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Department of Pediatrics (N.O.E.B., C.R.L.), School of Medicine, Laboratory of the Children’s Hospital "Prof. Pedro de Alcântara", Hospital das Clínicas (T.S.O.), University of São Paulo, São Paulo, BRAZIL
Address reprint requests to: Naila de Oliveira Elias Barbosa, M.D., Alameda Fernão Cardim n° 99 apartamento 11, Jardim Paulista, São Paulo—SP, CEP: 01403-020, BRAZIL. E-mail: naila{at}ajato.com.br
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ABSTRACT |
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 TOPFOOTNOTES ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSCONCLUSIONREFERENCES |
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Objective: To describe, in term newborn (NB) without IUGR, ionized magnesium (iMg) and total magnesium (TMg) concentrations in umbilical cord blood, on the third and seventh days of life and to compare these values with those of term NB with IUGR.
Methods: A prospective study was performed on 70 term NB divided into two groups: Group I—30 NB without IUGR and Group II—40 NB with IUGR. TMg concentrations were determined in sera by a classical colorimetric end point method (Cobas-Mira, Roche), and iMg was determined in whole blood by means of the Stat Profile-M analyzer (NOVA Biomedical).
Results: We found that in term NB without IUGR, TMg concentrations increased during the first week of life and were lower than those of NB with IUGR in cord blood (p < 0.05). NB without IUGR had decreased iMg concentrations in comparison to NB with IUGR in all sampling times, i.e., cord blood, third and seventh days of life (p < 0.001). iMg concentrations remained unchanged during the study period. We also found that all NB enrolled in the study presented with low iMg concentrations (reference interval 0.4–0.6 mmol/L).
Conclusion: The presence of IUGR may influence neonatal levels of magnesium, suggesting an effect on the modulation of this ion homeostasis, during the perinatal period.
Key words: intrauterine growth restriction, term newborn, magnesium, ionized magnesium, total magnesium
Abbreviations: iMg = Ionized magnesium • IUGR = intrauterine growth restriction • Mg = Magnesium • NB = newborn • TMg = total magnesium
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INTRODUCTION |
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TOPFOOTNOTESABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSCONCLUSIONREFERENCES |
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Although Mg is predominantly an intracellular cation, due to technical difficulties in the determination of its cellular content in various tissues, its plasmatic dosage has been used as a clinical parameter [3].
The concentration of serum total magnesium (TMg), which includes that bound to the proteins, the complexes and the ionized, was the first and the most easily measured form of Mg and is routinely used in clinical practice to access the circulating Mg [4,5]. The ionized fraction, however, is the physiologically active and presents a narrow normal range when compared to TMg, which contributes to its clinical relevance [1].
The recent development of an ion-selective electrode micromethod for iMg, has enabled a rapid determination of the iMg concentrations in small blood samples, which in turn has made possible to determine its fraction in the neonatal period and has contributed to clarify the action mechanisms of Mg [1].
There are few studies on Mg in the neonatal period, especially regarding the behavior of the ionized fraction. Furthermore, it is possible that nutritional factors, such as intrauterine growth restriction (IUGR), might lead to an imbalance of Mg homeostasis, which has not yet been fully explained.
The aim of this study was to describe the levels of iMg and TMg in term newborns (NB), without IUGR, in their 1st week of life and to compare these data with those from NB with IUGR.
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PATIENTS AND METHODS |
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TOPFOOTNOTESABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSCONCLUSIONREFERENCES |
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This research was approved by the Ethics Commissions of the Department of Pediatrics and by the Analysis of Research Projects, Clinical Directorship of the Hospital das Clínicas and University of São Paulo School of Medicine.
The exclusion criteria were: major malformations; genetic anomalies; congenital infections; twin births; exchange-transfusion within the first week of life; maternal disease liable to interfere in the metabolism of Mg, such as diabetes mellitus or gestational diabetes and hyperparathyroidism; and use of medications during the gestation or delivery that could affect the metabolism of Mg, such as magnesium sulfate.
NB with gestational age between 37 and 41
weeks were considered term. Gestational age at birth was based on the first day of the last menstruation period, whenever this differed by up to two weeks in relation to that indicated by the fetal ultrasound scan, if this had been performed by week 20 of gestation. In the absence of this exam or if it was accomplished after this gestational age, maternal information was used to indicate the definitive gestational age, if it differed to that given by the method of Capurro (1978) [6] by up to two weeks. When this difference was greater, the neonatal evaluation method was chosen.
The NB enrolled in the study were divided into two groups: Group I—without IUGR (n = 30); and Group II—with IUGR (n = 40).
The diagnosis of IUGR was based on birth weight <10th percentile for the gestational age and, besides this, a birth weight ratio (BWR), which is the ratio of the observed birth weight in a given infant to the 50th percentile for that infant’s gestational age <0.85 [7]. The reference values for the 50th percentile, in complete weeks of gestation, were obtained from the study by Alexander et al. [8].
