• Every year, an estimated 15 million babies are born preterm (before 37 completed weeks of gestation), and this number is rising. • Preterm birth complications are the leading cause of death among children under 5 years of age, responsible for approximately 1 million deaths in 2015 (1). • Three-quarters of these deaths could be prevented with current, cost-effective interventions. • Across 184 countries, the rate of preterm birth ranges from 5% to 18% of babies born. Preterm is defined as babies born alive before 37 weeks of pregnancy are completed. There are sub-categories of preterm birth, based on gestational age: • extremely preterm (less than 28 weeks) • very preterm (28 to 32 weeks) • moderate to late preterm (32 to 37 weeks). Preventing deaths and complications from preterm birth starts with a healthy pregnancy. Quality care before, between and during pregnancies will ensure all women have a positive pregnancy experience. WHO’s antenatal care guidelines include key interventions to help prevent preterm birth, such as counselling on healthy diet and optimal nutrition, and tobacco and substance use; fetal measurements including use of ultrasound to help determine gestational age and detect multiple pregnancies; and a minimum of 8 contacts with health professionals throughout pregnancy to identify and manage other risk factors, such as infections. Better access to contraceptives and increased empowerment could also help reduce preterm births. Preterm birth occurs for a variety of reasons. Most preterm births happen spontaneously, but some are due to early induction of labour or caesarean birth, whether for medical or non-medical reasons. Common causes of preterm birth include multiple pregnancies, infections and chronic conditions such as diabetes and high blood pressure; however, often no cause is identified. There could also be a genetic influence. Better understanding of the causes and mechanisms will advance the development of solutions to prevent preterm birth. More than 60% of preterm births occur in Africa and South Asia, but preterm birth is truly a global problem. In the lower-income countries, on average, 12% of babies are born too early compared with 9% in higher-income countries. Within countries, poorer families are at higher risk.

1. PRE-TERM BIRTH & ROLE OF PROGESTERONE
DR ALKA MUKHERJEE
DR APURVA MUKHERJEE
NAGPUR M.S. INDIA

2. DR ALKA MUKHERJEE
MBBS DGO FICOG FICMCH PGDCR PGDMLS MA(PSY)
Director & Consultant At Mukherjee Multispecialty Hospital
MMC ACCREDITATED SPEAKER
MMC OBSERVER MMC MAO – 01017 / 2016
Present Position
 Director of Mukherjee Multispecialty Hospital
 Hon.Secretary INTERNATIONAL COUNCIL FOR HUMAN RIGHTS
 Hon.Secretary NARCHI NAGPUR CHAPTER (2018-2020)
 Hon.Secretary AMWN (2018-2021)
 Hon.Secretary ISOPARB (2019-2021)
 Life member, IMA, NOGS, NARCHI, AMWN & Menopause
Society, India, Indian medico-legal & ethics association(IMLEA),
ISOPRB, HUMAN RIGHTS
 Founder Member of South Rapid Action Group, Nagpur.
 On Board of Super Specialty, GMC, IGGMC, AIIMS Nagpur,
NKPSIMS, ESIS and Treasury, Nagpur for “ WOMEN SEXUAL
HARASSMENT COMMITTEE.”
mukherjeehospital@yahoo.com
www.mukherjeehospital.com
https://www.facebook.com/
Mukherjee Multispeciality
https://www.instagram.com/
Achievement
 Winner of NOGS GOLD MEDAL – 2017-18
 Winner of BEST COUPLE AWARD in Social
Work - 2014
 APPRECIATION Award IMA - MS
 Past Position
 Organizing joint secretary ENDO-GYN
2019
 Vice President IMA Nagpur (2017-2018)
Vice President of NOGS(2016-2017)
Organizing joint secretary ENDO-GYN
Organizing secretary AMWICON – 2019

3. Introduction
• WHO defines preterm birth as all births before 37 completed
weeks of gestation, or fewer than 259 days from the first
date of a woman's last menstrual period
• Preterm labor is responsible for 75% of neonatal mortality
Indian Obstetrics & Gynecology. 2014; 4(2): 16-23
Emerg (Tehran). 2017; 5(1): e3.

