การดูแลภาวะเจ็บครรภ์คลอดและถุงน้ำคร่ำรั่วก่อนกำหนด

1. การดูแลภาวะเจ็บครรภ์คลอดและถุงน้ำคร่ำรั่วก่อนกำหนดการดูแลภาวะเจ็บครรภ์คลอดและถุงน้ำคร่ำรั่วก่อนกำหนด นพ.ธีระ ภิรมย์สวัสดิ์ ศูนย์อนามัยที่5 ราชบุรี 11/01/2017

2. ความสำคัญ • พบประมาณ10% ของการคลอด • ทารกเสียชีวิต โอกาสเสียชีวิตสูงขึ้น 15 เท่า • โอกาสพิการสูง สมอง สายตา • พัฒนาการช้า • ค่าใช้จ่ายในการรักษาสูงมาก

4. Topic outlines • Preterm birth: definition, incidence and etiologies • Prevention of preterm birth • Progesterone • Mode of action • Side effects • Route of administration • Progesterone for prevention of preterm birth (evidence based studies) • Preterm birth prevention: guidelines or recommendations • Management of preterm labor • RTCOG 2015 recommendations

5. Definition • Preterm birth: delivery before 37 weeks • Extremely preterm (<28 weeks) • Very preterm (28 to <32 weeks) • Moderate preterm (32 to <37 weeks) • Late preterm: 340/7to 366/7 weeks

9. Clinical circumstances associated with preterm birth • Spontaneous preterm labor with intact membranes • Preterm PROM • Indicated preterm delivery (1/3) • Maternal (e.g. pre-eclampsia) • Fetal (e.g. IUGR/fetal compromise

11. ปัจจัยเสี่ยงต่อการคลอดก่อนกำหนดปัจจัยเสี่ยงต่อการคลอดก่อนกำหนด

12. Spontaneouspretermbirth • Thetwomajorimportant riskfactors(singleton) arepreviouspretermbirthandcervicalshorteninginthesecondtrimester

13. Preterm birth: previous preterm birth • Recurrence risk 15-50% • The risk depends on the number and gestational age of previous births • Women with early spontaneous preterm births are far more likely to have subsequent spontaneous preterm births

14. Syndromic nature of a short cervix

15. Cervical length measurement (GA 16-24 wk)

16. Normal cervical length GA 14-28 wk: a normal, bell-shaped curve • 15 mm – 2nd centile • 20 mm – 5th centile • 25 mm – 10th centile • 35 mm – 50th centile • 45 mm – 90th centile Cervical length is not significantly affected by parity, race/ethnicity, or maternal height

17. Definition of short CL  TVS CL; GA 16-28 wk • ≤ 20 mm in women with no prior PTB • < 25 mm in women with a prior PTB

18. Risk factors of SPTB • Previous PTB • Short cervix • Multiple pregnancy

19. Why the United States preterm birth rate is declining The preterm birth rate in the US declined to 11.4% in 2013, the lowest level since 1997. Reasons: • A reduced teenage birth rate • Fewer higher-order multiple births • A public policy shift to prevent nonmedically indicated births at < 39 weeks’ gestation • Smoking bans in several stages • Interventions such as progesterone supplement, and the use of cerclage in selected populations Schoen CN, et al. Decline in preterm birth. Am J Obstet Gynecol 2015;213:175-80.

20. Strategy in the prevention of PTB Identification of risk factors 1. No prior history of PTB 2. Prior history of PTB 3. Twins (triplets) in the current pregnancy Short cervix at scan

21. Strategy in the prevention of PTB What is a short cervix? CL Risk factor No Risk factor <20(15) mm Prior PTB <25 mm Twins <25 mm Triplets <25 mm

22. Strategy in the prevention of PTB • Progesterone • Cervical cerclage • Cervical pessary

23. Progesterone and preterm birth prevention

24. “Progesterone deficient state” has been proposed to be a mechanism of disease in preterm labor

