Lungenreifetherapie mit Glukokortikoiden bei drohender Frühgeburt[1]

Zusammenfassung

Frühgeburtlichkeit ist häufige Ursache für perinatale Morbidität und Mortalität. Zu deren Senkung hat die Lungenreifebehandlung mit Glukokortikoiden maßgeblich beigetragen. 1994 wurden von den NIH Empfehlungen zur Durchführung der Lungenreifeinduktion publiziert und die Wirksamkeit wurde 1999 von der Cochrane Collaboration erneut evaluiert. Danach reduziert die antenatale Glukokortikoidapplikation signifikant die perinatale Morbidität und die Rate an RDS und Hirnblutungen bei Frühgeborenen zwischen der 24. und 34. SSW.

Der Wert der repetitiven Glukokortikoidgabe ist nicht hinreichend geklärt; insbesondere deren Einfluss auf die Geburtsgewichte der Kinder und auf die Entwicklung von Infektionen bei vorzeitigem Blasensprung sowie die Festlegung des optimalen Wiederholungsintervalls. Nach Glukokortikoidgabe muss passager mit einer Verminderung der Kindsbewegungen und der fetalen Herzfrequenzvariabilität gerechnet werden; nicht geklärt sind die Auswirkungen auf das intrauterine Wachstum, das maternale und fetale Immunsystem und spätere Erkrankungen einschließlich Atopien.

Bei vorzeitiger, nicht muttermundswirksamer Wehentätigkeit wird daher die Indikation zur antenatalen Gabe von Glukokortikoiden zunehmend kritischer beurteilt. Bei vorzeitigem Blasensprung senkt die antenatale Glukokortikoidgabe nicht die Rate an RDS, jedoch signifikant die an Hirnblutungen und an nekrotisierenden Enterokolitiden. Für die Lungenreifebehandlung mit Glukokortikoiden bei Diabetes mellitus und bei intrauteriner Wachstumsretardierung liegen bisher keine prospektivrandomisierten Studien vor. Bei schwerer Präeklampsie vermindert Betamethason die RDS-Häufigkeit und die neonatale Mortalität signifikant.

Ungeachtet des lückenhaftes Wissens und der potenziellen (Langzeit-) Auswirkungen auf Mutter und Kind bleibt die antenatale Glukokortikoidmedikation nach den Empfehlungen der NIH von 1994 gemeinsam mit der Behandlung dieser Schwangeren in einem Perinatalzentrum entscheidender Eckpfeiler im Vorgehen bei Frühgeburtlichkeit. Die Indikation zur repetitiven Gabe von Glukokortikoiden sollte allerdings sorgfältig geprüft werden.

Prematurity is a major cause of perinatal morbidity and mortality. Antenatal administration of glucocorticoids improves the neonatal outcome of preterm born infants. 1994 the NIH published recommendations for the use of glucocorticoids for women at risk of preterm delivery. A recent evaluation by the Cochrane Collaboration in 1999 showed that antenatal administration of glucocorticoids significantly reduced the rate of RDS and IVH in the gestational age between 24 and 34 weeks. Consequences of repeated courses of antenatal glucocorticoids are not sufficiently studied. The effectivity and safety regarding birth weights, infectious diseases, and the best timing remains unknown. Administration of glucocorticoids lowers fetal activity and heart rate variability. Effects on fetal growth, maternal and fetal immunosystem, and the development of atopic diseases are controversely discussed. Thus preterm labour not leading to a cervical ripening is not necessarily a reason for antenatal glucocorticoids. Antenatal glucocorticoids with PROM do not lower the rate of RDS but of IVH. No prospective randomized trial evaluated the effectivity of antenatal glucocorticoids in diabetes mellitus and IUGR. In preeclampsia betamethason could improve the rate of RDS and the neonatal outcome. Still our knowledge of antenatal glucocorticoid administration is not sufficient. But despite possible (longtime-) risks for mother and child the administration of glucocorticoids according to the guidelines of the NIH is a major part in the treatment of prematurity and improves the outcome of premature infants. The indication for multiple courses of glucocorticoids should be considered carefully.

