This study indicates that feeding intolerance, delayed full enteral nutrition, and longer mechanical ventilation are significantly associated with rising concentrations of serum Mg in neonatal circulation. Besides, those who were exposed to MgSO4 were more likely to be born smaller and growth-restricted, adjusted analysis revealed that exposure to MgSO4 per se correlates with higher rates of feeding intolerance, delayed full enteral nutrition, NEC, and BPD.
Our findings of undesired consequences of MgSO4 are not newly reported. However, a great preponderance of the trials was designed dichotomously, whether exposed or not [9–13, 18–20]. To us, our analysis is unique in that it investigated the impact of neonatal serum Mg levels of neuroprotective MgSO4 exposed preterm infants at a particular time on neonatal outcomes via a prospective observational methodology. To date, only a few studies have found a correlation between neonatal serum Mg levels and neonatal outcomes [21, 6]. Basu et al. assessed the first-day serum Mg concentrations of preterm infants who received neuroprotective MgSO4 and stratified the patients into four groups based on the serum levels [6]. The researchers revealed the correlation of serum Mg level > 4.5 mg/dl with mortality independent of gestational age and birth weight. Over and above, that analysis reported an increased rate of ROP, PDA, and delayed full enteral nutrition with fetal MgSO4 administration. Besides, the lack of exact timing of Mg sampling was a critical limitation of that study. Moreover, the implication of a high-dose MgSO4 regimen, namely 2 g hourly infusion up to 24 hours following 6 g load, was another restriction given the emerging evidence favoring adverse effects with cumulative dosage. ACTOMgSO4 and PREMAG studies, with low and intermediate dose regimens, respectively, demonstrated the impact of MgSO4 on lowering the risk of death or CP [2, 3]. Nonetheless, the BEAM study that was designed with a higher dose and larger patient group infers the potentially harmful effects, and excess mortality, despite a statistically insignificant difference [4]. Contrary to ours, a substantial proportion of the subjects had higher cord Mg levels that might end up with unfavorable short-term outcomes.
The effect of MgSO4 on intestinal injury has been a topic of concern in previous studies [7–14]. Rattray et al. identified an increased incidence of SIP/mortality in extremely preterm babies following antenatal MgSO4 [11]. On the other hand, a secondary analysis of a multicenter randomized trial conducted by Kamyar and colleagues revealed a higher NEC/mortality among babies < 26 weeks of gestation with antenatal administration of MgSO4. However, these findings and methodological design are in contrast with our study. Firstly, a higher dose regimen was adopted in that trial. Secondly, only extremely immature neonates with an increased risk for intestinal injury were incorporated. Rattray and colleagues speculated that not only MgSO4 but also other frequently used medications (morphine, indomethacin, and hydrocortisone) might have taken part in the surge of SIP via a synergistic effect in an already fragile group. While indomethacin was unavailable in our unit, the implementation of hydrocortisone and morphine was very limited in early postnatal life due to the drawback of the adverse neurodevelopmental outcome. Kamyar et al. analyzed the uncontemporary data of a study conducted between 1997 and 2004, investigating the impact of MgSO4 on preventing CP [10]. Despite the similar incidence between the two eras, a remarkable improvement has been accomplished in the management of NEC. While the relationship between NEC and MgSO4 remains controversial, our findings indicated an increased rate of NEC in the MgSO4 exposed group. It was speculated that this finding was not solely associated with MgSO4, but confounding factors like lower birth weight and higher IUGR rate might have taken part in that high NEC frequency.
