Basic & Clinical Pharmacology & Toxicology, 2014, 114, 318–322

Doi: 10.1111/bcpt.12166

Maternal Magnesium Sulphate Exposure Predicts Neonatal Magnesium Blood Concentrations Catherine M.T. Sherwin1, Alfred Balch1, Sarah C. Campbell1, Jeunesse Fredrickson2, Erin A.S. Clark2, Michael Varner2,3, Chris Stockmann1, E. Kent Korgenski4, Joshua L. Bonkowsky5 and Michael G. Spigarelli1 1 Division of Clinical Pharmacology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah, USA, 2MaternalFetal Medicine, Department of Obstetrics and Gynecology, University of Utah School of Medicine, Salt Lake City, Utah, USA, 3Intermountain Healthcare, Women and Newborns Clinical Program, Salt Lake City, Utah, USA, 4Intermountain Healthcare, Pediatric Clinical Program, Salt Lake City, Utah, USA and 5Division of Pediatric Neurology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah, USA

(Received 28 August 2013; Accepted 21 October 2013) Abstract: Tocolytic use of magnesium sulphate is associated with excess neonatal mortality and has been proposed to follow a dose–response relationship. This study aimed to define the correlation between maternal and neonatal magnesium blood concentrations. Magnesium blood concentrations were retrospectively obtained for mother–neonate pairs who were cared for at an Intermountain Healthcare facility from January 2009 to October 2011. Complete data were available for 231 mother–neonate pairs. Mean (SD) maternal and neonatal magnesium concentrations were 5.43  1.69 and 2.98  0.94 mg/dL, respectively. Maternal and neonatal magnesium concentrations were highly correlated (p < 0.001). In univariate analyses, residual unexplained variability was high (r2 = 0.19). However, further multivariate analyses revealed that caesarian section, severe pre-eclampsia and Apgar score at 5 min. were significantly associated with neonatal magnesium concentrations (p < 0.05 for all). Maternal magnesium concentrations correlate with neonatal exposure. This finding suggests that maternal monitoring deserves further evaluation as a marker of foetal toxicity.

Magnesium sulphate has important roles in modern obstetrics and neonatal care. In the past, magnesium sulphate was used as a tocolytic agent to prevent contractions [1]. However, a large meta-analysis has demonstrated that this practice increases the risk of foetal and neonatal death in a dose-dependent manner [2,3]. Currently, magnesium sulphate is used to prevent and treat eclamptic seizures [4]. Recent investigations have also explored the use of magnesium sulphate as a neuroprotective agent for pre-term neonates [5–7]. Elevated maternal magnesium sulphate concentrations are associated with toxic effects that range from diminished deep tendon reflexes to apnoea and electromechanical dissociation [8–11]. Hypocalcaemia can result from inhibition of parathyroid hormone, and many non-specific, but unpleasant, symptoms are commonly observed, such as nausea, vomiting and flushing [12]. Additionally, Riaz et al. [13] reported that neonates born to mothers who received magnesium sulphate were more likely to be hypotonic and had lower Apgar scores at birth. Early results from non-randomized trials suggested that foetal exposure to magnesium sulphate may reduce the risk of developing cerebral palsy among pre-term neonates [14]. Encouraged by these findings, the Magnesium and Neurologic Endpoints Trial (MagNET), randomized and controlled trial, was conducted to investigate the effects of antenatal magneAuthor for correspondence: Catherine Sherwin, Division of Clinical Pharmacology, Department of Pediatrics, University of Utah, 295 Chipeta Way/Williams Building, Salt Lake City, Utah 84108, USA (fax +1 801 585-9410, e-mail [email protected]).

sium sulphate upon neonatal neurological development [15]. Contrary to earlier reports, this trial revealed evidence of an increased risk of intraventricular haemorrhage and subsequent cerebral palsy among neonates exposed to magnesium sulphate [15]. The authors also reported that higher concentrations of ionized magnesium, the biologically active form of magnesium, were associated with an increased risk of intraventricular haemorrhage; however, the sample size was too small to assess whether magnesium sulphate reduced the incidence of cerebral palsy at 18 months of life. More recently, the United States Food and Drug Administration (FDA) revised magnesium sulphate prescription drug labels to indicate that there is ‘positive evidence of human foetal risk when the drug is used during pregnancy’ [16]. The revised guidelines now suggest that magnesium sulphate should not be prescribed for more than 7 days to prevent pre-term labour. In light of widespread antenatal magnesium sulphate use and the concern for neonatal toxicity, we sought to clarify the relationship between maternal and neonatal magnesium concentrations in the blood. Materials and Methods Study design. This was a retrospective observational study, in which medical records were reviewed for all patients who received antepartum magnesium sulphate and were admitted to an Intermountain Healthcare facility between 1 January 2009 and 30 October 2011. Intermountain Healthcare is a large, vertically integrated not-for-profit healthcare system in the Intermountain West that owns and operates 23

© 2013 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)