Frühgeburt - Lungenreife - Glukokortikoide - Evidence-based medicine

Prematurity - antenatal corticoids - evidence-based medicine

Literatur

1 Eingang: 24. 5. 2000 Angenommen nach Revision: 27. 7. 2000

• 01 Ventura  S J, Martin  J A, Curtin  S C, Mathews  T J. Report of final natality statistics, 1996. Mon Vital Stat Rep 1998: 1-99
• 02 Kramer  M S, Platt  R, Yang  H, et al. Secular trends in preterm birth: a hospital-based cohort study [published erratum appears in JAMA 1999 Feb 24; 281 (8): 705].  JAMA. 1998;  280 1849-1854
• 03 Goldenberg  R L, Rouse  D J. Prevention of premature birth.  New Engl J Med. 1998;  339 313-320
• 04 Towers  C V, Bonebrake  R, Padilla  G, Rumney  P. The effect of transport on the rate of severe intraventricular hemorrhage in very low birth weight infants.  Obstet Gynecol. 2000;  95 291-295
• 05 Crowley  P A. Antenatal corticosteroid therapy: a meta-analysis of the randomized trials, 1972 to 1994.  Am J Obstet Gynecol. 1995;  83 483-494
• 06 Effect of corticosteroids for fetal maturation on perinatal outcomes .Am J Obstet Gynecol. 1995 173: 246-252
• 07 Gardner  M O, Papile  L A, Wright  L L. Antenatal corticosteroids in pregnancies complicated by preterm premature rupture of membranes.  Obstet Gynecol. 1997;  90 555-564
• 08 Planer  B C, Ballard  R A, Ballard  P L, Cobum  C E, Boardman  C, Cnaan  A. Antenatal corticosteroid (ANCS) use in preterm labor in the USA [abstract].  Pediatr Res. 1996;  39 110A
• 09 Pratt  L, Magness  R R, Phernetton  T, Hendricks  S K, Abbott  D H, Bird  I M. Repeated use of betamethasone in rabbits: Effects of treatment variation on adrenal suppression, pulmonary maturation, and pregnancy outcome.  Am J Obstet Gynecol. 1999;  180 995-1005
• 10 Banks  B A, Cnaan  A, Morgan  M A, et al. Multiple courses of antenatal corticosteroids and outcome of premature neonates.  Am J Obstet Gynecol. 1999;  181 709-717
• 11 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
• 12 Kohlmann  H. Mögliche endokrine und immunologische Folgen pränataler Glukokortikoidgabe zur Prophylaxe des Neugeborenen-Respiratory-Distress-Syndroms.  Frauenarzt. 1999;  40 1173-1178
• 13 Seckl  J R, Chapman  K E. Medical and physiological aspects of the 11beta-hydroxysteroid dehydrogenase system.  Eur J Biochem. 1997;  249 361-364
• 14 Langley-Evans  S C, Phillips  G J, Bendiktsson  R, et al. Protein intake in pregnancy, placental glucocorticoid metabolism and the programming of hypertension in the rat.  Placenta. 1996;  17 169-172
• 15 Shams  M, Kilby  M D, Somerset  D A, et al. 11Beta-hydroxysteroid dehydrogenase type 2 in human pregnancy and reduced expression in intrauterine growth restriction.  Hum Reprod. 1998;  13 799-804
• 16 McCalla  C O, Nacharaju  V L, Muneyyirci  D O, Glasgow  S, Feldman  J G. Placental 11 beta-hydroxysteroid dehydrogenase activity in normotensive and pre-eclamptic pregnancies.  Steroids. 1998;  63 511-515
• 17 Hardy  D B, Pereria  L E, Yang  K. Prostaglandins and leukotriene B4 are potent inhibitors of 11beta-hydroxysteroid dehydrogenase type 2 activity in human choriocarcinoma JEG-3 cells.  Biol Reprod. 1999;  61 40-45
• 18 Florio  P, Franchini  A, Reis  F M, Pezzani  I, Ottaviani  E, Petraglia  F. Human placenta, chorion, amnion and decidua express different variants of corticotropin-releasing factor receptor messenger RNA.  Placenta. 2000;  21 32-37
