- Email: [email protected]
Magnesium for fetal neuroprotection
Clinical Opinion
www. AJOG.org
OBSTETRICS
Magnesium for fetal neuroprotection Shane A. Reeves, MD; Ronald S. Gibbs, MD; Steven L. Clark, MD
O
bservational data in the 1990s pointed to an association between decreased neurological morbidities in preterm infants and exposure to magnesium sulfate.1-3 Since this observation, the use of magnesium for neuroprotection to decrease the rate of cerebral palsy has been examined in 5 randomized controlled trials.4-9 Individually, the primary outcomes in each of these studies showed no difference when a composite measure of infant death or cerebral palsy was investigated. Only on secondary analysis was benefit seen in decreasing the rate of gross motor dysfunction. A metaanalysis by Doyle et al10 published in 2009 showed a significant reduction in cerebral palsy in infants exposed to magnesium sulfate (relative risk, 0.71; 95% confidence interval [CI], 0.55– 0.91). Additionally, the composite measure of infant death or cerebral palsy was likewise reduced in fetuses exposed to magnesium (relative risk, 0.85; 95% CI, 0.74 – 0.98). Because the analysis showed these benefits, and because there was no statistical increase in the rate of fetal or infant death with magnesium sulfate therapy, the authors concluded that the evidence now supports antenatal magnesium as a neuroprotective agent against cerebral palsy in fetuses ⬍32 weeks.10 Subsequent metaanalyses have shown similar findings.11,12
From the Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora, CO (Drs Reeves and Gibbs), and Hospital Corporation of America, Nashville, TN (Dr Clark). Received Sept. 27, 2010; revised Dec. 2, 2010; accepted Jan. 11, 2011. Reprints: Shane A. Reeves, MD, Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Mail Stop B1985, 12631 E. 17th Ave., Room 4001, Aurora, CO 80045. [email protected]. 0002-9378/$36.00 © 2011 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2011.01.014
202.e1
Available evidence now suggests that magnesium sulfate administered to mothers prior to early preterm delivery reduces the risk of cerebral palsy in surviving neonates. The American College of Obstetricians and Gynecologists along with the Society for Maternal-Fetal Medicine state that physicians who choose to administer magnesium sulfate for neuroprotection should do so in accordance with one of the larger randomized trials. Due to the heterogeneity of the methods, many clinicians may find it difficult to proceed with a therapeutic protocol that adheres to the available literature. Here, we present one reasonable approach that identifies the specific patients who qualify for magnesium sulfate therapy, and it outlines a treatment algorithm while addressing retreatment and concomitant tocolysis. Key words: cerebral palsy, magnesium sulfate, neuroprotection, preterm delivery Cite this article as: Reeves SA, Gibbs RS, Clark SL. Magnesium for fetal neuroprotection. Am J Obstet Gynecol 2011;204:202.e1-4.
With the recent surge of publications regarding magnesium benefits to neonates, the American College of Obstetricians and Gynecologists (ACOG) and Society for Maternal-Fetal Medicine released a joint clinical opinion in March 2010.13 The opinion states that “available evidence suggests that magnesium sulfate given before anticipated early preterm birth reduces the risk of cerebral palsy in surviving infants.” It then points out that physicians who choose to use magnesium sulfate for neuroprotection should do so in accordance with the protocols of one of the larger trials. One of the difficulties faced by the clinician is that the 2 largest trials utilized different protocols for magnesium administration and dosing. Many clinicians may find it challenging to create a protocol that properly adheres to the available studies. In addition, no specific guidelines exist to help with patient selection other than to recommend its use in women “at increased risk” of preterm delivery. Given the poor positive predictive value of most recognized risk factors for preterm birth, clinicians may find it difficult to identify patients who are optimal candidates for magnesium sulfate use for neuroprotection. Thus, at present, the clinician who simply wants to know “who to treat” and “how to treat” in order to be in compliance with the
American Journal of Obstetrics & Gynecology MARCH 2011
protocols of the published studies finds few helpful answers in the available literature or recommendations from professional organizations. Our purpose is to provide recommendations for one regimen of magnesium sulfate administration for neuroprotection of the neonate that is specific and reflects current literature. Given the current status of the literature, it is clear that other approaches are equally appropriate.
