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.

Carlos Ferreira Lopez

Researchers discover new gene variant for inherited amino acid-elevating disease

Carlos Ferreira Lopez

What’s known

Hypermethioninemia is a rare condition that causes elevated levels of methionine, an essential amino acid in humans. This condition stems from genetic variations inherited from one or both parents. Some forms of hypermethioninemia are recessive, meaning that two copies of defective genes are necessary to cause this disease. Other forms are dominant, meaning that only one copy can cause hypermethioninemia. Recessive forms of the disease tend to have more serious consequences, causing elevated methionine levels throughout life and leading to changes in the brain’s white matter visible on magnetic resonance imaging that can cause neurological problems. The dominant forms are generally thought to be largely benign and require minimal follow-up.

What’s new

A research team led by Carlos Ferreira Lopez, M.D., a medical geneticist at Children’s National Health System, discovered a new gene variant that had not been associated with hypermethioinemia previously when an infant who had tested positive for elevated methionine on newborn blood-spot screening came in for a follow-up evaluation. While the majority of dominant hypermethioninemia are caused by a genetic mutation known as MAT1A p.Arg264His, the child didn’t have this or any of the common recessive hypermethioninemia mutations. Genetic testing showed that she carried a different mutation to the MAT1A gene known as p.Ala259Val, of which she carried only a single copy. The child fit the typical profile of having the dominant form of the disease, with methionine levels gradually declining over time. Testing of her mother showed that she carried the same gene variant, with few consequences other than a hepatitis-like illness as a child. Because liver disease can accompany dominant hypermethioninemia, the infant’s doctors will continue periodic follow-up to ensure she remains healthy.

Questions for future research

Q: Besides the potential for harmful liver effects, does dominant hypermethioninemia have other negative consequences?

Q: How common is this gene variant, and are certain people at more risk for carrying it?

Source: Confirmation that MAT1A p.Ala259Val mutation causes autosomal dominant hypermethioninemia. Muriello, M.J., S. Viall, T. Bottiglieri, K. Cusmano-Ozog and C. R. Ferreira. Published by Molecular Genetics and Metabolism Reports December 2017.

Volumetric imaging of upper airways

Preemies’ narrowed upper airways may explain higher OSA risk

Volumetric imaging of upper airways

The airway structures of interest to the Children’s National research team included the nasopharynx (labeled red), oropharynx (labeled purple), hypopharynx (labeled green), adenoids (labeled yellow) and tonsils (labeled blue). The team displayed the volumetric imaging in three perpendicular planes and a three-dimensional model.
Credit: A. Smitthimedhin, et al, Clinical Imaging.

Infants born preterm have significantly lower nasopharyngeal and oropharyngeal volumes, compared with newborn peers carried to full term, and those lower airway volumes are independent of the infants’ gender, ethnicity or weight, according to a study published online Dec. 16, 2017 in Clinical Imaging.

According to the Centers for Disease Control and Prevention, 1 in 10 babies born in the United States is preterm, or born prior to the 37th gestational week. Premature birth leaves these children more susceptible to disordered breathing while sleeping, including obstructive sleep apnea (OSA), an ailment characterized by increased upper-airway resistance that narrows airways.

“In addition to finding some airway volumes were smaller in preterm infants, our results indicated both sets of newborns had similar hypopharyngeal volumes. This suggests that risk factors that lead to OSA are confined to the uppermost airway and do not appear to be explained by enlarged adenoids and tonsils,” says Anilawan Smitthimedhin, a Children’s National Health System radiology research fellow at the time the study was performed and lead author of the paper.

In order to diagnose OSA, clinicians now use bronchoscopy, but the method has limitations, including the need to insert a lighted instrument into the airway, which can affect pressure and resistance within the airway.

The Children’s National research team theorized that magnetic resonance imaging (MRI) could offer a non-invasive way to evaluate the upper airway, determine its anatomy and dynamic function, while shielding infants from radiation exposure that can accompany other imaging techniques.

They enrolled 96 infants who had undergone brain MRIs as part of an unrelated study about neonatal brain development. The newborns had a range of medical conditions, including suspected hypoxic ischemic encephalopathy, cardiac disease and seizures/movement disorders.

Forty-nine of the infants were born preterm; at the time of the MRI, their corrected mean gestational age was 38.4 weeks. Forty-seven of the newborns were born full term; they received MRIs at 1.7 weeks of age. The airway structures of interest included the nasopharynx (the upper part of the pharynx), oropharynx (located at the back of the mouth behind the oral cavity), hypopharynx (the entrance into the esophagus), adenoids and tonsils. The team displayed the volumetric imaging in three perpendicular planes and a three-dimensional model.

“Nasopharyngeal volume of full-term infants was 495.6 mm, compared with 221.1 mm in preterm infants. Oropharyngeal volume of full-term infants was 313.6 mm, compared with 179.3 mm in preterm infants,” Smitthimedhin says.

Aided by volumetric 3D data that more accurately measures airway and lymphoid tissue, the team proposes to study a larger group of infants to determine whether narrowing of the uppermost airways predisposes very young children to experiencing OSA later in life.

“Ultimately, our goal is to incorporate dedicated, dynamic MR imaging of the airway while children sleep, which would provide real-time, detailed information about the changes associated with sleep. This innovation holds the promise of leading to more accurate, non-invasive diagnosis of OSA in infants,” says Dorothy Bulas, M.D., chief of Diagnostic Imaging and Radiology at Children’s National.

Children’s National study co-authors include Radiologist Matthew Whitehead, M.D.; University of Maryland student Mahya Bigdeli; Pulmonologist Gustavo Nino Barrera, M.D.; Pulmonologist Geovanny Perez, M.D,; and Hansel Otero, who was at Children’s National when the research work was performed but now works at Children’s Hospital of Philadelphia.

the cerebral blood flow (CBF) maps, corresponding anatomical image aligned to the CBF map, and the regions of interest examined

Tracking preemies’ blood flow to monitor brain maturation

Blood is the conduit through which our cells receive much of what they need to grow and thrive. The nutrients and oxygen that cells require are transported by this liquid messenger. Getting adequate blood flow is especially important during the rapid growth of gestation and early childhood – particularly for the brain, the weight of which roughly triples during the last 13 weeks of a typical pregnancy. Any disruption to blood flow during this time could dramatically affect the development of this critical organ.

Now, a new study by Children’s National Health System researchers finds that blood flow to key regions of very premature infants’ brains is altered, providing an early warning sign of disturbed brain maturation well before such injury is visible on conventional imaging. The prospective, observational study was published online Dec. 4, 2017 by The Journal of Pediatrics.

“During the third trimester of pregnancy, the fetal brain undergoes an unprecedented growth spurt. To power that growth, cerebral blood flow increases and delivers the extra oxygen and nutrients needed to nurture normal brain development,” says Catherine Limperopoulos, Ph.D., director of the Developing Brain Research Laboratory at Children’s National and senior author of the study. “In full-term pregnancies, these critical brain structures mature inside the protective womb where the fetus can hear the mother and her heartbeat, which stimulates additional brain maturation. For infants born preterm, however, this essential maturation process happens in settings often stripped of such stimuli.”

The challenge: How to capture what goes right or wrong in the developing brains of these very fragile newborns? The researchers relied on arterial spin labeling (ASL) magnetic resonance (MR) imaging, a noninvasive technique that labels the water portion of blood to map how blood flows through infants’ brains in order to describe which regions do or do not receive adequate blood supply. The imaging work can be done without a contrast agent since water from arterial blood itself illuminates the path traveled by cerebral blood.