4. Classification of PTB
• Spontaneous:
– Approximately 40-50% are due to spontaneous preterm
labor with intact membranes and 25-40% due to preterm
premature rupture of the membranes (PPROM)
• Indicated:
– Deliberate intervention for variety of maternal or
obstetric indications 20-30%.
Preterm birth: Risk factors, interventions for risk reduction, and maternal prognosis. Upto Date
https://www.uptodate.com/contents/preterm-birth-risk-factors-interventions-for-risk-reduction-and-maternal-prognosis/print

5. CLASSIFICATION OF PRETERM BIRTH

6. Epidemiology
• Worldwide, 11.1% of infants
are born preterm every year
• PTB is the leading cause of
perinatal morbidity and
mortality
• It the 2nd most common cause
of death, after pneumonia, in
children under 5 years of age
Phillips C et al. BMJ Open 2017;7:e015402.

7. CAUSES OF PRETERM BIRTH

9. Pathophysiology
Obstetrics and Gynecology 7 Ed. Chapter 15. Preterm Labor.
(https://doctorlib.info/gynecology/obstetrics-gynecology/15.html)

11. Risk Factors – Maternal, Medical & Pregnancy
risk factors
• Previous PTB
• Short-cervical length
• Uterine anomalies
• <18 or > 35 years
• Vaginal bleeding
• Multiple gestation
• Assisted reproduction
• PPROM
Iran J Reprod Med. 2014 Jan; 12(1): 47–56.

12. Risk Factors – Maternal, Medical &
Pregnancy RF
• Genital & Urinary tract
infections Previous PTB
• Vaginal bleeding
• Cigarette smoking
• High or Low BMI
• Low socioeconomic status
• Ethnicity
• Fetal fibronectin +ve
• Surgical procedure of cervix
Iran J Reprod Med. 2014 Jan; 12(1): 47–56.

13. Etiology
• Cause unidentified in 50% of PTB
• Majority of women with risk factors have no PTB
• Many women with PTB have no risk factors
• 7%- singletons, 60% - Multiple gestation
BMC Pregnancy and Childbirth (2018) 18:107

14. Cervical Ultrasonography And The Prediction Of
Preterm Birth
• Strong inverse relationship between cervical length and
likelihood of spontaneous pre term birth before 35 weeks*
• Cervical length is stable in the first & second trimester
• Mid trimester evaluation of the cervix is important
N Eng J Med 1996; 334:567-72

15. Cervical Length
• Cervical length measurement can be used to identify
increased risk of preterm birth in asymptomatic women at <
24 weeks
• Definitely indicated in h/o PTB
• There is no consensus on the optimal timing or frequency of
serial evaluations of cervical length

16. Cervical length - Ultrasound
Trans vaginal.
Trans perineal
routes
Trans Abdominal

17. Transvaginal
• Ideal – May not be possible always
• Empty bladder and the vaginal probe should be placed in the
anterior fornix
• Three measurements should be made over a 5 min period
and the shortest measurement reported for clinical use

18. Reference Range
• A single cut-off 25mm between 18 and 24 weeks gestation
• Cervical length of 30mm (10th centile), 27mm (5th centile)
and 22mm (2.5th centile) gave relative risks of preterm birth
prior to 37 weeks of 3.8, 5.4 and 6.3 respectively
RANZCOG. July ZO17

19. Transabdominal USG
• Transabdominal partially full bladder is a potential first line
screening test
• A transabdominal cervical length greater than 35mm
precludes a transvaginal cervical length below 25mm with
over 95% sensitivity
RANZCOG. July ZO17

20. Cervical length Measurement
• Previous PTB
• Multiple pregnancy
• Uterine anomalies
• Excisional surgeries - Cervix
Australas J Ultrasound Med. 2013 Aug; 16(3): 124–134

