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SOLO

2016

RATIONALE FOR THE USE OF


PROGESTERONE IN PREGNANCY
G.C. DI RENZO, MD, PhD, FRCOG(hon) FACOG (hon) FICOG (hon)
Dept of Obstetrics and Gynecology & Centre of Perinatal and Reproductive Medicine,
University of Perugia, Perugia Italy
Utilisation in
therapy
amenorrhoea
dysfunctional uterine bleeding
premenstrual syndrome
endometrial hyperplasia
contraceptive (alone or in combination with an oestrogen)
hormonal support in luteal phase deficiency, both in AR
and in pregnancy maintenance
recurrent miscarriage
preterm labour
(Di Renzo et al., 2001).
The multiple physiological roles of progesterone, together with its
pharmacokinetics and pharmacodynamics, have been
extensively studied throughout the years.

Since 1935 progesterone has been synthesised and later on


become available on the market; during the following years its
use become common in clinical practice.

Hovewer, the use of progesterone in the pathophysiology of


pregnancy remains arguable for various reasons.
Reasons
few randomised controlled trials, with
different dosages and populations.

another important issue concerning


progesterone is the route in which the
hormone is administered. As a
consequence, there have been restrictions
in the therapeutic application of
progesterone in the prevention and
treatment of threatened miscarriage,
recurrent miscarriage and preterm birth.
PROGESTERONE ROLE IN MAINTAINING PREGNANCY
Progesterone: Role is Pregnancy From luteal phase support to preterm labor

Progesterone: Maintains pregnancy


1 Modulates maternal immune response
Druckmann R, et al. J Steroid Biochem Mol Biol. 2000
Szekeres-Bartho J, et al. Int Immunopharmacol. 2001
Di Renzo GC, et al. Gynec Endocrinol. 2012
2 Suppresses inflammatory response
Schwartz N, et al. Am J Obstet Gynecol. 2009

3 Reduces uterine contractility


Fanchin R, et al. Hum Reprod. 2000
Perusqua M, et al. Life Sci. 2001
Chanrachakul B, et al. Am J Obstet Gynecol. 2005

4 Improves utero-placental circulation


Liu J,et al. Mol Hum Reprod. 2007
Czajkowski K, et al. Fertil Steril. 2007
Changes in contractility in control and
P4-treated tissues

Ruddock NK et al Am J Obstet & Gynecol 2008


PROGESTERONE
&
RECURRENT
MISCARRIAGE
Evidence of Progesterone Efficacy
Removal of the corpus luteum during
pregnancy Abortion

Luteal phase insufficiency

Assisted reproductive technologies


experience with progesterone

RU 486 or Mifepristone (anti-


progesterone) for pregnancy termination
Progesterone level to predict miscarriage?

Qureshi NS., et al. Maturitas 2009;65S:S35-41


Lin YS., Liu CH. Int J Gynecol Obstet 1995;51:33-8
Miscarriage rates comparing natural progesterone versus no treatment

Study Type of Progesterone Treatment Control Odds ratio 95%CI


study formulation n (%) n (%)

Gerhard et al, RCT Suppository 3/26 (12) 5/26 (19) 0.54 0.07 3.25
1987

Nyboe RCT Pellet inserted 18/153 (12) 22/150 0.78 0.37 1.59
Anderson et into gluteal (15)
al, 2002 muscle

Swyer and RCT Suppository 11/60 (18) 13/53 (25) 0.69 0.25 1.88
Daley, 1953

Vignali and Clinical trial Cream 3/19 (16) 3/15 (20) 0.75 0.09 6.68
Centinalo,
2000

Clifford et al, RCT Suppository 4/20 (20) 7/26 (27) 0.68 0.12 3.29
1996
Progestogen
treatment reduces PI
and S/D of uterine
artery in threatened
miscarriage

Threatened miscarriage cases were treated by micronized vaginal progesterone 300mg or


Dydrogesterone 3x10mg for 6 weeks. Follow up was done every 2 weeks
Czajkowski K., et al. Fertil Steril 2008
Meta-analysis of trials for Progestins

Coomarasamy BMJ 2011


Meta-analysis of Progestins trials

Coomarasamy BMJ 2011


In a subgroup analysis of three trials involving
women who had recurrent miscarriages
progestogen treatment showed a statistically
significant decrease in miscarriage rate
compared to placebo or no treatment
(OR 0.38; 95% CI 0.20 to 0.70).