“In our study, very preterm infants had greater absolute cortical cerebral blood flow compared with full-term infants. Within regions, however, the insula (a region critical to experiencing emotion), anterior cingulate cortex (a region involved in cognitive processes) and auditory cortex (a region involved in processing sound) for preterm infants received a significantly decreased volume of blood, compared with full-term infants. For preterm infants, parenchymal brain injury and the need for cardiac vasopressor support both were correlated with decreased regional CBF,” Limperopoulos adds.

The team studied 98 preterm infants who were born June 2012 to December 2015, were younger than 32 gestational weeks at birth and who weighed less than 1,500 grams. They matched those preemies by gestational age with 104 infants who had been carried to term. The brain MRIs were performed as the infants slept.

Blood flows where it is needed most with areas of the brain that are used more heavily commandeering more oxygen and nutrients. Thus, during brain development, CBF is a good indicator of functional brain maturation since brain areas that are the most metabolically active need more blood.

the cerebral blood flow (CBF) maps, corresponding anatomical image aligned to the CBF map, and the regions of interest examined

This figure represents the cerebral blood flow (CBF) maps, corresponding anatomical image aligned to the CBF map, and the regions of interest examined. The scale indicates the quantitative value of the CBF map and is expressed in mL/100g/min. The data are from a preterm infant scanned at term age without evidence of brain injury. The insula (see black arrows in panel ‘D’) may be particularly vulnerable to the added stresses of the preterm infant’s life outside the womb.
Credit: M. Bouyssi-Kobar, et al., The Journal of Pediatrics.

“The ongoing maturation of the newborn’s brain can be seen in the distribution pattern of cerebral blood flow, with the greatest volume of blood traveling to the brainstem and deep grey matter,” says Marine Bouyssi-Kobar, M.S., the study’s lead author. “Because of the sharp resolution provided by ASL-MR images, our study finds that in addition to the brainstem and deep grey matter, the insula and the areas of the brain responsible for sensory and motor functions are also among the most oxygenated regions. This underscores the critical importance of these brain regions in early brain development. In preterm infants, the insula may be particularly vulnerable to the added stresses of life outside the womb.”

Of note, compromised regional brain structures in adults are implicated in multiple neurodevelopmental disorders. “Altered development of the insula and anterior cingulate cortex in newborns may represent early warning signs of preterm infants at greater risk for long-term neurodevelopmental impairments,” Limperopoulos says.

Research reported in this post was supported by the Canadian Institutes of Health Research, MOP-81116; the SickKids Foundation, XG 06-069; and the National Institutes of Health under award number R01 HL116585-01.

Human Rhinovirus

When a common cold may trigger early supportive care

Human Rhinovirus

A new study led by Children’s National Health System shows that in infants who were born severely premature, human rhinovirus infections appear to trigger airway hyper-reactivity, which leads to wheezing, hyperinflation and more severe respiratory disease.

Human rhinovirus (HRV), the culprit behind most colds, is the leading cause of hospitalization for premature babies. However, in very preterm children, exactly how HRV causes severe respiratory disease – and which patients may need more intensive observation and treatment – is less well understood.

A new study led by Children’s National Health System research-clinicians showed in children who were born severely premature, HRV infections seem to trigger an airway hyper-reactivity (AHR) type of disease, which leads to wheezing and air-trapping (hyperinflation) and more severe respiratory disease. This, in turn, increases the risk for hospitalization.

The study, published online Oct. 21, 2017 in Pediatrics and Neonatology, found that other signs of respiratory distress, such as low arterial blood oxygen or rapid shallow breathing, were no more common in severely premature children (less than 32 weeks of gestational age) than in kids born preterm or full-term. The findings have implications for administering supportive care sooner or more intensively for severely premature children than for other infants.

“When it comes to how they respond to such infections, severely premature children are quite different,” says Geovanny Perez, M.D., a specialist in pulmonary medicine at Children’s National and lead study author. “We’ve known they are more susceptible to human rhinovirus infection and have more severe disease. However, our study findings suggest that severely premature kids have an ‘asthma’ type of clinical picture and perhaps should be treated differently.”

The study team sought to identify clinical phenotypes of HRV infections in young children hospitalized for such infections. The team theorized that severely premature babies would respond differently to these infections and that their response might resemble symptoms experienced by patients with asthma.

“For a number of years, our team has studied responses to viruses and prematurity, especially HRV and asthma,” Dr. Perez says. “We know that premature babies have an immune response to HRV from the epithelial cells, similar to that seen in older patients with asthma. But we wanted to address a gap in the research to better understand which children may need closer monitoring and more supportive care during their first HRV infection.”

Geovanny Perez

“When it comes to how they respond to such infections, severely premature children are quite different,” says Geovanny Perez, M.D. “We’ve known they are more susceptible to human rhinovirus infection and have more severe disease. However, our study findings suggest that severely premature kids have an ‘asthma’ type of clinical picture and perhaps should be treated differently.”

In a retrospective cross-sectional analysis, the study looked at 205 children aged 3 years or younger who were hospitalized at Children’s National in 2014 with confirmed HRV infections. Of these, 71 percent were born full-term (more than 37 gestational weeks), 10 percent were preterm (32 to 37 gestational weeks) and 19 percent were severely premature (less than 32 gestational weeks).

Dr. Perez and his team developed a special respiratory distress scoring system based on physical findings in the children’s electronic medical records to assess the degree of lower-airway obstruction or AHR (as occurs in asthma) and of parenchymal lung disease. The physical findings included:

  • Wheezing;
  • Subcostal retraction (a sign of air-trapping/hyperinflation of the lungs), as can occur in pneumonia;
  • Reduced oxygen levels (hypoxemia); and
  • Increased respiratory rate (tachypnea).

The research team assigned each case an overall score. The severely premature children had worse overall scores – and significantly worse scores for AHR and hyperinflated lungs relative to children born late preterm or full-term.

“What surprised us, though, in this study was that the phenotypical characterization using individual parameters for parenchymal lung disease, such as hypoxemia or tachypnea, were not different in severe preterm children and preterm or full term,” says Dr. Perez. “On the other hand, our study found that severely preterm children had a lower airway obstruction phenotype associated with retractions and wheezing. Moreover there was a ‘dose effect’ of prematurity: Children who were born more premature had a higher risk of wheezing and retractions.”

Among the implications of this study, Dr. Perez sees the potential to use phenotypical (clinical markers, such as retractions and wheezing) and biological biomarkers to better personalize patients’ treatments. Dr. Perez and his team have identified biological biomarkers in nasal secretions of children with rhinovirus infection that they plan to combine with clinical biomarkers to identify which patients with viral infections will benefit from early supportive care, chronic treatments or long-term monitoring.

Dr. Perez says further research in this area should pursue a number of paths, including:

  • A longitudinal study to elucidate which children will benefit from asthma-like treatment, such as bronchodilators or corticosteroids;
  • A study of biomarkers, including microRNAs and other inflammatory molecules; or
  • Alternatively, a longitudinal study exploring the mechanism by which wheezing develops, perhaps looking at first and subsequent rhinovirus infections in babies born at different gestational ages.
newborn in incubator

Working to reduce brain injury in newborns

A new study from Children’s National Health System and Drexel University College of Medicine has identified a promising treatment to reduce or prevent brain injury in newborns who have suffered hypoxia-ischemia.

Research-clinicians at Children’s National Health System and Drexel University College of Medicine led the first study to identify a promising treatment to reduce or prevent brain injury in newborns who have suffered hypoxia-ischemia, a serious complication in which restricted blood flow deprives the brain of oxygen.

