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T2-Weighted Magnetic Resonance (MR) Imaging Brain Segmentation

Maternal mental health alters structure and biochemistry of developing fetal brain

Even when pregnant women have uncomplicated pregnancies and high socioeconomic status, when they experience elevated anxiety, stress or depression these prenatal stressors can alter the structure of the developing fetal brain and disrupt its biochemistry, according to Children’s National Hospital research published online Jan. 29, 2020, in JAMA Network Open.

The Children’s National research findings “have enormous scientific, clinical and public health implications,” Charles A. Nelson III, Ph.D.,  Boston Children’s Hospital, writes in a companion editorial.

“Previously we found that 65% of pregnant women who received a diagnosis of fetal congenital heart disease had elevated levels of stress. It’s concerning but not surprising that pregnant women who wonder if their baby will need open heart surgery would feel stress,” says Catherine Limperopoulos, Ph.D., director of the Center for the Developing Brain at Children’s National and the study’s senior author. “In this latest study, we ran the same panel of questionnaires and were surprised to find a high proportion of otherwise healthy pregnant women whose unborn babies are doing well also report high levels of stress.”

Anxiety and depression are the most common mental health problems during pregnancy. To learn more about the implications for the developing fetal brain, the Children’s National research team recruited 119 healthy volunteers with low-risk pregnancies from obstetric clinics in Washington, D.C., from Jan. 1, 2016, to April 17, 2019. The women’s mean age was 34.4 years old. All were high school graduates, 83% were college graduates, and 84% reported professional employment.

T2-Weighted Magnetic Resonance (MR) Imaging Brain Segmentation.

T2-Weighted Magnetic Resonance (MR) Imaging Brain Segmentation. Segmentation results of total brain (orange), cortical gray matter (green), white matter (blue), deep gray matter (brown), brainstem (yellow), cerebellum (light blue), left hippocampus (purple) and right hippocampus (red) on a 3-Dimensional reconstructed T2-weighted MR image of a fetus at 26.4 gestational weeks. The hippocampus plays a central role in memory and behavioral inhibition and contains high concentrations of corticosteroid receptors and, thus, this brain region is sensitive to stress. Credit: JAMA Network Open.

The team performed 193 fetal brain magnetic resonance imaging (MRI) sessions between 24-40 weeks gestation and measured the volume of the total fetal brain as well as the cortical gray matter, white matter, deep gray matter, cerebellum, brainstem and hippocampus volumes. On the same day as their MRI visit, the pregnant women completed validated questionnaires to measure maternal stress, anxiety and depression, answering questions such as “how do you feel right now,” “how do you generally feel” as well as the degree of stressful feelings they experienced the month prior.

Of the pregnant women in the study:

  • 27% tested positive for stress
  • 26% tested positive for anxiety
  • 11% tested positive for depression
  • Maternal anxiety and stress were associated with increased fetal cortical gyrification
  • Elevated maternal depression was associated with decreased creatine and choline levels in the fetal brain
  • Maternal stress scores decreased with increasing gestational age, while anxiety and depression did not

“We report for the first time that maternal psychological distress may be associated with increased fetal local gyrification index in the frontal and temporal lobes,” says Yao Wu, Ph.D., a research associate working with Limperopoulos at Children’s National and the study’s lead author. “We also found an association with left fetal hippocampal volume, with maternal psychological distress selectively stunting the left hippocampal volumetric growth more than the right. And elevated maternal depression was associated with decreased creatine and choline levels in the fetal brain,” Wu adds.

Late in pregnancy – at the time these women were recruited into the cohort study – the fetal brain grows exponentially and key metabolite levels also rise. Creatine facilitates recycling of adenosine triphosphate, the cell’s energy currency. Typically, levels of this metabolite rise, denoting rapid changes and higher cellular maturation; creatine also is known to support cognitive function. Choline levels also typically rise, marking cell membrane turnover as new cells are generated and support memory, mental focus and concentration.

“These women were healthy, and of high socioeconomic status and educational level, leading us to conclude that the prevalence of prenatal maternal psychological distress may be underestimated,” Limperopoulos adds. “While stress is an everyday reality for most of us, this is different because elevated stress during pregnancy can alter fetal brain programming. Our findings underscore the critical need to universally screen all pregnant women for prenatal psychological distress, even young mothers whose pregnancies wouldn’t otherwise raise red flags.”

In addition to Limperopoulos and Wu, Children’s National study co-authors include Yuan-Chiao Lu, Ph.D., research associate; Marni Jacobs, Ph.D., biostatistician; Subechhya Pradhan, Ph.D., research faculty; Kushal Kapse, MS, staff engineer; Li Zhao, Ph.D., research faculty; Nickie Niforatos-Andescavage, M.D., neonatologist; Gilbert Vezina, M.D., director of the neuroradiology program; and Adré  J. du Plessis, M.B.Ch.B., director, Fetal Medicine Institute. Research coordinators Catherine Lopez, MS, Kathryn Lee Bannantine, BSN, and Jessica Lynn Quistorff, MPH, assisted with subject recruitment.

Financial support for the research described in this post was provided by the National Institutes of Health under grant No. RO1 HL116585-01 and the Thrasher Research Fund under Early Career award No. 14764.