Cochrane Database Syst Rev 2008


Cochranes 3 previous studies +
El Zibdehs study on P4

The ORs were consistently in favor of


progestational therapy.
For every 5 women given progestin
treatment, there was 1 extra successful
outcome vs. no treatment.

Daya Maturitas 2009


47 cases
age 28-45
mean 37
previous abortion >2
APA 32%
ATA 33%
ANA 28%
AOA 2%
NK cells 40%
CD4/CD8 15%
Di Renzo, 2003
Successful treatment of immunologic abortion
with progesterone (high doses)
47
36 treated 11 controls

24 pregnants 7 pregnants

22 term pregnancies 7 no term pregnancies


Di Renzo et al., 2003
Women with
Delivery Abortion
2 abortions

No therapy (n=5) 2 (40%) 3 (60%)


Autoimmunity
Negative (n=10) ASA 100 mg/die (n=5) 5 (100%) 0

Autoimmunity
ASA 100 mg/die and
Positive (n=30) 28 (93%) 2 (7%)
Progesterone (n=30)

Women with No therapy (n=6)


3 (50%) 3 (50%)
>2 abortions

Autoimmunity ASA 100 mg/die (21) 18 (85%) 3 (15%)


Negative (n=27)

Autoimmunity ASA 100 mg/die and


Progesterone (n=34) 29 (85%) 5 (15%)
Positive (n=34)
The PROMISE trial (UK)
Principal objective:
Progesterone supplementation (Utrogestan 400 mg bid)
started between a positive pregnancy test and no later
than 6 weeks and continued until 12 weeks in women with
unexplained recurrent miscarriage increases the live birth
rate by at least 10% compared with placebo
Trial design
Randomised, double-blind, placebo controlled
Setting
8 centres (6 England; 1 Scotland; 1 Holland)

Number of participants
790
PROMISE trial results: safety outcomes

Coomarasamy A et al. N Engl J Med 2015;373:2141-2148


PROMISE trial results: by geographical location
Principal Outcome: No increase in live birth rate after
24 weeks by at least 10% compared with treatment
group vs placebo.

65.8% in P4 group versus 63.3% in placebo group (RR=1.04;


95%CI, 0.94 -1.15): absolute rate difference of 2.5%
points (NS) favouring P4.
In a post hoc analysis, by geographical location, 67.9% in P4
group versus 63.5% in placebo group (RR=1.07; 95%CI, 0.96
-1.20): absolute rate difference of 4.4 % points (NS)
favouring P4.

Coomarasamy A et al. N Engl J Med 2015;373:2141-2148


Limitations
Main limitation of the study:
Progesterone treatment was initiated only after urinary pregnancy test was confirmed, and
thus this study result cannot address, as the authors mention, whether progesterone
supplementation should be more effective in reducing the risk of miscarriage if
administered during the luteal phase of the cycle, BEFORE confirmation of pregnancy.

This is the first well designed Randomized Controlled trial with live birth rate as primary
outcome in this indication
(different from relative risk of miscarriage outcome in previous studies with progesterone 1
or dydrogesterone 2 ).
1 Haas DM, Ramsey PS. Progestogen for preventing miscarriage. Cochrane Database Syst Rev 2013; 10: CD003511.
2 Kumar A, Begum N, Prasad S, Aggarwal S, Sharma S. Oral dydrogesterone treatment during early pregnancy to
prevent recurrent pregnancy loss and its role in modulation of cytokine production: a double-blind, randomized,
parallel, placebo-controlled trial. Fertil Steril 2014;102(5): 1357.e3 1363.e3.
Limitations
Can we make a conclusion that progesterone doesnt
increase live birth rate in TM? NO

The results from PROMISE trial cannot be extrapolated to


the potential effectiveness of vaginal progesterone
treatment in threatened miscarriage (TM) which occurs in
up to 15% of pregnancies, (R Rai, Lancet 2006).

RM and TM are medical conditions with different


etiopathology. Recurrent miscarriage occurs in only 1% of
pregnancies with a broader multi-factorial etiopathology.
Limitations

Will there be any further study of Progesterone


treatment effect on TM? YES

The efficacy of vaginal progesterone capsules in


Threatened Miscarriage associated with
unexplained bleeding and pain in the early
pregnancy (N>4000) are investigated in the on-
going PRISM study
Results are expected in 2018.
SUMMARY
Natural micronized Progesterone has a role in
the prevention of RPL
Best way of administration seems to be the
vaginal route

Suggested dosage: 200-400 mg day from


conception or positive test to be continued until
20 wks.
If LPD increase to 600 mg/day
If patient at high risk of PTB continue up to 35
wks
SUMMARY

In the cases of RPL: To diagnose APS


LA and ACA positivity, 6-8 wks intervals.
If positive, give LWMH + Aspirin next pregnancy.