21. Transvaginal Cervical Length
• Shorter the cervical length, the greater the risk of PTB
– Recommend TVCL to women with identified or suspected
PTL (if available)
– Consider therapeutic interventions when TVCL is <25mm
Queensland Clinical Guideline: Preterm labour and birth
https://www.health.qld.gov.au/__data/assets/pdf_file/0019/140149/g-ptl.pdf

22. Biomarkers
A. Fetal fibronectin
 It is an extracellular matrix glycoprotein found between
the chorion and decidua – vaginal fluid < 18 weeks –
fusion of decidua and fetal membranes
 Positive result : 50 ng/mL
B. Inflammatory markers and cytokines

23. Fetal Fibronectin Test
• Current evidence suggest routine use of FFN alone in women
with threatened PTL is not justifiable
• Combination of CL and FFN assessment may improve
prediction of SPTB particularly in those with a CL of 15–30
mm
Moeun et al. Semin Perinatol. 2017 December ; 41(8): 445–451.

24. LONG TERM
CONSEQUENCES
IN
PRETERM
BABIES

25. Prevention Strategies In PTB
Frontiers In Immunology. REVIEW ARTICLE published: 19 November 2014. doi: 10.3389/fimmu.2014.00584

26. Cervical Cerclage – In which patients?
• In patients with
– History of preterm births, classically recurrent and
painless second trimester losses
– Shortening of the cervix on ultrasound imaging
– Short or dilated cervix on physical examination
Frontiers In Immunology. REVIEW ARTICLE published: 19 November 2014. doi: 10.3389/fimmu.2014.00584

27. CERVICAL CIRCLAGE
MACDONALDS/SHIRODKARS
J Matern Fetal Neonatal Med. 2019; 32(20): 3408-3414

28. Rescue Circlage
• For women between 16+0
and 27+6 weeks of
pregnancy
• Dilated cervix
• Exposed, unruptured fetal
membranes
Do not offer
• Signs of infection
• Active vaginal bleeding
• Uterine contractions

29. Management
• Admit for observation
• Consider if in-utero transfer
is indicated
• Offer analgesia
• Administer corticosteroids
• Measure TVCL (if available)
• Discuss plan with women
and document
• Clinical reassessment as
required

30. Tocolysis
• May delay birth
and allow:
– In utero-transfer
– Corticosteroid
administration
– MgSO4
administration

32. Tocolytics
• Beta agonists have a higher frequency of adverse effects
• Nifedipine, atosiban and COX-2 inhibitors – how they
compare with each other is unclear
• Use of multiple tocolytics should be avoided side effects

34. TOCOLYTICS
• Nifedipine and atosiban have comparable effectiveness in
delaying birth for up to 7 days
• Compared with beta-agonists nifidipine is associated with
improvement in neonatal outcome although they are no
long term data

35. Nifidipine
• Only oral drug
• Initial oral dose of 20mg followed by 3 to 4 times daily up to
48 hrs
• >60 mg per day – adverse reactions increase
Am J Obstet Gynecol. 2011 Feb; 204(2): 134.e1–134.20.

36. Atosiban
• Oxytocin antagonist
• Dose:
– Initial bolus of 6.75mg over in 1min followed by infusion
of 18mg/hr for 3 hours then 6mg/hr for up to 45 hrs (to a
max. of 330mg)
Clinical Medicine Insights: Women’s Health 2011:4 9–16

37. Tocolytics
• ? Benefit in preterm labor in multiple pregnancy
• ? Role in maintenance therapy – Not recommended
• Main role – To reduce the number of deliveries within 48hrs
or within 7days of commencing the drug

38. Tocolysis in Prevention of PTB
• Meta-analyses (Miyazaki C et al, 2016)
• No significant difference was found for the relative
effectiveness of tocolytics versus placebo
– for prolonging pregnancy in women with extremely preterm birth
(RR 1.04) or
– reducing the rate of perinatal deaths (RR 2.22)
• There is no evidence to draw conclusions on the
effectiveness of tocolytic therapy for women with
threatened extremely preterm birth, multiple gestations,
and growth-restricted babies
Miyazaki, C., Reprod Health 13, 4 (2016) doi:10.1186/s12978-015-0115-7

