Geburtshilfe Frauenheilkd 2004; 64(8): 781-792
DOI: 10.1055/s-2004-817791
Übersicht

Georg Thieme Verlag KG Stuttgart · New York

Lungenreifeinduktion mit Glukokortikoiden - einmalige oder wiederholte Applikation?[*]

Antenatal Corticosteroids to Prevent Respiratory Distress Syndrome - Are Single or Multiple Courses Better?H. H. Günter1 , K. Oehler1 , A. Scharf1 , H. Maul1 , C. Sohn1
  • 1Abteilung I: Pränatalmedizin, Geburtshilfe und allgemeine Gynäkologie, Zentrum Frauenheilkunde der Medizinischen Hochschule Hannover
Further Information

Publication History

Eingang Manuskript: 3. Oktober 2003 Eingang revidiertes Manuskript: 13. Oktober 2003

Akzeptiert: 11. Januar 2004

Publication Date:
04 August 2004 (online)

Zusammenfassung

Die Unsicherheit über die Wirkungsdauer einer antenatalen Glukokortikoidtherapie (ANC) zur Lungenreifung veranlasst einen großen Teil der Geburtshelfer zu wiederholten Applikationen. Tierversuche, aber auch Untersuchungen aus dem Bereich der Humanmedizin, lassen es möglich erscheinen, dass die Morbidität der Neonaten durch die wiederholte Kortisongabe zunimmt: Erhöhte neonatale Mortalität, ein geringeres Geburtsgewicht, Beeinträchtigung der mentalen und psychomotorischen Entwicklung, Anstieg der Infektmorbidität von Mutter und Kind, Beeinflussung der intrauterinen Programmierung durch Modifikation der hypothalamo-pituitär-adrenalen Achse mit Manifestation von Diabetes und Bluthochdruck im späteren Leben des Kindes. Bei Auswertung der aktuellen Literatur können diese diskutierten Komplikationen einer wiederholten ANC-Gabe jedoch keinesfalls als bewiesen gelten. Da andererseits die wiederholte ANC-Applikation lediglich mit einer unterschiedlich ausgeprägten Verminderung des Atemnotsyndroms korreliert, gibt es auch für die routinemäßige multiple Wiederholung der Steroidgabe keine wissenschaftliche Begründung. Bis die Ergebnisse größerer prospektiver, randomisierter Studien vorliegen, sollte jeder Schwangeren mit signifikanten Frühgeburtsbestrebungen zwischen der 24. und der 34. Schwangerschaftswoche (SSW) ein Zyklus z. B. Betamethason (2 × 12 mg im Abstand von 24 Stunden) appliziert werden. Aufgrund bisheriger Daten kann allenfalls die einmalige Wiederholung der Prophylaxe als sinnvoll und unbedenklich angesehen werden.

Abstract

The discussion on the application of multiple versus single courses of antenatal corticosteroids (ANC) for the prevention of respiratory distress syndrome (RDS) in newborns is still controversial. Since the benefits of ANC have been shown to be most significant within 7 to 10 days after treatment, many obstetricians tend to treat women with repeated courses of ANC if the risk of premature delivery persists. However, data from animal as well as from clinical studies suggest detrimental effects of multiple courses of ANC: an increase of neonatal mortality, low birth weight, retardation of mental, and psychomotoric development, an increase in infectious morbidity of the mother and the newborn, alterations of intra-uterine programming by modification of the hypothalamic-pituitary-adrenal axis with the consequence of an increased rate of diabetes and hypertension in later life. However, a detailed review of the literature fails to prove a causal relationship between multiple courses of ANC and the complications mentioned above. Conversely, only gradual decreases in the severity of RDS do not justify routine application of repeated courses of ANC. Until publication of the results of larger prospective randomised controlled trials, each pregnant woman at significant risk for premature delivery (24 - 34 weeks of gestation) should receive a single course of ANC (e.g. betamethasone, 2 × 12 mg in a 24-hour interval). Based on the data published, a second course of ANC can be considered as efficient and harmless.