Journal Reference:
Yao Wu, Yuan-Chiao Lu, Marni Jacobs, Subechhya Pradhan, Kushal Kapse, Li Zhao, Nickie Niforatos-Andescavage, Gilbert Vezina, Adré J. du Plessis, Catherine Limperopoulos. “Association of prenatal maternal psychological distress with fetal brain growth, metabolism and cortical maturation,” JAMA Network Open, 3(1): e1919940, 2020

Catherine Limperopoulos

Stressful pregnancies can leave fingerprint on fetal brain

Catherine Limperopoulos

“We were alarmed by the high percentage of pregnant women with a diagnosis of a major fetal heart problem who tested positive for stress, anxiety and depression,” says Catherine Limperopoulos, Ph.D., director of the Center for the Developing Brain at Children’s National and the study’s corresponding author.

When a diagnosis of fetal congenital heart disease causes pregnant moms to test positive for stress, anxiety and depression, powerful imaging can detect impaired development in key fetal brain regions, according to Children’s National Hospital research published online Jan. 13, 2020, in JAMA Pediatrics.

While additional research is needed, the Children’s National study authors say their unprecedented findings underscore the need for universal screening for psychological distress as a routine part of prenatal care and taking other steps to support stressed-out pregnant women and safeguard their newborns’ developing brains.

“We were alarmed by the high percentage of pregnant women with a diagnosis of a major fetal heart problem who tested positive for stress, anxiety and depression,” says Catherine Limperopoulos, Ph.D., director of the Center for the Developing Brain at Children’s National and the study’s corresponding author. “Equally concerning is how prevalent psychological distress is among pregnant women generally. We report for the first time that this challenging prenatal environment impairs regions of the fetal brain that play a major role in learning, memory, coordination, and social and behavioral development, making it all the more important for us to identify these women early during pregnancy to intervene,” Limperopoulos adds.

Congenital heart disease (CHD), structural problems with the heart, is the most common birth defect. Still, it remains unclear how exposure to maternal stress impacts brain development in fetuses with CHD.

The multidisciplinary study team enrolled 48 women whose unborn fetuses had been diagnosed with CHD and 92 healthy women with uncomplicated pregnancies. Using validated screening tools, they found:

  • 65% of pregnant women expecting a baby with CHD tested positive for stress
  • 27% of women with uncomplicated pregnancies tested positive for stress
  • 44% of pregnant women expecting a baby with CHD tested positive for anxiety
  • 26% of women with uncomplicated pregnancies tested positive for anxiety
  • 29% of pregnant women expecting a baby with CHD tested positive for depression and
  • 9% women with uncomplicated pregnancies tested positive for depression

All told, they performed 223 fetal magnetic resonance imaging sessions for these 140 fetuses between 21 and 40 weeks of gestation. They measured brain volume in cubic centimeters for the total brain as well as volumetric measurements for key regions such as the cerebrum, cerebellum, brainstem, and left and right hippocampus.

Maternal stress and anxiety in the second trimester were associated with smaller left hippocampi and smaller cerebellums only in pregnancies affected by fetal CHD. What’s more, specific regions — the hippocampus head and body and the left cerebellar lobe – were more susceptible to stunted growth. The hippocampus is key to memory and learning, while the cerebellum controls motor coordination and plays a role in social and behavioral development.

The hippocampus is a brain structure that is known to be very sensitive to stress. The timing of the CHD diagnosis may have occurred at a particularly vulnerable time for the developing fetal cerebellum, which grows faster than any other brain structure in the second half of gestation, particularly in the third trimester.

“None of these women had been screened for prenatal depression or anxiety. None of them were taking medications. And none of them had received mental health interventions. In the group of women contending with fetal CHD, 81% had attended college and 75% had professional educations, so this does not appear to be an issue of insufficient resources,” Limperopoulos adds. “It’s critical that we routinely to do these screenings and provide pregnant women with access to interventions to lower their stress levels. Working with our community partners, Children’s National is doing just that to help reduce toxic prenatal stress for both the health of the mother and for the future newborns. We hope this becomes standard practice elsewhere.”

Adds Yao Wu, Ph.D., a research associate working with Limperopoulos at Children’s National and the study’s lead author: “Our next goal is exploring effective prenatal cognitive behavioral interventions to reduce psychological distress felt by pregnant women and improve neurodevelopment in babies with CHD.”

In addition to Limperopoulos and Wu , Children’s National study co-authors include Kushal Kapse, MS, staff engineer; Marni Jacobs, Ph.D., biostatistician; Nickie Niforatos-Andescavage, M.D., neonatologist; Mary T. Donofrio, M.D., director, Fetal Heart Program; Anita Krishnan, M.D., associate director, echocardiography; Gilbert Vezina, M.D., director, Neuroradiology Program; David Wessel, M.D., Executive Vice President and Chief Medical Officer; and Adré  J. du Plessis, M.B.Ch.B., director, Fetal Medicine Institute. Jessica Lynn Quistorff, MPH, Catherine Lopez, MS, and Kathryn Lee Bannantine, BSN, assisted with subject recruitment and study coordination.

Financial support for the research described in this post was provided by the National Institutes of Health under grant No. R01 HL116585-01 and the Thrasher Research Fund under Early Career award No. 14764.

doctor checking pregnant woman's belly

Novel approach to detect fetal growth restriction

doctor checking pregnant woman's belly

Morphometric and textural analyses of magnetic resonance imaging can point out subtle architectural deviations associated with fetal growth restriction during the second half of pregnancy, a first-time finding that has the promise to lead to earlier intervention.

