This document discusses preterm labor and strategies for prevention. Some key points: - Preterm birth is a major global health issue, responsible for over 1 million neonatal deaths annually. India has the largest number of preterm births at over 3.5 million per year. - Risk factors for preterm birth include infections, previous preterm births, cervical insufficiency, uterine anomalies, and multiple pregnancies. Progesterone supplementation and cervical cerclage are used for prevention. - Studies show vaginal progesterone reduces the risk of early preterm birth in women with a short cervix, decreasing rates of respiratory distress syndrome and admission to the NICU. Oral micronized progesterone is also effective for

1. 1
Preterm labour
prevention
can we do more……..?
Dr.Gowthami Dumpala
MS OBG , FMAS

2. “Contraction (labour) before
37 weeks gestational age”
World:
 ~15 million preterm births
 Contributes to ~ 1 million
neonatal deaths and is the
leading cause of neonatal
mortality & morbidity
India:
 Largest number of preterm
births
 3.5 million/year of which
10% die due to direct
Top 5 countries:
India: 3,519,100
China: 1,172,300
Nigeria: 773,600
Pakistan: 748,100
Indonesia: 675,700
Incidence 1 in
10
2

3. Preterm births
(2014 data)
11.1-16.1% of
all births
≥750000 births
(in no.)
2022 Scenario
according to World
Health Organisation
Still a substantial
number!!!
Lancet Glob Health 2019; 7: e37–46
Preterm birth. World Health Organisation. Accessed from https://www.who.int/news-room/fact-sheets/detail/preterm-
birth#:~:text=In%20the%20lower%2Dincome%20countries,India%3A%203%20519%20100 on 2nd May 2022

4. 4
Subcategory Duration
Extremely preterm Less than 28 weeks.
Very preterm 28–32 weeks.
Late preterm 32–37 weeks.
Suspected/threatened preterm
labour
Uterine contractions without
cervical dilatation
Established preterm labour Uterine contractions plus
progressive cervical dilatation
more than 4 cm
FOGSI Focus – Prevention of Pre-Term Labour – 2017 accessed from https://www.fogsi.org/wp-content/uploads/fogsi-focus/fogsi-focus-ptl.pdf on 2nd May
2022

5. MODIFIABLE
 Environmental factors
 Maternal urogenital infections,systemic infections
 Maternal Smoking
 Suboptimal weight gain in pregnancy
 Maternal stress
NON MODIFIABLE
 Previous history of preterm labour/delivery (15-30% recurrence risk)
 Decidual thrombus/hemorrhage(abruption)
 PPROM
 Mechanical factors-multiple pregnancy, polyhydramnios
 Cervical insufficiency- idiopathic or iatrogenic(trauma or dilatation induced)
 Uterine distortion( fibroids,septate uterus)
 Harmonal changes
 , uteroplacental insufficiency
 Fetal anomalies,IUGR,abnormal lie presentation
 Genetic
 Extremes of maternal age
Causes are
multifactorial and
vary according to
gestation age
5
www.fogsi.org/wp-
content/uploads/tog/TOG_6_A
lgorithm_booklet_Final.pdf

6.  Commonest etiological factor world wide is
INFECTION.
 Several genetic, environmental and
physiological factors are associated with
preterm birth and contribute to uterine
activation ,labour and preterm birth
 The diverse etiology of preterm labour
makes its prediction difficult
6

7. PATHOPHYSIOLOGY
Fetal inflammatory
response syndrome
7

8.  Primary prevention for general population:
Lifestyle modification,cessation of smoking and
alcohol,diet control,weight management,supervised
antenatal care,modifying physical activity.
 Secondary prevention for higher risk group:
Screening for cervical parameters,FFN testing,antibiotics
for associated infections,progestreone
supplementation,cervical cerclage.
 Tertiary prevention when labour has been initiated:
Tocolytic agents,antenatal steroids,magnesium sulphate(
before 32weeks for neuroprophylaxis),antibiotics or
transferred to higher centres when required.
8

