Dr Sujoy Dasgupta was invited to deliver a lecture at BOGSCON (The Annual Conference of Bengal Obstetric and Gynaecological Society) held at Kolkata in December 2019

1. Sujoy Dasgupta
MBBS (Gold Medalist, Hons)
MS (OBGY- Gold Medalist)
DNB (New Delhi)
MRCOG (London)
Advanced ART Course for Clinicians (NUHS, Singapore)
Consultant: Reproductive Medicine, Genome Fertility Centre, Kolkata
• Managing Committee Member, Bengal Obstetric & Gynaecological Society
(BOGS)- 2019-20
• Secretary, Subfertility and Reproductive Endocrinology Committee, BOGS-
2019-20
• Winner, Prof Geoffrey Chamberlain Award, RCOG World Congress, London,
2019
Progesterone in Preterm Labour

2. Sir Isaac Newton,
1642
Napoleon Bonaparte,
1769
Charles Darwin,
1809
Mark Twain,
1835
Sir Winston Churchill,
1874
Wayde van Niekerk,
1992
Albert Einstein,
1879

3. Problems of PTB
• Mortality - 2% for infants born at 32 weeks,
>90% for those born at 23 weeks.
● periventricular leukomalacia
● cerebral palsy
● bronchopulmonary dysplasia.

4. The Burden of Preterm Birth
• In India, among the total 27 million babies born
annually, 3.6 million babies are born preterm, and
over 300,000 of these preterm babies die each year
because of associated complications
• India, with its highest number of PTBs & highest
number of preterm deaths worldwide, contributes
25% of the overall global preterm related deaths
*https://www.nibmg.ac.in/?q=content/preterm-birth-program

5. What we can do?
• Prediction
• Prevention

6. Previous Preterm Delivery-
Strongest Risk Factor
• After 1 preterm birth, the risk in the next
pregnancy is 20%.
• After 2 preterm deliveries, this risk
increases to 35–40%.

7. “Short cervix”
• TVS carried out at 16+0 to 24+0 weeks
• <25 mm

8. Case 1
• Mrs AB, 24-year
• P0+1, previous PTL at 22 wk

9. When to monitor for cervical length?

10. When to monitor for cervical length?
• Women with a history of one/ two
spontaneous second-trimester loss or preterm
delivery
• Serial sonographic assessment of the cervix is
usually performed between 14 and 24 weeks
of gestation.
RCOG Green-top Guideline No. 60, May 2011. Cervical Cerclage

11. Case 1 (Contd.)
• Mrs AB underwent TVS at 18 wk
• Cervical Length (CL) is 22 mm

12. Short cervix AND previous ≤2 spontaneous
PTL/ mid-trimester loss (16+0- 34+0 weeks)
• Ultrasound-indicated
cerclage
• Insertion of a cerclage as a
therapeutic measure in
cases of cervical length
shortening seen on TVS.
RCOG Green-top Guideline
No. 60, May 2011. Cervical
Cerclage
• Choice of
1. either prophylactic
cervical cerclage
2. OR prophylactic vaginal
progesterone
NICE guideline. 20 November
2015. Preterm labour and
birth.
nice.org.uk/guidance/ng25
.

13. Conde-Agudelo A, et al. Vaginal progesterone is as effective as cervical cerclage to
prevent preterm birth in women with a singleton gestation, previous spontaneous
preterm birth, and a short cervix: updated indirect comparison meta-analysis. Am J
Obstet Gynecol. 2018 Jul;219(1):10-25.

14. Progesterone- “Pro-Gestation”
• Essential for pregnancy preparation,
implantation, support and continuation
• Imunomodulator- induces the Th2 response,
essential for normal pregnancy
• Increases NO production → increases uterine
blood flow and endothelial adaptation
• Decreases contractility of myometrium

15. Dodd JM, et al. Prenatal administration of progesterone for preventing preterm birth in women
considered to be at risk of preterm birth. Cochrane Database Syst Rev. 2013 Jul 31;(7):CD004947.

