Original Research

Association of Duration of Neuroprotective Magnesium Sulfate Infusion With Neonatal and Maternal Outcomes Jessica A. McPherson, MD, Dwight J. Rouse, MD, MSPH, William A. Grobman, Anna Palatnik, MD, and David M. Stamilio, MD, MSCE OBJECTIVE: To evaluate the association of duration of magnesium sulfate infusion with stillbirth or death, cerebral palsy, and select adverse maternal and neonatal outcomes. METHODS: This is a secondary cohort analysis of women randomized to receive magnesium sulfate within a previously reported Maternal-Fetal Medicine Units Network prospective clinical trial. The association of antenatal infusion of magnesium sulfate for less than 12 hours, 12–18 hours, and greater than 18 hours on maternal and perinatal outcomes was compared. The primary outcome was cerebral palsy of any severity or death. Secondary outcomes included cerebral palsy, death, and select maternal and neonatal outcomes. Stratified and logistic regression analyses were used. The models were adjusted for race, gestational age at birth, time

From the Departments of Obstetrics and Gynecology, the University of North Carolina School of Medicine, Chapel Hill, North Carolina, Women & Infants Hospital of Rhode Island, Warren Alpert Medical School of Brown University, Providence, Rhode Island, and Feinberg School of Medicine, Northwestern University, Chicago, Illinois. The authors thank the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the Maternal-Fetal Medicine Units Network, and the Protocol Subcommittee for making this database publically available. The contents of this report represent the views of the authors and do not represent the views of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network or the National Institutes of Health. Dr. Rouse, Associate Editor of Obstetrics & Gynecology, was not involved in the review or decision to publish this article. Corresponding author: Jessica A. McPherson, MD, Department of Obstetrics and Gynecology, The University of North Carolina School of Medicine, 3010 Old Clinic Building, Campus Box 7516, Chapel Hill, NC 27599; e-mail: [email protected]. Financial Disclosure The authors did not report any potential conflicts of interest. © 2014 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. ISSN: 0029-7844/14

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since last magnesium sulfate, any magnesium sulfate at delivery, and eligibility criteria as appropriate. RESULTS: Of 933 women available for analysis, 356, 341, and 236 received antenatal magnesium sulfate infusion for a total of less than 12 hours, 12–18 hours, or greater than 18 hours, respectively. Any cerebral palsy or death occurred in 39 women (11.7%) who received magnesium sulfate less than 12 hours, 34 women (10.3%) who received 12–18 hours of magnesium sulfate, and 20 women (8.8%) who received greater than 18 hours of magnesium sulfate. There was no difference in death or cerebral palsy among groups (less than 12 hours as reference; adjusted odds ratio [OR] 1.03, 95% confidence interval [CI] 0.60–1.77 for 12–18 hours; adjusted OR 1.08, 95% CI 0.57–2.03 for greater than 18 hours). Select maternal adverse drug affects and neonatal morbidities were also similar across groups. CONCLUSION: The duration of antenatal magnesium sulfate infusion is not associated with risk of death or cerebral palsy. The optimal treatment duration needed for maximal neuroprotection remains unknown. (Obstet Gynecol 2014;124:749–55) DOI: 10.1097/AOG.0000000000000467

LEVEL OF EVIDENCE: II

C

erebral palsy, which results from an insult to the developing fetal or neonatal brain, is the most common childhood motor disability, affecting approximately 1 in 323 children.1–3 Preterm birth and low birth weight are known risk factors for the development of cerebral palsy. Given the increasing survival of preterm neonates, cerebral palsy has ongoing and escalating medical and economical consequences.1,2,4,5 In 2008, Rouse et al6 found that antenatal magnesium sulfate exposure to women at risk for preterm delivery reduced the risk of cerebral palsy in surviving children. The authors did not, however, assess the optimal magnesium sulfate infusion duration required

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to reduce the risk of cerebral palsy. Prior studies with similar results used smaller total doses of magnesium sulfate raising the question of optimal dosing.7,8 Based on limited data, one group of investigators suggested a dose-dependent adverse effect of magnesium sulfate on perinatal outcome.9 Although the optimal duration of antenatal magnesium sulfate infusion that decreases the risk of cerebral palsy has not been defined, the Committee on Obstetric Practice and the Society for MaternalFetal Medicine agrees that, “available evidence suggests magnesium sulfate given before anticipated early preterm birth reduces the risk of cerebral palsy in surviving infants.”10 The aim of our study was to estimate the association of duration of magnesium sulfate infusion with death, cerebral palsy at 2 years of life, and select adverse maternal and neonatal outcomes to aid in determining the optimal regimen.