• 19 Majjzoub  J A, McGregor  J A, Lockwood  C J, Smith  R, Snyder-Taggert  M, Schulkin  J. A central theory of preterm and term labour: putative role for corticotropin-releasing hormone.  Am J Obstet Gynecol. 1999;  180 232-242
• 20 Robinson  B G, Emanuel  R L, Frim  D M, Majzoub  J A. Glucocorticoid stimulates expression of corticotropine-releasing hormone gene in human placenta.  Proc Natl Acad Sci USA. 1988;  85 5244-5248
• 21 Phillips  D I, Barker  D J, Fall  C H, et al. Elevated plasma cortisol concentrations: a link between low birth weight and the insulin resistance syndrome?.  J Clin Endocrinol Metab. 1998;  83 757-760
• 22 Reis  F M, Fadalti  M, Florio  P, Petraglia  F. Putative role of placental corticotropin-releasing factor in the mechanisms of human parturition.  J Soc Gynecol Investig. 1999;  6 109-119
• 23 Blanford  A T, Murphy  B E. In vitro metabolism of prednisolone, dexamethasone, betamethasone and cortisol by human placenta.  Am J Obstet Gynecol. 1977;  127 164-267
• 24 Ward  R M. Pharmacologic enhancement of fetal lung maturation.  Clin Perinatol. 1994;  21 523-542
• 25 Muglia  L, Jacobson  L, Dikkes  P, Majzoub  J A. Corticotropin-releasing hormone deficiency reveals major fetal but not adult glucocorticoid need.  Nature. 1995;  373 427-432
• 26 Economides  D L, Nicolaides  K H, Linton  E A, Perry  L A, Chard  T. Plasma cortisol and adrenocorticotropin in appropriate and small for gestational age fetuses.  Fetal Ther. 1988;  3 158-164
• 27 White  E, Shy  K K, Benedetti  T J. Chronic fetal stress and the risk of infant respiratory distress syndrome.  Obstet Gynecol. 1986;  67 57-62
• 28 Lieberman  E, Torday  J, Barbieri  R, Cohen  A, Van  V H, Weiss  S T. Association of intrauterine cigarette smoke exposure with indices of fetal lung maturation.  Obstet Gynecol. 1992;  79 564-570
• 29 Curet  L B, Zachman  R D, Rao  A V, Poole  W K, Morrison  J, Burkett  G. Effect of mode of delivery on incidence of respiratory distress syndrome.  Int J Gynaecol Obstet. 1988;  27 165-170
• 30 Goldberg  J D, Cohen  W R, Friedman  E A. Cesarean section indication and the risk of respiratory distress syndrome.  Obstet Gynecol. 1981;  57 30-32
• 31 Procianoy  R S, Garcia-Prats  J A, Adams  J M, Silvers  A, Rudolph  A J. Hyaline membrane disease and intraventricular hemorrhage in small for gestational age infants.  Arch Dis Child. 1980;  55 502-505
• 32 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
• 33 Anwar  M A, Schwab  M, Poston  L, Nathanielsz  P W. Betamethasone-mediated vascular dysfunction and changes in hematological profile in the ovine fetus.  Am J Physiol. 1999;  H11 37-43
• 34 Terrone  D A, Rinehart  B K, Rhodes  P G, Roberts  W E, Miller  R C, Martin  J N. Multiple courses of betamethasone to enhance fetal lung maturation do not suppress neonatal adrenal response.  Am J Obstet Gynecol. 1999;  180 1349-1353
• 35 Derks  J B, Mulder  E JH, Visser  G HA. The effects of maternal betamethasone administration on the fetus.  Br J Obstet Gynaecol. 1995;  102 40-46
• 36 Dawes  G S, Serra-Serra  V, Moulden  M, Redman  C WG. Dexamethasone and fetal heart rate variation.  Br J Obstet Gynaecol. 1994;  101 675-679
