Download PDF
Z Geburtshilfe Neonatol 2016; 220(02): 58-65
DOI: 10.1055/s-0035-1564264
Originalarbeit
© Georg Thieme Verlag KG Stuttgart · New York

Wie verlässlich sind Metaanalysen? Eine Überprüfung am Beispiel der Magnesiumtokolyse

How Reliable are Meta-Analyses? An Appraisal Using the Example of Magnesium Tocolysis
P. Czekelius
1   em., Klinikum Konstanz, Frauenklinik, Konstanz
,
H. Wenzel
2   Independent Health Economic Consultant, Konstanz
› Author Affiliations
Further Information

Publication History

eingereicht  09 October 2014

angenommen nach Überarbeitung 21 September 2015

Publication Date:
04 March 2016 (online)

Also available at
    Permissions and Reprints

Zusammenfassung

Einleitung: Aufgrund einer Cochrane-Analyse Crowther’s et al. [3] zur Frage der Verhinderung von Frühgeburten wurde die Magnesiumtokolyse in den zuletzt gültigen Leitlinien der DGGG nicht mehr empfohlen. Weder verzögere sie eine Frühgeburt, noch verhindere sie sie. Darüber hinaus sei sie mit einer erhöhten kindlichen Mortalität assoziert. Diese Feststellung geht im Wesentlichen auf eine Untersuchung Mittendorfs et al. [4] zurück. In einer prinzipiell gleichlautenden Cochrane-Studie von 2014 haben Crowther et al. [6] ihre Ansicht bekräftigt.

Methode: Diese, nach langjähriger, erfolgreicher Magnesium-Tokolyse, überraschenden Behauptungen ergeben den Grund, die oben angeführten Arbeiten auf ihre Stichhaltigkeit zu überprüfen. Durch eine umfassende Literaturrecherche werden sie ergänzt und mit den Arbeiten, die die DGGG zu ihrer Maßnahme veranlasste, in Beziehung gesetzt.

Ergebnisse: Verbindliche Konsequenzen aus Metaanalysen lassen sich nur unter Beibehaltung strenger Standards ziehen. Die in den Cochranestudien Crowthers et al. [3] [6] berücksichtigten, sehr heterogenen Untersuchungen lassen Rückschlüsse auf mangelnde oder fehlende Wirkung von Magnesium als Tokolytikum nicht zu. Auch die von Mittendorf et al. [4] angegebenen kindlichen Todesfälle und weitere seiner Untersuchungen machen eine Verursachung durch Magnesium nicht wahrscheinlich.

Schlussfolgerung: Bei Metaanalysen sollte mit besonderer Sorgfalt auf Relevanz und tendenzfreie Auswahl miteingeschlossener Arbeiten geachtet werden. Um Fehlbeurteilungen vorzubeugen, scheint eine genaue Kenntnis der in eine Metaanalyse einbezogenen Untersuchungen unverzichtbar. Für die Ausgliederung der Magnesium-Tokolyse als präventive Maßnahme zur Verhinderung einer Frühgeburt gibt es z. Zt. keinen ausreichenden Grund. Langjährige, wissenschaftlich nachgewiesene Therapieerfolge sollten, im Sinne einer evidenzbasierten Medizin (EbM), in Metaanalysen miteinbezogen werden.

Abstract

Introduction: Crowther et al. [3] analysed the effectivity of magnesium tocolysis in preventing preterm birth. They conclude that there is no evidence for protection. In its latest guidelines, based on this Cochrane analysis, the German Association of Gynaecology and Obstetrics (DGGG) does not recommend any more the use of magnesium for tocolysis. Magnesium tocolysis is said neither to delay nor to prevent preterm birth. Moreover, magnesium could be responsible for increased mortality in infants. These conclusions are mostly based on the research of Mittendorf et al. [4]. In a Cochrane study from 2014, which in principal was identical to the study mentioned above [3], Crowther et al. [6] confirm the previous findings and conclusions.

Method: Having successfully applied magnesium tocolysis for many years, these surprising conclusions led us to review the soundness of the publications mentioned above. Combining the practical experience of many years with the results of a comprehensive literature retrieval, we finally contrasted this knowledge with the findings of the aforementioned publications that caused the DGGG to withdraw the recommendation for magnesium.