16. • After correction for multiple outcomes, progesterone had no significant effect
on the primary obstetric outcome (odds ratio adjusted for multiple
comparisons [OR] 0·86, 95% CI 0·61-1·22) or neonatal outcome (OR 0·62,
0·38-1·03), nor on the childhood outcome (cognitive score, progesterone
group vs placebo group, 97·3 [SD 17·9] vs 97·7 [17·5]; difference in means -
0·48, 95% CI -2·77 to 1·81).
• In this study, progesterone had NO significant beneficial or harmful effects
on the primary obstetric, neonatal or childhood outcome.

17. Romero R, Conde-Agudelo A, Da Fonseca E, O'Brien JM, Cetingoz E, Creasy GW, Hassan SS, Nicolaides KH.
Vaginal progesterone for preventing preterm birth and adverse perinatal outcomes in singleton gestations with
a short cervix: a meta-analysis of individual patient data. Am J Obstet Gynecol. 2018 Feb;218(2):161-180.

18. • Vaginal progesterone was associated with a significant reduction in the
risk of preterm birth <33 weeks of gestation (relative risk, 0.62; 95%
confidence interval, 0.47–0.81; P = .0006; high-quality evidence).
Moreover, vaginal progesterone significantly decreased the risk of preterm
birth <36, <35, <34, <32, <30, and <28 weeks of gestation; spontaneous
preterm birth <33 and <34 weeks of gestation; respiratory distress
syndrome; composite neonatal morbidity and mortality; birthweight
<1500 and <2500 g; and admission to the neonatal intensive care unit
(relative risks from 0.47-0.82; high-quality evidence for all).

19. Progeterone- Which Route?
Oral Vaginal IM
•Easiest way •Higher uterine
concentration
•Optimum blood level
•Can be taken anywhere •Needs privacy •Extremely painful
•Better acceptable and
tolerable to women
•10% may have vaginal
dryness/ irritability
•Abscess formation

20. • Retrospective cohort study
• 860 pregnancies included
• After adjustment, the proportion of PTB <37 weeks was found to be
non-inferior among pregnancies in which vaginal progesterone was
used compared to 17-OHPC (37.7% vs. 35.4%; IPW adjusted
difference: 2.2%, 90% CI: -4.3, 8.8).
• In women with a history of spontaneous PTB, we found vaginal
progesterone to be non-inferior to 17-OHPC for the prevention of
PTB.

21. Vaginal Progesterones
• Delivers where needed (“First uterine pass effect”)
– Direct diffusion : within 6 hrs of administration
– Counter-current exchange- concentrations in uterus : periphery - 14:1,
IM –1:1.
Vaginal Gel (8%) in Polycarbophil base
• Special applicator – easy to use with no wastage of drug
• Excellent vaginal moisturizing property1
1. Beckham et al, Clinical practice in sexuality, Vol.8, No.8/9. page 3-8

22. Oral Progesterone

23. Oral Progesterone
Natural Micronized
Progesterone (NMP)
Dydrogesterone

24. • Micronization reduces particle size to <10 mm to
– Increase surface area of the drug
– Enhances aqueous dissolution rate
– Enhances intestinal absorption
• Side effects of synthetic progestins can be
minimized or eliminated through the use of natural
progesterone
Micronized Progesterone

25. Boelig RC, Della Corte L, Ashoush S, McKenna D, Saccone G, Rajaram S, Berghella V. Oral
progesterone for the prevention of recurrent preterm birth: systematic review and metaanalysis.
Am J Obstet Gynecol MFM. 2019 Mar;1(1):50-62.

