Neonatology Archives

Perinatal hypoxia associated with long-term cerebellar learning deficits and Purkinje cell misfiring

August 20, 2018

The type of hypoxia that occurs with preterm birth is associated with locomotor miscoordination and long-term cerebellar learning deficits but can be partially alleviated with an off-the-shelf medicine, according to a study using a preclinical model.

Oxygen deprivation associated with preterm birth leaves telltale signs on the brains of newborns in the form of alterations to cerebellar white matter at the cellular and the physiological levels. Now, an experimental model of this chronic hypoxia reveals that those cellular alterations have behavioral consequences.

Chronic sublethal hypoxia is associated with locomotor miscoordination and long-term cerebellar learning deficits in a clinically relevant model of neonatal brain injury, according to a study led by Children’s National Health System researchers published online Aug. 13, 2018, by Nature Communications. Using high-tech optical and physiological methods that allow researchers to turn neurons on and off and an advanced behavioral tool, the research team finds that Purkinje cells fire significantly less often after injury due to perinatal hypoxia. However, an off-the-shelf medicine now used to treat epilepsy enables those specialized brain cells to regain their ability to fire, improving locomotor performance.

Step out of the car onto the pavement, hop up to the level of the curb, stride to the entrance, and climb a flight of stairs. Or, play a round of tennis. The cerebellum coordinates such locomotor performance and muscle memory, guiding people of all ages as they adapt to a changing environment.

“Most of us successfully coordinate our movements to navigate the three-dimensional spaces we encounter daily,” says Vittorio Gallo, Ph.D., Children’s Chief Research Officer and the study’s senior author. “After children start walking, they also have to learn how to navigate the environment and the spaces around them.”

These essential tasks, Gallo says, are coordinated by Purkinje cells, large neurons located in the cerebellum that are elaborately branched like interlocking tree limbs and represent the only source of output for the entire cerebellar cortex. The rate of development of the fetal cerebellum dramatically increases at a time during pregnancy that often coincides with preterm birth, which can delay or disrupt normal brain development.

“It’s almost like a short circuit. Purkinje cells play a very crucial role, and when the frequency of their firing is diminished by injury the whole output of this brain region is impaired,” Gallo says. “For a family of a child who has this type of impaired neural development, if we understand the nature of this disrupted circuitry and can better quantify it, in terms of locomotor performance, then we can develop new therapeutic approaches.”

Study authors Aaron Sathyanesan, Ph.D., Joseph Abbah, B.Pharm., Ph.D., Srikanya Kundu, Ph.D. and Vittorio Gallo, Ph.D.

The research team leveraged a fully automated, computerized apparatus that looks like a ladder placed on a flat surface, encased in glass, with a darkened box at either end. Both the hypoxic and control groups had training sessions during which they learned how to traverse the horizontal ladder, coaxed out of the darkened room by a gentle puff of air and a light cue. Challenge sessions tested their adaptive cerebellar locomotor learning skills. The pads they strode across were pressure-sensitive and analyzed individual stepping patterns to predict how long it should take each to complete the course.

During challenge sessions, obstacles were presented in the course, announced by an audible tone. If learning was normal, then the response to the tone paired with the obstacle would be a quick adjustment of movement, without breaking stride, says Aaron Sathyanesan, Ph.D., co-lead author. Experimental models exposed to perinatal hypoxia showed significant deficits in associating that tone with the obstacle.

“With the control group, we saw fewer missteps during any given trial,” Sathyanesan says. “And, when they got really comfortable, they took longer steps. With the hypoxic group, it took them longer to learn the course. They made a significantly higher number of missteps from day one. By the end of the training period, they could walk along all of the default rungs, but it took them longer to learn how to do so.”

Purkinje cells fire two different kinds of spikes. Simple spikes are a form of constant activity as rhythmic and automatic as a heartbeat. Complex spikes, by contrast, occur less frequently. Sathyanesan and co-authors say that some of the deficits that they observed were due to a reduction in the frequency of simple spiking.

Two weeks after experiencing hypoxia, the hypoxic group’s locomotor performance remained significantly worse than the control group, and delays in learning could still be seen five weeks after hypoxia.

Gamma-aminobutyric acid (GABA), a neurotransmitter, excites immature neurons before and shortly after birth but soon afterward switches to having an inhibitory effect within in the cerebellum, Sathyanesan says. The research team hypothesizes that reduced levels of excitatory GABA during early development leads to long-term motor problems. Using an off-the-shelf drug to increase GABA levels immediately after hypoxia dramatically improved locomotor performance.

“Treating experimental models with tiagabine after hypoxic injury elevates GABA levels, partially restoring Purkinje cells’ ability to fire,” Gallo says. “We now know that restoring GABA levels during this specific window of time has a beneficial effect. However, our approach was not specifically targeted to Purkinje cells. We elevated GABA everywhere in the brain. With more targeted and selective administration to Purkinje cells, we want to gauge whether tiagabine has a more powerful effect on normalizing firing frequency.”

In addition to Gallo and Sathyanesan, Children’s co-authors include Co-Lead Author, Srikanya Kundu, Ph.D., and Joseph Abbah, B.Pharm., Ph.D., both of Children’s Center for Neuroscience Research.

Research covered in this story was supported by the Intellectual and Developmental Disability Research Center under award number U54HD090257.

Making weight: Ensuring that micro preemies gain pounds and inches

August 13, 2018

Tory Peitz, R.N., (left) and Victoria Catalano, RDN, LD, CNSC, CLC, (right) Pediatric Dietitian Specialist in the Neonatal Intensive Care Unit at Children’s National Health System, measure the length of a micro preemie who weighed 1.5 pounds at birth.

A quality-improvement project to standardize feeding practices for micro preemies – preterm infants born months before their due date – helped to boost their weight and nearly quadrupled the frequency of lactation consultations ordered in the neonatal intensive care unit (NICU), a multidisciplinary team from Children’s National Health System finds.

According to the Centers for Disease Control and Prevention, about 1 in 10 infants in 2016 was preterm, born prior to completing 37 gestational weeks of pregnancy. Micro preemies are the tiniest infants in that group, weighing less than 1,500 grams and born well before their brain, lungs and organs like the liver are fully developed.

As staff reviewed charts for very low birth weight preterm infants admitted to Children’s NICU, they found dramatic variation in nutritional practices among clinicians and a mean decline in delta weight Z-scores, a more sensitive way to monitor infants’ weight gain along growth percentiles for their gestational age. A multidisciplinary team that included dietitians, nurses, neonatologists, a lactation consultant and a quality-improvement leader evaluated nutrition practices and determined key drivers for improving nutrition status.

“We tested a variety of strategies, including standardizing feeding practices; maximizing intended delivery of feeds; tracking adequacy of calorie, protein and micronutrient intake; and maximizing use of the mother’s own breast milk,” says Michelande Ridoré, MS, a Children’s NICU quality-improvement lead who will present the group’s findings during the Virginia Neonatal Nutrition Association conference this fall. “We took nothing for granted: We reeducated everyone in the NICU about the importance of the standardized feeding protocol. We shared information about whether infants were attaining growth targets during daily rounds. And we used an infographic to help nursing moms increase the available supply of breastmilk,” Ridoré says.

On top of other challenges, very low birth weight preterm infants are born very lean, with minimal muscle. During the third trimester, pregnant women pass on a host of essential nutrients and proteins to help satisfy the needs of the fetus’ developing muscles, bones and brain. “Because preterm infants miss out on that period in utero, we add fortification to provide preemies with extra protein, phosphorus, calcium and zinc they otherwise would have received from mom in the womb,” says Victoria Catalano, RDN, LD, CNSC, CLC, a pediatric clinical dietitian in Children’s NICU and study co-author. Babies’ linear growth is closely related to neurocognitive development, Catalano says. A dedicated R.N. is assigned to length boards for Children’s highest-risk newborns to ensure consistency in measurements.

Infants who were admitted within the first seven days of life and weighed less than 1,500 grams were included in the study. At the beginning of the quality-improvement project, the infants’ mean delta Z-score for weight was -1.8. By December 2018, that had improved to -1.3. And the number of lactation consultation ordered weekly increased from 1.1 to four.