39. Corticosteroids
FIGO recommendation
• Clinicians should offer a single course of prenatal
corticosteroids to all women between 24 and 34 weeks of
gestation who are at risk of preterm birth within 7 days.
Int J Gynecol Obstet 2019; 144: 352–355

40. Magnesium Sulphate
• For neuroprotection of the baby to women between 24+0 to 33 weeks
• 4gm intravenous loading dose MgSO4 over 20min, followed by an
intravenous infusion of 1gm/hr until the birth or for 12hrs (whichever is
sooner)
• Monitor for side effects – Maternal – DTR, Pain, Contractions
• Maintain Serum Mg level – 4-7mg/dl
• Keep antidote Calcium gluconate ready – 1 gm IV Over 3 minutes
• Observe newborn for 24-48 hours for magnesium effects if drug was
given to mother before the delivery.
J Gynecol Obstet Biol Reprod (Paris). 2016 Dec;45(10):1418-1433

41. INDICATIONS
FOR
USE
OF
PROGESTERONE

42. Progesterone Supplementation
• Used in prevention of PTB from decades
• Exact mechanism of action is unknown
• Two possible mechanisms of action are
– an anti-inflammatory action that may counteract the
inflammatory process that is involved in initiation of
labor
– Second is a possible functional withdrawal of
progesterone through changes in progesterone receptors
and their transcriptional activity at a tissue level
Front Immunol. 2014; 5: 584.

45. Actions of Progesterone on the Myometrium
• Decreases conduction of contractions
• Increases threshold for stimulation
• Decreases spontaneous activity
• Decreases number of oxytocin receptors
• Prevents formation of gap junctions

46. Recommendations for Use
(ACOG Oct, 2012)
• A women with a singleton gestation and prior SPTB should
be offered progesterone supplementation starting at 16-24
wks gestation, regardless of transvaginal ultrasound cervical
length, to reduce the risk of recurrent spontaneous PTB
• Vaginal progesterone is recommended as a management
option to reduce the risk of PTB in asymptomatic women
with an incidentally identified very short cervical length les
than or equal to 20mm before or at 24 wks of gestation

47. Recommendations for Use
(ACOG Oct, 2012)
• Progesterone treatment does not reduce the incidence of
PTB in women with twin or triplet gestation and therefore, is
not recommended as an intervention to prevent PTB in
women with multiple gestation
• Insufficient evidence exists to assess if progesterone and
cerclage together have an additive effect in reducing the risk
of PTB in women at high risk for PTB

48. Prenatal Administration of Progesterone for
preventing PTB In High Risk Women
• Cochrane Systemic Review, (Dodd JM et al. 2013)
• 36 RCTs (8523 women and 12,515 infants)
• Progesterone therapy significantly reduce the risk of
– preterm birth <34 weeks (RR 0.31 95% CI 0.14–0.69)
– preterm birth <37weeks (RR 0.55, 95% CI 0.42–0.74)
– perinatal death (RR 0.50, 95% CI 0.33–0.75)
• Progesterone therapy significantly reduce
– Need for assisted ventilation (RR 0.40, 95% CI 0.18–0.90)
– Necrotizing Enterocolitis (RR 0.30, 95% CI 0.10–0.89),and
– Admission to neonatal intensive care(RR 0.24, 95% CI 0.14–0.40)
Dodd JM et al. Cochrane Database Syst Rev. 2013 Jul 31;(7):CD004947.

49. Effectiveness of Progesterone
• 5-6 women with a previous sPTB would need to be treated
to prevent one birth <37 weeks
• 12 women with a previous sPTB birth would need to be
treated to prevent one birth <32 weeks
Meis et al. N Engl J Med. 2003 Jun 12;348(24):2379-85.

