Fetal Medicine

Natella Rakhamania

Natella Yurievna Rakhmanina named to regional HIV planning commission

Natella Rakhamania

Natella Yurievna Rakhmanina, M.D., Ph.D., FAAP, AAHIVS, director of Ryan White HIV Services at Children’s National Health System, was appointed a commissioner to the Washington, D.C., Regional Planning Commission on Health and HIV.

Dr. Rakhmanina will be among the District of Columbia board and commission appointees honored during a swearing-in ceremony on Sept. 17, 2018, at the Walter Washington Convention Center.

Looking back over the last decade, she says the District has made impressive progress in lowering the prevalence rate of human immunodeficiency virus (HIV), which in 2002 had 1,686 per 100,000 District residents diagnosed with AIDS.

“It was really high. I was stunned coming to clinic and seeing a large number of kids and adolescents in care and many suffering significant complications, as our treatment options were limited at the time,” she says.

Since that time, DC Health has made “incredible investments” and adopted innovative approaches, such as name-based reporting of HIV and a Red Carpet program, to ensure newly diagnosed people are quickly linked with care. As a proud partner of DC Health’s HIV/AIDS, Hepatitis, STD and TB Administration, Children’s National launched a campaign in 2009 to universally test adolescents for HIV in two pediatric emergency departments (ED), she says.

“All teenagers aged 13 and older who arrive for any medical diagnosis are offered an oral HIV test. Children’s National ED-based HIV screening program alone has tested 30,000 children at both of our emergency departments,” she says. “We’re still not at our goal. However, the prevalence of HIV had dropped to 1.9 percent in the latest department of health analysis. We are doing better. We have much fewer people dying from AIDS. We are diagnosing earlier.”

What’s more, trends in mother-to-child transmission, a major route of transmission for pediatric HIV, also have improved in D.C.

“In 2006, our maternal HIV transmission rates were among the highest in the nation. But, in 2013, 2014 and 2015 there were zero cases. We have seen some setbacks recently, however.  In 2016, there were three perinatally acquired cases and four in 2017, but these cases came out of the larger Metropolitan D.C. area,” she explains. “Every perinatally transmitted case for us is a red star. We work very closely with the regional departments of health. We really want to get back to zero cases of maternal transmission in the region.”

The regional planning commission meets several times per year to decide how to distribute federal funding in Washington and the Metropolitan D.C. area to support HIV prevention, diagnosis, treatment and care.

“My voice on the council is to make sure I speak up for services for mothers, children and adolescents,” Dr. Rakhmanina says. “The biggest challenge of HIV care remains treating children. There’s a good selection of medicines for adults, but not all are suited for kids. Young children in particular can’t be given one pill once a day. Really young children can’t swallow a pill. Using a liquid formulation, which kids prefer, may mean opening three different bottles twice daily and swallowing a liquid that often doesn’t taste good.”

Adolescents diagnosed with HIV also find medication adherence challenging, she says.

“At that age, they face a lot of challenges to self-acceptance and disease management, in part, because it’s not a physical disability. A young person with HIV may not feel anything,” she says. “They struggle with staying on daily medications. Many of them tell us they don’t want to think about HIV and face stigma.”

Another ongoing challenge is ensuring moms living with HIV remain on medicines after they’ve given birth.

“They’re tremendously committed to continuing treatment while pregnant: Treatment means their babies are born free of HIV,” she says. “That is a great success. Once the baby is born, many times the women bring their babies to be tested, but the woman’s own health becomes less of a priority. We see a drop in adherence once they have the baby.”

By serving on the commission, Dr. Rakhmanina aims to push to extend Children’s commitment to excellence beyond its walls.

Pregnant-Mom

Safeguarding fetal brain health in pregnancies complicated by CHD

Pregnant-Mom

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.”

Dr.-Jonas.-WSPCHS

Snapshot: The Sixth Scientific Meeting of the World Society for Pediatric and Congenital Heart Surgery

Dr.-Jonas.-WSPCHS

Dr. Richard Jonas shows surgical advancements using 3D heart models, which participants could bring back to their host institutions.