MATERIALS AND METHODS This study is a secondary cohort analysis of a previously reported multicenter randomized clinical trial completed by the Maternal-Fetal Medicine Units Network.6 The initial study recruited patients between 1997 and 2004 at 20 centers. Each participating center and the data coordinating center received institutional review board approval before the study. The present study, based on publicly available deidentified data, was considered exempt by the institutional review board at the University of North Carolina. The rigorous data collection procedures for the original study have been previously described.6 Importantly, infant follow-up data were obtained at 6, 12, and 24 months of age. All data were edited and validated on a regular basis. The inclusion criteria and randomization protocol for the initial prospective trial are previously detailed.6 Briefly, women were included in the initial trial if deemed to be at high risk for preterm delivery between 24 and 31 weeks of gestation because of rupture of membranes (between 22 and 31 weeks of gestation), spontaneous labor with cervical dilation of 4–8 cm, or anticipated indicated preterm delivery within 2–24 hours. Our analysis included only singleton, nonanomalous fetuses (diagnosed before or after birth) randomized to magnesium sulfate infusion who received the study drug. Women in the initial trial who were randomized to magnesium sulfate were given a loading dose (6 g over 20–30 minutes) followed by a maintenance infusion of 2 g per hour. After 12 hours, if delivery had not occurred and was not determined imminent, the magnesium sulfate was discontinued. If delivery was again threatened,

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the magnesium sulfate was restarted; if greater than 6 hours had passed since the drug was given, the magnesium sulfate loading dose was repeated on reinitiating therapy. Retreatment did not occur if open-label magnesium sulfate became indicated for preeclampsia, if a delay in delivery for retreatment would increase risk to the mother or fetus, or the gestational age reached 34 weeks. Study groups in the current study were defined by the total duration (in hours) of magnesium sulfate infusion received: less than 12 hours, 12–18 hours, or greater than 18 hours. If magnesium sulfate was discontinued and restarted, the cumulative duration of infused drug was used. The primary outcome was a composite of cerebral palsy (mild, moderate, or severe) or death (stillbirth or death before 15 months corrected age). Secondary outcomes included moderate-to-severe cerebral palsy or death, any cerebral palsy, moderateto-severe cerebral palsy, and death. Cerebral palsy was assessed and diagnosed at or beyond 2 years of life by an annually certified pediatrician or pediatric neurologist according to strict criteria.6 Additional secondary analyses included predefined select adverse obstetric and maternal outcomes and neonatal outcomes. Baseline characteristics among the three cohort study groups (less than 12 hours of magnesium sulfate, 12–18 hours, or greater than 18 hours) were compared using analysis of variance for continuous variables and the x2 or Fisher’s exact test for categorical variables as appropriate. Incidences of the primary and secondary outcomes were compared across study groups and the unadjusted relative risks with 95% confidence intervals (CIs) were estimated. Potential confounding factors and effect modifiers were identified in bivariate analyses. Logistic regression models were developed to estimate the independent risk of duration of magnesium sulfate for each outcome adjusting for confounding factors that were identified based on historical importance and in the unadjusted analyses. Backward stepwise selection was performed to reduce the number of variables in the regression model by assessing the magnitude of change in the effect size of remaining covariates. Differences in the explanatory model were tested using the likelihood ratio test or Wald test.11 Only statistically significant variables or those historically suggested to be important covariates were included in the final regression models and adjusted odds ratios (ORs) with 95% CIs were estimated (P,.05 was considered significant). Goodness of fit was assessed with the Hosmer–Lemeshow test for each regression model. Statistical analyses were performed using STATA 13.0 special edition.