There is a lack of data on the correlation between intestinal injury and neonatal serum Mg level yet [6, 14, 21]. Mikhael et al. grouped the cohort as babies of mothers who received MgSO4 in the last three or seven days before delivery and reported neonatal serum Mg levels taken in the first 72 hours of life [14]. No correlation was revealed between Mg implementation and NEC or SIP; even SGA infants who were administered MgSO4 were less likely to undergo NEC, SIP, or death. Besides, there is no evidence-based explanation for grouping the MgSO4 exposure as the last 3 or 7 days, and the researchers also stated the need for the studies on those exposed to MgSO4 in the last 24 hours before delivery. On the other hand, 72 hours postdelivery is a fairly wide range for serum Mg sampling, and differences in the timing of blood sampling might cause bias. The methodology was speculated to be based on the knowledge that the half-life of Mg is 43.2 hours and might stay in the body for up to seven days in newborn babies. However, it's conflicting how appropriate a method is to do such a grouping given the significant variability of renal clearance among the preterm infants in early life [8]. No previous study assessed gastrointestinal morbidity and neonatal serum Mg level at a particular time. Our findings indicate similarity in terms of NEC in higher and lower serum Mg level groups.
In our study, both MgSO4 exposure and higher serum Mg level were noted to be correlated with feeding intolerance and delayed full enteral feeding. Belden and colleagues put forth a higher rate of feeding intolerance in preterm babies of mothers who were exposed to MgSO4 at doses > 80 g for neuroprotection or preeclampsia [7]. In addition, the subgroup of babies < 1250 g was found to have been exposed to a higher dose of MgSO4, although the difference between the groups was statistically insignificant. Therefore, a very high dose regimen was adopted till birth in a patient group with a significantly higher gestational age and birth weight. However, we adopted a much lower MgSO4 dose protocol for neuroprotective aim, and the relationship between serum Mg level at the 6th hour of life and feeding intolerance was investigated for the first time in the literature to the best of our knowledge. Mg reduces gastrointestinal motility by hindering smooth muscle contraction by replacing calcium in smooth muscle cells. Since the kidneys are the only excretion route, it was speculated to entail feeding intolerance by staying in the body for a very long time, particularly in extremely preterm babies with limited renal function. Another reason might be delayed stooling that might be associated with antenatal MgSO4 exposure [22]. Besides, it's compelling to infer a cause-effect relationship since there is no clear, universally accepted definition for feeding intolerance. In addition, extremely preterm babies undergo at least one episode of feeding intolerance often as a sign of preterm morbidities during the hospital stay. Therefore, we used a single definition and informed all clinicians during the study.
MgSO4 exposed babies were more likely to experience BPD and more prolonged invasive/noninvasive ventilation in our study. On the other hand, once grouped based on the serum Mg level, the high and low serum Mg groups were similar in BPD incidence, while the duration of invasive ventilation was noted to be longer in the high Mg group. Narasimhulu et al. reported a higher incidence of BPD in babies exposed to MgSO4, but similar when grouped based on a serum Mg level, which was similar to our study [21]. It was speculated to be due to confounding factors such as IUGR, PPROM, and low birth weight in the MgSO4 group, as in NEC.
To our knowledge, this study is the first to have investigated the impact of serum Mg level at the 6th hour on short-term neonatal outcomes via a prospective, observational design. The low-dose regimen was adopted in all subjects for the neuroprotective purpose only. Based on the evidence of the potential link between high serum Mg levels and adverse outcomes, particularly for extremely low birth weight babies, implementing a low dosage with a limit of 24 hours was a significant strength of our study. Very few patients were noted to have serum Mg levels > 3.5 mg/dl, most likely due to the low dose protocol.
Nonetheless, our study has certain limitations. Although a single definition of feeding intolerance was utilized during the study period, it was challenging to mention a causal link given the wide range of etiology behind feeding intolerance. In addition, the range of optimal serum Mg concentration remains controversial. On the other hand, there is yet no universally accepted dose for neuroprotective effect in preterm infants. In the light of the current studies, it may be speculated that dose adjustment should be considered when it comes to extremely small preterm infants. Although we postulate serum Mg level cut-off as 2.5 mg/dL based on the previous data, the optimal neuroprotective concentration remains debatable due to restricted data. There is an urgent need for evidence to reveal the dose with the maximal neuroprotective efficacy and lowest side effect profile in the newborn. Evaluation of Mg levels and renal functions in future studies might help predict the optimal dose that should be given to preterm infants, considering that the only elimination way is through the kidneys.