brain as well as cortical features. Parental occupation and education levels encompassing populations with lower SES hinder early brain development, potentially affecting neural, social-emotional and cognitive function later in the infant’s life.

Having a clear understanding of early brain development can also help policymakers identify intervention approaches such as educational assistance and occupational training to support and optimize the well-being of people with low SES since they face multiple psychological and physical stressors that can influence childhood brain development, Lu et al. note in the study published in JAMA Network Open.

“While there has been extensive research about the interplay between socioeconomic status and brain development, until now little has been known about the exact time when brain development is altered in people at high-risk for poor developmental outcomes,” said Catherine Limperopoulos, Ph.D., director of the Developing Brain Institute and senior author. “There are many reasons why these children can be vulnerable, including high rates of maternal prenatal depression and anxiety. Later in life, these children may experience conduct disorders and impaired neurocognitive functions needed to acquire knowledge, which is the base to thrive in school, work or life.”

The findings suggest that fetuses carried by women with low socioeconomic backgrounds had decreased regional brain growth and accelerated brain gyrification and surface folding patterns on the brain. This observation in lower SES populations may in part be explained by elevated parental stress and may be associated with neuropsychiatric disorders and mental illness later in life.

In contrast, fetuses carried by women with higher education levels, occupation and SES scores showed an increased white matter, cerebellar and brainstem volume during the prenatal period, and lower gyrification index and sulcal depth in the parietal, temporal and occipital lobes of the brain. These critical prenatal brain growth and development processes lay the foundation for normal brain function, which ready the infant for life outside the womb, enabling them to attain key developmental milestones after birth, including walking, talking, learning and social skills.

There is also a knowledge gap in the association between socioeconomic status and fetal cortical folding — when the brain undergoes structural changes to create sulcal and gyral regions. The study’s findings of accelerated gyrification in low SES adds to the scientific record, helping inform future research, Limperopoulos added.

The Children’s National research team gathered data from 144 healthy women at 24 to 40 weeks gestation with uncomplicated pregnancies. To establish the parameters for socioeconomic status, which included occupation and education in lieu of family income, parents completed a questionnaire at the time of each brain magnetic resonance imaging (MRI) visit. The researchers used MRI to measure fetal brain volumes, including cortical gray matter, white matter, deep gray matter, cerebellum and brain stem. Out of the 144 participants, the scientists scanned 40 brain fetuses twice during the pregnancy, and the rest were scanned once. The 3-dimensional computational brain models among healthy fetuses helped determine fetal brain cortical folding.

Potential proximal risk factors like maternal distress were also measured in the study using a questionnaire accounting for 60% of the participants but, according to the limited data available, there was no significant association with low and high socioeconomic status nor brain volume and cortical features.

Authors in the study from Children’s National include: Yuan-Chiao Lu, Ph.D., Kushal Kapse, M.S., Nicole Andersen, B.A., Jessica Quistorff, M.P.H., Catherine Lopez, M.S., Andrea Fry, B.S., Jenhao Cheng, Ph.D., Nickie Andescavage, M.D., Yao Wu, Ph.D., Kristina Espinosa, Psy.D., Gilbert Vezina, M.D., Adre du Plessis, M.D., and Catherine Limperopoulos, Ph.D.

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.

Laura Sanapo

Children’s fetal medicine fellow named ‘Outstanding graduate student’

Laura Sanapo

Laura Sanapo, M.D., M.S.H.S., told the graduating class that two guiding themes defined her experience as a GW student: diversity and momentum.

Laura Sanapo, M.D., M.S.H.S., a fetal medicine fellow at Children’s Fetal Medicine Institute, was named “Outstanding graduate student” at The George Washington University School of Medicine & Health Sciences (GWSMHS) and was among two student speakers to address fellow graduates during the ceremony held May 19, 2018.

Dr. Sanapo was selected from a competitive field of top-tier graduate students from an array of academic programs, says Samar A. Nasser, Ph.D., M.P.H., PA-C, director of Clinical and Translational Research and Clinical Health Sciences at GWSMHS, who nominated her for the award. “She is one of the brightest students I have encountered. Because of her exceptional background, I recruited Dr. Sanapo to become an adjunct professor in our Clinical and Translational Research program and I look forward to co-teaching a course with her this fall.”

“I am extremely humbled and honored by this recognition for my ongoing research,” Dr. Sanapo says. “It is a privilege to join the GW faculty and contribute to the growth of an outstanding academic team and diverse group of students. I feel energized by such a collegial and dynamic environment.”

