Almost 800,000 Americans, and many more worldwide, are afflicted with cerebral palsy, the hallmark of which is nonprogressive motor dysfunction arising early in development.1 Preterm birth greatly increases the risk of cerebral palsy, and anywhere from one-third to one-half of newly diagnosed cerebral palsy is associated with preterm birth.2–6 Individual randomized trials, and meta-analyses thereof, demonstrate that intravenous magnesium sulfate given to mothers before early preterm birth significantly decreases the risk of cerebral palsy in their offspring with no increase in perinatal or infant mortality.7–13 The number needed to treat to prevent one case of disabling cerebral palsy varies from approximately 30–60 depending on the gestational age of treatment.14
Although the available clinical trials support the efficacy and safety of magnesium sulfate for cerebral palsy prevention, and guidelines from several countries endorse such use,15–18 the use of magnesium sulfate for this purpose has undergone very limited evaluation outside of the context of these trials. Thus, we evaluated the implementation and use of magnesium sulfate for cerebral palsy prevention over time in our large tertiary care women's hospital focusing on uptake, indications, and safety.
PATIENTS AND METHODS
In February 2008, Women & Infants Hospital of Rhode Island implemented a departmental guideline for the use of magnesium sulfate for the prevention of cerebral palsy modeled on the National Institutes of Health trial supporting this use.10 This guideline recommends a 6-g intravenous bolus followed by a constant infusion of 2 g per hour until delivery, or, if delivery is no longer deemed imminent, discontinuation until delivery threatens again, at which point the constant infusion is resumed, or, if 6 hours have elapsed, a repeat bolus infusion is administered followed by a constant infusion.
All told, approximately 8,500 women deliver at Women & Infants Hospital of Rhode Island annually—approximately 2,300 on the resident service, 600 on the maternal-fetal medicine service, and the remainder on various private services. Women were eligible for the protocol if they were admitted with a viable fetus at less than 32 weeks of gestation with one of the following diagnoses: 1) preterm labor defined by contractions and cervical change; 2) preterm premature rupture of membranes; or 3) an obstetric or medical indication for delivery before 32 weeks of gestation, eg, severe preeclampsia or fetal growth restriction. Although the National Institutes of Health trial protocol specified retreatment with magnesium up to 34 weeks of gestation (after previous enrollment before 32 weeks), for ease of implementation, our hospital guideline capped enrollment and retreatment at 31 weeks 6 days of gestation.
To assess uptake, indications, and safety, we analyzed data from 4 months before implementation of the guideline (October 2007 through January 2008) to establish a preprotocol baseline, and for the subsequent 3 years, with data collection ending February 2011. Institutional review board approval was obtained from Women & Infants Hospital of Rhode Island. To ascertain women eligible for this study, we queried our comprehensive pharmacy database to identify women who received either betamethasone or dexamethasone for fetal maturation during the study period. At Women & Infants Hospital of Rhode Island and its referring hospitals, only women who deliver precipitously before 34 weeks of gestation (without time for administration of medications) do not receive at least one injection of glucocorticoids for fetal maturation. Records of transfer to the maternal-fetal medicine service from an outside hospital were also queried to include patients who may have received betamethasone or dexamethasone at an outside institution but would otherwise qualify for inclusion.
Two of the authors (K.G. and K.B.) hand-abstracted the medical records (including admission notes, emergency room records, pharmacy data, laboratory results, and discharge summaries) of potentially eligible women and their neonates using standardized data collection forms. The primary outcome for this study was the temporal change in the percentage of eligible women who received magnesium sulfate before delivery. Secondary outcomes included use by gestational age at delivery, diagnosis (eg, preterm labor), service (maternal-fetal medicine compared with resident clinic compared with private), mode of delivery, and potentially magnesium-attributable maternal or perinatal complications. To assess for the possibility of overuse, we calculated the percentage of women treated with magnesium sulfate who delivered after 32, 34, and 37 weeks of gestation. Characteristics of magnesium sulfate dosing were recorded including times of initiation and discontinuation of infusion, bolus doses, number of repeat administrations, and total predelivery dose received. We collected the following neonatal information: Apgar scores, umbilical artery cord pH, need for resuscitation at delivery, individual morbidities or mortality, and any complications attributed to the mother having received magnesium sulfate.
