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Progesterone therapy to prevent premature birth: who, when, why and how? 

Progesterone therapy to prevent premature birth: who, when, why and how?  . Professor Dilly OC Anumba Chair in Obstetrics and Gynaecology Consultant in Obstetrics and Fetomaternal Medicine The University of Sheffield Medical School Sheffield UK. Outline. Epidemiology of preterm birth (PTB)

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Progesterone therapy to prevent premature birth: who, when, why and how? 

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  1. Progesterone therapy to prevent premature birth: who, when, why and how?  Professor Dilly OC Anumba Chair in Obstetrics and Gynaecology Consultant in Obstetrics and Fetomaternal Medicine The University of Sheffield Medical School Sheffield UK

  2. Outline • Epidemiology of preterm birth (PTB) • Current management challenges with preterm birth • Predicting preterm birth • Progesterone therapy- who, when, why and how? • Future issues

  3. Global burden of prematurity - 2005 • 12.9 million preterm births • Africa and Asia: 10.9M (85%) • Europe: 0.5M • North America: 0.5M • Latin America and the Caribbean: 0.9M • Reflects global health disparities Bulletin of the WHO, Beck et al 88 (1) 2010, 31-38

  4. Rising preterm rates

  5. indications Obstetric precursors of preterm birth Goldenberg Lancet 2008; 371: 75–84

  6. PrematurityPerinatal mortality/morbidity • Largest cause of perinatal death in non-anomalous fetuses (>70%) • developmental delay • visual impairment • chronic lung disease • cerebral palsy • <1500gm X10 more likely to be handicapped than >2500gm

  7. Trent Neonatal survey, Overall Disability at 30 Months for 314 Children Born at 22 -25 weeks Wood et al. NEJM 343 378.

  8. Cost of Preterm Birth 2005 PTB costs to US • $26.2 billion, or $51,600 for every infant • Medical care: $16.9 billion (65%). • Maternal delivery: $1.9 billion (7%) • Early intervention services: $611 million (2%) • special education services $1.1. billion (4 %) for • Lost household and labour market productivity $5.7 billion (22%) • Average 1st year medical costs 10 times greater for preterm ($32,325) than term infants ($3,325). • Source: Preterm Birth: Causes, Consequences and Prevention, Institute of Medicine (2006)

  9. Key management challenges • Diagnosis - of aetiological subtype • Screening/prediction – general vs. selected high risk groups • Prevention • Primary – population focussed programmes • Secondary – care for those at high risk • Tertiary – tocolytics and neonatal management for threatened and actual preterm birth

  10. The accuracy of most of the tests purported to be of value in prediction of spontaneous preterm birth was disappointing. Likelihood ratios as a measure of the tests’ ability to predict all mothers who will develop preterm birth spontaneously were particularly poor.”

  11. The uterine cervix has to remodel for birth

  12. Possible PTL Cx <3cm USS cervical length Main challenge SPTBPrediction Fetal fibronectin “Factor(s) X”

  13. At risk prediction and 2ry prevention

  14. Progesterone in preterm birth prevention - background Progesterone receptor-modulation during pregnancy • Initial evidence derived in early pregnancy from luteal phase support and IVF. • Receptor enhanced to sustain pregnancy • Receptor down-regulatedto modulate pregnancy loss- mifepristone. • In 2nd and 3rd trimesters, phase III trials demonstrate P supplementationprolongs gestation • women with premature cervical shortening • history of idiopathic spontaneous PTB (Meis 2003 NEJM)

  15. Progesterone in preterm birth prevention- background • Progestins reduce the rate of progressive cervical shortening • Exposure to natural P reduces uterine contraction frequency. • In contrast ex vivo clinical 17-OHPC associated with no change or increase in contraction frequency negating tocolysis as a potential mechanism for efficacy in PTB • Increased fetal CNS blood flow after treatment with supplemental P - ? fetal or neonatal neuroprotectionsimilar to early studies in adults. • These differing pharmacodynamic observations suggest P agents must be assessed independently for safety.

  16. P effects in cervix and decidua • Progestins alter collagen synthesis • limits collagenolysis • alters production of cytokines, nitric oxide, and prostaglandins • limits apoptosis • P receptor antagonist mifepristone impairs • decidual function • trophoblast proliferation/functioning • accelerates cervical ripening by enhancing collagenolysis

  17. 17OH PC risk • O’Brien Am J Perinatol 2012;29:665–672. The Kaplan-Meier curves from the study by Meis et al demonstrating a crossover between groups suggesting a potential for 17-hydroxyprogesterone caproate (17-OHP) to act differently in different subpopulations including the potential the drug has both antagonistic (left side of the curves from 27 weeks) and agonist activity (right side of the curves).