50. PROGESTERONE SUPPLEMENTATION
Type Route Dose (mg) Interval
17-alpha-OHPC Intramuscular injection 250 Weekly
Natural micronized
progesterone
Vaginal suppository 100, 200, 400 Daily
Vaginal gel 90 Daily
Oral capsule 200, 400 Daily
Obstet Gynecol Sci 2017;60(5):405-420

51. AVAILABLE PROGESTERONE
Vaginal Natural micronized progesterone suppositories
• Optimal dose and its efficacy in pre-term labour require further
evidence
• Daily administration
• Vaginal route results in higher concentrations in the uterus but
does not reach high and constant blood levels.
Vaginal progesterone gel
• Need specific applicator
Oral Capsule
• Metabolized in liver and loses its potency
• Irregular blood concentration
• Frequent side effects
Obstet Gynecol Sci 2017;60(5):405-420

52. 17 alpha-hydroxy-progesterone Caproate
(17-OHP)
• First introduced in 1950
• Synthetic progesterone with a longer half-life of 7
days
• Dose: 250mg/week
• Intramuscular injection
• Only US-FDA approved progestin for prevention
of pre-term birth
Progesterone
17-alpha-hydroxyprogesterone
Semin Perinatol. 2016 Aug;40(5):273-80.

53. Pharmacokinetics
Parameters
Absorption • Tmax : 4.6 (±1.7) days
• Half life: 7.8 days
Distribution • Extensively binds to plasma proteins
Metabolism • Undergoes in extensive reduction,
hydroxylation and conjugation
Excretion • Feces ~ 50%
• Urine ~ 30%

54. NICHD: MFMU Progesterone Trial
• Aim: To establish if weekly progesterone injections in
women with prior spontaneous preterm delivery (sPTD)
reduces the risk of PTD
• Design: double-masked, placebo-controlled trial
• Eligibility criteria: singleton pregnancy 16-20 wks with
documented previous sPTD
• Intervention: progesterone or placebo
• Primary outcome: delivery at < 37 weeks’
• Sample: 463 pregnant women
Meis et al. N Engl J Med. 2003 Jun 12;348(24):2379-85.

55. 0%
10%
20%
30%
40%
50%
60%
< 37 <35 <32
P<0.0001 P<0.0165 P<0.0180
17 P
17 P
17 P
Placebo
Placebo
Placebo
Meis et al. N Engl J Med. 2003 Jun 12;348(24):2379-85.

56. PROGESTERONE PREVENTS NEONATAL COMPLICATIONS
• Treatment with 17P resulted in improved neonatal
outcomes
• Reduced the likelihood of several complications
Meis et al. N Engl J Med. 2003 Jun 12;348(24):2379-85.

57. Compliance & Safety
• Compliance with the weekly injections was excellent
• 91.5% of the women received their injections at the
scheduled time
• Side effects were minor and were similar in the 17P and
placebo groups
Meis et al. N Engl J Med. 2003 Jun 12;348(24):2379-85.

58. Meta-analysis of 17P in pregnancy
• Meta-analysis by Keirse MJ, 1990
• 5 trials: high risk women with 17-hydroxyprogesterone caproate
injection
• Pooled analysis of results showed:
• Reduction in rates of preterm birth
Odds ratio 0.50, 95% CI: 0.30-0.85
• Reduction in rates of low birthweight
Odds ratio 0.46, 95% CI: 0.27-0.80
Keirse MJNC. Br J Obstet Gynecol 1990;97:149

59. 17-OHP in High Risk Women
• M Ibrahim et al. 2010
• N= 50 eligible women in their second trimester with a
history of previous preterm labor
• Treatment: 17-OHPC 250mg/week in 24th until the 34th
week or placebo
Middle East Fertility Society Journal. 2010; 15(1): 39-41

