Advancements in fetal neurology—gleaning information about a baby's outcome from genetics and inflammatory markers before birth—are transforming the field of pediatric neurology, experts said recently at the annual meeting of the Child Neurology Society.
But as the science marches forward, new questions are being raised, and it is adding a new, complicated dynamic to discussions between families and physicians, some of whom might not feel comfortable in the role, they said.
The information that can be derived from the fetus regarding a baby's future development has led to an acceleration of fetal neurology programs and research, said Taeun Chang, MD, director of the Neonatal Neurology and Neonatal Critical Care Program at Children's National Hospital in Washington, DC.
“This is why you're seeing more and more fetal and neonatal neurology programs around the country, because we recognize that this is the wave of the future,” Dr. Chang said. “Why wait for something to happen if you already know it's going to happen?”
Sarah Mulkey, MD, PhD, director of the Fetal, Transitional and Neonatal Neurology Fellowship at Children's National, underscored the importance of the role of fetal neurologists.
“They have the unique ability to counsel expectant parents with not only the fetal neurologic diagnosis, but how these findings could impact their child at birth and as they get older.”
The key to a fetal neurology program are expertise in fetal neuroimaging—with ultrasonography and MRI—and a multidisciplinary approach, from genetics, neurosurgery, cardiology, infectious disease, among other disciplines.
“One of the challenging aspects of the field is that the brain is in a rapid period of growth and development during the prenatal period,” Dr. Mulkey said. “A challenge thus is ‘predicting’ how the brain will continue to grow and develop after the time point at which we first image it.”
Among recent findings her center has produced are how the “normal” reference ranges that are used can affect a potential diagnosis of fetal microcephaly, and how diagnoses and prognoses often changed after referral to Children's National by an obstetric provider for abnormality of the posterior fossa on prenatal ultrasound—demonstrating that “a proper evaluation of the posterior fossa requires MRI, and this can be done well in the fetal period and can make a difference for prenatal counseling and pregnancy management.”
Finding Missense Mutations
Elliott Sherr, MD, PhD, director of the Brain Development Research Program at the University of California, San Francisco, said that research is making it clear that genetics will be a crucial component to predicting outcomes at the fetal stage, giving vital guidance to families needing to make difficult decisions and helping clinicians tackle medical problems sooner.
“Right now, when you think about outcomes the way people judge outcomes, is based on brain imaging,” he said. “There are obviously limitations to one's ability to predict outcomes just based on imaging.”
He added, “I think that we're probably okay at predicting outcomes when they're fairly unfavorable based on imaging findings, but beyond that I think our ability is quite limited.”
In his talk, he issued a “clarion call” for further advancement in harnessing the potential of genetics in fetal neurology. “We really need to nail that down,” he said.
Dr. Scherr pointed to work his lab has done assessing the KIF1A gene, which encodes a protein that belongs to the family of kinesins that act as motors for microtubules. Children with mutations to the gene have demonstrated progressive cerebellar and cerebral atrophy. The mutations associated with the most severe impairments—Thr99 and Arg216—were located immediately adjacent to the ATP binding pocket, Dr. Sherr said.
“If you can't hydrolyze ATP, then the protein's not going to work and that's why you have these more severe mutations,” he said.
Researchers further performed an assay showing how the microtubules get moved along by the wild-type kinesins, but the mutant kinesins leave them frozen in place.
“In this case both a computational tool as well as protein-based assay... can really give us lots of information,” he said.
Researchers have also been able to glean insight into outcomes from the DDX3X gene, which is associated with a range of neurodevelopmental disorders. Analyzing mutations of the gene, they found that missense mutations were associated with a more severe disorder.
“The idea is that the disorder is more severe if you tweak the protein instead of causing the protein to be decreased by 50 percent, which would happen in the frameshift or nonsense mutations,” Dr. Sherr said. “The idea again is that these informatics tools can give us hints.”
Genetics, he said, can give earlier clues about conditions such as polymicrogyria (PMG) and others.
“PMG is not always readily observable on imaging, maybe not until the late 20s” in weeks of gestation, he said. “If you're trying to make a decision about whether to move forward with a pregnancy—and that's obviously a complicated issue—then at 21, 22 weeks when lots of families are making those decisions, there's not a lot of good imaging data.”
On another front, researchers are gaining new understanding from inflammatory markers and the placenta, said Jennifer Armstrong, MD, MPH, director of the Perinatal and Hemorrhagic Stroke Programs at the University of Colorado.
In a study she led, researchers found interleukin-6 (IL-6) in the fetal cord blood is associated with moderate to severe neurologic disability at six months and later in babies who were born after pre-term premature rupture of membrane.
“Cytokines do seem to play a role in these fetal inflammatory patterns we seen in the placenta and then ultimately in long-term neurological outcomes,” Dr. Armstrong said.
Findings suggest that the “fetal inflammatory response of the placenta and funisitis appears to be the number one pathologic association between adverse neurological outcomes and stroke,” Dr. Armstrong said.
The field needs more programs that follow children for longer after birth, she said.
“It's so critical that we have clinical programs that follow these babies and do these neurodevelopmental assessments, because many of the programs—if we even have them— only go up to two years,” she said. “And it's actually these more long-term neurocognitive, neurobehavioral effects that we are seeing and actually impact children into adulthood.”
Preventing pre-term births, developing neuroprotection when babies are born early and helping the brain of pre-term babies reach the potential of full-term births are challenges that remain for the field, she said. But the field has research challenges, she said.
“If anything goes wrong when it's being made, it has major implications both for the baby and for the mom,” Dr. Armstrong said. “And there's just so much that we still don't know about just normal placental development. And there is no other animal that has a placenta like the human placenta.”
The Difficult Conversations
Dr. Chang said that while advancements in fetal neurology have led to vital information being known earlier, they also mean difficult conversations between physicians and expectant families. General child neurologists are sometimes called upon to do these consults, and it can be daunting because of the sometimes blurry ethical terrain.
“Everyone has their own ethical compass and for the most part you can go through seeing one patient after another without feeling challenged by a patient or situation—but when you get into certain environments where there's high intensity in decision-making, especially critical decision making because there's a time limit or a fatality component to it, that's where often times you may hit your ethical wall,” she said.
“You have to have these things as an individual, as a physician ... sort of squared away in your own head, otherwise you end up reflecting your own issues on the families.” Someone who is not comfortable with these issues should probably not be practicing fetal neurology, she said.
“It's not about me,” Dr. Chang said. “It's providing the best information to the parents.”
Other tips for conversing with families in difficult fetal neurology cases are establishing the expectant mother and family goals. Have they already received information from other physicians, or from the internet? Do they just want information, or are they seeking help with making decisions? This insight should be elicited before or at the start of a consult with the assistance of genetic counselors, she said.
Going through this process can also help a physician observe how well an expectant mother or family is processing information and be used to set the tone and pace of the consultation, Dr. Chang said.
Importantly, physicians should not forget to tell families what they do not have to worry about. “I think as doctors we often go, ‘Oh, your baby is critically ill, they may die,’ and then at some point we think, ‘They're going to survive,’ but we often forget to tell the family that.”