Morphometric and textural analyses of magnetic resonance imaging (MRI) can point out subtle architectural deviations that are associated with fetal growth restriction (FGR) during the second half of pregnancy. The first-time finding hints at the potential to spot otherwise hidden placental woes earlier and intervene in a more timely fashion, a research team led by Children’s National Hospital faculty reports in Pediatric Research.

“We found reduced placental size, as expected, but also determined that the textural metrics are accelerated in FGR when factoring in gestational age, suggesting premature placental aging in FGR,” says Nickie Andescavage, M.D., a neonatologist at Children’s National and the study’s lead author. “While morphometric and textural features can discriminate placental differences between FGR cases with and without Doppler abnormalities, the pattern of affected features differs between these sub-groups. Of note, placental insufficiency with abnormal Doppler findings have significant differences in the signal-intensity metrics, perhaps related to differences of water content within the placenta.”

The placenta, an organ shared by the pregnant woman and the developing fetus, delivers oxygen and nutrients to the developing fetus and ferries away waste products. Placental insufficiency is characterized by a placenta that develops poorly or is damaged, impairing blood flow, and can result in still birth or death shortly after birth. Surviving infants may be born preterm or suffer early brain injury; later in life, they may experience cardiovascular, metabolic or neuropsychiatric problems.

Because there are no available tools to help clinicians identify small but critical changes in placental architecture during pregnancy, placental insufficiency often is found after some damage is already done. Typically, it is discovered when FGR is diagnosed, when a fetus weighs less than 9 of 10 fetuses of the same gestational age.

“There is a growing appreciation for the prenatal origin of some neuropsychiatric disorders that manifest years to decades later. Those nine months of gestation very much define the breath of who we later become as adults,” says Catherine Limperopoulos, Ph.D., director of MRI Research of the Developing Brain at Children’s National and the study’s senior author. “By identifying better biomarkers of fetal distress at an earlier stage in pregnancy and refining our imaging toolkit to detect them, we set the stage to be able to intervene earlier and improve children’s overall outcomes.”

The research team studied 32 healthy pregnancies and compared them with 34 pregnancies complicated by FGR. These women underwent up to two MRIs between 20 weeks to 40 weeks gestation. They also had abdominal circumference, fetal head circumference and fetal femur length measured as well as fetal weight estimated.

In pregnancies complicated by FGR, placentas were smaller, thinner and shorter than uncomplicated pregnancies and had decreased placental volume. Ten of 13 textural and morphometric features that differed between the two groups were associated with absolute birth weight.

“Interestingly, when FGR is diagnosed in the second trimester, placental volume, elongation and thickness are significantly reduced compared with healthy pregnancies, whereas the late-onset of FGR only affects placental volume,” Limperopoulos adds. “We believe with early-onset FGR there is a more significant reduction in the developing placental units that is detected by gross measures of size and shape. By the third trimester, the overall shape of the placenta seems to have been well defined so that primarily volume is affected in late-onset FGR.”

In addition to Dr. Andescavage and Limperopoulos, study co-authors include Sonia Dahdouh, Sayali Yewale, Dorothy Bulas, M.D., chief of the Division of Diagnostic Imaging and Radiology, and Biostatistician, Marni Jacobs, Ph.D., MPH, all of Children’s National; Sara Iqbal, of MedStar Washington Hospital Center; and Ahmet Baschat, of Johns Hopkins Center for Fetal Therapy.

Financial support for research described in this post was provided by the National Institutes of Health under award number 1U54HD090257, R01-HL116585, UL1TR000075 and KL2TR000076, and the Clinical-Translational Science Institute-Children’s National.

Test tube with DNA

“Liquid biopsies” could track diffuse midline gliomas

Test tube with DNA

A multi-institutional team led by researchers at Children’s National in Washington, D.C., developed and tested “liquid biopsy,” a measure of circulating tumor DNA in patients’ cerebrospinal fluid and blood plasma. They show that quantifying the amount of circulating tumor DNA possessing key mutations characteristic of diffuse midline gliomas could reliably predict the tumors’ response to radiotherapy.

Diffuse midline gliomas are rare, diagnosed in fewer than 800 Americans every year, the majority of whom are children. These cancers arise in the cellular “glue” that holds the brain and spinal cord’s neurons together, grow swiftly and have no cure. About half of patients with these cancers, including diffuse intrinsic pontine glioma, die within one year of diagnosis.

Clinical trials are increasingly investigating new treatments that could offer hope for patients and their families. Yet, thus far, there have been few ways to track the progression of these conditions, offering little insight on whether a treatment is hitting its intended goal.

To solve this problem, a multi-institutional team led by researchers at Children’s National in Washington, D.C., developed and tested “liquid biopsy,” a measure of circulating tumor DNA in patients’ cerebrospinal fluid and blood plasma. They show that quantifying the amount of circulating tumor DNA possessing key mutations characteristic of these cancers could reliably predict the tumors’ response to radiotherapy. The scientists published their results online Oct. 15, 2018, in Clinical Cancer Research.

“We heard from our clinician colleagues that many kids were coming in and their magnetic resonance imaging (MRI) suggested a particular type of tumor. But it was always problematic to identify the tumor’s molecular subtype,” says Javad Nazarian, Ph.D., MSC, a principal investigator in Children’s Center for Genetic Medicine Research. “Our colleagues wanted a more accurate measure than MRI to find the molecular subtype. That raised the question of whether we could actually look at their blood to determine the tumor subtype.”