9. 1. High risk factors assessment
2 . TVS for cervical parameters ( Length,
funneling,elastography)
3 . Biochemical markers
 Fetal fibronectin >50ng/ml
 PIGFBP-1>1ng/ml(Actim partus test kit)
 PAMG-1>4ng/ml
 Cytokines and protiens –IL6, IL8
 Salivary estriol>1.8ng/ml
 Salivary progesterone<2575pg/ml
 Proteomic markers
4 Screening for bacterial vaginosis
Vaginal mirobiome
5. HUAM
9

10. COMPLICATIONS
Neonate
- Necrotizing enterocolitis,
- Intraventricular
hemorrhage,
- Bronchopulmonary
dysplasia
- Retinopathy of
immaturity
- Weak growth
- Presence of congenital
anomalies.
Infant
- Impaired
neurodevelopmenta
l outcome
- Behavioral issues
Suman V, Luther EE. Preterm Labor. [Updated 2021 Aug 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing;
2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK536939

11. Front Nutr. 2017 May 26;4:20. doi:

12. Prophylactic
Progesterones
and
cervical encerclage
12

13. ROLE OF
PROGESTERONE
Prevention of
Preterm Labour

14. 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
PPROM
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.

15. ROLE OF PROGESTERONE IN
PRETERM LABOUR
• Recent data suggest that
progesterone is crucial for
maintaining uterine
quiescence in the latter
weeks of pregnancy
• Functional withdrawal of
progesterone activity at
the uterine level is seen
at the onset of labour,
both at term and preterm
• This observation is the
basis of progesterone
supplementation in
prevention of preterm
labour
FOGSI Focus – Prevention of Pre-Term Labour – 2017 accessed from https://www.fogsi.org/wp-content/uploads/fogsi-focus/fogsi-focus-ptl.pdf on 2nd May
2022

16. ACTION OF
PROGESTERONE
AT VARIOUS
LEVELS
• Exogenous
progesterone
supplementation may
effectively restore the
same above actions, but
not all, of its action to
maintain uterine
quiescence.
• This explains why
spontaneous PTB is
preventable in some but
not the all women
FOGSI Focus – Prevention of Pre-Term Labour – 2017 accessed
from https://www.fogsi.org/wp-content/uploads/fogsi-
focus/fogsi-focus-ptl.pdf on 2nd May 2022

17. DISCLAIMER: Natural Micronized Progesterone SR (Sustained Release) is not approved for Preterm Labour
Am J Perinatol 2020;37:30–34

18. PREPARATIONS & DOSES
18
17-OH Progesterone
caproate
Micronised progesterone
Synthetic
MOA-inhibits uterine
contractions
•Route –IM
•Dose-250mg IM started in 2nd
trimester continued to
36+6weeks
•Common side effect-local
injection site reaction
•Potential concern – Risk of
hypospadias in male offspring
if given before 11weeks of
gestation
Natural
MOA-inhibits cervical ripening
•Route-Oral NMP, NMP SR
Vaginal-tab/gel
•Dose- 100-400mg
•Advantage-High
bioavailability and less
systemic side effects
•Diasdvantage –vaginal
irritation,daily dosage

19. NMP vs NMP-SR

20. BENEFITS OF ORAL NATURAL
MICRONIZED PROGESTERONE-
SUSTAINED RELEASE (NMP-SR)
OVER CONVENTIONAL ORAL NMP
• Reducing particle size of progesterone to <10 μm increased the
available surface area and improved the dissolution rate and intestinal
absorption
• SR formulation utilizes a hydrophilic matrix polymer that releases
micron-sized particles of progesterone in a controlled manner over 16–
24 hours.
• This gradual release of progesterone, together with a prolonged
elimination half-life of 18 hours and high protein binding (90–99%),
maintains serum progesterone concentrations with once-daily dosing
and improved tolerance.
Palshetkar N et al. Am J Perinatol 2019; 36:1-12

