Neonatal cardiovascular and cerebral function following antenatal maternal MgSO4

administration

Charalampos Kotidis1, Antonio Eleuteri2, A. Michael Weindling1, Andrew Sharp1, Zarko

Alfirevic1, Mark A. Turner1.
1
Department of Women’s and Children’s Health, University of Liverpool, Liverpool, UK.
2
Department of Medical Physics and Clinical Engineering, Royal Liverpool and Broadgreen
University Hospitals NHS Trust (RLBUHT), Liverpool, UK

Abstract

Objective To examine the relationship between the extent of maternal exposure to

magnesium sulphate (MgSO4) and neonatal magnesium concentrations (Mg2+),

echocardiographic and cerebral biomarkers.

Design Prospective convenience observational study.

Setting Tertiary medical centre.

Patients Neonates 24-28+6 weeks’ gestation and postnatal age ≤72 hours over a 2-year

period.

Intervention Non-randomly allocated administration of 4g MgSO4 for neuroprotection by

intravenous bolus followed by a continuous infusion of 1g/hour until delivery.

Main outcome measures Neonatal Mg2+, echocardiographic and cerebral biomarkers and

clinical outcomes.

Results A total of 51 neonates were recruited with median (IQR) GA 26.6 weeks (25.7-28.0)

and median birth weight (BW) 900 grams (760-1,080). Thirty-three mothers (65%) received

antenatal MgSO4 for neonatal neuroprotection. The median duration of MgSO4 infusion was

7.5 hours (IQR 3.0-12.0). There was a significant association of MgSO4 infusion duration and

neonatal Mg2+ (coefficient 0.21, F=13.7, P=0.0005). BMI was independently associated with
neonatal magnesium concentrations (coefficient -0.0029, F=6.86, P=0.0018). There was no

significant association between Mg2+ and BW, PDA score, cerebral oxygenation index or

Burdjalov score.

Conclusions

Maternal BMI and duration of MgSO4 infusion have significant impact on neonatal Mg2+ and

possibly on clinical outcomes. It is feasible to assess complex neonatal pharmacodynamic

measures and clinical outcomes. Further dose-finding studies should be based on

multicompartmental population PK studies that include maternal and neonatal

pharmacodynamic measures.

Keywords: Magnesium sulphate, antenatal, preterm infant, echocardiography, near-infrared

spectroscopy, amplitude integrated electroencephalography, neuroprotection.

Word count 2464

What is already known on this topic

 Antenatal maternal MgSO4 administration is an effective neuroprotective

intervention for preterm infants.

 The optimal dose and duration of antenatal maternal MgSO4 treatment remains

unknown due to limited pharmacokinetic data.

 The mechanism of action of MgSO4 is unknown and there are limited data for its

pharmacodynamic effects on neonatal cardiac and cerebral function.

What this study adds

• Maternal BMI and duration of MgSO4 infusion have significant impact on neonatal

Mg2+. Individualised dosing should be further explored.

• Mg2+ does not have significant effect on PDA score, cerebral oxygenation and

cerebral electrical activity.

• An antenatal intravenous MgSO4 infusion of at least 8 hours may be needed to

achieve neonatal Mg2+ above 1 mmol/L.

• Further dose-finding studies should be based on multicompartmental population PK

studies that include maternal and neonatal PD measures.

Introduction

Low dose antenatal magnesium sulphate (MgSO4) is commonly administered to the mother

to treat severe pre-eclampsia or provide neonatal neuroprotection (1-3). In animals high

dose magnesium can affect fetal brain organogenesis (4, 5). Neonatal adverse reactions to

maternal administration of MgSO4 before birth could include cardiovascular or neurological

sequelae (6, 7). Increased maternal serum magnesium concentrations have been associated

with lower 1-minute and 5-minute Apgar scores, intubation in the delivery room, hypotonia

and admission to special care (8), suggesting that neonatal safety should be balanced against

efficacy during dose selection.