Proposed protocol We propose the administration of magnesium sulfate for neuroprotection to women who meet one of the criteria in the Figure. This Figure also presents an algorithm for the administration of this medication to eligible mothers. Patients are considered eligible for magnesium sulfate for neuroprotection if they have a pregnancy with a gestational age between 23 weeks and 31 weeks and 6 days. This extends below the Rouse et al4 protocol because many institutions will begin neonatal resuscitation at a gestational age ⬍24 weeks. Modifications to our protocol can be made depending upon individualized institutional practices regarding the lower limit of gestational age where neonatal resuscitation will be attempted.
Obstetrics
www.AJOG.org
severe pulmonary disorders, or renal failure, may also not be candidates for magnesium sulfate therapy. Patients who meet eligibility (Figure) are given a loading dose of 6 g of magnesium sulfate over 20-30 minutes. A maintenance infusion of 2 g per hour is then continued for 12 hours or until delivery, whichever comes first.
FIGURE
Algorithm for selection of candidates and administration of magnesium sulfate for fetal neuroprotection
IV, intravenous. Reeves. Magnesium for fetal neuroprotection. Am J Obstet Gynecol 2011.
Patients are excluded from eligibility if there is no potential benefit to the fetus. Therefore, cases of intrauterine fetal demise and fetuses with lethal anomalies are not considered candidates for magnesium sulfate therapy. When palliative care is desired after delivery, such as in cases of lethal anomalies or aneuploidy with no plan for resuscitative measures,
Clinical Opinion
the benefits of magnesium sulfate are outweighed by the risks of therapy. Additionally, patients are not eligible for this specific protocol if the mother has severe preeclampsia, as these patients should be on standard magnesium sulfate protocols for seizure prophylaxis. Patients with maternal contraindications to magnesium, such as myasthenia gravis, certain
Retreatment The benefit of retreatment of patients who have completed an initial course of magnesium therapy is insufficiently documented in the current literature to justify any mandate either for or against such therapy. However, in the 2 largest trials published to date, the majority of patients delivered while receiving an infusion of the study drug (magnesium or placebo).4,5 Unfortunately, between the 2 studies, there is little uniformity in terms of duration of retreatment or the number of retreatment courses allowed. In our protocol, we present one option of retreatment with magnesium sulfate that is in accordance with the evidence provided up to this point. After discontinuation of magnesium sulfate, many patients will be observed on an antepartum service, and they may return later with a high risk of delivery within 12 hours. If ⬎6 hours have elapsed since discontinuation of the infusion, and the patient still meets eligibility criteria, a repeat 6-g bolus is given with a maintenance drip at 2 g per hour. If ⬍6 hours have elapsed since discontinuation of the medication, the 2 g per hour infusion rate can simply be restarted. Magnesium sulfate has been associated with increased neonatal mortality in several reports,14-16 but this was not confirmed in the study by Rouse et al.4 A follow-up analysis compared pregnancies exposed to the highest dose of magnesium sulfate to those with the lowest dose. It showed no difference in the rate of perinatal death (odds ratio, 1.01; 95% CI, 0.48 –2.10).17 Despite these conflicting results, because of potential harm to either the mother or the fetus, the goal is to only reinitiate magnesium sulfate in patients who are most likely to deliver in the next 12 hours. Minimizing the retreatment course to those patients
MARCH 2011 American Journal of Obstetrics & Gynecology
202.e2
Clinical Opinion
Obstetrics
where delivery is imminent should afford the newborn the benefits of magnesium sulfate while avoiding its potential harms.
