Magnesium Sulfate for Fetal Neuroprotection: Correlation between Maternal and Infant Serum Magnesium Concentrations-Juniper Publishers
Juniper Publishers-Journal of Pediatrics
Abstract
Background: Pregnant women at risk
for preterm labor are commonly treated with magnesium sulfate (MgSO4)
for fetal neuroprotection. Randomized controlled studies have shown that
this treatment is associated with decreased risk of cerebral palsy.
Nevertheless, the optimal MgSO4 dose for neuro protection has not been
determined. Moreover, some studies suggest a potential toxic effect
associated with high MgSO4 treatment dose and that elevated serum infant
Mg concentrations (iMgC) may also be associated with an increased risk
for various morbidities and mortality.
Objective: To determine the
correlation between maternal and infant serum Mg concentration among
preterm infants exposed to MgSO4 for neuroprotection. Finding a
correlation may contribute to decision-making regarding continuation or
discontinuation of maternal treatment prior to delivery.
Study Design: A total of 60 infants
born at <32 weeks gestational age and exposed to MgSO4 for
neuroprotection were enrolled. The correlation between maternal serum Mg
concentration (mMgC) drawn at <48 hours prior to birth and infant
iMgC drawn immediately after birth was assessed. Additional factors such
as total Mg treatment dose, interval between treatment initiation,
treatment discontinuation and birth, as well as other maternal and
infant characteristics were assessed as possible contributors.
Results: Complete data were
available for 60 mother-infant dyads. Mean infant gestational age was
28.8 ± 2.23 weeks. Median and inter quartile range (IQR) of total MgSO4
dose, mMgC and iMgC were 45g (25 88), 4.6 (4.1-5.3) and 3.8 (3.1-4.2)
mg/dL respectively. Maternal Mg concentration and iMgC correlated
significantly (r=0.433 p=0.001). In multiple regression analysis
duration between first loading and birth (b=-0.031 p=0.004) and female
gender (b=0.412 p=0.029) also correlated with iMgC.
Conclusion: Serum magnesium
concentration in preterm infants treated for neuroprotection correlates
with mMgC. This correlation may serve as a non-invasive tool for
estimation of fetal Mg concentration in exposed fetuses during maternal
treatment.
Keywords: Femur Fracture, Femoral Fracture, Child Abuse, NAI, Inflicted Injury, AustraliaAbbreviations: MgC: Infant Mg Concentrations; mMgC: Maternal Serum Mg Concentration; IQR: Interquartile Range; CP: Cerebral Palsy; ACOG: American College of Obstetrics and Gynecology; IVH: Intraventricular Hemorrhage; NICU: Neonatal Intensive Care Units
Background and Literature Review
In a retrospective case control study that was
published by Nelson et al. [1] in 1995, a decreased risk for cerebral
palsy (CP) was demonstrated among preterm infants exposed to tocolytic
MgSO4 compared to those not exposed. Subsequently, several large
prospective studies and a systematic review of the literature reinforced
these findings, advocating MgSO4 administration to reduce
the occurrence of CP and death among preterm infants [2-5]. In 2010, the
American College of Obstetrics and Gynecology (ACOG) published its
recommendations which supported the use of MgSO4 for fetal
neuroprotection. It also advocated the necessity of defining treatment
protocols and appropriate Mg dosage, as those used for neuroprotection
have been adopted empirically from protocols used for seizure
prophylaxis in preeclampsia [6]. Interestingly, studies that used a low
total dose of MgSO4 (<10 g) did not show any significant
adverse effects to exposed infants, while when higher doses were used,
mainly for tocolysis, a trend towards increased perinatal mortality was
demonstrated. Therefore the use of MgSO4 for tocolysis is
currently no longer recommended [3,4,7-12]. Other recent studies that
investigated early outcomes among preterm infants treated for
neuroprotection demonstrated an association with an increased risk for
intraventricular hemorrhage (IVH), impaired intestinal blood flow in the
first few hours after birth, spontaneous intestinal perforation,
increased admission to neonatal intensive care units (NICU) and need for
intubation [13-
16]. Taken together, these finding suggest a possible therapeutic
window for Mg, beyond which the neuroprotective effect
diminishes and adverse toxic effects occur. Currently, MgSO4
treatment for neuroprotection is commonly given when imminent
preterm labor is suspected. Nevertheless, studies investigating
the optimal total dose, optimal iMgC and appropriate timing
for achieving neuroprotection are lacking. Magnesium has been
shown to be transferred to the fetus through the placenta, so
that high maternal concentrations may theoretically result in
fetal hypermagnesemia [17]. A first step toward understanding
the above and also toward controlling iMgC for safety reasons
would be to confirm a correlation between maternal and infant
serum Mg concentration as well as to identify additional factors
that may affect this correlation. Such a correlation could serve as
an indirect tool to monitor exposed fetuses. The current study
aimed to answer these questions.
