PREVENTION OF PRETERM LABOUR - EVIDENCES FOR PROGESTERONE BY DR SHASHWAT JANI

1. Preventing PTL
Evidence Of Progesterone
Dr. Shashwat Jani
M. S. ( Obs – Gyn ), F.I.A.O.G.
Diploma in Advance Laparoscopy.
Consultant Assistant Professor,
Smt. N.H.L. Municipal Medical College.
Sheth V. S. General Hospital , Ahmedabad.
Mobile : +91 99099 44160.
E-mail : drshashwatjani@gmail.com

2. Safe Motherhood
Progesterone’s Role in safe motherhood
includes its use in -
 Luteal Phase Defect
 Recurrent Pregnancy Loss
 Preterm labour
 Multiple pregnancy and
 ART
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3. Major Causes of Preterm Birth
Norwitz ER,et al. Rev Obstet Gynecol. 2011 Summer;4(2):60-72.
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4. Previous preterm birth
• Strongest risk factor for future preterm delivery
• Data from McManemy et al:
– One preterm birth: 14-22 % risk.
– Two preterm births: 28 -42%
– Three or more: Up to 75%
A term birth decreases the risk of preterm birth in
subsequent pregnancies.
( Mc Manemy et al, 2007 )
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5. Mechanism of Action –
Progesterone in Prevention of PTL
At placenta,
Regulates timing of
labour via
controlling stress
hormone – CRH
In amniotic fluid,
Limits
prostaglandin
production
At Myometrium &
cervix,
Suppresses
inflammatory response
and myometrial
contractility
At fetal membrane,
Blocks pro-inflammatory
cytokines induced
apoptosis, preventing
PRROM
In patients at risk of PTL,
Progesterone Maintains uterine quiescence by acting at all 4 sites1
1. Norwitz E R et al, Rev Obstet Gynecol. 2011;4(2):60-72
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6. • Progesterone has an essential role in
maintaining pregnancy, primarily through
establishing uterine quiescence.
• This is achieved through suppression of
the calcium- calmodulin - myosin light chain
kinase system, reducing calcium flux and
altering the resting potential of smooth
muscle.
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7. Progesterone Levels
Normal Vs. Threatened prematurity
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8. Management of Preterm Labor
Betamethasone
Vaginal progesterone
Tocolysis for up to 48 hours.
GBS Chemoprophylaxis
Antibiotics for UTI
Magnesium sulfate for neuroprotection
– Between 24 and 32 weeks.
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9. Surfactant
Corticosteroids
Tocolysis
The Magic Bullet
Progesterone
3 levels of
Preventing
Preterm Labor
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10. Guidelines & Evidences–
PTL
1. Micronized Progesterone
2. Hydroxyprogesterone Caproate
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11. Guidelines –
Micronised Progesterone
Robust Evidences from
latest guidelines across globe
Western Australia guideline 2017
European Association of Perinatal Medicine 2017
French clinical practice guidelines 2016
FIGO 2015
ACOG 2012
SOGC 2008
StratOG by RCOG 2014
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12.  Route of administration:
 Initial studies of prophylactic use of injectable 17- OHPC suggested significant
reduction in the incidence of preterm labor.
 However down the years there has been a move away from parenteral to other
modes of administration ( vaginal and oral). Many studies using vaginal
progesterone have been published, however in our country most women are
reluctant to use intravaginal medications, more so in pregnancy.
 They are more comfortable with oral route of medication.