“We saw marked improvement in micro preemies’ nutritional status as we reduced the degree of variation in nutrition practices,” says Mary Revenis, M.D., NICU medical lead on nutrition and senior author for the research. “Our goal was to increase mean delta Z-scores even more. To that end, we will continue to test other key drivers for improved weight gain, including zinc supplementation, updating infants’ growth trajectories in the electronic medical record and advocating for expanded use of birth mothers’ breast milk,” Dr. Revenis says.

In addition to Ridoré, Catalano and Dr. Revenis, study co-authors include Caitlin Forsythe MS, BSN, RNC-NIC, lead author; Rebecca Vander Veer RD, LD, CNSC, CLC, pediatric dietitian specialist; Erin Fauer RDN, LD, CNSC, CLC, pediatric dietitian specialist; Judith Campbell, RN, IBCLC, NICU lactation consultant; Eresha Bluth MHA; Anna Penn M.D., Ph.D., neonatalogist; and Lamia Soghier M.D., Med., NICU medical unit director.

Safeguarding fetal brain health in pregnancies complicated by CHD

August 1, 2018

During the last few weeks of pregnancy, certain regions of the fetal brain experience exponential growth but also are more vulnerable to injury during that high-growth period.

Yao Wu, Ph.D., a research postdoctoral fellow in the Developing Brain Research Laboratory at Children’s National Health System, has received a Thrasher Research Fund early career award to expand knowledge about regions of the fetal brain that are vulnerable to injury from congenital heart disease (CHD) during pregnancy.

CHD, the most common birth defect, can have lasting effects, including overall health issues; difficulty achieving milestones such as crawling, walking or running; and missed days at daycare or school, according to the Centers for Disease Control and Prevention. Brain injury is a major complication for infants born with CHD. Catherine Limperopoulos, Ph.D., director of Children’s brain imaging lab, was the first to provide in vivo evidence that fetal brain growth and metabolism in the third trimester of pregnancy is impaired within the womb.

“It remains unclear which specific regions of the fetal brain are more vulnerable to these insults in utero,” Limperopoulos says. “We first need to identify early brain abnormalities attributed to CHD and understand their impact on infants’ later behavioral and cognitive development in order to better counsel parents and effectively intervene during the prenatal period to safeguard brain health.”

During the last few weeks of pregnancy, certain regions of the fetal brain experience exponential growth but also are more vulnerable to injury during that high-growth period. The grant, $26,749 over two years, will underwrite “Brain Development in Fetuses With Congenital Heart Disease,” research that enables Wu to utilize quantitative, non-invasive magnetic resonance imaging (MRI) to compare fetal brain development in pregnancies complicated by CHD with brain development in healthy fetuses of the same gestational age.Wu will leverage quantitative, in vivo 3-D volumetric MRI to compare overall fetal and neonatal brain growth as well as growth in key regions including cortical grey matter, white matter, deep grey matter, lateral ventricles, external cerebrospinal fluid, cerebellum, brain stem, amygdala and the hippocampus.

The research is an offshoot of a prospective study funded by the National Institutes of Health that uses advanced imaging techniques to record brain growth in 50 fetuses in pregnancies complicated by CHD who need open heart surgery and 50 healthy fetuses. MRI studies are conducted during the second trimester (24 to 28 weeks gestational age), third trimester (33 to 37 weeks gestational age) and shortly after birth but before surgery. In addition, fetal and neonatal MRI measurements will be correlated with validated scales that measure infants’ and toddlers’ overall development, behavior and social/emotional maturity.

“I am humbled to be selected for this prestigious award,” Wu says. “The findings from our ongoing work could be instrumental in identifying strategies for clinicians and care teams managing high-risk pregnancies to optimize fetal brain development and infants’ overall quality of life.”

The ‘secret sauce’ for high-performing NICUs

July 19, 2018

Quoting the literature, Lamia Soghier, M.D., Children’s NICU medical unit director, and Billie Lou Short, M.D., chief of Children’s Division of Neonatology, write that hospitals with strong performance-improvement programs share eight critical factors in common.

Leaders of neonatal intensive care units (NICUs) across the nation share the same play books as they strive to provide safe, high-quality medical and surgical care for vulnerable newborns. A growing number of quality collaborations share best practices and evidence-based guidelines across the nation in the hopes of replicating quality and safety success stories while minimizing harms.

Still, NICUs that use similar interventions in similar fashions often do not achieve identical results.

“This unexplained variability in outcomes between NICUs begs the question: What is the secret sauce? Why do some NICUs consistently outshine others in spite of the application of the same ‘potentially best practices,’ ” the leaders of Children’s award-winning NICU ask in an editorial published online July 12, 2018, by Archives of Disease in Childhood (ADC) – Fetal & Neonatal edition.

Quoting the literature, Lamia Soghier, M.D., Children’s NICU medical unit director, and Billie Lou Short, M.D., chief of Children’s Division of Neonatology, write that hospitals with strong performance-improvement programs share eight critical factors in common:

Strong performance-improvement leadership at the administrative and executive levels
Boards of Trustees who are actively involved and provide continuity in vision regardless of changes in senior hospital leadership
An effective oversight structure that avoids duplicating efforts
Expert performance-improvement staff who are trained in quality and safety and able to carry out projects successfully
Physicians who are involved and held accountable
Staff who are actively involved
Effective use of data in decision-making
Effective communication strategies for all stakeholders

The “‘secret sauce’ may lie in establishing systems that promote the culture of quality and safety rather than waiting for a reduction in morbidity,” write Drs. Soghier and Short.

For the second year running, Children’s neonatology division ranked No. 1 among NICUs ranked by U.S. News & World Report. Despite challenges inherent in being a “busy level IV NICU in a free-standing children’s hospital with a rapidly growing capacity, higher levels of complex patients, [the] presence of trainees on rounds and routine 3:1 and 2:1 staffing models,” Children’s NICU has continued to have the lowest rates of such objective quality measures as central line-associated bloodstream infections and unintended extubations, they write.

“We attribute our success to direct involvement of all levels of leadership in our unit in [performance improvement] PI initiatives, a dedicated local PI team, quality trained medical unit director, engagement of front-line staff in PI, the presence of local subject-matter experts, multidisciplinary diverse team both within the NICU and with other departments that bring an array of experiences and opinions and a supportive data infrastructure through local information technology, and use of the Children’s Hospital Neonatal Database that allows benchmarking to other non-delivery NICUs, Drs. Soghier and Short write. “Our team finds motivation in solving local issues routine in our work, and leadership prioritises these issues and promotes engagement of front-line staff.”

The commentary was a companion to “Using a Composite Morbidity Score and Cultural Survey to Explore Characteristics of High Proficiency Neonatal Intensive Care Units,” also published by ADC Fetal & Neonatal.

Screening for postpartum depression in the emergency department

June 29, 2018

“Some of these women had no idea how common postpartum depression was,” says Lenore Jarvis, M.D., M.Ed. “They thought they were crazy and felt alone and were bad moms.”

It’s a scenario that Children’s emergency medicine specialist Lenore Jarvis, M.D., M.Ed., has seen countless times: A mother brings her infant to the emergency department (ED) in the middle of the night with a chief complaint of the baby being fussy. Nothing she does can stop the incessant crying, she tells the triage nurse. When doctors examine the baby, they don’t see anything wrong. Often, this finding is reassuring. But, despite their best efforts to comfort her, the mother isn’t reassured and leaves the hospital feeling anxious and overwhelmed.

After these encounters, Dr. Jarvis wondered: Might the mother be the actual patient?

Postpartum depression (PPD) is the most common complication of childbirth, Dr. Jarvis explains, occurring in up to 20 percent of all mothers, and may be higher (up to 50 percent) in low-income and immigrant women. Far beyond simple “baby blues,” the mood disorder can have significant implications for the mother, her baby and the entire family. It can hinder mother-child bonding and lead to early discontinuation of breastfeeding, delayed immunizations, and child abuse and neglect. The associated effects on early brain development might cause cognitive and developmental delays for the infant and, later in life, can manifest as emotional and behavioral problems. PPD can disrupt relationships between parents. And suicide is the top cause of postpartum death.

