It’s a long road to

1. It’s a long road to Damascus

2. It’s a long road to Saturday April 25 Damascus

3. It’s a long road to Saturday April 25 No Visum !!!!! Damascus

4. It’s a long road to Tuesday April 28 Damascus

5. It’s a long road to Tuesday April 28 Midnight at Budapest. Connecting flight had already left Damascus

6. It’s a long road to Wednesday April 29 So, finally, here we are Damascus

8. Steroids and Tocolytics in preterm labour Gerard H.A. Visser University Medical Center Utrecht The Netherlands

9. Preterm delivery • Incidence has increased over the latest decades, • Despite all modern efforts regarding prevention and treatment ……………………..

10. Work seriously for a better future

11. Sir Graham Liggins

12. Serendipity Lambs born preterm were more viable after antenatal glucocorticoid administration (Liggins, 1969)

13. Antenatal corticosteroids 1969 – Liggins 1972 – first RCT 1994 – 15 RCT 2006 – 21 RCT

14. Antenatal steroids: RCT’s over the decades So there is a case to give corticosteroids in women at risk of preterm delivery between 24 weeks (23 weeks?, McEnvoy, 08) and 34 weeksBetamethasone is more effective than dexamethasone; but be aware of its effects on FHR variation and movements (Roberts and Dalziel, Cochrane, 2006)

15. 14 more extubated by 7 days 11 less have CLD 7 less will die 14 avoid late CS treatment 6 more have GI bleeding 4 more have GI perforation 12 have cerebral palsy 14 have abnormal neurological development at follow-up Early neonatal treatment with corticosteroids For every 100 babies treated… (data from 19 RCT; Halliday, 2001)

16. Fetal versus neonatal dose 0.05–0.20 mg/day for 2 days 0.5 mg/kg/day for many days

17. Fetal versus neonatal dose 0.05–0.20 mg/day for 2 days 0.5 mg/kg/day for many days Potent drugs may have potent side effects

18. Apoptosis following antenatal corticosteroids in mice Saline Saline Dexamethasone Dexamethasone 250 140 120 200 * * 100 150 80 * Apoptotic cells in DG Apoptotic cells in CA * 60 100 * * 40 50 20 0 0 E16 E18 P0 P5 P10 P20 Adult E16 E18 P0 P5 P10 P20 Adult (Noorlander et al, Dev Neurobiol, 2008)

19. Cell proliferation following antenatal corticosteroids in mice 20,000 Saline * 18,000 Dexamethasone 16,000 14,000 12,000 * Ki-67 positive cells in DG 10,000 8,000 6,000 4,000 2,000 * * * 0 E18 P0 P5 P10 P20 Adult (Noorlander et al, Dev Neurobiol, 2008)

20. Molecular analysis 600 500 400 Total number Ki-67positive cells 300 200 100 0 Saline Dexamethasone Decreased number of proliferating cells in hippocampus after dexamethasone

21. Behavioural analysis Camera Light Morris water maze: Hippocampus dependent learning and memory task Visual Cue Morris water maze HiddenPlatform 18 16 14 12 10 Velocity (cm/sec) 8 No difference in swimming speed Saline 6 Dexamethasone 4 2 0 1 2 3 4 5 Time (days)

22. Saline Saline Dexamethasone Dexamethasone Behavioural analysis Visible platform Hidden platform 100 100 Saline Saline Dexamethasone Dexamethasone 80 80 * 60 60 * Latency (sec) Latency (sec) * 40 40 * * 20 20 0 0 1 2 3 4 5 1 2 3 1,600 1,600 1,200 1,200 Distance swum (cm) Distance swum (cm) 800 800 * * 400 400 0 0 1 2 3 4 5 1 2 3 Time (days) Time (days) Impaired learning and memory after dexamethasone treatment

23. Peripheral analysis: Liver Saline Dexamethasone Pericentral areas of fibrosis that extends to portal fields

24. Peripheral analysis: Heart Saline Dexamethasone Myocytes → thin layer of collagen, indicating degeneration of myocytes replaced by fibrous tissue