Consequences of brain injury resulting from oxygen deprivation affect the entire lifespan and range from mild (learning disabilities) to severe (inability to breathe, walk, talk or see). This complication can occur during or before birth due to maternal/placental problems, such as placental abruption or cord prolapse, or due to fetal/newborn issues, such as asphyxia due to labor difficulties, infection, fetal-maternal bleeding or twin-to-twin transfusion.

Published in Neonatology on Oct. 13, 2017, the study evaluated newborn experimental models exposed to hypoxia-ischemia. The experimental models were given standard cooling therapy (therapeutic hypothermia) alone and in combination with a selective Src kinase inhibitor, PP2, that blocks a regulatory enzyme of apoptosis (cell death), which intensifies as a result of hypoxia-ischemia. The Food and Drug Administration has approved a Src kinase inhibitor as an oncology treatment. This study is the first to test the benefits of blocking this enzyme in reducing the neurological damage caused by brain hypoxia-ischemia.

“In hypoxia-ischemia, CaM kinase is over-activated, but hypothermia has been shown to decrease this enzyme’s activation. We theorized that a Src kinase inhibitor, in addition to hypothermia, would further attenuate the activation of CaM kinase IV and that the result might be less brain damage,” explains Panagiotis Kratimenos, M.D., Ph.D., the study’s lead author, and a specialist in neonatology and neonatal neurocritical care at Children’s National. “From this study, we were pleased that this seems to be the case.”

The research team assessed neuropathology, adenosine triphosphate and phosphocreatine  concentrations as well as CaM kinase IV activity. The CaM kinase IV activity in cerebral tissue was 2,002 (plus or minus 729) with normal oxygen levels and in normal temperatures, 4,104 (plus or minus 542) in hypoxia with hypothermia treatment, and 2,165 (plus or minus 415) in hypoxia with hypothermia treatment combined with PP2 administration.

The authors conclude that hypothermia alone attenuated the over-activation of CaM kinase IV and improved neuropathology after hypoxia. However, the combination of hypothermia with Src kinase inhibition following hypoxia further attenuated the increased activation of CaM kinase IV, compared with hypothermia alone in the newborn experimental model brain.

Currently, the only treatment for hypoxia-ischemia is therapeutic hypothermia. Starting in the first six hours of life, doctors in the neonatal intensive care unit lower a baby’s temperature by about 3 degrees Celsius for three days. This therapy is proven to reduce neural defects by up to 30 percent, yet many infants still have poor outcomes even after the therapeutic cooling treatment.

“In oxygen deprivation of the brain, the pathways leading to cell death are over-activated, including the nuclear enzyme CaM kinase IV. We sought to intervene in this pathway to reduce the heightened cell death, which leads to brain damage,” explains Dr. Kratimenos, an assistant professor of pediatrics at The George Washington University School of Medicine and Health Sciences whose research focus is neonatal encephalopathy and therapeutic hypothermia.

To continue preclinical research into this approach, Dr. Kratimenos envisions studying the effect of other types of small molecule inhibitors to target the apoptotic cascade, perhaps in multiple doses, eliminating the potential side effects, and determining the best dose and duration of treatment.

“If confirmed by further studies, this approach─in combination with cooling─may help to further attenuate neurological damage that babies suffer after experiencing hypoxia-ischemia,” says Dr. Kratimenos.

The study co-authors include Ioannis Koutroulis, M.D., Ph.D., a faculty member in Children’s Division of Emergency Medicine; and Amit Jain, M.D.; Shadi Malaeb, M.D.; and the world-renowned neonatologist and pioneer in bioenergetics of the brain, Maria Delivoria-Papadopoulos, M.D., all of the Drexel University College of Medicine.

nurse holding newborn baby

Continuous EEG monitoring better predicts HIE outcomes

nurse holding newborn baby

For newborns who experience a serious complication that deprives their brain of oxygen, continuously monitoring brain activity and examining how the electrical signals evolve may be a more reliable way to identify infants most at risk for brain injury.

For newborns who experience a serious complication that deprives their brain of oxygen, continuously monitoring brain activity and examining how the electrical signals evolve may be a more reliable way to identify infants most at risk for brain injury, compared with doing evaluations at discreet intervals, according to a prospective cohort study led by Children’s National Health System research-clinicians.

Amplitude-integrated electroencephalogram (aEEG) is a bedside tool that permits clinicians to monitor the complex electrical activity of the child’s brain over time. It’s a positive sign when an aEEG shows babies beginning to sleep and wake normally by the time they are 3 days old. Conversely, severely abnormal aEEG readings in the first days of life predict poor outcomes.

The Children’s team used aEEG with infants born with hypoxic-ischemic encephalopathy (HIE), one of the most severe complications that can affect full-term infants. During pregnancy, birth or shortly after birth, a hypoxic-ischemic event can occur that impedes blood flow and oxygen delivery to the brain, resulting in destruction of brain tissue. Cooling (therapeutic hypothermia) is now standard for newborns with HIE in order to stave off life-long consequences, but deaths and neurodevelopmental disability still can occur.

“We know whole-body cooling – or lowering the body’s temperature by about 3 degrees Celsius – can help vulnerable newborns survive and can protect their brains from suffering profound injuries,” says An N. Massaro, M.D., a Children’s National neonatologist and senior author of the study published online Sept. 28, 2017 in American Journal of Perinatology.  “What we were trying to determine with this study is whether evaluating the pattern of evolution of the aEEG as a whole provides more information compared with looking at snapshots in time.”

Eighty infants undergoing therapeutic cooling who met the inclusion criteria were enrolled in the five-year study, one of the largest such studies to date. The babies weighed more than 1,800 grams and were older than 35 weeks’ gestational age at birth, and either needed prolonged resuscitation after birth or had low APGAR scores – a measure of how well newborns fare outside the womb. Continuous recordings of EEG data occurred from the time of admission up to 12 hours after the infants’ temperatures were raised to normal and aEEG tracings were calculated.

After the therapeutic cooling blankets were removed, the infants underwent at least one magnetic resonance imaging (MRI) scan prior to discharge. During the routine follow-up check at about 18 months of age, the HIE survivors’ cognitive and motor skills were assessed using validated instruments.

Fifty-six of the infants in the study had favorable outcomes. Twenty-four infants had adverse outcomes, including 15 with severe brain injury detected by MRI and nine infants who died. These children had lower APGAR scores at five minutes, and were more likely to have severe HIE and to have experienced more frequent seizures.

“Infants whose aEEG abnormalities do not improve were at increased risk: Infants who do not reach a discontinuous background pattern by 15.5 hours of life, achieve cycling by 45.5 hours after birth and who fail to achieve continuous normal voltage by 78 hours after birth are most at risk for adverse outcomes,” Dr. Massaro says. “In addition to defining worrisome trends, we found that overall assessment of continuous aEEG readings through the course of hypothermia treatment provide the most meaningful predictive power. This means we can speak with families at the bedside with more confidence about their child’s outcomes after the infant undergoes cooling therapy.”

Related Resources

Sarah Mulkey

Fetal MRI plus ultrasound assess Zika-related brain changes

Sarah Mulkey

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

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

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

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

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

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

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

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

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

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

What Children’s has learned about congenital Zika infection

Roberta DeBiasi

Roberta DeBiasi, M.D., M.S., outlined lessons learned during a pediatric virology workshop at IDWeek2017, one of three such Zika presentations led by Children’s National research-clinicians during this year’s meeting of pediatric infectious disease specialists.