60. Neonatal Outcome Between Progesterone & Placebo Groups
Middle East Fertility Society Journal. 2010; 15(1): 39-41
• Delivery at <37 gestational weeks was reduced by 20% compared with the
placebo group
• Neonatal delivery, birth weight, NICU stay, and Apgar scores were more favorable
in the 17-OHCP group
• 17-OHPC was effective drug in prevention of preterm birth
PCU – pre-natal care utilization
NICU – Neonatal Intensive Care Unit

61. Efficacy of Progesterone for Prevention of Preterm Birth
• Preterm birth (PTB) occurs in 5-18% of pregnancies
• This review supports the efficacy of prophylactic progesterone
Sykes L, Bennett PR. Best Pract Res Clin Obstet Gynaecol.
2018;52:126‐136.
Understanding if, How, and Why Women with
Prior Spontaneous Preterm Births are Treated
with Progestogens: A National Survey of
Obstetrician Practice Patterns
• Vaginal progesterone 100 mg or placebo, with a significant
reduction of PTB < 37 weeks (13.8% vs. 28.5%; p = 0.05)
Gallagher JR et al. AJP Rep. 2018 Oct; 8(4): e315–e324

62. https://www.medscape.com/answers/260998-168197/what-is-the-efficacy-of-progesterone-therapy-to-reduce-
preterm-labor
(accessed on 24th May 2020)

63. NIH
• The only preventive drug therapy is progesterone, given to
women who are at higher risk of preterm birth
• This reduces chances of preterm birth by one third
• Therapy starts at 16 weeks and continues to 37 weeks of
pregnancy

64. ACOG Oct, 2019
• Clinical guidance : PROLONG STUDY
• Trial comparing the efficacy of 17-OHPC 250mg i.m. injection
weekly compared with placebo
• Large multicentre trial randomised, controlled, double blind
trial from Nov.2009 to Oct.2018
• Almost 1877 women, at 93 facilities across 9 countries
• Women were randomised between 16-20 weeks of gestation

65. • Fernandez-Macias R et al. 2019
• Objective : To determine whether mid-trimester 17-OHPC reduces
the risk of recurrent preterm birth and adverse perinatal
outcomes
• Selection criteria: Inclusion criteria were women between 16 and
26+6 weeks of pregnancy with history of preterm delivery in any
pregnancy randomized to either 17-OHPC or placebo/no
treatment
Int J Gynaecol Obstet. 2019 Nov;147(2):156-164

66. 17-Progesterone caproate In Prevention of Recurrent PTB
• Four Studies included
• The reduction in neonatal death
was 68%
Int J Gynaecol Obstet. 2019 Nov;147(2):156-164
p=0.021p=0.001
p=0.004
17-OHPC reduces the risk of
• recurrent preterm birth before 37 weeks of pregnancy,
• neonatal death, and birthweight less than 2500 g in women with non-selected cervical
length in the 2nd trimester

67. Supplementation with progestogens in the first trimester of
pregnancy to prevent miscarriage in women with unexplained
recurrent miscarriage: a systemic review and meta-analysis of
randomized, controlled trials
Saccone G et al. . Fertil Steril. 2017;107(2):430‐438

68. Progesterone – Vaginal or I.M. in PTB
• Debate is ON
• For whom & what stage
• ? Patient preference and compliance

69. THE EPPPIC Trial
• Evaluating Progestogens for Prevention of Preterm Birth
International Collaborative (EPPPIC)
• Evaluate:
– Effectiveness of progestogen versus no active
intervention
– Effectiveness of vaginally administered progesterone
versus 17-OHPC versus oral progesterone
Syst Rev. 2017 Nov 28; 6(1): 235

70. Summary
• Pre-term birth is a major public health problem
• Pre-term is leading cause of morbidity and death of newborn
infants
• First and only agent to date approved for marketing by the
United States Food and Drug Administration (FDA) for
prevention of recurrent preterm birth
• Trials of 17-OHPC have shown consistent efficacy in reducing
pre-term delivery in women with a history of a previous pre-
term delivery