26. • There was a higher rate of maternal adverse effects with
oral progesterone that included dizziness (relative risk,
2.95; 95% confidence interval, 1.47e5.90) somnolence
(relative risk, 2.06; 95% confidence interval, 1.29e3.30),
and vaginal dryness (relative risk, 2.37; 95% confidence
interval, 1.10- 5.11); no serious adverse effects were noted.
• Further randomized study on oral progesterone
compared with other established therapies for the
prevention of recurrent preterm birth are warranted.
Boelig RC, Della Corte L, Ashoush S, McKenna D, Saccone G, Rajaram S, Berghella V. Oral
progesterone for the prevention of recurrent preterm birth: systematic review and metaanalysis.
Am J Obstet Gynecol MFM. 2019 Mar;1(1):50-62.

27. Only vaginal P is effective

28. Jarde A, Lutsiv O, Beyene J, McDonald SD. Vaginal progesterone, oral progesterone, 17-
OHPC, cerclage, and pessary for preventing preterm birth in at-risk singleton pregnancies: an
updated systematic review and network meta-analysis. BJOG 2019;126:556–567.
• Included 40 trials (11 311 women).
• Vaginal progesterone was the only
intervention with consistent effectiveness for
preventing preterm birth in singleton at risk
pregnancies overall and in those with a
previous preterm birth.

29. Case 2
• Mrs PS, 31-year
• P0+0
• During anomaly scan (19 wk), CL 20 mm

30. Incidental finding of short cervix
RCOG Green-top Guideline No. 60, May 2011. Cervical Cerclage
No intervention
NICE guideline. 20 November 2015. Preterm labour and birth.
nice.org.uk/guidance/ng25
Prophylactic vaginal progesterone

31. Case 3
• Mrs BM, 35-year
• P0+3- (18 wk, 22 wk, 23 wk)

32. Previous ≥3 mid-trimester losses
History-indicated cerclage
• A history-indicated suture is performed as a
prophylactic measure in asymptomatic
women and normally inserted electively at 12–
14 weeks of gestation.
RCOG Green-top Guideline No. 60, May 2011. Cervical Cerclage

33. Final report of the Medical Research Council/Royal College of Obstetricians and
Gynaecologists multicentre randomised trial of cervical cerclage. MRC/RCOG
Working Party on Cervical Cerclage. Br J Obstet Gynaecol 1993;100:516–23.
• Of six prespecified subgroup analyses, only
women with a history of ≥3 pregnancies
ending before 37 weeks of gestation
benefitted from cerclage, which halved the
incidence of preterm delivery before 33 weeks
of gestation (15% versus 32%, P < 0.05).

34. • The time has come for professional societies to reexamine
their recommendations offering only cerclage to patients with
a history of preterm birth and a short cervix. Vaginal
progesterone does not require anesthesia or surgery and it
is as effective as cerclage.

35. Case 3 (Contd.)
• Mrs BM underwent cerclage at 14 wk
• Anomaly scan (21 wk) revealed CL 18 mm

36. RCOG Green-top Guideline No. 60, May 2011. Cervical Cerclage

37. • A case control study
• Despite both groups having clinically significant
shortened cervical lengths and cervical cerclage in situ,
adjunct vaginal progesterone treatment resulted in
older gestational age at birth and higher birth weight.

38. Case 4
• Mrs PC, 28-year
• P0+0, DCDA twin, spontaneous conception

39. RCOG Green-top Guideline No. 60, May 2011. Cervical Cerclage

40. • No benefit of cervical cerclage in reducing preterm delivery in
twin pregnancies.
• A trend towards harm with an increased risk of perinatal death,
• No reduction in a composite of adverse neonatal outcome
• Increased risk of low birthweight, respiratory distress syndrome
1. Rafael T, Berghella V, Berghella V, Odibo AO, To MS, Rust OA, Althuisius SM. Cerclage for short cervix
on ultrasonography: meta-analysis of trials using individual patient-level data. Obstet Gynecol
2005;106:181–9
2. Alfirevic Z. Cervical stitch (cerclage) for preventing preterm birth in multiple pregnancy. Cochrane
Database Syst Rev 2014; (9):CD009166.
3. Saccone G, Rust O, Althuisius S, Roman A, Berghella V. Cerclage for short cervix in twin pregnancies:
systematic review and meta-analysis of randomized trials using individual patient-level data. Acta Obstet
Gynecol Scand 2015;94:352–8.
Do NOT put cerclage in multiples

