Role of progesterone in Pregnancy

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  • Preterm Birth
  • Every 5 minutes 50 preterm babies are born world wide
  • PTB leading cause of neonatal morbidity & mortality
  • Progesterone in Preterm
  • RCT, double blind placebo controlled trial. Study halted at interim analysis when primary outcome was noted to be significant
  • Swelling/lump 17P > placebo
  • Role of progesterone in Pregnancy

    1. 1. Role of progesterone in Pregnancy Dr.Jyoti Agarwal Dr. Sharda Jain
    2. 2. TWO PARTS Part - I Role of progesterone in preterm birth Part - II Role of progesterone in Infertility treated patients
    3. 3. Preterm Birth • • For both mother & child preterm birth is a disaster. It is one of the grimmest & heart breaking statistics in medicine Puts a Huge Financial Burden
    4. 4. Key facts (WHO - 2012) • Every year, 15 million babies are born preterm and this number is rising. • 1.1 million babies die annually from preterm birth complications. Three-quarters of them can be saved with current, cost-effective interventions, even without intensive care facilities.
    5. 5. Incidence of Preterm Birth in India • 15 - 21% (Singh, Singh, & Shikha, 2007) • Extreme prematurity contributes to more than 28% of neonatal deaths. • 2/3 of preterm births occur bet. 34-37 wks. Preterm births in United States: 11.6%, Sweden: 5.6%, China: 7.4%.
    6. 6. The 10 countries with the greatest number of preterm births: • • • • • • • • • • India: China: Nigeria: Pakistan: Indonesia: The United States of America: Bangladesh: The Philippines: The Democratic Republic of Congo: Brazil: 3 519 100 1 172 300 773 600 748 100 675 700 517 400 424 100 348 900 341 400 279 300
    7. 7. Every 5 minutes 50 preterm babies are born world wide The Lancet Editorial 2006;368:339
    8. 8. How do we quantify the emotional toll It is a devastating scenario, to say the least
    9. 9. The Prognosis of Preterm Neonates is a Function of Gestational Age at Birth © PJS Major perinatal challenge of 21 st century
    10. 10. PREVENTION OF PTL, WHY ? Premature newborns Perinatal morbidity & mortality Admission in NICU & Increased expenditure Cost effective burden on individuals & families Improves our society productivity
    11. 11. Term Labor Late preterm Moderately preterm Very preterm Preterm Labor ( 34-36 wks) (32-34 wks) ( < 32 wks)
    12. 12. PREDICTORS OF PTL  Prev. history of PTL  Uterine abnormalities  Cervical abnormalities  Advanced maternal age  Obesity  Lower socio – economic group  STDs during pregnancy  Multiple Pregnancy A history of spontaneous preterm birth is one of the strongest predictors for a preterm birth in a subsequent pregnancy
    13. 13. Interventions to prevent PTB  Prenatal care Social support  Lifestyle changes Smoking cessation Improved nutrition     Trials of acute care of PTL show little benefit in prevention of PTB Cerclage Infections Home uterine activity monitoring Tocolytic medications
    14. 14. Progesterone in Preterm Progesterone is “indispensable” for normal pregnancy “Progesterone deficient state” has been proposed to be a Mechanism in Preterm Labor Arpard Csapo
    15. 15. Pro = For Gesterone = Gestation Progesterone “see – saw theory” Csapo Am J Anat 1956
    16. 16. A progesterone withdrawal “prepares” the uterus for the action of uterotonic agents
    17. 17. Evidence that suspension of progesterone action is important in human parturition Administration of anti-progestins (RU-486 or onapristone) can induce abortion and cervical ripening Kovacs L et al. Contraception 1984; 29: 399 Crowley WF. N EJM 1986; 18: 1607 Chwalisz K. 1994 Human Reproduction 1994;9:131 Bygdeman et al. Human Reproduction 1994;9:120
    18. 18. HOW PROGESTERONE WORKS ? for successful  Favorable changes in the endometrium implantation & maintenance of pregnancy  Suppresses immunity to prevent rejection of fetal cells  Induces myometrial quiescence by suppressing     Cytokines PGs Response to oxytocin Prevents formation of gap junction Nature’s Natural Immunosuppresant
    19. 19. Cervix is the predominant site of supplemental progesterone action • Modulate gene expression in cervix both in presence and absence of inflammation. • Blocks type 1 collagen degradation in cervix. Xu H, AJOG, 2008
    20. 20. PROGESTERONE & PREVENTION OF PRE TERM BIRTH • Small trials in 1970’s and 80’s • Suggested – Reduction in preterm birth
    21. 21. Meta - analysis of 17P use • Seven placebo – controlled trials • 15 – 70% • No significant in PTB in perinatal morbidity & mortality Conflicting evidence because Mixed population in the study like recurrent pregnancy loss, active PTL Small no. of patients included in the studies Variable dosing IM , vaginal
