Vitamin D as an Adjuvant Therapy in Neonatal Hypoxia: Is it Beneficial?

Author(s): Adel A. Hagag*, Mohamed S. El Frargy, Amal E. Abd El-Latif.

Journal Name: Endocrine, Metabolic & Immune Disorders - Drug Targets
(Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders)

Volume 19 , Issue 3 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Background: Neonatal hypoxic ischemic encephalopathy (HIE) is a potentially devastating disorder associated with significant mortality and long-term morbidity.

Objective: The aim of this study was to study the role of vitamin D as an adjuvant therapy for management of neonatal HIE.

Patients and Methods: This study was carried out on 60 neonates with HIE grade II who were diagnosed according to modified Sarnat staging and were divided in to 2 groups: Group I: Included 30 neonates with Sarnat grade II HIE who received single daily oral dose of vitamin D3 (1000 IU) for 2 weeks in addition to daily subcutaneous (SC) human recombinant erythropoietin (2500 IU/kg) for 5 days and IM or IV magnesium sulphate 250 mg/kg within half an hour of birth, and subsequently 125 mg/kg at 24 and 48 hours of life. Group II: Included 30 neonates with HIE grade II who received erythropoietin and magnesium sulphate as group I but without vitamin D. Two blood samples were taken from all neonates included in both groups; the 1st at diagnosis and the 2nd after 2 weeks of therapy. This study included also 30 healthy neonates as a control group. All neonates included in this study were subjected to: complete clinical examination with assessment of Apgar score at 5 and 10 minutes, measurement of arterial blood gases and serum 25 (OH) vitamin D, calcium, phosphorus, S100-B and IL-17 levels.

Results: Before therapy, there were no significant differences between group I and II in PH, PO2 and PCO2 (p= 0.294, 0.462, 0.758 respectively), but after 2 weeks of therapy, there were significantly higher PH levels in group I compared with group II (p <0.001) while there were no significant differences between group I and II regarding PO2 and PCO2. Before therapy, there were no significant differences in serum 25(OH) vitamin D levels between group I and II while there were significantly lower serum 25(OH) vitamin D levels in group I and II compared with controls (P1; comparison between group I and II = 0.742, P2; comparison between group I and controls = 0.001 and P3; comparison between group II and controls = 0. 001). There were no significant differences between group I and II and between group I and II and control as regard serum calcium (P1= 0.943, P2= 0.875 and P3= 0.764) and phosphorus (P1= 0.862, P2= 0.921, P3= 0.786). There were no significant differences between group I and II regarding serum IL-17 levels while there were significantly lower serum IL-17 levels in group I and II compared with controls (P1 = 0.457, P2 = 0.043 and P3 = 0.023). Before therapy, there were no significant differences in serum S100-B levels between group I and II while there were significantly higher serum S100-B levels in group I and II compared with control (P1 = 0.381, P2 = 0.001 and P3= 0.001) but after therapy, there were significantly higher S100-B levels in group II compared with group I and significantly higher S100-B levels in group I and II compared with control (P1= 0.001, P2= 0.043, P3 = 0.001). There were significant negative correlations in group I between serum S100-B and PH and between S100-B and serum vitamin D before and after therapy.

Conclusion: Vitamin D was found to improve the cases of group I as demonstrated by the reduction of serum S100-B levels after vitamin D therapy.

Recommendations: Extensive multicenter studies are required on a large number of patients with Sarnat grade II HIE with longer duration of follow up to give valid recommendations about the use of vitamin D as an adjuvant therapy in Sarnat grade II HIE.

Keywords: Hypoxic ischemic encephalopathy, S100-B, Vitamin D status, neonates, erythropoietin, seizures.