Neither Leucocyte immunization nor IVIG do


apply for a treatment in cases with RPL.

Use of LWMH and /or aspirin in prevention of RPL


in hereditary thrombophilia, apart from APS,
is recommended but not substantiated.
Correct the immune deficiency

Corticosteroids:
5 ~ 20mg / day orally.
Aspirin :
75mg / day orally.
Heparin:
Low molecular weight heparin 2-4000 IU / day,
subcutaneous injection.
PRETERM BIRTH
Preterm parturition syndrome
(following the key features of these syndromes)

1. multiple etiologies are implicated in the pathophysiology such as intrauterine


infection/inflammation, uterine ischemia, uterine over-distension, cervical
disease, endocrine disorders, abnormal allogenic recognition, allergy-like
reaction
2. the pathologic condition of short cervix leading to this disorder is chronic
in nature
3. fetal involvement has been demonstrated in patients with microbial invasion
of the amniotic cavity
4. the inclination to use a mechanism of host defense may be determined by
gene-environmental interaction
5. the adaptive nature of the clinical manifestation has been proposed in
case of microbial invasion of the amniotic cavity, in which the onset of preterm
labour and delivery can be considered as a mechanism of defense against
intrauterine infection
The Preterm Parturition Syndrome

Uterine Cervical Progesterone


Over distension Disease Deficiency

Abnormal
Stress-
Allogenic
Nutrition
Recognition

Vascular Allergy

Infection Unknown

Romero R, Chaiworapongsa T, Yoon BH, Mazor M, Kusanovic JP, Gotsch F, Hassan SS


PREVENTION
PREVENTION:
IN WHICH CASES?
Strategy in the prevention

Identification of risk factors


Prior history of preterm birth
1-No prior history of PTB
Twin pregnancy
2-Prior history of early PTB
3-Twins in the current
Short cervix at scanpregnancy
Short cervix at scan
UTERO-CERVICAL ANGLE

ACUTE OBTUSE
WHICH TOOLS?
Strategy in the prevention
Progesterone in women with
previous preterm birth
Main results
36 RCTs included 8523 women
12515 infants

Progesterone vs placebo for women with a past history of


spontaneous PTB
Perinatal mortality 6 studies N =1453 RR 0.50 [95% CI 0.33 to 0.75)]
Preterm birth < 34 weeks 5 studies N = 602 RR 0.31 [95% CI 0.14 to 0.69)]

Preterm birth < 37 weeks 10 studies N =1750 RR 0.55 [95% CI 0.42 to 0.74)]

Infant birth weight < 2500 g 4 studies N = 692 RR 0.58 [95% CI 0.42 to 0.79)]

Use of assisted ventilation 3 studies N = 633 RR 0.40 [95% CI 0.18 to 0.90)]


Necrotizing enterocolitis 3 studies N =1170 RR 0.30 [95% CI 0.10 to 0.89)]
Neonatal death 6 studies N =1453 RR 0.45 [95% CI 0.27 to 0.76)]
Admission to NICU 3 studies N = 389 RR 0.24 [95% CI 0.14 to 0.40)]
Statistically significant reduction
1 study N= 148 MD** 4.47 [95% CI 2.15 to 6.79)].
Statistically significant increase in pregnancy prolongation weeks

No differential effects in terms of route of administration, time of therapy initiation and dose of
progesterone for majority of outcomes examined.
Vaginal progesterone for the
prevention of recurrent preterm birth

More effective than intramuscular


progestogen therapy

Less adverse effects

Maher MA, Abdelaziz A, Ellaithy M, Bazeed MF. Acta Obstet Gynecol Scand. 2013;92:215-22.
Progesterone in women with
a short cervix
Romero R, Nicolaides K, Conde-Agudelo A, Tabor A, O'Brien JM, Cetingoz E, Da Fonseca E, Creasy GW, Klein
K, Rode L, Soma-Pillay P, Fusey S, Cam C, Alfirevic Z, Hassan SS; Am J Obstet Gynecol. Feb 2012
Primary Outcome