Use of concomitant tocolysis Tocolytic use in this country is a widely debated topic made even more confusing in a setting where a traditional tocolytic is used for neuroprotection rather than uterine quiescence. In 2006, Grimes and Nada14 published a Current Commentary questioning its use as a primary tocolytic agent. A Cochrane review published in 2002 showed that magnesium sulfate was no more effective than alternative agents in preventing preterm delivery in 48 hours, ⬍34 weeks, or ⬍37 weeks.15 In fact, in a subanalysis in this review, magnesium sulfate was no better than placebo in preventing these outcomes.15 This led many in the country to transition to other agents with seemingly similar efficacy and less maternal and fetal side effects. Some reports have stated that with high doses (⬎48 g total), magnesium sulfate has been associated with an increase in neonatal mortality.14-16 This dose would typically be approached or exceeded with even 24 hours of tocolysis, a number less than half of the often strived for 48-hour window needed to obtain maximal potential therapeutic benefit from antenatal steroid administration. Our protocol does not use magnesium as a tocolytic agent, but as an agent for neuroprotection of the prematurely born infant. However, concomitant tocolysis is often desired by clinicians beyond the 12 hours of magnesium administration proposed in this protocol. Here, we present one method of concomitant tocolytic administration that allows for adherence to the literature using magnesium sulfate as a fetal neuroprotective agent. In several metaanalyses, calcium channel blockers and indomethacin have been associated with a decrease in preterm birth.18-20 Either of these 2 agents would be a reasonable drug to use as a concomitant tocolytic when prevention of preterm birth is desired. Nifedipine is a commonly used calcium channel blocker that may decrease myometrial 202.e3
contractions due to inhibition of calcium influx. It is contraindicated in cases of hypotension and known maternal coronary artery disease since it may increase the risk of myocardial ischemia.21 There is a theoretical concern of combining magnesium and calcium channel blockers as case reports have suggested that concomitant use of the 2 agents may occasionally result in neuromuscular blockade.22,23 This may lead some clinicians to have reservations in initiating nifedipine tocolysis during magnesium use for fetal neuroprotection. However, there are data showing that the combined use of magnesium sulfate and calcium channel blockers do not increase the risk of serious complications in preeclamptic patients.24,25 In fact, in the largest trial to date, the Magpie trial, 30% of patients enrolled were exposed to both nifedipine and magnesium, and no adverse events were reported.26 It seems that the theoretical concern of significantly increased risk of neuromuscular blockade is not well supported in the literature. An alternative agent to nifedipine is indomethacin, which is contraindicated in patients with severe renal or hepatic impairment, patients with oligohydramnios, or in gestational ages ⬎32 weeks as it has been associated with premature closure of the ductus arteriosus.21 Some authors have suggested that it is preferred over nifedipine secondary to superior tolerance with equal efficacy at ⬍32 weeks.20 Either drug is a reasonable option, and use of the optimal tocolytic will depend upon clinic circumstances. For this reason, we describe a protocol using either nifedipine or indomethacin as a tocolytic agent when magnesium has been initiated for neuroprotection. Patients meeting criteria in the Figure begin magnesium therapy as above. If concomitant tocolysis is desired, indomethacin therapy is initiated with a 50-g oral loading dose followed by 25 g orally every 6 hours for a total of 48 hours. This drug is contraindicated in patients with a gestational age ⬎32 weeks, platelet dysfunction or bleeding disorders, hepatic or renal dysfunction, gastrointestinal or ulcerative disease, and anaphylactic reactions to aspirin. Alternatively, nifedi-
American Journal of Obstetrics & Gynecology MARCH 2011
www.AJOG.org pine can be given with a loading dose of 10 mg orally every 20 minutes up to a total of 30 mg or until uterine activity declines. A total of 10-20 mg is then repeated every 6 hours for a total of up to 48 hours. Its use is contraindicated in patients with hypotension (⬍90/50 mm Hg), cardiac disease, and severe renal impairment.21 Tocolysis can be initiated at any time, as data indicating the optimal timing of administration of this therapy are lacking. This can be given with the loading dose of magnesium sulfate, during administration of the magnesium drip, or it can be initiated after cessation of magnesium at the 12-hour mark. Tocolysis is generally stopped after 48 hours, allowing for the desired window to be achieved for steroid benefit to the fetus.