• 37 Barker  D JP, Bull  A R, Osmond  C, Simmonds  S J. Fetal and placental size and risk of hypertension in adult life.  BMJ. 1990;  301 259-262
• 38 Nyirenda  M J, Seckl  J R. Intrauterine events and the programming of adulthood disease: The role of fetal glucocorticoid exposure (Review).  Int J Mol Med. 1998;  2 607-614
• 39 Cunningham  D S, Evans  E E. The effects of betamethasone on maternal cellular resistance to infection.  Am J Obstet Gynecol. 1991;  165 610-615
• 40 Vermillion  S T, Soper  D E, Chasedunn  R J. Neonatal sepsis after betamethasone administration to patients with preterm premature rupture of membranes.  Am J Obstet Gynecol. 1999;  181 320-327
• 41 Dahlgren  J, Boguszewski  M, Rosberg  S, Albertsson  W K. Adrenal steroid hormones in short children born small for gestational age.  Clin Endocrinol (Oxf). 1998;  49 353-361
• 42 Terrone  D A, Smith  L J, Wolf  E J, Uzbay  L A, Sun  S, Miller  R C. Neonatal effects and serum cortisol levels after multiple courses of maternal corticosteroids [see comments].  Obstet Gynecol. 1997;  90 819-823
• 43 Bakker  J M, Schmidt  E D, Kroes  H, et al. Effects of short-term dexamethasone treatment during pregnancy on the development of the immune system and the hypothalamo-pituitary adrenal axis in the rat.  J Neuroimmunol. 1995;  63 183-191
• 44 Bakker  J M, Schmidt  E D, Kroes  H, et al. Effects of neonatal dexamethasone treatment on hypothalamo-pituitary adrenal axis and immune system of the rat.  J Neuroimmunol. 1997;  74 69-76
• 45 Bakker  J M, van den Dobbelsteen  G P, Kroes  H, et al. Long-term gender-specific effects of manipulation during pregnancy on immune and endocrine responsiveness in rat offspring.  J Neuroimmunol. 1998;  82 56-63
• 46 Kavelaars  A, van d Pompe  G, Bakker  J M, et al. Altered immune function in human newborns after prenatal administration of betamethasone: enhanced natural killer cell activity and decreased T cell proliferation in cord blood.  Pediatr Res. 1999;  45 306-312
• 47 Baud  O, Foix-L'Helias  L, Kaminski  M, et al. Antenatal glucocorticoid treatment and cystic periventricular leukomacia in very premature infants.  N Engl J Med. 1999;  341 1190-1196
• 48 Mulder  E J, Derks  J B, Visser  G H. Antenatal corticosteroid therapy and fetal behaviour: a randomised study of the effects of betamethasone and dexamethasone [see comments].  Br J Obstet Gynaecol. 1997;  104 1239-1247
• 49 Crowley  P. Prophylactic corticosteroids for preterm birth (Cochrane Review). In: The Cochrane Library, Issue 1, 2000. Oxford: Update Software;
• 50 Elimian  A, Verma  U, Visintainer  P, Nergesh  T. Effectiveness of multidose antenatal steroids.  Obstet Gynecol. 2000;  95 34-36
• 51 Abbassi  S, Hirsch  D, Davis  J, et al. Effect of single versus multiple courses of antenatal corticosteroids on maternal and neonatal outcome.  Am J Obstet Gynecol. 2000;  182 1243-1249
• 52 McNamara  M F, Bottoms  S F. The incidence of respiratory distress syndrome does not increase when preterm delivery occurs greater than 7 days after steroid administration.  Aust N Z J Obstet Gynaecol. 1998;  38 8-10
• 53 Tucker  J M, Goldenberg  R L, Davis  R O, Copper  R L, Winkler  C L, Hauth  J C. Etiologies of preterm birth in an indigent population: is prevention a logical expectation?.  Obstet Gynecol. 1991;  77 343-347
