Retrospective studies by Pritchard and Chelsey evaluated serum magnesium concentrations in women receiving intramuscular magnesium sulfate who experienced eclamptic seizures. These studies suggested a therapeutic range for serum magnesium of 4.8–8.4 mg/dL.1,2 This therapeutic range was also supported by a study by Sibai et al.3
In a pharmacokinetic model, we demonstrated that, in women who received a 4-g intravenous (IV) loading dose followed by a 2-g/h IV maintenance dose, obese women take took approximately twice as long as women of mean body weight in the sample to achieve these previously accepted therapeutic serum magnesium concentrations.4 Therefore, the aim of the current study was to prospectively validate our pharmacokinetic model that suggested dosing alterations are needed based on body mass index (BMI, calculated as weight in kilograms divided by height in meters squared).
In this prospective, randomized controlled trial we enrolled women who met the following criteria: aged 15–45 years with preeclampsia or at high-risk of developing preeclampsia, BMI of 35 or higher, and at least 32 weeks of gestation. We excluded women with serum creatinine levels greater than 1.1 mg/dL. The study was approved by the Oregon Health and Science University Institutional Review Board, and the trial was registered at ClinicalTrials.gov (NCT02835339).
After consent, women were randomized in 1:1 allocation to one of two magnesium sulfate treatment groups: a 4-g IV loading dose administered over 20 minutes followed by a 1-g/h IV maintenance dose (the Zuspan regimen, which is standard at our institution), or a 6-g IV loading dose administered over 20 minutes followed by a 2-g/h IV maintenance dose. Simple randomization was performed using the random number generator function in OpenEpi 3.01 (open-source software for epidemiologic statistics) by a member of the research team not involved with recruitment or data entry. Magnesium was administered only if criteria for preeclampsia with severe features were met.5
Neither the managing clinicians nor the patients were blinded to the treatment group. Serum magnesium concentrations were obtained at baseline, and at 1 hour, 4 hours and at the time of delivery after magnesium sulfate administration. The primary outcome was the proportion of women with serum magnesium concentrations of less than 4.8 mg/dL 4 hours after magnesium administration. The main secondary outcome of interest was the proportion of women who had subtherapeutic serum magnesium concentrations at the time of delivery.
Data on demographic, obstetric, and neonatal covariates were collected and included maternal age, race, serum creatinine concentration, time to delivery after administration, BMI, mode of delivery, parity, gestational age, Apgar scores, neonatal respiratory distress syndrome, and neonatal intensive care admission. Self-reported maternal side effect data were collected prospectively by nursing staff during magnesium administration, including flushing, sedation, nausea, vomiting, and pain at IV site. Objective evaluation for magnesium toxicity was performed every 4 hours during magnesium administration, which included urine output, patellar tendon reflexes, respiratory rate, and blood pressure evaluation.
Sample size estimates were based on Brookfield4 and Tudela6 data, considering their estimates of the proportion of women with subtherapeutic serum magnesium concentrations less than 4.8 mg/dL in these studies. We used a BMI threshold of 35 because the Brookfield study suggests that the most profound changes in magnesium disposition occur in women with this level of obesity.4
We assumed that 80% of women in the standard group with the 4-g IV loading dose followed by the 1-g/h IV maintenance dose would have subtherapeutic concentrations and that 35% of women in the alternate group with the 6-g IV loading dose followed by the 2-g/h IV maintenance dose would have subtherapeutic concentrations 4 hours after magnesium sulfate administration. Assuming alpha=0.05 and power of 80%, a sample size of 18 women per group was planned to be able demonstrate a risk ratio of greater than two for subtherapeutic serum magnesium concentrations in the standard Zuspan dosing group.
Traditional univariate analysis with Fisher exact test or χ2 for categorical variables and t test for comparison of means or Mann-Whitney U test for comparison of medians for continuous data were used where appropriate. Normality was assessed using the Shapiro-Wilk test. P<.05 was considered statistically significant for our primary outcome measure and P<.01 for secondary outcomes.
Between July 12, 2016, and March 14, 2019, 89 women were approached for participation; ultimately, 37 were enrolled (Fig. 1). There were no baseline differences between the two groups (Table 1). A significantly greater proportion of women administered the Zuspan regimen had subtherapeutic serum magnesium concentrations at 4 hours (100% [95% CI 59–100] vs 63% [95% CI 41–81]; P=.01) compared with women administered the higher dose regimen (Table 2). Similarly, at time of delivery, a significantly greater proportion of women administered the Zuspan regimen had subtherapeutic concentrations (92% [95% CI 66–100] vs 27% [95% CI 12–51]; P<.01) compared with women administered the alternate regimen. Women in the alternate higher dose group (6-g IV loading followed by 2-g/h IV maintenance) had significantly higher serum magnesium concentrations at 4 hours and at time of delivery compared with women in the Zuspan group (Table 2).
