NEONATAL ENCEPHALOPATHY: THE ROLE OF GENETICS IN ESTABLISHING CAUSATION

by Carrie Barber Uncategorized

In this blog, I’ll be reviewing the importance of considering genetic and metabolic disorders when evaluating neonatal encephalopathy or cerebral palsy cases.  I’ll review the features of genetic disorders that mimic encephalopathy, as well as offer recommendations specific to elements of the medical record to review when reviewing a case for merit.  Lastly, I’ll review findings in the newborn assessment that prompts suspicion for genetic causation.

Genetic conditions and metabolic disorders can mimic the signs and symptoms of neonatal encephalopathy.  In a genetically susceptible fetus (a fetus already affected by a genetic disorder), maternal infection (E.g., chorioamnionitis: an acute inflammation of the membranes and chorion of the placenta, typically due to a bacterial infection in the setting of ruptured membranes) and fetal hypoxia (inadequate oxygen supply) can compound the adverse outcomes for these newborns. 

Neonatal Encephalopathy and Hypoxic Ischemic Encephalopathy (HIE):  The recommendation is that these two terms not be used interchangeably as not all cases of neonatal encephalopathy are caused by hypoxia and ischemia (decreased blood flow).  Very few cases of cerebral palsy are due to severe hypoxia or ischemia at birth (CDC; MacLennan et al., 2015).   

  • Neonatal encephalopathy is defined as a syndrome of disturbed neurological function in the earliest days of life in the infant born at or after 35 weeks of gestation manifested by subnormal level of consciousness or seizures, often accompanied by difficulty initiating and maintaining respiration and depression of tone and reflexes (AAP, ACOG, 2019).
  • Neonatal encephalopathy is often mis-labeled as hypoxic ischemic encephalopathy (HIE) based on historical assumptions that all cases of neonatal encephalopathy are caused by HIE, therefore, termed HIE. This has resulted in the terms being used interchangeably (AAP, ACOG, 2019).

The Role of Genetics: Genetic susceptibility, along with the number, duration, severity and timing of insult (if applicable); gestational age; presence of fetal growth restriction; and placental function all affect cellular health and neonatal long-term outcome (AAP, ACOG, 2019).  There are multifactorial causes of neonatal encephalopathy.  Genetic causes of encephalopathy and cerebral palsy need to be considered when establishing causation.  Genetic variations are risk factors for cerebral palsy.  Examples include, but are not limited to, single nucleotide polymorphisms in genes involved in inflammation and coagulation.  Another example includes the allele of the apolipoprotein E gene associated with ischemic stroke (AAP, ACOG, 2019). The presence of variants of uncertain significance (VUS) in gene testing requires further evaluation which may include tracing the variant in other family members who have or do not have the same health condition. Variants can be either pathologic, benign, or unknown. These unknown variants involve variations in a genetic sequencing for which the association with disease risk is unclear. Therefore, the disease cannot be ruled out (NIH, 2023).

Distinguishing Neonatal Encephalopathy from Features of Genetic Disorders Mimicking Encephalopathy: Clear documentation of appropriate care and evaluation should support evidence-based conclusions. 

  • Review the parents past medical history, as well as history since the birth of the affected child.
  • Review the prenatal record including all fetal surveillance (non-stress tests ‘NST’s’ and biophysical profile’s ‘BPP’s’) and all ultrasounds (imaging and reports).
  • Review the labor and delivery record, including the placenta pathology report and consider consultation with a placental pathologist.  Be aware of the findings associated with an increased risk of encephalopathy (E.g., funisitis ‘inflammation of the umbilical cord’ combined with a diagnostic finding of chorioamnionitis; vasculopathy ‘lesions on the placenta which can be on the fetal or maternal side causing impaired blood flow’ (AAP, ACOG, 2019).
  • Review the physical examination findings of the newborn (review the newborn admission record and subsequent treating records if transfer to a higher level of care occurred).
  • Review the child’s medical history for physical changes observed over time (review the following records:  pediatric, behavioral pediatric, neurology, neuropsychology, and all brain imaging performed ‘imaging and reports’).