Children’s liquid biopsy, which remains at the research phase, starts with a simple blood draw using the same type of needle as is used when people donate blood. When patients with brain tumors provide blood for other laboratory testing, a portion of it is used for the DNA detective work. Just as a criminal leaves behind fingerprints, tumors shed telltale clues in the blood. The team at Children’s National searches for the histone 3K27M (H3K27M), a mutation associated with worse clinical outcomes.

“With liquid biopsy, we were able to detect a few copies of tumor DNA that were hiding behind a million copies of healthy DNA,” Nazarian says. “The blood draw and liquid biopsy complement the MRI. The MRI gives the brain tumor’s ZIP code. Liquid biopsy gives you the demographics within that ZIP code.”

Working with collaborators around the nation, Children’s National continues to refine the technology to improve its accuracy.

Even though this research technique is in its infancy, the rapid, cheap and sensitive technology already is being used by people around the globe.

“People around the world are sending blood to us, looking for this particular mutation, H3K27M,” says Lindsay B. Kilburn, M.D., a neurooncologist, principal investigator at Children’s National for the Pacific Pediatric Neuro-Oncology Consortium, and study co-author. “In many countries or centers children to not have access to teams experienced in taking a biopsy of tumors in the brainstem, they can perform a simple blood draw and have that blood processed and analyzed by us. In only a few days, we can provide important molecular information on the tumor subtype previously only available to patients who had undergone a tumor biopsy.”

With that DNA finding, physicians can make more educated therapeutic decisions, including prescribing medications that could not have been given previously, Nazarian adds.

In addition to Nazarian and Dr. Kilburn, study co-authors include Eshini Panditharatna, Madhuri Kambhampati, Heather Gordish-Dressman, Ph.D., Suresh N. Magge, M.D., John S. Myseros, M.D., Eugene I. Hwang, M.D., and Roger J. Packer, M.D., all of Children’s National; Mariam S. Aboian, Nalin Gupta, Soonmee Cha, Michael Prados and Co-Senior Author Sabine Mueller, all of University of California, San Francisco; Cassie Kline, UCSF Benioff Children’s Hospital;  John R. Crawford, UC San Diego; Katherine E. Warren, National Cancer Institute; Winnie S. Liang and Michael E. Berens, Translational Genomics Research Institute; and Adam C. Resnick, Children’s Hospital of Philadelphia.

Financial support for the research described in the report was provided by the V Foundation for Cancer Research, Goldwin Foundation, Pediatric Brain Tumor Foundation, Smashing Walnuts Foundation, The Gabriella Miller Kids First Data Resource Center, Zickler Family Foundation, Clinical and Translational Science Institute at Children’s National under award 5UL1TR001876-03, Piedmont Community Foundation, Musella Foundation for Brain Tumor Research, Mathew Larson Foundation, The Lilabean Foundation for Pediatric Brain Cancer Research, The Childhood Brain Tumor Foundation, the National Institutes of Health and American Society of Neuroradiology.

zika virus

Neuroimaging essential for Zika cases

zika virus

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

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

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

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

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

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

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

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

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

Early lipids in micropreemies’ diets can boost brain growth

preterm brain scans

Segmentation of a preterm brain T2-weighted MRI image at 30 gestational weeks [green=cortical grey matter; blue=white matter; grey=deep grey matter; cyan=lateral ventricle; purple=cerebellum; orange=brainstem; red=hippocampus; yellow=cerebrospinal fluid].

Dietary lipids, already an important source of energy for tiny preemies, also provide a much-needed brain boost by significantly increasing global brain volume as well as increasing volume in regions involved in motor activities and memory, according to research presented during the Pediatric Academic Societies 2019 Annual Meeting.

“Compared with macronutrients like carbohydrates and proteins, lipid intake during the first month of life is associated with increased overall and regional brain volume for micro-preemies,” says Catherine Limperopoulos, Ph.D., director of MRI Research of the Developing Brain at Children’s National and senior author. “Using non-invasive magnetic resonance imaging, we see increased volume in the cerebellum by 2 weeks of age. And at four weeks of life, lipids increase total brain volume and boost regional brain volume in the cerebellum, amygdala-hippocampus and brainstem.”

The cerebellum is involved in virtually all physical movement and enables coordination and balance. The amygdala processes and stores short-term memories. The hippocampus manages emotion and mood. And the brainstem acts like a router, passing messages from the brain to the rest of the body, as well as enabling essential functions like breathing, a steady heart rate and swallowing.

According to the Centers for Disease Control and Prevention, about 1 in 10 U.S. babies is born preterm, or before 37 weeks gestation. Regions of the brain that play vital roles in complex cognitive and motor activities experience exponential growth late in pregnancy, making the developing brains of preterm infants particularly vulnerable to injury and impaired growth.

Children’s research faculty examined the impact of lipid intake in the first month of life on brain volumes for very low birth weight infants, who weighed 1,500 grams or less at birth. These micro-preemies are especially vulnerable to growth failure and neurocognitive impairment after birth.