1 Herrn Prof. em. Dr. med. Dr. med. h. c. J. Schneider zum 75. Geburtstag gewidmet

Literatur

  • 1 Abbasi S, Hirsch D, Davis J, Tolosa J, Stouffer N, Debbs R, Gerdes J S. Effect of single versus multiple courses of antenatal corticosteroids on maternal and neonatal outcome.  Am J Obstet Gynecol. 2000;  182 1243-1249
  • 2 American College of Obstetricians and Gynecologists . Committee opinion No. 273. Antenatal corticosteroid therapy for fetal maturation.  Obstet Gynecol. 2002;  99 871-873
  • 3 Ballard P L. Hormones and lung maturation. Ballard P Monographs on Endocrinology. Vol. 28. Berlin; Springer-Verlag 1986: 1-345
  • 4 Ballard P L, Ballard R A. Scientific basis and therapeutic regimens for use of antenatal glucocorticoids.  Am J Obstet Gynecol. 1995;  173 254-262
  • 5 Ballard P L, Granberg J P, Ballard R A. Glucocorticoid levels in maternal and cord serum after prenatal betamethasone therapy to prevent respiratory distress syndrome.  J Clin Invest. 1975;  56 1548-1554
  • 6 Ballard P L, Ning Y, Polk D, Ikegami M, Jobe A H. Glucocorticoid regulation of surfactant components in immature lambs.  Am J Physiol. 1997;  273 L1048-1057
  • 7 Banks B A, Cnaan A, Morgan M A, Parer J T, Merrill J D, Ballard P L, Ballard R A. Multiple courses of antenatal corticosteroids and outcome of premature neonates.  Am J Obstet Gynecol. 1999;  181 709-717
  • 8 Banks B A, Macones G, Cnaan A, Merrill J D, Ballard P L, Ballard R A. Multiple courses of antenatal corticosteroids are associated with early severe lung disease in preterm neonates.  J Perinatol. 2002;  22 101-107
  • 9 Benediktsson R, Lindsay R S, Noble J, Seckl J R, Edward C R. Glucocorticoid exposure in utero: new model for adult hypertension.  Lancet. 1993;  34 339-341
  • 10 Bradley B S, Kumar S P, Mehta P N, Ezhuthachan S G. Neonatal cushingoid syndrome resulting from serial courses of antenatal betamethasone.  Obstet Gynecol. 1994;  83 869-872
  • 11 Brocklehurst P, Gates S, McKenzie-McHarg K, Alfirevic Z, Chamberlain G. Are we prescribing multiple courses of antenatal corticosteroids? A survey of practice in the UK.  Br J Obstet Gynaecol. 1999;  106 977-979
  • 12 Caughey A B, Parer J T. Recommendations for repeat courses of antenatal corticosteroids: A decision analysis.  Am J Obstet Gynecol. 2002;  186 1221-1229
  • 13 Chien L Y, Ohlsson A, Sechia M MK, Boulton J, Sankaran K, Lee S K. The Canadian Neonatal Network . Variations in antenatal corticosteroid therapy: A persistent problem despite 30 years of evidence.  Obstet Gynecol. 2002;  99 401-408
  • 14 Clark P M. Programming of the hypothalamopituitary-adrenal axis and the fetal origins of adult disease hypothesis.  Eur J Pediatr. 1998;  157 S7-10
  • 15 Crowley P A. Antenatal corticosteroid therapy: a meta-analysis of the randomized trials, 1972 to 1994.  Am J Obstet Gynecol. 1995;  173 322-335
  • 16 Crowley P. Prophylactic corticosteroids for preterm birth (Cochrane Review). The Cochrane library, Issue 2. Oxford; Update Software 2000
  • 17 Crowley P. Prophylactic corticosteroids for preterm birth (Cochrane Review). The Cochrane Library, Issue 1. Oxford; Update Software 2003
  • 18 Dean F, Matthews S G. Maternal dexamethasone treatment in late gestation alters glucocorticoid receptor mRNA in the fetal guinea pig brain.  Brain Res. 1999;  846 253-259
  • 19 Dirnberger D R, Yoder B A, Gordon M C. Single versus repeated-courses of antenatal corticosteroids: outcomes in singleton and multiple-gestation pregnancies.  Am J Perinat. 2001;  18 267-277
  • 20 Doyle L W, Ford G W, Rickards A L, Kelly E A, Noni M D, Callanan C, Olinsky A. Antenatal corticosteroids and outcome at 14 years of age in children with birth weight less than 1501 grams (abstract).  Pediatrics. 2000;  106 127
