Background: Neonatal jaundice is a common major problem; on the other hand, it is suggested that there is a correlation between plasma magnesium concentrations and hyperbilirubinemia during the neonatal period. Objectives: The study aims to validate a previously reported risk index for predicting the magnesium level of plasma for moderate to severe hyperbilirubinemia in infant neonates. Methods: A cross-sectional correlation study was performed on 93 term newborns with indirect hyperbilirubinemia admitted in neonatology unit of a children hospital and plasma magnesium level of moderate to severe Neonatal hyperbilirubinemia were determined, and statistical analysis was performed. Results: Authors did not find any statistically meaningful positive or negative correlation between plasma Mg level and bilirubin in patients studied; however, comparison of Mg level in two groups of severe and moderate hyperbilirubinemia showed decreased dispersion of medium Mg level in the severe group. Conclusions: Serum magnesium concentration is not useful in anticipation of which newborn infant will develop hyperbilirubinemia. Copyright Â© 2020, Journal of Comprehensive Pediatrics

Ehsanipour, F.

Khosravi, N.

Mirfakhraee, H.

Norouzi, E.

eprints Iran University of Medical Sciences

Uncorrected ProofJ Compr Ped. In Press(In Press):e94278.Published online 2020 January 1.doi: 10.5812/compreped.94278.Research ArticleSerum Magnesium Levels in Neonatal Jaundice: Is There anyCorrelation Between Hypermagnesemia and Moderate to SevereHyperbilirubinemia in Term Newborns?Fahimeh Ehsanipour 1, Elahe Norouzi 2, *, Nastaran Khosravi 1 and Hosna Mirfakhraee 11Iran University of Medical Sciences, Tehran, Iran2Rasoul-e-Akram Medical Center, Iran University of Medical Sciences, Tehran, Iran*Corresponding author: Assistant Professor of Pediatrics, Neonatologist, Rasoul-e-Akram Medical Center, Iran University of Medical Sciences, Niayesh St., Sattarkhan Blvd.,Tehran, Iran. Tel: +98-9123495772, Email: elahenorouzimd@gmail.comReceived 2019 May 23; Revised 2019 November 30; Accepted 2019 December 08.AbstractBackground: Neonatal jaundice is a common major problem; on the other hand, it is suggested that there is a correlation betweenplasma magnesium concentrations and hyperbilirubinemia during the neonatal period.Objectives: The study aims to validate a previously reported risk index for predicting the magnesium level of plasma for moderateto severe hyperbilirubinemia in infant neonates.Methods: A cross-sectional correlation study was performed on 93 term newborns with indirect hyperbilirubinemia admitted inneonatology unit of a children hospital and plasma magnesium level of moderate to severe Neonatal hyperbilirubinemia weredetermined, and statistical analysis was performed.Results: Authors did not find any statistically meaningful positive or negative correlation between plasma Mg level and bilirubinin patients studied; however, comparison of Mg level in two groups of severe and moderate hyperbilirubinemia showed decreaseddispersion of medium Mg level in the severe group.Conclusions: Serum magnesium concentration is not useful in anticipation of which newborn infant will develop hyperbilirubine-mia.Keywords: Newborn, Magnesium, Hyperbilirubinemia, Bilirubin, Jaundice1. BackgroundHyperbilirubinemia, a common problem in neonateinfants (1-3), is seen in about 80% of preterm and 60% ofterm newborns during the first days of life (4, 5). Bilirubinis considered as a neurotoxic agent (3, 6), injures neural cellmembranes and damages membrane enzymes and recep-tors (7-9), and results in neurologic deficit in infants (10).Furthermore, structures such as N-methyl D-aspartate(NMDA) receptor, located in the synaptic surface of thecell membrane structure, is subjected to the bilirubin in-jury; therefore, neurologic development and learning andmemory disorders in childhood is due.Many reports have suggested magnesium (Mg) as aneuroprotective factor, which protects central nervous sys-tem against hypoxia, and comprises supportive effects ofneurons (11-14). Physiologic effects of Mg are opposite ofbilirubin neurotoxic effects (15, 16). Mg is one of the mostimportant NMDA regulatory antagonists in the neural sur-face, which reverses the damaging cell membrane mecha-nisms by receptor blocking, and finally, leads to neural sys-tem protection.Hence, it seems that plasma Mg level manifests themetabolic and physiologic states of a neonate with hyper-bilirubinemia.2. ObjectivesAlthough Mg regulatory and protective effects on theNMDA receptor is completely known, Mg and hyperbiliru-binemia relation is not studied well. This study is designedto assess any relation between Mg plasma level and moder-ate to severe hyperbilirubinemia.3. MethodsThis was a correlation study carried out on 93 termneonates admitted to the Aliasghar Children HospitalCopyright © 2020, Journal of Comprehensive Pediatrics. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided theoriginal work is properly cited.Uncorrected ProofEhsanipour F et al.Neonatal Ward in Tehran, IR Iran, during Apr. to Sep.2012. The inclusion criteria was moderate to severe hy-perbilirubinemia required treatment in term neonates,according to Bhutani nomogram, nearly 16 to 20 mg/dLfor patients with moderate hyperbilirubinemia, and morethan 20 mg/dL for severely affected neonates. The exclu-sion criteria included anemia with hemoglobin less than8.7 g/dL or hemolysis evidence, G6PD enzyme deficiency,red blood cell membrane disorders, MgSO4 use in the pre-natal period, and major congenital anomalies.Every infant has undergone two blood sampling.Serum Mg level was analyzed by the Becton DickinsonVacutainer system, France, measured by the Ion-selectiveelectrode (ISE) method. Serum bilirubin was assayed withcolorimetric method by the use of Diazotized Sulfanilicacid reaction; Roche diagnostic kit, USA.Hyperbilirubinemia was classified into two groups ofsevere (total bilirubin more than 20 mg/dL) and moder-ate (total bilirubin ≤ 20 mg/dL). Mg level greater than 2.3mg/dL was defined as hypermagnesemia, and Mg level lessthan 1.5 mg/dL was assumed as hypomagnesemia.Data analysis was performed by the use of SPSS 17. Var-ious parameters co-efficient were assessed by the Pearsontest. Group comparison was carried out by Ki square andindependent t-test, according to the qualitative or quanti-tative nature of P value; and P values less than 0.05 wereassumed statistically meaningful.4. ResultsAmong 93 jaundiced term neonates with moderate tosevere hyperbilirubinemia, 39% were female; and 61% weremale. Moderate hyperbilirubinemia, in a study popula-tion, was 88.2% (82 patients), and frequency of severe hy-perbilirubinemia was 11.8% (11 of 93 patients). Among theinfants studied, medium serum bilirubin level was 18.29± 1.8 mg/dL (with range of 12.3 to 24 mg/dL), and mediumplasma Mg level was 1.9 ± 0.3 mg/dL (range of 1.3 to 2.7mg/dL).In neonates with moderate hyperbilirubinemia,medium serum bilirubin was 17.7 ± 1.27 mg/dL, andmedium infant age was 6.8 ± 3.9 days, with medium birthweight of 3018 ± 413 grams; medium plasma Mg level was1.9 ± 0.3 mg/dL.In neonates with severe hyperbilirubinemia, mediumserum bilirubin was 22.11± 1.19, medium infant age was 6.6± 3.3 days, and medium infant weight at birth was 3091 ±639 grams; medium severe Mg level was 1.9 ± 0.2 mg/dL.According to this study the relation of hyperbilirubine-mia with infant sex (P = 0.368), neonate age (P = 0.89), andbirth weight (P = 0.63) was not statistically meaningful.Statistical analysis didn’t reveal any meaningful corre-lation between hyperbilirubinemia and high plasma Mglevel (P = 0.368), or low plasma Mg level (P = 0.305).Comparison of Mg level in two groups of severe andmoderate hyperbilirubinemia showed decreased disper-sion of medium Mg level in the severe group, however, thisfinding is not statistically meaningful (P > 0.05).5. DiscussionMagnesium, the second frequent intracellular cation,is essential for fetal growth, and Mg deficiency in preg-nancy is associated with eclampsia or pre-eclampsia, pre-mature labor, prolonged duration of maternal hospitaliza-tion, and infant low birth weight (15).Relevant past studies have demonstrated neuropro-tective effects of ionized Mg (11-14). On the other hand,neurotoxic property of indirect bilirubin (10) proposedthe hypothesis about the relationship between plasmaMg and bilirubin level in hyperbilirubinemic newborn in-fants. Sapkota found a significant difference in the Mgconcentrations before and after phototherapy correspond-ingly bilirubin levels before and after phototherapy andconcluded that phototherapy could decrease serum Mglevel as much as Bilirubin. He concluded that there wasa positive relation between serum Mg and bilirubin levelsand propounded that rising of Mg in hyperbilirubinemiamight be a compensatory mechanism against toxic effectsof bilirubin (16).The recent study revealed the Mg level in infants withsevere hyperbilirubinemia a little higher than the moder-ate hyperbilirubinemic group (1.90 ± 0.3 mg/dL and 1.91± 0.2 mg/dL, respectively), which was not statistically sig-nificant. Past studies propounded contradictory opinionson this subject. Dennery et al., referred to a positive corre-lation of serum Mg level and hyperbilirubinemia severity;and thought that increased cell damage is the cause of hy-permagnesemia. There are some reports representing thatbilirubin not only harms neurons, but also affects othertypes of cells by their toxic effects (17).Ilves et al. (18) and Engle and Elin (19) reported in-creased serum Mg level in asphyxia. Furthermore, Olofs-son et al. (20), and Sarici et al. (21), thought that hyper-magnesemia leads to acidosis and hypoxemia, which inturn, may cause irreparable effects in neural