The team enrolled 68 micro-preemies who were 32 weeks gestational age and younger when they were admitted to Children’s neonatal intensive care unit during their first week of life. They measured cumulative macronutrients – carbohydrates, proteins, lipids and calories – consumed by these newborns at 2 and 4 weeks of life. Over years, Limperopoulos’ lab has amassed a large database of babies who were born full-term; this data provides unprecedented insights into normal brain development and will help to advance understanding of brain development in high-risk preterm infants.

“Even after controlling for average weight gain and other health conditions, lipid intake was positively associated with cerebellar and brainstem volumes in very low birthweight preterm infants,” adds Katherine M. Ottolini, the study’s lead author.

According to Limperopoulos, Children’s future research will examine the optimal timing and volume of lipids to boost neurodevelopment for micro-preemies.

Pediatric Academic Societies 2019 Annual Meeting presentation

  • “Early lipid intake improves brain growth in premature infants.”
    • Saturday, April 27, 2019, 1:15-2:30 p.m. (EST)

Katherine M. Ottolini, lead author; Nickie Andescavage, M.D., Attending, Neonatal-Perinatal Medicine and co-author; Kushal Kapse, research and development staff engineer and co-author; and Catherine Limperopoulos, Ph.D., director of MRI Research of the Developing Brain and senior author, all of Children’s National.

An-Massaro

Looking for ‘help’ signals in the blood of newborns with HIE

An Massaro

“This data support our hypothesis that a panel of biomarkers – not a one-time test for a single biomarker – is needed to adequately determine the risk and timing of brain injury for babies with HIE,” says An N. Massaro, M.D.

Measuring a number of biomarkers over time that are produced as the body responds to inflammation and injury may help to pinpoint newborns who are more vulnerable to suffering lasting brain injury due to disrupted oxygen delivery and blood flow, according to research presented during the Pediatric Academic Societies 2019 Annual Meeting.

Hypoxic-ischemic encephalopathy (HIE) happens when blood and oxygen flow are disrupted around the time of birth and is a serious birth complication for full-term infants. To lessen the chance of these newborns suffering permanent brain injury, affected infants undergo therapeutic cooling, which temporarily lowers their body temperatures.

“Several candidate blood biomarkers have been investigated in HIE but we still don’t have one in clinical use.  We need to understand how these markers change over time before we can use them to direct care in patients,” says An N. Massaro, M.D., co-director of the Neonatal Neurocritical Care Program at Children’s National and the study’s senior author. “The newborns’ bodies sent out different ‘help’ signals that we detected in their bloodstream, and the markers had strikingly different time courses. A panel of plasma biomarkers has the potential to help us identify infants most in need of additional interventions, and to help us understand the most optimal timing for those interventions.”

Past research has keyed in on inflammatory cytokines and Tau protein as potential biomarkers of brain injury for infants with HIE who are undergoing therapeutic cooling. The research team led by Children’s faculty wanted to gauge which time periods to measure such biomarkers circulating in newborns’ bloodstreams. They enrolled 85 infants with moderate or severe HIE and tapped unused blood specimens that had been collected as cooling began, as well as 12, 24, 72 and 96 hours later. The infants’ mean gestational age was 38.7 weeks, their mean birth weight was about 7 pounds (3.2 kilograms), and 19% had severe brain disease (encephalopathy).

Cytokines – chemicals like Interleukin (IL) 6, 8 and 10 that regulate how the body responds to infection, inflammation and trauma – peaked in the first 24 hours of cooling for most of the newborns. However, the highest measure of Tau protein for the majority of newborns was during or after the baby’s temperature was restored to normal.

“After adjusting for clinical severity of encephalopathy and five-minute Apgar scores, IL-6, IL-8 and IL-10 predicted adverse outcomes, like severe brain injury or death, as therapeutic hypothermia began. By contrast, Tau protein measurements predicted adverse outcomes during and after the infants were rewarmed,” Dr. Massaro says.

IL-6 and IL-8 proteins are pro-inflammatory cytokines while IL-10 is considered anti-inflammatory.  These chemicals are released as a part of the immune response to brain injury. Tau proteins are abundant in nerve cells and stabilize microtubules.

“This data support our hypothesis that a panel of biomarkers – not a one-time test for a single biomarker – is needed to adequately determine the risk and timing of brain injury for babies with HIE,” she adds.

Pediatric Academic Societies 2019 Annual Meeting presentation

  • “Serial plasma biomarkers of brain injury in infants with hypoxic ischemic encephalopathy (HIE) treated with therapeutic hypothermia (TH).”
    • Saturday, April 27, 2019, 6 p.m. (EST)

Meaghan McGowan, lead author; Alexandra C. O’Kane, co-author; Gilbert Vezina, M.D.,  director, Neuroradiology Program and co-author; Tae Chang, M.D., director, Neonatal Neurology Program and co-author; and An N. Massaro, M.D., co-director of the Neonatal Neurocritical Care Program and senior author; all of Children’s National; and co-author Allen Everett, of Johns Hopkins School of Medicine.

Stat Madness 2019

Vote for Children’s National in STAT Madness

Stat Madness 2019

Children’s National Health System has been selected to compete in STAT Madness for the second consecutive year. Our entry for the bracket-style competition is “Sensitive liquid biopsy platform to detect tumor-released mutated DNA using patient blood and CSF,” a new technique that will allow kids to get better treatment for an aggressive type of pediatric brain tumor.

In 2018, Children’s first-ever STAT Madness entry advanced through five brackets in the national competition and, in the championship round, finished second. That innovation, which enables more timely diagnoses of rare diseases and common genetic disorders, helping to improve kids’ health outcomes around the world, also was among four “Editor’s Pick” finalists, entries that spanned a diverse range of scientific disciplines.

