2012 utrogestan natural micronized progesterone - from luteal phase defect to preterm birth
TRANSCRIPT
Delfin A. Tan, M.D.Section of Reproductive Endocrinology and InfertilityDepartment of Obstetrics and GynecologySt. Luke’s Medical Center Quezon City
From luteal phase defect to preterm birth
Utrogestan® Natural micronized progesterone
Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth 2
DisclosureAll the statements and opinions expressed in this presentation are those of the speaker and are not intended to reflect the views and position of the sponsor.
Delfin A. Tan, MD
3Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
Outline Part 1 Utrogestan®: pharmacology
2 Luteal phase defect3 Recurrent early pregnancy loss4 Preterm birth
History of spontaneous preterm deliveryPreterm laborAsymptomatic sonographically short cervix at midtrimester
5 Conclusions
4Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
Utrogestan®: pharmacologyPart 1
5Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
Utrogestan® The only original natural micronized progesteroneFeatures Exact chemical duplicate of progesterone of ovarian origin (not a
progestin)
Synthesized from natural precursor (diogenin) extracted from wild yams (Dioscorea sp)
Optimal bioavailability via oral and vaginal route obtained by micronization and oil suspension
www.besins-healthcare.com
Wild yam Micronized progesterone
Peanut oil (long-chain fatty acid)
Utrogestan® 100 mg
Utrogestan® 200 mg
6Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
Exogenous progesterone/progestins in clinical use: different molecules, different biological activities
Natural progesterone ≠ dydrogesterone ≠ 17-OH Progesterone caproate
Natural progesterone C21H30O2
Utrogestan®, oral, vaginal
Retroprogesterone or dydrogesterone C21H28O2
Duphaston®, oral
17-OH Progesterone caproate
Makena®, injectable
Schindler AE, et al. Maturitas. 2003 Dec 10;46 Suppl 1:S7-S16.
Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth 7
Classification of progestinsNatural ProgesteroneSynthetic Retroprogesterone Dydrogesterone
Structurally related to progesterone
Pregnane derivatives
17-OH Progesterone caproate, OH-progesterone heptanoate, gestronone caproate, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, medrogestone, cyproterone acetate
Norpregnane derivatives
Demegestone, promegestone, nomegestrol acetate, nestorone, trimegestone
Structurally related to testosterone
Estranes Lynestrenol, levonorgestrel, norethisterone/norethindrone, norethindrone acetate, ethynodiol diacetate, norgestrienone, dienogest, norethynodrel
Gonanes Norgestrel, desogestrel, gestodene, norgestimate
Spirolactone-derived DrospirenoneDruckmann R. Gynecology Forum 2004;9(2).
8Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
Use of exogenous progesteroneDifferent routes of administration: different pharmacokinetics and dynamicsIntramuscular Oral Vaginal (preferred)Supraphysiological plasma concentrations
Rapid increase in plasma concentration followed by gradual decrease
First liver pass effect with several biological active metabolites
Specific activity on different target organs (uterus, brain...)
Stable plasma concentrations and consistent tissue levels
First uterine pass effect with targeted delivery into the endometrium
Minimal systemic effects
Devroey P, et al. Int J Fertil. 1989 May-Jun;34(3):188-93. Miles RA, et al. Fertil Steril. 1994 Sep; 62(3):485-90.
Tavaniotou A, et al. Hum Reprod Update. 2000 Mar-Apr;6(2):139-48. Perusquía M, et al. Life Sci. 2001 May 18;68(26):2933-44. Schumacher M, et al. Endocr Rev. 2007 Jun;28(4):387-439.
Devroey P, et al. Int J Fertil. 1989 May-Jun;34(3):188-93. Tavaniotou A, et al. Hum Reprod Update. 2000 Mar-Apr;6(2):139-48. Cicinelli E, et al. Obstet Gynecol. 2000 Mar;95(3):403-6.
9Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
Micronized progesterone absorption: effects of route of administration Vaginal vs oral administration Vaginal vs intramuscular administration
Circulating P levels higher after vaginal administration
Target tissue P levels higher after vaginal administration
Nahoul K, et al. Maturitas. 1993 May;16(3):185-202. Miles RA, et al. Fertil Steril. 1994 Sep;62(3):485-90.
10Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
Vaginally administered progesterone: thepreferred route1 First uterine pass
effect2 Better bioavailability
of progesterone in uterus
3 Achieves adequate endometrial secretory transformation
4 Minimal systemic undesirable effects
Tavaniotou A, et al. Hum Reprod Update. 2000 Mar-Apr;6(2):139-48.
Migration through cervical tissue and lower uterine segment up to fundus
Vaginal application of progesterone
11Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
Luteal phase defectPart 2
12Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
DefinitionsLuteal phase defect
1 If serum mid-luteal phase progesterone level is <10 ng/mL; mid-luteal phase P levels do not always reflect endometrial maturationJordan J, et al. Fertil Steril. 1994 Jul;62(1):54-62. Batista MC, et al. Fertil Steril. 1994 Apr;61(4):637-44.
2 Most reasonable consensus: lag of >2 days in endometrial histological development compared to expected day of cycleJones GS. Curr Opin Obstet Gynecol. 1991 Oct;3(5):641-8. Dawood MY. Curr Opin Obstet Gynecol. 1994 Apr;6(2):121-7.
Luteal phase support
Administration of exogenous hormones to support implantation and early development of embryowww.ivf-worldwide.com.
13Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
Luteal phase defect (luteal phase deficiency or insufficiency)Prevalence1-4 ~8% in natural cycles in normally ovulating women
with primary or secondary infertilityAlmost all patients in stimulated IVF cycles
Etiology5 Iatrogenic Supraphysiological steroid levels in stimulated cycles of IVF and other assisted reproductive technologies
Other mechanisms
Abnormal follicle productionDefective corpus luteum functionFailure of uterine lining to respond to normal progesterone levels
1Rosenberg SM, et al. Fertil Steril. 1980 Jul;34(1):17-20. 2Ubaldi F, et al. Fertil Steril. 1997 Mar;67(3):521-6. 3Kolibianakis EM, et al. Fertil Steril. 2003 Aug;80(2):464-6. 4Macklon NS, Fauser BC. J Reprod Fertil Suppl. 2000;55:101-8. 5Fatemi HM. F. V & V in ObGyn. 2009;1(1):30-46.
14Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
Luteal phase defect: mechanism
Fatemi HM. F, V & V in ObGyn. 2009;1(1):30-46.
15Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
Role of physiological progesteronePrepares the endometrium for implantation
1 Promotes differentiation of endometrial stromal and epithelial cellsNorwitz ER, et al. N Engl J Med. 2001 Nov;345(19):1400-8.
2 Reduces physiological cell death occurring just before menstruationLovely LP, et al. J Clin Endocrinol Metab. 2005 Apr;90(4):2351-6.
16Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
Vaginal progesterone: fewer signs of luteal phase deficiency during stimulated cyclesEndometrial development in GnRHa/hMG stimulated cycles with or without luteal phase support
Bourgain C, et al. Hum Reprod. 1994 Jan;9(1):32-40.
Delayed In phase Advanced Dissynchrony0
20
40
60
80
100
Effects of luteal phase support on endometrial development (% of cycles)
No LPS hCG E2V + P im 100 mgE2V + P vag 600 mg P vag 600 mg
Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
Vaginal micronized progesterone: more effective than oral dydrogesterone in creating 'in-phase' secretory endometrium Study 6 Patients with premature ovarian failure primed with estrogen and received oral
dydrogesterone or vaginal micronized progesterone in 2 subsequent cyclesWith micronized progesterone With dydrogesterone
Endometrial biopsy on day 21 after micronized progesterone: coiled glands with active secretion and minimal residual vacuoles, stromal edema and absence of mitotic activity. The maturation corresponds to day 6 of the luteal phase (HES, 200x).
Endometrial biopsy on day 21 after dydrogesterone: small glands with minimal coiling and persistent homogeneous subnuclear vacuoles and pseudostratified nuclei, no stromal edema, and focal mitotic activity. The maturation corresponds to day 2-3 of the luteal phase (HES, 200x).
Continued →
Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
Vaginal micronized progesterone: more effective than oral dydrogesterone in creating 'in-phase' secretory endometrium continued →
Fatemi HM, et al. Hum Reprod. 2007 May;22(5):1260-3. Epub 2007 Jan 16.