On July 22, 2018, more than 700 cardiac specialists met in Orlando, Fla. for the Sixth Scientific Meeting of the World Society for Pediatric and Congenital Heart Surgery (WSPCHS 2018).

The five-day conference hosted a mix of specialists, ranging from cardiothoracic surgeons, cardiologists and cardiac intensivists, to anesthesiologists, physician assistants and nurse practitioners, representing 49 countries and six continents.

To advance the vision of WSPCHS – that every child born with a congenital heart defect should have access to appropriate medical and surgical care – the conference was divided into eight tracks: cardiac surgery, cardiology, anesthesia, critical care, nursing, perfusion, administration and training.

Richard Jonas, M.D., outgoing president of WSPCHS and the division chief of cardiac surgery at Children’s National Health System, provided the outgoing presidential address, delivered the keynote lecture on Transposition of the Great Arteries (TGA) and guided a surgical skills lab with printed 3-D heart models.

Other speakers from Children’s National include:

  • Gil Wernovsky, M.D., a cardiac critical care specialist, presented on the complex physiology of TGA, as well as long-term consequences in survivors of neonatal heart surgery, including TGA and single ventricle.
  • Mary Donofrio, M.D., a cardiologist and director of the Fetal Heart Program, presented “Prenatal Diagnosis: Improving Accuracy and Planning Delivery for babies with TGA,” “Systemic Venous Abnormalities in the Fetus,” “Intervention for Fetal Lesions Causing High Output Heart Failure” and “Fetal Cardiac Care – Can We Improve Outcomes by Altering the Natural History of Disease?”
  • Gerard Martin, M.D., a cardiologist and medical director of global services, presented “Is the Arterial Switch as Good as We Thought It Would Be?” and “Impact, MAPIT, NCPQIC – How and Why We Should All Embrace Quality Metrics.”
  • Pranava Sinha, M.D., a cardiac surgeon, presented the abstract “Cryopreserved Valved Femoral Vein Homografts for Right Ventricular Outflow Tract Reconstruction in Infants.”

Participants left with knowledge about how to diagnose and treat complex congenital heart disease, and an understanding of the long-term consequences of surgical management into adulthood. In addition, they received training regarding standardized practice models, new strategies in telemedicine and collaborative, multi-institutional research.

“It was an amazing experience for me to bring my expertise to a conference which historically concentrated on surgical and interventional care and long-term follow-up,” says Dr. Donofrio. “The collaboration between the fetal and postnatal care teams including surgeons, interventionalists and intensive care doctors enables new strategies to be developed to care for babies with CHD before birth. Our hope is that by intervening when possible in utero and by planning for specialized care in the delivery room, we can improve outcomes for our most complex patients”.

The Johns Hopkins University School of Medicine, Florida Board of Nursing, American Academy of Nurse Practitioners National Certification Program, American Nurses Credentialing Center and the American Board of Cardiovascular Perfusion provided continuing medical credits for eligible providers.

“I was so proud to be a member of the Children’s National team at this international conference,” notes Dr. Wernovsky. “We had to the opportunity to share our experience in fetal cardiology, outpatient cardiology, cardiac critical care, cardiac nursing and cardiac surgery with a worldwide audience, including surgical trainees, senior cardiovascular surgeons and the rest of the team members necessary to optimally care for babies and children with complex CHD. In addition, members of the nursing staff shared their research about advancements in the field. It was quite a success – both for our team and for all of the participants.”

Graph showing magnesium reduces arrhythmia risk

Magnesium helps prevent postsurgical arrhythmias in pediatric patients

Graph showing magnesium reduces arrhythmia risk

Magnesium (Mg) helps reduce arrhythmias, irregular heart rhythms, in adults. It also helps alleviate the symptoms of postoperative atrial fibrillation, or AFib, which can lead to blood clots, stroke and heart failure. Can it help prevent postsurgical arrhythmias in pediatric patients with congenital heart disease?