“Children’s National researchers collaboratively work across divisions and departments to ensure that innovations discovered in our laboratories reach clinicians in order to improve patient care,” says Mark Batshaw, M.D., Children’s Executive Vice President, Chief Academic Officer and Physician-in-Chief. “It’s gratifying that Children’s multidisciplinary approach to improving the lives of children with brain tumors has been included in this year’s STAT Madness competition.”

Pediatric brain cancers are the leading cause of cancer-related death in children younger than 14. Children with tumors in their midline brain structures have the worst outcomes, and kids diagnosed with diffuse midline gliomas, including diffuse intrinsic pontine glioma, have a median survival of just 12 months.

“We heard from our clinician colleagues that many kids were coming in and their magnetic resonance imaging (MRI) suggested a particular type of tumor. But it was always problematic to identify the tumor’s molecular subtype,” says Javad Nazarian, Ph.D., MSC, a principal investigator in Children’s Center for Genetic Medicine Research. “Our colleagues wanted a more accurate measure than MRI to find the molecular subtype. That raised the question of whether we could actually look at their blood to determine the tumor subtype.”

Children’s liquid biopsy, which remains at the research phase, starts with a simple blood draw using the same type of needle as is used when people donate blood. When patients with brain tumors provide blood for other laboratory testing, a portion of it is used for the DNA detective work. Just as a criminal leaves behind fingerprints, tumors shed telltale clues in the blood. The Children’s team searches for the histone 3.3K27M (H3K27M), a mutation associated with worse clinical outcomes.

“With liquid biopsy, we were able to detect a few copies of tumor DNA that were hiding behind a million copies of healthy DNA,” Nazarian says. “The blood draw and liquid biopsy complement the MRI. The MRI gives the brain tumor’s ZIP code. Liquid biopsy gives you the demographics within that ZIP code.”

Working with collaborators around the nation, Children’s National continues to refine the technology to improve its accuracy. The multi-institutional team published findings online Oct. 15, 2018, in Clinical Cancer Research.

Even though this research technique is in its infancy, the rapid, cheap and sensitive technology already is being used by people around the globe.

“People around the world are sending blood to us, looking for this particular mutation, H3K27M, ” says Lindsay B. Kilburn, M.D., a Children’s neurooncologist, principal investigator at Children’s National for the Pacific Pediatric Neuro-Oncology Consortium, and study co-author. “In many countries or centers, children do not have access to teams experienced in taking a biopsy of tumors in the brainstem, they can perform a simple blood draw and have that blood processed and analyzed by us. In only a few days, we can provide important molecular information on the tumor subtype previously only available to patients that had undergone a tumor biopsy.”

“With that DNA finding, physicians can make more educated therapeutic decisions, including prescribing medications that could not have been given previously,” Nazarian adds.

The STAT Madness round of 64 brackets opened March 4, 2019, and the championship round voting concludes April 5 at 5 p.m. (EST).

In addition to Nazarian and Dr. Kilburn, study co-authors include Eshini Panditharatna, Madhuri Kambhampati, Heather Gordish-Dressman, Ph.D., Suresh N. Magge, M.D., John S. Myseros, M.D., Eugene I. Hwang, M.D. and Roger J. Packer, M.D., all of Children’s National; Mariam S. Aboian, Nalin Gupta, Soonmee Cha, Michael Prados and Co-Senior Author Sabine Mueller, all of University of California, San Francisco; Cassie Kline, UCSF Benioff Children’s Hospital; John R. Crawford, UC San Diego; Katherine E. Warren, National Cancer Institute; Winnie S. Liang and Michael E. Berens, Translational Genomics Research Institute; and Adam C. Resnick, Children’s Hospital of Philadelphia.

Financial support for the research described in the report was provided by the V Foundation for Cancer Research, Goldwin Foundation, Pediatric Brain Tumor Foundation, Smashing Walnuts Foundation, The Gabriella Miller Kids First Data Resource Center, Zickler Family Foundation, Clinical and Translational Science Institute at Children’s National under award 5UL1TR001876-03, Piedmont Community Foundation, Musella Foundation for Brain Tumor Research, Matthew Larson Foundation, The Lilabean Foundation for Pediatric Brain Cancer Research, The Childhood Brain Tumor Foundation, the National Institutes of Health and American Society of Neuroradiology.

Dr. Benjamin Martin examines a patient

Understanding Legg-Calvé-Perthes disease

Dr. Benjamin Martin examines a patient

Legg-Calvé-Perthes disease, which affects between five and 10 of every 100,000 children each year, is so rare that it can sometimes be challenging for clinicians to know how best to care for affected patients.

That’s why in 2011 a group of pediatric orthopaedic specialists led by Texas Scottish Rite Children’s Hospital created an international study group dedicated to using research to improve the care of kids with Perthes, a hip disorder characterized by a loss of blood flow to the immature femoral head. Children’s National orthopaedic surgeon Benjamin Martin, M.D., has participated in the group since its launch.

Recently, Dr. Martin and two study group colleagues published a review study that outlines common imaging modalities used in the diagnosis and treatment of Perthes disease.