Conclusion We have presented a protocol for the administration of magnesium sulfate for neuroprotection that is consistent with the available literature and the recommendations of ACOG. This protocol goes beyond current published recommendations in its more clearly defined but vitally important specification of patient selection. Our combined experience with physicians practicing in hundreds of obstetric facilities throughout the United States suggests that lack of such specific guidelines contributes significantly to the slow adoption of such protocols outside of select academic centers. In the absence of definitive clinical trials, the achievement of uniform patterns of care based on a single, specific, appropriate approach has been demonstrated to improve quality in other areas of medicine.27 Such uniformity is a hallmark of patient safety efforts outlined by the Institute of Medicine.28 Future clinical trials demonstrating the benefit of magnesium sulfate infusion in each subset of patients described in the Figure would be welcome and would lead to potential modification of this protocol. Meanwhile, we believe the uniformity of care promoted by such specific guidelines by itself is likely to encourage use of this agent and improve clinical outcomes. Clinical anarchy is not the only alternative when the perfect ran-
www.AJOG.org domized, double-blinded, placebo-controlled, crossover trial is unavailable. We wish to emphasize again that this specific approach is simply one way to be in compliance with current reasonable care. In light of current data, numerous variations and alternatives would be equally appropriate. However, for clinicians considering adoption of such therapy, this seems a good place to begin. f REFERENCES 1. Nelson KB, Grether JK. Can magnesium sulfate reduce the risk of cerebral palsy in very low birthweight infants? Pediatrics 1995;95:263-9. 2. Schendel DE, Berg CJ, Yeargin-Allsopp M, Boyle CA, Decoufle P. Prenatal magnesium sulfate exposure and the risk for cerebral palsy or mental retardation among very low-birth-weight children aged 3 to 5 years. JAMA 1996;276: 1805-10. 3. Paneth N, Jetton J, Pinto-Martin J, Susser M. Magnesium sulfate in labor and risk of neonatal brain lesions and cerebral palsy in low birth weight infants: the neonatal brain hemorrhage study analysis group. Pediatrics 1997; 99:E1. 4. Rouse DJ, Hirtz DG, Thom E, et al. A randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy. N Engl J Med 2008;359:895-905. 5. Crowther CA, Hiller JE, Doyle LW, Haslam RR. Effect of magnesium sulfate given for neuroprotection before preterm birth: a randomized controlled trial. JAMA 2003;290:2669-76. 6. Mittendorf R, Dambrosia J, Pryde PG, 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. 7. Magpie Trial Follow-up Study Collaborative Group. The Magpie trial: a randomized trial comparing magnesium sulphate with placebo for pre-eclampsia; outcome for children at 18 months. BJOG 2007;114:289-99.
Obstetrics 8. Marret S, Marpeau L, Zupan-Simunek V, et al; for PREMAG Trial Group. Magnesium sulphate given before very-preterm birth to protect the infant brain: the randomized controlled PREMAG trial. BJOG 2007;114:310-8. 9. Marret S, Marpeau L, Follet-Bouhamed C, et al. Effect of magnesium sulphate on mortality and neurologic morbidity of the very-preterm newborn with two-year neurologic outcome: results of the prospective PREMAG trial. Gynecol Obstet Fertil 2008;36:278-88. 10. Doyle LW, Crowther CA, Middleton P, Marret S, Rouse D. Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus. Cochrane Database Syst Rev 2009; 1:CD004661. 11. Costantine MM, Weiner SJ; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Effects of antenatal exposure 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. ACOG Committee on Obstetric Practice; Society for Maternal-Fetal Medicine. Committee opinion No. 455: magnesium sulfate before anticipated preterm birth for neuroprotection. Obstet Gynecol 2010;115:669-71. 14. Grimes DA, Nada K. Magnesium sulfate tocolysis: time to quit. Obstet Gynecol 2006; 108:986-9. 15. Crowther CA, Hiller JE, Doyle LW. Magnesium sulphate for preventing preterm birth in threatened preterm labor. Cochrane Database Syst Rev 2002;4:CD001060. 16. Scudiero R, Khoshnood B, Pryde PG, Lee KS, Wall S, Mittendorf R. Perinatal death and tocolytic magnesium sulfate. Obstet Gynecol 2000;96:178-82. 17. Rouse DJ. Magnesium sulfate for the prevention of cerebral palsy. N Engl J Med 2009; 360:189-90.