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13. • A review article by Chairperson Infertility
committee FOGSI found that Oral Natural
Micronized Progesterone Sustained Release (SR)
formulation represents a therapeutic advance in
this direction offering 'therapeutic compliance'
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14. Progesterone as an alternative to
cervical cerclage
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15. Rowe T, J Obstet Gynaecol Can 2014;36(4):291–2
Progesterone as an alternative to
cervical cerclage
StratOG: the RCOG’s online learning resource, 2014 endorses1
Use of Progesterone as an alternative to cervical cerclage in women with
previous preterm delivery or mid-trimester loss and a short cervix (<25mm) on
ultrasound at 20-37 weeks’ gestation
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16. Progesterone as an alternative to
cervical cerclage – An Indian experience
PREGNANCY OUTCOME IN SHORT CERVIX: PROGESTERONE VS
CERVICAL ENCERCLAGE
The present study was conducted to compare the outcome of pregnancy with short
cervix with natural micronized progesterone and cervical cerclage
A prospective, randomized comparative study - total of 50 cases of short cervix. Out
of 50 cases, 25 cases each were divided in two groups
Group A: Given natural micronized progesterone 200mg Cap BID /or 300mg SR OD
Group B: Underwent cerclage procedure.
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17. Progesterone as an alternative to
cervical cerclage – An Indian experience
Conclusion:
Natural Micronized Progesterone is as effective as cervical cerclage
in prevention of premature labour in a women with singleton
pregnancy with short cervix.
Use of NMP is more preferable in clinical practice because it is non-
invasive technique, easy to administer and the patients do not suffer
from surgical and anesthesia procedure related adverse effects such
as pain, headache, vomiting and other complications.
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18. Adjuvant Progesterone in patients
with Cervical Cerclage
• The Spontaneous PTB rate at <36 weeks in the adjuvant group was
significantly lower than in the non-adjuvant group (17% vs 51%, P < 0.05).
Adjuvant progesterone therapy was significantly associated with a
reduction in SPTB at <36 weeks (adjusted odds ratio, 0.12; 95% confidence
interval, 0.02-0.69, P < 0.05) even after adjusting for known covariates,
including a visible membrane size of ≥4 cm, gestational age, prior SPTB,
and use of amnioreduction.
• Conclusion: Adjuvant progesterone therapy
with physical-exam-indicated cervical cerclage
was associated with reductions in SPTB, low
birth weight, and neonatal intensive care unit
admission.
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J Obstet Gynaecol Res. 2016 Dec;42(12):1666-1672.28-Aug-18 18

19. 2018 Meta-analysis
Progesterone for prevention of PTL
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• 5 studies combined – Favors progesterone
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20. 2016 Meta-Analysis
including data from OPPTIMUM study
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21. Meta-analysis
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22. Oral Micronized Progesterone Prevents
Recurrent Spontaneous PTB – Indian Study
• Randomised, double-blind study
• N=33 patients with prior PTB
• Dosage: Oral 400mg progesterone daily from 16 to 34 weeks
Progesterone gp Placebo gp
Recurrent spontaneous
PTB
26.3% 57.1%
Mean serum P4 level at 28
wks
122.6 pg/mL 90.1 pg/mL
Oral Micronised Progesterone was associated with a trend toward a
reduction in RSPB and an increase in the maternal serum
progesterone
Glover MM et al, Am J Perinatol. 2011 May;28(5):377-81.
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23. Patients at risk of PTL (including
multiple gestation) – Indian study
• Inclusion criteria
preterm labour upto 37 weeks of gestation, Cardiac Activity present in recent scan,
previous H/o preterm labor, previous H/O abortions, and patients having H/o of
infection in present pregnancy, multiple gestation in present pregnancy.
Natu N et al. Int J Reprod Contracept Obstet Gynecol. 2017 May;6(5):1797-1799
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24. Patients at risk of PTL (including multiple
gestation) – Indian study
Natu N et al. Int J Reprod Contracept Obstet Gynecol. 2017 May;6(5):1797-1799
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25. GUIDELINES – PTL
1. Micronised Progesterone
2. Hydroxyprogesterone Caproate
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26. After a 15 year quiescence…
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27. Progesterone – Previous PTB
17 P
250 mg / week
IM
Multicentric RCT
Meis et al
NEJM 2003
17 P treated women had a significantly lower incidence of preterm
delivery (37, 35, 32 weeks) and babies had lower incidence of IVH,
NEC and need for supplemental O2.
