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Evolving approach to preterm birth management

Moscow. Evolving approach to preterm birth management. Making progress: the evidence for vaginal micronized progesterone. Eduardo Borges da Fonseca - Brazil. Evidence for vaginal micronized progesterone. Strategy in the prevention . Identification of risk factors.

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Evolving approach to preterm birth management

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  1. Moscow Evolving approach to preterm birth management Making progress: the evidence for vaginal micronized progesterone Eduardo Borges da Fonseca - Brazil

  2. Evidence for vaginal micronized progesterone Strategy in the prevention Identification of risk factors • Previous history of preterm birth • Twin pregnancy • Short cervix at mid-gestation scan Asymptomatic Preterm labour False labour True labour VS Symptomatic • Assess the cervical length by TVS • Fetal fibronectin

  3. Luteectomy No Ab D&C (n=10) Abortion D&C 7 pregnant women <7 wks Tubal ligation + luteectomy+ progesterone No miscarrige Miscarrage (n = 8) (n = 33) Progesterone and pregnancy maintenance - 57 pregnant desired tubal ligation (GA – 64/7 to 86/7 wks) 35 Tubal ligation 25 Progesterone level (ng/ml) <7 wks – tubal ligation (control) No Ab D&C (n=6) <7 wks – tubal ligation + luteectomy 20 >8 wks – tubal ligation + luteectomy 15 10 5 Csapo, A et al. The effect s of luteectomy and progesterone replacement therapy in early pregnant patients, Am. J. Obstet. Gynecol. 1973,115: 759-65. CsapoA. The Fetus and Birth. Ciba Foundation Symposium 47; 1977. 0 Arapad I. Csapo, 1918-1981 Washignton University School of Medicine 0 4 8 12 16 Days after luteectomy

  4. Preterm delivery Preterm labour Low birth weight (2,500gr) 0.1 0.3 0.5 1 2 3 4 Scientific evidence Émile Papiernik Keirse, M. Progestogen administration in pregnancy may prevent preterm delivery? Br. J. Obstet. Gynaecol., 97: 149-54, 1990.

  5. Recent scientific evidence RCT: vaginal prophylatic P4 vs placebo in high risk group Single-center, randomized, double-blind, placebo-controlled trial Enrolled 142 asymptomatic singleton pregnant womenathigh risk for preterm delivery due to one of the following risk factors: • At least 1 previous spontaneous preterm birth <37 wks • Incompetent cervix • Uterine malformation Vaginal progesterone (100mg) daily at night Gestational age at intake: 25 weeks (24-26 wks). Fonseca EB et al. Am J Obstet Gynecol. 2003;188:419-424.

  6. Gestation Week 22 2 4 6 8 10 20 26 28 30 32 34 24 Group A Progesterone 100 mg QD (n=72) Group B Placebo QD (n=70) Note: Women in preterm labourwere treated with intravenous tocolytic therapy. UC monitoring with external tocodynamometer for 60 min Recent scientific evidence RCT: Methods Aim: to evaluate the effect of vaginal progesterone in decreasing the incidence of preterm delivery in a high risk population Fonseca EB et al. Am J Obstet Gynecol. 2003;188:419-424.

  7. 52% 85% Recent scientific evidence RCT: conclusion Placebo ,n=70 P4,n=72 • Progesterone • Halves the incidence of preterm delivery • Reduces the frequency of contractions • Improves the ß-adrenergictocolyticresponse 22 (31.4%) 14 (19.4%) Preterm labour 8 (36.4%) 12 (85.7%)* Delay >72hrs * p < 0.01 Fonseca EB et al. Am J Obstet Gynecol. 2003;188:419-424.

  8. Placebo (N=125) 30,517 pregnancies at 20-25 wks Progesterone (N=125) 40 82% 30 Accepted 24,620 pregnancies 20 1.7% 10 413 short cervix (<15 mm) 0 Spontaneous delivery at <34 wk 60% 250 randomized Short cervical length RCT: Micronized progesterone (200mg/night) at 24-34 weeks Preterm delivery reduction RR, 0.56; 95% CI (0.36 to 0.86) 44% reduction Fonseca et al. N Engl J Med. 2007; 357 (5):450.

  9. Remaining pregnant 100 % Progesterone 90 80 Placebo 70 60 25 26 27 28 29 30 31 32 34 Gestation (wks) Short cervical length RCT: Micronized progesterone (200mg/night) at 24-34 wks Outcome Placebo P4 Delivery before 34 wks 34.4% 19.2% * Spontaneous All 36.0% 20.8% * Perinatal outcome Fetal death 0.7% 0.7% Neonatal death 5.1% 1.5% Birth weight <1500g 19.6% 13.2% Morbidity (IVH, RDS, NEC) 13.8% 8.2% Therapy (NICU,Ventil) 32.6% 25.0% PTD <34wks: 44% reduction Fonseca et al. N Engl J Med. 2007; 357 (5):450.

  10. Evidence: twin pregnancy Effect of progesterone gel for the prevention of preterm birth in twin pregnancy (N=500) • Randomized either to daily vaginal progesterone gel 90 mg (n=250) or to placebo gel (n=250) for 10 weeks. • GA at intake: 24 wks. • Primary outcome: delivery or IUD before 34 wks. • Analysis was by intention to treat. • Additionally, a meta-analysis of published and unpublished data in twin pregnancy was performed to establish the efficacy of P4 in prevention of early PTB or IUD. Norman et al. The Lancet. 2009; 373: 2034-40.

