preterm labour and its causes, guidelines in short v=cervix, twin gestation

1. ROLE OF PROGESTERONE IN PRETERM LABOUR
Let Them Bloom Fully

3. FLOW OF PRESENTATION
• Pre-term labour
• International Guidelines – PTL
• PTL prevention in specific conditions
• Short cervix
• History of pre-term birth
• Twin gestation with short cervix
• Maintenance tocolysis
• Risk of PTL in IVF/ICSI conceived pregnancies
• Which Progesterone is best?

4. INTRODUCTION – PRE-TERM LABOUR
“Contraction (labour) before 37
weeks gestational age”
World:
• ~15 million preterm births
• Contributes to ~ 1 million
neonatal deaths
India:
• Largest number of preterm
births
• 3.5 million/year
Quinn JA, et al. Vaccine. 2016 Dec 1; 34(49): 6047–6056.
World Health Organization. Preterm birth—fact sheet 363. Nov 2015. www.who.int/
Top 5 countries:
India: 3,519,100
China: 1,172,300
Nigeria: 773,600
Pakistan: 748,100
Indonesia: 675,700
More than 1 in 10
babies born early

5. MAJOR CAUSES OF PRETERM BIRTH
Norwitz ER,et al. Rev Obstet Gynecol. 2011 Summer;4(2):60-72.

6. 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

7. LATEST INTERNATIONAL GUIDELINES
SOGC 2008
ACOG 2012
StratOG by RCOG 2014
FIGO 2015
NICE guideline 2015
French clinical practice guidelines 2016
European Association of perinatal medicine 2017
Western Australia PTB prevention key initiative 2017

8. INTERNATIONAL GUIDELINES - PTL
8
ACOG guideline, 2012
Recommends2
Daily Progesterone
supplementation in a
woman with history
of prior PTB
Woman without
history of prior PTB
but at risk due to
short cervix (≤20mm
at ≤24 weeks)
SOGC guideline
2008
Recommends3
Daily Progesterone
supplementation
for
• Women with
history of
previous PTB
• Women with
short cervix
(≤15mm at 22-
26 weeks)
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
1. Rowe T, J Obstet Gynaecol Can 2014;36(4):291–2
2 Committee on Practice Bulletins—Obstetric, ACOG, Obstet Gynecol. 2012 Oct;120(4):964-73
3. Farine D et al, J Obstet Gynaecol Can 2008;30(1):67–71

9. NICE GUIDELINE PTL, NOV
2015
https://www.nice.org.uk/guidance/ng25/resources/preterm-labour-and-birth-pdf-

10. 2015 FIGO GUIDELINE (INTERNATIONAL
FEDERATION OF GYNECOLOGY AND
OBSTETRICS)
FIGO recommends the following:
1. Sonographic cervical length measurement should be performed in all
pregnant patients at 19–23 6/7 weeks of gestation using transvaginal
ultrasound. This can be done at the same time as the ultrasound
performed for the anatomical survey.
2. Women with a sonographic short cervix (<25 mm) diagnosed in the
mid-trimester should be offered daily vaginal micronized
progesterone treatment for the prevention of preterm birth and
neonatal morbidity.
3. The progesterone formulation to be used is vaginal micronized
progesterone (200 mg vaginal soft capsules) nightly or vaginal
micronized progesterone gel (90 mg) each morning.
4. Universal cervical length screening and vaginal progesterone
treatment (90mg vaginal gel or 200mg micronized vaginal soft
capsules) is a cost-effective model for the prevention of preterm birth.

11. PREGNANCY LOSS: FRENCH CLINICAL
PRACTICE GUIDELINES, 2016
• Among women with a threatened late miscarriage, an
isolated undilated shortened cervix (<25 mm on ultrasound)
and no uterine contractions, daily treatment with vaginal
progesterone up to 34 weeks of gestation is recommended
(Grade A).
• Among women with a threatened late miscarriage and an
isolated undilated shortened cervix (<25 mm on ultrasound),
cerclage is only indicated for those with a history of either
late miscarriage or preterm delivery (Grade A).
European Journal of Obstetrics & Gynecology and Reproductive Biology 201 (2016) 18–26
11

12. PRETERM LABOR AND BIRTH MANAGEMENT:
RECOMMENDATIONS FROM THE EUROPEAN
ASSOCIATION OF PERINATAL MEDICINE 2017
Summary of recommendations
• Sonographic cervical length measurement is
recommended in all pregnant patients regardless of
obstetrical history at 18–23 6/7 weeks of gestation
using transvaginal ultrasound
• Asymptomatic women with a sonographically short
cervix (25 mm) at mid gestation,
• Either with singleton or twin pregnancy and
• Regardless of their obstetrical history should be
offered vaginal progesterone treatment for the
prevention of preterm birth and neonatal
morbidity.
Di Renzo GC et al, J Matern Fetal Neonatal Med. 2017 Sep;30(17):2011-2030.