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28. Conflicting Reports – Implications
• Efficacy of an intervention depends on
baseline risk
• Patient selection improves efficacy
• Ultrasound measured cervical length is the
best predictor of preterm birth risk
Celik E et al, Ultrasound Obstet Gynecol 2008
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29. Which Molecule To Prefer
In Which Conditions?
N. Micronised Progesterone
Or
17-hydroxyprogesterone Caproate
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30. Dr Shashwat Jani.
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31. Indication for Progesterone & 17-OHPC
Progesterone 17-Hydroxyprogesterone
caproate
Clinical Indication
History of preterm birth Yes (In women with short
cervix)
Yes
Short cervical length Yes No
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32. Dr Shashwat Jani.
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33. 33
17P: Side Effects and Precautions
Precautions
– Discontinue if thrombosis or thromboembolism occurs
– Consider discontinuing if allergic reactions occur
– Decreased glucose tolerance: Monitor pre-diabetic and
diabetic women
– Fluid retention: Monitor women with conditions that may
be affected by fluid retention, such as preeclampsia,
epilepsy, cardiac or renal dysfunction
– Depression: Monitor women with a history of clinical
depression; discontinue if depression recurs
MakenaTM Prescribing Information, Ther-Rx Corporation St. Louis, MO February, 2011
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34. 17P: Contraindications
 Current or history of thrombosis or thromboembolic disorders
 Known or suspected breast cancer, other hormone-sensitive
cancer, or history of these conditions
 Undiagnosed abnormal vaginal bleeding unrelated to pregnancy
 Cholestatic jaundice of pregnancy
 Liver tumors, benign or malignant, or active liver disease
 Uncontrolled hypertension
MakenaTM Prescribing Information, Ther-Rx Corporation St. Louis, MO February, 2011
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35. • A randomized, double-blind, placebo-controlled trial of 150
women with at least one PTB received Oral Micronised
Progesterone for prevention of preterm birth.
• Oral Micronised Progesterone reduced the risk of PTB
between 28 and 31 weeks plus 6 days, NICU admissions, and
neonatal morbidity and mortality in high risk patients.
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36. • A randomized trial of Oral Micronised Progesterone
(400mg OD) for prevention of recurrent
spontaneous preterm birth (RSPB) showed a trend
towards reduction in RSPB with increase in maternal
serum progesterone level.
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Glover MM et al,Am J Perinatol. 2011 May;28(5):377-81 )
28-Aug-18 36

37. PTL PREVENTION –
SPECIFIC CONDITIONS
1. Risk Of PTL In IVF/ICSI Pregnancies
2. Maintenance Tocolysis
3. Twin Gestation
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38. 1. Risk of PTL in IVF/ICSI pregnancies
In conclusion,
• the administration of 400 mg natural progesterone from mid trimester
reduced the incidence of preterm birth in singleton in IVF/ICSI
pregnancies
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39. 2. Maintenance Tocolysis after arrested
preterm labour
• A double-blind, randomized, placebo-controlled trial
• Patients: Pregnant women at 24–34 weeks of singleton pregnancy were
recruited after successful tocolysis with nifedipine therapy
• Preterm labor was defined as 4 contractions per 20 minutes or 8 per 60 minutes
associated with progressive change in cervix or cervical dilation of more than 1
cm or at least 80% cervical effacement
• All women with threatened preterm labor received intravenous hydration
therapy (500 mL of intravenous lactated Ringer solution), betamethasone (12 mg
intramuscularly, followed by another 12 mg after 24 hours), and tocolysis with
nifedipine per hospital protocol (initial dose of 20 mg, followed by 10–20 mg
every 4–6 hours)
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40. Maintenance Tocolysis after arrested
preterm labour
• Nifedipine tocolysis was continued until uterine contractions had subsided
for at least 12 hours. After the arrest of preterm labor, patients were
recruited for the study within 48 hours of acute tocolysis.
• Arrested preterm labor was defined as no uterine contractions for at least
12 hours on nifedipine tocolysis.
• One group was offered 200mg Oral Micronised
Progesterone daily, other group was offered placebo
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41. Maintenance Tocolysis after arrested
preterm labour
Dr Shashwat Jani.