Endocrine profile on day 21 Oral DG
Vaginal P
P value
Mean P, µg/L
0.3 8.6 0.013
Mean LH, IU/L
22.5 12.9 0.049
Mean FSH, IU/L
23.9 13.0 0.047
1 2 3 4 5 60
2
4
6
8
2 2
6
3
4
2
7 7
3
5
6
5
Endometrial histological dating in the luteal phase for each patient
(biopsy on day 21)
Oral dydrogesteroneVaginal micronized progesterone
Patients
19Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
Vaginal micronized progesterone for luteal phase support after assisted reproductionPooled results of 13 major randomized controlled studies
*Most frequent daily dosage: 600
mg
Smitz J, et al. Hum Reprod. 1992 Feb;7(2):168-75. Mochtar MH, et al. Hum Reprod. 1996 Aug;11(8):1602-5. Chillik C, et al. Assisted Reprod Rev 1997; 7: 29:33. Friedler S, et al. Hum Reprod. 1999 Aug;14(8):1944-8. Lightman A, et al. Hum Reprod. 1999 Oct;14(10):2596-9. Williams SC, et al. Fertil Steril. 2001 Dec;76(6):1140-3. Ludwig M, et al. Eur J Obstet Gynecol Reprod Biol. 2002 Jun 10;103(1):48-52. Gorkemli H, et al. Gynecol Obstet Invest. 2004;58(3):140-4. Kleinstein J; Luteal Phase Study Group. Fertil Steril. 2005 Jun;83(6):1641-9. Fatemi HM, et al. Hum Reprod. 2006 Oct;21(10):2628-32. Simunic V, et al. Fertil Steril. 2007 Jan;87(1):83-7. Geber S, et al. Reprod Biomed Online. 2007 Feb;14(2):155-8. Lam PM, et al. Gynecol Endocrinol. 2008;24(12):674-80.
Clinical pregnancy rate/transfer
Ongoing pregnancy rate/transfer
0
10
20
3030
22.7
Pregnancy rate, %, with micronized proges-terone* as luteal phase support (n=1730 pa-
tients)
20Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
0.2
0.6
1
1.4
0.91 0.940000000000001
0.54
Risk (OR, 95% CI) with vaginal progesterone vs intramuscular progesterone
Vaginal route preferred
oEasieroLess painfuloLess time-consumingoLess discomfort
Luteal phase support: comparable outcomes with vaginal and intramuscular progesterone; vaginal route preferred
Meta-analysis of RCTs on progesterone luteal support in IVF cycles (1982-2008)
Zarutskie PW, Phillips JA. Fertil Steril. 2009 Jul;92(1):163-9.
21Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
For IUI cycles: luteal phase support improves pregnancy outcomes Study 71 Infertility patients undergoing intrauterine insemination
supported with vaginal progesterone once daily from day after insemination for 14 days (n=132 cycles) or not supported (n=126 cycles)
Results
Maher MA. Eur J Obstet Gynecol Reprod Biol. 2011 Jul;157(1):57-62. Epub 2011 Apr 21.Clinica
l pregn
ancy
/pati
ent
Clinica
l pregn
ancy
/cycle
Live birt
h/pati
ent
Livebirt
h/cycle
020406080
54.9
29.5 35.2
9.8
35.219.8 18.9
5.5
Supported cycles Unsupported cycles
P=0.016
P=0.07
P=0.001
P=0.001
22Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
Luteal phase supportConclusions 1 Micronised progesterone is the
standard of care for LPS.Tavaniotou A, et al. Hum Reprod Update 2000 Mar-Apr;6(2):139-48. Daya S, Gunby JL. Cochrane Database Syst Rev. 2008 Jul;(3):CD004830.
2 The vaginal route of administration of natural micronised progesterone is the treatment of choice for LPS.Smitz J et al. Hum Reprod 1993 Jan; 8(1):40-5. Pritts EA, Atwook AK. Hum Reprod 2002 Sep;17(9):2287-99. Propst AM et al. Fertil Steril 2001 Dec;76(6):1144-9.
23Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
Recurrent early pregnancy lossPart 3
24Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
Maintenance of early pregnancy
Implanted embryo (~14 days after conception)
and the processes necessary for
maintenance of an early pregnancy.
VEGF vascular endothelial growth factor
hCG human chorionic gonadotropin
Norwitz ER, et al. N Engl J Med. 2001 Nov 8;345(19):1400-8.
25Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
Recurrent first trimester abortion: due to luteal phase defect, treated successfully with progesteroneStudy Progesterone profiles in women with luteal phase defect vs women
with normal cyclesResults 1988
1 Women with normal cycles vs women with LPD
More progesterone production in luteal phase (discriminatory level of serum P: ≤21 nmol/L*)
2 Women with recurrent abortion
Incidence of LPD: 40%Successful pregnancies after treatment with P: 81%
*Provides a diagnostic test with 70% sensitivity and 71% specificity.
Daya S, et al. Am J Obstet Gynecol. 1988 Feb;158(2):225-32.
26Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
Threatened abortion: vaginal micronized progesterone improves uteroplacental circulationStudy 53 Patients with threatened abortion and a living embryo treated with 300 mg
micronized vaginal progesterone or 30 mg oral dydrogesterone daily for 6 weeks
Blood flow indices in the spiral arteries with micronized vaginal progesterone use
Blood flow indices in the spiral arteries with dydrogesterone use
Czajkowski K, et al. Fertil Steril. 2007 Mar;87(3):613-8. Epub 2006 Nov 27.
02468
0.86 0.78 0.722.2 1.73 1.44
7.6
4.9
3.02
Resistance index Pulsatile indexSystolic/diastolic ratio
02468
0.75 0.81 0.772.09 2.48
1.65
5.6 5.34.05
Resistance index Pulsatile index Systolic/diastolic ratio
P = 0.009
P = 0.0059
P = 0.007
NS
27Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
Progestogen reduced miscarriage rates in women with recurrent miscarriages
Study Meta-analysis of 15 trials involving 2118 women
Results 2008
Haas DM, Ramsey PS. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD003511.
00.40.81.2
0.98 0.38
Risk (Peto OR, 95% CI) of miscarriage with progestogen treatment vs placebo/no treat-
ment
28Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
PROgesterone in recurrent MIScarriagEs (PROMISE) studyStudy Randomized, double-blind, placebo-controlled multi-
centre trial on first trimester progesterone therapy in women with a history of unexplained recurrent miscarriages
Principal objective
Progesterone, 400 mg pessaries twice daily, started soon as possible after a positive pregnancy test (and no later than 6 weeks gestation) and continued to 12 weeks of gestation, compared to placebo, to increase live births beyond 24 completed weeks by at least 10%
Status On-going; anticipated end date: 01/05/2012http://www.imperial.ac.uk/
29Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
Preterm birthPart 4
30Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
Preterm delivery, defined as birth before 37 completed weeks of gestation, is the leading cause of perinatal morbidity and mortality.
Arisoy R, Yayla M. J Pregnancy. 2012;2012:201628. Epub 2012 Feb 22.
31Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
Role of physiological progesteroneMaintains pregnancy
1 Modulates maternal immune responsesDruckmann R, et al. J Steroid Biochem Mol Biol. 200 Dec;97(5):389-96 4. Szekeres-Bartho J, et al. Int Immunopharmacol. 2001 Jun;1(6):1037-48.
2 Reduces uterine contractilityFanchin R, et al. Hum Reprod. 2000 Jun;15 Suppl 1:90-100. Perusquía M, et al. Life Sci. 2001 May 18;68(26):2933-44. Chanrachakul B, et al. Am J Obstet Gynecol. 2005 Feb;192(2):458-63.
3 Improves utero-placental circulationLiu J,et al. Mol Hum Reprod. 2007 Dec;13(12):869-74 9. Czajkowski K, et al. Fertil Steril. 2007 Mar;87(3):613-8.
4 Suppresses fetal inflammatory responseSchwartz N, et al. Am J Obstet Gynecol. 2009 Aug 201(2): 211.e1-9.
32Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
History of spontaneous preterm delivery
Preterm birth
33Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
Progesterone beneficial for prevention of preterm delivery in high-risk women Review 4 RCTs involving 1462 high-risk women
Rossi AC, D’Addaro V. Anatol J Obstet Gynecol. 2009;2:1.
