Intrapartum Magnesium Sulfate and the Potential for Cardiopulmonary Drug-Drug Interactions

Abstract

Objective

This study sought to determine the frequency of possible cardiopulmonary drug-drug interactions among pregnant women who received intrapartum magnesium sulfate (MgSO₄).

Methods

Pregnant women admitted to an Intermountain Healthcare facility between January 2009 and October 2011 were studied if they received one or more doses of MgSO₄. Concomitant medications were electronically queried from an electronic health records system. Adverse events were identified using administrative discharge codes. The frequency of cardiopulmonary drug-drug interactions was compared among women who did, and did not, receive aminoglycoside antibiotics, antacids / laxatives, calcium channel blockers, corticosteroids, diuretics, neuromuscular blocking agents, and vitamin D analogs, all of which are contraindicated for patients receiving MgSO₄.

Results

Overall, 683 women received intrapartum MgSO₄ during the study period. A total of 219 MgSO₄ potentially interacting drugs were identified among 155 (23%) unique patients. The most commonly identified potentially interacting agents included calcium channel blockers (26%), diuretics (25%), and antacids / laxatives (19%). Longer hospital stays were significantly associated with increasing numbers of MgSO₄ interacting drugs (P<0.001). Three of 53 (6%) women who received furosemide experienced a cardiac arrest, compared to 0 of 618 (0%) women who did not receive furosemide (Fisher’s Exact Test P<0.001).

Conclusion

Intrapartum administration of drugs that interact with MgSO₄ is common and associated with prolonged hospital stays and potentially cardiopulmonary drug-drug interactions. Caution is warranted when prescribing MgSO₄ in combination with known interacting medications.

INTRODUCTION

Magnesium sulfate (MgSO₄) is currently used in pregnancy for prevention and treatment of pre-eclampsia and eclampsia, and more recently, for fetal neuroprophylaxis prior to preterm birth. While a Cochrane Review of women at risk of preterm birth who received MgSO₄ demonstrated a neuroprotective effect for the fetus,¹ the United States Food and Drug Administration (FDA) recently revised MgSO₄ prescription drug labels to indicate that there is “positive evidence of human fetal risk when the drug is used during pregnancy.”² This change was prompted following a review of the published literature in which 18 cases of skeletal abnormalities were reported among neonates exposed to MgSO₄ for a mean duration of 10 weeks.^3–6 The recently updated FDA guidelines now caution that MgSO₄ should not be used for more than 7 days to prevent pre-term labor.² Although MgSO⁴ has been used historically to prevent pre-term labor,⁷ several randomized controlled trials have now confirmed that it is ineffective as a tocolytic.^8–11

Many adverse events can result from MgSO₄ administration. One of the most serious is the neuromuscular blockade which can be observed on a continuum from diminished deep tendon reflexes to somnolence to flaccid paralysis.¹² The diaphragm and other respiratory muscles may also be affected and cause respiratory compromise.¹² It has long been recognized that MgSO₄ administration alters maternal calcium metabolism when used alone or when used concurrently with calcium-channel blockers such as nifedipine.¹³ Magnesium also acts as a calcium channel antagonist, and therefore, can cause bradycardia, hypotension, electrocardiogram changes (i.e., P–Q interval prolongation and widened QRS complex), and at very high levels, cardiac arrest.¹⁴ Hypocalcemia can also result from MgSO₄ therapy by inhibition of parathyroid hormone.¹⁵ The potential also exists for severe and/or prolonged respiratory depression which can result from the concomitant use of aminoglycoside antibiotics and other neuromuscular blocking agents.^16,17 Many other drugs and drug classes have been identified that interact with MgSO₄, which can result in an increased pharmacological effect or increased risk of magnesium toxicity, both of which increase the potential for adverse events.¹⁸

The extent to which pregnant women receiving MgSO₄ are simultaneously exposed to potentially-interacting drugs is unknown. In this study, the prescribing patterns of concomitant drugs were evaluated along with the frequency with which pregnant women were exposed to MgSO₄ and one or more potentially-interacting drugs. As a secondary objective, the frequency of cardiopulmonary drug-drug interactions and their impact upon clinical outcomes were examined.

MATERIALS AND METHODS

Ethics approval

Ethical approval was granted for this retrospective chart review study. This study was reviewed and granted a waiver of informed consent by the University of Utah and Intermountain Healthcare Institutional Review Boards.