New research from Children’s National Health System finds a 25- or 50-mg dose of Mg used during congenital heart surgery (CHS) helps prevent arrhythmias, especially junctional ectopic tachycardia (JET) and atrial tachycardia (AT), common arrhythmias following CHS, according to a study published in the August 2018 edition of The Journal of Thoracic and Cardiovascular Surgery.

To reach this conclusion, the researchers separated 1,871 CHS patients from Children’s National into three groups: a control group of 750 patients who had surgery without Mg, a group of 338 patients receiving a 25-mg /kg dose of Mg during surgery and a group of 783 patients receiving a 50-mg/kg dose of Mg during surgery. The data looked at CHS cases over eight years, from 2005 to 2013, to determine if Mg administration during surgery alleviates postoperative arrhythmias and if the amount, measured by a 25- or 50-mg/kg dose, makes a difference.

“This study, the first conducted in pediatric patients, finds administering magnesium during congenital heart surgery reduces the likelihood of postsurgical arrhythmias,” says Charles Berul, M.D., a study author and the chief of cardiology at Children’s National. “We don’t detect a dose-dependent relationship, which means a small or larger amount of magnesium is equally effective at preventing arrhythmias following surgery.”

The researchers found that up to one-third of CHS patients experience postoperative arrhythmias, with JET and AT accounting for more than two-thirds of arrhythmias following CHS. They note that despite the administration of Mg during surgery, there continues to be a high incidence of postoperative arrhythmias – affecting 18 percent or about one in five CHS patients.

“We hope this study guides future research to see if adding new or additional agents to magnesium eliminates, or further reduces, postoperative arrhythmias,” notes Dr. Berul. “For now, we’re happy to find an algorithm to put into practice and to share with other medical centers, as a way to help pediatric patients recover from congenital heart surgery—stronger, faster and with a reduced risk of complications.”

The researchers note that postoperative arrhythmias impact the recovery period of CHS, increase the duration of intubation and CICU stay and prolong hospital stay.

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

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:

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 12th 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.

An-Massaro

Keeping an eye on autonomic function for infants with HIE

An-Massaro

“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.

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.

Anna Penn

Protecting the fetal brain from harm

Anna Penn

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.

distressed woman holding baby

When depression lingers after the NICU

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., 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.

Preemie Baby

Brain food for preemies

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.

An-Massaro

How EPO saves babies’ brains

An-Massaro

“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,” says An Massaro, M.D.

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:

“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.

Dorothy Bulas

Dorothy Bulas, M.D., receives the Society for Pediatric Radiology’s highest honor

Dorothy Bulas

Dorothy Bulas, M.D. F.A.C.R., F.A.I.U.M., F.S.R.U., chief of diagnostic imaging and radiology in the Division of Diagnostic Imaging and Radiology at Children’s National Health System, is being recognized at the 2018 Society for Pediatric Radiology Annual Meeting with their most distinguished honor, the Gold Medal.

The Society of Pediatric Radiology (SPR) Gold Medal is awarded to pediatric radiologists who have contributed greatly to the SPR and their subspecialty of pediatric radiology as a scientist, teacher, personal mentor and leader.

Initially, Dr. Bulas completed her residency in pediatrics. During a pediatric radiology rotation at John Hopkins University, she realized how much she loved problem solving and using emerging imaging modalities and went on to complete her radiology residency at Albert Einstein Hospital. Soon after, Dr. Bulas moved to Washington, D.C. to complete a pediatric radiology fellowship at her professional home, Children’s National.

Since the completion of her fellowship, Dr. Bulas views her role in the advancement of fetal imaging as her most significant professional contribution. She has published 131 papers, one of her most recent as a co-author on “Neuroimaging findings in normocephalic infants with Zika virus” in Pediatric Neurology. Dr. Bulas is also a co-author of the textbook entitled Fundamental and Advanced Fetal Imaging and has authored 35 book chapters.

She has served as program director of the Radiology Fellowship Program at Children’s National since 2005 where she has impacted medical students, residents and fellows from the United States and abroad.

