The Severity of Neuronal Damage in Neonatal Hypoxic–Ischemic Encephalopathy: Does Vitamin-D Status Matter?

Reply to: The Severity of Neuronal Damage in Neonatal Hypoxic-Ischemic Encephalopathy: Does Vitamin D Status Matter?

We read the recently published article titled “Neonatal Vitamin D Status Is Associated with the Severity of Brain Injury in Neonatal Hypoxic-Ischemic Encephalopathy: A Pilot Study” by McGinn et al with great interest.[1] The authors have concluded that there was a significant inverse association between 25-hydroxyvitamin D (25OHD) concentration and brain injury on magnetic resonance imaging (MRI). However, we wish to add certain points.

The authors have also concluded that there was a trend toward decreased ventilator days in neonates receiving higher doses of vitamin D in the first week of life (p = 0.062); However, the authors decided to provide higher dose supplement of vitamin D in those with vitamin D levels <50 ng/mL. Thus, indirectly this indicates that neonates with lower vitamin-D levels had decreased ventilator days, which seems to contradict the primary conclusion of the study that lower vitamin-D level is associated with early adverse outcome of hypoxic–ischemic encephalopathy (HIE). Moreover, the authors have considered vitamin-D level <30 ng/mL as the cut-off for vitamin D insufficiency following the recommendations by Endocrine Society and American Association for Clinical Endocrinologists.[2] Still, how they chose the cut-off for providing vitamin-D oral supplementation of 800 IU instead of 400 IU for those neonates with vitamin-D levels <50 ng/mL is not evident from the article. The rationale for this decision by authors would have been more informative.

Moreover, they estimated that neonates receiving formula feed rather than breastfeeding and those with >3 kg birth weight received higher vitamin-D supplements. Thus, the authors could have described whether they are proposing in turn that the neonates receiving formula feed and higher birth weight have better short-term outcome. The authors have mentioned that the multivariate logistic regression analysis was not possible due to the small sample size. But the authors could have performed this analysis by including some of the independent variables for whom the number of patients in each subgroup was at least 10. A general guideline regarding multivariate logistic regression is a minimum of 10 cases with the least frequent outcome for each independent variable required to form a suitable model.[3] As the number of confounding variables is many as denoted by authors themselves, such as sex, race, gestational age at birth, and use of therapeutic hypothermia, which could have more impact on the neurological outcome than serum 25OHD concentration, the reliability of result is significantly compromised in absence of adjustment for these variables. Some important confounding variables not mentioned by the authors are the presence of seizures and comorbid neonatal sepsis, which have been shown to have a definitive impact on short-term and long-term neurological outcomes. Similarly, abnormalities in amplitude-integrated electroencephalogram (EEG) recordings are recommended, being performed while a neonate is on therapeutic hypothermia, as one of the strongest predictors of adverse neurological outcomes, and the authors should have mentioned that in the article.[4]

While mentioning serum 25OHD concentrations, the authors should have also mentioned serum albumin, calcium, phosphorus, and alkaline phosphatase concentrations and diastolic blood pressure. While serum calcium, phosphorous, and alkaline phosphatase levels are significantly affected by serum 25OHD concentrations, lower serum albumin levels in HIE make more lipophilic 25OHD available for tissue uptake or renal conversion and reduce its serum level.[5] Hypothermia treatment might also reduce significantly serum albumin concentrations which positively correlated with serum 25OHD levels in the children receiving hypothermia.[6]

The prevalence of vitamin-D insufficiency was significantly low as compared with the most previous studies measuring their level in children with HIE. Although the authors have attributed this to the different laboratory assessment methods, ideally they should have compared with the prevalence of serum 25OHD levels in neonates without HIE available from retrospective records at their center or studies done in neonates belonging to same demographic profile.

Lastly, the authors have mentioned serum 25OHD levels in mother but did not correlate it with the 25OHD levels in those neonates, in whom it was first measured in <48 hours of life. Early serum 25OHD levels in neonates are likely to be affected by mothers as shown in previous studies and deficient mothers can be replaced as a preventive neuroprotective strategy in such cases.[7]

Publication History

Received: 08 August 2020

Accepted: 08 November 2020

Article published online:
28 January 2021

• References

• 1 McGinn EA, Powers A, Galas M, Lyden E, Peeples ES. Neonatal vitamin D status is associated with the severity of brain injury in neonatal hypoxic-ischemic encephalopathy: a pilot Study. Neuropediatrics 2020; 51 (04) 251-258
• 2 Sharawat IK, Dawman L. Bone mineral density and its correlation with vitamin D status in healthy school-going children of Western India. Arch Osteoporos 2019; 14 (01) 13
• 3 Sperandei S. Understanding logistic regression analysis. Biochem Med (Zagreb) 2014; 24 (01) 12-18
• 4 De Haan TR, Langeslag J, van der Lee JH, van Kaam AH. A systematic review comparing neurodevelopmental outcome in term infants with hypoxic and vascular brain injury with and without seizures. BMC Pediatr 2018; 18 (01) 147
• 5 Sharawat IK. Hypervitaminosis D with dyslipidemia: an unusual scenario. Indian Pediatr 2016; 53 (02) 174-175
• 6 Lowe DW, Hollis BW, Wagner CL. et al. Vitamin D insufficiency in neonatal hypoxic-ischemic encephalopathy. Pediatr Res 2017; 82 (01) 55-62
• 7 Anusha K, Hettiaratchi U, Gunasekera D, Prathapan S, Liyanage G. Maternal vitamin D status and its effect on vitamin D levels in early infancy in a tertiary care centre in Sri Lanka. Int J Endocrinol 2019; 2019: 9017951