The umbilical cord blood was collected through venous puncture in the fetal face of the placenta, soon after its extraction, by the author herself. On days 3 and 7 of life, additional blood collections were performed by the author, from a superficial blood vessel with easy access. The collection was programmed to coincide with the venous puncture performed for routine laboratory tests in these NB.
The total volume of blood obtained in each collection was 2 ml. The first 1 ml was put in a heparinized syringe (S-Monovette ® with 50 UI of lithium heparin/ml of blood, balanced with calcium; SARSTEDT) for gasometry, iMg and iCa. This sample was sent to the laboratory cooled with ice, and the analysis was performed soon after sampling. The second 1 ml of blood was drained for dosage of TMg (dry tube with gel separator, BD Vacutainer). After retraction of clot at room temperature for 1 hour, serum samples were obtained after centrifugation at 3000 rpm for 10 minutes. Then, two aliquots of approximately 100 µL of serum were stored at –20°C until the time of analysis.
The determination of iMg was performed by means of an ion-selective electrode microtechnique, using a NOVA Stat Profile-M Analyzer (NOVA Biomedical Corporation, Waltham, Massachusetts) at the Laboratory of the Children’s Hospital, Hospital das Clínicas [9].
TMg was determined by an end-point colorimetric method in Cobas Mira Roche Diagnostic System Inc. equipment. The method is based on the reaction of magnesium with xylidyl blue in alkaline solution containing EGTA to mask the calcium in the sample. Briefly, 50 µL of each serum sample were added to 400 µL of buffer 1 (Tris-(hydroxymethyl) aminomethane/6-aminocapronic acid, pH 11.25, 500 mmol/L and EGTA 90 µmol/L). Then, buffer 2 containing xylidyl blue 0.28 mmol/L was added. In alkaline solution Mg forms a purple complex with xylidil blue, a diazonium salt. TMg is thereafter measured photometrically via the decrease in the xylidyl blue absorbance (wavelengths 600 nm and 505 nm). Tests were performed in duplicate thus requiring a minimum serum volume of 100 µL [10].
Statistical Analysis
The sample size calculus was based on the presupposition that there was a difference of 30% between the means of iMg seric concentrations in the two groups. A pre-test was performed including 20 term newborns without IUGR, in which was obtained a mean iMg concentration of 0.23 mmol/L and a standard deviation of 0.08 mmol/L. These were considered the reference iMg concentrations. Based on these results, and an 
= 5% and a power of the test of 80%, the n calculated for each group was 20.
Mean values were compared by the Student’s t test or with Mann-Whitney parametric test when suppositions for the test were not satisfied. Anova one-way or Kruskall-Wallis was used for analysis of the continuous variables. The comparison of proportions was carried out by Fischer’s Exact Test or the Chi-square Test. Values of p < 0.05 were considered statistically significant.
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RESULTS |
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TOPFOOTNOTESABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSCONCLUSIONREFERENCES |
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All infants enrolled in the study were breast-fed.
The frequency of tabagism among the mothers was evaluated and just 3 (10.0%) in the group without IUGR and 6 (15.0%) in the group with IUGR were light smokers (<10 cigarettes/day).
The NB were divided into two groups: Group I—NB without IUGR (n = 30, 42.9%); and Group II—NB with IUGR (n = 40, 57.1%).
There was no difference between the groups in terms of gender (Table 1).
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Table 2 describes the mean and standard deviation of iMg and TMg concentrations in the two groups. TMg concentrations increased from 1.67 ± 0.25 mg/dL at birth to 1.86 ± 0.25 mg/dL in day 7 of life in the group without IUGR (p < 0.05) and remained unchanged in the group with IUGR. The mean value of 1.67 ± 0.25 mg/dL found in cord blood of NB without IUGR was lower than the value 1.83 ± 0.39 mg/dL in the group with IUGR (p < 0.05). iMg concentrations remained unchanged during the first week of life in both groups. NB without IUGR had lower iMg concentrations in comparison to NB with IUGR in all sampling times (p < 0.001).
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DISCUSSION |
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Although the levels of TMg at various ages have already been established, these are not as useful clinically, as would be those for iMg, which reflect more closely the intracellular activity of the ion [1]. This is particularly so in the neonatal period, during which there are metabolic adaptations that increase the risk of disturbances occurring.
Studies into the evolution of the serum levels of TMg in the neonatal period during the first week of life, have presented conflicting results. Some authors have described a gradual increase in the levels of TMg up to 48 hours of life, with a stabilization until day 7 of life [11–13]. Other authors, however, have reported that there is no change in these values over the first one to 12 hours of life [14] or during the first week of life [15].
In the present study, a progressive and statistically significant increase was observed in the serum concentrations of TMg in the control NB (Group I), throughout the first week of life (Table 2).