Juul, S.E.; Comstock, B.A.; Heagerty, P.J.; Mayock, D.E.; Goodman, A.M.; Hauge, S.; Gonzalez, F.; Wu, Y.W. High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL): A Randomized Controlled Trial - Background, Aims, and Study Protocol. Neonatology, 2018, 113(4), 331-338.
Sun, H.; Juul, H.M.; Jensen, F.E. Models of hypoxia and ischemia-induced seizures. J. Neurosci. Methods, 2016, 260, 252-260.
Chalak, L.; Latremouille, S.; Mir, I.; Sánchez, P.J.; Sant’Anna, G. A review of the conundrum of mild hypoxic-ischemic encephalopathy: Current challenges and moving forward. Early Hum. Dev., 2018, 120, 88-94.
Zaigham, M.; Lundberg, F.; Olofsson, P. Protein S100B in umbilical cord blood as a potential biomarker of hypoxic-ischemic encephalopathy in asphyxiated newborns. Early Hum. Dev., 2017, 112, 48-53.
Muengtaweepongsa, S.; Srivilaithon, W. Targeted temperature management in neurological intensive care unit. World J. Methodol., 2017, 7(2), 55-67.
Martinello, K.; Hart, A.R.; Yap, S.; Mitra, S.; Robertson, N.J. Management and investigation of neonatal encephalopathy: 2017 update. Arch. Dis. Child. Fetal Neonatal Ed., 2017, 102(4), F346-F358.
Chaparro-Huerta, V.; Flores-Soto, M.E.; Merin Sigala, M.E.; Barrera, D.E.; León, J.C.; Lemus-Varela, M.L.; Torres-Mendoza, B.M.; Beas-Zárate, C. Proinflammatory Cytokines, Enolase and S-100 as Early Biochemical Indicators of Hypoxic-Ischemic Encephalopathy Following Perinatal Asphyxia in Newborns. Pediatr. Neonatol., 2017, 58(1), 70-76.
Beharier, O.; Kahn, J.; Shusterman, E.; Sheiner, E. S100B - a potential biomarker for early detection of neonatal brain damage following asphyxia. J. Matern. Fetal Neonatal Med., 2012, 25, 1523-1528.
Yıldız, E.P.; Ekici, B.; Tatlı, B. Neonatal hypoxic ischemic encephalopathy: an update on disease pathogenesis and treatment. Expert Rev. Neurother., 2017, 17(5), 449-459.
Bell, S.G. Hypoxic-Ischemic Encephalopathy and Serum Magnesium Monitoring and Maintenance. Neonatal Netw., 2016, 35(3), 159-163.
Yvonne, W.W.U.; Fernando, F. Gonzale. Erythropoietin: A novel therapy for hypoxic-ischaemic encephalopathy? Dev. Med. Child Neurol., 2015, 57(S3), 34-39.
Stessman, L.E.; Peeples, E.S. Vitamin D and Its Role in Neonatal Hypoxic-Ischemic Brain Injury. Neonatology, 2018, 113(4), 305-312.
Mia, A.H.; Akter, K.R.; Rouf, M.A.; Islam, M.N.; Hoque, M.M.; Hossain, M.A.; Chowdhury, A.K. Grading of perinatal asphyxia by clinical parameters and agreement between this grading and Sarnat & Sarnat stages without measures. Mymensingh Med. J., 2013, 22(4), 807-813.
Anderson-Berry, A.; Thoene, M.; Wagner, J.; Lyden, E.; Jones, G.; Kaufmann, M.; Van Ormer, M.; Hanson, C. Randomized trial of two doses of vitamin D3 in preterm infants <32 weeks: Dose impact on achieving desired serum 25(OH)D3 in a NICU population. PLoS One, 2017, 12(10), e0185950.
Elmahdy, H.; El-Mashad, A.R.; El-Bahrawy, H.; El-Gohary, T.; El-Barbary, A.; Aly, H. Human recombinant erythropoietin in asphexia neonatorum: Pilot trial. Pediatrics, 2010, 125(5), e1135-e1142.
Gathwala, G.; Khera, A.; Singh, I. Magnesium therapy in birth asphyxia. Indian J. Pediatr., 2006, 73(3), 209-212.
Elliott, J.P.; Morrison, J.C.; Bofill, J.A. Risks and Benefits of Magnesium Sulfate Tocolysis in Preterm Labor (PTL). AIMS Public Health, 2016, 3(2), 348-356.
Kleinman, M.E.; Chameides, L.; Schexnayder, S.M.; Samson, R.A.; Hazinski, M.F.; Atkins, D.L.; Berg, M.D.; de Caen, A.R.; Fink, E.L.; Freid, E.B.; Hickey, R.W.; Marino, B.S.; Nadkarni, V.M.; Proctor, L.T.; Qureshi, F.A.; Sartorelli, K.; Topjian, A.; Van der Jagt, E.W.; Zaritsky, A.L. Part 14: Pediatric advanced life support: 2010 American heart association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation, 2010, 122(18)(Suppl. 3), S876-S908.