13. CLINICAL GUIDELINE – WESTERN
AUSTRALIA 2017

14. PTL PREVENTION IN SPECIFIC
CONDITIONS
1. Short cervix
2. History of pre-term birth
3. Twin gestation with short cervix
4. Maintenance tocolysis
5. Risk of PTL in IVF/ICSI conceived pregnancies
6. As an alternative to cervical cerclage

15. 1. SHORT CERVIX
• Relative Risk of SPTD < 35 wks by % of cervical length
at 24 wks
Iams JD, et al, N Engl J Med. 1996 Feb 29;334(9):567-72.

16. 1. SHORT CERVIX
Patient enrolment – 18 to ~23 weeks
Progesterone dosage: 90mg gel
everyday

17. 1. SHORT CERVIX
• Result
Conclusion:
Intravaginal progesterone enhances preservation of
cervical length in women at high risk for preterm birth.

18. 1. SHORT CERVIX – UPDATED
META-ANALYSIS 2016
• 5 trials, n=974 women
• Inclusion: Women with a singleton gestation and a mid-trimester
sonographic CL ≤25mm
• Progesterone dosage: Progesterone gel 90mg, Progesterone
capsules 200mg or 100mg

19. 1. SHORT CERVIX – UPDATED
META-ANALYSIS 2016
Conclusion:
• This updated systematic review and meta-analysis
reaffirms that vaginal progesterone reduces the risk of
preterm birth and neonatal morbidity and mortality in
women with a singleton gestation and a mid-trimester
CL ≤25mm, without any deleterious effects on
neurodevelopmental outcome.
• Clinicians should continue to perform universal
transvaginal CL screening at 18–24weeks of gestation
in women with a singleton gestation and to offer
vaginal progesterone to those with a CL ≤25mm.

20. 2. PATIENTS WITH PRIOR
PRE-TERM BIRTH
• Risk of recurrent pre-term birth
LS et al,: Epigemiology of preterm birth: Results from a longitudinal study of births in
Norway. In Elder MG: Preterm Labor. London, Butterworths, 1981, p17.

21. ORAL MICRONISED PROGESTERONE
PREVENTS RECURRENT
SPONTANEOUS PTB (RSPB)
• 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
Micronised Progesterone was associated with a trend
toward a reduction in RSPB and an increase in the
maternal serum progesterone
Am J Perinatol. 2011 May;28(5):377-81.

22. Acta Obstet Gynecol Scand. 2013 Feb;92(2):215-22
PROGESTERONE & 17-OHPC FOR
PREVENTION OF PTB
• Prospective randomised study on 580 women with prior history
of PTB
• Duration: Treatment started from 14-18 weeks until 36 weeks
Group Vaginal
Progesterone
(n=238)
Hydroxyprogesteron
e caproate Inj
(n=226)
Formulation 90mg gel daily 250mg IM inj once
weekly
Treatment
compliance
94.1% 90.8%
All deliveries ≥34
weeks
83.4% 74.3%
All deliveries <34
weeks
16.6% 25.7%
Adverse effects 7.5% 14.1%
Vaginal progesterone was more effective than
intramuscular 17-OHPC for the prevention of preterm birth
and had fewer adverse effects

23. 3. TWIN GESTATION WITH
SHORT CERVIX
• Meta-analysis of 6 RCT
• N=303 patients – Twin gestation & short-cervix

24. 3. TWIN GESTATION WITH
SHORT CERVIX
• Result:

25. 3. TWIN GESTATION WITH
SHORT CERVIXResult:
• Vaginal progesterone, compared with placebo/no treatment, was
associated with a statistically significant reduction in the risk of
preterm birth <33weeks’ gestation (31.4% vs 43.1%; RR, 0.69
moderate-quality evidence).
• Vaginal progesterone administration was associated with a
significant decrease in
• The risk of preterm birth <35, <34, <32 and <30weeks’ gestation
(RRs ranging from 0.47 to 0.83),
• Neonatal death (RR, 0.53),
• Respiratory distress syndrome (RR, 0.70),
• Composite neonatal morbidity and mortality (RR, 0.61),
• Use of mechanical ventilation (RR, 0.54) and
• Birth weight<1500 g (RR, 0.53) (all moderate-quality evidence).

26. 3. TWIN GESTATION WITH
SHORT CERVIX
Conclusion:
• Administration of vaginal progesterone to
asymptomatic women with a twin gestation and a
sonographic short cervix in the mid-trimester reduces
the risk of preterm birth occurring at <30 to<35
gestational weeks, neonatal mortality and some
measures of neonatal morbidity, without any
demonstrable deleterious effects on childhood
neurodevelopment.