  • 21 Driul L, Furlan R, Macagno F, Pezzani I, Plaino L, Ianni A, Casarsa S, Zavarise D, Marchesoni D. Neonatal sepsis after multiple courses of antenatal corticosteroids.  Minerva Ginecol. 2003;  55 37-42
  • 22 Elimian A, Verma U, Visintainer P, Tejani N. Effectiveness of multidose antenatal steroids.  Obstet Gynecol. 2000;  95 34-36
  • 23 Erickson K, Schmidt L, Santesso D L, Schulkin J, Gregory K, Hobel C. Obstetrician-Gynecologists' knowledge and training about antenatal corticosteroids.  Obstet Gynecol. 2001;  97 140-146
  • 24 Esplin M S, Fausett M B, Smith S, Oshiro B T, Porter T F, Branch D W, Varner M W. Multiple courses of antenatal steroids are associated with a delay in long-term psychomotor development in children with birth weights ≤ 1500 grams [abstract].  Am J Obstet Gynecol. 2000;  182 S24
  • 25 Esters D M, Pass J, Egan J FX. Serial betamethasone use in a clinic practice: Does it effect fetal growth? [abstract].  Am J Obstet Gynecol. 2000;  182 S57
  • 26 Evans N. Cardiovascular effects of dexamethasone in the preterm infant.  Arch Dis Child Fetal Neonatal Ed. 1994;  70 F25-30
  • 27 Fisher J E, Smith R S, Lagraneur R, Lorenz R P. Gestational diabetes mellitus in women receiving beta-adrenergic and corticosteroids for threatened preterm delivery.  Obstet Gynecol. 1997;  90 880-883
  • 28 Ford L R, Willi S M, Hollis B W, Wright N M. Suppression and recovery of the neonatal hypothalamic-pituitary-adrenal axis after prolonged dexamethasone therapy.  J Pediatr. 1997;  131 722-726
  • 29 French N P, Hagan R, Evan S, Godfrey M, Newnham J P. Repeated antenatal corticosteroids (CS): behaviour outcomes in a regional population of very preterm infants.  Pediatr Res. 1998;  43 214A
  • 30 French N P, Hagan R, Evans S F, Godfrey M, Newnham J P. Repeated antenatal corticosteroids: size at birth and subsequent development.  Am J Obstet Gynecol. 1999;  180 114-121
  • 31 Guinn D A, Atkinson W M, Sullivan L, Lee M J, MacGregor S, Parilla B V, Davies J, Hanlon-Lundberg K, Simpson L, Stone J, Wing D, Ogasawara K, Muraskas J. Singel vs. weekly courses of antenatal corticosteroids for women at risk of preterm delivery. A randomized controlled trial.  JAMA. 2001;  286 1581-1587
  • 32 Guinn D A, Atkinson W M, Sullivan L, Lee M J, MacGregor S, Parilla B V, Davies J, Hanlon-Lundberg K, Simpson L, Stone J, Wing D, Ogasawara K, Muraskas J. Single vs. weekly courses of antenatal corticosteroids for women at risk of preterm delivery. A randomized controlled trial (in reply).  JAMA. 2002;  287 189
  • 33 Helal K J, Gordon M C, Lightner C R, Barth Jr W H. Adrenal suppression induced by betamethasone in women at risk for premature delivery.  Obstet Gynecol. 2000;  96 287-290
  • 34 Howie R N, Liggins G C. The New Zealand study of antepartum glucocorticoid treatment. Farrell PM Lung Development: Biological and Clinical Perspectives. Vol. II. London; Academic Press 1982: 255-265
  • 35 Huang W L, Beazley L D, Quinlivan J A, Evans S F, Newnham J P, Dunlop S A. Effect of corticosteroids on brain growth in fetal sheep.  Obstet Gynecol. 1999;  94 213-218
  • 36 Ikegami M, Jobe A H, Newnham J, Polk D H, Willet K E, Sly P. Repetitive prenatal glucocorticoids improve lung function and decrease growth in preterm lambs.  Am J Respir Crit Care Med. 1997;  156 178-184
  • 37 Ikegami M, Polk D H, Jobe A H, Newnham J, Sly P, Kohan R, Kelly R. Effect of interval from fetal corticosteroid treatment to delivery on postnatal lung function of preterm lambs.  J Appl Physiol. 1996;  80 591-597
