Zusammenfassung
Die Frühgeburtenrate konnte in den letzten 10 Jahren nicht gesenkt werden. Klinisches Leitsymptom der Frühgeburt sind meist vorzeitige Wehen, die nur behandelt werden sollten, wenn gleichzeitig zervikale Veränderungen vorliegen. Vorzeitige Wehen werden seit mehr als 30 Jahren mit Tokolytika behandelt. Das ideale Tokolytikum existiert bisher nicht. Ziele der Tokolyse sind eine Prolongation der Schwangerschaft für mindestens 48 Stunden zur Lungenreifeinduktion, der In-utero-Transfer in ein Perinatalzentrum und die Senkung der perinatalen/neonatalen Morbidität und Mortalität. In Deutschland zugelassen sind Betaagonisten, Magnesiumsulfat und Atosiban. Betaagonisten sind zwar effektiv, aber mit einem breiten Spektrum an mütterlichen Nebenwirkungen belastet. Magnesiumsulfat erwies sich in einer jüngsten Cochrane-Analyse als ineffektiv. Indomethacin ist nicht zur Tokolyse zugelassen, sollte nur über 48 Stunden gegeben werden und führt zu fetalen Nebenwirkungen. NO-Donatoren sind hinsichtlich ihrer tokolytischen Wirkung so effektiv wie Betaagonisten, allerdings ist die Datenlage bisher nicht ausreichend. Kalziumkanalblocker (Nifedipin) sind zur Tokolyse nicht zugelassen, weisen eine höhere tokolytische Wirksamkeit auf als Betaagonisten, es fehlen allerdings direkte Vergleichsuntersuchungen mit Atosiban. Der Oxytocinantagonist Atosiban hat die gleiche tokolytische Effizienz wie Betaagonisten, aber eine signifikant niedrigere Rate an maternalen Nebenwirkungen. Nachteil von Atosiban sind die hohen Kosten. Deshalb empfiehlt es sich, Atosiban in bestimmten geburtshilflichen Situationen einzusetzen. Derzeit werden Oxytocinantagonisten der zweiten Generation entwickelt, die auch zur Erhaltungstherapie geeignet sind.
Abstract
In spite of advances in obstetric care, the rate of prematurity has not decreased over the past decade. The leading symptom of prematurity is mostly preterm labour, which should only be treated if cervical changes are present. For 30 years preterm labour has been treated with tocolytic agents; however, the perfect tocolytic drug which is completely safe for both the mother and the fetus and will stop preterm labour in every case does not exist. The goals of tocolysis are prolongation of pregnancy for at least 48 hours to allow the in-utero-transfer to a perinatal center to induce lung maturation and the reduction of perinatal/neonatal morbidity and mortality. In Germany, beta agonists, magnesium sulfate and atosiban are licensed. Beta agonists are highly effective, but are associated with a broad spectrum of maternal side effects. A recent Cochrane analysis has shown that magnesium sulfate is ineffective in preventing birth. Indomethacin is not licensed for tocolytic therapy and should only be given for 48 hours because of constriction of the fetal ductus arteriosus; its administration is associated with severe neonatal complications. Nitric oxide donors are as effective as beta agonists regarding tocolytic efficacy, however these agents cannot be recommended for clinical practice until further data from large trials are available. Calcium channel blockers (nifedipine) are not licensed; their tocolytic efficacy is superior to that of beta agonists, however the ideal dosage and formulation are unclear. Comparative studies with atosiban are necessary. The oxytocin antagonist atosiban has been shown to have a similar tocolytic efficacy as beta agonists. The advantage of atosiban over beta agonists is the significantly lower rate of maternal side effects, the disadvantage is the high price. Therefore it is recommended to use atosiban in special obstetric conditions. At present a second generation of selective oxytocin antagonists are being developed, suitable for maintenance therapy.
Schlüsselwörter
Tokolyse - Betaagonisten - Magnesiumsulfat - Kalziumkanalblocker - Atosiban - mütterliche und kindliche Nebenwirkungen
Key words
Tocolysis - betaagonists - magnesium sulfate - calcium channel blockers - atosiban - maternal and fetal side effects
Literatur
-
1
ACOG Practice Bulletin .
Behandlung von vorzeitigen Wehen.
Frauenarzt.
2003;
44
1200-1204
-
2
Afschar P, Schöll W, Bader A, Bauer M, Winter R.
A prospective randomised trial of atosiban versus hexoprenaline for acute tocolysis and interuterine resuscitation.
Br J Obstet Gynaecol.
2004;
111
316-318
-
3
Akerlund M.
Oxytocin antagonist in the treatment of preterm labour.
Fetal and Maternal Med Rev.