    22. 22. THE NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT (NICHD) AND MATERNAL-FETAL MEDICAL UNITS (MFMU) TRIAL Meis, N Engl J Med 2003 Northen, Obst & Gynaecol. 2007
    23. 23. Participating Centers of the MFMU Network • • • • • • • • • • • • Wake Forest University • University of Tennessee • University of AlabamaBirmingham • University of Utah • Magee-Womens Hospital • Thomas Jefferson University • University of Miami • Columbia University • University of North Carolina Case Western Reserve University George Washington University Wayne State University University of Chicago University of Cincinnati University of Texas, Southwestern Ohio State University University of Texas, San Antonio Brown University University of Texas, Houston Northwestern University
    24. 24. NICHD/MFMU 17 α-Hydroxyprogesterone Caproate New England Journal of Medicine, 2003; 348 (24)
    25. 25. 17P – NICHD (Meis, 2003, NEJM) Primary outcome: PTB < 37 weeks EGA
    26. 26. 17P – NICHD (Meis, 2003, NEJM) PTB rates 17P 54.9% Placebo p< 0.01 30.7% 19.6% 11.4% 20.6% PTB < 32 weeks PTB < 35 weeks 36.3% PTB <37 weeks
    27. 27. 17P – NICHD (Meis, 2003, NEJM) Weekly 17P • 34% • 33% • 42% reduction in PTB < 37 weeks reduction in PTB < 35 weeks reduction in PTB < 32 weeks
    28. 28. 17P – NICHD (Meis, 2003, NEJM) Neonatal morbidity 17P 41.1% * Placebo 27.2% 23.8% * 13.9% 8.6% Birthweight < 2500gram Birthweight < 1500gram 14.9% 5.9% 2.6% Neonatal death 5.2% * 1.3% IVH Supplemental O2 * p < 0.05
    29. 29. Effectiveness of Treatment With 17P • 6 women with a previous spontaneous preterm birth would need to be treated to prevent one birth <37 weeks • 12 women with a previous spontaneous preterm birth would need to be treated to prevent one birth <32 weeks
    30. 30. 17 –P side effects Symptom % Soreness 34.2 Swelling 14.1 Itching 11.3 Bruising 6.7 Rebarber, 2007, Diabetes Care 17-P associated with 3 x increased risk of GDM single retrospective study 12.9% vs. 4.9%
    31. 31. 17 – P: Safety  17-P exposed infants • Less perinatal morbidity • rates of NEC, IVH, need for O2 RDS, Bronchopulmonary dysplasia No evidence of virilization of female offspring Meis, N Engl J Med 2003 Northen, Obst & Gynaecol. 2007
    32. 32. 17 – P: Safety 4 year outcome of exposed children No congenital anomalies Normal neurological development Obstet Gynecol 2007;110:865–872.
    33. 33. Secondary analysis of RCT by MFMU Meta – analysis RCTs vs 33-47% • 17P Risk of PTB : 25-31% recur. PTB if prev PTB < 34 wks • 17P doesn’t rec PCB if prev PTB > 34 wks Sponge, Obstet Gynaecol 2005
    34. 34. Obstet Gynecol 2003;102:1115-6
    35. 35. ACOG Committee Opinion Oct 2008 Acknowledges the benefits of progesterone in high risk populations with prior PTB. Further studies are needed to evaluate - Optimal Preparations - Dosages - Route of administration
    36. 36. MFMU Concluded Weekly injections of 17- α Hydroxyprogesterone Caproate can provide significant and powerful protection against recurrent preterm birth and improve the neonatal outcome for pregnancies at risk 17P cost effective
    37. 37. ACOG/MFMU Recommendations • Recommended – Prevention of recurrent PTB • Current singleton pregnancy • Prior preterm birth • Considered – Asymptomatic short cervix (<25mm) – Routine screening not recommended Obstetrics and Gynecology, Vol 112(4), 2008
    38. 38. VAGINAL PROGESTERONE TRIAL  RCT 142 patient with h/o 1 pre. PTB  Daily 100mg Vg suppo. from 24 to 34 wks of pregnancy vs Placebo Significant benefit : Progesterone grp Lower PTB < 37 wks ( 14% vs 29% ) Lower PTB < 34 wks ( 3% vs 19% )
    39. 39. Vaginal progesterone trials • deFonseca, Am J Obstet Gyneol, 2003 – 100mg micronized vaginal progesterone – reduction in PTB <34 weeks in progesterone group (2.7% vs. 18.6%) • O’Brien, Ultrasound Ob/Gyn, 2007 – Vaginal progesterone gel, 600 patients – 90 mg progesterone (Crinone®) – No difference in PTB < 32 weeks
    40. 40. Oral Progesterone & PTL Indian Study 2009 (Raj et al. Int. J Gynaecol Obstet 2009) • RCT - 150 women with at least one PTB • Received 100 mg of OMP or placebo twice a day ) from 18-24 weeks until 36 weeks Indian Study Inference     Significant decrease in rate of PTB Better birth weight of the new born Shorter stay in NICU Better APGAR score
    41. 41. Twin pregnancy ‘STOPPIT trial’ A randomised, doubleblind, placebo-controlled study • 500 women • Daily vaginal progesterone gel 90 mg (n=250) or to placebo gel (n=250) for 10 weeks from 24 weeks' gestation