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Prolongation of latency period with progesterone can be explained
by various mechanisms resulting in uterine quiescence.
Progesterone relaxes myometrial smooth muscle, blocks the action of
oxytocin, inhibits the formation of gap junctions and prostaglandin synthesis,
and has anti-inflammatory properties.
In conclusion, maintenance tocolysis with oral micronized progesterone significantly
prolonged pregnancy and decreased the number of preterm births.
The present results support the use of micronized progesterone as a maintenance
tocolytic for prolongation of pregnancy in cases of arrested preterm labor.
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42. Twin Gestation – Risk of PTL
Meta-analysis
2017
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43. Twin Gestation – Risk of PTL
Meta-analysis
2017
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44. Twin Gestation – Risk of PTL2016
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45. PTL in Twin gestation2016
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46. Progesterone in high risk pregnancy –
Twin gestation with short cervix
• Vaginal progesterone 200 mg BID from 16-28 weeks of
gestation decreases spontaneous preterm birth rate
• Progesterone helps to prolong pregnancy up to term or late preterm
• Decreases the incidences of neonatal morbidity of neonate (APGAR score, Birth
weight, NICU stay, Neonatal complications)
Christian medical college, Vellore
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47. Hydroxyprogesterone caproate –
Twins
Fonseca EB et al, NEJM 2007
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48. Safety Issues With Progesterone
• Side effects: Injection site reaction ( 17 P ),
urticaria (65%), vaginal discharge (4-9%)
• NO teratogenic effects
• NO rise in mid trimester loss
• No risk of gestational diabetes
• BW <2500 gm but no increase in neonatal
morbidity/ mortality
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49. The First Uterine Pass Effect
Bulletti et al. Hum Reprod. 1997;12:1073.
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50. • Natural Micronised Progesterone
• Hydroxyprogesterone caproate
Which Progesterone ???
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51. Progestogens
Natural
Micronized progesterone
• Natural - Chemical structure
exactly equivalent to endogenous
progesterone
• Micronization improves Oral
bioavailability, making oral
administration possible
• USFDA Pregnancy category B
• No effect on mood, HDL-
cholesterol & pregnancy
outcomes
Synthetic progestins
• Synthetic - Chemical structure
different from endogenous
progesterone – for eg. 17-
Hydroxyprogesterone caproate,
Dydrogesterone
• Affects mood, Decreases HDL
cholesterol levels
• Adversely affects pregnancy
outcome
• May cause fluid retention
Apgar BS, et al .Am Fam Physician. 2000 Oct 15;62(8):1839-46, 1849-50.
Elizur SE, et al. Fertil Steril. 2008; 89(6): 1595-602
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52. Which Progesterone?
Oral
Progesteron
e SR tablet
300mg OD
Vaginal
Cap /
Pessary
200 mg
BID
Gel (8%)
90 mg OD
Injections
(17OHP)
250 mg/wk
Injection
NMP
100mg
every 3rd
day
Tolerability,
Side effects
Better
bioavailabilit
y, Less
sedation,
Once daily
Effective,
Divided
dose
Effective,
Once Daily
dose
Local side
effects +
Less
painful
Pharmaco
kinetics
High plasma and tissue concentration
Efficacy Effective in selected populations
Cost per
day
Rs 48 Rs 46 Rs 95 Rs 21 Rs. 33
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53. Safety: Natural Micronised
Progesterone
Based on 35 years of prospective fetal safety study of progesterone exposure
during pregnancy, conducted at
Pop Paul IV institute USA
(Route of administration: Oral or/and Intramuscular or/and vaginal)
No increase in risk of any congenital anomalies
Progesterone is not a cardiac teratogen
1. Hilgers TW et al, Issues Law Med 2015;30(2):159-68
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54. Natural Micronised Progesterone – Safety
• TGA – Therapeutic Goods Administration, Australia (similar to US FDA)