Preterm
delivery
Birthweigh
t <1500 g
Neonatal death
01020304050
34
102
42
17
4
Treatment outcome, %
Progesterone Controls
Preterm
delivery
Birthweigh
t <1500 g
Neonatal death
00.20.40.60.8
11.2
0.49 0.600000000000001 0.5
Treatment outcome (OR, 95% CI) with progesterone vs con-
trols P=0.01
P=0.02
P=0.04
34Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
Micronized progesterone prevents preterm delivery
da Fonseca EB, et al. Am J Obstet Gynecol. 2003 Feb;188(2):419-24. Fonseca EB, et al. Fetal Medicine Foundation Second Trimester Screening Group. N Engl J Med. 2007 Aug 2;357(5):462-9. Rai P, et al. Int J Gynaecol Obstet. 2009 Jan;104(1):40-3. Majhi P, et al. J Obstet Gynaecol. 2009 Aug;29(6):493-8. Cetingoz E, et al. Arch Gynecol Obstet. 2011 Mar;283(3):423-9.
Fonseca EB, et al. 2003
Fonseca EB, et al. 2007
Raj P, et al. 2009 Majhi P, et al. 2009 Cetingoz E, et al. 2011
0102030405060
2.8
19.2
29.7
48.8
18.6
34.4
50
6
24.3
Preterm delivery <34 weeks in major randomized controlled studiesProgesterone Placebo
Fonseca EB, et al. 2003
Fonseca EB, et al. 2007
Raj P, et al. 2009 Majhi P, et al. 2009 Cetingoz E, et al. 2011
010203040506070
13.8
39.2
12
4028.5
59.5
38
57.2
Preterm delivery <37 weeks in major randomized controlled studies
Progesterone Placebo
NS
P=0.002
P=0.002
P=0.001
P=0.64P=0.01
P=0.03
P=0.002
P=0.0027
P=0.036
35Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
Micronized progesterone prevent preterm deliveryPooled results
5 Major RCTs with
micronized progesterone
in preterm delivery
da Fonseca EB, et al. Am J Obstet Gynecol. 2003 Feb;188(2):419-24. Fonseca EB, et al. Fetal Medicine Foundation Second Trimester Screening Group. N Engl J Med. 2007 Aug 2;357(5):462-9. Rai P, et al. Int J Gynaecol Obstet. 2009 Jan;104(1):40-3. Majhi P, et al. J Obstet Gynaecol. 2009 Aug;29(6):493-8. Cetingoz E, et al. Arch Gynecol Obstet. 2011 Mar;283(3):423-9.
Preterm delivery <34 weeks Preterm delivery <37 weeks05
1015202530354045
14.71
33.3329.56
40.91
Preterm delivery, %, with micronized progesterone use vs placebo
Micronized progesterone Placebo
36Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
PREDICT study: vaginal progesterone did not prevent preterm delivery in twin pregnanciesStudy 677 Women with twin pregnancies treated daily with progesterone
pessaries or placebo pessaries starting from 20-24 weeks until 34 weeks’ gestation (from 17 centers in Denmark and Austria)
Rode L, et al; PREDICT Group. Ultrasound Obstet Gynecol. 2011 Sep;38(3):272-80. Progesterone Placebo0
5
10
15
20
25
30
15.318.5
Incidence of delivery before 34 weeks, %
At 6 months At 18 months150
170
190
210
230
250
215
193
218
194
Mean Ages and Stages Ques-tionnaire (ASQ) scores of infants
Placebo Progesterone
OR 0.8, 95% CI 0.5-1.2Pooled OR 1.06, 95% CI 0.86-1.31P=0.45
P=0.89
37Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
Preterm labor Preterm birth
38Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
Progesterone Control0
10
20
30
40
50
36.1
24.5
Mean latency until delivery, days
P = 0.037
Progesterone Control0
10
20
30
40
50
36.7 34.5
Gestational age at delivery, weeks
Vaginal progesterone after successful parenteral tocolysis associated with longer latency preceding delivery
Study 70 Women with threatened preterm labor randomized, after arrest of uterine activity, to receive progesterone suppository 400 mg daily until delivery or no treatment
Continued →
P = 0.041
Progesterone Control1000
1500
2000
2500
3000
3500
3101.54
2609.39
Birthweight according to treatment, g
P = 0.002
39Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
Vaginal progesterone after successful parenteral tocolysis associated with longer latency preceding delivery cont’d
Borna S, Sahabi N. Aust N Z J Obstet Gynaecol. 2008 Feb;48(1):58-63.