• 54 Guzman  E R, Mellon  C, Vintzileos  A M, Ananth  C V, Walters  C, Gipson  K. Longitudinal assessment of endocervical canal length between 15 and 24 weeks' gestation in women at risk for pregnancy loss or preterm birth.  Obstet Gynecol. 1998;  92 31-37
• 55 Rozenberg  P. [New markers of the risk of preterm delivery].  Bull Acad Natl Med. 1998;  182 1455-1468
• 56 Leitich  H, Brunbauer  M, Kaider  A, Egarter  C, Husslein  P. Cervical length and dilatation of the internal cervical os detected by vaginal ultrasonography as markers for preterm delivery: A systematic review.  Am J Obstet Gynecol. 1999;  181 1465-1472
• 57 Jawny  J. Der vorzeitige Blasensprung.  Frauenarzt. 1999;  40 1165-1172
• 58 Ragosch  V, Weitzel  H. Zum Beitrag von J. Jawny: „Der vorzeitige Blasensprung”.  Frauenarzt. 1999;  40 1548-1550
• 59 Ragosch  V, Dudenhausen  W, Grauel  L, Schneider  K TM, Vetter  K, Weitzel  H. Empfehlungen zum Vorgehen beim vorzeitigen Blasensprung.  Frauenarzt. 2000;  41 271-272
• 60 Morales  W J, Washington  S D, Lazar  A J. The effect of chorioamnionitis on perinatal outcome in preterm gestation.  J Perinatol. 1987;  7 105-110
• 61 Lewis  D F, Brody  K, Edwards  M S, Brouillette  R M, Burlison  S, London  S N. Preterm premature ruptured membranes: a randomized trial of steroids after treatment with antibiotics.  Obstet Gynecol. 1996;  88 801-805
• 62 Mercer  B M. Management of preterm premature rupture of the membranes.  Clin Obstet Gynecol. 1998;  41 870-882
• 63 Imseis  H M, Iams  J D. Glucocorticoid use in patients with preterm premature rupture of the fetal membranes [published erratum appears in Semin Perinatol 1996 Dec; 20(6): 595].  Semin Perinatol. 1996;  20 439-450
• 64 Bar  H I, Barnhard  Y, Scarpelli  S A, Orvieto  R, Ben  R, Divon  M Y. Gestational diabetes and preterm labour: is glycaemic control a contributing factor?.  Eur J Obstet Gynecol Reprod Biol. 1997;  73 111-114
• 65 Bourbon  J R, Farrell  P M. Fetal lung development in the diabetic pregnancy.  Pediatr Res. 1985;  19 253-267
• 66 Matti  P, Pistoia  L, Fornale  M, Brunn  E, Zardini  E. [Prevalence of RDS in diabetic pregnancy].  Minerva Ginecol. 1996;  48 409-413
• 67 Jacobs  H C, Bogue  C W, Pinter  E, Wilson  C M, Warshow  J B, Gross  I. Fetal lung mRNA levels of Hox genes are differentially altered by maternal diabetes and butyrate in rats.  Pediatric Res. 1998;  44 99-104
• 68 Blank  A, Grave  G D, Metzger  B E. Effects of gestational diabetes on perinatal morbidity reassessed.  Diabetes Care. 1995;  18 127-129
• 69 Pollack  R N, Divon  M Y. Intrauterine growth retardation: definition, classification and etiology.  Clin Obstet Gynecol. 1992;  35 99-107
• 70 Elimian  A, Verma  U, Canterino  J, Shah  J, Visintainer  P, Tejani  N. Effectiveness of antenatal steroids in obstetric subgroups.  Obstet Gynecol. 1999;  93 174-179
• 71 Schiff  E, Friedman  S A, Mercer  B M, Sibai  B M. Fetal lung maturity is not accelerated in preeclamptic pregnancies.  Am J Obstet Gynecol. 1993;  169 1096-1101
• 72 Amorim  M M, Santos  L C, Faundes  A. Corticosteroid therapy for prevention of respiratory distress syndrome in severe preeclampsia.  Am J Obstet Gynecol. 1999;  180 1283-1288