Results: To draw binding consequences from a meta-analysis is possible only when stringent quality guidelines are observed. The studies that were included in the Cochrane review of Crowther et al. [3] are very heterogeneous and are not suitable for concluding on poor or even lacking effectiveness of magnesium tocolysis. Furthermore, the cases of infant deaths, as stated by Mittendorf et al. [4], are very unlikely caused by magnesium.

Conclusion: When including studies in a meta-analysis special attention has to be given to the relevance and unbiased selection of studies. To prevent any misjudgment, a thorough knowledge of the included studies seems essentiell. There is not sufficient evidence to withdraw the recommendation for applying magnesium tocolysis as a preventive measure to prevent preterm birth. In the sense of evidence-based medicine, long-standing, scientifically proven therapeutic success should be incorporated into the meta-analysis as well.

Schlüsselwörter

Metaanalyse - Cochrane-Review - Tokolyse - Magnesium - Frühgeburtstherapie

Key words

meta-analysis - cochrane review - tocolysis - magnesium - therapy for preterm birth

Condensed Content

 

  • Literatur

  • 1 Lanier J. Digital Maoism. The hazards of the new online collectivism. Edge 30.05.2006
    PubMedGoogle Scholar
  • 2 Raspe H. Konzept und Methoden der Evidenz-basierten Medizin: Besonderheiten, Stärken, Grenzen, Schwächen und Kritik. Hg. . Deutsches Netzwerk Evidenzbasierte Medizin e. V. Online verfügbar unter http://www.ebm-netzwerk.de/was-ist-ebm/images/konzepte_ebm_raspe.pdf/view zuletzt geprüft am 16.09.2014
    PubMedGoogle Scholar
  • 3 Crowther CA, Hiller JE, Doyle LW. Magnesium sulphate for preventing preterm birth in threatened preterm labour. 2002 Cochrane-Review, Wiley
    PubMedGoogle Scholar
  • 4 Mittendorf R, Covert R, Boman J et al. Is tocolytic magnesium sulphate associated with increased total paediatric mortality?. Lancet 1997; 350: 1517-1518
    CrossrefPubMedGoogle Scholar
  • 5 Schneider H, Husslein P, Schneider KTM. Geburtshilfe. 2000. Springer; 478
    CrossrefGoogle Scholar
  • 6 Crowther CA, Brown J, McKinlay CJD et al. Magnesium sulphate for preventing preterm birth in threatened preterm labour. 2014 Cochrane-Review, Wiley
    PubMedGoogle Scholar
  • 7 Kumar D, Zourla P, Barnes AG. In vitro and in vivo effects of magnesium sulfate on human uterine contractility. Am J Obstet Gynecol 1963; 86: 1036
    CrossrefPubMedGoogle Scholar
  • 8 Wiest W in Künzel W, Darda S. Tokolyse. Springer; 1984. 72 und 75
    Crossref
  • 9 Walder RY, Landau D, Meyer P et al. Mutation of TRPM6 causes familial hypomagnesemia with secondary hypocalcemia. Nat Genet 2000; 31: 171-174
    PubMedGoogle Scholar
  • 10 Golf S. Pharmakokinetik und Bioverfügbarkeit von Magnesiumverbindungen. Pharmazeutische Zeitung online 2006 11. Online verfügbar unter http://www.pharmazeutische-zeitung.de/index.php?id=889 zuletzt abgerufen am 09.02.2015
    PubMedGoogle Scholar
  • 11 Mittendorf R, Janeczek S, McMillan W et al. Mechanisms of mortality in the magnesium and neurologic endpoints trial (MAGNET TRIAL): fetal inflammatory respons syndrome (FIRS). Am J Obstet gynecol 2001; 185: 151
    PubMedGoogle Scholar
  • 12 Mittendorf R, Pryde P, Khoshnood B et al. If tocolytic magnesium sulfate is associated with excess total pediatric mortality, what is its impact?. Obstet Gynrcol 1998; 92: 308-311