She told the graduating class that two guiding themes defined her experience as a GW student: diversity and momentum. Diversity, she told the group “means the spark that generates new ideas and growth” and momentum is the feeling of being “propelled forward by being part of a university that feels like a lively workshop of ideas.”

Prior to joining Children’s National Health System in 2014, Dr. Sanapo served with distinction at the University of Maryland School of Medicine and Thomas Jefferson University School of Medicine, conducting original research and frequently publishing in peer-reviewed journals.

Under the mentorship of Adré J. du Plessis, M.B.Ch.B., M.P.H., chief of Children’s Division of Fetal and Transitional Medicine, Dr. Sanapo investigated the role of advanced ultrasound techniques in assessing fetal vasoreactivity in pregnancies complicated by such conditions as intrauterine growth restriction, Dr. Nasser wrote in the nomination letter. In that study, the research team is trying to better understand how a healthy fetus controls blood flow throughout the body, including to the lungs and brain.

In addition to evaluating and counseling in high-risk pregnancies complicated by complex fetal malformations, Dr. Sanapo performed research and clinical ultrasounds daily. What’s more, Dr. Sanapo often scheduled appointments after-hours for patients unable to complete ultrasounds during normal business hours and was an integral part of the team that counseled women through difficult pregnancies.

“‘These women are especially vulnerable and they deserve 100 percent of my time, knowledge, energy and empathy,’  ” Dr. Nasser recalls Dr. Sanapo explaining. “Laura often goes above and beyond her responsibilities as a fellow to assist these women in need.”

Dr. du Plessis notes that Dr. Sanapo has been a valued clinical leader at Children’s Fetal Medicine Institute, shepherding a multidisciplinary team that includes genetic counselors, specialists in maternal-fetal medicine, radiologists, pediatric neurologists and nurses.

“When Children’s National and Inova announced a three-year, $2.8 million research and education collaboration in maternal, fetal and neonatal medicine last January, Laura’s contributions were pivotal in ensuring the research collaboration’s early success,” Dr. du Plessis adds.

Children’s National Fetal Medicine Institute hosts 2nd annual International Symposium on the Fetal Brain

The Children’s National Health System Fetal Medicine Institute hosted the 2nd annual International Symposium on the Fetal Brain in August 2017 in Washington, D.C.

Speakers at this year’s symposium focused on the following four areas:

  • Brain Development in an Unsupportive In Utero Environment – Diagnosis and Consequences
  • Supporting Brain Development in the Ex Utero Fetus: How Far Are We From Optimal?
  • Genomic and Epigenomic Mechanisms Underlying Differences in Brain Development
  • The Emergence of Consciousness and Pain Sensation

Adré J. du Plessis, M.B.Ch.B., M.P.H., Director of the Fetal Medicine Institute and Division Chief of Fetal and Transitional Medicine hosted the conference. In his opening remarks Dr. du Plessis noted “Our goal has been to gather together a diverse group from across the spectrum of disciplines focused on the well-being of the fetal brain and to engage all disciplines together.”

Diana-Bianchi-at-ISFB

Diana Bianchi, MD gives her keynote presentation on non-invasive fetal testing at the second annual International Symposium on the Fetal Brain.

Invited, internationally renowned speakers presented on diverse topics, including Diana Bianchi, Director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development who spoke on the “Non-Invasive Fetal Testing Beyond Karyotype: What’s in it for the Fetal Brain?”

A new component to the symposium was the clinically-focused breakfast breakout sessions, created based on feedback from attendees of the 2016 Symposium. Sessions covered varied topics such as “Fetal Ultrasound: the Cornerstone of Fetal Neurodiagnosis,” “The Essentials of Neurogenetic Testing,” “Developing a Transitional Fetal-Neonatal Program” and “Using MRI to Advance Fetal Neurodiagnosis.”

The conference started with an exciting discussion by Alistair Gunn, M.B.Ch.B., Head of the Department of Physiology at the University of Auckland. His presentation “Fetal Heart Rate: What It Does and Does Not Tell Us” explored the considerable body of evidence that essentially all decelerations are mediated by chemoreflex responses to repeated hypoxia and that the parasympathetic autonomic nervous system is the critical regulator of both fetal heart rate and heart rate variation in labor.

Following a voting process from the symposium’s external speakers, the inaugural Andrea Poretti Abstract Award was presented to Katherine Ottolini for her poster titled: Breastmilk Feeds Improve Brain Microstructural Development in Very Premature Infants.

For more information about the sessions and speakers at the 2017 Symposium, please visit our website.

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.