42% reduction in the rate of


preterm birth <33 weeks

Romero R, Nicolaides K, Conde-Agudelo A, Tabor A, OBrien J, Cetingoz E, DA Fonseca E,


Creasy G, Klein K, Rode L, Soma-Pillay P, Fusey S, Cam C, Alfirevic Z, Hassan S. Am J Obstet Gynecol 2011;12:003
Progesterone reduced the
rate of Respiratory Distress
Syndrome by 61%

placebo 7.6% vs. progesterone 3% vs. p=0.03

Hassan SS, Romero R, Vidyadhari D, et al. Ultrasound Obstet Gynecol. 2011 Jul;38(1):18-31
Is Synthetic Injectable Progesterone
effective for the treatment of a short cervix?

NOT EFFECTIVE FOR


THE TREATMENT
OF A SHORT CERVIX
www.makena.com/

www.google.images.com

Grobman WA et al. Am J Obstet Gynecol. 2012 Nov;207(5):390.e1-8


Cost-Effectiveness Analysis

Am J Obstet Gynecol Vol. 208 No. 1 January, 2013 p. S66 - Supplement

Werner EF et al., Ultrasound Obstet Gynecol. 2011 Jul;38(1):32-7


Should all women be
screened with transvaginal
ultrasound for cervical
length?
Am J Obstet Gynecol 2012 Feb; 206(2):101-3
World Health Organization
10 Principles for Good Screening Test
1. Condition = Important Health Problem

2. Available Treatment

3. Facilities Available for Diagnosis

4. Recognizable Latent Phase

5. Suitable Test or Examination

6. Test Acceptable to Population

7. Natural history of disease adequately understood

8. Policy for treatment

9. Cost of case-finding economically balanced with care

10. Case-finding should be continuing process


Wilson JMG, Jungner G. World Health Organization 1968
Coombs, AC. Am J Obstet Gynecol 2012 Feb; 206(2):101-3
International Federation of Gynecology and Obstetrics
International Federation of Gynecology and Obstetrics
Working Group on Best Practice in Maternal-Fetal Medicine

Chair: G C Di Renzo Expert members ex officio:


S Arulkumaran, FIGO
Expert members: M Hod, EAPM
E Fonseca, Brasil C Hanson, SM Committee
S Hassan, USA L Cabero, CBET Committee
M Kurtser, Russia Y Ville, ISUOG
S Nambiar, Malaysia M Hanson, DOHaD
K Nicolaides, UK V Berghella, SMFM
N Malhotra, India PP Mastroiacovo, Clearinghouse
N Sierra, Mexico JL Simpson, March of Dimes
H Yang, China D Bloomer, GLOWM
FIGO BEST PRACTICE REPORT

Gian Carlo Di Renzo (Chair), E Fonseca, S Hassan, M Kurtzer, M Leis,


N Malhotra, K Nicolaides, H Yang, S Arulkumaran (FIGO President),
Pmastroiacovo, M Hod, Y Ville, L Cabero, C Hanson, J Simpson

International Journal of Gynecology and Obstetrics: 128(2015)80-82


Challenges in preterm birth
prevention and management

Strategy in the prevention

FIGO recommendations regarding the use of TVS CxL and


vaginal progesterone for the prevention of PTB

International Journal of Gynecology and Obstetrics xxx (2014) xxxxxx


Cervical length and progesterone
for the prevention of preterm birth
Sonographic Cervical length screening in all women 19 23 6/7
weeks using transvaginal ultrasound

Women with a cervical length < 25 mm should be treated with


daily vaginal progesterone for the prevention of preterm birth and
neonatal morbidity

Progesterone formulation 200 mg or 90 mg daily

Universal cervical length screening and vaginal progesterone is a


cost-effective model for the prevention of preterm birth

In cases in which transvaginal ultrasound is not available, other


methods to assess cervical length can be considered
International Journal of Gynecology and Obstetrics: 128(2015)80-82
Metanalysis: short cervix &
vaginal natural progesterone

Vaginal
Relative risk (fixed) progesterone Placebo Weight Relative risk
Study (95% CI) n/N n/N (%) (95% CI)

Fonseca 2007 23/114 39/112 30.4 0.58 (0.37-0.90)

O'Brien 2007 4/12 6/19 3.6 1.06 (0.37-2.98)

Hassan 2011 26/235 43/223 34.1 0.57 (0.37-0.90)

Cetingoz 2011 1/4 1/4 0.8 1.00 (0.09-11.03)