As a previous chair member for numerous organizations, Dr. Bulas currently co-chairs the American College of Radiology’s pediatric radiology education committee. She is a founding member of the Image Gently Alliance, where she chaired the outreach campaign to parents and wrote brochures, web material and articles. Dr. Bulas is also a founder of the World Federation of Pediatric Imaging.

Dr. Bulas was honored as an outstanding teacher with the Edward Singleton-Hooshang Taybi Award for Excellence in Education from the SPR and this past fall and as the Outstanding Educator in 2017 by the Radiological Society of North America.

Robin Steinhorn

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

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 Thorasic 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.

Sudeepta Basu

GABA concentration in pre-term brain increases with gestational age

Sudeepta Basu

“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.
Vittorio Gallo

Perinatal brain injury headlines American Society for Neurochemistry

Vittorio Gallo

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.

Sarah Mulkey

MRI finds novel brain defects in Zika-exposed newborns

Sarah Mulkey

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

banner year

2017: A banner year for innovation at Children’s National

banner year

In 2017, clinicians and research faculty working at Children’s National Health System published more than 850 research articles about a wide array of topics. A multidisciplinary Children’s Research Institute review group selected the top 10 articles for the calendar year considering, among other factors, work published in high-impact academic journals.

“This year’s honorees showcase how our multidisciplinary institutes serve as vehicles to bring together Children’s specialists in cross-cutting research and clinical collaborations,” says Mark L. Batshaw, M.D., Physician-in-Chief and Chief Academic Officer at Children’s National. “We’re honored that the National Institutes of Health and other funders have provided millions in awards that help to ensure that these important research projects continue.”

The published papers explain research that includes using imaging to describe the topography of the developing brains of infants with congenital heart disease, how high levels of iron may contribute to neural tube defects and using an incisionless surgery method to successfully treat osteoid osteoma. The top 10 Children’s papers:

Read the complete list.

Dr. Batshaw’s announcement comes on the eve of Research and Education Week 2018 at Children’s National, a weeklong event that begins April 16, 2018. This year’s theme, “Diversity powers innovation,” underscores the cross-cutting nature of Children’s research that aims to transform pediatric care.

foods rich in folate

An ironclad way to prevent neural tube defects? Not yet

foods rich in folate

Researchers have known for decades that folate, a vitamin enriched in dark, leafy vegetables; fruit; nuts; and other food sources, plays a key role in preventing neural tube defects.

Every year, about 3,000 pregnancies in the U.S. are affected by neural tube defects (NTDs) –  birth defects of the brain, spine and spinal cord. These include anencephaly, in which a major part of the brain, skull and scalp is missing; and spina bifida, in which the backbone and membranes around the spinal cord don’t close properly during fetal development. These structural birth defects can have devastating effects: In the best cases, they might lead to mild but lifelong disability; in the worst cases, babies don’t survive.

Researchers have known for decades that folate, a vitamin enriched in dark, leafy vegetables; fruit; nuts; and other food sources, plays a key role in preventing NTDs. To help get more folate into pregnant women’s diets, wheat flour in the U.S. and many other countries is often fortified with folic acid, a synthetic version of this vitamin, as part of an intervention credited with significantly reducing the incidence of NTDs.

But folic acid supplementation isn’t enough, says Irene E. Zohn, Ph.D., a principal investigator at the Center for Neuroscience Research at Children’s National Health System who studies how genes and the environment interact during development. A significant number of NTDs still occur, suggesting that other approaches – potentially, other nutrients in the maternal diet – might provide further protection.

That’s why Zohn and colleagues decided to investigate iron. Iron deficiency is one of the most common micronutrient deficiencies in women of childbearing age, Zohn explains. Additionally, iron and folate deficiencies often overlap and signal overall poor maternal diets.

The idea that iron deficiency might play a role in NTDs came from studies by Zohn and colleagues of the flatiron mutant line of experimental models. This experimental model line has a mutation in a gene that transports iron across cell membranes, including the cells that supply embryos with this critical micronutrient.