Catherine Limperopoulous

The brain’s fluid-filled spaces during growth

Catherine Limperopoulous

Catherine Limperopoulous, Ph.D., and her colleagues used volumetric MRIs to assess how the ventricles, cerebrospinal fluid and the rest of the fetal brain normally change over time.

The human brain is not one solid mass. Buried within its gray and white matter are a series of four interconnected chambers, called ventricles, which produce cerebrospinal fluid. These ventricles are readily apparent on the fetal ultrasounds that have become the standard of prenatal care in the United States and most developed countries around the world. Abnormalities in the ventricles’ size or shape – or both – can give doctors an early warning that fetal brain development might be going awry.

But what is abnormal? It is not always clear, says Catherine Limperopoulos, Ph.D., director of the Developing Brain Research Laboratory at Children’s National Health System. Limperopoulos explains that despite having many variations in fetal ventricles, some infants have completely normal neurodevelopmental outcomes later. On the other hand, some extremely subtle variations in shape and size can signal problems.

On top of these complications are the tools clinicians typically use to assess the ventricles. Limperopoulos explains that most early indications of ventricle abnormalities come from ultrasounds, but the finer resolution of magnetic resonance imaging (MRI) can provide a more accurate assessment of fetal brain development. Still, both standard MRI and ultrasound provide only two-dimensional pictures, making it difficult to quantify slight differences in the volume of structures.

To help solve these problems, Limperopoulos and her colleagues recently published a paper in Developmental Neuroscience that takes a different tack. The team performed volumetric MRIs – a technique that provides a precise three-dimensional measure of structural volumes – on the brains of healthy fetuses to assess how the ventricles, cerebrospinal fluid and the rest of the brain normally change over time. Limperopoulos’ team recently performed a similar study to assess normal volumetric development in the brain’s solid tissues.

Previous studies published on comparable topics typically used information gathered from subjects who initially had clinical concerns but eventually were dismissed from these studies for not having worrisome diagnoses in the end. This might not truly reflect a typical population of pregnant women, Limperopoulos says.

Working with 166 pregnant women with healthy pregnancies spanning from 18 to 40 weeks gestation, the researchers performed volumetric MRIs on their singleton fetuses that covered every week of this second half of pregnancy. This technique allowed them to precisely calculate the volumes of structures within the fetal brain and get an idea of how these volumes changed over time within the group.

Their results show that over the second and third trimester:

  • The lateral ventricles, the largest ventricles found in the cerebrum with one for each brain hemisphere, grew about two-fold;
  • The third ventricle, found in the forebrain, grew about 23-fold;
  • The fourth ventricle, found in the hindbrain, grew about eight-fold;
  • And the extra-axial cerebrospinal fluid, found under the lining of the brain, increased about 11-fold.

The total brain volume increased 64-fold over this time, with the parenchyma – the solid brain tissue that encompasses gray and white matter – growing significantly faster than the cerebrospinal fluid-filled spaces.

Limperopoulos points out that the ability to measure the growth of the brain’s fluid-filled spaces relative to the surrounding brain tissue can provide critical information to clinicians caring for developing fetuses. In most cases, knowing what is normal allows doctors to reassure pregnant women that their fetus’ growth is on track. Abnormalities in these ratios can provide some of the first signals to alert doctors to blockages in cerebrospinal fluid flow, abnormal development, or the loss of brain tissue to damage or disease. Although the neurodevelopmental outcomes from each of these conditions can vary significantly, traditional ultrasounds or MRIs might not be able to distinguish these possibilities from each other. Being able to differentiate why cerebrospinal fluid spaces have abnormal shapes or sizes might allow doctors to better counsel parents, predict neurological outcomes, or potentially intervene before or after birth to mitigate brain damage.

“By developing a better understanding of what’s normal,” Limperopoulos says, “we can eventually identify reliable biomarkers of risk and guide interventions to minimize risks for vulnerable fetuses.”

Drs. DeBiasi and du Plessis

Zika virus, one year later

Drs. DeBiasi and du Plessis

A multidisciplinary team at Children’s National has consulted on 66 Zika-affected pregnancies and births since May 2016.

The first pregnant patient with worries about a possible Zika virus infection arrived at the Children’s National Health System Fetal Medicine Institute on Jan. 26, 2016, shortly after returning from international travel.

Sixteen months ago, the world was just beginning to learn how devastating the mosquito-borne illness could be to fetuses developing in utero. As the epidemic spread, a growing number of sun-splashed regions that harbor mosquitoes that efficiently spread the virus experienced a ballooning number of Zika-affected pregnancies and began to record sobering birth defects.