41. Progesterone to prevent PTB in Twin
1. Overall twin pregnancy
2. Twin with Short cervix
• No significant difference in reducing the
delivery <34 weeks
• Norman JE, Mackenzie F, Owen P, Mactier H, Hanretty K, Cooper S, et al.
Progesterone for the prevention of preterm birth in twin pregnancy (STOPPIT): a
randomised, double-blind, placebo-controlled study and metaanalysis. Lancet
2009;373:2034–40.
• McNamara HC, Wood R, Chalmers J, Marlow N, Norrie J, MacLennan G, et al.
STOPPIT Baby Follow-up Study: the effect of prophylactic progesterone in twin
pregnancy on childhood outcome. PLoS One 2015;10:e0122341.

42. Jarde A, et al. Preterm birth prevention
in twin pregnancies with progesterone,
pessary or cerclage: a systematic
review and meta-analysis. BJOG
2017;124: 1163–73.
• Comparing progesterone, cerclage and
the cervical pessary for prevention of
PTB in unselected twin pregnancies
• No reduction in PTB rates with any of
the interventions.
• Some secondary outcomes were reduced
with vaginal progesterone only (very low
birth weight, [RR 0.71, 95% CI 0.52–
0.98], and need for mechanical
ventilation, [RR 0.61, 95% CI 0.45–
0.82]).
• Vaginal progesterone provided a
protective effect over the control with
regards to adverse perinatal outcome
(RR 0.57, 95% CI 0.47–0.70).
• However, the number of women in
the subgroup was small, thus limited
conclusions can be inferred.
Schuit E, et al. Effectiveness of
progestogens to improve perinatal
outcome in twin pregnancies: an
individual participant data meta-analysis.
BJOG 2015;122:27–37.

44. Case 5
• Mrs PS, 37-year
• P0+0, conceived with IVF
• Singletone pregnancy

45. Cavoretto P, Candiani M, Giorgione V, Inversetti A, Abu-Saba MM, Tiberio F, Sigismondi C, Farina
A. Risk of spontaneous preterm birth in singleton pregnancies conceived after IVF/ICSI treatment:
meta-analysis of cohort studies. Ultrasound Obstet Gynecol. 2018 Jan;51(1):43-53.

47. • A single-centre prospective placebo-controlled randomized study
was performed. A total of 313 IVF/ICSI pregnant patients were
randomized into two groups for either treatment with daily 400 mg
vaginal natural progesterone or placebo, starting from mid-
trimester up to 37 weeks or delivery.
• There was a significantly lower preterm birth rate in singleton
pregnancies in the natural progesterone arm (OR 0.53, 95% CI
0.28–0.97).
• No significant difference between both arms in twin pregnancies
(OR 0.735, 95% CI 0.36–2).

48. Yet to know

49. Yet to know

50. Is progesterone safe?
• Maternal adverse events, congenital anomalies and adverse
neurodevelopmental and health outcomes at 2 years of age did not
differ between groups.
Romero R, et al. Vaginal progesterone for preventing preterm birth and adverse
perinatal outcomes in singleton gestations with a short cervix: a meta-analysis
of individual patient data. Am J Obstet Gynecol. 2018 Feb;218(2):161-180.
• No significant beneficial or harmful effects on the primary
obstetric, neonatal or childhood outcome.
Norman JE, et al. Vaginal progesterone prophylaxis for preterm birth (the
OPPTIMUM study): a multicenter, randomized, double-blind trial. Lancet
2016;387:2106-16.

51. International Guidelines/References

52. Summary
• Progesterone is safe and effective in prevention of
PTB
• Especially for those with risk factors- previous PTL,
short cervix
• Further research- twin, IVF pregnancy
• Progesterone has several advantages over the
cerclage
• Vaginal progesterone is preferred to other routes of
administration