To determine if NTDs develop in these mutant experimental models because of reduced iron transport, the researchers devised a simple experiment: They took female adult experimental models with the mutation and separated them into four groups. For several weeks, one group ate a diet that was high in folic acid. Another group ate a diet high in iron. The third group ate a diet high in both folic acid and iron. The fourth group ate standard chow. All of these experimental models then became pregnant with embryos that harbored the flatiron mutation, and the researchers assessed the offspring for the presence of NTDs.

Irene Zohn

“We were hoping that iron supplements would be the next folic acid, but it did not turn out that way,” says Irene E. Zohn, Ph.D. “Even though our results demonstrate that iron is important for proper neural tube development, giving extra iron definitely has its downsides.”

As they reported in Birth Defects Research, the dietary interventions successfully increased iron stores: Experimental model mothers whose diets were supplemented with iron, folic acid or both had increased concentrations of these micronutrients in their blood.

The dietary interventions also affected their offspring. While about 80 percent of flatiron mutant embryos fed a standard diet during pregnancy had NTDs, feeding a diet high in iron prevented NTDs in half of the offspring. This lower rate was similar in the offspring of mothers fed a diet high in both folic acid and iron, but not for those whose mothers ate just a diet high in folic acid. Those embryos had NTD rates as high as those who ate just the standard chow, suggesting that low iron was the cause of the high rates, not low folic acid.

Together, Zohn says, these experiments show that iron plays an important role in the development of the neural tube and that deficits in iron might cause some cases of NTDs. However, she notes, reducing NTDs isn’t nearly as simple as supplementing pregnant women’s diets with iron. In the same study, the researchers found that when they gave normal experimental models that didn’t have the flatiron mutation concentrated iron supplements – amounts akin to what doctors might prescribe for human patients with very severe iron-deficiency anemia – folate stores dropped.

That’s because these two micronutrients interact in the body with similar sites for absorption and storage in the intestines and liver, Zohn explains. At either the intestines or liver or at both locations, an iron overload might interfere with the body’s ability to absorb or use folate.

At this point, she says, giving high doses of iron routinely during pregnancy doesn’t look like a feasible way to prevent NTDs.

“We were hoping that iron supplements would be the next folic acid, but it did not turn out that way,” Zohn says. “Even though our results demonstrate that iron is important for proper neural tube development, giving extra iron definitely has its downsides.”

Zohn’s team plans to continue to investigate the role of iron, as well as the role of other micronutrients that might influence neural tube development.

Zohn’s coauthors include Bethany A. Stokes, The George Washington University, and Julia A. Sabatino, Children’s National.

Research reported in this story was supported by a grant from the Board of Visitors, Eunice Kennedy Shriver National Institute of Child Health & Human Development under award number R21-HD076202, the National Center for Research Resources under award number UL1RR031988, Children’s Research Institute and the National Institutes of Health under grant P30HD040677.

Pregnant-Mom

MRI opens new understanding of fetal growth restriction

Pregnant-Mom

Quantitative MRI can identify placental dysfunction complicated by fetal growth restriction earlier, creating the possibility for earlier intervention to minimize harm to the developing fetus.

A team of researchers has found that quantitative magnetic resonance imaging (MRI) can identify pregnancies where placental dysfunction results in fetal growth restriction (FGR), creating the possibility for earlier FGR detection and intervention to augment placental function and thus minimize harm to the fetal brain.

The study, published online in the Journal of Perinatology, reports for the first time that in vivo placental volume is tied to global and regional fetal brain volumes.

Placental insufficiency is a known risk factor for impaired fetal growth and neurodevelopment. It may cause the fetus to receive inadequate oxygen and nutrients, making it difficult to grow and thrive. The earlier placental insufficiency occurs in a pregnancy, the more serious it can be. But detecting a failing placenta before the fetus is harmed has been difficult.

One additional challenge is that a fetus may be small because the placenta is not providing adequate nourishment. Or the fetus simply may be genetically predisposed to be smaller. Being able to tell the difference early can have a lifelong impact on a baby. Infants affected by FGR can experience behavioral problems, learning difficulties, memory and attention deficits, and psychiatric issues as the child grows into adolescence and adulthood.