“There are many imaging options out there, including recent advances in MRI, that can add to our knowledge of the disease and how to treat it so kids have optimal outcomes,” Dr. Martin says. “Our goal was to review what’s out there, how it’s used, and identify any shortcomings of these approaches for this particular patient population.”

The authors note that imaging, in various forms, has been a crucial contributor to understanding and treatment of this disease since it was first discovered. Today, radiography remains the most common imaging technique used to diagnose and follow Perthes over time. However, some MRI applications may offer additional insight into the disorder.

Perfusion MRI allows for early understanding of extent of disease and perfusion patterns may correlate with outcomes. Diffusion weighted imaging (DWI) MRI is another promising avenue for tracking disease progression. Additionally, dynamic MRI might provide range of motion assessments that could be used in the surgical planning process.

This study was one of a handful that the international Perthes group has published so far, with several more currently under development. Exploring treatments and technology applications will enhance early diagnosis and treatment for Perthes, which is a crucial component of treatment success and improved quality of life for affected children.

Sarah Mulkey

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

Sarah Mulkey

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

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

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

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

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

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

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

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

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

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

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

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

Companion editorial: Revealing the effects of Zika

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

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

Chima Oluigbo examines a patient

Eradicating epilepsy with Visualase

Chima Oluigbo examines a patient

Chima Oluigbo, M.D., and his team are using Visualase to identify and eliminate seizure foci and provide patients with a minimally invasive procedure for treating epilepsy.

About one in 26 people will be diagnosed with epilepsy in their lifetime. That adds up to about 3.4 million people in the U.S., or about 1 percent of the population nationwide. This condition can have huge consequences on quality of life, affecting whether children will learn well in school, eventually drive a car, hold down a job or even survive into adulthood.

For most of those that develop epilepsy, medications can keep seizures in check. However, for about a third of patients, this strategy doesn’t work, says Chima Oluigbo, M.D., an attending neurosurgeon at Children’s National Health System. That’s when he and his team offer a surgical fix.

Epilepsy surgery has come a long way, Dr. Oluigbo explains. When he first began practicing in the early 2000s, most surgeries were open, he says – they involved making a long incision in the scalp that can span half a foot or more. After drilling out a window of skull that can be as long as five inches, surgeons had to dig through healthy brain to find the abnormal tissue and remove it.

Each part of this “maximally invasive” procedure can be traumatic on a patient, Dr. Oluigbo says. That leads to significant pain after the procedure, extended hospital stays of at least a week followed by a long recovery. There are also significant risks for neurological complications including stroke, weakness, paralysis, speech problems and more.

However, open surgery isn’t the only option for epilepsy surgery anymore. Several new minimally invasive alternatives are now available to patients and the most promising, Dr. Oluigbo says, is called Visualase. He and his team are the only surgeons in the region who perform this procedure.

In Visualase surgeries, Dr. Oluigbo and his colleagues start by making a tiny incision, about 5 millimeters, on the scalp. Through this opening, they bore an even tinier hole into the skull and thread a needle inside that’s about 1.6 millimeters wide. “The brain barely notices that it’s there,” he says.

The tip of this wire holds a laser. Once this tip is placed directly at the seizure foci – the cluster of nerve cells responsible for generating a seizure – the patient is placed in an intraoperative magnetic resonance imaging (MRI) device. There, after checking the tip’s precise placement, the surgeons turn the laser on. Heat from the laser eradicates the foci, which the surgeons can see in real time using MRI thermography technology. The margins of the destroyed tissue are well-defined, largely sparing healthy tissue.

After the wire is removed, the incision is closed with a single stitch, and patients go home the next day. The majority of patients are seizure free, with rates as high as 90 percent for some types of epilepsy, Dr. Oluigbo says. Although seizure-free rates are also high for open procedures, he adds, Visualase spares them many of open surgeries’ painful and difficult consequences.

“Having done both open surgeries and Visualase,” Dr. Oluigbo says, “I can tell you the difference is night and day.”

Although open procedures will still be necessary for some patients with particularly large foci that are close to the surface, Dr. Oluigbo says that Visualase is ideal for treating medication-resistant cases in which the foci are buried deep within the brain. A typical example is a condition called hypothalamic hamartoma, in which tumors on the hypothalamus lead to gelastic seizures, an unusual seizure type characterized by uncontrollable laughing. He also uses Visualase for another condition called tuberous sclerosis, in which waxy growths called tubers develop in the brain, and for cancerous and benign brain tumors.

It’s gratifying to be able to help these children become seizure-free for the rest of their lives, says Dr. Oluigbo – even more so with the numerous updates he receives from families telling him how much this procedure has improved their children’s lifestyle.

“Visualase has completely changed the way that we approach these patients,” Dr. Oluigbo says. “It’s extraordinary to see the effects that this one procedure can have on the quality of life for patients here at Children’s National.”

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.

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.

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.

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.

Javad Nazarian

Liquid biopsy spots aggressive brainstem cancer earlier

Javad Nazarian

A Children’s National research team led by Javad Nazarian, Ph.D., M.S.C., tested whether circulating tumor DNA in patients’ blood and cerebrospinal fluid would provide an earlier warning that pediatric brainstem tumors were growing.

A highly aggressive pediatric brain cancer can be spotted earlier and reliably by the genetic fragments it leaves in biofluids, according to a study presented by Children’s National Health System researchers at the Society for Neuro-Oncology (SNO) 2017 Annual Meeting. The findings may open the door to non-surgical biopsies and a new way to tell if these tumors are responding to treatment.