Respira
tory
distre
ss sy
ndrome
Low birt
hweight
Recurre
nt pre
term la
bor
Admission to
intensiv
e care
unit
Neonatal sepsis
0
20
40
60
10.8
2735.1
24.3
5.4
36.451.5 57.6
39.4
18.2
Prevalence, %, of complications of preterm labor
Progesterone Control
P = 0.021 P = 0.205
P = 0.136
P = 0.002P = 0.092
40Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
Asymptomatic sonographically short cervix at midtrimester
Preterm birth
41Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
Midtrimester cervical length <25 mm predict preterm birth in high-risk womenStudy 153 Women with prior spontaneous preterm birth 17(0)-34(6/7) weeks
screened by transvaginal sonography for cervical length; 153 had CL <25 mm and 672 had CL ≥25 mm
Results Relationship
between cervical
length groups and
birth <35 weeks
Owen J, et al; Vaginal Ultrasound Trial Consortium. Am J Obstet Gynecol. 2010 Oct;203(4):393.e1-5.
42Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
In women with short cervix, vaginal progesterone treatment reduces risk of preterm birth Study Cervical length measured by transvaginal ultrasonography at 20 to 25
weeks of gestation in 14,620 pregnant women413 (1.7%) had cervical length ≤15 mm: treated with progesterone vaginal capsule 200 mg each night or placebo from 24 to 34 weeks
Continued →
Spontaneous de-livery <34
weeks
Birth weight <2500 g
Birth weight <1500 g
Neonatal morbidity
Neonatal death 0
0.4
0.8
1.2
1.6
0.56
0.960.68 0.59
0.34
Risk of maternal and perinatal outcomes (RR, 95% CI) with vaginal progesterone use vs placebo
P=0.007 P=0.81 P=0.20 P=0.17P=0.13
43Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
In women with short cervix, vaginal progesterone treatment reduces risk of preterm birth continued →
Kaplan–Meier plot of the probability of continued
pregnancy without delivery among patients receiving
vaginal progesterone as compared with placebo
Fonseca EB, et al. Fetal Medicine Foundation Second Trimester Screening Group. N Engl J Med. 2007 Aug 2;357(5):462-9.
Cumulative percentage of continued pregnancies
44Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
Vaginal progesterone in asymptomatic women with sonographic short cervix reduces risk of preterm birth and neonatal morbidityMeta-analysis (2011): 5 Trials of high quality with 775 women and 827 infants
Romero R, et a. Am J Obstet Gynecol. 2012 Feb;206(2):124.e1-124.e19. Epub 2011 Dec 11.
0.2
0.4
0.6
0.8
1
0.50.58
0.69
0.48
0.57 0.545
0.75
0.66
Effects (RR, 95% CI) of vaginal progesterone in asymptomatic women with sonographic short cervix (≤25 mm) in midtrimester
Preterm birth <28 wk
Preterm birth <33 wk
Preterm birth <35 wk
Respiratory distress
syndrome
Composite neonatal
morbidity/ mortality
Birthweight <1500 g
Admission to NICU
Requirement for
mechanical ventilation
45Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
‘Universal cervical-length screening and vaginal progesterone prevents early preterm births, reduces neonatal morbidity and is cost saving: doing nothing is no longer an option.’Campbell S. Ultrasound Obstet Gynecol. 2011 Jul;38(1):1-9. doi: 10.1002/uog.9073.
46Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
Prevention of preterm birthReview
Level A evidence
da Fonseca EB, et al. Semin Perinatol. 2009 Oct;33(5):334-7. Romero R, et a. Am J Obstet Gynecol. 2012 Feb;206(2):124.e1-124.e19. Epub 2011 Dec 11. Borna S, Sahabi N. Aust N Z J Obstet Gynaecol. 2008 Feb;48(1):58-63.
47Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
ConclusionsPart 5
48Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth
Utrogestan: indications and dosages 1 Luteal phase
defect/supportIVF cycles: 400 mg to 600 mg/day in 2 or 3 divided doses from hCG injection until 12th week of pregnancyCOH-IUI: 200 mg at bedtime daily for 14 days or until 12th weeks of pregnancy
2 Recurrent early pregnancy loss
200 mg to 400 mg until 12th week of pregnancy800 mg/day (PROMISE study)
3 History of preterm birth 200 mg/day from 24 weeks to 34 weeks of pregnancy
4 Preterm labor During tocolysis: 400 mg every 6-8 hoursMaintenance phase: 200 mg 3x daily until 36th week of pregnancy
5 Asymptomatic sono-graphically short cervix
200 mg/day from 24 weeks to 34 weeks of pregnancy
Based on current review and modified from www.besins-healthcare.com.