The optimal dosage regimen for maternal MgSO4 treatment remains unknown (5, 9, 10). The

materno-placento-fetal unit is a multicompartment system that reflects multiple

physiological influences (11). Among pregnant women a two-compartment model for

magnesium concentrations is appropriate, although a one compartment model has a better

fit during pre-eclampsia (12). Brookfield et al developed a population PK model of maternal

concentrations and cord blood (13). They found that maternal weight and a diagnosis of

preeclampsia significantly affect maternal and neonatal serum magnesium levels. Maternal

exposure was associated with significantly higher magnesium concentrations in neonatal

samples within 48 hours of birth (14). This descriptive data is not sufficient to develop dosing

recommendations in the absence of a pharmacokinetic (PK) model, and information about

the relationship between neonatal serum ionised magnesium concentrations (hereafter

indicated as Mg2+) and effects on the neonate. That is, there are no reports of perinatal PK

and neonatal pharmacodynamics (PD). In order to support the design of a study that

integrates maternal and neonatal PK and PD data, we conducted a perinatal feasibility study.

We tested the hypothesis that the extent of antenatal administration of magnesium to the
mother is associated with neonatal characteristics that reflect the function of organs likely to

be affected by magnesium; namely the heart and brain.

The objectives of this study were to examine the relationship between the extent of

maternal exposure to MgSO4 and Mg2+, echocardiographic and cerebral biomarkers.

Methods

This was a prospective convenience observational study recruiting neonates 24-28+6 weeks’

gestation and postnatal age ≤72 hours.

Patient identification

Mothers with threatened premature labour or planned iatrogenic preterm delivery were

approached in the maternity ward and asked for consent pre- or postnatally.

Recruitment

Neonates admitted or transferred to Liverpool Women’s Hospital during the first three days

after birth from November 2014 until December 2016 were included in the study. Exclusion

criteria were: non-viability; chromosomal anomalies or other malformations likely to affect

cardiovascular adaptation; intraventricular haemorrhage (IVH) grade 3 or 4 in the initial

cranial ultrasound scan.

Obstetric management

When clinically appropriate and possible, 4g of MgSO4 for neuroprotection was given by

intravenous bolus over 20 min followed by continuous infusion of 1g/hour until delivery in

accordance with national guidelines (2, 15). MgSO4 was administered either for maternal

and fetal neuroprotection in cases of severe preeclampsia or for fetal neuroprotection in the

case of non-preeclamptic indications for preterm delivery, such as severe fetal growth

restriction or spontaneous preterm labour.

Data collection

Maternal assessment included: age; BMI; antenatal history, scans, medicines (including

steroids); indication and duration of MgSO4 administration; reason for not receiving MgSO4;

mode of delivery. Neonatal records were reviewed for gender, gestation age (GA), BW,
APGAR scores at 1 and 5 minutes, cord pH and base excess, patent ductus arteriosus (PDA)

and death. Cerebral injury was defined by cranial ultrasonography (CUS) and dichotomised

into “mild” (IVH grade 0-2) or “severe injury” (IVH grade 3 or 4) according to Papile criteria

(16).

Echocardiography. A Vivid E9 machine with a 12-Hz probe (GE Medical, Milwaukee, USA)

was used daily during the first three days after birth. A PDA severity score was calculated

(17).

Digital amplitude integrated electroencephalography (aEEG). Recordings were performed for

four hours on each of the first three days after birth using an Olympic Brainz Monitor (Natus

Medical Incorporated, Munich, Germany). Hydrogel electrodes were applied to the neonatal

scalp after skin preparation, using the two parietal positions (P3 and P4) and a reference

electrode placed on the shoulder. Impedance was kept at <10 kΩ. The Burdjalov score was

used to assess the aEEG trace (18-20).

Near infrared spectroscopy (NIRS). Cerebral oxygenation was assessed using a NIRO-200NX

oximeter (Hamamatsu Photonics, Fukuoka, Japan) during aEEG monitoring. The probe was

placed preferably on the left fronto-parietal site and stabilised with an elastic band.

Sampling frequency was set at 1 Hz. Recordings were performed for 4 hours each day. The

cerebral tissue oxygenation index (cTOI) was used as a continuous estimate of cerebral

venous oxygen saturation. The mean cTOI was calculated from the artefact free periods.

Neonatal management: Clinical management was at the discretion of the attending clinician.

Echocardiographic findings were not revealed to the clinical team unless directly requested.

PDA was treated with ibuprofen if: PDA diameter >2mm, left atrial:aortic ratio>1.8, and

infant needed ongoing ventilatory support.

Serum magnesium. Mg2+ was analysed by enzymatic assay (isocitrate dehydrogenase) on the

Architect ci8200 System platform (Abbott laboratories, London, UK). Daily samples were

obtained as part of routine clinical care. Parenteral magnesium supplementation was

commenced on the third day of life, so measurements were not affected by parenteral

magnesium.