    PubMedGoogle Scholar
  • 13 Mittendorf R, Pryde P. Tocolytic magnesium sulfate: are the epidemiologic data reassuring?. Am J Obstet Gynecol 1998; 179: 280
    PubMedGoogle Scholar
  • 14 Mittendorf R, Covert R, Elin R et al. Umbilical cord serum ionized magnesium level and total pediatric mortality. Obstet Gynecol 2001; 98: 75-78
    PubMedGoogle Scholar
  • 15 Mittendorf R, Dambrosia J, Dammann O et al. Association between maternal serum ionized magnesium levels at delivery and neonatal intraventricular hemorrhage. J Pediatr 2002; 140: 540-546
    CrossrefPubMedGoogle Scholar
  • 16 Aramayo JFJ, Martinez FJ, Rosales CL. Terapia tocolytica con sulfato de magnesio y terbutalina para la inhibicion del trabajo de parto pretérmino. Ginec Obstet Mex 1990; 58: 265-269
    PubMedGoogle Scholar
  • 17 Armson BA, Samuels P, Miller F et al. Evaluation of maternal fluid dynamics during tocolytic therapy with ritodrine hydrochloride and magnesium sulfate. Am J Obstet Gynecol 1992; 167: 758-765
    CrossrefPubMedGoogle Scholar
  • 18 Beall MH, Edgar BW, Paul Rh et al. A comparison of ritodrine, terbutalne, and magnesium sulfate for the suppression of preterm labor. Am J Obstet Gynecol 1985; 153: 854-859
    CrossrefPubMedGoogle Scholar
  • 19 Chau AC, Gabert HA, Miller JM. A prospective comparison of terbutaline and magnesium for tocolysis. Obstet Gynecol 1992; 80: 847-851
    PubMedGoogle Scholar
  • 20 Cotton DB, Strassner HT, Hill LM et al. Comparison of magnesium sulfate, terbutaline and a placebo for inhibition of preterm labor. J Reproduct Med 1984; 29: 92-97
    PubMedGoogle Scholar
  • 21 Cox SM, Sherman ML, Leveno KJ. Randomized investigation of magnesium sulfate for prevention of preterm birth. Am J Obstet Gynecol 1990; 163: 772-767
    PubMedGoogle Scholar
  • 22 El-Sayed YY, Riley ET, Holbrook Jr. RH et al. Randomized comparison of intravenous nitroglycerin and magnesium sulfate for treatment of preterm labor. Obstet Gynecol 1999; 93: 79-83
    CrossrefPubMedGoogle Scholar
  • 23 Floyd RC, MCLaughlin BN, Martin RW et al. Comparison of magnesium and nifedipine for primary tocolysis and idiopathic preterm labor. Am J Obstet Gynecol AJOG 1992; 166: 446
    PubMedGoogle Scholar
  • 24 Fox MD, Allbert JR, McCaul JF et al. Neonatal morbidity between 24 and 37 weeks’ gestation. J Perinat 1993; XIII: 349-353
    PubMedGoogle Scholar
  • 25 Glock JL, Morales WJ. Efficacy and safety of nifedipine versus magnesium sulfate in the management of preterm labor: a randomized study. Am J Obstet Gynecol 1993; 169: 960-964
    CrossrefPubMedGoogle Scholar
  • 26 Haghighi L. Prevention of preterm delivery: nifedipine or magnesium sulfate. Intern J Gynecol Obstet 1999; 66: 297-298
    CrossrefPubMedGoogle Scholar
  • 27 Hollander DI, Nagey DA, Marcos J et al. Magnesium sulfate and ritodrine hydrochloride: a randomized comparison. Am J Obstet Gynecol 1987; 156: 631-637
    CrossrefPubMedGoogle Scholar
  • 28 Larmon JE, Ross BS, May WL et al. Oral nicardipine versus intravenous magnesium sulfate for the treatment of preterm labor. Am J Obstet Gynecol 1999; 181: 1432-1437
    CrossrefPubMedGoogle Scholar
  • 29 Ma L, Yan R, Xiao W et al. Magnesium sulfate in prevention of preterm labor. Zhong hua yi xue za zhi 1992; 72: 158-161
    PubMedGoogle Scholar