Children diagnosed with diffuse midline histone 3 K27M mutant (H3K27M) glioma face a poor prognosis with a median survival time of only nine months after the pediatric brainstem cancer is diagnosed. Right now, clinicians rely on magnetic resonance imaging (MRI) to gauge how tumors are growing, but MRI can miss very small changes in tumor size. The Children’s research team led by Javad Nazarian, Ph.D., M.S.C., scientific director of Children’s Brain Tumor Institute, tested whether circulating tumor DNA in patients’ blood and cerebrospinal fluid would provide an earlier warning that tumors were growing. Just as a detective looks for fingerprints left at a scene, the new genetic analysis technique can detect telltale signs that tumors leave behind in body fluids.

“We continue to push the envelope to find ways to provide hope for children and families who right now face a very dismal future. By identifying these tumors when they are small and, potentially more responsive to treatment, our ultimate aim is to help children live longer,” says Eshini Panditharatna, B.A., study lead author. “In addition, we are hopeful that the comprehensive panel of tests we are constructing could identify which treatments are most effective in shrinking these deadly tumors.”

The researchers collected biofluid samples from 22 patients with diffuse intrinsic pontine glioma (DIPG) who were enrolled in a Phase I, Pacific Pediatric Neuro-Oncology Consortium clinical trial. Upfront and longitudinal plasma samples were collected with each MRI at various stages of disease progression. The team developed a liquid biopsy assay using a sensitive digital droplet polymerase chain reaction system that precisely counts individual DNA molecules.

“We detected H3K27M, a major driver mutation in DIPG, in about 80 percent of cerebrospinal fluid and plasma samples,” Panditharatna says. “Similar to adults with central nervous system (CNS) cancers, cerebrospinal fluid of children diagnosed with CNS cancers has high concentrations of circulating tumor DNA. However, after the children underwent radiotherapy, there was a dramatic decrease in circulating tumor DNA for 12 of the 15 patients (80 percent) whose temporal plasma was analyzed.”

Nazarian, the study senior author adds: “Biofluids, like plasma and cerebrospinal fluid, are suitable media to detect and measure concentrations of circulating tumor DNA for this type of pediatric glioma. Liquid biopsy has the potential to complement tissue biopsies and MRI evaluation to provide earlier clues to how tumors are responding to treatment or recurring.”

Support for this liquid biopsy study was provided by the V Foundation, Goldwin Foundation, Pediatric Brain Tumor Foundation, Smashing Walnuts Foundation, the Zickler Family Foundation, the Piedmont Community Foundation, the Musella Foundation, the Mathew Larson Foundation and Brain Tumor Foundation for Children.

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.”

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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.

Spectral data shine light on placenta

preemie baby

A research project led by Subechhya Pradhan, Ph.D., aims to shed light on metabolism of the placenta, a poorly understood organ, and characterize early biomarkers of fetal congenital heart disease.

The placenta serves as an essential intermediary between a pregnant mother and her developing fetus, transporting in life-sustaining oxygen and nutrients, ferrying out waste and serving as interim lungs, kidneys and liver as those vital organs develop in utero.

While the placenta plays a vital role in supporting normal pregnancies, it remains largely a black box to science. A research project led by Subechhya Pradhan, Ph.D., and partially funded by a Clinical and Translational Science Institute Research Award aims to shed light on placenta metabolism and characterize possible early biomarkers of impaired placental function in fetal congenital heart disease (CHD), the most common type of birth defect.

“There is a huge information void,” says Pradhan, a research faculty member of the Developing Brain Research Laboratory at Children’s National Health System. “Right now, we do not have very much information about placenta metabolism in vivo. This would be one of the first steps to understand what is actually going on in the placenta at a biochemical level as pregnancies progress.”

The project Pradhan leads will look at the placentas of 30 women in the second and third trimesters of healthy, uncomplicated pregnancies and will compare them with placentas of 30 pregnant women whose fetuses have been diagnosed with CHD. As volunteers for a different study, the women are already undergoing magnetic resonance imaging, which takes detailed images of the placenta’s structure and architecture. The magnetic resonance spectroscopy scans that Pradhan will review show the unique chemical fingerprints of key metabolites: Choline, lipids and lactate.

Choline, a nutrient the body needs to preserve cellular structural integrity, is a marker of cell membrane turnover. Fetuses with CHD have higher concentrations of lactate in the brain, a telltale sign of a shortage of oxygen. Pradhan’s working hypothesis is that there may be differing lipid profiles and lactate levels in the placenta in pregnancies complicated by CHD.  The research team will extract those metabolite concentrations from the spectral scans to describe how they evolve in both groups of pregnant women.

“While babies born with CHD can undergo surgery as early as the first few days (or sometimes hours) of life to correct their hearts, unfortunately, we still see a high prevalence of neurodevelopmental impairments in infants with CHD. This suggests that neurological dysfunctional may have its origin in fetal life,” Pradhan says.

Having an earlier idea of which fetuses with CHD are most vulnerable has the potential to pinpoint which pregnancies need more oversight and earlier intervention.

Placenta spectral data traditionally have been difficult to acquire because the pregnant mother moves as does the fetus, she adds. During the three-minute scans, the research team will try to limit excess movement using a technique called respiratory gating, which tells the machine to synchronize image acquisition so it occurs in rhythm with the women’s breathing.