There were no statistically significant differences in maternal side effects between the two groups; however, the absolute rates of nausea and flushing were higher in the alternate dosing group. Nausea was reported in 10.5% of women who received the alternate 6-g IV loading dose followed by the 2-g/h IV maintenance dose and in 5.5% of women who received the Zuspan regimen. Flushing was reported by 5.2% of women who received the higher dose, compared with 0% in those who received the standard Zuspan regimen. The only magnesium toxicity reported was a loss of patellar tendon reflexes, where this was noted once in each of the dosing groups. The highest serum magnesium concentration achieved by any woman was 7.4 mg/dL. There were no significant differences observed in neonatal outcomes between the two dosing groups (Appendix 1, available online at http://links.lww.com/AOG/C83).
We found that a significantly greater proportion of obese women with preeclampsia have therapeutic serum magnesium concentrations (defined as serum magnesium concentration of 4.8 mg/dL or higher) for eclamptic seizure prophylaxis when administered a magnesium sulfate regimen of a 6-g IV loading dose followed by a 2-g/h IV maintenance dose, compared with women who receive a 4-g IV loading dose followed by a 1-g/h IV maintenance dose.
There has been an increasing research effort to tailor magnesium sulfate dosing administered to pregnant and postpartum women to maximize benefits, minimize side effects, and address challenges in resource limited settings.4–12 Interestingly, recent data published by Du et al8 that apply pharmacokinetic data to women with preeclampsia from the Magpie trial13 suggest that the therapeutic serum concentration to prevent the first seizure is likely closer to 3.6 mg/dL, with multiple regimens available to achieve this concentration.7,8 When we used 3.6 mg/dL as the threshold for a therapeutic serum concentration in the participants from the current study, we still found that, 4 hours after administration, 95% of women in the alternate dosing group had therapeutic concentrations, compared with 31% of women in the standard Zuspan group; by the time of delivery, 100% of women receiving the 6-g IV loading dose followed by 2-g/h maintenance dose had therapeutic concentrations, compared with 50% of women receiving the 4-g IV loading followed by the 1-g/h IV maintenance dose. The findings from our study support the previous retrospective trials and prospective pharmacokinetic modelling that show dosing requirements increase with BMI to achieve serum magnesium concentrations on par with women of the mean body weight in pregnancy, regardless of which threshold is used to define a therapeutic serum magnesium concentration.4,6,7
An unanswered question from this study is whether the increased alternate dose of magnesium sulfate actually decreases rates of seizures in the obese population. This study was not powered to examine eclampsia as an outcome and there is no evidence to date to suggest women in the United States with higher BMIs are more likely to experience eclampsia as a result of lower serum magnesium concentrations.14 No woman in our trial experienced eclampsia. Therefore, we caution against universally applying the study findings to obese women without also considering the potential for increased toxicity with higher dosing regimens.
Strengths of the study include the fact that dosing selection was based on prospective pharmacokinetic data and the alternate higher dosing regimen selected for the trial is one that has been used clinically and in other trials for preeclampsia and other indications. This was a randomized trial, and, although there was no blinding of clinicians or participating women, we used a concrete objective outcome of serum magnesium concentrations. It is unlikely that the unblinded nature of the trial would have an effect on the primary outcome.
Limitations of the trial include those of generalizability to the most extremely obese patients seen in obstetric settings today and, as mentioned, limited statistical power to evaluate clinical outcomes. We also acknowledge that magnesium sulfate regimens vary greatly within the United States and internationally, and many institutions did not adopt the Zuspan regimen as the standard after the Magpie trial was published.13,15 This may limit the generalizability of the findings where the alternate higher dose regimen used in this trial is already administered as standard treatment.
Women with BMIs of 35 or higher are significantly more likely to achieve therapeutic serum magnesium concentrations (defined as serum magnesium concentration of 4.8 mg/dL or higher) for eclampsia prophylaxis when administered a 6-g IV loading dose followed by a 2-g/h IV maintenance dose, compared with women who received a 4-g IV loading dose followed by a 1-g/h IV maintenance dose.
Authors' Data Sharing Statement
- Will individual participant data be available (including data dictionaries)? Individual deidentified participant data (including data dictionaries) will be shared at the request of other researchers.
- What data in particular will be shared? All data used in the production of this manuscript will be shared.
- What other documents will be available? Study related documents, including the study protocol, will be available upon request.
- When will data be available (start and end dates)? Data will become available upon publication of the manuscript for 12 months.
- By what access criteria will data be shared (including with whom, for what types of analyses, and by what mechanism)? Criteria to access sharing data include inquiries directly to the Principal Investigator, to inform future research planning, by password-protected files.
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