Mothers are supposed to be screened routinely for PPD at postpartum visits with their maternal or pediatric health care providers. In addition, several medical professional societies – including the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists – now recommend screening for PPD in the prenatal and postnatal periods and during routine well-child visits in the outpatient setting. But these screenings often don’t happen, Dr. Jarvis says, either because doctors aren’t following the recommendations or parents aren’t attending these visits due to barriers to health care access or other problems.

One way to sidestep these challenges, she says, is to provide PPD screening in the emergency setting.

“The ED becomes the safety net for people who are not routinely accessing regular checkups for themselves and their children,” Dr. Jarvis says. “If a mother is having an acute crisis in the middle of the night and feeling anxious and depressed, they often come to the emergency department for help.”

Dr. Jarvis and colleagues launched a pilot study in the Children’s ED to screen for PPD. For eight months beginning June 2015, the researchers invited English- and Spanish-speaking mothers who arrived at the ED with infants 6 months old or younger with complaints that didn’t necessitate immediate emergency care to take a short questionnaire on a computer tablet. This questionnaire included the Edinburgh Postnatal Depression Scale, a well-validated tool to screen for PPD, along with basic sociodemographic questions and queries about risk factors that other studies previously identified for PPD.

Just over half agreed to participate. When Dr. Jarvis and colleagues analyzed the results from these 209 mothers, they found that 27 percent scored positive for PPD, more than the average from previous estimates. Fourteen of those mothers reported having suicidal thoughts. Surprisingly, nearly half of participants reported that they’d never been screened previously for PPD, despite standing recommendations for routine screenings at mother and baby care visits, the research team writes in findings published online May 5, 2018, in Pediatric Emergency Care.

Based on the screening results, the researchers implemented a range of interventions. All mothers who participated in the study received an informational booklet from the March of Dimes on PPD. If mothers scored positive, they also received a local PPD resource handout and were offered a consultation with a social worker. Those with a strongly positive score were required to receive a social worker consultation and were given the option of “warm-line” support to PPD community partners, a facilitated connection to providers who offer individual or group therapy or home visits, or to a psychiatrist who might prescribe medication. Mothers with suicidal thoughts were assessed by a physician and assisted by crisis intervention services, if needed.

When the researchers followed up with mothers who screened positive one month later, an overwhelming majority said that screening in the ED was important and that the resources they were given had been key for finding help. Many commented that even the screening process seemed like a helpful intervention.

“Some of these women had no idea how common PPD was. They thought they were crazy and felt alone and were bad moms,” Dr. Jarvis says. “For someone to even ask about PPD made these women aware that this exists, and it’s something people care about.”

Many thanked her and colleagues for the follow-up call, she adds, saying that it felt good to be cared for and checked on weeks later. “It goes to show that putting support systems in place for these new mothers is very important,” she says.

Dr. Jarvis and ED colleagues are currently collaborating with social workers, neonatology and other Children’s National Health System care partners to start screening mothers in the neonatal intensive care unit (NICU) and ED for PPD. They plan to compare results generated by this universal screening to those in their study. These findings will help researchers better understand the prevalence of PPD in mothers with higher triage acuity levels and how general rates of PPD for mothers in the ED and NICU compare with those generated in past studies based on well-child checks. Eventually, she says, they would like to study whether the interventions they prescribed affected the known consequences of PPD, such as breastfeeding, timely immunization rates and behavior outcomes.

“With appropriate care and resources,” Dr. Jarvis adds, “we’re hoping to improve the lives of these women and their families.”

In addition to Dr. Jarvis, the lead study author, Children’s co-authors include Kristen A. Breslin, M.D., M.P.H.; Gia M. Badolato, M.P.H.; James M. Chamberlain, M.D.; and Monika K. Goyal, M.D., MSCE, the study’s senior author.

Making the grade: Children’s National is nation’s Top 5 children’s hospital

June 26, 2018

Children’s National rose in rankings to become the nation’s Top 5 children’s hospital according to the 2018-19 Best Children’s Hospitals Honor Roll released June 26, 2018, by U.S. News & World Report. Additionally, for the second straight year, Children’s Neonatology division led by Billie Lou Short, M.D., ranked No. 1 among 50 neonatal intensive care units ranked across the nation.

Children’s National also ranked in the Top 10 in six additional services:

Neurology and Neurosurgery (No. 5), led by Roger Packer, M.D., and Robert Keating, M.D.
Nephrology (No.6), led by Marva Moxey-Mims, M.D., FASN
Cancer (No. 7), led by Jeffrey Dome, M.D., Ph.D.
Orthopedics (No. 8), led by Matthew Oetgen, M.D.
Pulmonary (No. 9), led by Anastassios Koumbourlis, M.D., M.P.H., and
Diabetes and Endocrinology (a tie for No. 10), led by Fran Cogen, M.D., acting division co-chief

For the eighth year running, Children’s National ranked in all 10 specialty services, which underscores its unwavering commitment to excellence, continuous quality improvement and unmatched pediatric expertise throughout the organization.

“It’s a distinct honor for Children’s physicians, nurses and employees to be recognized as the nation’s Top 5 pediatric hospital. Children’s National provides the nation’s best care for kids and our dedicated physicians, neonatologists, surgeons, neuroscientists and other specialists, nurses and other clinical support teams are the reason why,” says Kurt Newman, M.D., Children’s President and CEO. “All of the Children’s staff is committed to ensuring that our kids and families enjoy the very best health outcomes today and for the rest of their lives.”

The excellence of Children’s care is made possible by our research insights and clinical innovations. In addition to being named to the U.S. News Honor Roll, a distinction awarded to just 10 children’s centers around the nation, Children’s National is a two-time Magnet^® designated hospital for excellence in nursing and is a Leapfrog Group Top Hospital. Children’s ranks seventh among pediatric hospitals in funding from the National Institutes of Health, with a combined $40 million in direct and indirect funding, and transfers the latest research insights from the bench to patients’ bedsides.

“The 10 pediatric centers on this year’s Best Children’s Hospitals Honor Roll deliver exceptional care across a range of specialties and deserve to be highlighted,” says Ben Harder, chief of health analysis at U.S. News. “Day after day, these hospitals provide state-of-the-art medical expertise to children with complex conditions. Their U.S. News’ rankings reflect their commitment to providing high-quality care.”

The 12^th annual rankings recognize the top 50 pediatric facilities across the U.S. in 10 pediatric specialties: cancer, cardiology and heart surgery, diabetes and endocrinology, gastroenterology and gastrointestinal surgery, neonatology, nephrology, neurology and neurosurgery, orthopedics, pulmonology and urology. Hospitals received points for being ranked in a specialty, and higher-ranking hospitals receive more points. The Best Children’s Hospitals Honor Roll recognizes the 10 hospitals that received the most points overall.

This year’s rankings will be published in the U.S. News & World Report’s “Best Hospitals 2019” guidebook, available for purchase in late September.

Keeping an eye on autonomic function for infants with HIE

June 8, 2018

“By including heart rate variability measurements and other markers of autonomic function in our current predictive armamentarium,” says An Massaro, M.D., “we may be able to offer new hope for infants with HIE.”

In about two to three in every 1,000 full-term births, babies develop a neurological condition called hypoxic ischemic encephalopathy (HIE) when their brains receive insufficient oxygen. HIE can be a devastating condition, leading to severe developmental or cognitive delays or motor impairments that become more evident as the child grows older. Despite improvements in care – including therapeutic hypothermia, a whole-body cooling method administered shortly after birth that can slow brain damage – about half of children with this condition die from neurological complications by age 2.

Finding ways to identify children with the most severe HIE could help researchers focus their efforts and provide even more intense neuroprotective care, explains An Massaro, M.D., a neonatologist at Children’s National Health System. But thus far, it’s been unclear which symptoms reflect the extent of HIE-induced brain damage.