21. BENEFITS OF ORAL NATURAL MICRONIZED
PROGESTERONE-SUSTAINED RELEASE
(NMP-SR) OVER CONVENTIONAL ORAL NMP
• The controlled release of drug
particles during intestinal
transit facilitates lymphatic
absorption of intact drug into
the systemic circulation from
the small intestine and direct
entry of the drug into the
systemic circulation via the
mucosal lining of the colon.
• By circumventing first-pass
metabolism, active circulating
drug elicits the desired
therapeutic effect while
minimizing the risk of
metabolite-related adverse
effects.
Palshetkar N et al. Am J Perinatol 2019; 36:1-12

22. • Clinical usage and safety profile of NMP SR in pregnancy has been
recently assessed in several studies. The largest of those was the NAP-
DELAY study
• Multicenter drug utilization surveillance study conducted in 2016 on 185
high-risk pregnancies receiving NMP SR
• Oral NMP SR formulation was frequently initiated between 16 and 26
weeks of pregnancy and was continued until 34 weeks
• The most common preferred dosage in the study was 300-mg single
dose, with the mean dose of NMP SR used in the study ranging from
271.4 to 311.1 mg, depending on the indication
Am J Perinatol 2020;37:35–36

23. • In all the 185 cases, the pregnancies continued till 34th week with no
significant adverse events, except for two cases of spotting, who were
receiving 200-mg once daily for subchorionic hemorrhage, or 400-mg
once daily for uterine fibroid with subchorionic hemorrhage.
• Rates of these centrally mediated
adverse events were
comparatively lower than those
previously noted with the
immediate-release formulations of
oral natural micronized
progesterone
The study concluded that the natural
progesterone remained a
physiological and safer option for
long-term progesterone
supplementation in high-risk
pregnancies.
Am J Perinatol 2020;37:35–36

24. Am J Perinatol 2020;37:12–18
This study was conducted to evaluate the efficacy of oral NMP SR
progesterone therapy for
(1) the prevention of miscarriages in pregnant women experiencing
threatened abortion and
(2) the prevention of preterm labor.
This is a prospective, randomized, multicentric clinical study in
Indian pregnant women with threatened abortion to determine
the safety, efficacy, and tolerability of
Group A: oral NMP SR tablets 400 mg OD
Group B: oral NMP SR tablets 200 mg BID
Group C: vaginal NMP 200 mg capsule BID
2020

26. ORAL NMP SR IN THREATENED
ABORTION & PREVENTION OF
PRETERM LABOUR
Conclusion
• Progesterone therapy in the form of oral NMP SR is as effective as
vaginal route in preventing miscarriage in pregnant women at risk of
threatened abortion and further helps to prevent preterm labor with
better compliance.
• With respect to route of administration, it was seen that oral and vaginal
routes are equally efficacious for management of threatened abortion
and prevention of preterm labor.
Am J Perinatol 2020;37:12–18

27. SURVEY BASED STUDIES FOR ORAL NMP-
SR
Survey based studies for Oral NMP-SR
S. No Indication
% that preferred NMP-SR
A real-world
national
survey of 925
Indian
gynaecologists
(year 2016)
Epidemiologic
al surveillance
study to assess
the clinical
role of Natural
Micronized
progesterone
for High risk
pregnancy
cases: CLASS
Survey (2017)
(n=1030)
1. Prevention of PTD 10%
2. Women with prior history of
PTB*
65%
Prophylaxis Natural Progesterone was suggested from 16th till 34th

28. SURVEY BASED STUDIES FOR ORAL NMP-SR:
CLASS SURVEY RESULTS
Doses used in cases with previous history of preterm
birth
200 OD 34.4%
300 OD 35%
400 OD 20.9%
Initiation week for Oral NMP-SR
16 wk 63.4%
20 wk 8.1%
24 wk 17.3%

29. 2018

30. VAGINAL NATURAL
MICRONIZED
PROGESTERONE
GEL
Preterm Labour

31. 2022
Care A. BMJ 2022;376:e064547
Sixty one trials (17 273 pregnant women) contributed data for the analysis of at
least one outcome.