OPPTIMUM 2016 33/133 38/118 31.1 0.77 (0.52-1.14)

Combined 87/498 127/476 100.0 0.66 (0.52-0.83)

0.1 0.2 0.3 0.5 1 2 3 5 10 Test for heterogeneity: I2 = 0%


Favors vaginal progesterone Favors placebo Test for overall effect: Z = 3.44, P = 0.0006
European Association of Perinatal Medicine
Study Group on Preterm birth

REVISION 2016

Guidelines for the management


of spontaneous preterm labour

J Perinat Med 2006 57


J Mat Fet Neon Med 2011

57
EAPM study group members

Di Renzo, Gian Carlo Italy (Chair)


Houbinont, Corinne Belgium
Radzinsky, Victor Russia
Wielgos, Miroslaw Poland
Visser, Gerry The Netherlands
Cabero, Luis Spain ( co-Chair)
Facchinetti, Fabio Italy
Helmer, Hanns Austria
Papantoniou, Nikolas Greece
Mikhailov, Anton Russia
Jacobsson, Bo Sweden
Shennan, Andrew UK
Stener Jorgensten, Jan Denmark
Preventive tools
Asymptomatic women with a sonographically short cervix
(25 mm) regardless of obstetrical history should be offered
vaginal progesterone treatment for the prevention of
preterm birth and neonatal morbidity. Two forms of vaginal
micronized progesterone can be used daily: 200 mg vaginal
soft capsules or 90 mg vaginal gel .
Women with prior history of PTB or late second trimester
abortion should be offered 17 OHP-C weekly injection starting
early in the 2nd trimester or vaginal progesterone based on
individual benefits/risks evaluation with the patient
60
Comparison of Strategies used for
Screening in Medicine
Test Number needed to screen

Pap Smear for Cervical Cancer1 1140

Mammography more than 50 years1 543

Mammography between 40 and 49 years1 3125

Prostate-specific Antigen for Prostate Cancer2 1254

Ultrasound cervical length to prevent one case


357
of PTB < 33 weeks (<25 mm)3
Ultrasound cervical length to prevent one case
218
of neonatal morbidity/mortality (<25 mm)3

1. Gates TJ, et al. Am Fam Physician 2001;63:513-22


2. Loeb S, et al. J Clin Oncol 29:464-467
Romero R, Conde A, Number needed to screen 3. Romero R, Conde-Agudelo A, unpublished.
Comparison with other Interventions in
Perinatal Medicine/Obstetrics

Intervention To prevent: RR (95% CI) NNT (95% CI)

Magnesium sulfate Eclampsia 0.41 (0.29-0.58) 100 (50-100)

Magnesium sulfate Cerebral palsy 0.69 (0.55-0.88) 52 (31-154)

RDS 0.66 (0.59-0.73) 11 (9-14)


Antenatal
corticosteroids
Neonatal death 0.69 (0.58-0.81) 22 (16-36)

Preterm birth <33


0.55 (0.33-0.92) 11 (8-87)
Vaginal progesterone in weeks
short cervix
RDS 0.39 (0.17-0.92) 22 (12-186)

NNT: Number Needed to Treat


THE FUTURE?
A role for progesterone in human neurodevelopment

Progesterone prophylaxis for preterm birth

OPPTIMUM study: significant decrease in brain injury on ultrasound


scan.
Norman (2016) Lancet

Estradiol + progesterone replacement in extremely preterm infants


(outcomes at 5 years)

Trends toward improved bone mineral accretion.


Reduced incidence of chronic lung disease.

Modestly improved neurological outcomes.

Trotter (2012) J Clin Endocrinol Metab 97, 1041


Pilot studies aimed at replacing missing progesterone
and estradiol in 61 extremely preterm infants
Placebo Progesterone
(Kaufman assessment)
Cognitive functions

Duration of treatment (days)

Significant time-response relationships


for cerebral palsy, spasticity, ametropia
Trotter (2012) J Clin Endocrinol Metab 97, 1041
CONCLUSIONS
Progesterone/
Vaginal
Cerclage/ Best
Progesterone
Education/ Pessary (?)/ Practices
Counseling Others

Ultrasound Healthcare
Access to Implementation/ Systems/
care Markers Insurance
Ultrasound Coverage
The real voyage of discovery consists not in
seeking new landscapes, but in having new eyes.
Marcel Proust

Preventing adverse pregnancy outcome


with progesterone