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Because the sample size was fixed, we did not perform a sample size estimate before this study. However, based on total sample size, exposure rate (magnesium sulfate duration category), and outcome rate of 10%, assuming a power of 80% and an a of 0.05, this study had sufficient statistical power to detect a 1.8-fold increase risk for the primary outcome (cerebral palsy or death) and a twofold increased risk of death. The study has limited power for the more rare outcomes of any cerebral palsy type and moderate to severe cerebral palsy as well as for other low-prevalence outcomes (eg, maternal pulmonary complications, neonatal seizures, and intraventricular hemorrhage). Based on the same statistical assumptions and baseline outcome rates of 2% and 4% for any cerebral palsy and moderate-to-severe cerebral palsy, the detectable relative risks are 2.5 and 3.5, respectively. Smaller clinically significant outcome differences between groups will not be detected.

RESULTS In the initial prospective trial, 1,188 fetuses (1,096 women) were randomized to receive antenatal magnesium sulfate. There were 933 women available for this analysis after exclusions (Fig. 1). Among the 933 women, there were 892 with complete primary outcome data at 2 years of follow-up. Of the 933 women, 356 received a total infusion of less than 12 hours of magnesium sulfate (mean duration 8.764.3 hours), 341 women received 12–18 hours (mean duration

14.061.7 hours), and 236 women received greater than 18 hours (mean duration 26.8 68.4 hours). In most aspects, the three groups were similar. However, they differed in several characteristics including body mass index, gestational age at delivery, whether magnesium sulfate was running at delivery, hours since receiving magnesium sulfate if not running at delivery, and eligibility criteria (Table 1). Approximately 44% of all patients did not have magnesium sulfate infusing at the time of delivery. Women who received magnesium sulfate for less than 12 hours served as the reference group. There was no difference in the risk of the composite primary outcome of any cerebral palsy or death in this reference group compared with women who received 12–18 hours of magnesium sulfate (adjusted OR 1.03, 95% CI 0.60–1.77) or to women who received greater than 18 hours of magnesium sulfate (adjusted OR 1.08, 95% CI 0.57–2.03). The regression model for “any cerebral palsy or death” adjusted for race, gestational age at birth, and time since last receiving magnesium sulfate if not running at delivery (Table 2). There was no difference in the risk of the composite of moderate-to-severe cerebral palsy or death after adjusting for gestational age at birth, time since last magnesium sulfate, and eligibility criteria. Continuing to use less than 12 hours of magnesium sulfate as the reference, there was no difference in any cerebral palsy (including cerebral palsy diagnosed before death) when compared with 12–18 hours of

Fetuses randomized to magnesium sulfate (n=1,188) Excluded fetuses (twin pregnancies; n=184)

Fetuses remaining (n=1,004)

Excluded (n=71) Major anomalies: 44 Did not receive magnesium sulfate: 15 Exposure data missing: 3 Incomplete data: 9

Women analyzed (n=933) Complete primary outcome data available: 892

Fig. 1. Flow diagram of study participants. McPherson. Neuroprotective Magnesium Sulfate Duration. Obstet Gynecol 2014.

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Magnesium sulfate 18 hours (n=236) Complete primary outcome data available: 227

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Table 1. Baseline Characteristics of Women Receiving Magnesium Sulfate for Neuroprotection (N5933) Duration of Magnesium Sulfate Administration (h) Characteristic Maternal age (y) Advanced maternal age (35 y or older) BMI (kg/m2) BMI 30 or greater Race African American Caucasian Hispanic Other Married Education level (y) Alcohol use Tobacco use Illicit drug use Diabetes Nulliparous Previous preterm delivery No prenatal care Gestational age at randomization (wk) Gestational age at delivery (wk) Gestational age at delivery less than 37 wk Gestational age at delivery less than 34 wk Chorioamnionitis Steroid administration Study magnesium sulfate on at delivery (yes) Any magnesium sulfate (open-label or study) running at delivery Hours since last magnesium sulfate infusion (all patients) If delivery at less than 32 wk of gestation Magnesium sulfate received before randomization Open-label magnesium sulfate received after randomization Open-label magnesium sulfate received anytime Eligibility criteria PROM Advanced preterm labor Indicated preterm delivery Cervical dilation on admission (cm) Cervical dilation at randomization if advanced preterm labor (cm)