The Washington, D.C. patient’s concerns were well-founded. Exposure to Zika virus early in her pregnancy led to significant fetal brain abnormalities, and Zika virus lingered in the woman’s bloodstream months after the initial exposure — longer than the Centers for Disease Control and Prevention (CDC) then thought was possible.

The research paper describing the woman’s lengthy Zika infection, published by The New England Journal of Medicine, was selected as one of the most impactful research papers written by Children’s National authors in 2016.

In the intervening months, a multidisciplinary team at Children National has consulted on 66 pregnancies and infants with confirmed or suspected Zika exposure. Thirty-five of the Zika-related evaluations were prenatal, and 31 postnatal evaluations assessed the impact of in utero Zika exposure after the babies were born.

The continuum of Zika-related injuries includes tragedies, such as a 28-year-old pregnant woman who was referred to Children’s National after imaging hinted at microcephaly. Follow-up with sharper magnetic resonance imaging (MRI) identified severe diffuse thinning of the cerebral cortical mantle, evidence of parenchymal cysts in the white matter and multiple contractures of upper and lower extremities with muscular atrophy.

According to a registry of Zika-affected pregnancies maintained by the CDC, one in 10 pregnancies across the United States with laboratory-confirmed Zika virus infection has resulted in birth defects in the fetus or infant.

“More surprising than that percentage is the fact that just 25 percent of infants underwent neuroimaging after birth – despite the CDC’s recommendation that all Zika-exposed infants undergo postnatal imaging,” says Roberta L. DeBiasi, M.D., M.S., chief of the Division of Pediatric Infectious Diseases and co-director of the Congenital Zika Virus Program at Children’s National. “Clinicians should follow the CDC’s guidance to the letter, asking women about possible exposure to Zika and providing multidisciplinary care to babies after birth. Imaging is an essential tool to accurately monitor the growing baby’s brain development.”

Adré du Plessis, M.B.Ch.B., M.P.H., director of the Fetal Medicine Institute and Congenital Zika Virus Program co-leader, explains the challenges: ”When it comes to understanding the long-term consequences for fetuses exposed to the Zika virus, we are still on the steepest part of the learning curve. Identifying those children at risk for adverse outcomes will require a sustained and concerted multidisciplinary effort from conception well beyond childhood.”

In addition to counseling families in the greater Washington, D.C. region, the Children’s research team is collaborating with international colleagues to conduct a clinical trial that has been recruiting Zika-infected women and their babies in Colombia. Pediatric Resident Youssef A. Kousa, D.O., Ph.D., M.S., and Neurologist Sarah B. Mulkey, M.D., Ph.D., will present preliminary findings during Research and Education Week 2017.

In Colombia as well as the District of Columbia, a growing challenge continues to be assessing Zika’s more subtle effects on pregnancies, developing fetuses and infants, says Radiologist Dorothy Bulas, M.D., another member of Children’s multidisciplinary Congenital Zika Virus Program.

The most severe cases from Brazil were characterized by interrupted fetal brain development, smaller-than-normal infant head circumference, brain calcifications, enlarged ventricles, seizures and limbs folded at odd angles. In the United States and many other Zika-affected regions, Zika-affected cases with such severe birth defects are outnumbered by infants who were exposed to Zika in utero but have imaging that appears normal.

In a darkened room, Dr. Bulas pores over magnified images of the brains of Zika-infected babies, looking for subtle differences in structure that may portend future problems.

“There are some questions we have answered in the past year, but a number of questions remain unanswered,” Dr. Bulas says. “For neonates, that whole area needs assessment. As the fetal brain is developing, the Zika virus seems to affect the progenitor cells. They’re getting hit quite early on. While we may not detect brain damage during the prenatal period, it may appear in postnatal images. And mild side effects that may not be as obvious early on still have the potential to be devastating.”

pregnancy

New Children’s National and Inova collaboration

pregnancy

A new research collaboration will streamline completion of retrospective and prospective research studies, shedding light on myriad conditions that complicate pregnancies.

A new three-year, multi-million dollar research and education collaboration in maternal, fetal and neonatal medicine aims to improve the health of pregnant women and their children. The partnership between Children’s National Health System and Inova will yield a major, nationally competitive research and academic program in these areas that will leverage the strengths of both health care facilities and enhance the quality of care available for these vulnerable populations.

The collaboration will streamline completion of retrospective and prospective research studies, shedding light on a number of conditions that complicate pregnancies. It is one of several alliances between the two institutions aimed at improving the health and well-being of children in Northern Virginia and throughout the region.

“The Washington/Northern Virginia region has long had the capability to support a major, nationally competitive research and academic program in maternal and fetal medicine,” says Adre du Plessis, M.B.Ch.B., Director of the Fetal Medicine Institute at Children’s National and a co-Principal Investigator for this partnership. “The Children’s National/Inova maternal-fetal-neonatal research education program will fill this critical void.