Clinical Opinion
18. King J, Flanady V, Cole S, Thornton S. Cyclo-oxygenase (COX) inhibitors for treating preterm labor. Cochrane Database Syst Rev 2005;2:CD001992. 19. King JF, Flanedy V, Papatsonis D, Dekker G, Carbonne B. Calcium channel blockers for inhibiting preterm labor; a systematic review of the evidence and a protocol for administration of nifedipine. Aust N Z J Obstet Gynaecol 2003;43:192-8. 20. Haas DM, Imperiale TF, Kirkpatrick PR, Klein RW, Zollinger TW, Golichowski AM. Tocolytic therapy: a meta-analysis and decision analysis. Obstet Gynecol 2009;113:585-94. 21. ACOG Committee on Practice Bulletins. ACOG practice bulletin number 43: management of preterm labor. Obstet Gynecol 2003; 101:1039-47. 22. Ben Ami M, Giladi Y, Shalev E. The combination of magnesium sulphate and nifedipine: a cause of neuromuscular blockade. Br J Obstet Gynaecol 1994;101:262-3. 23. Snyder SW, Cardwell MS. Neuromuscular blockade with magnesium-sulfate and nifedipine. Am J Obstet Gynecol 1989;161:35-6. 24. Magee LA, Miremadi S, Li J, et al. Therapy with both magnesium sulfate and nifedipine does not increase the risk of serious magnesium-related maternal side effects in women with preeclampsia. Am J Obstet Gynecol 2005;193:153-63. 25. Scardo JA, Vermillion ST, Hogg BB, Newman RB. Hemodynamic effects of oral nifedipine in preeclamptic hypertensive emergencies. Am J Obstet Gynecol 1996;175:336-8. 26. Altman D, Carroli G, Duley L, et al. Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie trial: a randomized placebo-controlled trial. Lancet 2002;359:1877-90. 27. Rosenbrand K, Van Croonenborg J, Wittenberg J. Guideline development. Stud Health Technol Inform 2008;139:3-21. 28. Committee on Quality of Health Care in America, Institute of Medicine. Crossing the quality chasm: a new health system for the 21st century. Washington, DC: National Academy Press; 2001:122-23.
MARCH 2011 American Journal of Obstetrics & Gynecology
202.e4
www. AJOG.org
OBSTETRICS
Magnesium for fetal neuroprotection Shane A. Reeves, MD; Ronald S. Gibbs, MD; Steven L. Clark, MD
O
bservational data in the 1990s pointed to an association between decreased neurological morbidities in preterm infants and exposure to magnesium sulfate.1-3 Since this observation, the use of magnesium for neuroprotection to decrease the rate of cerebral palsy has been examined in 5 randomized controlled trials.4-9 Individually, the primary outcomes in each of these studies showed no difference when a composite measure of infant death or cerebral palsy was investigated. Only on secondary analysis was benefit seen in decreasing the rate of gross motor dysfunction. A metaanalysis by Doyle et al10 published in 2009 showed a significant reduction in cerebral palsy in infants exposed to magnesium sulfate (relative risk, 0.71; 95% confidence interval [CI], 0.55– 0.91). Additionally, the composite measure of infant death or cerebral palsy was likewise reduced in fetuses exposed to magnesium (relative risk, 0.85; 95% CI, 0.74 – 0.98). Because the analysis showed these benefits, and because there was no statistical increase in the rate of fetal or infant death with magnesium sulfate therapy, the authors concluded that the evidence now supports antenatal magnesium as a neuroprotective agent against cerebral palsy in fetuses ⬍32 weeks.10 Subsequent metaanalyses have shown similar findings.11,12
From the Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora, CO (Drs Reeves and Gibbs), and Hospital Corporation of America, Nashville, TN (Dr Clark). Received Sept. 27, 2010; revised Dec. 2, 2010; accepted Jan. 11, 2011. Reprints: Shane A. Reeves, MD, Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Mail Stop B1985, 12631 E. 17th Ave., Room 4001, Aurora, CO 80045. [email protected]. 0002-9378/$36.00 © 2011 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2011.01.014
202.e1
Available evidence now suggests that magnesium sulfate administered to mothers prior to early preterm delivery reduces the risk of cerebral palsy in surviving neonates. The American College of Obstetricians and Gynecologists along with the Society for Maternal-Fetal Medicine state that physicians who choose to administer magnesium sulfate for neuroprotection should do so in accordance with one of the larger randomized trials. Due to the heterogeneity of the methods, many clinicians may find it difficult to proceed with a therapeutic protocol that adheres to the available literature. Here, we present one reasonable approach that identifies the specific patients who qualify for magnesium sulfate therapy, and it outlines a treatment algorithm while addressing retreatment and concomitant tocolysis. Key words: cerebral palsy, magnesium sulfate, neuroprotection, preterm delivery Cite this article as: Reeves SA, Gibbs RS, Clark SL. Magnesium for fetal neuroprotection. Am J Obstet Gynecol 2011;204:202.e1-4.