Less Than 12 (n5356)

12–18 (n5341)

Longer Than 18 (n5236)

26.266.6 50 (14.1) 25.866.6 117 (32.9)

25.966.2 38 (11.1) 26.766.8 119 (34.9)

26.166.3 26 (11.1) 24.866.2 62 (26.3)

147 (41.3) 147 (41.3) 54 (15.2) 8 (2.3) 178 (50.1) 11.962.6 32 (8.9) 91 (25.6) 27 (7.6) 19 (5.3) 130 (36.5) 88 (24.7) 32 (8.9) 28.362.5 30.163.5 342 (96.1) 309 (86.8) 34 (9.6) 343 (96.4) 118 (33.2) 121 (33.9)

159 (46.6) 108 (31.7) 65 (19.1) 9 (2.6) 162 (47.5) 11.662.5 29 (8.5) 88 (25.8) 37 (10.9) 14 (4.1) 113 (33.1) 107 (31.4) 23 (6.7) 28.162.4 29.562.9 336 (98.5) 320 (93.8) 43 (12.6) 336 (98.5) 217 (63.6) 218 (63.9)

273.56471.0

P

Missing Data

.88 .41 .005 .08 .25

0 0 95 95 0

104 (44.1) 85 (36.0) 43 (18.2) 4 (1.7) 125 (53.2) 11.762.3 22 (9.3) 72 (30.5) 29 (12.3) 12 (5.1) 86 (36.4) 64 (27.1) 16 (6.8) 28.562.5 30.162.6 235 (99.6) 224 (94.9) 33 (13.9) 228 (96.6) 182 (77.1) 183 (77.5)

.39 .12 .94 .35 .14 .73 .59 .14 .46 .12 .04 .009 ,.001 .22 .17 ,.01 ,.001

2 3 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

104.56303.1

45.96179.1

,.001

0

110.36192.3 70 (19.7) 8 (2.3)

34.2679.2 59 (17.3) 7 (2.1)

9.6649.7 38 (16.1) 4 (1.7)

,.001 .51 .90

0 0

80 (22.5)

65 (19.1)

41 (17.4)

.27 .003

1 0

396 (83.1) 44 (12.4) 16 (4.5) 1.661.9 4.961.1

314 (92.1) 23 (6.7) 4 (1.2) 1.261.5 4.761.11

202 (85.6) 29 (12.3) 5 (2.1) 1.461.8 4.761.1

.005 .45

79 0

BMI, body mass index; PROM, premature rupture of membranes. Data are mean6standard deviation or absolute n (%) unless otherwise specified.

magnesium sulfate or greater than 18 hours of magnesium sulfate after adjusting for gestational age at delivery and magnesium sulfate running at delivery. There was no difference across study groups in moderate-to-severe cerebral palsy after adjusting for gestational age at birth. Finally, there was no difference in death across study groups after adjusting for gestational age at birth, time since last magnesium sulfate, and eligibility criteria.

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In additional secondary analyses evaluating duration of magnesium sulfate infusion on select obstetric and maternal outcomes, there was no difference in the rate of any maternal adverse drug event when comparing study groups of magnesium sulfate infusion less than 12 hours, 12–18 hours, and greater than 18 hours. An adverse event referred to events recorded in relation to receiving the study drug and included flushing, sweating, pain at the intravenous

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Table 2. Outcomes of Women Receiving Magnesium Sulfate Duration of Magnesium Sulfate Administration (h) Outcome Any cerebral palsy or death Unadjusted OR (95% CI) Moderate-to-severe cerebral palsy or death Unadjusted OR (95% CI) Any cerebral palsy‡ Unadjusted OR (95% CI) Moderate-to-severe cerebral palsy Unadjusted OR (95% CI) Death Unadjusted OR (95% CI)

Less Than 12 (n5334)

12–18 (n5331)

Longer Than 18 (n5227)

39 (11.7) Reference 32 (9.6)

34 (10.3) 0.87 (0.53–1.41) 29 (8.8)

20 (8.8) 0.73 (0.41–1.29) 17 (7.5)