“This new partnership will help to establish a closer joint education program between the two centers, working with the OB/Gyn residents at Inova and ensuring their involvement in Children’s National educational programs and weekly fetal case review meetings,” Dr. du Plessis adds.

Larry Maxwell, M.D., Chairman of Obstetrics and Gynecology at Inova Fairfax Medical Campus and a co-Principal Investigator for the collaboration, further emphasizes that “Inova’s experience in caring for women and children — combined with genomics- and proteomics-based research — will synergize with Children National’s leadership in neonatal pediatrics, placental biology and fetal magnetic resonance imaging (MRI) to create an unprecedented research consortium. This will set the stage for developing clinically actionable interventions for mothers and babies in metropolitan District of Columbia.”

Children’s National, ranked No. 3 nationally in neonatology, has expertise in pediatric neurology, fetal and neonatal neurology, fetal and pediatric cardiology, infectious diseases, genetics, neurodevelopment and dozens of additional pediatric medical subspecialties. Its clinicians are national leaders in next-generation imaging techniques, such as MRI. Eighteen specialties and 50 consultants evaluate more than 700 cases per year through its Fetal Medicine Institute. In mid-2016, Children’s National created a Congenital Zika Virus Program to serve as a dedicated resource for referring clinicians and pregnant women. The hospital performs deliveries in very high-risk, complex situations, but does not offer a routine labor and delivery program.

Inova Fairfax Medical Campus is home to both Inova Women’s Hospital and Inova Children’s Hospital. Inova Women’s Hospital is the region’s most comprehensive and highest-volume women’s hospital — delivering more than 10,000 babies in 2016. Inova Children’s Hospital serves as Northern Virginia’s children’s hospital —providing expert care in pediatric and fetal cardiology, cardiac surgery, genetics, complex general surgery, neurology, neurosurgery and other medical and surgical specialties. Its 108-bed Level IV neonatal intensive care unit is one of the largest and most comprehensive in the nation. Inova’s Translational Medicine Institute includes a genomics lab, as well as a research Institute focused on studies designed to build genetic models that help answer questions about individual disease. Each of these specialties is integrated into the Inova Fetal Care Center — which serves as a connection point between Inova Women’s and Children’s Hospitals. The Inova Fetal Care Center provides complex care coordination for women expecting infants with congenital anomalies or with other fetal concerns. Because Inova Women’s Hospital and Inova Children’s Hospital are co-located, women are able to deliver their babies in the same building where their children will receive care.

The research collaboration will support research assistants; tissue technicians; a placental biologist; as well as support for biomedical engineering, fetal-neonatal imaging, telemedicine, regulatory affairs and database management. The joint research projects that will take place under its auspices include:

  • Fetal growth restriction (FGR), which occurs when the failing placenta cannot support the developing fetus adequately. FGR is a major cause of stillbirth and death, and newborns who survive face numerous risks for multiple types of ailments throughout their lives. A planned study will use quantitative MRI to identify signs of abnormal brain development in pregnancies complicated by FGR.
  • Placental abnormalities, including placenta accreta. A planned study will combine quantitative MRI studies on the placenta during the third trimester and other points in time with formal histopathology to identify MRI signals of placenta health and disease.
  • Microcephaly, a condition that is characterized by babies having a much smaller head size than expected due to such factors as interrupted brain development or brain damage during pregnancy. While the global Zika virus epidemic has heightened awareness of severe microcephaly cases, dozens of pregnancies in the region in recent years have been complicated by the birth defect for reasons other than Zika infection. A planned study will examine the interplay between MRI within the womb and head circumference and weight at birth to examine whether brain volume at birth correlates with the baby’s developmental outcomes.

Setting a baseline for healthy brain development

Catherine Limperopoulos, Ph.D., and colleagues performed the largest magnetic resonance imaging study of normal fetal brains in the second and third trimesters of pregnancy.

Starting as a speck barely visible to the naked eye and ending the in utero phase of its journey at an average weight of 7.5 pounds, the growth of the human fetus is one of the most amazing events in biology. Of all the organs, the fetal brain undergoes one of the most rapid growth trajectories, expanding over 40 weeks from zero to 100 billion neurons — about as many brain cells as there are stars in the Milky Way Galaxy.