2002;
13
31-41
-
4
Beattle R B, Helmer H, Lehan K S, Lamont R F, McNamara H. et al .
Emerging issues over the choice of nifedipine, beta-agonists and atosiban for tocolysis in spontaneous preterm labour - a proposed systematic review by the International Preterm Labour Council.
J Obstet Gynaecol.
2004;
24
213-215
-
5 Beinder E. Persönliche Mitteilung,. 2004
-
6 Besinger P E, Jannucci T A. Tocolytic therapy. Elder MG, Lamont RF, Romero R Preterm Labour. New York; Churchill Livingstone 1997: 243-297
-
7
Bisits A, Madson G, McLean M, O'Callahan S, Smith R, Giles W.
Corticotropin-releasing hormone: a biochemical predictor of preterm delivery in a pilot randomised trial of the treatment of preterm labor.
Am J Obstet Gynecol.
1998;
178
862-866
-
8
Childress C H, Katz V L.
Nifedipine and its indications in obstetrics and gynaecology.
Obstet Gynaecol.
1994;
83
616-624
-
9
Coomarasamy A, Knox E M, Gee H, Song F, Khan K S.
Effectiveness of nifedipine versus atosiban for tocolysis in preterm labour: a meta-analysis with a indirect comparison of randomised trials.
Br J Obstet Gynaecol.
2003;
110
1045-1049
-
10
Costeloe K, Hennessy E, Gibson A T, Marlow N, Wilkinson A R.
The EPI Cure study: outcome to discharge from hospital for infants born at the threshold of viability.
Pediatrics.
2000;
106
659-671
-
11 Creasy R K. Early detection of preterm labour. Queenan JT, Hobbins JC Protocols for High Risk Pregnancies. 3rd Edition. London; Blackwell Science 1996: 535-538
-
12 Crowther C A, Hiller J E, Doyle L W. Magnesium sulphate for preventing preterm birth in threatened preterm labor. (Cochrane Review) Oxford; The Cochrane Library Issue 2 2002
-
13 Duckitt K, Thornton S. Nitric oxid donors for the treatment of preterm labour. Oxford; Cochrane Database Syst Rev 2003: CD 002,860
-
14
Economy K E, Abuhamas A Z.
Calcium channel blockers as tocolytics.
Semin Perinatol.
2001;
25
264-271
-
15
El-Sayed Y, Riley E, Holbrook H, Cohen S, Chithara U, Druzin M.
Randomized comparison of intravenous nitroglycerin and magnesium sulfate for treatment of preterm labour.
Obstet Gynecol.
1999;
93
79-83
-
16
Ferguson J I, Dyson D C, Holbrook R HJ, Schulz T, Stevenson D K.
Cardiovascular and metabolic effects associated with nifedipine and ritodrine tocolysis.
Am J Obstet Gynecol.
1989;
161
788-795
-
17
Finnström O, Otterblad Olansson P, Sedin G. et al .
The Swedish national prospective study on extremely low birth weight (ELBW) infants. Incidence, mortality, morbidity and survival in relation to level of care.
Acta paediatrica.
1997;
86
503-511
-
18 Friese K. Infektion und Frühgeburt. 55. Kongress der Deutschen Gesellschaft für Gynäkologie und Geburtshilfe, 14. - 17. 9. 2004, Hamburg.
-
19
Goldenberg R L, Davis R Q, Baker R C.
Indomethacin-induced oligohydramnios.
Am J Obstet Gynaecol.
1989;
160
1196-1197
-
20 Goodwin T M, Randall H, Perry K. A Report On Infant Outcomes at 6, 12 and 24 Months After the Use of Atosiban in the Management of Preterm Labor. New Orleans USA; ACOG Meeting 1998
-
21
Goodwin T M, Valenzuela G, Silver H.
Treatment of preterm labor with the oxytocin antagonist atosiban.
Am J Perinatol.
1996;
13
143-146
-
22
Gyetvai K, Hannah M E, Hodnett E D, Ohlsson A.
Tocolytics for preterm labor: a systematic review.
Obstet Gynecol.
1999;
94
869-877
-
23
Heinen-Kammerer T, Motzkat K, Rychlik R.
Kosten-Effektivitäts-Analyse verschiedener Tokolyse-Schemata.
Krankenhauspharmazie.
2002;
24
45-49
-
24
Helmer H, Schleußner E, Husslein P.
Kosten-Nutzen-Relation der tokolytischen Therapie unter DRG-Gesichtspunkten.
Geburtsh Frauenheilk.
2004;
64
429-432
-
25
Hodges R, Barkehall-Thomas A, Trippett C.
Maternal hypoxia associated with nifedipine for threatened preterm labour.
Br J Obstet Gynaecol.