MAGNESIUM CONCENTRATIONS IN NEONATES

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hospitals, including a tertiary-care children’s hospital. Patients were identified by searching the Intermountain Healthcare Enterprise Data Warehouse (EDW), which includes admissions for antenatal, perinatal and emergency room visits, plus laboratory testing and pharmacy records. This study evaluated mother–neonate pairs where each had one or more documented magnesium concentrations measured from the blood (including serum or plasma magnesium concentrations) during their hospital stay. Prior to data collection, this study was approved by the Institutional Review Boards of the University of Utah and Intermountain Healthcare. Data extracted for pregnant women included demographics and vital statistics, length of stay, magnesium sulphate treatment details, concomitant medications, diagnoses, pregnancy-related conditions, mode of delivery, anthropomorphic measurements, vital signs, age at delivery, weight and height. For neonates born after maternal magnesium sulphate treatment, the following data were available: sex, race/ethnicity, birth weight, gestational age, Apgar scores at 1 and 5 min., presence of multiple gestation, administration of any other medications within 48 hr of birth, length of hospitalization, all neonatal magnesium concentrations, and requirement for and length of mechanical ventilation.

were performed using SAS Inc., Cary, NC, USA).

Magnesium sulphate dosing. Standardized intravenous magnesium sulphate administration protocols were used across the Intermountain Healthcare system. A loading dose of 4–6 g was administered over 15–30 min., followed by 1–2 g/hr given as a continuous infusion. In clinical practice, medication administration was not titrated to a specific therapeutic range, but was administered via standardized protocols, with the patient carefully monitored for evidence of toxicity [17].

Table 1. Characteristics of the matched mother–neonate pairs with magnesium concentrations available.

Analytical method. All blood samples were collected as part of standard of care and analysed at Intermountain Laboratory Services. Blood samples were collected in a serum separator tube or tube containing lithium heparin. Serum/plasma samples were analysed by quantitative colorimetric immunochemistry spectrophotometry for total magnesium concentration (VITROSâ, model 51FS; Ortho, Clinical Diagnostics, Rochester, NY, USA). The reference interval for blood magnesium was 1.6–2.3 mg/dL for all mothers and neonates [18]. The laboratory critical values for patients younger than 18 years of age are ≤1.2 mg/dL or >4.0 mg/dL. For patients older than 18 years, the laboratory critical values are ≤1.2 mg/dL or >6.0 mg/dL. Statistical methods. Descriptive statistics were used to characterize the study cohort. Continuous variables are reported as the mean [ standard deviation (SD)]. Binary and categorical variables are presented according to their frequency (%). Linear regression models were constructed to determine the direction and magnitude of the association between maternal and neonatal magnesium concentrations. Initially, a univariate analysis was performed that was then followed by an exploratory stepwise linear regression process in which maternal and neonatal demographic, clinical and laboratory parameters were evaluated as potential covariates. The following covariates were evaluated: mean maternal magnesium concentration; maternal age (years); maternal body mass index (BMI) at delivery; maternal height and weight at delivery; method of delivery (Caesarean section versus vaginal delivery); gestational age at onset of labour and at delivery; multiple gestation; maternal pregnancy weight gain and pre-pregnancy weight; the presence and severity of pre-eclampsia and eclampsia; neonatal Apgar scores at 1 and 5 min.; neonatal C-reactive protein (CRP) concentrations; serum creatinine; human serum albumin concentrations; and conjugated and unconjugated bilirubin concentrations. Covariate selection was performed using Mallows’ Cp criterion [19]. Significant covariates were then tested in a linear mixed-effects model with a random neonatal between-subject effect. All statistical analyses

for Windows version 9.3 (SAS Institute

Results Antenatal magnesium sulphate was administered to 212 mothers who delivered 231 neonates during the study period. Demographic and clinical characteristics of these mother–neonate pairs are presented in Table 1. The majority of these women had early-onset deliveries (70%), and many were complicated by severe pre-eclampsia (67%). A total of 1,033 maternal magnesium concentrations were obtained with a mean of 5.4 (SD  1.7) mg/dL. An excess of 90% of measured maternal magnesium concentrations was classified as abnormally high, defined as a value >2.3 mg/dL (table 2). The 231 matched neonates had a total of 650 measured magnesium concentrations available, with a mean of 3.0

Maternal characteristics at the time of delivery

Mean ( SD)

Age (years) Height (cm) Pre-pregnancy weight (kg) Current weight (kg) Estimated weight gain/loss during pregnancy (kg) Estimated body mass index (BMI) at time of delivery (n = 212 unique mothers)

28.0 165 77.3 90.6 13.3 33.3

Neonatal characteristics at the time of delivery Gestational age (week) Neonatal birthweight (kg) Neonatal APGAR score at 1 min.

Maternal magnesium sulphate exposure predicts neonatal magnesium blood concentrations.

Tocolytic use of magnesium sulphate is associated with excess neonatal mortality and has been proposed to follow a dose-response relationship. This st...
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