That’s why Dr. Massaro and colleagues embarked on a study published in the May 2018 issue of Journal of Pediatrics. The team sought to determine whether dysfunction of the autonomic nervous system (ANS) – the auto-pilot part of the nervous system responsible for unconscious bodily functions, such as breathing and digestion – reflected in routine care events can be used as a marker for brain injury severity.

The researchers collected data from 25 infants who were treated for HIE with therapeutic hypothermia at Children’s National. Thanks to multi-modal monitoring, these babies’ medical records hold a treasure trove of information, explains Rathinaswamy B. Govindan, Ph.D., a staff scientist in Children’s Advanced Physiological Signals Processing Lab.

In addition to including continuous heart rate tracings and blood pressure readings that are standard for many infants in the neonatal intensive care unit (NICU), they also recorded cerebral near infrared spectroscopy, a monitor that measures brain tissue oxygen levels. The investigators performed detailed analyses to evaluate how these monitor readings change in response to a variety of routine care events, such as diaper changes, heel sticks, endotracheal tube manipulations and pupil examinations.

The researchers stratified these infants based on how dysfunctional their ANS behaved by using heart rate variability as a marker: The fewer natural fluctuations in heart rate, the more damaged their ANS was thought to be. And they also used non-invasive brain magnetic resonance imaging (MRI) to determine brain damage. They then compared this information with the babies’ physiological responses during each care event.

Their findings show that infants with impaired ANS, based on depressed heart rate variability before the care event, had significantly different responses to these care events compared with babies with intact ANS.

For stimulating interventions, such as diaper changes and heel sticks, both heart rate and blood pressure increased in babies with intact ANS but decreased in babies with impaired ones.
Shining a light in their pupils led to an expected decreased heart rate with stable blood pressure in ANS-intact infants, but in ANS-impaired infants, there was no responsive change in heart rate and, additionally, a decrease in blood pressure was observed.
Responses were similar between the two groups during breathing tube manipulations, except for a slight increase in heart rate a few minutes later in the ANS-impaired group.

These results, Govindan explains, suggest that a real-time, continuous way to assess ANS function may offer insights into the expected physiological response for a given infant during routine NICU care.

“This is exactly the type of additional information that intensivists need to pinpoint infants who may benefit from additional neuroprotective support,” he says. “Right now, it is standard practice to monitor brain activity continuously using electroencephalogram and to check the status of the brain using MRI to assess the response to therapeutic cooling. Neither of these assessments can be readily used by neonatologists at the bedside in real-time to make clinical decisions.”

Assessing ANS function in real-time can help guide neuroprotective care in high-risk newborns by providing insight into the evolving nature of brain damage in these infants, Dr. Massaro adds.

Beyond simply serving as a biomarker into brain injury, poor ANS function also could contribute to the development of secondary injury in newborns with HIE by stymieing the normal changes in heart rate and blood pressure that help oxygenate and heal injured brains. The researchers found that the cumulative duration of autonomic impairment was significantly correlated with the severity of brain injury visible by MRI in this group of infants.

“By including heart rate variability measurements and other markers of autonomic function in our current predictive armamentarium,” says Dr. Massaro, “we may be able to offer new hope for infants with HIE.”

In addition to Dr. Massaro, the Senior Author, study co-authors include Lead Author, Heather Campbell, M.D.; Rathinaswamy B. Govindan, Ph.D., Children’s Advanced Physiological Signals Processing Lab; Srinivas Kota, Ph.D.; Tareq Al-Shargabi, M.S.; Marina Metzler, B.S.; Nickie Andescavage, M.D., Children’s neonatalogist; Taeun Chang, M.D., Children’s neonatal and fetal neurologist; L. Gilbert Vezina, M.D., attending in Children’s Division of Diagnostic Imaging and Radiology; and Adré J. du Plessis, M.B.Ch.B., M.P.H., chief of Children’s Division of Fetal and Transitional Medicine.

This research was supported by the Clinical and Translational Science Institute at Children’s National under awards UL1TR000075 and 1KL2RR031987-01 and the Intellectual and Developmental Disabilities Research Consortium within the National Institutes of Health under award P30HD040677.

Children’s urology fellow wins best basic science award

May 29, 2018

Rebecca Zee

Rebecca Zee, a Children’s urology fellow, was awarded the best basic science prize at the Societies for Pediatric Urology annual meeting for her abstract describing a novel treatment to prevent ischemia reperfusion injury following testicular torsion.

Occurring in 1 in 4,000 males, testicular torsion occurs when the testis twists along the spermatic cord, limiting blood supply to the testicle. Despite prompt surgical intervention and restoration of blood flow, up to 40 percent of patients experience testicular atrophy due to a secondary inflammatory response, or ischemia reperfusion injury. Cytisine, a nicotine analog that the Food and Drug Administration approved for smoking cessation, recently has been found to activate a novel anti-inflammatory cascade, limiting the post-reperfusion inflammatory response.

“Administration of cytisine was recently found to limit inflammation and preserve renal function following warm renal ischemia,” Zee says. “We hypothesized that cytisine would similarly prevent ischemia reperfusion injury and limit testicular atrophy following testicular torsion.”

Using an established experimental model, Zee and colleagues induced unilateral testicular torsion by anesthetizing the adult male experimental models and rotating their right testicles by 720 degrees for two hours. In the treatment arm, the preclinical models were given cytisine as a 1.5 mg/kg injection one hour before or one hour after creating the testicular torsion. Eighteen hours after blood flow was restored to the right testis, total leukocyte infiltration and inflammatory gene expression were evaluated. Thirty days later, the researchers measured testicular weight and evaluated pro-fibrotic genes.

“We found that the administration of cytisine significantly decreases long-term testicular atrophy and fibrosis following testicular torsion,” says Daniel Casella, M.D., a urologist at Children’s National Health System and the study’s senior author. “What is particularly exciting is that we found similar long-term outcomes in the group that was given cytisine one hour after the creation of testicular torsion. This scenario is much more clinically applicable, given that we would not be able to treat patients until they present with testicular pain,” Dr. Casella adds.

Additional research is needed to determine the optimal cytisine dosing and administration regimen, however the researchers are hopeful that they can transition their findings to a pilot clinical trial in the near future.

In addition to Zee and Dr. Casella, the multi-institutional team included Children’s co-authors Nazanin Omidi, Christopher Bayne, Michael Hsieh, M.D., and Evaristus Mbanefo, in addition to Elina Mukherjee and Sunder Sims-Lucas, Ph.D., from the University of Pittsburgh.

Financial support for this work was provided by the Joseph E. Robert Jr. Center for Surgical Care.

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

May 25, 2018

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.

Protecting the fetal brain from harm

May 25, 2018

Ongoing placental dysfunction and allopregnanolone loss, not the increase that was expected due to stress, may alter cortical development in complicated pregnancies and put babies at risk, says Anna Penn, M.D., Ph.D.

Researchers long have known that allopregnanolone (ALLO), a derivative of the hormone progesterone, is produced in adults’ brains during times of acute stress and modulates how easily the brain’s neurons fire. ALLO also is produced in the placenta during fetal development, one of more than 200 different hormones that each uniquely contribute to fostering a smooth pregnancy and maintaining a fetus’ overall health. Although ALLO is thought to protect the developing brain in pregnancies complicated by conditions that might harm it, such as high blood pressure, how its levels evolve during pregnancy and in newborns shortly after birth has remained unknown.

Now, a new study presented during the Pediatric Academic Societies (PAS) 2018 annual meeting suggests that the placenta ramps up ALLO production over the second trimester, peaking just as fetuses approach full term.

To investigate this phenomenon, Anna Penn, M.D., Ph.D., a neonatologist/neuroscientist at Children’s National Health System, and colleagues created a designer experimental model to study how premature loss of ALLO alters orderly brain development. Knowing more about the interplay between ALLO and normal development of the cortex, the outer layer of the cerebrum, is a first step that could lead to strategies to rescue this vital brain region.

“The cortex is basically the brain’s command-and-control center for higher functions. In our experimental model, it develops from the middle of gestation through to the end of gestation. If ALLO levels are disrupted just as these cells are being born, neurons migrating to the cortex are altered and the developing neural network is compromised,” says Dr. Penn, senior author of the research presented at PAS 2018. “We’re concerned this same phenomenon occurs in human infants whose preterm birth disrupts their supply of this essential hormone.”