Statistical analysis. Statistical analysis was performed using the R statistical package and the

rms library. Demographic factors were assessed using descriptive statistics.

A linear multivariate regression model was fitted. The model linearly regresses Mg2+ against

IVH severity, BW, BMI, cTOI, PDA score, Burdjalov score and MgSO4 administration, and the

latter’s interaction with the previous covariates (see Table 2 for results of the analysis.)

Due to repeated measurements taken in time, intra-subject correlation of observations is a

possibility, so estimation of the covariance matrix of the model parameters was performed

using Huber’s nonparametric “sandwich” estimator (21). Due to incomplete observations of

most of the factors (only 62 complete observations over a total of 92), a conditional multiple

imputation algorithm was applied (Bayesian Alternating Conditional Expectations) (21). The

imputation process was repeated 10 times, resulting in 10 different realisations of the data

set. Based on the imputed data sets, 10 models were fitted, and the parameters averaged to

obtain the final model parameters.

Following model fit, graphical assessment of the relationship between Mg2+ (as a function of

time) and MgSO4 administration and BMI (dichotomised according to the median for ease of

visualisation) was performed using robust nonparametric regressions by local second degree

polynomials fitting (21). Point-wise 95% confidence intervals have also been calculated. The Commented [AE1]: I only kept graphs of the covariates that the
model shows are statistically significant. This improves the
readability and emphasises the outcome of the analysis.
same technique was used to graphically assess the interaction between Mg2+and MgSO4
infusion duration for the subset of the data represented by those mothers who were

administered MgSO4.

The study protocol was approved by North West Lancaster ethics committee, REC reference:

14/NW/1274.
Results

Fifty-one neonates were recruited with median GA 26.6 weeks [Interquartile range (IQR)

25.7-28.0] and median BW 900 grams (IQR 760-1,080) (Table 1). The rest of the background

demographic variables are shown in Table 1. Thirty-three mothers (65%) received antenatal

MgSO4 for neuroprotection (including seven who had preeclampsia) and eighteen did not

receive due to reasons indicated in Table 1. Half of the neonates who did not receive MgSO4

were transferred from another hospital where MgSO4 administration for neuroprotection

was not a standard practice and the rest were due to emergency situations.

The median duration of MgSO4 infusion was 7.5 hours (IQR 3.0-12.0). Overall, regression

analysis showed a statistically significant association between MgSO4 exposure and Mg2+

during the first three days after birth (coefficient 0.21, F= 5.31, P=0.0024, Table 2). Figure 1

suggests that the relationship is nonlinear, so it can’t be described by a single parameter.

However, the model coefficient provides a simple estimate of the “trend” evidenced in the

graph.

Neonatal data Commented [AE2]: Why this additional section? These should
be part of the results?
Commented [U3]: This part of the results. I wanted just to
BW and maternal BMI are the background demographic parameters which may have a separate antenatal and postnatal relationships. We may remove it.

significant effect on the cerebral and cardiovascular biomarkers and severity of cerebral

injury. There was no significant association between Mg2+ and BW, PDA score, cerebral

oxygenation index, Burdjalov score or IVH (Table 2). Maternal BMI was associated with

neonatal magnesium concentrations (coefficient -0.0029, F=6.86, P=0.0018). There is also

moderate evidence of an interaction between BMI and MgSO4 exposure (coefficient -0.0078,

F=5.01, P=0.028). Figure 2 shows a graphical representation of these associations and

interactions. There was no significant association between Mg2+ and other clinical variables
Commented [AE4]: To what model variables do these
correspond? If this is an artefact of the previous multiple tests it
(APGAR scores at 1 and 5 minutes, cord pH, cord base excess or death). should be removed.
Discussion

This is the first study to examine the complex interaction of antenatal MgSO4 administration

with neonatal magnesium levels and neonatal haemodynamics using echocardiography,

NIRS and aEEG simultaneously in the first three days after birth. We found that MgSO4

administration, infusion duration and maternal BMI had a significant influence on Mg2+.

MgSO4 administration and Mg2+ did not have a significant effect on cardiovascular and

cerebral biomarkers following multivariate analysis.

