Tocolytic therapy

1
Tocolytic therapy clinical experience

• Session 5 Chairman
• Professor Werner Rath
• Rheinisch-Westfalische Technische Hochschule,
  Aachen, Germany

1st International Preterm Labour Congress,
Montreux, Switzerland, June 2002
2
The history of tocolysis

• Professor Marc Keirse
• Flinders University of South Australia, Adelaide,
  Australia

1st International Preterm Labour Congress,
Montreux, Switzerland, June 2002
3
WHO 1950
prematurity birthweight
2,500 g or less
? 2,500 g concept
Yllpö A. Zur Physiologie, Klinik und zum
Schicksal der Frühgeborenen. Z Kinderheilk
1920 24 1-110
Marc Keirse
4
WHO 1950
prematurity birthweight
2,500 g or less
WHO 1961
prematurity gestation of less than 37
weeks
Marc Keirse
5
III. Symposion über Physiologie und
Pathologie der Wehentätigkeit
Würzburg, 1964
?????
contraction
K.H. Mosler Tokolyse
?????
to dissolve
Zentralblatt für Gynäkologie, 1965
Marc Keirse
6
relaxin
salicylate
flufenamic acid
ritodrine
diazoxide
indomethacin
isoxsuprine
fenoterol
magnesium sulphate
atosiban
salbutamol
orciprenaline
naproxen
mesuprine
buphenine
sulindac
terbutaline
glyceryl trinitrate
nifedipine
Marc Keirse
7
King, Keirse, Grant Chalmers, 1985 Tocolysis -
the case for and against
24 hours 48 hours 1 week 10 days 2 weeks
? delay of birth
? preterm birth
? infant outcome
Marc Keirse
8
What are the realistic expectations of a
tocolytic agent?

• Professor Nick Fisk
• Queen Charlottes and Chelsea Hospital, London,
  UK
• Dr Graeme Smith
• Queens University, Kingston, Canada

1st International Preterm Labour Congress,
Montreux, Switzerland, June 2002
9
Placebo controlled RCTs
All tocolytics 17 studies n2284
Gyetvai et al 1999
Odds ratio
Nick Fisk
10
Rationale for tocolysis

• Improve survival
• lt 27-28 weeks
• Allow time for steroids
• lt 34 weeks
• Allow time for in-utero transfer

Nick Fisk
11
Do beta-mimetics improve perinatal outcome?
Perinatal death Respiratory distresssyndrome Intr
aventricular haemorrhage Necrotising
enterocolitis Patent ductus
Odds ratio
Nick Fisk
12
Tocolysis in the management of multiple pregnancy

• Professor Joachim Dudenhausen
• Humboldt University of Berlin, Berlin, Germany

1st International Preterm Labour Congress,
Montreux, Switzerland, June 2002
13
Indications for atosiban in multiple pregnancies
(Charité 2002)

• Women in preterm labour and other risks
• cardiovascular disease
• SIH / pre-eclampsia
• diabetes mellitus Type I

Joachim Dudenhausen
14
Tocolytic efficiency in multiple pregnancies
Undelivered
48 h
7
days
Atosiban
75
61
n44
Beta-agonist
93
76
n60
p0.003
p0.07
Worldwide Atosiban vs Beta-agonists Study Group,
2001
Joachim Dudenhausen
15
The development and introduction of anti-oxytocic
tocolytics

• Dr Ronald Lamont
• Northwick Park Hospital, Harrow, UK

1st International Preterm Labour Congress,
Montreux, Switzerland, June 2002
16
Basic pharmacology and mechanism of action

• Atosiban is a competitive OT receptor antagonist
  that binds to membrane bound myometrial cell OT
  receptors resulting in
• a) Dose dependent inhibition of OT stimulated
  IP3 production with ? release of stored
  intracellular Ca2 in SR
• b) Closure of voltage gated channels in
  myometrial cell membrane to prevent influx of
  Ca2 into the myometrial cell
• c) Prevents OT mediated release of PG from
  decidua and fetal membranes which potentiate
• a) and b)

Ronald Lamont
17
Risk of adverse effects

• CVS/CNS/Renal No evidence of AE
• Milk let-down reflex No evidence of AE
• PPH No evidence
• Placental transfer UBV levels 10-12 of MUV
• levels
• Tachyphylaxis OT versus atosiban effect in
• IP3 formation
• Ca2 mobilisation
• OT receptor numbers
• OT desensitisation of cells to OT and loss of
  OT receptors
• Atosiban no alteration of sensitivity of
  pregnant myometrium to OT

Ronald Lamont
18
Exploring the role of Tractocile in everyday
clinical practice

• Dr Hanns Helmer
• University of Vienna, Vienna, Austria

1st International Preterm Labour Congress,
Montreux, Switzerland, June 2002
19
Effectiveness after 48 hours treatment with
atosiban tocolytic success 79
163
200
150
n
100
44
1
50
0
delivery
pregnant
n.e.
Hanns Helmer
20
Tocolytic effect on labour
PTL, ? 4 contr. per 30 min
12,00
10,00
8,00
Number of contr./30 min
6,00
5.43
4,00
2,00
1.62
0,00
without treatment
30min after start of treatment
Hanns Helmer
21
Days gained after tocolysis
80
70
60
41.0
50
31.0
40
d
30
20
9.3
10
0
all
PTL
prom
mean /- STD
Hanns Helmer