Few studies have addressed the potential association of seizures with the outcomes of preterm infants. This study compared the demographic, perinatal, and neonatal factors as well as neurodevelopmental outcomes of inborn ELBW infants surviving to 36 weeks PMA with and without clinical seizures in the NICHD NRN sites. Importantly, our multivariate model adjusted for the potential confounding effects of several morbidities to which seizures and adverse outcomes are commonly attributed, including infection, meningitis, severe IVH, and PVL. After these adjustments, a significant association remained between clinical seizures and late death or NDI among ELBW infants.
Seizures in neonates arise as a consequence of neural injury, resulting from hypoxia, ischemia, or metabolic disturbances such as hypoglycemia or hypocalcemia.23
Possible sequelae of seizure activity in the developing CNS include altered neuronal circuitry, decreased neurogenesis, impaired learning, and brain injury.24–26
There are also potential detrimental effects of anticonvulsant therapy to the developing CNS.27
A National Institutes of Health workshop on the treatment of neonatal seizures emphasized the need for well-designed clinical trials with long-term follow-up as an endpoint, rather than seizure control.28
Previous studies have explored the association between clinical seizures and adverse outcomes among preterm survivors. NRN investigators have reported higher unadjusted rates of clinical seizures of ELBW infants who survived to 18 to 22 months corrected age with NDI, CP, and MDI < 70.14, 29
Neubauer et al examined 135 ELBW survivors at school age and found a 9% rate of clinical seizures in their cohort, of whom 33% had severe IVH.15
Although adjustments were performed for some obstetric and neonatal morbidities, the small sample size precluded a statistically significant association between seizures and an abnormal outcome. Because these studies examined only surviving infants, there was possible underreporting of adverse outcomes such as death.
Pisani et al examined the 24–30 month outcome of 51 preterm (≤ 36 weeks GA) infants with video EEG-confirmed seizures and reported an unfavorable outcome in 80% of the cohort.16
Similarly, Ronen et al found a 42% rate of death and a 46% rate of disability among survivors in 26 preterm infants with seizures over a 10-year follow-up period.30
The strengths of these two studies lie in the selection of infants following a diagnosis of seizures. However, the lack of a control group did not permit analysis of the independent association between seizures and adverse outcome.
A recent analysis by Glass et al examined the association between clinical seizures and neurodevelopmental outcomes in a cohort of term newborns at risk for hypoxic-ischemic injury.31
All infants had magnetic resonance imaging (MRI) performed and neurodevelopmental evaluation at 4 years of age. Infants with seizures were more likely to have an abnormal neurologic examination, and increasing severity of seizures was associated with a decline in the full-scale intelligence quotient. After adjusting for the degree of brain injury on MRI, seizures were independently associated with adverse outcome, suggesting that neurologic injury may result from seizures, particularly within neuronal structures, such as the hippocampus, that may not be fully visualized on conventional MRI.
Overall, infants with clinical seizures in our study had a greater illness severity compared with the control group, perhaps as a result of their lower GA and BW. Higher rates of severe IVH, cystic PVL, and infection were seen in the seizure group, and these CNS events have been associated with an increased rate of seizures32
and adverse outcomes14
in other studies. Indeed, the frequent overlap between seizures and many comorbidities has limited the ability to determine the independent contribution of seizures to the outcomes of ELBW infants. A significant advantage of our study is the large sample size of ELBW infants, including more than 400 infants with clinical seizures. We were able to investigate the association of clinical seizures with adverse outcome after adjusting for multiple comorbidities. By limiting our eligibility criteria to infants who survived until 36 weeks, we attempted to eliminate over-reporting of early death, which could have preceded a diagnosis of seizures. Even with a criterion of survival to 36 weeks PMA, late death was observed more frequently in the clinical seizure group compared with control.
A shortcoming of this study was the limited information regarding the circumstances and timing of clinical seizures during the hospital course. No data were available regarding the association of seizures with clinical events, and neither the extent of seizure burden nor anticonvulsant therapy were documented. It was also not possible to determine the number of infants with clinical seizures whose EEG did not confirm electrographic seizure activity. The diagnosis of severe IVH or PVL was determined only by cranial ultrasound; hence, the full extent of brain injury in this cohort may be underestimated. Lastly, fewer than 25% of the infants with clinical seizures had EEG-confirmed events. It is unclear if this reflects the efficacy of anticonvulsant medication or the decision-making of the medical team in obtaining an EEG.
The clinical diagnosis of seizures in neonates can be challenging, owing to the immaturity of the neonatal CNS. Rather than exhibiting classic tonic-clonic manifestations, seizure activity in neonates is often subtle and difficult to distinguish from normal newborn behavior, with preterm infants being even more likely to demonstrate subtle clinical manifestations of seizures.23
The broad range in the rate of clinical seizures among NRN centers in our study reflects this diagnostic challenge. The perception of clinical seizures can be highly qualitative, and infants perceived as being more ill may be more likely to be diagnosed with seizures. Murray et al reported that only one-third of electrographic seizures in term born infants were associated with clinical symptoms and that two-thirds of these clinical manifestations were unrecognized or misinterpreted by neonatology staff.33
Further, Shah et al recently demonstrated electrographic seizures using routine amplitude-integrated EEG (aEEG) in 11 of 51 preterm infants < 30 weeks GA (21%), though only 2 infants (18%) demonstrated a clinical correlate.34
Therefore, rates of clinical seizures, including the present study, likely underestimate the true incidence of seizure activity in the preterm population.
Despite the possible pitfalls in the classification of clinical seizures, this study demonstrates that clinical seizure activity and movements perceived as clinical seizures in ELBW infants surviving to 36 weeks PMA are associated with a greater odds of late death or NDI, independent of demographic, perinatal, and neonatal morbidities typically considered to be significant contributors to adverse outcome. Further, these data suggest that the neonatal clinical seizures may be considered a marker for poor outcome. More aggressive surveillance for electrographic seizure activity in preterm infants through more routine use of continuous aEEG monitoring or conventional EEG, particularly in those with known cerebral injury, will provide more accurate data regarding the true prevalence of seizures. Future studies aimed at determining the independent risk of seizures with adverse outcomes should document the timing of seizures in relation to other neonatal morbidities, the use of anticonvulsant therapies, and confirmation of electrographic seizure control using continuous aEEG or frequent EEG recordings. We speculate that aggressive detection and treatment of seizures has the potential to improve outcomes in ELBW infants, however a prospective study is required to confirm this hypothesis.