Antenatal maternal exposure associations with neonatal magnesium concentrations

There is limited evidence regarding MgSO4 PK in pregnancy (22). The MgSO4 PK profile after

intravenous administration can be described by a 2-compartment model with a rapid

distribution alpha phase, followed by a relative slow beta phase of elimination (12).

However, the presence of preeclampsia seems to alter the Mg2+ pharmacokinetics as other

investigators have described a one-compartment model (23). MgSO4 half-life in eclamptic

mothers is four hours, but can be increased with renal failure (24).

We found that neonatal Mg2+ increased during the first three days after birth in neonates

not treated with MgSO4 as previously reported (25), but remained stable in neonates

exposed to MgSO4 and in levels higher than those considered “normal”. We did not report

any Mg2+ toxic effects, but the study was not specifically designed to investigate toxicity. The

supranormal Mg2+ need further investigation as its biological actions were proved beneficial

(1). The assessment of normality in the preterm population is a difficult task, but future

studies should be designed in view of the present findings to assess the “ideal” or “normal”

range.

The duration of MgSO4 infusion is an important factor affecting the Mg2+ as it determines the

total amount of MgSO4 administered to mothers and neonates and is consistent with
previous studies (26). Neonates in this study needed a maternal MgSO4 infusion for more

than 8 hours to achieve Mg2+ levels above 1 mmol/L (Figure 1). This may indicate the need of

at least 8 hours of infusion before birth for neuroprotective effects to be evident or that the

loading dose used in this centre is inadequate. However, another study did not find an

association between infusion duration and neonatal outcomes (10).

Maternal BMI had also a statistically significant effect on Mg2+ (Figure 2 suggests the effect is

stronger on days 2 and 3.) Τhe clinical significance of BMI on Mg2+ is mild as an increased

BMI by 20 units will decrease Mg2+ by around 0.06mmol/L without MgSO4 infusion, and by

0.2mmol/L with MgSO4 infusion. Previous studies found that women with higher BMI

needed longer MgSO4 infusion to reach a steady state, suggesting that they may benefit

from a tailored loading dose. Pregnancy may be associated with increased drug dilution,

particularly in women with more weight gain (13). Women with higher BMI have lower

maternal Mg2+ that were considered sub-therapeutic for preventing seizures (27, 28).

Heart associations with neonatal magnesium concentrations

Our multivariate model did not find a significant association between Mg2+ levels and PDA

score (including interactions of the latter with MgSO4.) This is consistent with previous

reports that found that antenatal MgSO4 produced no consistent cardiovascular effects in

the neonate in the first 24 hours (29). However, other investigators found that higher levels

of serum magnesium at birth, but within normal limits, were associated with a delayed

closure of the ductus arteriosus, and mild but not severe IVH (30).

Brain associations with neonatal magnesium concentrations

There is limited evidence regarding the effect of Mg2+ on cerebral haemodynamics and

function. Our model did not find any significant association between Mg2+ and cTOI or

cerebral electrical activity. Verhagen et al. found that treating pregnant women with
labetalol and/or MgSO4 may influence cerebral oxygen extraction in their offspring shortly

after birth as this intervention decreased FTOE on the first day after birth (31). Neonates

exposed to MgSO4 had similar systemic and cerebral hemodynamics, but lower cFTOE

compared to non-exposed. These findings suggest reduced cerebral metabolism may be a

component of the neuroprotective actions of antenatal MgSO4. The observed lack of an

association between MgSO4 and IVH through the interaction with Mg2+ is consistent with the
most recent Cochrane meta-analysis that found no significant association between MgSO4
Commented [AE5]: The model doesn’t test association
between MgSO4 and IVH, only whether their interaction is
associated with Mg2+. Or did you mean something else?
Commented [U6]: Should we mention that

and the incidence of IVH (1).

Study limitations

This was an observational study with a small number of participants not specifically designed

to assess the effect of MgSO4 on neonatal haemodynamics and underpowered to detect

significant neonatal outcomes. Due to consent issues and other competing studies, a small

number of neonates were recruited from the first day after birth when the haemodynamic

changes are expected to be more significant and the difference in neonatal magnesium

levels higher.