cells. Some re-searchers suggested ionized Mg as a NMDA receptor block-ing ion. Hyperactivity of NMDA receptors on the neu-ron membrane, during the intrauterine period, leads toischemic encephalopathy; bilirubin affects NMDA in thisway, and magnesium ion acts as a neuroprotective sub-stance by blocking the NMDA receptors in neural cells.In the animal models studied, increased bilirubin level2 J Compr Ped. In Press(In Press):e94278.Uncorrected ProofEhsanipour F et al.changed the membrane NMDA receptor activity and led toneuronal injuries (7-9, 22).Sakamoto et al. (23), demonstrated that there isn’t anyassociation between plasma and cerebrospinal fluid Mglevel in patients with cerebral injuries; this may be due tothe blood brain barrier presence. This finding is compat-ible with our study results. On the other hand, Sarici etal. (24), explained that elevated plasma Mg level in neona-tal diseases such as respiratory distress syndrome or hy-perbilirubinemia is due to acidosis and hypoxia resultingfrom generalized cellular damage including erythrocytesand neurons and extracellular movement of principally in-tracellular Mg ion (24). In a study performed by Yasser etal., the mean levels of plasma Mg were significantly higherin hemolytic unconjugated hyperbilirubinemic neonatescompared to controls and non-hemolytic cases, which wasthought to be due to the extracellular movement of Mgfrom erythrocytes (25).Pintov et al., did not find any significant correlationbetween the highest serum bilirubin concentrations andcord serum concentrations of zinc, magnesium, and cop-per. They concluded that cord serum concentrations ofmagnesium, zinc, and copper were not predictive thatwhich newborns would develop hyperbilirubinemia; theirreport is coordinated with the recent study (26).There are some other paradoxical reports in the liter-ature review, which may be due to prematurity. Perveenet al., showed that copper and magnesium remained incord blood plasma at much less concentrations comparedwith the mother throughout the last trimester suggestingthat the gestational age may have a major role in plasmaMg level in neonates and resulting adverse effects of hy-perbilirubinemia (27). Cultural and socioeconomic differ-ences due to genetic, geographical, and nutritional diver-sity may be involved in the paradoxical results. Baig et al.,studied on zinc, copper, magnesium, calcium, and phos-phorous levels in maternal and cord blood and demon-strated that Mg levels were higher in Pakistani women’sblood in comparison of cord blood (28).5.1. ConclusionsSerum concentrations of magnesium were not prof-itable in the prediction of which neonates would de-velop moderate to severe indirect hyperbilirubinemia. Al-though, we did not find any statistically meaningful posi-tive or negative correlations between plasma Mg level andbilirubin in patients studied; comparison of Mg level intwo groups of severe and moderate hyperbilirubinemiashowed decreased dispersion of medium Mg level in severegroup.It is recommended that plasma Mg levels need to bestudied in jaundiced neonates in comparison to patientswithout considerable jaundice; and also, plasma Mg levelsin mothers of neonates with hyperbilirubinemia. Further-more, comparison of NMDA receptor numbers in healthyand jaundiced neonates or animal models may be a subjectof future studies.FootnotesAuthors’ Contribution: Study concept and design:Fahimeh Ehsanipour, Nastaran Khosravi, and ElaheNorouzi; acquisition of data: Hosna Mirfakhraee andFahimeh Ehsanipor; analysis and interpretation of data:Hosna Mirfakhraee; drafting of the manuscript: ElaheNorouzi; critical revision of the manuscript for importantintellectual content: Elahe Norouzi; statistical analysis:Hosna Mirfakhraei; administrative, technical, and ma-terial support: Fahimeh Ehsanipour; study supervision:Fahimeh Ehsanipour and Nastaran KhosraviConflict of Interests: We have no financial interests re-lated to the material in the manuscript.Ethical Approval: The study protocol conforms to theethical guidelines of the 1975 Declaration of Helsinki as re-flected in a prior approval by the Institution’s Human Re-search Committee (IR.IUMS.REC.1391.4903).Funding/Support: We did not have any financial supportor grant regarding this study.Informed Consent: In regards to the ethics of experimen-tation, informed consent was obtained from each patient’sparent included in the study.References1. 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Serum magnesium levels in neonatal jaundice: Is there any correlation between hypermagnesemia and moderate to severe hyperbilirubinemia in term newborns?

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Serum magnesium levels in neonatal jaundice: Is there any correlation between hypermagnesemia and moderate to severe hyperbilirubinemia in term newborns?

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