Some authors, for instance Marcus et al. (1998) [1] and Cook; Mimouni (1997) [11] refer to a mean value for iMg 0.48 mmol/L (0.40 to 0.56), using the NOVA 8 machine. Dollberg et al. (2001) [16] found a mean value for iMg in umbilical cord blood of 0.28 mmol/L (0.12 to 0.40) and at 2 to 4 hours of life, of 0.30 mmol/L (0.20 to 0.40), this time using the NOVA M instrument. The electrode of the NOVA M is more specific and interacts insignificantly with other cations, thereby producing lower values than the NOVA 8. Therefore, the values for these levels should be interpreted carefully in function of the type of electrode used [16,9].
In this study, the measurement of iMg was done in NB, without risk factors and appropriate intrauterine growth, through the NOVA M machine and mean values of iMg obtained were within the normal range described previously and without significant variation during the first week of life [9] (Table 3).
It should be emphasized, however, that there have been few such studies into the course of the serum levels of iMg in the first week of life. In the first 24 hours of life, Cook; Mimouni (1997) [11] demonstrated that there is no alteration in the concentrations of iMg.
It has been well documented in the literature that disturbances in intrauterine nutrition can increase the risk of perinatal morbidity and mortality. IUGR, in turn, provides an outstanding example of such situations of deviation from normality, since it refers to fetuses that failed to reach their inherent growth potential, thus characterizing a pathological reduction in this parameter [17].
In clinical practice, the indicators of individual growth potential and of rate of intrauterine growth are not very well defined, consequently there are no standard parameters for diagnosing this condition [18].
In the present study, to increase the precision during the selection of those cases with IUGR, the authors used the criterion of birth weight <10th on the Curve of Alexander [8] and associated this to a second criterion of nutritional classification, namely a BWR ratio <0.85. In this way newborn which were small but nevertheless normal were excluded [7].
Several experimental studies have shown that fetus of severe Mg deprived mothers can maintain seric Mg levels equal or higher than their mothers [19]. The placenta active transport of Mg is seen as the main type of transport [20]. The study of Shaw et al. (1990), demonstrated the presence of an active transport of Mg from the mother to the fetus, against a concentration gradient [21].
In the presence of IUGR many placenta modifications are described, as an uncomplete adaptative remodeling of the spiral arteries that supply the intervillous space of the placenta with maternal blood, atherosclerosis-like lipid depositions and thrombotic infartation [22]. As a consequence, the nutrients and oxygen transport to the fetus could be reduced, as well as the active transport of Mg, which is dependent of ATP.
The higher iMg/TMg relation observed in the IUGR group, could be the result of a low TMg in these newborns. Considering Durlach study [23], in which TMg is appointed as the most reliable indicator of total body Mg, this one would be also reduced, and this would be in accordance to this smaller placental transport of nutrients in the presence of intrauterine growth restriction, resulting in nutritional deficiencies.
Nevertheless, the analysis of the results from the present research demonstrated statistically significant differences in the concentrations of umbilical cord TMg between groups I and II (p < 0.05). The group with IUGR presented higher values, which could indicate that IUGR did not reduce the placental transport of Mg, as reported by some authors [24].
Likewise, the mean levels of iMg detected in the three main collection times in the group with IUGR were higher than in the group without IUGR (p < 0.001) (Table 2). Therefore, the higher iMg/TMg relation observed was probably a reflex of a higher iMg concentration than TMg in the presence of intrauterine growth restriction. It is possible that unknown adapting mechanisms could be enhanced by the intrauterine situation of IUGR, protecting the fetus against the lower Mg offer.
The higher levels of iMg observed in these NB could also be explained by the presence of intrauterine oscillations in the oxygenation and pH, as elements in the process of nutritional restriction, which could lead to the deviation of Mg from the intracellular to the extracellular compartment [25,26]. Besides this, the reduction in the placental transfer of calcium, also due to this process, could also lead to the low iCa/iMg ratio observed in NB with IUGR (Table 5). As a consequence, a secondary elevation of the parathyroid hormone (PTH), with repercussions on these concentrations could occur. In addition to these factors, the smaller renal mass in NB with IUGR is associated to a lower production of 1.25-dihydroxyvitamin D (1.25-(OH)2D and the "resistance" to PTH, with an even greater increase in the serum concentrations of this hormone, which could worsen the bone demineralization and lead to an elevation in the plasmatic concentration of Mg [24,27].
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CONCLUSION |
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TOPFOOTNOTESABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSCONCLUSIONREFERENCES |
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The determination of values of TMg and iMg in the neonatal period, in the presence and absence of IUGR, can be used as a reference for further studies that investigate the behavior of this ion in other situations involving deviation from the normal levels.
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FOOTNOTES |
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TOPFOOTNOTESABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSCONCLUSIONREFERENCES |
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Received August 25, 2003. Accepted March 18, 2004.
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REFERENCES |
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TOPFOOTNOTESABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSCONCLUSIONREFERENCES |
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This article has been cited by other articles:
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  C. R. Leone and N. O.E. Barbosa Magnesium and Perinatal Asphyxia NeoReviews, September 1, 2007; 8(9): e387 - e393. [Abstract] [Full Text] [PDF]
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