In our study of VLBWI, we observed a 28.7% incidence of IVH among 191 very preterm infants, which was higher than the reported severe IVH incidence in the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network study in 2016, which was only 7.5%.9 However, the mean gestational age in our study group was 27–28 weeks of age, weighing 1-1.1 kg in our VLBWI. A prior study investigating the IVH prevalence in premature Israeli infants according to weight and gestational age similarly reports IVH incidence of 20.9% 6, which was similar to our IVH rate of 28.7%. Among the multifactorial pathogenetic risks for IVH, abnormalities of the hemodynamic systems certainly play a role. We found that VLBWIs experiencing refractory hypotension within the first week of life who ultimately needed hydrocortisone to maintain appropriate blood pressure were at high risk for severe IVH (stages 3–4). Refractory hypotension can be a risk factor in the very preterm population, with an estimated incidence of 20–45% 10, which is associated with IVH.5
Until the early 2000s, the postnatal steroid dexamethasone was used widely as clinical trials reported that dexamethasone reduced the risk of death or BPD in VLBWI; however, this benefit was outweighed by a possible increased risk of neurodevelopmental impairment.11–13 While many randomized and control trials (RCTs) have also shown adverse neurodevelopmental outcomes after postnatal dexamethasone treatment for BPD, no multicenter RCT studies have demonstrated adverse effects on the long-term outcomes after hydrocortisone therapy.14 This is because dexamethasone is 40 to 50 times more potent than hydrocortisone and longer- acting at 18 to 24 hours. 15 Hydrocortisone targets both glucocorticoid and mineralocorticoid receptors, which may cause a less harmful effect on neurodevelopmental outcomes.15
The more severe hospital morbidities in the VLBWI group exposed to early hydrocortisone use in our study are directly related to increased severity of illness in VLBWI, especially when it occurred in the first 72 hours of life, as reported by Jonathan et al.16 Similar to our study, refractory hypotension is reported to be associated with severe IVH, poor long-term neurodevelopment (permanent neurological injuries/deficits or cerebral palsy), and even death.17–18 Our study also reported higher mortality in the severe IVH group (34.5%) and 38 (69.1%) VLBWIs in the severe IVH group. Overall, VLBWI experiencing refractory hypotension within the first week of life indicates hemodynamic instability and changes in cerebral blood flow, which increases the incidence of severe IVH.
Some studies have highlighted the negative effects of vasopressors in compromising cerebral autoregulation.19 The vasoconstrictive effects of inotropic drugs could worsen the hypoxia-hypoperfusion status of the periventricular areas of the immature brain and result in glutamate- and free radical-induced damage to preoligodendrocytes, which are the precursors of oligodendrocytes that eventually form the white matter.20 In fact, studies reported that the use of inotropes was associated with increased severe IVH in infants born before 32 weeks gestation.21–22 This may be because hemodynamic instability and changes in cerebral blood flow are increased risks of IVH.23
Infants with refractory hypotension experienced mostly adrenal insufficiency, shock or RDS, demonstrating the importance of the severity of illness within a week of life and possibly suggesting a causal relationship with severe IVH. In our study, our center only used hydrocortisone as an alternative to dexamethasone to minimize the negative effect on neurodevelopmental outcomes. Since hydrocortisone targets both glucocorticoid and mineralocorticoid receptors, it has less potent toxicity than dexamethasone, suggesting that appropriate use of hydrocortisone may not develop complications such as brain toxicity. A current practice survey showed that hydrocortisone treatment has already been implemented in many neonatal units across the world.24 Hydrocortisone use can also counter the untoward effects of cytokines and hemodynamic shock on cellular toxicity 25 and may improve the inflammatory process and effectively reduce cytokine- and hypofusion-induced cellular and white matter injury. Our study has several limitations in its observational nature: (i) the retrospective study design, which might not be appropriate for confirming the examined relationships; (ii) the relatively small sample size of the study group; (iii) hidden disabilities may subsequently have become apparent later, and many infants might have important developmental lags that were not classified as impairments; and (iv) many clinical conditions that may originate from prematurity itself. However, the strength of our study is the observation of neurodevelopmental outcomes by the Bayley Scales of Infant and Toddler Development III at a corrected age of 18 months as a long-term study.
In summary, we concluded that refractory hypotension within a week of life and seizures may be predictors of the severity of IVH. Severe IVH (grades 3–4) was also significantly associated with an increased risk of neurodevelopmental outcome at corrected 18 months.