classified Natural Micronised Progesterone as Pregnancy
category ‘A’ drug
Pregnancy Category A
• Drugs which have been taken by a large number of pregnant women and
women of childbearing age without any proven increase in the frequency
of malformations or other direct or indirect harmful effects on the fetus
having been observed. https://www.tga.gov.au/prescribing-medicines-pregnancy-database
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55. Progesterone Sustained Release (SR) tablets
• Immediate release formulation releases 80% content in first 4 hours where
metabolism is high - Complaint of sedation & dizziness
• Sustained release formulation releases only 20% content in first 4 hours
which minimizes metabolism – Less sedation & dizziness
• Gradual release of progesterone for >16 hours sufficing once daily dosage
Immediate release
formulation Sustained release
formulation
Time (Hrs)
%drug
release
0 4 8 12 16
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56. Advantage of Progesterone Sustained
Release (SR) tablets
1. Reduced sedation & dizziness
• As per a study published in International Journal of Medical Research &
Health Sciences on Oral NMP SR
Incidence of Drowsiness was 0.6%1
(153 patients, Oral NMP 300 mg SR was the most commonly prescribed formulation)
2. Once-a-day dosing convenience
• Drug release for >16 hours & long elimination half-life allows once-a-day dosing
convenience
1. Int J Med Res Health Sci. 20144;3(4):975-976
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57. Advantage of Progesterone Sustained
Release (SR) tablets
3. Improved bioavailability
Bioavailability with Oral NMP SR tablets
• As per UK MHRA guideline, ≥ 14 ng/ml serum progesterone
level is required in luteal phase
• Mean mid-luteal serum progesterone level (ng/ml) with Oral NMP SR in
premenopausal women
Formulation Mean mid-luteal Serum Progesterone
level (ng/ml)1,2
NMP SR 400 46.2
NMP SR 300 36.1
NMP SR 200 20.6
1. Journal of Clinical and Diagnostic Research. 2016 Jan, Vol-10(1): QC08-QC10
2. Journal of Clinical and Diagnostic Research. 2016 Feb, Vol-10(2): QE01-QE04
After 7 oral daily dosage
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58. Reference Patients at risk Daily dose & duration
Western Australia
2017A
Short cervix between 16 and 24 weeks’ gestation 200mg until 36 weeks
Cervix length is <10 mm, management can include
cervical cerclage, vaginal progesterone, or both
History of spontaneous preterm birth (with or without
preterm pre-labour rupture of membranes) between 20
and 34 weeks’ gestation.
200mg each night from 16 to
36 weeks gestation
European Association
of Perinatal Medicine
20171
Short cervix (25 mm) at mid gestation, either with
singleton or twin pregnancy and regardless of their
obstetrical history
_
French Clinical Practice
Guidelines 20162
Threatened late miscarriage characterized by an
isolated undilated short cervix (<25 mm) & no uterine
contractions
90-200mg up to 34 wks
NICE Guideline 20153 With or without history of spontaneous preterm birth
or mid-trimester loss between 16-34 wks & short cervix
at 16-24 wks
_
FIGO 20154 Short cervix (<25 mm at 19-24 wks) 90-200mg from diagnosis of
short cervix up to ~37 wks
StratOG 20155 As an alternative to cervical cerclage in woman with
prior PTB or Short cervix CL <25 mm at 20 to 37 weeks
Up to 37 weeks
ACOG 20126 Woman with or without prior PTB & short cervix CL ≤20
mm at ≤24 weeks
From 16-24 weeks of
gestation
SOGC 20087 Prior PTB or
Short cervix CL <15 mm at 22-26 weeks
100mg or
200mg
International guidelines/references support use of Progesterone for prevention of
preterm birth
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59. Take Home Message
• Risk of PTL: Short cervix (<25mm at 20-24
wks), Multiple gestation, History of PTB
• Guidelines across globe support Progesterone
treatment for prevention of PTL & associated
morbidity & mortality
• Micronised Progesterone is better option over
17-Hydroxyprogesterone caproate in term of
safety profile.
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60. 28-Aug-18 60
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