Study Design
This study is a retrospective chart review of infants admitted
to a single tertiary care NICU between January 2012 and February
2015. Included in the study were all preterm infants born <32
weeks’ gestation during the study period without congenital
anomalies or known genetic disorders whose mothers were
treated with MgSO4 for the indication of neuroprotection during
pregnancy. Only those whose mothers had MgSO4 infusion and
documented serum Mg concentration within <48 hours prior to
delivery and also documented iMgC within two hours after birth
were included. Pregnant women at imminent risk of preterm
delivery receive an intravenous loading dose of 5 g MgSO4 over
30 minutes, followed by continuous infusion of 2 g per hour for
12 hours. If delivery does not occur within 12 hours, treatment is
discontinued. Infusion may be resumed if imminent labor is again
perceived. If more than six hours elapsed since discontinuation
of the initial infusion, an additional loading dose is given.
Maternal Mg concentration is drawn 6-7 hours after initiation
of treatment and repeated again after 24 hours if treatment
has been continued. According to hospital laboratories, normal
serum Mg concentration ranges from 1.9 to 2.7 mg/dL. Infant
Mg concentration is routinely screened immediately after initial
stabilization as part of admission blood workup (among those
who were exposed to magnesium). This practice was initiated
in our NICU due to the known adverse effects associated with
elevated Mg concentrations in adults.
Data Collection and Neonatal Outcomes
Data were collected from medical maternal and infant charts
using a specific data collection form and included the following:
date of first maternal loading dose and first mMgC (6 hours after
loading dose), number of total loading doses, total Mg dose until
delivery, last available mMgC. Also documented were indication
of which MgSO4 treatment was given, multiple pregnancy,
maternal age, gestation number and mode of delivery. Infants’ characteristics included gender, gestational age, birth weight,
Apgar scores and iMgC after birth. This study was approved
by the hospital Institutional Review Board. The Hospital Ethics
Committee waived the need for informed consent, as this was an
observational audit of normal practice.
Statistical Analysis
Data were summarized using central tendency (mean,
median), spread tendency (standard deviation, inter quartile
range, minimum and maximum) and proportions as appropriate
in order to characterize the study cohort. Pearson correlation
was constructed to determine the direction and magnitude of the
association between maternal and infant Mg concentrations. A
multiple linear stepwise regressions including different potential
covariates such as maternal and infant characteristics to predict
infant Mg concentrations was conducted. All statistical analyses
were performed using SPSS version 21. A P-value of <0.05 was
considered statistically significant.
Results
A total of 346 infants were born during the study period at
<32 weeks gestational age. Magnesium sulfate was administered
to 232 (67.0%) mothers. A total of 60 mother-infant dyads met the
study criteria i.e., MgSO4 was administered for neuroprotection
within 48 hours prior to delivery, mMgC were documented
during this period and iMgC was documented after birth. Table 1
shows baseline characteristics of the participants. Table 2 shows
MgSO4 treatment characteristics as well as iMgC and mMgC.
The median (IQR) maternal and iMgC were 4.6 (4.1-5.3) and 3.8
(3.1-4.2) mg/dL, respectively. We found positive and significant
correlation between mMgC and iMgC (r= 0.0443 p=0.001) (Figure
1). However, the explained variability was R2 = 0.188 (18.8%),
indicating that other variables may also be needed to explain
the iMgC. Multivariate analyses were performed using stepwise
linear regression to estimate whether selected clinical and
demographic characteristics may further predict the observed
variability in iMgC. (The following variables were included in the multivariate model: last documented mMgC, interval between
last documented maternal mMgC and birth, mMgC six hours
from first loading, total maternal MgSO4 dose, duration between
withholding treatment and delivery, interval between first Mg
loading dose and delivery, number of maternal loading doses,
maternal age, multiple gestation, mode of delivery, gestational
age, infant gender, Apgar scores at 1 min. Table 3 displays the
results of the final analysis (final step). The residual unexplained
variability increased (R 2 = 0.34). Preterm infants whose mothers
had a higher mMgC, a shorter time interval between first Mg
loading dose and delivery and female gender had a higher Mg
concentration.
Discussion
The present study is the first to provide evidence
for a correlation between maternal and infant serum Mg
concentrations among preterm infants (< 32 weeks GA) exposed
to MgSO4 for neuroprotection. It is also the first to account for
detailed factors associated with maternal treatment, such as
total exposure dose and time interval between initiation and
withholding treatment and birth. The statistical analysis points
to substantial variability (R2~0.19), which could be explained
by the contribution of additional factors. Gender and time
interval between first loading dose and birth were identified as
significant contributors, thus increasing the R2 value to 0.34. The
importance of the above findings is twofold: First, they provide
evidence that maternal blood sampling during MgSO4 infusion
may be useful in predicting iMgC when given for neuroprotection.