With the recent surge of publications regarding magnesium benefits to neonates, the American College of Obstetricians and Gynecologists (ACOG) and Society for Maternal-Fetal Medicine released a joint clinical opinion in March 2010.13 The opinion states that “available evidence suggests that magnesium sulfate given before anticipated early preterm birth reduces the risk of cerebral palsy in surviving infants.” It then points out that physicians who choose to use magnesium sulfate for neuroprotection should do so in accordance with the protocols of one of the larger trials. One of the difficulties faced by the clinician is that the 2 largest trials utilized different protocols for magnesium administration and dosing. Many clinicians may find it challenging to create a protocol that properly adheres to the available studies. In addition, no specific guidelines exist to help with patient selection other than to recommend its use in women “at increased risk” of preterm delivery. Given the poor positive predictive value of most recognized risk factors for preterm birth, clinicians may find it difficult to identify patients who are optimal candidates for magnesium sulfate use for neuroprotection. Thus, at present, the clinician who simply wants to know “who to treat” and “how to treat” in order to be in compliance with the
American Journal of Obstetrics & Gynecology MARCH 2011
protocols of the published studies finds few helpful answers in the available literature or recommendations from professional organizations. Our purpose is to provide recommendations for one regimen of magnesium sulfate administration for neuroprotection of the neonate that is specific and reflects current literature. Given the current status of the literature, it is clear that other approaches are equally appropriate.
Proposed protocol We propose the administration of magnesium sulfate for neuroprotection to women who meet one of the criteria in the Figure. This Figure also presents an algorithm for the administration of this medication to eligible mothers. Patients are considered eligible for magnesium sulfate for neuroprotection if they have a pregnancy with a gestational age between 23 weeks and 31 weeks and 6 days. This extends below the Rouse et al4 protocol because many institutions will begin neonatal resuscitation at a gestational age ⬍24 weeks. Modifications to our protocol can be made depending upon individualized institutional practices regarding the lower limit of gestational age where neonatal resuscitation will be attempted.
Obstetrics
www.AJOG.org
severe pulmonary disorders, or renal failure, may also not be candidates for magnesium sulfate therapy. Patients who meet eligibility (Figure) are given a loading dose of 6 g of magnesium sulfate over 20-30 minutes. A maintenance infusion of 2 g per hour is then continued for 12 hours or until delivery, whichever comes first.
FIGURE
Algorithm for selection of candidates and administration of magnesium sulfate for fetal neuroprotection
IV, intravenous. Reeves. Magnesium for fetal neuroprotection. Am J Obstet Gynecol 2011.