32. • Vaginal progesterone was associated with a significant reduction in
the risk of preterm birth <33 weeks of gestation (RR 0.62, 95% CI 0.47-
0.81, P=0.0006; high-quality evidence)
• Vaginal progesterone significantly decreased the risk of (high-quality
evidence)
• preterm birth <36, <35, <34, <32, <30and <28wks
• spontaneous preterm birth <33 and <34
2018
RESULTS
Data were available from 974 women (498 assigned to vaginal progesterone, 476
assigned to placebo) with a cervical length ≤25 mm participating in five high-
quality trials
OBJECTIVE —To determine whether vaginal progesterone prevents preterm birth and
improves perinatal outcomes in asymptomatic women with a singleton gestation and
a midtrimester sonographic short cervix

33. Vaginal progesterone significantly decreased the risk of (high-quality evidence)
• Respiratory distress syndrome
• Composite neonatal morbidity and mortality
• Birthweight <1500 and <2500
• Admission to the neonatal intensive care unit (RRs from 0.47 to 0.82)
• There were seven (1.4%) neonatal deaths in the vaginal progesterone group and 15
(3.2%) in the placebo group (RR 0.44, 95% CI 0.18-1.07, P=0.07; low-quality
evidence)
2018
Am J Obstet Gynecol. 2018 February ; 218(2): 161–180.
Vaginal progesterone decreases the risk of preterm birth
and improves perinatal outcomes in singleton gestations
with a midtrimester sonographic short cervix, without
any demonstrable deleterious effects on childhood
neurodevelopment.
RESULTS (contd)

34. • Vaginal progesterone, compared to placebo, significantly reduced (RRs
from 0.29 to 0.68)
• Risk of preterm birth <35 and <32 weeks of gestation
• Composite perinatal morbidity/mortality
• Neonatal sepsis
• Composite neonatal morbidity
• Admission to the neonatal intensive care unit
2018
RESULTS
Five trials comparing vaginal progesterone vs placebo (265 women) and 5
comparing cerclage vs no cerclage (504 women) were included.
OBJECTIVE —To compare the efficacy of vaginal progesterone and cerclage in preventing
preterm birth and adverse perinatal outcomes in women with a singleton gestation, previous
spontaneous preterm birth, and a midtrimester sonographic short cervix.
DISCLAIMER: Natural Micronized Progesterone Gel is not approved for Preterm Labour Indication
Am J Obstet Gynecol. 2018 July ; 219(1): 10–25. doi:10.1016/j.ajog.2018.03.028.

35. RECOMMENDATIONS ACCORDING TO VARIOUS
STUDIES
Study (year) Recommendations
Wani (2020) With respect to route of administration, it was seen that oral and
vaginal routes are equally efficacious for management of Threatened
Abortion and Prevention of Preterm labor. Oral NMP SR offers better
compliance and convenience to vaginal capsules
Boelig et al (2019) Oral progesterone appears to be effective for the prevention of
recurrent preterm birth and a reduction in perinatal morbidity and
mortality rates in asymptomatic singleton gestations with a history of
previous spontaneous preterm birth compared with placebo
Palshetkar et al
(2019)
The oral progesterone may be preferable in view of patient
compliance. Oral supplementation with sustained release progesterone
may show improved patient compliance
Piyush and
Krishnaprasad
(2018)
Oral natural micronized progesterone sustained release (NMP SR) can
be suggested for “primary” or “secondary” prophylaxis strategy for
high-risk pregnancies. Natural progesterone represents physiological
yet safer option for long-term supplementation in these cases while
avoiding complications of preterm delivery or infant mortality