  • 30 Miller JM, Keane MWD, Horger III EO. A comparison of magnesium sulfate and terbutaline for arrest of preterm labor. J Reproduct Med 1982; 27: 348-351
    PubMedGoogle Scholar
  • 31 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. Obstet Gynecol 2002; 186: 1111-1118
    PubMedGoogle Scholar
  • 32 Morales WJ, Madhav H. Efficacy and safety of indomethacin compared with magnesium sulfate in the management of preterm labor; a randomized study. Am J Obstet Gynecol 1993; 169: 97-102
    CrossrefPubMedGoogle Scholar
  • 33 Schorr SJ, Ascarelli MH, Rust OA et al. Ketorolac is a safe and effective drug for acute tocolysis. Am J Obstet Gynecol 1997; 176 SPO Abstracts: S7
    PubMedGoogle Scholar
  • 34 Sciscione A, Gorman R, Schlossman P et al. A randomized prospective study of intravenous magnesium sulfate, ritodrine, and subcutaneous terbtaline as treatments for preterm labor. Am J Obstet Gynecol 1993; SPO Abstracts 376
    PubMedGoogle Scholar
  • 35 Steer CM, Petrie RH. A comparison of magnesium sulfate and alcohol for the prevention of preterm labor. Am J Obstet Gynecol 1977; 129: 1-4
    CrossrefPubMedGoogle Scholar
  • 36 Tchilinguirian Ng, Najem R, Sullivan GB et al. The use of ritodrine and magnesium sulfate in the arrest of premature labor. Intern J Gynaec Obstet 1984; 22: 117-123
    PubMedGoogle Scholar
  • 37 Wilkins IA, Lynch L, Mehalek KE et al. Efficacy and side effects of magnesium sulfate and ritodrine as tocolytic agents. Am J Obstet Gynecol 1988; 159: 685-689
    CrossrefPubMedGoogle Scholar
  • 38 Zhu B, Fu Y. treatment of preterm labor with ritodrine. Zhong hua fu chan ke za zhi 1996; 31: 721-723
    PubMedGoogle Scholar
  • 39 Bundesinstitut für Arzneimittel und Medizinprodukte. Schreiben an pharmazeutische Unternehmer vom 18.05.2009. Gesch. Z. 75-3821-V-12268-352518/08 Online verfügbar unter http://www.bfarm.de/SharedDocs/Downloads/DE/Arzneimittel/Pharmakovigilanz/Risikoinformationen/RisikoBewVerf/m-r/magnesium_schreiben.pdf?__blob=publicationFile&v=2 zuletzt abgerufen am: 10.02.2015
    PubMedGoogle Scholar
  • 40 Altmann DG, Royston P. The cost of dichotomizing continuous variables. BMJ 2006; 332: 1080
    PubMedGoogle Scholar
  • 41 Hauth JC, Goldenberg RL, Nelson KG et al. Reduction of cerebral palsy with maternal MgSO4 treatment in newborns weighing 500-1000 G. Am J Obstet Gynecol 1995; 172: 419
    PubMedGoogle Scholar
  • 42 Nelson KB, Grether JK. Can magnesium sulfate reduce the risk of cerebral palsy in very low birthweight infants?. Pediatrics 1995; 95: 263-269
    PubMedGoogle Scholar
  • 43 Schendel DE, Berg CJ, Yeargin-Allsopp M et al. Prenatal magnesium sulfate exposure and the risk for cerebral palsy or mental retardation among very low-birth-weight children aged 3 to 5 years. YAMA 1996; 276: 1805-1810
    PubMedGoogle Scholar
  • 44 Finesmith RB, Roche K, Yellin PB et al. Effect of magnesium sulfate on the development of cystic periventricular leucomalacia in preterm infants. Am J Perinatology 1997; 14: 303-307
    Article in Thieme ConnectPubMedGoogle Scholar
  • 45 Marrer S, Marpeau L, Zupan-Simunek V et al. Magnesium sulfate given before very-preterm birth to protect infant brain: the randomized, controlled PREMAG trial. BJOG: an international journal of obstetrics and gynecology 2007; 114: 310-318
    PubMedGoogle Scholar