Implications for future work

There is an urgent need for a well-designed study of the relationship between antenatal

MgSO4 and perinatal pharmacokinetics and pharmacodynamics to indicate the optimal dose

and infusion duration (32). In the light of our results, points to consider in the planning

(design and sample size) of the perinatal PK-PD studies are the need: 1) to resolve the

interactions between BW, maternal BMI, GA and pre-eclampsia; 2) to explore whether the

loading dose for mother is not sufficient to attain steady state for the fetus and whether

personalising the loading dose is effective; 3) for sufficient participants to explore

biomarkers of brain and haemodynamic function and their relationships to magnesium; 4)

the potential for different relationships between the variables on different days after birth.

Conclusion

Maternal BMI and duration of MgSO4 infusion (and their interaction) have significant impact

on neonatal Mg2+ that may merit changes to the dosing regimen, for example a personalised

loading dose. There is not enough evidence of an association of Mg2+ with PDA score,

cerebral oxygenation and cerebral electrical activity. Dose finding studies should be based

on multicompartmental population PK studies that include maternal and neonatal PD

measures.
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 Table 1 Maternal and neonatal demographics among those with and
without antenatal MgSO4 administration Commented [AE7]: The header is in a different format than
Table 2. Which one is appropriate for the journal?

No antenatal MgSO4 Antenatal MgSO4

Patients 18 (35) 33 (65)

Maternal age (years) 32 (31-35) 31 (26-34)

Maternal booking BMI 24.7 (23.6-37.1) 26.2 (22-32.4)

IUGR, n (%) 1 (5.5) 4 (12)

Chorioamnionitis, n (%) 4 (22) 11 (33)

PIH, n (%) 1 (5.5) 7 (21)

Spontaneous preterm labour, n (%) 17 (33) 26 (51)

1 Home birth

8 Transfers from another

hospital

2 Cord prolapse

2 Placenta abruption

2 Not enough time

3 Not considered
Antenatal steroids, n (%)
No 2 (4) 0
1 dose 5 (10) 6 (12)
2 doses 11 (21) 27 (53)
Mode of delivery, n (%)

Vaginal 12 (24) 16 (31)

Emergency caesarean 6 (12) 14 (27)

MgSO4 infusion duration (hours) 0 7.5 (3-12)

Male, n (%) 11 (21) 21 (41)

Gestation (w) 26.5 (25.7-27.7) 26.7 (25.4-28.2)

Birth weight (Kg) 0.92 (0.718-1.17) 0.89 (0.76-0.975)

Cord BE (mmol/L) -6.4 (-0.6-(-16.3)) -3.4 (-2-(-6.1))

APGAR 5’ 8 (3-9) 7 (6-8)

Data presented as median and IQR. BMI: Body mass index, PROM: prolong rupture of membranes, PIH: Pregnancy induced
hypertension, BE: base excess.
Table 2. Linear regression model of neonatal Mg concentrations and associated variables

and biomarkers Commented [c8]: We need to make the interaction with MgSO4
more understandable/ What would you write?
Commented [U9]: I meant to explain in the text what the
Factor Coefficient F P-value asterisk symbolises.
Commented [AE10]: Since the coefficient is positive, it means
Antenatal MgSO4 administration 0.21 5.31 0.0024
that as MgSO4 increases, the Mg concentration increases, which is
the behaviour we see in Fig. 1. Note however, that the graph in Fig.
BMI -0.0029 6.86 0.0018
1 seems to suggest a nonlinear relationship which cannot be
BMI * MgSO4 -0.0078 5.01 0.028 described by a single coefficient. So, the coefficient 0.21 that we
have here could be interpreted as an estimate of the “trend” of the
BW 0.0022 0.51 0.60 graph in Fig. 2. I added this explanation in the text.

BW * MgSO4 0.15 0.61 0.44

PDA score 0.0015 0.48 0.62
PDA * MgSO4 0.0039 0.22 0.64
aEEG 0.0002 1.82 0.17
aEEG * MgSO4 0.017 1.82 0.18
cTOI -0.000036 0.13 0.88
cTOI * MgSO4 0.0052 0.20 0.65
IVH severity -0.066 1.66 0.20
IVH * MgSO4 -0.014 0.03 0.86
Commented [U11]: Antonio could you please change the titles?
MgSO4 instead of MGSO4
Mg2+ (mmol/L) instead of Mg
Days after birth instead of day
And make the titles bold and more prominent
Commented [AE12]: I removed the figure as it’s redundant.
Figure 1. The relationship between duration of antenatal MgSO4 infusion and neonatal Mg2+
concentrations.
Figure 2. Impact of BMI and antenatal MgSO4 administration on neonatal magnesium
concentrations.