  • 38 Jazayeri A, Gavrila D, Sincich T. Repeated antenatal corticosteroid treatments. Do they reduce neonatal morbidity?.  J Reprod Med. 2001;  46 788-790
  • 39 Jenkins T M, Wapner R J, Thom E A, Spong C Y. Are weekly courses of antenatal steroids beneficial or dangerous (letter)?.  JAMA. 2002;  287 187-188
  • 40 Jobe A H, Newnham J P, Moss T J, Ikegami M. Differential effects of maternal betamethasone and cortisol on lung maturation and growth in fetal sheep.  Am J Obstet Gynecol. 2003;  188 22-28
  • 41 Jobe A H, Wada N, Berry L M, Ikegami M, Ervin M G. Single and repetitive maternal glucocorticoid exposures reduce fetal growth in sheep.  Am J Obstet Gynecol. 1998;  178 880-885
  • 42 Leung T N, Lam P M, NG P C, Lau T K. Repeated courses of antenatal corticosteroids: Is it justified?.  Acta Obstet Gynecol Scand. 2003;  82 589-596
  • 43 Levitt N S, Lindsay R S, Holmes M C, Seckl J R. Dexamethasone in the last week of pregnancy attenuates hippocampal glucocorticoid receptor gene expression and elevates blood pressure in the adult offspring in the rat.  Neuroendocrinology. 1996;  64 412-418
  • 44 Liggins G C, Howie R N. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants.  Pediatrics. 1972;  50 515-525
  • 45 Marinelli K A, Burke G S, Herson V C. Effects of dexamethasone on blood pressure in premature infants with bronchodysplasia.  J Pediatr. 1997;  130 594-602
  • 46 McEvoy C, Bowling S, Williamson K, Collins J, Tolaymat L, Maher J. Timing of antenatal corticosteroids an neonatal pulmonary mechanics.  Am J Obstet Gynecol. 2000;  183 895-899
  • 47 McKenna D S, Wittber G M, Nagaraja H N, Samuels P. The effect of repeated doses of antenatal corticosteroids on maternal adrenal function.  Am J Obstet Gynecol. 2000;  183 669-673
  • 48 Modi H, Lewis H, Al-Naqeeb N, Ajayi-obe M, Doré C J, Rutherford M. The effects of repeated antenatal glucocorticoid therapy on the developing brain.  Pediatr Res. 2001;  50 581-585
  • 49 Murphy K E, Hannah M, Brocklehurst P. Single vs. weekly courses of antenatal corticosteroids for women at risk for preterm delivery: a randomized controlled trial (letter to the editor).  JAMA. 2002;  287 188-189
  • 50 National Institutes of Health Consensus Development Panel . Antenatal corticosteroids revisited: Repeat Courses - National Institutes of Health Consensus Development Conference Statement, August 17 - 18, 2000.  Obstet Gynecol. 2001;  98 144-146
  • 51 National Institutes of Health Consensus Conference . Effect of corticosteroids for fetal maturation on perinatal outcomes. NIH Consensus Development Panel on the effect of corticosteroids for fetal maturation on perinatal outcomes.  JAMA. 1995;  273 413-418
  • 52 Ng P C, Lam C WK, Lee C H, Ma K C, Fok T F, Chan I HS, Wong E. Reference ranges and factors affecting the human corticotropin-releasing hormone test in preterm, very low birth weight infants.  J Clin Endocrinol Metab. 2002;  87 4628
  • 53 Planer B C, Ballard R A, Ballard P L, Coburn C, Boardman A, Cnaan A. Use of antenatal corticosteroids (ANCS) in USA [abstract].  Am J Obstet Gynecol. 1998;  174 A576
  • 54 Pratt L, Waschbusch L, Ladd W, Gangnon R, Hendricks S K. Multiple vs. single betamethasone therapy. Neonatal and maternal effects.  J Reprod Med. 1999;  44 257-264
  • 55 Quinlivan J A, Beazley L D, Evans S F, Newham J P, Dunlop S A. Retinal maturation is delayed by repeated, but not single, maternal injections of betamethasone in sheep.  Eye. 2000;  14 93-98
  • 56 Quinlivan J A, Evans S F, Dunlop S A, Beazley L D, Newnham J P. Use of carticosteroids by Australian obstetricians - a survey of clinical practice.  Aust N J Obstet Gynaecol. 1998;  38 1-7