To better understand the human placental hormone pattern, the research team analyzed cord blood or serum samples collected within the first 36 hours of life for 61 preterm newborns born between 24 to 36 gestational weeks. They compared those preemie samples with samples drawn from 61 newborns carried to term who were matched by race, gender, size for gestational age, delivery method and maternal demographics.

They used liquid-chromatography-tandem mass spectrometry, a technique that can precisely analyze trace levels of compounds, to compare levels of 27 different steroids, including ALLO and its precursors as well as better-known adrenal gland hormones, such as cortisol and 17-Hydroxyprogesterone.

“Pregnancies complicated by hypertension tended to correlate with lower ALLO levels, though this finding did not reach statistical significance. This suggests that ongoing placental dysfunction and ALLO loss, not the increase that we expected to be caused by stress, may alter cortical development in these pregnancies and put babies at risk,” Dr. Penn adds. “In addition, having the largest neonatal sample set to date in which multiple steroid hormones have been measured can provide insight into the shifting hormone patterns that occur around 36 weeks gestation, just prior to term. Hopefully, restoring the normal hormonal milieu for preemies or other at-risk newborns will improve neurological outcomes in the future.”

In addition to Dr. Penn, study co-authors include Caitlin Drumm, MedStar Georgetown University Hospital; Sameer Desale, MedStar Health Research Institute; and Kathi Huddleston, Benjamin Solomon and John Niederhuber, Inova Translational Medicine Institute.

Getting to the heart of cardiac output

May 24, 2018

Baby in the NICU

To keep infants in the neonatal intensive care unit (NICU) as healthy as possible, it’s important to keep close tabs on their vital signs. During their NICU stay, most babies have continuous monitoring of their blood pressure, respiratory rate and blood oxygen saturation. And although continuous monitoring of heart rate is also typically standard, other information about heart function – such as cardiac output, a measure of how well the heart is pumping blood – remains a challenge to obtain in these vulnerable babies.

Clinical markers like blood pressure, heart rate and urine output are available, but they are indirect measures of cardiac output, how much blood the heart pumps per minute. Less invasive techniques, such as Doppler ultrasound, can be imprecise. Respiratory mass spectrometry or catheterization would provide more precision by directly calculating cardiac output but carry risks or are not feasible for neonates.

Clinicians at Children’s National Health System hypothesized that COstatus monitors could offer a way to directly measure cardiac output among neonates. The COstatus monitor – a minimally invasive way to measure hemodynamics – captures cardiac output, total end diastolic volume, active circulation volume and central blood volume.

The research team tested the approach by leveraging ultrasound dilution: Injecting saline, which has an ultrasound velocity of 1533m/second, slows the ultrasound velocity of blood from its normal rate of 1580m/second and produces a dilution curve.

“It is feasible to directly measure neonatal cardiac output by ultrasound dilution via the COstatus monitor in the first two weeks of life with no adverse events,” says Khodayar Rais-Bahrami, M.D., a Children’s neonatologist and senior author for the research presented during the Pediatric Academic Societies 2018 annual meeting. “When we took consecutive measurements, we saw very little variance in the parameters.”

The COstatus monitor uses an extracorporeal loop that is connected to arterial and venous catheters. The 12 neonates included in the study already had umbilical venous catheters as well as either a peripheral arterial line or umbilical arterial catheter. The infants ranged in weight from 0.72 to 3.74 kg and were born at 24 to 41.3 gestational weeks.

The infants’ cardiac output was measured 54 times from 1 to 13 days of life. Up to two measurement sessions occurred daily for a maximum of four days. The mean cardiac output was 0.43 L/minute with a mean cardiac index of 197mL/kg/minute.

Future research will describe normal cardiac output ranges for neonates as well as how these measurements evolve during the first week of life.

In addition to Dr. Rais-Bahrami, study co-authors include Simranjeet S. Sran, M.D., and Mariam Said, M.D., a Children’s neonatologist.

When depression lingers after the NICU

May 23, 2018

distressed woman holding baby

Roughly half a million babies end up in the neonatal intensive care unit (NICU) each year in the U.S., often sending their parents on a wild emotional rollercoaster. Like other new parents, many parents feel symptoms of depression when their child leaves the NICU. For the majority, these depressive symptoms lift over time. But for others, depression can persist, affecting their well-being and relationships, including those with their new babies.

Thus far, it’s been unclear which parents are at a higher risk for this lasting depression. However, a new study led by Children’s researchers and presented at the Pediatric Academic Societies 2018 annual meeting suggests that parents whose depression lingers six months after their child’s NICU discharge tend to share certain demographic characteristics: They’re younger, have less education and care for more than one child.

“Using a validated screening tool, we found that 40 percent of parents in our analyses were positive for depression at the time their newborn was discharged from the NICU,” says Karen Fratantoni, M.D., M.P.H., a Children’s pediatrician and the lead study author. “It’s reassuring that, for many parents, these depressive symptoms ease over time. However for a select group of parents, depression symptoms persisted six months after discharge. Our findings help to ensure that we target mental health screening and services to these more vulnerable parents,” Dr. Fratantoni adds.

The study is an offshoot from “Giving Parents Support (GPS) after NICU discharge,” a large, randomized clinical trial exploring whether providing peer-to-peer parental support after NICU discharge improves babies’ overall health as well as their parents’ mental health.

Mothers of preterm and full-term infants who are hospitalized in NICUs are at risk for peripartum mood disorders, including postpartum depression. The Children’s research team sought to determine how many parents of NICU graduates experience depression and which characteristics are shared by parents with elevated depression scores.

They included 125 parents who had enrolled in the GPS clinical trial in their exploratory analyses and assessed depressive symptoms using a 10-item, validated screening tool, the Center for Epidemiological Studies Depression Scale (CES-D). Eighty-four percent of the parents were women. Nearly 61 percent of their infants were male and were born at a median gestational age of 37.7 weeks and mean birth weight of 2,565 grams. The median length of time these newborns remained in the NICU was 18 days.

When the newborns were discharged, 50 parents (40 percent) had elevated CES-D scores. By six months after discharge, that number dropped to 17 parents (14 percent).Their mean age ranged from 26.5 to 30.6 years old.

“Parents of NICU graduates who are young, have less education and are caring for other children are at higher risk for persistent symptoms of depression,” says Dr. Fratantoni. “We know that peripartum mood disorders can persist for one year or more after childbirth so these findings will help us to better match mental health care services to parents who are most in need.”

An American College of Obstetricians and Gynecologists’ committee opinion issued May 2018 calls for all women to have contact with a maternal care provider within the first three weeks postpartum and to undergo a comprehensive postpartum visit no later than 12 weeks after birth that includes screening for postpartum depression and anxiety using a validated instrument.

Study co-authors include Lisa Tuchman, M.D., MPH, chief, Children’s Adolescent and Young Adult Medicine Division; Randi Streisand, Ph.D., Children’s interim chief of Psychology and Behavioral Health; Nicole S. Herrera; Katherine Kritikos and Lamia Soghier, M.D., Children’s neonatologist.

Brain food for preemies

May 23, 2018

Preemie Baby

Babies born prematurely – before 37 weeks of pregnancy – often have a lot of catching up to do. Not just in size. Preterm infants typically lag behind their term peers in a variety of areas as they grow up, including motor development, behavior and school performance.

New research suggests one way to combat this problem. The study, led by Children’s researchers and presented during the Pediatric Academic Societies 2018 annual meeting, suggests that the volume of carbohydrates, proteins, lipids and calories consumed by very vulnerable premature infants significantly contributes to increased brain volume and white matter development, even though additional research is needed to determine specific nutritional approaches that best support these infants’ developing brains.

During the final weeks of pregnancy, the fetal brain undergoes an unprecedented growth spurt, dramatically increasing in volume as well as structural complexity as the fetus approaches full term.

One in 10 infants born in the U.S. in 2016 was born before 37 weeks of gestation, according to the Centers for Disease Control and Prevention. Within this group, very low birthweight preemies are at significant risk for growth failure and neurocognitive impairment. Nutritional support in the neonatal intensive care unit (NICU) helps to encourage optimal brain development among preterm infants. However, their brain growth rates still lag behind those seen in full-term newborns.