Study design

Pregnant women who were hospitalized and received intravenous MgSO₄ at an Intermountain facility from January of 2009 through October 2011 were identified. Patients receiving one or more doses of MgSO₄ were included in this study. Demographics, concomitant medications given ± 48 hours from MgSO4 administration, and clinical outcomes were obtained electronically by querying Intermountain’s electronic data warehouse system.

Magnesium sulfate dosing

Standardized MgSO₄ administration protocols are used at Intermountain facilities. Typically, a standard loading dose of 4–6 grams was infused over 15–30 minutes, followed by 1–2 grams/hour administered as a continuous infusion. This standardized dosing regimen may differ slightly between the 17 institutions studied and whether treatment was for preeclampsia/eclampsia and/or fetal neuroprophylaxis. MgSO₄ administration was not targeted to achieve a specific therapeutic range; however, patients were monitored for signs and symptoms of toxicity.¹⁹

Assessment of cardiopulmonary drug-drug interactions

The adverse effects of MgSO₄ have primarily been attributed to its action as a smooth muscle relaxant.²⁰ At high serum magnesium levels (>15 mEq/L) cardiac arrest and acute respiratory failure have been reported.²¹ Cardiopulmonary adverse events were identified in this population of pregnant women using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9) discharge diagnosis codes. Patients with cardiac arrest and acute respiratory failure were initially identified using ICD-9 codes (427.5 and 511.81, respectively) and their medical records were then manually reviewed to confirm the diagnosis.

Statistical methods

Descriptive statistics were used to calculate the number of MgSO₄ drug-drug interactions. Drug interactions classified as ‘major’ or ‘moderate’ according to a clinical significance classification algorithm featured on Drugs.com were evaluated in this study.¹⁸ This classification scheme incorporates data from Micromedex^™, Cerner Multum^™, and Wolters Kluwer^™ and was current as of 18 June 2013.

A generalized logistic regression model with a categorical number / extent-of-interactions term was used to evaluate the influence of MgSO₄ drug-drug interactions upon total hospital length of stay. Pairwise t-tests were used to assess the significance of the drug-drug interaction upon the mean hospital length of stay. Categorical variables were compared using the χ² test or Fisher’s exact test, as appropriate. All statistical analyses were performed in Stata 11.2 (StataCorp, College Station, TX) and R 3.0.1 (R Foundation for Statistical Computing, Vienna, Austria).

RESULTS

Demographic and clinical characteristics

Overall, 683 women received intravenous MgSO₄ over the study period. Of these, 130 (19%) received MgSO₄ for the treatment of mild or not-otherwise-specified pre-eclampsia. Severe pre-eclampsia was documented as the primary indication for treatment in 341 (50%) cases and eclampsia in 8 (1%) cases. There were 267 (39%) diagnosed with early-onset delivery. Diagnosis of both pre-eclampsia / eclampsia and early-onset delivery was common and occurred in 210 (31%) of these cases. The mean age of these women was 27.4 (standard deviation (SD) ± 5.6) years (Table 1). Most women had singleton pregnancies (96%) and delivered at a mean gestational age of 35.5 (± 3.2) weeks. Newborn weights ranged from 680 to 5520 (mean 2546) grams.

Table 1.

Demographic and clinical characteristics of the 683 women who received intrapartum magnesium sulfate and their newborn infants.

Maternal characteristics at the time of delivery	Mean (± SD)
Age (yrs)	27.4 (± 5.6)
Height (cm)	165.2 (± 17.6)
Pre-pregnancy weight (kg)	74.5 (± 20.6)
Current weight (kg)	88.5 (± 20.5)
Estimated weight gain/loss during pregnancy (kg)	13.9 (± 8.1)
Estimated body mass index (BMI) at time of delivery	32.6 (± 7.5)
Maternal race / ethnicity	Number (%)
American Indian / Alaskan Native	9 (1%)
Asian	12 (2%)
Black	8 (1%)
Hispanic	108 (16%)
Pacific Islander	16 (2%)
White	517 (76%)
Other	4 (1%)
Unknown / Not reported	9 (1%)
Maternal diagnoses *	Number (%)
Mild pre-eclampsia / not otherwise specified	130 (19%)
Severe pre-eclampsia	341 (50%)
Eclampsia	8 (1%)
Early-onset delivery	267 (39%)
Early-onset delivery plus Pre-eclampsia / eclampsia	210 (31%)
Monitoring of magnesium serum concentrations	Number (%)
Mothers with one concentration measured	673 (99%)
Median (range; IQR) concentrations measured/patient	2 (1–18; IQR 1–3)
Mean ± SD of 1st concentrations measured	5.0 ± 1.9 mg/dL
Newborn characteristics
Gestational age at delivery, weeks	35.5 (± 3.2)
Birthweight, grams	2,546 (± 792)

^*Sums to more than 100% due to patients with multiple overlapping diagnoses (e.g., pre-eclampsia and early-onset delivery).