2004;
111
380-381
-
26
Ingemarsson I, Lamont R.
Un update on the controversies of tocolytic therapy for the prevention of preterm birth.
Acta Obstet Gynecol Scand.
2003;
82
1-9
-
27
Jeyabalan A, Caritis S N.
Pharmakologic inhibition of preterm labour.
Clin Obstet Gynecol.
2002;
45
99-113
-
28
Kähler C, Schleussner E, Moether A, Seewald H-J.
Clinical effects of transdermal nitroglycerine therapy on fetal and maternal perfusion in preterm labour, preeclampsia and intrauterine growth retardation.
Eur J Obstet Gynecol Reprod Biol.
2000;
91
58
-
29
Keirse M JNC.
New perspectives for the effective treatment of preterm labour.
Am J Obstet Gynecol.
1995;
173
618-628
-
30 King J F, Flenady V J, Papatsonis D NM, Dekker G A, Carbonne B. How to interpret and utilise the Cochrane Review on calcium channel blockers for inhibiting preterm labour. Oxford: Cochrane Database Systematic Reviews, Issue 2, Update Software Ltd. 2003
-
31 King J F, Flenady V J, Papatsonis D NM, Dekker G A, Carbonne B. Calcium channel blockers for inhibiting preterm labor (Cochrane Review). Chicester UK: Cochrane Library, Issue 4, J. Wiley Ltd. 2003
-
32
King J F, Grant A, Keirse M JNC, Chalmers J.
Betamimetics in preterm labour: an overview of the randomised controlled trials.
Br J Obstet Gynaecol.
1988;
95
211-222
-
33
Klam S L, Leduc L.
Management options for preterm labour in Canada.
J Obstet Gynecol Can.
2004;
26
339-349
-
34
Lamont R F.
Reply to article by King et al.
Aust N Z J Obstet Gynaecol.
2004;
44
275-277
-
35
Lamont R F. and the International Preterm Labour Council .
Evidence-based labour ward guideline for the diagnosis, management and treatment of spontaneous preterm labour.
J Obstet Gynecol.
2003;
23
469-478
-
36
Lees C, Lojacono A, Thompson C, Danti L, Black R. et al .
Glyceryl trinitrate and ritodrine in tocolysis: an international multicenter randomized trial.
Obstet Gynecol.
1999;
94
403-408
-
37
Lurie S, Sadon O, Aroya Z B, Glezerman M.
Atosiban treatment for uterine hyperactivity during active labor: a pilot study.
J Perinat Med.
2004;
32
137-139
-
38
Lurie S, Gur D, Sadan O, Glezerman M.
Relationship between uterine contractions and serum magnesium levels in patients treated for threatened preterm labour with intravenous magnesium sulphate.
J Obstet Gynaecol.
2004;
24
247-248
-
39
Magowan R A, Pain M, Juszcak B E, McInnery K.
Neonates mortality among Scottish preterm singleton births.
Neonatal Intensive Care.
1999;
12
47-50
-
40
Mathews T J, Curtin S L, Mac Dorman M F.
Infant mortality statistics from the 1998 period linked with birth/infant death data set.
Natl Vital Stat Rep.
2000;
48
1-25
-
41
Melin P.
Oxytocin antagonists in preterm labour and delivery.
Baillieres Clin Obstet Gynaecol.
1993;
7
577-600
-
42
Melin P, Trojnar J, Johansson B. et al .
Synthetic antagonists of the myometrial response to vasopressin and oxytocin.
J Endocrinol.
1986;
111
125-131
-
43
Mittendorf R, Covert R, Boman J. et al .
Is tocolytic magnesium sulphate associated with increased total paediatric mortality?.
Lancet.
1997;
250
1517-1518
-
44
Moise K J.
The effect of advancing gestational age on the frequency of fetal ductal constriction secondary to maternal indomethacin use.
Am J Obstet Gynecol.
1993;
168
350-354
-
45
Norton M E, Mersill J, Cooper B, Kuller J A, Clyman R J.
Neonatal complications after the administration of indomethacin for preterm labour.
N Engl J Med.
1993;
329
1602-1607
-
46
Oei S G, Mol B W, de Kleine M J, Brolman H A.
Nifedipine versus ritrodine for suppression of preterm labor: a meta-analysis.
Acta Obstet Gynecol Scand.
1999;
78
783-788
-
47
Oei S G, Oei S K, Brolman H A.
Myocardial infarction during nifedipine therapy for preterm labour.
N Engl J Med.
1999;
340
154
-
48
Papatsonis D NM, Carbonne B, Dekker G A, King J F, Flenady V J.
Letter to the editor: update on the controversies of tocolytic therapy for the prevention of preterm birth.
Acta Obstet Gynecol Scand.