36. RECOMMENDATIONS
ACCORDING TO VARIOUS
STUDIES
Study (year) Recommendations
Ashoush et al
(2017)
Oral micronized progesterone is effective in preventing
spontaneous preterm delivery. The additional advantages of
oral administration, affordability, and high safety profile make it
worth recommending, at least for further research
Malik and
Krishnaprasad
(2016)
Natural progesterone administered orally as sustained-release
(SR) formulation have significant beneficial role in LPD, LPS in
ART, bad obstetrics history, and for preterm labor. The monolith
dissolution controlled delivery system of oral NMP SR offers
improved patient compliance and convenience due to once a
day dosing and clinically feasible option as it achieves midluteal
“therapeutic” levels of Sr. progesterone ≥14 ng/mL as
suggested by MHRA guidelines
Am J Perinatol 2020;37:41–42

37. VARIOUS CLINICAL SCENARIOS
WHERE PROGESTERONE IS
RECOMMENDED
37

38. PREVIOUS PTB
• In women with a previous PTB,supplementation with
Hydroxyprogesterone caproate 250mg intramuscularly weekly or
micronised progesterone 100-200mg/day is started in the second
trimester(16-20weeks) and continued through 36+6weeks of
gestation.(Cochrane database)
• Serial cervical length ultrasound examinations from 14- 24weeks of
gestation should be performed and cerclage is considered if cervical
length ≤25mm.
38

39. SHORT CERVIX
• The preferred approach to prevent PTB in asymptomatic women with a
sonographically short cervix (≤25mm) is to start supplementation with
100mg vaginal progesterone upon diagnosis and to continue upto
36+6weeks
• Weekly Intramuscular hydroxyprogesterone caproate(250mg or 500mg)
did not reduce the risk of PTB in some studies.
39

40. • PPROM in current pregnancy- progesterone supplementation not
useful.
• H/O prior PPROM with PTB- benefit from progesterone in this
pregnancy
• Pregnancy with threatened PTL or established PTL –
progesterone did not reduce the risk of PTB
• TWIN PREGNANCY- neither 17 OHPC nor micronised
progesterone decreased the risk of PTB
• Pregnancy after ART or with uterine anomaly-there is paucity of
data on efficacy of progesterone
• The role of progesterone supplementation in women at high risk
of PTB and positive FFN has no supportive strong evidence.
40

41. CERVICAL ENCERCLAGE
• Prophylactic/elective cerclage should be considered in women
with history of more than two prior spontaneous preterm
births/second trimester losses
• Short cervix with history of PPROM in prev pregancy or cervical
trauma(NICE)
• Cochrane review concluded that
there is no evidence that cerclage
is an effective intervention in
multiple gestation.
41

42. 42

43. 43

44. METHODS OF CERCLAGE
• Trans vaginal cerclage-mcdonalds cerclage
• High trans vaginal cerclage-shirodkars
• Transabdominal cerclage
44

45. TOCOLYTICS ROLE?
• Only short term therapy is recommended
• Goal- to buy time for corticosteriod dosage, MgSo4 for neuroprotection
or to shift to a teritiary center for NICU care.
• Tocolysis is indicated for PTL between 24 and 34 wks.
• Maintainance tocolysis is ineffective and not recommended
45

46. ADJUNCTIVE
TREATMENTS???
• Antibiotics shouldnot be used to prolong gestation in women with PTL
and intact membranes
• Antibiotics are recommended in case of PPROM
• Bedrest for prevention of PTB shouldnot be routinely recommended
• Abstinence from sexual intercourse doesnot decrease the incidence of
PTL
46

47.  Prediction of PTL is done through risk factor screening,cervical
assessment and other biochemical genomic and proteomic markers
 Despite much research there is currently no single marker which can
accurately predict PTL.
 Combination of biochemical markers along with cervical parameters
increases the predictive value
 Progesterones and encerclage has proven benefit in preventing PTL
in pts with previous h/o PTB and short cervix
47

48. THANK YOU