25. Dexamethasone induces precocious aging and reduced lifespan in mice Implications for the human…?

27. Impact of corticosteroids on the human hippocampus (19 infants, 25–32 weeks, who died <4 days after delivery; Wijnberger et al, 2002)

28. Again, that was just to remind you, that… • Corticosteroids are very potent drugs, and… • Potent drugs may have serious side effects

29. 160 37% 140 120 22% 100 80 14% 60 40 20 0 1 2 3 4 5 6 7 8 9 10 11 12 20 Number of courses In 40% of 420 European Centres >3 courses will be given (Eurail, 2001)

30. Cochrane, 2007 Crowther and Harding, 5 RCTs

31. Should steroids be repeated?

32. Side effects multiple courses, at birth

33. 2-year follow up (Crowther et al, NEJM, 2007)

34. 2-year follow up (Wapner et al, NEJM, 2007) * 5 of 6 cases >3 courses, 5 >32 weeks of gestation

35. Should steroids be repeated? • Yes, there is a case to repeat steroids if not delivered <32 (30?) weeks • Two courses ( 1–2 weeks apart) should be more than sufficient…

36. Lancet December 2008

37. MACS trial, results

38. MACS trial, delivered < 32 weeks

39. Direct side effects Decreased birth weight and head circumference MACS, Lancet December 2008

40. Rescue course >2 wks after initial treatment and before 33 wks rescue control N 223 214 Delivery< 34 wks 55% 55% Delivery< 34 wks:* Composite morbidity 44% 64% OR 0.45 RDS 41% 62% All infants: Composite morbidity 32% 43% OR 0.65 RDS 30% 41% * Also sign for surfactant, need for ventilator; Garite et al Am J O&G March 2009

41. Should steroids be repeated? • ?????, probably slight improvement in morbidity • Better to give one rescue course than routinely repeating a corticosteroid course • Please remember, corticosteroids are very potent drugs, with serious side effects when given to the neonate ( in higher doses) and in animals

42. Most importantly • Use of corticosteroids may well be reduced by a better identification of women who really are at increased risk of preterm delivery (CL measurement, fibronectin) • Question: How many of your patients who received corticosteroids actually delivered preterm?

43. Tocolytic drugs Mg-So4, NO donors do not work

44. Calcium channel blockers: Side effects Case reports: Oei,1999;Hodges,2004;Verhaert,2004;Vaast,2004;Van Geijn,2005;Nassar,2007;Gatault, 2008;Perbet.2008

45. 7 cases of severe dyspnea • 6 twins, 1 singleton • Nifedipine 100-150 mg/day. Co-medication in 5 • Admission Intensive Care : 5 ( intubation 3, rebreathing mask 2) • Respiratory complications are due to unequal ventilation/perfusion in the lungs in the presence of a physiologically elevated diaphram due to pregnancy. Nifedipine results in perfusion of atelectatic areas that are not well ventilated Lenglet, van Geijn et al., Free Univ Amsterdam. Ned T.Geneesk, 2007;151:198-205

46. However,….. • Case reports give no information on the actual incidence of side effects, since the number treated is missing. • RCTs on tocolytics have generally been restricted to well-defined low risk populations, e.g. excluding multiples, PPROM, women with diabetes, heart disease hypertension etc • So, with respect to maternal safety, there was, until recently, no prospective study comparing maternal adverse drug reactions to different tocolytics in a normal clinical setting

47. Adverse drug reactions to tocolytic treatment • Prospective cohort study on 1,920 women in the Netherlands and Flanders • Adverse drug reaction: Any adverse event that led to discontinuation of treatment and that was suspected to be causally related to treatment de Heus R, et al. BMJ 2009

48. Tocolytics and complicated pregnancies

49. Tocolytic drugs • So, apparently in the Netherlands and Flanders the underlying maternal condition is not taken into account, when deciding which tocolytic drug to use

50. Side effects observed after tocolytics *Dyspnoea n=6; hypotension n=4; lung edema n=2; hypoxia n=1; cardiac failure n=1. de Heus R, et al. BMJ 2009