The Congenital Zika Virus Program at Children’s National Health System provides a range of advanced testing and services for exposed and infected fetuses and newborns. Data that the program has gathered in evaluating and managing Zika-affected pregnancies and births may offer instructive insights to other centers developing similar programs.

The program evaluated 36 pregnant women and their fetuses from January 2016 through May 2017. Another 14 women and their infants were referred to the Zika program for postnatal consultations during that time.

“As the days grow shorter and temperatures drop, we continue to receive referrals to our Zika program, and this is a testament to the critical need it fulfills in the greater metropolitan D.C. region,” says Roberta L. DeBiasi, M.D., M.S., chief of the Division of Pediatric Infectious Diseases and co-leader of the program. “Our multidisciplinary team now has consulted on 90 dyads (mothers and their Zika-affected fetuses/infants). The lessons we learned about when and how these women were infected and how their offspring were affected by Zika may be instructive to institutions considering launching their own programs.”

Dr. DeBiasi outlined lessons learned during a pediatric virology workshop at IDWeek2017, one of three such Zika presentations led by Children’s National research-clinicians during this year’s meeting of pediatric infectious disease specialists.

“The Zika virus continues to circulate in dozens of nations, from Angola to the U.S. Virgin Islands. Clinicians considering a strategic approach to managing pregnancies complicated by Zika may consider enlisting an array of specialists to attend to infants’ complex care needs, including experts in fetal imaging, pediatric infectious disease, physical therapists, audiologists, ophthalmologists and radiologists skilled at reading serial magnetic resonance images as well as ultrasounds,” Dr. DeBiasi says. “At Children’s we have a devoted Zika hotline to triage patient and family concerns. We provide detailed instructions for referring institutions explaining protocols before and after childbirth, and we provide continuing education for health care professionals.”

Of the 36 pregnant women possibly exposed to Zika during pregnancy seen in the program’s first year, 32 lived in the United States and traveled to countries where Zika virus was circulating. Two women had partners who traveled to Zika hot zones. And two moved to the Washington region from places where Zika is endemic. Including the postnatal cases, 89 percent of patients had been bitten by Zika-tainted mosquitoes, while 48 percent of women could have been exposed to Zika via sex with an infected partner.

Twenty percent of the women were exposed before conception; 46 percent were exposed to Zika in the first trimester of pregnancy; 26 percent were exposed in the second trimester; and 8 percent were exposed in the final trimester. In only six of 50 cases (12 percent) did the Zika-infected individual experience symptoms.

Zika infection can be confirmed by detecting viral fragments but only if the test occurs shortly after infection. Twenty-four of the 50 women (nearly 50 percent) arrived for a Zika consultation outside that 12-week testing window. Eleven women (22 percent) had confirmed Zika infection and another 28 percent tested positive for the broader family of flavivirus infections that includes Zika. Another detection method picks up antibodies that the body produces to neutralize Zika virus. For seven women (14 percent), Zika infection was ruled out by either testing method.

“Tragically, four fetuses had severe Zika-related birth defects,” Dr. DeBiasi says. “Due to the gravity of those abnormalities, two pregnancies were not carried to term. The third pregnancy was carried to term, but the infant died immediately after birth. The fourth pregnancy was carried to term, but that infant survived less than one year.”

Catherine Limperopoulous

Brain impairment in newborns with CHD prior to surgery

Catherine Limperopoulous

Children’s National researchers led by Catherine Limperopoulos, Ph.D., demonstrate for the first time that the brains of high-risk infants show signs of functional impairment before they undergo corrective cardiac surgery.

Newborns with congenital heart disease (CHD) requiring open-heart surgery face a higher risk for neurodevelopmental disabilities, yet prior studies had not examined whether functional brain connectivity is altered in these infants before surgery.

Findings from a Children’s National Health System study of this question suggest the presence of brain dysfunction early in the lives of infants with CHD that may be associated with neurodevelopmental impairments years later.

Using a novel imaging technique, Children’s National researchers demonstrated for the first time that the brains of these high-risk infants already show signs of functional impairment even before they undergo corrective open heart surgery. Looking at the newborns’ entire brain topography, the team found intact global organization – efficient and effective small world networks – yet reduced functional connectivity between key brain regions.

“A robust neural network is critical for neurons to travel to their intended destinations and for the body to carry out nerve cells’ instructions. In this study, we found the density of connections among rich club nodes was diminished, and there was reduced connectivity between critical brain hubs,” says Catherine Limperopoulos, Ph.D., director of the Developing Brain Research Laboratory at Children’s National and senior author of the study published online Sept. 28, 2017 in NeuroImage: Clinical. “CHD disrupts how oxygenated blood flows throughout the body, including to the brain. Despite disturbed hemodynamics, infants with CHD still are able to efficiently transfer neural information among neighboring areas of the brain and across distant regions.”

The research team led by Josepheen De Asis-Cruz, M.D., Ph.D., compared whole brain functional connectivity in 82 healthy, full-term newborns and 30 newborns with CHD prior to corrective heart surgery. Conventional imaging had detected no brain injuries in either group. The team used resting state functional connectivity magnetic resonance imaging (rs-fcMRI), a imaging technique that characterizes fluctuating blood oxygen level dependent signals from different regions of the brain, to map the effect of CHD on newborns’ developing brains.

The newborns with CHD had lower birth weights and lower APGAR scores (a gauge of how well brand-new babies fare outside the womb) at one and five minutes after birth. Before the scan, the infants were fed, wrapped snugly in warm blankets, securely positioned using vacuum pillows, and their ears were protected with ear plugs and ear muffs.

While the infants with CHD had intact global network topology, a close examination of specific brain regions revealed functional disturbances in a subnetwork of nodes in newborns with cardiac disease. The subcortical regions were involved in most of those affected connections. The team also found weaker functional connectivity between right and left thalamus (the region that processes and transmits sensory information) and between the right thalamus and the left supplementary motor area (the section of the cerebral cortex that helps to control movement). The regions with reduced functional connectivity depicted by rs-fcMRI match up with regional brain anomalies described in imaging studies powered by conventional MRI and diffusion tensor imaging.

“Global network organization is preserved, despite CHD, and small world brain networks in newborns show a remarkable ability to withstand brain injury early in life,” Limperopoulos adds. “These intact, efficient small world networks bode well for targeting early therapy and rehabilitative interventions to lower the newborns’ risk of developing long-term neurological deficits that can contribute to problems with executive function, motor function, learning and social behavior.”

mom and baby

Improving NICU discharge for families and staff

mom and baby

The day of discharge from a neonatal intensive care unit (NICU) can be overwhelming for families and for hospital staff. A Children’s National Health System team found that beginning discharge education early, communicating in ways attuned to families’ needs and using a classroom setting to teach hands-on skills for newborn care can improve parents’ experience during the discharge process, according to a study presented at the 2017 American Academy of Pediatrics (AAP) national conference.

“So much innovation in our NICU comes from listening to parents,” says Michelande Ridoré, M.S., program lead in Children’s Division of Neonatology. “Beyond caring for the child, we also care for the family, and input from parents helps improve our processes and improve parents’ readiness to care for their child when a NICU baby is ready to go home.”

With discharge, the first hint of a problem in the NICU came from lagging Press Ganey scores, measures of families’ satisfaction with their overall hospital experience. Parents whose very sick infants had round-the-clock care felt overwhelmed by the array of skills they needed to learn to replicate that care at home. NICU staff determined the root cause of the problem and, using the Institute for Healthcare Improvement’s Model for Improvement, former NICU parents, nurse educators, family support specialists and quality improvement managers crafted strategies to ameliorate them.