Reference 14 (4.2) Reference 6 (1.8) Reference 27 (8.1) Reference

0.91 9 0.64 4 0.60 25 0.90

0.76 4 0.41 1 0.22 17 0.89

(0.54–1.55) (2.7) (0.27–1.50) (1.2) (0.17–2.05) (7.6) (0.52–1.57)

(0.41–1.41) (1.8) (0.13–1.26) (0.4) (0.03–1.76) (7.5) (0.47–1.66)

Adjusted OR Adjusted OR (95% CI) for (95% CI) for 12– 18 h or Longer Longer Than 18 h 1.03* (0.60–1.77)

1.08* (0.57–2.03)

1.11† (0.62–1.97)

1.13† (0.57–2.24)

0.61§ (0.26–1.43)

0.44§ (0.14–1.38)

0.64k (0.18–2.30)

0.26k (0.03–2.17)

1.10¶ (0.60–2.03)

1.41¶ (0.70–2.85)

OR, odds ratio; CI, confidence interval. * Adjusted for race, gestational age at birth, time since last dose of magnesium sulfate. † Adjusted for gestational age at birth, time since last dose of magnesium sulfate, eligibility category. ‡ Any cerebral palsy includes cerebral palsy that precedes death. § Adjusted for gestational age at birth, any magnesium sulfate at delivery. k Adjusted for gestational age at birth. ¶ Adjusted for gestational age at birth, time since last dose of magnesium sulfate, eligibility category.

catheter site, nausea or vomiting, respiratory depression, pulmonary edema, or stopping the infusion. There was no difference in “significant” adverse drug events defined as respiratory depression, pulmonary edema, and drug discontinuation. The rate of cesarean delivery was different among groups (Table 3). When evaluating neonatal outcomes by duration of magnesium sulfate infusion received, there was no

difference in birth weight or the rates of low 5-minute Apgar score, need for resuscitation in the delivery room, necrotizing enterocolitis, retinopathy of prematurity, respiratory distress syndrome, need for mechanical ventilation, bronchopulmonary dysplasia, seizures, or cranial ultrasound findings (Table 4). Neonatal intensive care unit admission was not different among groups after adjusting for gestational age at delivery (data not shown).

Table 3. Obstetric Outcomes and Adverse Events (N5933) Duration of Magnesium Sulfate Administration (h) Outcome

Less Than 12 12–18 (n5356) (n5341)

Any adverse drug event§ Significant adverse drug event§ Pulmonary edema Respiratory depression Infusion stopped because of adverse event§ or patient refusal Cesarean delivery

273 9 3 2 45

(76.7) (2.5) (0.8) (0.6) (12.6)

130 (36.5)

257 2 2 0 12

(75.4) (0.6) (0.6) (0) (3.5)

136 (39.9)

Longer Than 18 (n5236) 187 5 1 4 8

OR* (95% CI)

OR† (95% CI)

(79.2) (2.1) (0.4) (1.7) (3.4)

0.93 (0.66–1.32) 0.23 (0.05–1.06) 0.69 (0.12–4.18) — 0.25 (0.13–0.49)

1.16 0.83 0.50 3.05 0.24

64 (27.1)

1.15 (0.85–1.57)

0.65 (0.45–0.93)

P‡

(0.78–1.73) .55 (0.28–2.52) .08 (0.05–4.84) .81 (0.55–16.79) .18 (0.11–0.49) ,.001 .01

OR, odds ratio; CI, confidence interval. Data are absolute n (%) unless otherwise specified. Any adverse event defined as flushing, sweating, pain at intravenous site, nausea or vomiting, respiratory depression, pulmonary edema, or infusion stopped. Significant adverse events defined as respiratory depression, pulmonary edema, or drug discontinued by the physician as a result of adverse drug effects. * Odds ratio for 12–18 h group compared with less than 12 h group. † Odds ratio for greater than 18 h group compared with less than 12 h group. ‡ P value is for x2 for trend. § Adverse drug event refers to events recorded in relation to receiving study drug.