  18. Progesterone receptor antagonism-miscarriage/previable pregnancy • Conflicting data for 17-OHPC • rhesus monkeys showed 100% fetal loss rate with exposure, not found in other primate species studies • Supports thesis of differences in response based on P receptor genotype. • FDA concern about pregnancy loss from review of data for 17-OHPC for PTB prevention. • 5 losses prior to viability in treatment group in Meiset al 2003 vs none in women given placebo, but non-significant difference.59

  19. Risks of 17-OHPC -miscarriage • Meiss et al: 5 losses treated group vs 0 controls, crossover in Kaplan Meier, unlike Caritis et al no difference • Coombs et al: triplets – 13 losses treated vs. 0 in placebo, crossover in Kaplan Meier • 3 large RCTs showed no difference • Rouse et al • Coombs et al • Lim et al • Norman et al STOPPIT trial, non-significant increase in loss with natural P.

  20. P Receptor Antagonism Risk:Early Preterm Birth • ?Paradoxic increase in PTB risk • Twin trial - reduction in pregnancy duration with 17-OHPC treatment by survival analysis (p = 0.02) Combs AJOG 2011;204:221, e1–e8 • PTB reduced in most phase III singleton trials of natural or synthetic hormone. • Largest trial to date of 17-OHPC (n=657) with a short cervix – no increased risk of PTB. GrobmanAJOG 2012;206(S1):S367

  21. Progesterone Receptor Antagonism Risk: Altered Fetal Growth • May alter fetal growth by impairing placentation • Fetal growth rates may differ to differing progestins • Most RCTs – no effect on fetal growth • Further study required

  22. Excess P Receptor Agonism: Altered Metabolism and Immune Response • Increased risk of gestational diabetes with systemic 17-OHPC (RebarberDiabetes Care 2007;30:2277–2280; Waters ObstetGynecol 2009;114:45–49), data conflicting (Gyamfi Am J ObstetGynecol 2009;201:392, e1–e5) • Alteration of immune response • Anti-inflammatory activity vsimpaired immunocompetency • Mice – higher rate of maternal death. • Symptomatic women/PPROM treated with high-dose progestins - any risks. • Small trials no adverse maternal or fetal effects • Effect on fetal immune status unknown

  23. Dose and safety issues • Supplemental natural hormone • PV or PR progesterone 90 or 200mg daily: likely within physiologic range, better safety profile than synthetic progestins. • IM 17-OHPC 250 mg weekly empiric • Safety of P may vary with pathophysiology/ time of treatment - further studies needed eg suspected infection

  24. Effect of vaginal progesterone on pretermbirth <33 weeks of gestation

  25. Twins and PTB prediction and treatment

  26. Effect of vaginal progesterone on preterm birth and perinatal outcomes in singleton and twin gestations

  27. Indications for progesterone for preterm birth prevention • Previous history of recurrent preterm birth – one or two? • Perhaps two but also for one if cervix shortening demonstrated serially • Unexplained mid-trimester miscarriage • Proven cervical shortening mid-trimester scan • < 25mm, ? 15mm, ?20mm • Combined with cerclage or as substitute? • When in doubt scan serially and demonstrate shortening

  28. Timing of progesterone? • Unclear • Most trials from mid-trimester- 18 to 20 wks • Could pure progesterone be started earlier in first trimester since it has no antagonistic effects? • For how long? • Until 34, 36 weeks

  29. AN suspicion of cervical weakness History of 2nd trimester miscarriage(s) Very preterm deliveries Previous failed cervical cerclage Screen for infection/bacterial vaginosis at booking Cervical length at 16-18wks Normal cervical length/no funnelling 1-2 weekly FU Cervical shortening and funnelling ? Cerclage, give progesterone Normal cervical length at 24wks Routine ANC Follow-up

  30. Previous preterm delivery ?1 preterm delivery <28 weeks 2 previous preterm deliveries Screen for infection/bacterial vaginosis at booking ?progesterone Cervical length at 22wks + fFN assessment Cervical shortening and funnelling/ +vefFN , give progesterone Normal cervical length/no funnelling -ve fFN Normal cervical length at 24-26wks Cerclage, continue progesterone Routine ANC Follow-up

  31. Algorithm for use of progestogens in prevention of PTB – Berghella 2012 AJOG

  32. Summary/ Conclusion RCTs indicate that: • Women with singleton gestations, no prior PTB, and short CL <20mm at 24 weeks - vaginal progesterone, 90-mg gel or 200-mg suppository, associated with reduction in PTB and perinatal morbidity/mortality (Fonseca 2007). • Universal CL screening of singleton gestations without prior PTB for the prevention of PTB controversial. Some evidence of cost benefit potential • Singleton, prior PTB 20-36 wks - 17OHPC 250 mg IM wkly, from 16-20 until 36 wks, reasonable option OR • vaginal P for the same pregnancy duration

  33. Summary/ Conclusion • In these women, if TV US CL shortens <25mm at 24 weeks, cervical cerclage may be offered. • Progestogens not associated with prevention of PTB in women, with or without a short CL: • Multiple gestation • Preterm labour • Preterm premature rupture of membranes.

  34. Future direction • Best formulation of P • Best dose • Best time to start • Best time to stop • Side effects and contraindications • Replace or supplement cerclage? • In preterm premature rupture of membranes • In recurrent mid-trimester miscarriage • Following LETTZ, congenital uterine malformations

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