Already, Children’s NICU parents can “room in,” sleeping in their child’s room overnight as discharge nears in order to practice caring for a child with complex care needs. Children’s goal was to increase the number of discharge education sessions so that 90 percent of parents would receive discharge guidance more than 24 hours before their newborn was released from the NICU. The sessions included such staples as how to bathe and feed newborns who often were intubated; the benefits of skin-to-skin contact that characterizes kangaroo care; the child’s diagnosis and immunization status; optimal placement while sleeping; a hearing test and a car seat test, among other information.

“When we speak with parents, they said ‘I had no idea my car seat expired. I had no idea I needed to stay for a car seat test. You had an x, y and z list for me to take my child home. Now, I’ve interacted with someone who told me about that check list and how important it is,’ ” Ridoré says.

Many parents received the one-hour sessions in a classroom setting. On the door to their child’s room, they received alerts indicating whether they had completed courses. Beside the bed was a poster to help track progress toward discharge goals.

According to the study authors, the initiative boosted the number of parents who received discharge training in the 24 hours prior to discharge by 27 percent, a figure that grew over time to a 36 percent boost in such timely communication. Satisfaction scores improved and, in interviews, NICU staff said the process improvements streamlined how much time it takes to prepare families for discharge.

“Preparing parents for discharge in a classroom setting was a successful way to increase the number of families who receive this education before their child prepares to leave the NICU,” Ridoré says. “Families and nurses are happy. In the next phase of this research, we will quantify improvements in satisfaction and further refine pre-discharge training sessions.”

Latina mother playing with her baby boy son on bed

Helping parents of babies leaving NICU cope

Latina mother playing with her baby boy son on bed

A study team from Children’s National tried to determine factors closely associated with poor emotional function in order to identify at-risk parents most in need of mental health support.

Nearly half of parents reported depressive symptoms, anxiety and stress when their infants were discharged from the neonatal intensive care unit (NICU), and parents who were the most anxious were the most depressed. A Children’s National Health System team presented these research findings during the 2017 American Academy of Pediatrics (AAP) national conference.

Because their infants’ lives hang in the balance, NICU parents are at particular risk for poor emotional function, including mood disorders, anxiety and distress. Children’s National Neonatologist Lamia Soghier, M.D., and the study team tried to determine factors closely associated with poor emotional function in order to identify at-risk parents most in need of mental health support.

The study team enrolled 300 parents and infants in a randomized controlled clinical trial that explored the impact of providing peer-to-peer support to parents after their newborns are discharged from the NICU. The researchers relied on a 10-item tool to assess depressive symptoms and a 46-question tool to describe the degree of parental stress. They used regression and partial correlation to characterize the relationship between depressive symptoms, stress, gender and educational status with such factors as the infant’s gestational age at birth, birth weight and length of stay.

Some 58 percent of the infants in the study were male; 58 percent weighed less than 2,500 grams at birth; and the average length of stay for 54 percent of infants was less than two weeks. Eighty-nine percent of parents who completed the surveys were mothers; 44 percent were African American; and 45 percent reported having attained at least a college degree. Forty-three percent were first-time parents.

About 45 percent of NICU parents had elevated Center for Epidemiological Studies Depression Scale (CES-D) scores.

“The baby’s gender, gestational age at birth and length of NICU stay were associated with the parents having more pronounced depressive symptoms,” Dr. Soghier says. “Paradoxically, parents whose newborns were close to full-term at delivery had 6.6-fold increased odds of having elevated CES-D scores compared with parents of preemies born prior to 28 weeks’ gestation. Stress levels were higher in mothers compared with fathers, but older parents had lower levels of stress than younger parents.”

Dr. Soghier says the results presented at AAP are an interim analysis. The longer-term PCORI-funded study continues and explores the impact of providing peer support for parents after NICU discharge.

premature baby in hospital incubator

Improving neonatal intubation training to boost clinical competency

premature baby in hospital incubator

A research team from Children’s National Health System outlined gaps between current simulation training and clinical competency among pediatric residents and then shared recommendations to address them.

Redesigning the mannequins used in medical simulation training could improve residents’ readiness for clinical practice. Presenting at the 2017 American Academy of Pediatrics (AAP) national conference, a research team from Children’s National Health System outlined gaps between current simulation training and clinical competency among pediatric residents and then shared recommendations to address them.

The team noted that the transfer of skill from simulations to clinical encounters does not occur readily. They identified a number of differences between working with a training mannequin and caring for an actual infant: The mannequin’s tongue and head do not move naturally, no fluid lubricates its mouth and throat and, when tilting the head to insert the endotracheal tube, the mannequin’s neck does not flex realistically.

“Current mannequins lack physical and functional fidelity and those shortcomings take a toll on competency as pediatric residents transition from practice simulation sessions to the actual clinic,” says Children’s National Neonatologist Lamia Soghier, M.D., lead author of the poster presented during AAP. “Our work tried to tease out the most important differences between simulating neonatal intubation and actual clinical practice in order to ensure the next generation of mannequins and practice sessions translate to improved clinical competency.”

The study team conducted in-depth interviews with 32 members of the clinical staff, including attending neonatologists and second- and third-year fellows, asking about critical differences in environment, equipment and context as they participated in practice intubations as well as actual intubations in the clinic.

Four key themes emerged, Dr. Soghier and co-authors say:

  • Mannequins’ vocal cords are marked clearly in white, a give-away for trainees tasked with correctly identifying the anatomical feature. In addition, the mannequins are so stiff they need more force when practicing how to position them properly. In the NICU, using that much force could result in trauma.
  • Because current equipment does not simulate color change with a Pedi-Capa non-toxic chemical that changes color in response to exhaled carbon dioxidetrainees can develop poor habits.
  • Training scenarios need to be designed with the learner in mind offering an opportunity to master tasks in a step-by-step fashion, to practice appropriate sedation techniques and for beginners to learn first before being timed.
  • There is a marked mismatch between the feel of a simulated training and the electric urgency of performing the same procedure in the clinic, eroding trainees’ ability to adjust to wildcards in the clinic in real time.

“We carefully design our sessions to provide trainees with the suite of skills they will need to perform well in clinic. Still, there is more we can do inside the hospital and in designing the next generation of mannequins to lead to optimal clinical outcomes,” Dr. Soghier adds. “As a whole, mannequins need to more closely resemble an actual newborn, with flexible vocal cord design in natural colors. The mannequin’s neck should flex with more degrees of freedom. The model’s skin and joints also need to be more flexible, and its head and neck need to move more naturally.”

Baby in the NICU

Reducing harm, improving quality in the NICU

Baby in the NICU

American health care is some of the most expensive in the world. To help make it more affordable, numerous efforts in all areas of medicine – from cancer care to primary care to specialized pediatrics – are focused on finding ways to improve quality and patient safety while also cutting costs.

About half a million babies born in the United States – or 10 percent to 15 percent of U.S. births – end up in the neonatal intensive care unit (NICU), most due to prematurity and very low birth weights. These vulnerable babies often need respiratory support in the form of a ventilator, which supplies oxygen to their lungs with a plastic endotracheal tube (ETT).

The typical care for these infants often involves frequent X-rays to verify the proper position of the tube. However, the American Academy of Pediatrics has counseled health care providers that ordering a daily chest X-ray simply to verify positioning of the ETT ratchets up costs without improving patient safety.

A quality-improvement initiative by Children’s National Health System’s NICU finds that these chest X-rays can be performed just twice weekly, lessening the chances of a breathing tube popping out accidentally, reducing infants’ exposure to radiation and saving an estimated $1.6 million per year.