27. 4. MAINTENANCE TOCOLYSIS AFTER
ARRESTED PRETERM LABOR
• A systematic review and meta-analysis of 9 randomized
controlled trial. (2016)
• Result: Nifedipine and progesterone were used for
maintenance tocolysis.
• Compared to placebo treatment or no treatment,
maintenance tocolysis with progesterone could significantly
prolong the delivery gestational weeks [standard mean
difference (SMD) 1.64; 95% confidence interval (CI), 1.21,
2.07; p < 0.00001], reduce the proportion of patients with
delivery before 37 weeks (risk ratio 0.63; p= 0.001), and
increase the birth weight (SMD 317.71; p < 0.0001).
However, no such benefits were observed after
maintenance tocolysis with nifedipine.
Taiwan J Obstet Gynecol. 2016 Jun;55(3):399-404

28. CONCLUSION
• :
• Our results with maintenance tocolysis with progesterone
may be useful for patients who had an episode of threatened
preterm labor successfully treated with acute tocolytic
therapy.

29. 4. MAINTENANCE TOCOLYSIS
• 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)
M. Choudhary et al. / International Journal of Gynecology and Obstetrics 126 (2014) 60–63

30. 4. MAINTENANCE TOCOLYSIS
M. Choudhary et al. / International Journal of Gynecology and Obstetrics 126 (2014) 60–63
30
Tocolytics
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 studywithin 48
hours of acute tocolysis.
Arrested preterm labor was
defined as no uterine
contractions for at least 12
hours on nifedipine tocolysis.
Maintenance Tocolysis
One group was offered 200mg
Oral Micronised Progesterone
daily, other group was offered
placebo

31. 4. MAINTENANCE
TOCOLYSIS
Result
• The mean latency period was significantly longer in Progesterone
group (33.29 ± 22.16 vs 23.07 ± 15.42 days; P = 0.013).
M. Choudhary et al. / International Journal of Gynecology and Obstetrics 126 (2014) 60–63

33. 5. RISK OF PTL IN IVF/ICSI CONCEIVED
PREGNANCIES
• The frequency of spontaneous preterm birth is higher in singleton
pregnancies conceived by IVF/ICSI as compared with
spontaneously conceived singleton pregnancies.
• In twin IVF/ICSI pregnancy, there is a 10-fold increased age and
parity-adjusted risk of delivery before 37 weeks and 7.4-fold
increased risk before 32 weeks as compared with singleton
pregnancy
• N=250 pregnant IVF/ICSI patients
• Dosage: 200mg BID
Reprod Biomed Online. 2012 Aug;25(2):133-8.

34. 5. RISK OF PTL IN IVF/ICSI
CONCEIVED PREGNANCIES

35. Conclusion
The administration of 400 mg vaginal natural
progesterone from mid trimester reduced the incidence
of preterm birth in singleton, but not in twin, IVF/ICSI
pregnancies.

36. 6. PROGESTERONE AS AN
ALTERNATIVE TO CERVICAL
CERCLAGE

37. Rowe T, J Obstet Gynaecol Can 2014;36(4):291–2
6. 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

38. 6. 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 /
300mg SR
Group B: Underwent cerclage procedure.

39. 6. 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 anaesthesia procedure related adverse effects such as pain,
headache, vomiting and other complications.
It is also not associated with any hospital stay and is very economical.
Using vaginal progesterone saves time for patients as well as doctors.

40. WHICH PROGESTERONE?
• Natural Micronised Progesterone
• Hydroxyprogesterone caproate

41. PROGESTOGENS
• 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 - 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
Natural
Micronized progesterone
Synthetic progestins
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

42. Progesterone 17-Hydroxyprogesterone
caproate
Clinical Indications
History of preterm birth Yes (In women with short
cervix)
Yes
Short cervical length
(No prior history of PTB)
Yes No
Effective in twin gestation Yes2 No
2

43. 43

44. DYDROGESTERONE – NOT
EFFECTIVE IN PTL
• Various studies have shown that Dydrogesterone is not effective in
prevention of PTL and Dydrogesterone is not approved for PTL
prevention
• A randomized, double blinded, placebo controlled trial of oral
dydrogesterone supplementation in the management of preterm
labor - 2016 article
• The primary aim of this study was to evaluate the effect of oral
dydrogesterone on the recurrent uterine contraction in PTL. The
secondary aims were to evaluate latency period, gestational age at
delivery, pregnancy outcomes, neonatal outcomes, compliance and
side effects. A randomized, double blinded, placebo controlled trial
was conducted. 48 pregnant women at 24–34 weeks gestation with
PTL were either randomized to study group receiving tocolytic
treatment combined with oral dydrogesterone (20 mg daily) or to
placebo group receiving tocolytic treatment combined with oral
placebo.

45. DYDROGESTERONE – NOT
EFFECTIVE IN PTL
• Recurrent rates of uterine contraction were comparable between
groups (87.5% vs 91.7%, p = 0.64). Latency periods were not
different between dydrogesterone and placebo group
(32.7 ± 20.2 days vs 38.2 ± 24.2 days, p = 0.39). There were also
no differences in gestational age at delivery, pregnancy
outcomes, neonatal outcomes, compliance and side effects.
• Adjuvant treatment with oral dydrogesterone 20 mg/day could
not decrease the rates of recurrent uterine contraction and
prolong latency period in preterm labor management when
compared to placebo.

46. Let’s ensure FULL bloom