American College of Obstetricians and Gynecologists. Task force on hypertension in pregnancy. Washington, DC. Obstet. Gynecol., 2013, 122(5), 1122-1131.
American Regent: Magnesium sulfate injection, USP Safety data sheet according to Occupational Safety and Health Administration (OSHA) Hazard Communication Standard Rule- 29 CFR 1910.1200 and the Canadian Hazardous Products Act and the Fed eral Register, 2012 March 26, 77(58), Page 1 of 8. Rules and Regulations Revision Date: 11/10/2015 Date of issue: 11/10/2015.
Mohammadnia, M.; Solgi, G.; Ranjbar, M.; Shahrestani, T.; Edalat, R.; Razavi, A.; Nikbin, B.; Pourmand, G.; Amirzargar, M.; Sarafnejad, A.; Amirzargar, A.A. Serum levels of interleukin (IL)-10, IL-17, transforming growth factor (TGF)-β1, and interferon-γ cytokines and expression levels of IL-10 and TGF-β1 genes in renal allograft recipients after donor bone marrow cell infusion. Transplant. Proc., 2011, 43(2), 495-499.
Yeh, P.; Emary, K.; Impey, L. The relationship between umbilical cord arterial pH and serious adverse neonatal outcome: Analysis of 51,519 consecutive validated samples. BJOG, 2012, 119, 824-831.
Conway, J.M.; Walsh, B.H.; Boylan, G.B.; Murray, D.M. Mild hypoxic ischaemic encephalopathy and long term neurodevelopmental outcome - A systematic review. Early Hum. Dev., 2018, 120, 80-87.
Herrera-Marschitz, M.; Perez-Lobos, R.; Lespay-Rebolledo, C.; Tapia-Bustos, A.; Casanova-Ortiz, E.; Morales, P.; Valdes, J.L.; Bustamante, D.; Cassels, B.K. Targeting sentinel proteins and extrasynaptic glutamate receptors: A therapeutic strategy for preventing the effects elicited by perinatal asphyxia? Neurotox. Res., 2018, 33(2), 461-473.
Lowe, D.W.; Hollis, B.W.; Wagner, C.L.; Bass, T.; Kaufman, D.A.; Horgan, M.J.; Givelichian, L.M.; Sankaran, K.; Yager, J.Y.; Katikaneni, L.D.; Wiest, D.; Jenkins, D. Vitamin D insufficiency in neonatal hypoxic-ischemic encephalopathy. Pediatr. Res., 2017, 82(1), 55-62.
Mutlu, M.; Sarıaydın, M.; Aslan, Y.; Kader, Ş.; Dereci, S.; Kart, C.; Yaman, S.Ö.; Kural, B. Status of vitamin D, antioxidant enzymes, and antioxidant substance in neonates with neonatal hypoxic-ischemic encephalopathy. J. Matern. Fetal Neonatal Med., 2016, 29(14), 2259-2263.
Alvira-Botero, X.; Perez-Gonzalez, R.; Spuch, C.; Vargas, T.; Antequera, D.; Garzón, M.; Bermejo-Pareja, F.; Carro, E. Megalin interacts with APP and the intracellular adapter protein FE65 in neurons. Mol. Cell. Neurosci., 2010, 45(3), 306-315.
Schreiber, A.; Theilig, F.; Schweda, F.; Hocherl, K. Acute endotoxemia in mice induces downregulation of megalin and cubilin in the kidney. Kidney Int., 2012, 82, 53-59.
Anderson, R.L.; Ternes, S.B.; Strand, K.A.; Rowling, M.J. Vitamin D homeostasis is compromised due to increased urinary excretion of the 25-hydroxycholecalciferol-vitamin D-binding protein complex in the Zucker diabetic fatty rat. Am. J. Physiol. Endocrinol. Metab., 2010, 299, E959-E967.
Balden, R.; Selvamani, A.; Sohrabji, F. Vitamin D deficiency exacerbates experimental stroke injury and dysregulates ischemia-induced inflammation in adult rats. Endocrinology, 2012, 153, 2420-2435.
Chun, R.F.; Peercy, B.E.; Orwoll, E.S.; Nielson, C.M.; Adams, J.S.; Hewison, M. Vitamin D and DBP: the free hormone hypothesis revisited. J. Steroid Biochem. Mol. Biol., 2014, 144(Pt A), 132- 137.