Second, these findings may be used for future studies targeted
to define the optimal iMgC for achieving fetal neuroprotection
on the one hand and preventing toxic effect on the other. A
correlation between maternal and cord/infant serum Mg
concentration with a similar high unexplained variability (R2=
0.19) has already been demonstrated in two studies [18,19]. In
these studies, however, MgSO4 was administered for a different
indication (i.e., preeclampsia), and the study population was
born at an older gestational age. Sherwin et al. [19] found that
the high unexplained variability improved after accounting
for other confounders, so that cesarean section and multiple
gestations were identified as associated with lower iMgC while
pregnancies complicated by preeclampsia resulted in a higher
iMgC concentration. No association between iMgC and maternal
BMI or weight change during pregnancy was demonstrated.
Sherwin did not account for factors associated with maternal
treatment regimen as potential confounders. Boriboonhirunsarn
et al. [18] studied the correlation between maternal and cord
blood Mg concentration. Like the study by Sherwin, in this study
MgSO4 was used to treat preeclampsia and most infants were
not preterm (mean age of 38.1 weeks). Cord blood was sent
immediately after delivery for Mg analysis. A positive direct correlation was found between total maternal and cord blood Mg
concentration, total treatment dosage and duration of infusion.
We also identified the duration between treatment initiation and
birth as correlating with iMgC but not total exposure dose. An
explanation of the absence of such a correlation may rely on the
difference between the treatment protocols for preeclampsia
vs. neuroprotection. While the preeclamptic women in the
Boriboonhirunsarn study were treated continuously for a mean
duration of five hours, those treated for neuroprotection were
treated intermittently for a mean of three days. It is possible that
treatment-free intervals which occur frequently when MgSO4
is given for neuroprotection caused fluctuations in blood Mg
concentration .
Fetal Mg balance has not been thoroughly studied due
to the apparent ethical and technical issues in doing so (i.e.,
direct measurement of fetal Mg level would require fetal blood
sampling). This balance is thought to be regulated by a number
of mechanisms, including placental transport and reabsorption
in the fetal kidney [20]. Fetal serum Mg concentration has been
shown to increase within one hour of maternal treatment with
MgSO4 for tocolysis, with urinary excretion via the fetal kidney
leading to an amniotic fluid buildup three hours after exposure
thout ever exceeding the concentration measured in maternal
serum [17,21]. Gestational age was not found to correlate with
iMgC as fractional excretion of Mg was the same in premature
infants as in term infants (<2%) [22]. The present study
supports the above finding, as iMgC was also not found to be
associated with birth weight or gestational age. The association
between iMgC and gender has not been described previously.
Additional studies are required to clarify this finding. The “best
MgSO4 dosage” or “optimal iMgC” for achieving neuroprotection
has not been defined, nor has the exact mechanism through
which magnesium decreases risk of developing cerebral palsy. A
putative therapeutic window for Mg has been suggested, below
which there is no measurable effect and above which there is no
added value though fetal toxicity may take place [10,11,23]. In
animals studies a high dose of MgSO4 has been suggested to cause
neuronal death in various brain areas [24]. In preterm infants not
exposed to MgSO4, increased baseline serum Mg concentrations
were associated with unfavorable developmental outcome [12].
In the present study, the median Mg exposure dose was high
compared to the one used in published randomized trials (45vs.
4-31gr) that investigated MgSO4 treatment for neuroprotection
[3,4,7]. In this study, we calculated total Mg exposure dose as the
amount of Mg given to the women from the first loading dose
until the time of birth. Although our institutions’ MgSO4 protocol
for neuroprotection is based on protocols published in the
literature, a higher total exposure dose was achieved. In clinical
practice high total exposure doses are unavoidable as the total
number of allowed repeated doses has not defined and repeated
treatment courses are indicated as long as there is a threat of
premature delivery. This practice exposes fetuses to repeated
courses of MgSO4, resulting in total exposure doses significantly
higher than those studied. These data are alarming in light of the gap in knowledge regarding the optimal treatment dose and the
evidence for toxicity associated with high exposure dose. The
current study did not find a correlation between the number
of loading doses or total exposure dose and iMgC. The above
highlights the importance of long-term follow-up studies of
infants exposed to repeated Mg treatment and in relation to total
Mg dose. Our study has several limitations. The major limitation
is its relatively small sample size and the retrospective method
of data collection. In addition, there was variability between
the mothers in terms of total Mg treatment dosage and timing
of mMg sampling in relation to the time of delivery. As timing
of preterm delivery usually cannot be predicted, this obstacle
probably cannot be overcome. Nevertheless, several biases were
eliminated. The study cohort included only preterm neonates
born prior to 32 weeks. It also included only those treated with
MgSO4 for the indication of neuroprotection. We also excluded
mothers that were not exposed to treatment within 48 hours
prior to delivery, thus reducing some of the biases inherent in
the study method.
Summary and Conclusion
In summary, our data show that there is a correlation between
mMgC and iMgC among preterm infants exposed to MgSO4
for neuroprotection. Additional variables, among them those
associated with maternal treatment regimen, were also shown
to potentially affect iMgC. We have also shown that in practice
fetuses are exposed to much higher doses than those studied
in randomized trials. Taken together these data point out the
ACOG’s call for the need of further study of optimal magnesium
protocol and dosage when given for neuroprotection.
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