“The new Children’s National protocol reduced the rate of chest X-rays per patient day without increasing the rate of unintended extubations,” says Michelande Ridoré, M.S., program lead in Children’s division of neonatology, who presented the research during the 2017 American Academy of Pediatrics (AAP) national conference. “That not only helps to improve patient safety – for newborns who are admitted to the NICU for longer periods, there is the additional benefit of providing significant savings to the health care system.”

Children’s NICU staff assessed how many chest X-rays were being performed per patient day before and after the protocol change, which applied to all intubated newborns in the NICU whose health condition was stable. Newborns had been undergoing a median of 0.45 chest X-rays per patient day. After the quality improvement project, that figure dropped to 0.23 chest X-rays per patient day.

When the project started in July 2015, the NICU’s monthly X-ray expenditure was $289,520. By the end of 2015, that monthly X-ray spend had fallen to $159,424 – resulting in nearly $1.6 million in annual savings.

The more restrictive strategy for ordering chest X-rays was a core component of a broader quality improvement effort aimed at lowering the number of unplanned extubations, which represent the fourth most common complication experienced by newborns in the nation’s NICUs.

“When you reduce the frequency of patients in the unit being moved, you decrease the chances of the breathing tube coming out accidentally,” Ridoré says. “By reducing unplanned extubations in the NICU, we can improve overall clinical outcomes, reduce length of stay, lower costs and improve patient satisfaction.”

When a breathing tube is accidentally dislodged, newborns can experience hypoxia (oxygen deficiency), abnormally high carbon dioxide levels in the blood, trauma to their airway, intraventricular hemorrhage (bleeding into the fluid-filled areas of the brain) and code events, among other adverse outcomes. What’s more, a patient with an unintended extubation can experience a nearly doubled hospital stay compared with the length of stay for newborns whose breathing tubes remain in their proper places. Each unplanned extubation can increase the cost of care by $36,000 per patient per admission.

To tackle this problem, Children’s National created the Stop Unintended Extubations “SUN” team. The team created a package of interventions for high-risk patients. Within one month, unintended extubations dropped from 1.18 events per 100 ventilator days to 0.59 events during the same time frame. And, within five months, that plummeted even further to 0.41 events per 100 ventilator days.

Their ultimate goal is to whittle that rate down even further to 0.3 events per 100 ventilator days, which has occurred sporadically. And the NICU notched up to 75 days between unintended extubations.

“Unintended extubation rates at Children’s National are lower than the median reported on various quality indices, but we know we can do more to enhance patient safety,” Ridoré says. ”Our SUN team will continue to address key drivers of this quality measure with the aim of consistently maintaining this rate at no more than 0.3 events per 100 ventilator days.”

Vittorio Gallo

How the environment helps to shape the brain

Vittorio Gallo

“The strength, duration and timing of environmental experience influences plasticity in brain circuitry, which is made up of communication cables called axons that link neurons throughout the brain and are coated by myelin, a fatty substance that helps nerve impulses speed from place to place,” says Vittorio Gallo, Ph.D., Chief Research Officer at Children’s National and senior study author.

Researchers have long known that babies of all kinds need to be exposed to rich, complex environments for optimal brain health and potential. Exposure to new sights, sounds and other sensory experiences appears to be critical for strengthening infants’ developing brains and encouraging smoothly running neural networks. Until recently, little was known about the biological mechanisms behind this phenomenon.

In a review article published online Aug. 22, 2017 in Trends in Neurosciences, Children’s National Health System researchers discuss the role of environmental stimuli on the development of myelin—the fatty insulation that surrounds the extensions that connect cells throughout the nervous system and make up a large part of the brain’s white matter. Positive influences, such as exposure to a large vocabulary and novel objects, can boost the growth of myelin. Conversely, negative influences, such as neglect and social isolation, can harm it, potentially altering the course of brain development.

“The strength, duration and timing of environmental experience influences plasticity in brain circuitry, which is made up of communication cables called axons that link neurons throughout the brain and are coated by myelin, a fatty substance that helps nerve impulses speed from place to place,” says Vittorio Gallo, Ph.D., Chief Research Officer at Children’s National and senior study author. “As it responds to environmental stimuli, the brain continually shores up myelin’s integrity. Just as important, damaged myelin can leave gaps in the neural network which can lead to cognitive, motor and behavioral deficits.”

According to Gallo and study lead author Thomas A. Forbes, a pool of oligodendrocyte progenitor cells (OPCs) specialize in making myelin and do so from childhood into adulthood. The resulting oligodendrocyte cells (OLs) form an important working partnership with axons. From approximately 23 to 37 weeks’ gestation, OLs develop in the fetal brain and they continue to be generated after birth until adolescence.

“This dynamic feedback loop between myelin plasticity and neuronal excitability is crucial,” Forbes says. “It helps to strengthen motor and cognitive function and permits children and adults to learn new skills and to record new memories.”

In utero, genetics plays an outsized role in the initial structure of white matter, which is located in the subcortical region of the brain and takes its white color from myelin, the lipid and protein sheath that electrically insulates nerve cells. Defects in the microstructural organization of white matter are associated with many neurodevelopmental disorders. Once infants are born, environmental experiences also can begin to exert a meaningful role.

“The environment can be viewed as a noninvasive therapeutic approach that can be employed to bolster white matter health, either on its own or working in tandem with pharmacologic therapies,” Gallo adds. “The question is how to design the best environment for infants and children to grow and to achieve the highest cognitive function. An enriched environment not only involves the opportunity to move and participate in physical exercise and physical therapy; it is also an environment where there is novelty, new experiences and continuously active learning. It is equally important to minimize social stressors. It’s all about the balance.”

Among the potential interventions to boost brain power, independent of socioeconomic status:

  • Exposing children to new and different objects with an opportunity for physical activity and interaction with a number of playmates. This type of setting challenges the child to continuously adapt to his or her surroundings in a social, physical and experiential manner. In experimental models, enriched environments supported brain health by increasing the volume and length of myelinated fibers, the volume of myelin sheaths and by boosting total brain volume.
  • Exposure to music helps with cognition, hearing and motor skills for those who play an instrument, tapping multiple areas of the brain to work together collaboratively. Diffusion tensor imaging (DTI) reveals that professional pianists who began playing as children have improved white matter integrity and plasticity, Gallo and Forbes
  • At its heart, active learning requires interacting with and adapting to the environment. Generating new OLs influences learning new motor skills in the very young as well as the very old. And cognitive training and stimulation shapes and preserves white matter integrity in the aging.
  • DTI studies indicate that four weeks of integrative mind-body training alters myelination and improves white matter efficiency with especially pronounced changes in the area of the brain responsible for self-regulation, impulse control and emotion.
  • Voluntary exercise in experimental models is associated with OPCs differentiating into mature OLs. Imaging studies show a positive relationship between physical fitness, white matter health and the brain networks involved in memory.

Conversely, such negative influences as premature birth, poor nutrition, disease, neglect and social isolation can degrade myelin integrity, compromising the person’s ability to carry out basic motor skills and cognitive function. Usually, the pool of OPCs expands as the fetus is about to be born. But brain injury, lack of oxygen and restricted blood supply can delay maturation of certain brain cells and can cause abnormalities in white matter that diminish the brain’s capacity to synthesize myelin. Additional white matter insults can be caused by use of anesthesia and stress, among other variables.