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Table 4. Neonatal Outcomes (n5948) Duration of Magnesium Sulfate Administration (h) Outcome

Less Than 12 (n5356)

12–18 (n5341)

Birth weight (g) 1,4746632 1,3906557 5-min Apgar score less than 7 63 (17.7) 58 (17.1) Resuscitation in delivery room None 70 (19.7) 63 (18.5) Oxygen blow-by 90 (25.3) 90 (26.4) Oxygen bag, mask, or both 47 (13.2) 60 (17.6) Intubation 135 (37.9) 114 (33.4) Chest compressions 14 (3.9) 14 (4.1) Necrotizing enterocolitis 33/354 (9.3) 31/341 (9.1) Retinopathy of prematurity 81/354 (22.1) 84 (24.6) Respiratory distress syndrome 174/354 (49.2) 166 (48.7) Mechanical ventilation 187/354 (52.8) 174/341 (51.0) Bronchopulmonary dysplasia 67/354 (18.1) 60 (17.6) Seizures 6/354 (1.4) 6/341 (1.8) Cranial ultrasound findings Any intraventricular 67/335 (20.0) 58/327 (17.7) hemorrhage Grade III or IV 4/335 (1.2) 5/327 (1.5) intraventricular hemorrhage

Longer Than 18 (n5236) 1,4646480 32 (13.6) 36 80 42 75 3 23/234 40 110 115/234 38 3/234

(15.3) (33.9) (17.8) (31.8) (1.3) (9.8) (17.1) (47.1) (49.2) (16.2) (1.3)

OR* (95% CI)

OR† (95% CI)

P‡

0.95 (0.64–1.41)

0.73 (0.46–1.16)

.12 .37 .07

0.97 1.16 0.98 0.93 0.96 1.25

1.11 0.73 0.92 0.86 0.87 0.91

(0.61–1.86) (0.48–1.12) (0.66–1.28) (0.62–1.20) (0.56–1.36) (0.21–3.83)

.96 .09 .87 .68 .84 .88

(0.58–1.63) (0.81–1.64) (0.73–1.32) (0.69–1.25) (0.66–1.41) (0.38–3.39)

43/230 (18.7)

0.86 (0.58–1.27)

0.92 (0.60–1.41)

.76

1/230 (0.4)

1.28 (0.34–4.83)

0.36 (0.04–2.25)

.42

OR, odds ratio; CI, confidence interval. Data are mean6standard deviation, n (%), or absolute n/N (%) unless otherwise specified; total number listed only if there are missing data. * Odds ratio for 12–18-hour group compared with less than 12 h group. † Odds ratio for greater than 18-hour group compared with less than 12 h group. ‡ P value is for x2 for trend (categorical) or analysis of variance (continuous).

DISCUSSION Our secondary cohort study provides evidence that among fetuses exposed to antenatal neuroprotective magnesium sulfate, there is no difference in the rate of cerebral palsy or death regardless of whether the total duration of magnesium sulfate infused is less than 12 hours, 12–18 hours, or greater than 18 hours. Furthermore, there are no differences in maternal adverse drug affects or neonatal morbidities based on duration of magnesium sulfate infused. Thus, neuroprotective magnesium sulfate infusion duration and therefore magnesium sulfate cumulative dose does not appear to be associated with variability in risk reduction for cerebral palsy, risk of other neonatal morbidities, or risk of maternal adverse drug events. There have been multiple randomized clinical trials suggesting the beneficial effects of magnesium sulfate for cerebral palsy prevention in preterm neonates. Although the cumulative findings support a therapeutic benefit, each trial used a different protocol for magnesium sulfate infusion. Magnesium sulfate regimens ranged from a 4-g bolus with no maintenance infusion to a 4-g bolus with a 1-g continuous infusion, to a 6-g bolus with a 2-g continuous infusion.6–8

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There has been concern by one investigational group that magnesium sulfate may be associated with adverse outcomes in a dose-related fashion.9 Mittendorf et al found higher serum umbilical cord ionized magnesium sulfate levels in neonates with adverse outcomes. The primary concern about the study design is that dose of magnesium sulfate was determined by the amount of cervical dilation. Therefore, the observed association between magnesium sulfate level and adverse neonatal outcome may be the result of confounding by indication rather than a true association. Our findings refute the contention that higher dosing of magnesium sulfate is associated with worse neonatal morbidity. Our study has several strengths. The database used is derived from prospectively collected data from a well-characterized, comprehensive multicenter clinical trial and the data have been previously validated. Information bias is minimized given the prospective nature of the database and the strictly defined exposure status and outcomes. Given that the initial study was focused on the effects of magnesium sulfate therapy, the data regarding drug administration and side effects are complete with little missing data.