We assumed a baseline receipt of antenatal magnesium sulfate of 20% (for prophylaxis against eclampsia). Therefore, to detect at least a 20% absolute increase (β=.2, two-tailed α=.05) in the administration of magnesium sulfate from 2007 through 2011, 91 patients per comparison year were required. To account for possible missing data, we oversampled 100 patients from 2008, 2009, and 2010 (each), who were randomly selected from among all eligible patients with the use of a random number generator. All patients meeting inclusion criteria from the years 2007 and 2011 were included. The time period analyzed started 4 months before initiation of the hospital guideline and continued 3 years after. Data analysis was performed with SAS 9.2. Categorical variables were compared using χ2 or Fisher’s exact test. Continuous variables were compared using t test or Wilcoxon rank-sum test for two groups or Kruskal-Wallis test for more than two groups. The Cochran-Armitage trend test was used to assess linear trends in magnesium administration.
Three hundred seventy-three patients were included. Demographics were similar for patients who did and did not receive magnesium (Table 1). In the 4 months preceding the implementation of the guideline, 8 of 40 eligible women (20%, 95% confidence interval [CI] 9.1–35.6%) received magnesium sulfate before delivery, only two of whom did not have severe preeclampsia. In the final 2 months of the study period, 93.9% (95% CI 79.8–99.3%) of eligible patients received magnesium sulfate before delivery, reflecting an absolute increase in use of 73.9% (Table 2). Among patients who actually delivered before 32 weeks of gestation (N=274), 28% (95% CI 12.1–49.4%) received predelivery magnesium sulfate in 2007 compared with 93.1% (95% CI 77.2–99.2%) in 2011 (Table 3). Of these, magnesium sulfate was infusing at the time of delivery (a protocol goal) in 16% (95% CI 4.5–36.1%) in 2007 and 86.2% (95% CI 68.3–96.1%) in 2011 (Table 4). Magnesium dosing did not vary significantly over the study period; the median number of treatments was one, the total predelivery median dose (per administration episode) ranged from 15 to 48 g, and the median duration of therapy (per administration episode) ranged from 3 to 12 hours (Table 5).
Among eligible patients who received magnesium sulfate, 57.7% received a 6-g bolus (as recommended in our hospital guideline), 17.7% received a 4-g bolus, and 24.6% received only the 2-g/h infusion. Concurrent tocolysis was used in 122 patients (49.4% of eligible patients). Of these, 95.1% received Indocin, 16.4% received nifedipine, and 2.5% received terbutaline (some received more than one).
Because by 2010 administration of magnesium sulfate to eligible patients was the norm, we analyzed factors associated with receipt and nonreceipt of magnesium sulfate from this point forward. Magnesium administration was almost universal among patients diagnosed with preeclampsia, preterm labor, or preterm premature rupture of membranes (95.4%), whereas patients delivered for fetal growth restriction were significantly less likely to receive predelivery magnesium (44%, P<.001). Although the maternal-fetal medicine (n=145) and resident (n=88) services initially administered magnesium at a higher rate than the private service (n=140), by the end of the study period, the rates across services converged (Fig. 1).
Rates of neonatal outcomes, including Apgar scores at 1 and 5 minutes, cord pH, need for immediate resuscitation, neonatal intensive care unit admission, duration of neonatal intensive care unit stay, individual neonatal morbidities (data not shown), and neonatal mortality, did not differ significantly in the magnesium exposed and unexposed groups for neonates who delivered before 32 weeks of gestation (Table 6). There were no reports of neonatal hypotonia in neonates exposed to magnesium. Umbilical cord blood serum magnesium concentrations among the 42 neonates (a minority) who were exposed to magnesium and had their concentration measured ranged from 1.7 mg/dL to 5.7 mg/dL with a median of 3.4 mg/dL. Notably, the majority of patients who received magnesium sulfate ultimately delivered preterm: 84.2% before 32 weeks of gestation, 88.9% before 34 weeks of gestation, and 93.6% before 37 weeks of gestation.