“Few studies have investigated the impact of early macronutrient and caloric intake on microstructural brain development in vulnerable preterm infants,” says Katherine Ottolini, lead author of the Children’s-led study. “Advanced quantitative magnetic resonance imaging (MRI) techniques may help to fill that data gap in order to better direct targeted interventions to newborns who are most in need.”

The research team at Children’s National Health System enrolled 69 infants who were born younger than 32 gestational weeks and weighed less than 1,500 grams. The infants’ mean birth weight was 970 grams and their mean gestational age at birth was 27.6 weeks.

The newborns underwent MRI at their term-equivalent age, 40 weeks gestation. Parametric maps were generated for fractional anisotropy in regions of the cerebrum and cerebellum for diffusion tensor imaging analyses, which measures brain connectivity and white matter tract integrity. The research team also tracked nutritional data: Grams per kilogram of carbohydrates, proteins, lipids and overall caloric intake.

“We found a significantly negative association between fractional anisotropy and cumulative macronutrient/caloric intake,” says Catherine Limperopoulos, Ph.D., director of Children’s Developing Brain Research Laboratory and senior author of the research. “Curiously, we also find significantly negative association between macronutrient/caloric intake and regional brain volume in the cortical and deep gray matter, cerebellum and brainstem.”

Because the nutritional support does contribute to cerebral volumes and white matter microstructural development in very vulnerable newborns, Limperopoulos says the significant negative associations seen in this study may reflect the longer period of time these infants relied on nutritional support in the NICU.

In addition to Ottolini and Limperopoulos, study co-authors include Nickie Andescavage, M.D., Attending, Children’s Neonatal-Perinatal Medicine; and Kushal Kapse.

How EPO saves babies’ brains

May 22, 2018

Researchers have discovered that treating premature infants with erythropoietin can help protect and repair their vulnerable brains.

The drug erythropoietin (EPO) has a long history. First used more than three decades ago to treat anemia, it’s now a mainstay for treating several types of this blood-depleting disorder, including anemia caused by chronic kidney disease, myelodysplasia and cancer chemotherapy.

More recently, researchers discovered a new use for this old drug: Treating premature infants to protect and repair their vulnerable brains. However, how EPO accomplishes this feat has remained unknown. New genetic analyses presented at the Pediatric Academic Societies 2018 annual meeting that was conducted by a multi-institutional team that includes researchers from Children’s National show that this drug may work its neuroprotective magic by modifying genes essential for regulating growth and development of nervous tissue as well as genes that respond to inflammation and hypoxia.

“During the last trimester of pregnancy, the fetal brain undergoes tremendous growth. When infants are born weeks before their due dates, these newborns’ developing brains are vulnerable to many potential insults as they are supported in the neonatal intensive care unit during this critical time,” says An Massaro, M.D., an attending neonatologist at Children’s National Health System and lead author of the research. “EPO, a cytokine that protects and repairs neurons, is a very promising therapeutic approach to support the developing brains of extremely low gestational age neonates.”

The research team investigated whether micro-preemies treated with EPO had distinct DNA methylation profiles and related changes in expression of genes that regulate how the body responds to such environmental stressors as inflammation, hypoxia and oxidative stress. They also investigated changes in genes involved in glial differentiation and myelination, production of an insulating layer essential for a properly functioning nervous system. The genetic analyses are an offshoot of a large, randomized clinical trial of EPO to treat preterm infants born between 24 and 27 gestational weeks.

The DNA of 18 newborns enrolled in the clinical trial was isolated from specimens drawn within 24 hours of birth and at day 14 of life. Eleven newborns were treated with EPO; a seven-infant control group received placebo.

DNA methylation and whole transcriptome analyses identified 240 candidate differentially methylated regions and more than 50 associated genes that were expressed differentially in infants treated with EPO compared with the control group. Gene ontology testing further narrowed the list to five candidate genes that are essential for normal neurodevelopment and for repairing brain injury:

Neurogenin 1, a transcription factor that governs the progression of neurogenesis
FOS like 1, implicated in development of cognitive deficits after oxygen depravation (hypoxia)
Mitogen-activated protein kinase 8 interacting protein 2, encodes a scaffolding protein broadly expressed in the brain. Experimental models that lack this protein display autistic tendencies.
Resistance to inhibitors of cholinesterase 8 homolog A, an essential player in generating new brain cells and
Major histocompatibility complex, class II, DR alpha, a central player in proper immune system function.

“These findings suggest that EPO’s neuroprotective effect may be mediated by epigenetic regulation of genes involved in the development of the nervous system and that play pivotal roles in how the body responds to inflammation and hypoxia,” Dr. Massaro says.

In addition to Dr. Massaro, study co-authors include Theo K. Bammler, James W. MacDonald, biostatistician, Bryan Comstock, senior research scientist, and Sandra “Sunny” Juul, M.D., Ph.D., study principal investigator, all of University of Washington.

Research and Education Week awardees embody the diverse power of innovation

April 30, 2018

cnmc-research-education-week

“Diversity powers innovation” was brought to life at Children’s National April 16 to 20, 2018, during the eighth annual Research and Education Week. Children’s faculty were honored as President’s Award winners and for exhibiting outstanding mentorship, while more than 360 scientific poster presentations were displayed throughout the Main Atrium.

Two clinical researchers received Mentorship Awards for excellence in fostering the development of junior faculty. Lauren Kenworthy, Ph.D received the award for Translational Science and Murray M. Pollack, M.D., M.B.A., was recognized in the Clinical Science category as part of Children’s National Health System’s Research and Education Week 2018.

Dr. Kenworthy has devoted her career to improving the lives of people on the autism spectrum and was cited by former mentees as an inspirational and tireless counselor. Her mentorship led to promising new lines of research investigating methods for engaging culturally diverse families in autism studies, as well as the impact of dual language exposure on cognition in autism.

Meanwhile, Dr. Pollack was honored for his enduring focus on motivating early-career professionals to investigate outcomes in pediatric critical care, emergency medicine and neonatology. Dr. Pollack is one of the founders of the Collaborative Pediatric Critical Care Research Network. He developed PRISM 1 and 2, which has revolutionized pediatric intensive care by providing a methodology to predict mortality and outcome using standardly collected clinical data. Mentees credit Dr. Pollack with helping them develop critical thinking skills and encouraging them to address creativity and focus in their research agenda.

In addition to the Mentorship and President’s Awards, 34 other Children’s National faculty, residents, interns and research staff were among the winners of Poster Presentation awards. The event is a celebration of the commitment to improving pediatric health in the form of education, research, scholarship and innovation that occurs every day at Children’s National.

Children’s Research Institute (CRI) served as host for the week’s events to showcase the breadth of research and education programs occurring within the entire health system, along with the rich demographic and cultural origins of the teams that make up Children’s National. The lineup of events included scientific poster presentations, as well as a full slate of guest lectures, educational workshops and panel discussions.

“It’s critical that we provide pathways for young people of all backgrounds to pursue careers in science and medicine,” says Vittorio Gallo, Ph.D., Children’s chief research officer and CRI’s scientific director. “In an accelerated global research and health care environment, internationalization of innovation requires an understanding of cultural diversity and inclusion of different mindsets and broader spectrums of perspectives and expertise from a wide range of networks,” Gallo adds.

“Here at Children’s National we want our current and future clinician-researchers to reflect the patients we serve, which is why our emphasis this year was on harnessing diversity and inclusion as tools to power innovation,” says Mark L. Batshaw, M.D., physician-in-chief and chief academic officer of Children’s National.

“Research and Education Week 2018 presented a perfect opportunity to celebrate the work of our diverse research, education and care teams, who have come together to find innovative solutions by working with local, national and international partners. This event highlights the ingenuity and inspiration that our researchers contribute to our mission of healing children,” Dr. Batshaw concludes.

Awards for the best posters were distributed according to the following categories:

Basic and translational science
Quality and performance improvement
Clinical research
Community-based research and
Education, training and program development.