  • 57 Ragosch V, Weitzel H. Derzeitiger Stand der Lungenreifeinduktion zur Vermeidung eines neonatalen Atemnotsyndroms.  Gynäkologe. 1995;  28 203-210
  • 58 Rotmensch S, Vishne T H, Celentano C, Dan M, Ben-Rafael Z. Maternal infectious morbidity following multiple courses of betamethasone.  J Infect. 1999;  39 49-54
  • 59 Sinervo K, Lange I. Maternal and neonatal outcomes following single versus multiple courses of corticosteroids [abstract].  Am J Obstet Gynecol. 2000;  182 S52
  • 60 Smith L M, Qureshi N, Chao C R. Effects of single and multiple courses of antenatal glucocorticoids in preterm newborns less than 30 weeks' gestation.  J Matern Fetal Med. 2000;  9 131-135
  • 61 Stewart J D, Sienko A E, Gonzalez C L, Christensen H D, Rayburn W F. Placebo-controlled comparison between a single dose and a multidose of betamethasone in accelerating lung maturation of mice offspring.  Am J Obstet Gynecol. 1998;  179 1241-1247
  • 62 Tabor B L, Rider E D, Ikegami M, Jobe A H, Lewis J F. Dose effects of antenatal corticosteroids for induction of lung maturation in preterm rabbits.  Am J Obstet Gynecol. 1991;  164 675-681
  • 63 Terrone D A, Smith L G, Wolf E J, Uzbay L A, Sun S, Miller R C. Neonatal effects and serum cortisol levels after multiple courses of maternal corticosteroids.  Obstet Gynecol. 1997;  90 819-823
  • 64 Thorp J A, Jones A MH, Hunt C, Clark R. The effect of multidose antenatal betamethasone on maternal and infant outcomes.  Am J Obstet Gynecol. 2001;  184 196-202
  • 65 Uno H, Lohmiller L, Thieme C, Kemnitz J W, Engle M J, Roecker E B, Farrell P M. Brain damage induces by prenatal exposure to dexamethasone in fetal rhesus macaques. I. Hippocampus.  Brain Res Dev Brain Res. 1990;  53 157-167
  • 66 Vermillion S T, Bland M L, Soper D E. Effectiveness of a rescue dose of antenatal betamethasone after an initial single course.  Am J Obstet Gynecol. 2001;  185 1086-1089
  • 67 Vermillion S T, Soper D E, Bland M, Newman R B. Effectiveness of antenatal corticosteroid administration after preterm premature rupture of the membranes.  Am J Obstet Gynecol. 2000;  183 925-929
  • 68 Vermillion S T, Soper D E, Newman R B. Neonatal sepsis and death after multiple courses of antenatal betamethasone therapy.  Am J Obstet Gynecol. 2000;  183 810-814
  • 69 Vermillion S T, Soper D E, Newman R B. Is betamethasone effective longer than 7 days after treatment?.  Obstet Gynecol. 2001;  97 491-493
  • 70 Walfisch A, Hallak M, Mazor M. Multiple courses of antenatal steroids: Risks and benefits.  Obstet Gynecol. 2001;  98 491-497
  • 71 Wallace E M, Stenson B. Antenatal corticosteroid prescribing: setting standards of care.  BJOG. 1997;  104 1262-1266
  • 72 Wijnberger L DE, Mostert J M, van Dam K I, Mol B WJ, Brouwers H, Visser G H. Comparison of single and repeated antenatal corticosteroid therapy to prevent neonatal death and morbidity in the preterm infant.  Early Human Development. 2002;  67 29-36
  • 73 Yeh T F, Lin Y J, Huang C C, Chen Y J, Lin C H, Lin H C, Hsieh W S, Lien Y J. Early dexamethasone therapy in preterm infants: a follow-up study.  Pediatrics. 1998;  101 E7
  • 74 Yunis K A, Bitar F F, Hayek P, Mrouch S M, Mikati M. Transient hypertrophic cardiomyopathy in the newborn following multiple doses of antenatal corticosteroids.  Am J Perinatol. 1999;  16 17-21

1 Herrn Prof. em. Dr. med. Dr. med. h. c. J. Schneider zum 75. Geburtstag gewidmet

OA PD Dr. med. Hans Heinrich Günter

Zentrum Frauenheilkunde der Medizinischen Hochschule Hannover im Krankenhaus Oststadt

Podbielskistraße 380

30659 Hannover

Email: hhguentermhh@gmx.net

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