Patients are excluded from eligibility if there is no potential benefit to the fetus. Therefore, cases of intrauterine fetal demise and fetuses with lethal anomalies are not considered candidates for magnesium sulfate therapy. When palliative care is desired after delivery, such as in cases of lethal anomalies or aneuploidy with no plan for resuscitative measures,
Clinical Opinion
the benefits of magnesium sulfate are outweighed by the risks of therapy. Additionally, patients are not eligible for this specific protocol if the mother has severe preeclampsia, as these patients should be on standard magnesium sulfate protocols for seizure prophylaxis. Patients with maternal contraindications to magnesium, such as myasthenia gravis, certain
Retreatment The benefit of retreatment of patients who have completed an initial course of magnesium therapy is insufficiently documented in the current literature to justify any mandate either for or against such therapy. However, in the 2 largest trials published to date, the majority of patients delivered while receiving an infusion of the study drug (magnesium or placebo).4,5 Unfortunately, between the 2 studies, there is little uniformity in terms of duration of retreatment or the number of retreatment courses allowed. In our protocol, we present one option of retreatment with magnesium sulfate that is in accordance with the evidence provided up to this point. After discontinuation of magnesium sulfate, many patients will be observed on an antepartum service, and they may return later with a high risk of delivery within 12 hours. If ⬎6 hours have elapsed since discontinuation of the infusion, and the patient still meets eligibility criteria, a repeat 6-g bolus is given with a maintenance drip at 2 g per hour. If ⬍6 hours have elapsed since discontinuation of the medication, the 2 g per hour infusion rate can simply be restarted. Magnesium sulfate has been associated with increased neonatal mortality in several reports,14-16 but this was not confirmed in the study by Rouse et al.4 A follow-up analysis compared pregnancies exposed to the highest dose of magnesium sulfate to those with the lowest dose. It showed no difference in the rate of perinatal death (odds ratio, 1.01; 95% CI, 0.48 –2.10).17 Despite these conflicting results, because of potential harm to either the mother or the fetus, the goal is to only reinitiate magnesium sulfate in patients who are most likely to deliver in the next 12 hours. Minimizing the retreatment course to those patients
MARCH 2011 American Journal of Obstetrics & Gynecology
202.e2
Clinical Opinion
Obstetrics
where delivery is imminent should afford the newborn the benefits of magnesium sulfate while avoiding its potential harms.
Use of concomitant tocolysis Tocolytic use in this country is a widely debated topic made even more confusing in a setting where a traditional tocolytic is used for neuroprotection rather than uterine quiescence. In 2006, Grimes and Nada14 published a Current Commentary questioning its use as a primary tocolytic agent. A Cochrane review published in 2002 showed that magnesium sulfate was no more effective than alternative agents in preventing preterm delivery in 48 hours, ⬍34 weeks, or ⬍37 weeks.15 In fact, in a subanalysis in this review, magnesium sulfate was no better than placebo in preventing these outcomes.15 This led many in the country to transition to other agents with seemingly similar efficacy and less maternal and fetal side effects. Some reports have stated that with high doses (⬎48 g total), magnesium sulfate has been associated with an increase in neonatal mortality.14-16 This dose would typically be approached or exceeded with even 24 hours of tocolysis, a number less than half of the often strived for 48-hour window needed to obtain maximal potential therapeutic benefit from antenatal steroid administration. Our protocol does not use magnesium as a tocolytic agent, but as an agent for neuroprotection of the prematurely born infant. However, concomitant tocolysis is often desired by clinicians beyond the 12 hours of magnesium administration proposed in this protocol. Here, we present one method of concomitant tocolytic administration that allows for adherence to the literature using magnesium sulfate as a fetal neuroprotective agent. In several metaanalyses, calcium channel blockers and indomethacin have been associated with a decrease in preterm birth.18-20 Either of these 2 agents would be a reasonable drug to use as a concomitant tocolytic when prevention of preterm birth is desired. Nifedipine is a commonly used calcium channel blocker that may decrease myometrial 202.e3