  • 46 Rouse D, Hirtz D, Thom E et al. Magnesium sulfate for the prevention of cerebral palsy. New Engl J Med 2008; 359: 895-905
    CrossrefPubMedGoogle Scholar
  • 47 Conde-Agudelo A, Romero R. Antenatal magnesium sulfate for the prevention of cerebral palsy in preterm infants < 34 weeks’ gestation: a systematic review and meta-analysis. Am J Obstet Gynecol 2009; 200: 595-609
    CrossrefPubMedGoogle Scholar
  • 48 Martin H, Uring-Lambert B, Adrian M et al. Effects of long term dietary intake of magnesium on oxidative stress, apoptosis and ageing in rat liver. Magnesium Research 2008; 21: 124-130
    PubMedGoogle Scholar
  • 49 Doyle LW, Crowther CA, Middleton P. Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus. 2009 Cochrane-Review, Wiley
    PubMedGoogle Scholar
  • 50 Han S, Crowther CA, Moore V. Magnesium maintenance therapy for preventing preterm birth after threatened preterm labour. 2013 Cochrane-Review, Wiley
    PubMedGoogle Scholar
  • 51 Ricci JM, Hariharan S, Helfgott A et al. Oral tocolysis with magnesium chloride: a randomized controlled prospective clinical trial. Am J Obstet Gynecol 1991; 1654: 603-610
    PubMedGoogle Scholar
  • 52 Ridgeway LE, Muise K, Patterson RM et al. A prospective randomized comparison of oral terbutalin and magnesium oxide for the maintenance of tocolysis. Am J Obstet Gynecol 1990; 163: 879-882
    CrossrefPubMedGoogle Scholar
  • 53 Rust O, Bofill J, Arriola R et al. The clinical efficacy of oral tocolytic therapy. Am J Obstet Gynecol 1996; 175: 838-842
    CrossrefPubMedGoogle Scholar
  • 54 Holcomb WL, Daftery A, Petrie RH. Magnesium tocolysis: is “weaning” important?. Am J Obstet Gynecol 1991; 164: 375
    PubMedGoogle Scholar
  • 55 Haas DM, Imperiale TF, Kirkpatrick PR et al. Tocolytic therapy. A meta-analysis and decision analysis. Obstet Gyneco 2009; 113: 585-594
    CrossrefPubMedGoogle Scholar
  • 56 Haas DM, Caldwell DM, Kirkpartick P et al. Tocolytic therapy for preterm delivery: systematic review and network meta-analysis. BMJ 2012; 345: e6226 DOI: 1-16.
    CrossrefPubMedGoogle Scholar
  • 57 Lewis DF. Magnesium sulfate: the first-line tocolytic. Obstet Gynecol Clin N Am 2005; 32: 485-500
    CrossrefPubMedGoogle Scholar
  • 58 Hunter LA, Gibbins KJ. Magnesium sulfate: past, present, and futur. J Midwifery Womens Health 2011; 56: 566-574
    CrossrefPubMedGoogle Scholar
  • 59 Mercer BM, Merlino AA. Magnesium sulfate for preterm labor and preterm birth. 2009; 114: 650-668
    PubMedGoogle Scholar
  • 60 Wolf HT, Hegaard HK, Greisen G et al. Treatment with magnesium sulphate in preterm birth: A systematic review and meta-analysis of observational studies. J Obstet Gynecol 2012; 32: 135-140
    CrossrefPubMedGoogle Scholar
  • 61 Constantin MM, Weiner SJ, Kennedy Shrivet E. Effects of antenatal exposure to magnesium sulfate on neuroprotection and mortality in preterm infants. Obstet Gynecol 2009; 114: 354-364
    CrossrefPubMedGoogle Scholar
  • 62 Elliott JP, Lewis DF, Morrison JC et al. Defense of magnesium sulfate. 2009; 113: 1342-1348
    PubMedGoogle Scholar
  • 63 Grimes DA, Nanda K. Magnesium Sulfat Tocolysis. Time to Quit. Obstet Gynecol 2006; 108: 986-989 zuletzt geprüft am 16.09.2014
    Google Scholar
  • 64 Sackett DL, Strauss SF, Richardson WS et al. Evidence-based medicine: how to practise and teach EBM. 2nd (Ed.). London: Churchill-Livingstone; 2000
    Google Scholar