The environmental influence has the potential to be “the Archimedes’ Lever to appropriating WM development among a limited range of only partially efficacious treatment options,” the authors conclude.

mitochondria

Mitochondria key for repairing cell damage in DMD

mitochondria

A research team led by Jyoti K. Jaiswal, M.S.C., Ph.D., found that dysfunctional mitochondria prevent repair of muscle cells in Duchenne muscular dystrophy.

What’s known

Duchenne muscular dystrophy (DMD), one of the most severe forms of muscular dystrophy, is caused by a defect in the dystrophin gene. The protein that this gene encodes is responsible for anchoring muscle cells’ inner frameworks, or cytoskeletons, to proteins and other molecules outside these cells, the extracellular matrix. Without functional dystrophin protein, the cell membranes of muscle cells become damaged, and the cells eventually die. This cell death leads to the progressive muscle loss that characterizes this disease. Why these cells are unable to repair this progressive damage has been unknown.

What’s new

A research team led by Jyoti K. Jaiswal, M.S.C., Ph.D., a principal investigator in the Center for Genetic Medicine Research at Children’s National Health System, investigated this question in two experimental models of DMD that carry different mutations of the dystrophin gene. The researchers monitored the effects of the lack of functional dystrophin protein in these preclinical models on the level and function of muscle cell. They found that mitochondria – organelles that act as powerhouses to supply the chemical energy to drive cellular activities – are among the first to be affected. They found that the decline in mitochondrial level and activity over time in these experimental models preceded the onset of symptoms. The research team also looked at the ability of the experimental models’ muscle cells to repair damage. As the muscle cell mitochondria lost function, the cells’ ability to repair damage also declined. Efforts to increase mitochondrial activity after these organelles became dysfunctional did not improve muscle repair. This suggests that poor muscle repair may not be caused by a deficit in energy production by mitochondria.

Questions for future research

Q: Does similar mitochondrial dysfunction occur in human patients with DMD?
Q: How can the mitochondrial dysfunction be prevented?
Q: Is there a way to reverse mitochondrial dysfunction to better preserve the ability of muscle cells to repair from DMD-related damage?

Source: “Mitochondria mediate cell membrane repair and contribute to Duchenne muscular dystrophy.” Vila, M.C., S. Rayavarapu, M.W. Hogarth, J.H. Van der Meulen, A. Horn, A. Defour, S. Takeda, K.J. Brown, Y. Hathout, K. Nagaraju and J.K. Jaiswal. Published by Cell Death and Differentiation February 2017.

LCModel output from 32 GA baby

Understanding the long-term consequences of prematurity

LCModel output from 32 GA baby

Children’s National Health System researchers processed H1-MRS data using LCModel software to calculate absolute metabolite concentrations for N-acetyl-aspartate (NAA), choline (Cho) and creatine (Cr). Preterm infants had significantly lower cerebellar NAA (p=<0.025) and higher Cho (p=<0.001) when compared with healthy term-equivalent infants. The area of the brain within the red box is the cerebellum, the region of interest for this study.

Premature birth, a condition that affects approximately 10 percent of births in the United States, often is accompanied by health problems ranging from difficulties breathing and eating to long-term neurocognitive delays and disabilities. However, the reasons for these problems have been unclear.

In a study published online Aug. 15, 2017 in Scientific Reports, a team of Children’s National Health System clinician-researchers reports that prematurity is associated with altered metabolite profiles in the infants’ cerebellum, the part of the brain that controls coordination and balance. Pre-term infants in the study had significantly lower levels of a chemical marker of nerve cell integrity and significantly higher concentrations of a chemical marker of cellular membrane turnover.

“These data suggest that interrupting the developing fetal brain’s usual growth plan during gestation – which can occur through early birth, infection or experiencing brain damage – might trigger a compensatory mechanism. The infant’s brain tries to make up for lost time or heal injured tissue by producing a certain type of cells more quickly than it normally would,” says Catherine Limperopoulos, Ph.D., director of the Developing Brain Research Laboratory at Children’s National and senior study author. “The more sensitive imaging technique that we used also revealed nerve cell damage from brain injuries extends beyond the site of injury, a finding that contrasts with what is found through conventional magnetic resonance imaging (MRI).”

It has long been clear that prematurity – birth before 37 weeks gestation – is accompanied by a number of immediate and long-term complications, from potential problems breathing and feeding at birth to impairments in hearing and sight that can last throughout an individual’s life.

Neurocognitive developmental delays often accompany pre-term birth, many of which can have long-lasting consequences. Studies have shown that children born prematurely are more likely to struggle in school, have documented learning disabilities and experience significant delays in developing gross and fine motor skills compared with children born at full-term.

Several studies have investigated the root cause of these issues in the cerebrum, the structure that takes up the majority of the brain and is responsible for functions including learning and memory, language and communication, sensory processing and movement. However, the cerebellum – a part of the brain that plays an important role in motor control – has not received as much research attention.

In the new study, Limperopoulos and colleagues used a specialized MRI technique that allowed them to parse out differences in which molecules are present in the cerebellum of full-term infants compared with premature infants. Their findings show a variety of differences that could offer clues to explain developmental differences between these two populations – and potentially identify ways to intervene to improve outcomes.

The researchers recruited 59 premature infants, born at 32 or fewer weeks’ gestation, and 61 healthy, full-term infants. Each baby received a special type of MRI known as proton magnetic resonance spectroscopy, or H1-MRS, that measures the concentrations of particular molecules in the brain. The full-term infants had these MRIs shortly after birth; the pre-term infants had them at 39 to 41 weeks gestational age, or around the time that they would have been born had the pregnancy continued to term.

Looking specifically at the cerebellum, the researchers found that the pre-term infants overall had significantly lower concentrations of N-acetyl-aspartate (NAA), a marker of the integrity of nerve cells. They also had significantly higher concentrations of choline, a marker of cell membrane integrity and membrane turnover.

Concentrations of creatine, a marker of stores of cellular energy, were about the same overall between the two groups. However, the researchers found that brain injuries, which affected 35 of the pre-term infants but none of the full-term infants, were associated with significantly lower concentrations of NAA, choline and creatine. Having a neonatal infection, which affected 21 of the pre-term infants but none of the full-term ones, was associated with lower NAA and creatine.

The findings could offer insight into exactly what’s happening in the brain when infants are born pre-term and when these vulnerable babies develop infections or their brains become injured – conditions that convey dramatically higher risks for babies born too early, Limperopoulos says. The differences between the full-term babies and the pre-term ones reflect disturbances these cells are experiencing at a biochemical level, she explains.

Limperopoulos and colleagues note that more research will be necessary to connect these findings to what is already known about developmental problems in pre-term infants. Eventually, she says, scientists might be able to use this knowledge to develop treatments that might be able to change the course of brain development in babies born too early, getting them on track with infants born at term.

“We know that the bodies of pre-term infants demonstrate a remarkable ability to catch up with peers who were born at full-term, in terms of weight and height. Our challenge is to ensure that preemies’ brains also have an opportunity to develop as normally as possible to ensure optimal long-term outcomes,” Limperopoulos says.

Patricio Ray

Toward a better definition for AKI in newborns

Patricio Ray

The National Institute of Diabetes and Digestive and Kidney Diseases convened a meeting of expert neonatologists and pediatric nephrologists, including Dr. Patricio Ray, to review state-of-the-art knowledge about acute kidney injury in neonates and to evaluate the best method to assess these patients’ kidney function.

Each year, thousands of infants in the United States end up in neonatal intensive care units (NICUs) with acute kidney injury (AKI), a condition in which the kidneys falter in performing the critical role of filtering waste products and excess fluid from the blood to produce urine. Being able to identify neonates during the early stages of AKI is critical to doctors and clinician-scientists who treat and study this condition, explains Patricio Ray, M.D., a nephrologist at Children’s National Health System.