25. Proposed mechanisms of action reportedfor progesterone to prevent preterm birth • Stimulate transcription of ZEB1 and ZEB2, which inhibit connexin 43 (gap-junction protein that helps synchronize contractile activity) and oxytocin-receptor gene • Decrease prostaglandin synthesis, infection-mediated cytokine production (antiinflammatory effects) by fetal membranes/placenta • Changes in PR-A and PR-B expression (decreased PR-A/PR-B ratio keeps uterus quiescent) • Membrane-bound PR in myometrium • PRs, when stimulated by progesterone, help selected gene promotion, or prevent binding of other factors • Interfere with cortisol-mediated regulation of placental gene expression • Nongenomic pathways • Reduce cervical stromal degradation in cervix • Alter barrier to ascending inflammation/infection in cervix • Reduce contraction frequency in myometrium • Attenuate response to hemorrhage/inflammation in decidua • Alter estrogen synthesis in fetal membranes/placenta • Alter fetal endocrine-mediated effects

26. Progesterone in pregnancy maintenance • Myometrial quiescence • Inhibit cervical ripening Progesterone: a key hormone for pregnancy maintenance

27. Progesterone Side effects Maternal : headache, nausea, coughing, localirritation, andbreasttension GDM? Fetal: no teratogenic effects Long term effects ?

28. Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trial Vaginal progesterone had no harm on outcomes in children at 2 years of age (vaginal progesterone = 430 VS placebo = 439). Norman JE, et al. Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trial. Lancet 2016 Feb 23.

30. Evidence based studies (till October 2016)

31. Progesterone for the prevention of preterm birthin singleton pregnancy

32. Conclusions • The use of progesterone is associated with benefits in infant health following administration in women considered to be at increased risk of preterm birth due either to a prior preterm birthor where a short cervix has been identified on ultrasound examination. Dodd JM, Jones L, Flenady V, Cincotta R, Crowther CA. Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth. Cochrane Database of Systematic Reviews 2013, Issue 7.

33. Prevention of SPTB :Which one is superior? • 17-alpha-hydroxyprogesterone caproate (17OHPC), vaginal progesterone, oral progesterone • Cost, compliance, side effects, adverse reactions, long term effects (mother and baby)

34. Singleton gestations

35. 17 OHPC Singleton gestations and prior SPTB (unknown or normal CL) Based mostly on this clinical trial , 17-OHPC has been recommended for all women with prior SPTB 20-36 6/7wk

36. 17- α hydroxyprogesteronecaproatedoes not prevent preterm birth in patients with a short cervix

37. Vaginal progesterone Many studies show that vaginal progesterone can reduce PTB in • Singleton gestations, prior SPTB, unknown or normal CL • Singleton gestations, no prior SPTB, short CL • Singleton gestations, prior SPTB, short CL

38. Vaginal progesterone, but not 17-OHPC, has local anti-inflammatory effects at the maternal-fetal interface and the cervix, and protects against endotoxin-induced PTB Furcron AE, et al. Vaginal progesterone,but not 17 OHPC, has anti-inflammatory effects at the murine maternal-fetal interface. Am J ObstetGynecol 2015

39. Prevention of SPTB in singleton pregnancy Vaginal progesterone is superior to 17-OHPC

40. Cervical cerclage

42. Singleton gestations, short CL Cervical cerclage

43. Singleton gestations, prior PTB, short CL Cervical cerclage

44. Cervical pessary • Be used for cervical insufficiency

47. Cervical pessary Conclusions • The cervical pessary seems an affordable, safe, and reliable alternative for prevention of PTB in a singleton pregnancy with short CL (< 25 mm) at midtrimester (GA 18-24 wk). • In view of the differences in outcomes between Hui et al. and the PECEP trial, further research is urgently needed to confirm the efficacy of cerclage pessary in prevention of preterm birth.

48. Progesterone for the prevention of preterm birthin preterm labor

49. Progesterone for the prevention of preterm birth in preterm labor Conclusions: • Progesterone may attenuate the shortening of cervical length and reduce the frequency of uterine contractions. • There is currently insufficient evidence to recommend progesterone for primary adjunctive tocolysis and maintenance tocolysis.

50. Progesterone for the prevention of preterm birth in PPROM Conclusions: • Insufficient evidence to assess effect of progesterone in women with PPROM