This report describes the uptake and use of magnesium sulfate for cerebral palsy prevention over time. Clinically relevant aspects of this description include near universal uptake with 93% use in the final months of the study period, and well-targeted, parsimonious administration, with an 84% rate of delivery before 32 weeks of gestation among recipients and a median number of magnesium infusions of one. In the setting of delivery for fetal growth restriction, magnesium sulfate was underused, representing an obvious area for improvement in our hospital. Importantly, we found no evidence of either maternal or perinatal harm associated with the implementation of the magnesium sulfate protocol.
The goal of this study was to evaluate practice change in the setting of implementation of a hospital guideline regarding a protocol for magnesium sulfate use for neuroprophylaxis. That is, our goal was to assess whether the rate of use of magnesium sulfate changed over time but not why. Although the guideline was announced at a faculty meeting, there was no formal implementation plan. The maternal-fetal medicine service quickly adopted the use of magnesium sulfate for cerebral palsy prevention, and the clinic and private services followed thereafter. During the study time period, accumulating evidence was published supporting the use of magnesium for the prevention of cerebral palsy in preterm neonates, including reviews, meta-analyses, and an American College of Obstetricians and Gynecologists Committee Opinion, which may have also contributed to practice change.7,10–14,16
In a PubMed search (performed August 1, 2012) using the terms “magnesium,” “cerebral palsy,” and “neuroprophylaxis,” we found one study that assessed the clinical use of magnesium sulfate for neuroprophylaxis. Ow et al19 evaluated 330 women admitted to an Australian tertiary hospital from 23 to 32 weeks in the year after implementation of a magnesium neuroprotection protocol. They reported a 73% rate of magnesium exposure among neonates who delivered before 32 weeks of gestation. Like in our study, there were no serious maternal or perinatal complications attributed to magnesium.
One potential limitation of our study is the method by which we ascertained eligible gravidas. It is possible that women who received betamethasone or dexamethasone at an outside institution may have been improperly excluded from our analysis if betamethasone or dexamethasone was not ordered for them in our hospital. Although at Women & Infants Hospital of Rhode Island, all direct hospital-to-hospital transfers are admitted to the maternal-fetal medicine service (and thus these patients were identified through query of maternal-fetal medicine transfer records), a patient who presented on her own accord after receiving betamethasone or dexamethasone previously would not be included.
Another limitation of our study is that it was powered to detect changes in the use of magnesium sulfate over time, but not to detect adverse outcomes associated with magnesium sulfate use. Although no mothers or perinates had complications that were attributed to magnesium sulfate, our statistical power to detect such complications was low. Additionally, our ability to evaluate morbidity as it relates to magnesium sulfate use depends on whether such morbidity was identified and recorded. We can say that of the 42 neonates who had recorded serum magnesium levels, none had a dangerously elevated value. Fortunately, data from the randomized trials of magnesium sulfate for cerebral palsy prevention provide reassurance about safety. In more than 3,000 women who received magnesium as part of randomized trials to evaluate fetal neuroprophylaxis, there have been no recorded life-threatening events or deaths. Similarly, pooled data from the randomized trials establish that magnesium sulfate has no effect on perinatal mortality (relative risk 1.04, 95% CI 0.92–1.17). Moreover, data from the largest trial demonstrate that when magnesium sulfate is used for neuroprotection, it does not increase the rate of neonatal hypotonia10 and that cord blood magnesium concentration does not correlate with the need for neonatal resuscitation.20
In summary, our data support the feasibility of implementing a protocol for the use of magnesium sulfate for the prevention of cerebral palsy among gravidas at imminent risk of delivery before 32 weeks of gestation. Although we implemented our protocol without the use of a checklist, it is possible that use of a tailored checklist such as the recently released American College of Obstetricians and Gynecologists Patient Safety Checklist “Magnesium Sulfate Before Anticipated Preterm Birth for Neuroprotection”21 would further enhance the optimization of magnesium sulfate administration for cerebral palsy prevention.