Interacting medications

A total of 219 MgSO₄ drug-drug interactions were identified among this cohort of pregnant women. At least one MgSO₄ drug-drug interaction was detected for 155 (23%) unique patients (Table 2). As shown in Figure 2, the majority of MgSO₄ drug interactions occurred among women who were concomitantly prescribed calcium channel blockers (e.g., nifedipine), diuretics (e.g., furosemide), and antacids / laxatives (e.g., magnesium hydroxide). A minority (2%) received the aminoglycoside agent gentamicin, which has been reported to potentiate the neuromuscular blocking activity of magnesium (Table 3).¹⁷

Table 2.

Frequency of identified drug interactions among pregnant women receiving magnesium sulfate (MgSO₄).

Total number of patients receiving MgSO4	683 (100%)
Patients with one or more drug-drug interaction(s)	155 (23%)
MODERATE* (Moderately Significant) Interaction	142 (21%)
1 Interacting drug	105 (15%)
2 Interacting drugs	25 (4%)
3 Interacting drugs	10 (1%)
4 Interacting drugs	1 (<1%)
5 Interacting drugs	1 (<1%)
MAJOR* (Highly Significant) Interaction	13 (2%)
1 MAJOR interacting drug	4 (1%)
1 MAJOR and 1 MODERATE interacting drug	6 (1%)
1 MAJOR and 2 MODERATE interacting drugs	3 (<1%)

^*Moderate and major drug-drug interactions were classified according to the drug interaction classification featured on Drugs.com.¹⁸ Data sources include Micromedex^™, Cerner Multum^™, Wolters Kluwer^™ and others.

Figure 2.

Total hospital length of stay among women who received intrapartum magnesium sulfate (MgSO₄) by the number and type of identified drug-drug interactions. White circles represent mean values and black bars indicate 95% confidence intervals. Major drug-drug interactions were classified according to the drug interaction classification scheme featured on Drugs.com.¹⁸

Table 3.

Classification and potential risks associated with interacting drugs.

Drug Class	Classification of Drug Interaction*	Potential Risk
Aminoglycoside antibiotics	Major	Possess neuromuscular blocking activity; Potential additive pharmacological effect
Antacids / laxatives	Moderate	May increase the risk of magnesium toxicity
Calcium channel blockers	Moderate	May result in hypotension and neuromuscular blockade
Corticosteroids	Moderate	Potential for significant loss of electrolytes; Potentiates the risk of hypokalemia
Diuretics	Moderate	May potentiate the pharmacological effects of diuretics
Neuromuscular-blocking agents	Moderate	Magnesium salts may enhance the effects of neuromuscular-blocking agents
Vitamin D analogs	Moderate	Increases the risk of hypermagnesemia; Potential additive pharmacological effect

^*Moderate and major drug-drug interactions were classified according to the drug interaction classification featured on Drugs.com.¹⁸ Data sources include Micromedex^™, Cerner Multum^™, Wolters Kluwer^™ and others.

Adverse drug-drug interactions

A cardiopulmonary adverse event occurred among 13 of 155 (8%) women who received one or more MgSO₄ interacting drugs. None of the 531 women who did not receive an interacting drug experienced a cardiopulmonary adverse event (Fisher’s Exact test P<0.001). Twelve of the 13 (92%) cardiopulmonary adverse events were documented among pregnant women who simultaneously received a diuretic agent. The most commonly identified diuretic was furosemide, which accounted for 11 (85%) of the cardiopulmonary adverse drug-drug interactions. Three of 53 (6%) women who received furosemide with MgSO₄ experienced a cardiac arrest as compared to 0 of 618 who did not receive furosemide (Fisher’s Exact test P<0.001). Additionally, 9 (17%) furosemide-treated women developed acute respiratory failure as compared to 2 of 618 (0.3%) women who did not receive furosemide (Fisher’s Exact Test P<0.001).

Clinical outcomes

Women who were prescribed one or more potentially MgSO₄ interacting drugs delivered earlier (mean gestational age 35 vs. 36 weeks; P=0.01) and gave birth to newborns with lower birth weights (mean 2400 vs. 2587 grams; P=0.01). Additionally, maternal hospital stays were prolonged among women who had a MgSO₄ drug-drug interaction identified (Figure 2). Among women who received intrapartum MgSO₄ without the concomitant administration of a potentially interacting medication the mean hospital length of stay was 3.4 (± 2.5) days, as compared to 4.7 (± 5.6) days among women who were prescribed one potentially interacting drug and 7.8 (± 14.0) days among women who received two or more potentially interacting drugs (P<0.001 for all).