This exponential growth is part of what gives humans our unique abilities to use language or have abstract thoughts, among many other cognitive skills. It also leaves the brain extremely vulnerable should disruptions occur during fetal development. Any veering off the developmental plan can lead to a cascade of results that have long-lasting repercussions. For example, studies have shown that placental insufficiency, or the inability of the placenta to supply the fetus with oxygen and nutrients in utero, is associated with attention deficit hyperactivity disorder, autism, and schizophrenia.

Recent research has identified differences in the brains of people with these disorders compared with those without. Despite the almost certain start of these conditions within the womb, they have remained impossible to diagnose until children begin to show clinical symptoms. If only researchers could spot the beginnings of these problems early in development, says Children’s National Health System researcher Catherine Limperopoulos, Ph.D., they might someday be able to develop interventions that could turn the fetal brain back toward a healthy developmental trajectory.

“Conventional tools like ultrasound and magnetic resonance imaging (MRI) can identify structural brain abnormalities connected to these problems, but by the time these differences become apparent, the damage already has been done,” Limperopoulos says. “Our goal is to be able to pick up very early deviations from normal in the high-risk pregnancy before an injury to the fetus might become permanent.”

Before scientists can recognize abnormal, she adds, they first need to understand what normal looks like.

In a new study published in Cerebral Cortex, Limperopoulos and colleagues begin to tackle this question through the largest MRI study of normal fetal brains in the second and third trimesters of pregnancy. While other studies have attempted to track normal fetal brain growth, that research has not involved nearly as many subjects and typically relied on data collected when fetuses were referred for MRIs for a suspected problem. When the suspected abnormality was ruled out by the scan, these “quasi-controls” were considered “normal” — even though they may be at risk for problems later in life, Limperopoulos explains.

By contrast, the study she led recruited 166 healthy pregnant women from nearby low-risk obstetrics practices. Each woman had an unremarkable singleton pregnancy and ended up having a normal full-term delivery, with no evidence of problems affecting either the mother or fetus over the course of 40 weeks.

At least one time between 18 and 39 gestational weeks, the fetuses carried by these women underwent an MRI scan of their brains. The research team developed complex algorithms to account for movement (since neither the mothers nor their fetuses were sedated during scans) and to convert the two-dimensional images into three dimensions. They used the information from these scans to measure the increasing volumes of the cerebellum, an area of the brain connected to motor control and known to mediate cognitive skills; as well as regions of the cerebrum, the bulk of the brain, that is pivotal for movement, sensory processing, olfaction, language, and learning and memory.

Their results in uncomplicated, full-term pregnancies show that over 21 weeks in the second half of pregnancy, the cerebellum undergoes an astounding 34-fold increase in size. In the cerebrum, the fetal white matter, which connects various brain regions, grows 22-fold. The cortical gray matter, key to many of cerebrum’s functions, grows 21-fold. And the deep subcortical structures (thalamus and basal ganglia), important for relaying sensory information and coordination of movement and behavior, grow 10-fold. Additional examination showed that the left hemisphere has a larger volume than the right hemisphere early in development, but sizes of the left and right brain halves were equal by birth.

By developing similar datasets on high-risk pregnancies or births—for example, those in which fetuses are diagnosed with a problem in utero, mothers experience a significant health problem during pregnancy, babies are born prematurely, or fetuses have a sibling diagnosed with a health problem with genetic risk, such as autism—Limperopoulos says that researchers might be able to spot differences during gestation and post-natal development that lead to conditions such as schizophrenia, attention deficit hyperactivity disorder and autism spectrum disorder.

Eventually, researchers may be able to develop fixes so that babies grow up without life-long developmental issues.

“Understanding ‘normal’ is really opening up opportunities for us to begin to precisely pinpoint when things start to veer off track,” Limperopolous says. “Once we do that, opportunities that have been inaccessible will start to present themselves.”

Congenital Zika Viral Infection Linked to Significant Fetal Brain Abnormalities

mosquito

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What’s Known
According to the Centers for Disease Control and Prevention, Zika viral transmission is occurring extensively throughout Central and South America. Like other mosquito-borne viruses, Zika virus can be passed by pregnant women to developing fetuses. Unlike these other viruses, Zika has been implicated in a growing number of cases of Brazilian infants born with microcephaly, a condition characterized by undersized heads and severe brain damage. The precise strategy that the Zika virus uses to elude the immune system and the reason why fetal brain cells are particularly vulnerable remain unknown.

What’s New
A 33-year-old Finnish woman was 11 weeks pregnant when she and her husband traveled on vacation to Mexico, Guatemala, and Belize in late November 2015. The pair was bitten by mosquitoes during their trip, particularly in Guatemala. One day after returning to their Washington, DC home, the woman got sick, experiencing eye pain, muscle pain, a mild fever, and a rash. A series of early ultrasounds showed no sign of microcephaly or brain calcifications. A fetal ultrasound at the 19th week and a fetal MRI at the 20th week, however, revealed severe brain damage.