    42. 42. PROGESTERONE IN TWIN PREGNANCY Delivery before 34 weeks of pregnancy • 24.7% progesterone group • 19.4% - placebo group Rate of adverse events - not different The meta-analysis confirmed - progesterone does not prevent early preterm birth in women with twin pregnancy Norman JE et al. Lancet 2009 Jun Combs CA et al. AM J Obstet Gynecol. 2011
    43. 43. PROGESTERONE IN TRIPLET PREGNANCY (56 women ) Composite neonatal morbidity - similar (38% vs 41%) Mean gestational age at delivery - (31.9 vs 31.8 wk ) In triplet pregnancy - prophylactic treatment with 17P did not reduce neonatal morbidity or prolong gestation . Combs CA et al. AM J Obstet Gynecol. 2010
    44. 44. VAGINAL PROGESTERONE & SHORT CERVIX • Large multinational (53), randomised, double blind, placebo- controlled trial • 547 patients with h/o PTB or short cx <30mm • TVS cervical length meaurements 18 wks • 28 wks • Daily intravaginal P4 gel 90 mg Change in the cervical length >2mm PTB 3.6% vs 18% in placebo Ultrasound obst gynae 2009
    45. 45. TVS findings to suggest cervical incompetence • shortening of endocervical canal (< 25mm) • Funneling of the internal os ( >1.5cm) • Prolapse of membranes into the cervix Normal cervix Short length cervix
    46. 46. Progesterone Preserves Cervical Length – Results from O’Brien et al.2009 Intravaginal progesterone preserves cervical length & reduces the rate of spontaneous early pre-term delivery
    47. 47. New international study • 5 high quality RCT , 775 women, 827 infants • Vaginal progesterone reduces rate of preterm birth by 45% • Vaginal P4 was effective in women with short cervix. • This is the first study to show that vag P4 is effective in reducing the rate of neonatal complications in twin gestation Romero,etal AJOG 2012
    48. 48. Progesterone as a Tocolytic • 6 trials have been reported • Various progesterone compounds used • None of the trials found a significant prolongation of pregnancy . Progesterone treatment of women with active uterine contractions should be discouraged outside of research protocols Cochrane database syst rev 2010 Jan
    49. 49. Take home recommendations For prevention of PTL in women with h/o PTL 17 alpha-hydroxy progesterone 250 mg im Weekly or Progesterone 100 mg daily Vaginally SOGC RECOMMENDATION Jan2008 J. Pbst. Gynecol Can 2008;
    50. 50. For Prevention of PTL in women with short cervix (< 25 mm at 22-26 wks) Progesterone 200 mg daily vaginally The therapy should be started at 20 weeks gestation and stopped when the risk of prematurity is low SOGC RECOMMENDATION Jan2008 J. Pbst. Gynecol Can 2008
    51. 51. Part - II Role of progesterone in Infertility treated patients
    52. 52. Role of progesterone to support early pregnancy in infertility treated patients
    53. 53. Luteal phase defect PROBLEMATIC AND CONTROVERSIAL As Currently there are no reproducible, physiologically relevant and practical clinical standard test to diagnose LPD
    54. 54. Progesterone and miscarriage There is insufficient evidence to evaluate the effect of progesterone supplementation in pregnancy to prevent a miscarriage. It was only in 2011 that Cochrane meta analysis suggested that progesterone supplementation has beneficial effects in patients with Recurrent Pregnancy Loss.
    55. 55. Recent Cochrane review concluded no significant difference between different routes of progesterone supplementation. Equal number of studies support both vaginal & intramuscular route
    56. 56. Various routes Oral Easy route Micronized form Only 10 % absorbs Not very effective. First hepatic pass Intramuscular Reliable & consistent plasma level of P4 Rapidly absorb in 2-8 hrs. P4 level maintain for > 72 hrs. Difficult & very painful inj Side effects like sedation Local reaction & abscess. & hypnosis Non compliance by pt. Vaginal Targeted organ delivery High conc. In uterus & endometrium First uterine pass effect Minimal systemic side effect Good Pt. compliance Self administration, no prick of needle
    57. 57. New Evidence is coming up as large PROMISE is multicentre study currently on the Way PROMISE PROgesterone in MIScarriagE trial
    58. 58. Good things do come in small packages but definitely not this one.
    59. 59. Progesterone is the drug of choice Doing nothing is no longer an alternative
    60. 60. ‘An ounce of prevention is better than a pound of cure’ Thank you
    61. 61. & ADDRESS 35 , Defence Enclave, Opp. Preet Vihar Petrol Pump, Metro pillar no. 88, Vikas Marg , Delhi – 110092 CONTACT US 011-22414049, 42401339 WEBSITE : www.lifecarecentre.in www.drshardajain.com www.lifecareivf.com E-MAIL ID Sharda.lifecare@gmail.com Lifecarecentre21@gmail.com info@lifecareivf.com

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