COMMENT

Pregnant women are frequently prescribed MgSO₄ with one or more concomitant medications that are known to interact and have the potential to result in toxicity.²² The most commonly prescribed classes of MgSO₄ interacting drugs included diuretics, calcium channel blockers, and antacids / laxatives. Women who received a MgSO₄ interacting drug had longer hospital stays and a lower gestational age at delivery. Concomitant administration of the diuretic agent furosemide was associated with higher rates of cardiac arrest and acute respiratory failure.

Acute or chronic hypertensive disorders affect up to 8% of pregnant women in the United States.²³ Complications of pre-eclampsia, including severe hypertension requiring pharmacotherapy and major fluid imbalances that cause cerebral or pulmonary edema, typically occur within the first two weeks after delivery.²⁴ Orally administered diuretics, such as furosemide, are thought to decrease the need for antihypertensive therapies, reduce the incidence of side effects, and shorten hospital stays.²⁵ However, laxatives may potentiate the pharmacological effects of diuretics.²⁶ MgSO₄ can cause significant fluid and electrolyte loss, the effects of which may be additive to those of diuretics.²⁷ Metabolic imbalances – including the depletion of sodium, potassium, magnesium, and zinc – may occur and have been associated with heart failure and cardiac arrhythmias.^28,29 In this study, it was found that the concomitant administration of MgSO₄ and furosemide was associated with an increased risk of cardiopulmonary adverse events, which may have occurred as a consequence of profound fluid loss and electrolyte imbalances.

Other commonly identified MgSO₄ interacting drugs included calcium channel blockers and antacids / laxatives. Calcium channel blockers are routinely used to treat pregnancy-induced hypertension; however, guidelines from the National Heart Lung and Blood Institute advise clinicians to avoid concomitantly administering calcium channel blockers and MgSO₄ on the basis of two case reports that described two cases of severe maternal hypotension and two cases of transient neuromuscular blockade.^30–32 In this study, nearly 1 in 10 pregnant women simultaneously received MgSO₄ and a calcium channel blocker and two (4%) experienced a cardiopulmonary drug-drug interaction. Several case reports have described iatrogenic magnesium overdoses resulting in cardiac conduction delays, asystole, apnea, and coma following the concomitant administration of MgSO₄ and another magnesium-containing antacid / laxative.^33,34 Although pregnancy results in a physiologic increase in renal function,³⁵ more than 1 in 20 pregnant women in this study contemporaneously received MgSO₄ and another magnesium-containing antacid / laxative. In this population, close clinical monitoring for signs and symptoms of magnesium toxicity is warranted.

The interpretation of this study’s findings is subject to several limitations. First, we have reported an association between several drugs that are known to interact with MgSO₄ and their impact upon clinical outcomes, however due to the observational retrospective design of this study we cannot determine causality nor control for concurrent illness or disease severity. Therefore, we cannot rule out that the clinical differences described herein are not secondary to drug-drug interactions. Clinical caution is therefore warranted when considering the use of these drugs concurrently.³⁶ Second, the use of ICD-9 discharge codes may lead to misclassification of adverse drug-drug interactions; however, medical records were manually reviewed for each of the patients who had an ICD-9 code for cardiac arrest or acute respiratory failure and they were found to feature 100% agreement. Furthermore, in a separate control cohort of 299 women who received intrapartum furosemide alone over the same timeframe, none experienced a cardiac arrest or an episode of acute respiratory failure. Lastly, it was not possible to associate number of maternal MgSO₄ doses with the development of adverse events, although this warrants future study.

The concomitant administration of MgSO₄ and other drugs known to result in adverse drug interactions is common among pregnant women. The number of MgSO₄ drug-drug interactions was associated with both longer hospital stays and lower gestational age at delivery. Moreover, several women experienced cardiac arrest and acute respiratory failure. MgSO₄ drug-drug interactions occurred most frequently among patients receiving concomitant diuretics, calcium channel blockers, and antacids / laxatives. All obstetric care providers should be aware of these cardiopulmonary drug-drug interactions and consider prescribing non-interacting medications when alternative therapies are available.

Figure 1.

Drug classes identified in magnesium sulfate (MgSO₄) drug-drug interactions among hospitalized pregnant women.