Chiang, L.M.; Chen, W.Y.; Yang, Y.C.; Jeng, M.J. Elevation of serum S100 protein concentration as a marker of ischemic brain damage in extremely preterm infants. J. Chin. Med. Assoc., 2015, 78(10), 610-616.
Distefano, G.; Curreri, R.; Betta, P.; Isaja, M.T.; Romeo, M.G.; Amato, M. Serial protein S-100 serum levels in preterm babies with perinatal asphyxia and periventricular white matter lesions. Am. J. Perinatol., 2002, 19(6), 317-322.
Zaigham, M.; Lundberg, F.; Hayes, R.; Undén, J.; Olofsson, P. Umbilical cord blood concentrations of ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) in neonates developing hypoxic-ischemic encephalopathy. J. Matern. Fetal Neonatal Med., 2016, 29(11), 1822-1828.
Gazzolo, D.; Pluchinotta, F.; Bashir, M.; Aboulgar, H.; Said, H.M.; Iman, I.; Ivani, G.; Conio, A.; Tina, L.G.; Nigro, F.; Li Volti, G.; Galvano, F.; Michetti, F.; Di Iorio, R.; Marinoni, E.; Zimmermann, L.J.; Gavilanes, A.D.; Vles, H.J.; Kornacka, M.; Gruszfeld, D.; Frulio, R.; Sacchi, R.; Ciotti, S.; Risso, F.M.; Sannia, A.; Florio, P. Neurological abnormalities in full-term asphyxiated newborns and salivary S100B testing: the “cooperative multitask against brain injury of neonates” (CoMBINe) international study. PLoS One, 2015, 10(1), e0115194.
Zaigham, M.; Lundberg, F.; Olofsson, P. Protein S100B in umbilical cord blood as a potential biomarker of hypoxic-ischemic encephalopathy in asphyxiated newborns. Early Hum. Dev., 2017, 112, 48-53.
Massaro, A.N.; Wu, Y.W.; Bammler, T.K.; Comstock, B.; Mathur, A.; McKinstry, R.C.; Chang, T.; Mayock, D.E.; Mulkey, S.B.; Van Meurs, K.; Juul, S. Plasma biomarkers of brain injury in neonatal hypoxic-ischemic encephalopathy. J. Pediatr., 2018, 194, 67-75.
Wang, K.K.; Yang, Z.; Zhu, T.; Shi, Y.; Rubenstein, R.; Tyndall, J.A.; Manley, G.T. An update on diagnostic and prognostic biomarkers for traumatic brain injury. Expert Rev. Mol. Diagn., 2018, 18(2), 165-180.
Krähn, G.; Kaskel, P.; Sander, S.; Waizenhöfer, P.J.; Wortmann, S.; Leiter, U.; Peter, R.U. S100β is a more reliable tumor marker in peripheral blood for patients with newly occurred melanoma metastases compared with MIA, albumin and lactate-dehydrogenase. Anticancer Res., 2001, 21(2B), 1311-1316.
Ferriero, D.M. Neonatal brain injury. N. Engl. J. Med., 2004, 351, 1985-1995.
Chaparro-Huerta, V.; Flores-Soto, M.E.; Sigala, M.E.M.; de León, J.B.C.; Lemus-Varela, M.L.; Torres-Mendoza, B.M.; Beas-Zárate, C. Proinflammatory cytokines, enolase and S-100 as early biochemical indicators of hypoxic-ischemic encephalopathy following perinatal asphyxia in newborns. Pediatr. Neonatol., 2017, 58(1), 70-76.
Bruce, D.; Yu, S.; Ooi, J.H.; Cantorna, M.T. Converging pathways lead to overproduction of IL-17 in the absence of vitamin D signaling. Int. Immunol., 2011, 23, 519-528.
Zhang, H.; Shih, D.Q.; Zhang, X. Mechanisms underlying effects of 1, 25-Dihydroxyvitamin D3 on the Th17 cells. Eur. J. Microbiol. Immunol. (Bp.), 2013, 3(4), 237-240.
Jenkins, D.D.; Lee, T.; Chiuzan, C.; Perkel, J.K.; Rollins, L.G.; Wagner, C.L.; Katikaneni, L.P.; Bass, W.T.; Kaufman, D.A.; Horgan, M.J.; Laungani, S.; Givelichian, L.M.; Sankaran, K.; Yager, J.Y.; Martin, R. Altered circulating leukocytes and their chemokines in a clinical trial of therapeutic hypothermia for neonatal hypoxic ischemic encephalopathy. Pediatr. Crit. Care Med., 2013, 14(8), 786-795.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [341 - 348]
Pages: 8
DOI: 10.2174/1871530319666181204151044

Article Metrics

PDF: 32