The brain of the 21-week-old aborted fetus weighed only 30 grams. Zika RNA, viral particles, and infectious virus were detected, and Zika virus isolated from the fetal brain remained infectious when tested. The concentration of virus was highest in the fetal brain, umbilical cord, and placenta. The mother remained infected with Zika virus at 21 weeks, some 10 weeks after her initial infection.

Questions for Future Research

  • Could serial measurements and blood tests more accurately detect and, ultimately, predict fetal abnormalities following Zika virus infection?
  • Why does the Zika virus replicate with ease within the womb?
  • At which stage of pregnancy are fetuses most vulnerable?
  • Which specific brain cells does Zika target?

Source:Zika Virus Infection with Prolonged Maternal Viremia and Fetal Brain Abnormalities.” R.W. Driggers, C.Y. Ho, E.M. Korhonen, S. Kuivanen, A.J. Jääskeläinen, T. Smura, D.A. Hill, R. DeBiasi, G. Vezina, J. Timofeev, F.J. Rodriguez, L. Levanov, J. Razak, P. Iyengar, A. Hennenfent, R. Kennedy, R. Lanciotti, A. du Plessis, and O. Vapalahti. The New England Journal of Medicine. June 2, 2016.

Drs. DeBiasi and du Plessis

Suspected domestic zika virus infection in Florida underscores the importance of ongoing vigilance

Drs. DeBiasi and du Plessis

Federal health officials continue to investigate the first possible cases of domestic Zika virus transmission in Florida. In light of the growing number of Zika infections, the vast majority of which have been associated with foreign travel, vigilance for additional cases is warranted – particularly as summer heat intensifies and mosquito populations grow. The Centers for Disease Control and Prevention (CDC) now advises that all pregnant women in the continental United States and U.S. territories be evaluated for Zika infection at each prenatal care visit. The CDC also recognizes that Zika-exposed infants will require long-term, multidisciplinary care.

In mid-May, Children’s National Health System Fetal Medicine Institute and Division of Pediatric Infectious Disease announced the formation of a Congenital Zika Virus Program to serve as a dedicated resource for referring clinicians and for pregnant women to receive counseling and science-driven answers about the impact of the Zika virus on pregnancies and newborns. Children’s clinicians have consulted on 30 pregnancies or births with potential Zika virus exposure and/or infection. As of Aug. 31, eight were Zika-positive or probable. One of the pregnancies was the subject of an article published by The New England Journal of Medicine.

”While we’re hopeful there are few local cases, the Congenital Zika Virus Program has been developing emergency response plans in collaboration with local departments of health to prepare for any eventuality,” says Roberta DeBiasi, MD, MS, Chief of the Division of Infectious Disease and Congenital Zika Virus Program co-leader.

Over the years, Children’s National has invested in equipment and highly trained personnel, building world-class expertise in infectious diseases, pediatric neurology, pediatric cardiology, genetics, neurodevelopment, and other specialties. Children’s clinicians are recognized leaders in next-generation imaging techniques, such as fetal MRI, which detects more subtle and earlier indications of impaired brain growth. A variety of divisions work together to offer multidisciplinary support and coordinated care to infants born with special needs. As the nation braces for the possible expansion of Zika virus infection to other states, Children’s National is facilitating the multi-step process of testing blood, urine, and tissue with state health departments, helping to ensure timely and precise information. Children’s National specialists guide Zika-affected pregnancies through the fetal period and are able to oversee and coordinate the care of Zika-affected infants after delivery. Care and clinical support is provided by a multidisciplinary team of pediatric neurologists, ophthalmologists, audiologists, physical and occupational therapists, infectious disease experts, and neurodevelopmental physicians.

The Children’s National multidisciplinary team includes:

  • Adre du Plessis, M.B.Ch.B., Director of the Fetal Medicine Institute, Chief of the Fetal and Transitional Medicine Division, and Congenital Zika Virus Program co-leader;
  • Roberta DeBiasi, M.D., M.S., Chief of the Division of Infectious Disease and Congenital Zika Virus Program co-leader;
  • Cara Biddle, M.D., M.P.H., Medical Director, Children’s Health Center, and a bilingual expert on complex care;
  • Dorothy Bulas, M.D., Radiologist in the Division of Diagnostic Imaging and Radiology;
  • Taeun Chang, M.D., Director, Neonatal Neurology Program in the Division of Neurophysiology, Epilepsy and Critical Care Neurology;
  • Sarah Mulkey, M.D., Ph.D., Fetal-Neonatal Neurologist, Fetal Medicine Institute;
  • Lindsay Pesacreta, M.S., F.N.P.-B.C., Board-Certified Family Nurse Practitioner; and
  • Gilbert Vezina, M.D., attending Radiologist in the Division of Diagnostic Imaging and Radiology and Director of the Neuroradiology Program.