Consider Further Evaluation: When obvious congenital defects are present at the time of birth, this should prompt further evaluation and consideration that a genetic cause may exist.  Additional diagnoses should be considered in the neonate presenting initially with encephalopathy (AAP, ACOG, 2019).

Phenotype: AAP, ACOG (2019) identifies phenotype as the observable characteristics in an individual resulting from their genes; the clinical presentation of an individual with a particular genetic constitution.

Clues in the Newborn Assessment that May Point to a Genetic Cause:

  • Findings that are significant that should increase the level of suspicion that a genetic disorder may be the cause, in the presence of hypotonia, impaired level of consciousness, seizures, or periods of apnea occurring without explanation:  
    •  Disproportionate fetal growth: A small or large head circumference compared to the length of the body may point to a genetic neurological disorder. 
    • The absence of an intrapartum event (examples include, but are not limited to, a non-reassuring fetal heart rate, prolonged second stage labor, Apgar score of less than 5 at 5 minutes, placenta abruption) (AAP, ACOG, 2019)

Metabolic Disorders and Encephalopathy: Metabolic disorders (inborn errors of metabolism) may manifest in the first few days to weeks of life with features that mimic neonatal encephalopathy.  Metabolic disorders may cause or contribute to some cases of neonatal encephalopathy.  There are well over 48 known metabolic disorders that can cause neonatal encephalopathy.  Prompt identification of newborns with a metabolic disorder is essential to initiate prompt dietary changes and treatment in an effort to prevent neonatal morbidity and mortality (AAP, ACOG, 2019).

  • Newborn screening is a public health service done in each U.S. state.
  • Each state’s public health department decides both the number and types of conditions on its testing panel.
  • Most states allow parents to opt out for religious or other reasons.
  • Be aware of your state’s newborn screening program requirements.
  • Every newborn should have a newborn metabolic screening performed between 24-36 hours of life.
  • According to the most current CDC data available, approximately 12,500 newborns annually are diagnosed with one of the conditions detected through newborn screening. This means that almost 1 out of every 300 newborns screened is diagnosed with a metabolic disorder (NICHD).

Conclusion: When evaluating a neonatal encephalopathy and/or cerebral palsy case for causation (either medically or legally), consider the contribution of genetic and metabolic disorders.  Be aware that hypoxic ischemic encephalopathy (HIE) may mimic encephalopathy and other features associated with a genetic disorder.

Accurate diagnosis is essential, not only to establish causation, but to support the family with a plan of care with the inclusion of genetic counseling if applicable.  Accurate diagnosis is also crucial for the understanding of future risk of recurrence.

References:

American Academy of Pediatrics, American College of Obstetricians and Gynecologists, (2019). Neonatal encephalopathy and neurologic outcomes, 2nd Ed.

Centers for Disease Control and Prevention. Retrieved on 1/26/23 from,  https://www.cdc.gov/ncbddd/cp/causes.html

MacLennan et al., 2015. American Journal of Obstetrics and Gynecology. Cerebral palsy: causes, pathways, and the role of genetic variants.

National Institute of Child Health and Human Development. Retrieved on 1/26/23 from, https://www.nichd.nih.gov/health/topics/newborn/conditioninfo/infants-screened#

National Institute of Health (2023). National Human Genome Research Institute. Variant of uncertain significance (VUS). Retrieved on 1/26/23 from, https://www.genome.gov/genetics-glossary/Variant-of-Uncertain-Significance-VUS

P.S. COMMENT AND SHARE – Do you have a complex neonatal encephalopathy or cerebral palsy case that involved multiple factors, including genetics, that influenced causation?

Barber Medical Legal Nurse Consulting, LLC is available to review complex neonatal encephalopathy and cerebral palsy cases. Email their medical legal consulting team today at: Contact@Barbermedicallegalnurse.com