2. Wood NS, Marlow N, Costeloe K, Chir B, Gibson AT, Wilkinson AR. Neurologic and developmental disability after extremely preterm birth. EPICure Study Group. N Engl J Med 2000;343:378–84.
3. Kuban KC, Leviton A. Cerebral palsy. N Engl J Med 1994;330:188–95.
4. Marlow N. Neurocognitive outcome after very preterm birth. Arch Dis Child Fetal Neonatal Ed 2004;89:F224–8.
5. 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.
6. Winter S, Autry A, Boyle C, Yeargin-Allsopp M. Trends in the prevalence of cerebral palsy in a population-based study. Pediatrics 2002;110:1220–5.
7. Doyle LW, Crowther CA, Middleton P, Marret S, Rouse D. Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus. The Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: CD004661. DOI: 10.1002/14651858.CD004661.pub3.
8. Marret S, Marpeau L, Zupan-Simunek V, Eurin D, Leveque C, Hellot M, et al.; PREMAG trial group. Magnesium sulphate given before very-preterm birth to protect infant brain: the randomized controlled PREMAG trial. BJOG 2007;114:310–8.
9. 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.
10. 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.
11. Costantine MM, Weiner SJ; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Effects of antenatal expose to magnesium sulfate on neuroprotection and mortality in preterm infants: a meta-analysis, Obstet Gynecol 2009;114:354–64.
12. Conde-Agudelo A, Romero R. Antenatal magnesium sulfate for the prevention of cerebral palsy in preterm infants less than 34 weeks’ gestation: a systematic review and metaanalysis. Am J Obstet Gynecol 2009;200:595–609.
13. Reeves S, Gibbs R, Clark S. Magnesium for fetal neuroprotection. Am J Obstet Gynecol 2011;204:e1–4.
14. Rouse DJ. Magnesium sulfate for the prevention of cerebral palsy. Am J Obstet Gynecol 2009;200:610–2.
15. Magee L, Sawchuck D, Synnes A, von Dadelszen P. SCOG Clinical Practice Guideline. Magnesium sulphate for fetal neuroprotection. J Obstet Gynaecol Can 2011;33:516–29.
16. Magnesium sulfate before anticipated preterm birth for neuroprotection. Committee Opinion No. 455. American College of Obstetricians and Gynecologists. Obstet Gynecol 2010;115:669–71.
17. Peebles DM, Kenyon AP. Magnesium sulphate to prevent cerebral palsy following preterm birth. Scientific Advisory Committee Opinion Paper 29. Proc Royal Coll Obstetricians Gynaecologists; 2011:1–7.
18. The Antenatal Magnesium Sulphate for Neuroprotection Guideline Development Panel. Antenatal magnesium sulphate prior to preterm birth for neuroprotection of the fetus, infant and child: National clinical practice guidelines. Adelaide (Australia): The University of Adelaide; 2010.
19. Ow LL, Kennedy A, McCarthy EA, Walker SP. Feasibility of implementing magnesium sulphate for neuroprotection in a tertiary obstetric unit. Aust N Z J Obstet Gynecol 2012;52:356–60.
20. Johnson L, Mapp DC, Rouse DJ, Spong CY, Mercer BM, Leveno KJ, et al.. Association of cord blood magnesium concentration and neonatal resuscitation. J Pediatr 2012;169:573–7.e1.
© 2013 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.
21. Patient safety checklist: magnesium sulfate before anticipated preterm birth. Obstet Gynecol 2012;120:432–3.