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Our study is not without limitations. We are restricted to variables that exist in the established database and there are some variables that are not available and some with missing data, however, rarely greater than 5% within a single variable. Notably, the study groups differed in several baseline characteristics. Multivariable regression analysis, however, was used to adjust for these measured differences minimizing effects of confounding and leaving only unmeasured potential residual bias. Also, the sample size was based on the original trial and not determined specifically for this analysis. However, this cohort is large enough to detect a clinically significant difference in the risk of the primary outcome and in the risk of neonatal death among exposure groups. The study is also well powered to detect clinically significant differences in many other predefined maternal and neonatal outcomes, but power was limited for less frequent outcomes such as maternal pulmonary edema or respiratory depression and neonatal seizures or severe cerebral palsy. Based on our secondary analysis, we cannot make definitive clinical recommendations for a specific neuroprotective magnesium sulfate regimen. However, our study suggests that neuroprotection may be achieved equally at lower doses. REFERENCES

cerebral palsy, co-occurring autism spectrum disorders, and motor functioning—autism and Developmental Disabilities Monitoring Network, USA, 2008. Dev Med Child Neurol 2014;56:59–65. 3. Bax M, Goldstein M, Rosenbaum P, Leviton A, Paneth N, Dan B, et al. Proposed definition and classification of cerebral palsy, April 2005. Dev Med Child Neurol 2005; 47:571–6. 4. Cummins SK, Nelson KB, Grether JK, Velie EM. Cerebral palsy in four northern California counties, births 1983 through 1985. J Pediatr 1993;123:230–7. 5. Kancherla V, Amendah DD, Grosse SD, Yeargin-Allsopp M, Van Naarden Braun K. Medical expenditures attributable to cerebral palsy and intellectual disability among Medicaidenrolled children. Res Dev Disabil 2012;33:832–40. 6. Rouse DJ, Hirtz DG, Thom E, Varner MW, Spong CY, Mercer BM, et al. A randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy. N Engl J Med 2008; 359:895–905. 7. Crowther CA, Hiller JE, Doyle LW, Haslam RR; Australasian Collaborative Trial of Magnesium Sulphate (ACTOMg SO4) Collaborative Group. Effect of magnesium sulfate given for neuroprotection before preterm birth: a randomized controlled trial. JAMA 2003;290:2669–76. 8. Marret S, Marpeau L, Zupan-Simunek V, Eurin D, Lévêque C, Hellot MF, et al. Magnesium sulphate given before verypreterm birth to protect infant brain: the randomised controlled PREMAG trial*. BJOG 2007;114:310–8. 9. Mittendorf R, Dambrosia J, Pryde PG, Lee KS, Gianopoulos JG, Besinger RE, et al. Association between the use of antenatal magnesium sulfate in preterm labor and adverse health outcomes in infants. Am J Obstet Gynecol 2002;186:1111–8.

1. Centers for Disease Control and Prevention. Data & statistics for cerebral palsy. Available at: http://www.cdc.gov/ncbddd/cp/ data.html. Retrieved January 28, 2014.

10. Magnesium sulfate before anticipated preterm birth for neuroprotection. Committee Opinion No. 455. American College of Obstetricians and Gynecologists. Obstet Gynecol 2010;116: 669–71.

2. Christensen D, Van Naarden Braun K, Doernberg NS, Maenner MJ, Arneson CL, Durkin MS, et al. Prevalence of

11. Hosmer DW, Lemeshow S. Applied logistic regression. New York (NY): John Wiley & Sons; 2000.

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Association of duration of neuroprotective magnesium sulfate infusion with neonatal and maternal outcomes.

To evaluate the association of duration of magnesium sulfate infusion with stillbirth or death, cerebral palsy, and select adverse maternal and neonat...
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