2004;
83
414
-
49
Pierzynski P, Lemancewicz A, Reinheimer T, Akerlund M, Laudanski T.
Inhibition effect of barusiban and atosiban on oxytocin-induced contractions of myometrium from preterm and term pregnant women.
J Soc Gynecol Investig.
2004;
14
384-387
-
50
Rath W, Beinder E.
Die Tokolyse im Licht der Cochrane Database, internationaler und nationaler Guidelines.
Geburtsh Frauenheilk.
2004;
64
639-644
-
51
Rath W, Dudenhausen J W.
Alte und neue Tokolytika - eine aktuelle Diskussion um Nutzen, Nebenwirkungen und Kosten (Editorial).
Geburtsh Frauenheilk.
2003;
63
119-123
-
52
Royal College of Obstetricians and Gynecologists .
Tocolytic drugs for women in preterm labour.
Clinical guideline.
2002;
1 (B)
4
-
53
Sanchez-Ramos L, Kaunitz A M, Gaudier F L, Delke J.
Efficacy of maintenance therapy after acute tocolysis: a meta-analysis.
Am J Obstet Gynecol.
1999;
181
484-490
-
54
Schindler A E.
Prävention der Frühgeburtlichkeit durch Gestagene.
Z Geburtsh Neonatol.
2004;
208
165-169
-
55
Schleußner E, Möller A, Groß W, Kähler C, Möller U. et al .
Maternal and fetal side effects of tocolysis using transdermal nitroglycerin or intravenous fenoterol combined with magnesium sulfate.
Eur J Obstet Gynecol Reprod Biol.
2003;
106
14-19
-
56
Scudiero R, Khoshnood B, Pryde P G. et al .
Perinatal death and tocolytic magnesium sulfate.
Obstet Gynecol.
2000;
96
178-182
-
57
Smith G N, Walker M C, McGrath M J.
Randomized, double-blind, placebo-controlled trial assessing nitroglycerin as a tocolytic.
Br J Obstet Gynaecol.
1999;
106
736-739
-
58 Spätling L. Tokolyse, was ist gesichert, was ist Zukunft. 55. Hamburg: 55. Kongress der Deutschen Gesellschaft für Gynäkologie und Geburtshilfe, 14. - 17. 9. 2004.
-
59
Tsatsaris V, Carbonne B, Cabrol D.
Atosiban for preterm labour.
Drugs.
2004;
64
375-382
-
60
Tsatsaris V, Papatsonis D, Goffinet F, Dekker G A, Garbonne B.
Tocolysis with nifedipine or beta-adrenergie agonists: a meta-analysis.
Obstet Gynecol.
2001;
97
840-847
-
61
Vaast P, Dubreucq-Fossaert S, Houfflin-Debarge V, Provost-Helon N, Ducloy-Bouthors A-S. et al .
Acute pulmonary oedema during nicardipine therapy for premature labour.
Eur J Obstet Gynecol Reprod Biol.
2004;
113
98-99
-
62
Valenzuela G J, Sanchez-Ramos L, Romero R.
Maintenance treatment of preterm labor with the oxytocin antagonist atosiban. The Atosiban PTL-098 Study Group.
Am J Obstet Gynecol.
2000;
182
1184-1190
-
63
Valenzuela G I, Craig J, Bernhardt M D.
Plazental passage of the oxytocin antagonist atosiban.
Am J Obstet Gynecol.
1995;
172
1304-1306
-
64
van Veen A J, Pelinak M J, van Pampus M G, Erwich J JHM.
Severe hypotension and fetal death due to tocolysis with nifedipine.
Br J Obstet Gynaecol.
DOI: DOI: 10.111/j1471-O528.2004.00480.x
-
65
Verhaert D, van Acker R.
Acute myocardial infarction during pregnancy.
Acta Cardiol.
2004;
59
331-339
-
66
Villar J, Ezuurra E J.
Preterm delivery syndrome: The unmet need.
Res Clin Forums.
1994;
16
9-38
-
68
Wood N S, Marlow N, Costeloe K, Gibson A T, Wilkinson A R.
Neurologic and developmental disability after extremely preterm birth, EPICure Study Group.
New Engl J Med.
2000;
343
378-384
-
67
Worldwide Atosiban versus Beta-agonists Study Group .
Effectiveness and safety of the oxytocin antagonist atosiban versus beta-adrenergic agonists in the treatment of preterm labour.
Br J Obstet Gynaecol.
2001;
108
133-142
Prof. Dr. med. Werner Rath
Frauenklinik für Gynäkologie und Geburtshilfe
Universitätsklinikum Aachen
Pauwelsstraße 30
52072 Aachen
Email: wrath@ukaachen.de