  11. New evidence: twin pregnancy Meta-analysis of the effect of progesterone in the prevention of preterm delivery <34 wks (N=1,173) Meta-analysis confirmed: progesterone does not prevent early preterm birth in women with twin pregnancy (pooled OR 1.16, 95% CI 0.89-1.51). • Square shows the OR for each study and the horizontal line depicts the 95% CIs. • Vertical line, at the odds ratio of unity, corresponds to the line of no effect • Open diamond indicates the final odds ratio with 95% CI overall

  12. Symptomatic patients Role of progesterone during and/or after acute trocolysis Preterm labour False labour True labour VS • Assess the cervical length by TVS • Fetal fibronectin

  13. Study Rationale Tocolytics and progesterone P4 enhances the effect of ritodrine in isolated pregnant human myometrium Cumulative effect of natural progesterone Association progesterone and ritodrine • Natural progesterone reduces the myometrialoxytocin-induced contraction • Overnight incubation with progesterone significantly inhibited contractility • Natural progesterone enhances the relaxant action of ritodrine Chanrachakul et al.Am J Obstet Gynecol. 2005; 192, 350-9

  14. Symptomatic patients Progesterone for maintenance tocolytic therapy after threatened preterm labour: a RCT (N=70) Outcome Control (N=33) Progesterone (N=37) P Primaryoutcome Latency (day, mean+ SD) Gestacional age at delivery (wks, mean+ SD) Recurrenceofpretermlabour [N(%)] 24.5 + 27.2 34.5 + 1.2 19 (57.6%) 36.7 + 17.9 36.7 + 1.5 13 (35.1%) 0.037 0.041 0.092 Secondaryoutcome RDS [N (%)] Birthweight (g, mean+ SD) LBW [N (%)] 12 (36.4%) 2609.39 + 662.9 17 (51.5%) 4 (10.8%) 3109.39 + 662.9 10 (27.0%) 0.021 0.002 0.04 Borna & Sahabi. Aust N Z J ObstetGynaecol. 2008; 48:58-63.

  15. Evidence for micronized progesterone “ Although it is not yet time to treat all women at risk for preterm birth with supplemental progesterone, it is not too soon to hope that these early reports will be followed by larger series showing not only a decline in preterm birth but a reduction in perinatal morbidity and mortality as well ” Jay Iams, Associate Editor of AJOG 2003 Feb 188(2):303

  16. Progestogens for Preterm Birth Prevention: A Systematic Review and Meta-Analysis Progestogensprevents PTB Prior PTB RR, 95% BCI Reduction 0.75, 0.68-0.88 yes Twins No 7 studies - Lack of effectiveness for multiple gestations. PTL 0.62, 0.47-0.79 yes Short CxL 0.52, 0.36-0.70 yes Likis, et.al. Obstetrics & Gynecology. VOL. 120, NO. 4, OCT 2012.

  17. Making progress: evidence for micronized progesterone IPD-M: vaginal progesterone in women with an asymptomatic US short cervix in the midtrimester decreases preterm delivery (N=775) Romero et al. AJOG. 2012:206:124.

  18. Making progress: evidence for micronized progesterone IPD-M: vaginal progesterone in women with an asymptomatic US short cervix in the midtrimester decreases preterm delivery (N=775) and this reduction has been translated in improvement of neonatal morbidity and mortality

  19. ACOG THE AMERICAN CONGRESS OF OBSTETRICIANS AND GYNECOLOGISTS ACOG recommendations, 2008 • Progesterone for the prevention of recurrent preterm birth should be offered to women with a singleton pregnancy and a prior spontaneous PTB due to spontaneous preterm labor or premature rupture of membranes. • Current evidence does not support the routine use of progesterone in women with multiple gestations. • Progesterone for asymptomatic women with an incidentally identified very short cervical length (less than 15 mm) may be considered; however, routine cervical length screening is not recommended. • The ACOG Committee on Obstetric Practice and the Society for Maternal Fetal Medicine believe that further studies are needed to determine if there are other indications for progesterone therapy for the prevention of PTD ACOG Committee on Obstetric Practice. Obstet Gynecol. 2008;112:963-65.

  20. Guidelines EU, 2011 1 • Women with prior history of PTB, the early prophylaxis with either P4 micronized or 17 OHP-C to prevent recurrence. SMFM, 2012 2 • Women with singleton gestations, no prior PTB, and short CL at 24 weeks, vaginal progesterone is associated with reduction in PTB and perinatal morbidity and mortality, and can be offered in these cases. SOGC, 2008 3 • Women with previous history of PTL and/or short cervix (<15mm at 22-26 wks) could be used as indications for progesterone. 1. Di Renzo, et.al., The Journal of Maternal-Fetal and Neonatal Medicine, 2011. 2. Berghella, V. & SMFM Publications Committee, American Journal of Obstetrics & Gynecology, May 2012. 3. Farine, D. et.al., J ObstetGynaecol Can 2008; 30(1):67-71.

  21. Making progress: evidence for micronized progesterone NNT: Number Needed to Treat

  22. Making progress: evidence for micronized progesterone NNT: Number Needed to Treat

  23. Making progress: evidence for micronized progesterone NNT: Number Needed to Treat

  24. Making progress: evidence for micronized progesterone NNT: Number Needed to Treat

  25. Making progress: evidence for micronized progesterone NNT: Number Needed to Treat

  26. Risk factor Previous preterm Short cervix (TVS) Twin pregnancy In conclusion Symptomatic Asymptomatic Preterm labour Specific risk factors YES Study YES MICRONISED PROGESTERONE Vaginally(100-300 mg) 1-2 x day(16tha 36thwks) NO

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