[Updated Sept. 13, 2016]

New program provides science-driven answers about zika virus’s impact on pregnancies

Drs. DeBiasi and du Plessis

Each week, as temperatures rise, the likelihood increases that the United States will experience domestic Zika virus transmission. Indeed, such domestic Zika transmission already is occurring in Puerto Rico and the U.S. Virgin Islands. The Children’s National Health System Fetal Medicine Institute and Division of Pediatric Infectious Disease announced the formation of a Congenital Zika Virus Program to serve as a dedicated resource for referring clinicians and for pregnant women to receive counseling and science-driven answers about the impact of the Zika virus on their pregnancies.

Over years, Children’s National has invested in equipment and highly trained personnel, building expertise in infectious diseases, pediatric neurology, pediatric cardiology, genetics, neurodevelopment, and other specialties. Children’s clinicians are recognized as national leaders in next-generation imaging techniques, such as fetal MRI, and a variety of divisions work together to offer multidisciplinary support and coordinated care to infants born with special needs. As the nation prepares for the Zika virus, Children’s National is facilitating the multi-step process of blood testing, helping to ensure timely and precise information. Children’s National specialists are able to guide Zika-affected pregnancies through the fetal period and can oversee the care of Zika-affected infants after delivery. Care and clinical support is provided by a multidisciplinary team of pediatric neurologists, physical therapists, infectious disease experts, and neurodevelopmental physicians.

Catherine Limperopoulos

Connection between abnormal placenta and impaired growth of fetuses discovered

CLimperopoulous

A team of researchers used 3-D volumetric magnetic resonance imaging (MRI) in an innovative study that reported that when the placenta fails to grow adequately in a fetus with congenital heart disease (CHD), it contributes to impaired fetal growth and premature birth. Fetal CHD involves an abnormality of the heart and is associated with increased risk for neurodevelopmental morbidity.Until now, CHD in the fetus and its relationship to placental function has been unknown. But the advanced fetal imaging study has shown for the first time that abnormal growth in the fetus with CHD relates to impaired placental growth over the third trimester of pregnancy. Catherine Limperopoulos, PhD, Director of Children’s National Developing Brain Research Laboratory in the Division of Diagnostic Imaging and Radiology, is the senior author of the study published in the September 2015 issue of the journal Placenta, “3-D Volumetric MRI Evaluation of the Placenta in Fetuses With Complex Heart Disease.”

Specifically, the decreased 3-D volumetric MRI measurements of pregnant women reported in this study suggest placental insufficiency related to CHD. The placenta nourishes and maintains the fetus, through the delivery of food and oxygen. Its volume and weight can determine fetal growth and birth weight.

Abnormality in placental development may contribute to significant morbidity in this high risk-population. This study shows impaired placental growth in CHD fetuses is associated with the length of the pregnancy and weight at birth. Nearly 1 in every 100 babies is born in the United States with a congenital heart defect.

Developing the capacity to examine the placenta non-invasively using advanced MRI is needed to identify early markers of impaired placental structure and function in the high-risk pregnancy. This is a critical first step towards developing strategies for improved fetal monitoring and management, Dr. Limperopoulos says.

“We are trying to develop the earliest and most reliable indicators of placental health and disease in high-risk pregnancies. Our goal is to bring these early biomarkers into clinical practice and improve our ability to identify placental dysfunction,” Dr. Limperopoulos says. “If we can develop the capacity to reliably identify when things begin to veer off course, we then have a window of opportunity to develop therapies to restore function.”

The study used in-vivo 3-D MRI studies and explored placental development and its relationship to neonatal outcomes by comparing placental volumetric growth in healthy pregnancies and pregnancies complicated by CHD.

While mortality rates continue to decrease steadily in newborns diagnosed with complex CHD, long-term neurodevelopmental impairments are recognized with increasing frequency in surviving infants, Dr. Limperopoulos says.

“Our goal is to better support the developing fetus with CHD. We can best accomplish this if we develop technology that can allow us to safely and effectively monitor the fetal-placental unit as a whole throughout pregnancy,” Dr. Limperopoulos says.

“This is the new frontier, not only to ensure survival but to safeguard the fetus and to ensure the best possible quality of life,” she says.