contractions due to inhibition of calcium influx. It is contraindicated in cases of hypotension and known maternal coronary artery disease since it may increase the risk of myocardial ischemia.21 There is a theoretical concern of combining magnesium and calcium channel blockers as case reports have suggested that concomitant use of the 2 agents may occasionally result in neuromuscular blockade.22,23 This may lead some clinicians to have reservations in initiating nifedipine tocolysis during magnesium use for fetal neuroprotection. However, there are data showing that the combined use of magnesium sulfate and calcium channel blockers do not increase the risk of serious complications in preeclamptic patients.24,25 In fact, in the largest trial to date, the Magpie trial, 30% of patients enrolled were exposed to both nifedipine and magnesium, and no adverse events were reported.26 It seems that the theoretical concern of significantly increased risk of neuromuscular blockade is not well supported in the literature. An alternative agent to nifedipine is indomethacin, which is contraindicated in patients with severe renal or hepatic impairment, patients with oligohydramnios, or in gestational ages ⬎32 weeks as it has been associated with premature closure of the ductus arteriosus.21 Some authors have suggested that it is preferred over nifedipine secondary to superior tolerance with equal efficacy at ⬍32 weeks.20 Either drug is a reasonable option, and use of the optimal tocolytic will depend upon clinic circumstances. For this reason, we describe a protocol using either nifedipine or indomethacin as a tocolytic agent when magnesium has been initiated for neuroprotection. Patients meeting criteria in the Figure begin magnesium therapy as above. If concomitant tocolysis is desired, indomethacin therapy is initiated with a 50-g oral loading dose followed by 25 g orally every 6 hours for a total of 48 hours. This drug is contraindicated in patients with a gestational age ⬎32 weeks, platelet dysfunction or bleeding disorders, hepatic or renal dysfunction, gastrointestinal or ulcerative disease, and anaphylactic reactions to aspirin. Alternatively, nifedi-
American Journal of Obstetrics & Gynecology MARCH 2011
www.AJOG.org pine can be given with a loading dose of 10 mg orally every 20 minutes up to a total of 30 mg or until uterine activity declines. A total of 10-20 mg is then repeated every 6 hours for a total of up to 48 hours. Its use is contraindicated in patients with hypotension (⬍90/50 mm Hg), cardiac disease, and severe renal impairment.21 Tocolysis can be initiated at any time, as data indicating the optimal timing of administration of this therapy are lacking. This can be given with the loading dose of magnesium sulfate, during administration of the magnesium drip, or it can be initiated after cessation of magnesium at the 12-hour mark. Tocolysis is generally stopped after 48 hours, allowing for the desired window to be achieved for steroid benefit to the fetus.
Conclusion We have presented a protocol for the administration of magnesium sulfate for neuroprotection that is consistent with the available literature and the recommendations of ACOG. This protocol goes beyond current published recommendations in its more clearly defined but vitally important specification of patient selection. Our combined experience with physicians practicing in hundreds of obstetric facilities throughout the United States suggests that lack of such specific guidelines contributes significantly to the slow adoption of such protocols outside of select academic centers. In the absence of definitive clinical trials, the achievement of uniform patterns of care based on a single, specific, appropriate approach has been demonstrated to improve quality in other areas of medicine.27 Such uniformity is a hallmark of patient safety efforts outlined by the Institute of Medicine.28 Future clinical trials demonstrating the benefit of magnesium sulfate infusion in each subset of patients described in the Figure would be welcome and would lead to potential modification of this protocol. Meanwhile, we believe the uniformity of care promoted by such specific guidelines by itself is likely to encourage use of this agent and improve clinical outcomes. Clinical anarchy is not the only alternative when the perfect ran-
www.AJOG.org domized, double-blinded, placebo-controlled, crossover trial is unavailable. We wish to emphasize again that this specific approach is simply one way to be in compliance with current reasonable care. In light of current data, numerous variations and alternatives would be equally appropriate. However, for clinicians considering adoption of such therapy, this seems a good place to begin. f REFERENCES 1. Nelson KB, Grether JK. Can magnesium sulfate reduce the risk of cerebral palsy in very low birthweight infants? Pediatrics 1995;95:263-9. 2. Schendel DE, Berg CJ, Yeargin-Allsopp M, Boyle CA, Decoufle P. Prenatal magnesium sulfate exposure and the risk for cerebral palsy or mental retardation among very low-birth-weight children aged 3 to 5 years. JAMA 1996;276: 1805-10. 3. Paneth N, Jetton J, Pinto-Martin J, Susser M. Magnesium sulfate in labor and risk of neonatal brain lesions and cerebral palsy in low birth weight infants: the neonatal brain hemorrhage study analysis group. Pediatrics 1997; 99:E1. 4. Rouse DJ, Hirtz DG, Thom E, et al. A randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy. N Engl J Med 2008;359:895-905. 5. Crowther CA, Hiller JE, Doyle LW, Haslam RR. Effect of magnesium sulfate given for neuroprotection before preterm birth: a randomized controlled trial. JAMA 2003;290:2669-76. 6. Mittendorf R, Dambrosia J, Pryde PG, 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. 7. Magpie Trial Follow-up Study Collaborative Group. The Magpie trial: a randomized trial comparing magnesium sulphate with placebo for pre-eclampsia; outcome for children at 18 months. BJOG 2007;114:289-99.
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Clinical Opinion
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