Each winner illustrated promising advances in the development of new therapies, diagnostics and medical devices.

Diversity powers innovation: Denice Cora-Bramble, M.D., MBA
Diversity powers innovation: Vittorio Gallo, Ph.D.
Diversity powers innovation: Mark L. Batshaw, M.D.

Children’s National senior vice president elected to American Pediatric Society leadership

April 17, 2018

Robin Steinhorn

Robin Steinhorn, M.D., Senior Vice President of Center for Hospital-Based Specialties at Children’s National Health System, was elected by her peers to become vice president and president-elect of the American Pediatric Society (APS) beginning May 2018 at the annual Pediatric Societies Meeting in Toronto, Canada. Dr. Steinhorn will serve in this role for one year and will then become the Society’s president in May 2019 for a one-year term.

Dr. Steinhorn is a globally recognized physician-leader, researcher and clinician in the fields of neonatal perinatal medicine and fetal pulmonary development. She was elected to the APS Council in 2015 and currently holds a seat on the American Board of Pediatrics’ Board of Directors.

“Dr. Steinhorn has devoted her professional career to advancing the field of pediatrics through exemplary leadership in related societies, as well as editorial oversight of cutting-edge research,” says David Wessel, M.D., executive vice president and chief medical officer of Hospital and Specialty Services at Children’s National. “This elevated role with the APS will enable her to further share her expertise to benefit children on a national and international level.”

Dr. Steinhorn serves as associate editor of the Journal of Pediatrics and is also a contributing editor for NEJM Journal Watch’s Pediatric and Adolescent Medicine. Additionally, she sits on the editorial boards of Pediatric Critical Care Medicine and Pulmonary Circulation. Dr. Steinhorn is an elected fellow of the American Heart Association and a member of both the Perinatal Research Society and the American Thoracic Society.

Founded in 1888, the American Pediatric Society is the oldest and most prestigious academic pediatric organization in North America. Members are elected to APS based on their accomplishments as academic leaders in pediatrics and goal to shape the future of academic pediatrics. Mark L. Batshaw, M.D., physician-in-chief and chief academic officer of Children’s National preceded Dr. Steinhorn as APS President from 2016-2017.

“This is a tremendous honor, and it is a special privilege to follow Dr. Batshaw’s sound leadership. I look forward to leveraging the collective leadership and research accomplishments by our members to improve the health of infants and children throughout the U.S.,” said Dr. Steinhorn.

Dr. Steinhorn joined Children’s National in 2015 after a successful tenure as professor and chair of the department of pediatrics at the University of California, Davis (UCD) School of Medicine and as physician-in-chief, UCD Children’s Hospital. Previously, she was vice chair of the department of pediatrics and chief of the division of neonatology at Northwestern University and the Ann & Robert H. Lurie Children’s Hospital of Chicago.

Dr. Steinhorn’s clinical and academic interests have focused primarily on fetal and neonatal pulmonary vascular development. Her translational work has spanned from in vitro studies, to experimental models and clinical trials. In addition to her own translational research program, she has participated in numerous multicenter trials that have helped define the clinical treatment of pulmonary hypertension during the neonatal period. Her clinical research work also has addressed other topics, such as harmonization of electronic health records for clinical research and telemedicine support of neonatal care in small rural hospitals.

Additionally, Dr. Steinhorn is particularly passionate about mentoring faculty and supporting the growth and career development of young neonatologists and scientists, with several having developed their own research laboratories and assumed division leadership positions. She was selected as a “Top Doctor” by Northern Virginia Magazine in 2018.

GABA concentration in pre-term brain increases with gestational age

April 13, 2018

“A more complete understanding of the diagnostic and prognostic importance of GABA and glutamate in the preterm brain will help us to direct treatment strategies for the most vulnerable preterm infants at risk of brain injury,” says Sudeepta K. Basu, M.D.

The major neurotransmitters gamma-aminobutyric acid (GABA) and glutamate are pivotal to fetal and newborn brain development and influence evolution of brain injury and repair following preterm birth. Magnetic resonance spectroscopy (MRS) enables in vivo measurement of brain metabolites. However, GABA and glutamate are found in the developing brain in low concentrations, and their weak signal can be swamped by the stronger signal of more dominant metabolites.

A Children’s research team reports findings from a pilot study utilizing an innovative technique of MRS to reliably measure in vivo GABA in the developing preterm brain. The groundbreaking research done by the team that includes Principal Investigator Sudeepta K. Basu, M.D., neonatology attending at Children’s National Health System, is very unique and original since there are no existing data of in vivo GABA concentrations in the developing cerebellum. Under the mentorship of Catherine Limperopoulos, Ph.D., director of Children’s Developing Brain Research Laboratory, the team of multi-disciplinary specialists is pursuing cutting-edge technologies in advanced MRI neuroimaging to explore brain development and injury in preterm infants.

The research, presented at the Eastern Society for Pediatric Research (ESPR) annual meeting by Dr. Basu, was honored with the “2018 Meritorious Poster Award.” The research titled “Distinct temporal trends of GABA and glutamate in the cerebellum and frontal cortex of preterm infants” reports, for the first time, positive temporal trends in the specific regions of the developing brain intricately involved in cognitive and motor functions. This work lays the foundation for developing novel ways to diagnose, monitor and investigative brain protective therapies for vulnerable prematurely born infants.

The Children’s team performed non-sedated MRS in 44 preterm infants whose mean gestational age at birth was 26.5 weeks, placing voxels at the middle of the cerebellum and the right frontal cortex. GABA and GIx (glutamate combined with glutamine) were positively correlated with post-menstrual age in the frontal cortex, but not the cerebellum. At the ESPR meeting, the team also presented for the first time that caffeine, a neuroprotective agent in preemies, leads to increased in vivo GABA concentration in the developing frontal cortex.

“Open questions include whether these findings reflect varying paces of maturation and vulnerability to injury among specific regions of the brain. Also, the relationship between clinical factors and medication exposure and changes in the concentration of these neurotransmitters may guide brain protective therapies in future,” Dr. Basu says. “A more complete understanding of the diagnostic and prognostic importance of GABA and glutamate in the preterm brain will help us to direct treatment strategies for the most vulnerable preterm infants at risk of brain injury.”

Children’s senior fellows from Division of Neonatology made four platform presentations during the ESPR conference:

“Caffeine increases GABA/Cr ratio in frontal cortex of preterm infants on spectroscopy.” Aditi Gupta; Sudeepta K. Basu, M.D.; Mariam Said, M.D.; Subechhya Pradhan, Linda White; Kushal Kapse; Jonathan Murnick, M.D., Ph.D.; Taeun Chang, M.D.; and Catherine Limperopoulos, Ph.D.
“Impact of early nutrition on microstructural brain development in VLBW Infants.” Katherine M. Ottolini, Nickie Andescavage, M.D.; Kushal Kapse; and Catherine Limperopoulos, Ph.D.
“Direct measurement of neonatal cardiac output utilizing the CO status monitor.” Simranjeet S. Sran, Mariam Said, M.D.; and Khodayar Rais-Bahrami, M.D.
“Cerebro-cerebellar diaschisis in preterm infants following unilateral cerebral parenchymal injury.” Huma Mirza, Yao Wu, Kushal Kapse, Jonathan Murnick, M.D., Ph.D.; Taeun Chang, M.D.; and Catherine Limperopoulos, Ph.D.

Pediatric ophthalmology celebrates 75th anniversary in Washington, D.C.

April 5, 2018

Angeline M. Parks Visiting Professor Sean P. Donahue, M.D., Ph.D., (front left) enjoys a light moment during the celebration of the 75th anniversary while Anthony Sandler, M.D., Children’s surgeon in chief, senior vice president of the Joseph E. Robert Jr. Center for Surgical Care and director of the Sheikh Zayed Institute, speaks to the group.

After 75 years dedicated to the eyes of children, the world’s pediatric ophthalmologists gathered in Washington, D.C., the specialty’s birthplace, to share the latest research and innovation in the field. The group gathered for a joint meeting of the International Strabismological Association (ISA) and the American Association for Pediatric Ophthalmology and Strabismus (AAPOS), which was held March 18-22, 2018.