“Our study proved that MRI can more accurately determine which pregnancies are at greater risk for impaired fetal health or compromised placenta function,” says Nickie Andescavage, M.D., the study’s lead author and a specialist in neonatology and neonatal neurology and neonatal critical care at Children’s National Health System. “The earlier we can identify these pregnancies, the more thoughtful we can be in managing care.”

Dr. Andescavage’s research focus has been how fetal growth affects labor, delivery and postnatal complications.

Nickie-Andescavage-Niforatos

“Our study proved that MRI can more accurately determine which pregnancies are at greater risk for impaired fetal health or compromised placenta function,” says Nickie Andescavage, M.D., the study’s lead author.

“We don’t have a good understanding of why FGR happens, but we do know it’s hard to identify during pregnancy because often there are no signs,” says Dr. Andescavage. “Even when detected, it’s hard to follow. But if we’re aware of it, we can better address important questions, like when to deliver an at-risk fetus.”

In the study, the team measured placental and fetal brain growth in healthy, uncomplicated pregnancies and in pregnancies complicated by FGR. A total of 114 women participated, undergoing ultrasound, Doppler ultrasound and MRI imaging to measure placental volume and fetal brain volume.

An ultrasound test is often what detects FGR, but the measurements generated by ultrasound can be non-specific. In addition, reproducibility issues with 3D sonography limit its use as a standalone tool for placental assessment. Once FGR is detected via ultrasound, this study showed that complementary MRI provides more accurate structural measures of the fetal brain, as well as more detail and insight into placental growth and function.

“Our team has studied FGR for a few years, using imaging to see that’s happening with the fetus in real time,” says Dr. Andescavage. “The relationship of placental volume and fetal brain development had not been previously studied in utero.”

In pregnancies complicated by FGR, MRI showed markedly decreased placental and brain volumes. The team observed significantly smaller placental, total brain, cerebral and cerebellar volumes in these cases than in the healthy controls. The relationship between increasing placental volume and increasing total brain volume was similar in FGR and in normal pregnancies. However, the study authors write “the overall volumes were smaller and thus shifted downward in pregnancies with FGR.”

In addition, FGR-complicated pregnancies that also showed abnormalities in Doppler ultrasound imaging had even smaller placental, cerebral and cerebellar volumes than pregnancies complicated by FGR that did not have aberrations in Doppler imaging.

Since this study showed that quantitative fetal MRI can accurately detect decreased placental and brain volumes when FGR is present, Dr. Andescavage believes this imaging technique may give doctors important new insights into the timing and possibly the mechanisms of brain injury in FGR.  “Different pathways can lead to FGR. With this assessment strategy, we could potentially elucidate those,” she adds.

Using quantitative MRI to identify early deviations from normal growth may create opportunities for future interventions to protect the developing fetal brain. New treatments on the horizon promise to address placental health. MRI could be used to investigate these potential therapies in utero. When those therapies become available, it could allow doctors to monitor treatment effects in utero.

Study co-authors include Adré J. du Plessis, M.B.Ch.B., M.P.H., Director of Children’s Fetal Medicine Institute; Marina Metzler; Dorothy Bulas, M.D., FACR, FAIUM, FSRU, Chief of Children’s Division of Diagnostic Imaging and Radiology; L. Gilbert Vezina, M.D., Director of Children’s Neuroradiology Program; Marni Jacobs; Catherine Limperopoulos, Ph.D., Director of Children’s Developing Brain Research Laboratory and study senior author; Sabah N. Iqbal, MedStar Washington Hospital Center; and Ahmet Alexander Baschat, Johns Hopkins Center for Fetal Therapy.

Research reported in this post was supported by the Canadian Institutes of Health Research, MOP-81116; the National Institutes of Health under award numbers UL1TR000075 and KL2TR000076; and the Clinical and Translational Science Institute at Children’s National.

Neonatal baby

Multidisciplinary experts help CDC’s Zika research

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

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

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

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

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

Cara-Biddle-and-Sarah-Mulkey

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

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

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