Without an accurate definition and early identification of newborns with AKI, it is difficult for doctors to limit the use of antibiotics or other medications that can be harmful to the kidneys. Neonates who have AKI should not receive large volumes of fluids, a treatment that can cause severe complications when the kidneys do not properly function.

Until recently, there was no standard definition for AKI, leaving doctors and researchers to develop their own guidelines. Lacking set criteria led to confusion, Dr. Ray says. For example, different studies estimating the percentage of infants in NICUs with AKI ranged from 8 percent to 40 percent, depending on which definition was used. In 2012, a group known as the Kidney Disease Improved Global Outcome (KDIGO) issued practice guidelines for AKI that provide a standard for doctors and researchers to follow. They focus largely on measuring the relative levels of serum creatinine, a protein produced by muscles that is filtered by the kidneys, and the amount of urine output, which typically declines in adults and older children with failing kidneys.

The problem with these guidelines, Dr. Ray explains, is they are not sensitive enough to identify newborns experiencing the early stages of AKI during the first week of life. Newborns can have high serum creatinine levels during the first week of life due to residual levels transferred from mothers through the placenta. Also, because their kidneys are immature, failure often can mean higher – not diminished – urine production.

In 2013, the National Institute of Diabetes and Digestive and Kidney Diseases, part of the National Institutes of Health, convened a meeting of leading neonatologists and pediatric nephrologists – including Dr. Ray – to review state-of-the-art knowledge about AKI in neonates and to evaluate the best manner to assess kidney function in these patients. They published a summary of their discussion online June 12, 2017 in Pediatric Research.

Among other findings, the group concluded that the current definition of AKI lacks the sensitivity needed to identify the early stages of AKI in neonates’ first week of life. They also said that more research was needed to fill this gap.

That’s where Dr. Ray’s current research comes in. Working with fellow Children’s Nephrologist Charu Gupta, M.D., and Children’s Neonatologist An Massaro, M.D., the three clinician-scientists reviewed the medical records of 106 infants born at term with a condition known as hypoxic ischemic encephalopathy (HIE), in which the brain doesn’t receive enough oxygen. Not only does this often lead to brain injury, but it also greatly increases the risk of AKI.

Because these babies had been followed closely in the NICU to assess the possibility of AKI, their serum creatinine had been checked frequently. The researchers found that about 69 percent of the infants with HIE followed at Children’s National never developed signs of kidney failure during their first week of life. These babies’ serum creatinine concentrations dropped by 50 percent or more by the time they were 1 week old, about the same as reported previously in healthy neonates. Another 12 percent of the infants with HIE developed AKI according to the definition established by the KDIGO group in 2012. These infants:

  • Required more days of mechanical ventilation and medications to increase their blood pressure
  • Had higher levels of antibiotics in their bloodstreams
  • Retained more fluid
  • Had lower urinary levels of a molecule that their kidneys should have been cleared and
  • Had to stay in the hospital longer

A third group of the infants with HIE, about 19 percent, did not meet the standard criteria for AKI. However, these babies had a rate of decline of serum creatinine that was significantly slower than the normal newborns and the infants with HIE who had excellent outcomes. Rather, their outcomes matched those of infants with established AKI.

Dr. Ray notes that by following the rate of serum creatinine decline during the first week of life physicians could identify neonates with impaired kidney function. This approach provides a more sensitive method to identify the early stages of AKI in neonates. “By looking at how fast babies were clearing their serum creatinine compared with the day they were born, we could predict how well their kidneys were working,” he says. Dr. Ray and colleagues published these findings July 2016 in Pediatric Nephrology.

He adds that further studies will be necessary to confirm the utility of this new approach to assess the renal function of term newborns with other diseases and preterm neonates. Eventually, he hopes this new approach will become uniform clinical practice.

Catherine Limperopoulos

A closer look at the placenta to predict FGR

Catherine Limperopoulos

Using three-dimensional magnetic resonance imaging, a Children’s National research team that included Catherine Limperopoulos, Ph.D., characterized the shape, volume, morphometry and texture of placentas during pregnancy and, using a novel framework, predicted with high accuracy which pregnancies would be complicated by fetal growth restriction.

Early in development, cells from the fertilized egg form the placenta, a temporary organ that serves as an interface between the mother and her growing offspring. When things go right, as occurs in the vast majority of pregnancies, the placenta properly delivers nutrients from the mother’s diet and oxygen from the air she breathes to the developing fetus while siphoning away its waste products. This organ also plays important immune-modulating and endocrine roles.

However, in a number of pregnancies, the placenta does not do an adequate job. Unable to effectively serve the fetus, a variety of adverse conditions can develop, including preeclampsia, fetal growth restriction (FGR), preterm birth and even fetal death.

Despite the key role that the placenta plays in fetal health, researchers have few non-invasive ways to assess how well it works during pregnancy. In fact, placental disease might not be suspected until very late.

In a new study, a team of Children’s National Health System research scientists is beginning to provide insights into the poorly understood placenta.

Using three-dimensional (3D) magnetic resonance imaging (MRI), the research team characterized the shape, volume, morphometry and texture of placentas during pregnancy and, using a novel framework, predicted with high accuracy which pregnancies would be complicated by FGR.

“When the placenta fails to carry out its essential duties, both the health of the mother and fetus can suffer and, in extreme cases, the fetus can die. Because there are few non-invasive tools that reliably assess the health of the placenta during pregnancy, unfortunately, placental disease may not be discovered until too late – after impaired fetal growth already has occurred,” says Catherine Limperopoulos, Ph.D., co-director of research in the Division of Neonatology at Children’s National Health System and senior author of the study published online July 22 in Journal of Magnetic Resonance Imaging. “Identifying early biomarkers of placental disease that may impair fetal growth and well-being open up brand-new opportunities to intervene to protect vulnerable fetuses.”

The Children’s research team acquired 124 fetal scans from 80 pregnancies beginning at the 18th gestational week and continuing through the 39th gestational week. Forty-six women had normal pregnancies and healthy fetuses while 34 women’s pregnancies were complicated by FGR, defined by estimated fetal weight that fell below the 10th percentile for gestational age. The placenta was described by a combination of shape and textural features. Its shape was characterized by three distinct 3D features: Volume, thickness and elongation. Its texture was evaluated by three different sets of textural features computed on the entire placenta.

“The proposed machine learning-based framework distinguished healthy pregnancies from FGR pregnancies with 86 percent accuracy and 87 percent specificity. And it estimated the birth weight in both healthy and high-risk fetuses throughout the second half of gestation reasonably well,” says the paper’s lead author, Sonia Dahdouh, Ph.D., a research fellow in Children’s Developing Brain Research Laboratory.

“We are helping to pioneer a very new frontier in fetal medicine,” Limperopoulos adds. “Other studies have developed prediction tools based on fetal brain features in utero. To our knowledge, this would be the first proposed framework for semi-automated diagnosis of FGR and estimation of birth weight using structural MRI images of the placental architecture in vivo. This has the potential to address a sizable clinical gap since we lack methods that are both sufficiently sensitive and specific to reliably detect FGR in utero.”

The research team writes that its findings underscore the importance of future studies on a larger group of patients to expand knowledge about underlying placenta mechanisms responsible for disturbed fetal growth, as well as to more completely characterize other potential predictors of fetal/placental development in high-risk pregnancies, such as genetics, physiology and nutrition.