“This year marks the 75th anniversary of our specialty, which was founded right here, at Children’s National, in Washington, D.C., when Dr. Frank Costenbader restricted his practice exclusively to children and began to train residents in the nuance of treating children’s eyes,” says Mohamad S. Jaafar, M.D., chief of the Division of Ophthalmology at Children’s National Health Center. “It is a tremendous honor to welcome my colleagues back to the birthplace of pediatric ophthalmology on this grand occasion.”

In advance of the larger meeting, Children’s Division of Ophthalmology welcomed some of the international attendees to Children’s National for a special gathering on Saturday, March 17, 2018.

The event at Children’s featured a special lecture by this year’s Angeline M. Parks Visiting Professor, Sean P. Donahue, M.D., Ph.D. Dr. Donahue is the Sam and Darthea Coleman Chair in Pediatric Ophthalmology and Chief of Pediatric Ophthalmology at the Children’s Hospital at Vanderbilt. This Annual Visiting Professorship was established by the members of the Costenbader Society (The Children’s National Pediatric Ophthalmology Alumni Society) in memory of Angeline M. Parks, the wife of pediatric ophthalmologist Marshall M. Parks, M.D., to carry on her legacy of establishing a warm and supportive environment between physician and spouse, which benefits the physicians and their young patients.

Three former division chiefs of Ophthalmology at Children’s National, Drs. Costenbader, Parks and Friendly, have national lectureships established in their names to reflect their contributions to the field. Dr. Frank Costenbader, the society’s namesake, established the sub-specialty of pediatric ophthalmology. Dr. Parks founded the Children’s Eye Foundation and the AAPOS, and David S. Friendly, M.D., codified pediatric ophthalmology fellowship training across the United States.

Honor Awards for Children’s pediatric ophthalmologists at ISA-AAPOS

During the ISA-AAPOS meeting, two current Children’s National pediatric ophthalmologists were recognized with Honor Awards for their long-term dedication to pediatric ophthalmology, their patients, and their engagement in the AAPOS to advance the field.

William Madigan, M.D., vice chief of Ophthalmology at Children’s, a professor of surgery at the Uniformed Services University of the Health Sciences, and a clinical professor of Ophthalmology and Pediatrics at the George Washington University School of Medicine and Health Sciences. He was recognized by AAPOS for his long-time service, including:

Chair of the organization’s audit committee and the Costenbader Lecture selection committee.
Membership on the fellowship directors’ committee that developed nationwide requirements for pediatric ophthalmology fellowships and established the certification process to insure high quality and uniform education in the specialty.
Invited lectures in Shanghai, China; Geneva, Switzerland; and Sao Paolo, Brazil, among others.
Many posters and presentations about clinical and research topics of importance for members of the AAPOS and other distinguished professional societies.

Marijean Miller, M.D., director of Neonatal Ophthalmology, division research director at Children’s National and clinical professor of Ophthalmology and Pediatrics at the George Washington University School of Medicine and Health Sciences, was recognized by AAPOS for her cumulative contributions to the society, including:

Multiple memberships on vital committees, including AAPOS’s training and accreditation committee and audit committee.
Presentation of original research via posters and oral presentations on topics including best practices in neonatal clinical care, innovative tools and applications and advocacy for patients and their families.

“We are so grateful to have a team that continues the tradition of excellence in pediatric ophthalmology here at Children’s National,” Dr. Jaafar says. “Drs. Madigan and Miller exemplify the dedication of our division to caring for the children we serve, and to advancing our field. Congratulations to both!”

X-linked genes help explain why boys of all ages face higher respiratory risk

April 5, 2018

A multi-institution research team that includes Children’s National Health System attempted to characterize gender-based epigenomic signatures in the human airway early in children’s lives with a special attention to defining DNA methylation patterns of the X chromosome.

Human airways already demonstrate gender-based differences in DNA methylation signatures at birth, providing an early hint of which infants may be predisposed to develop respiratory disorders like asthma later in life, a research team reports in a paper published online April 3, 2018, in Scientific Reports.

It’s clear that boys and young men are more likely to develop neonatal respiratory distress syndrome, bronchopulmonary dysplasia, viral bronchiolitis, pneumonia, croup and childhood asthma. Unlike boys, girls have an additional copy of the X chromosome, which is enriched with immune-related genes, some of which play key roles in the development of respiratory conditions. Methylation prevents excessive gene activity in X-linked genes, however much remains unknown about how this process influences infants’ risk of developing airway diseases.

A multi-institution research team that includes Children’s National Health System attempted to characterize gender-based epigenomic signatures in the human airway early in children’s lives with a special attention to defining DNA methylation patterns of the X chromosome.

“It’s clear as we round in the neonatal intensive care unit that baby boys remain hospitalized longer than girls and that respiratory ailments are quite common. Our work provides new insights about gender differences in airway disease risk that are pre-determined by genetics,” says Gustavo Nino, M.D., a Children’s pulmonologist and the study’s senior author.

“Characterizing early airway methylation signatures holds the promise of clarifying the nature of gender-based disparities in respiratory disorders and could usher in more personalized diagnostic and therapeutic approaches.”

The research team enrolled 12 newborns and infants in the study and obtained their nasal wash samples. Six of the infants were born preterm, and six were born full term. The researchers developed a robust gender classification algorithm to generate DNA methylation signals. The machine learning algorithm identified X-linked genes with significant differences in methylation patterns in boys, compared with girls.

As a comparison group, they retrieved pediatric nasal airway epithelial cultures from a study that looked at genomic DNA methylation patterns and gene expression in 36 children with persistent atopic asthma compared with 36 heathy children.

The team went on to classify X-linked genes that had significant gender-based X methylation and those genes whose X methylation was variable.

“These results confirm that the X chromosome contains crucial information about gender-related genetic differences in different airway tissues,” Dr. Nino says. “More detailed knowledge of the genetic basis for gender differences in the respiratory system may help to predict, prevent and treat respiratory disorders that can affect patients over their entire lifetimes.”

In addition to Dr. Nino, study co-authors include Lead Author Cesar L. Nino, bioinformatics scientist, Pontificia Universidad Javeriana; Geovanny F. Perez, M.D., co-director of Children’s Severe Bronchopulmonary Dysplasia Program; Natalia Isaza Brando, M.D., Children’s neonatology attending; Maria J. Gutierrez, Johns Hopkins University School of Medicine; and Jose L. Gomez, Yale University School of Medicine.

Financial support for this research was provided by the National Institutes of Health under award numbers AI130502-01A1, HL090020, HL125474-03, HD001399, UL1TR000075 and KL2TR000076.

Perinatal brain injury headlines American Society for Neurochemistry

April 4, 2018

Dr. Gallo’s research could have major implications for overcoming the common behavioral and developmental challenges associated with premature birth.

Children’s National Chief Research Officer Vittorio Gallo, Ph.D., recently had the honor of presenting a presidential lecture at the 48th Annual Meeting of the American Society for Neurochemistry (ASN). The lecture focused on his lifelong investigations of the cellular and molecular mechanisms of white matter development and injury, including myelin and glial cells – which are involved in the brain’s response to injury.

Specifically, he outlined the underlying diffuse white matter injury observed in his lab’s pre-clinical model of perinatal hypoxia, and presented new, non-invasive interventions that promote functional recovery and attenuate developmental delay after perinatal injury in the model. Diffuse white matter injuries are the most frequently observed pattern of brain injury in contemporary cohorts of premature infants. Illuminating methods that might stimulate growth and repair of such injuries shows promise for potential noninvasive strategies that might mitigate the long-term behavioral abnormalities and developmental delay associated with premature birth.

Dr. Gallo’s work in developmental neuroscience has been seminal in deepening understanding of cerebral palsy and multiple sclerosis. During his tenure as center director, he transformed the Center for Neuroscience Research into one of the nation’s premier programs.

ASN gathers nearly 400 delegates from the neurochemistry sector each year, including bench and clinical scientists, principal investigators, graduate students and postdoctoral fellows all actively involved in research from North America and around the world.