Progesterone

supplementation

can prevent preterm birth

in women with short cervical

length

in second trimester

pregnancy

Class 15, 1st yearIntrodução à Medicina II 28th May 2010

Mestrado Integrado em Medicina

Intervention

Outcome

Population

Summary

1. Background Preterm Birth Second trimester pregnancy Cervix Progesterone

2. Motivations

3. Aims

4. Methodology

5. Results

6. Conclusions

7. References

1. Background Preterm birth (PTB): Birth before 37 weeks of

gestation [1,2]

Cervix: Lower end of uterus

Normal: 3-5 cm [3]

Short: Inferior to 2.5cm [2]

Second trimester

pregnancy 15th-28th week

Progesterone[1 ] How HY,et al, 2009 [2] Lee HJ, et al,, 2009 [3] Grimes-Dennis J, et al, 2007

Summary

1. Background

2. Motivations

3. Aims

4. Methodology

5. Results

6. Conclusions

7. References

How HY, Sibai BM, Progesterone for the prevention of preterm birth: indications, when to initiate, efficacy and safety,2009

Lee HJ, MD, PhD et. al, Management of Pregnancies With Cervical Shortening: A Very Short Cervix Is a Very Big Problem, 2009

2. Motivations

Summary

1. Background

2. Motivations

3. Aims

4. Methodology

5. Results

6. Conclusions

7. References

3. Aims

Summarize the available information and explain the

possible controversies

Assess the efficacy of progesterone supplementation in the

prevention of PTB associated to short cervical length in

second trimester pregnancy

Assess the effects of different types of progesterone and

types of progesterone administration

Summary1. Background

2. Motivations

3. Aims

4. Methodology:

4.1. Selection criteria

4.2. Query selection

4.3. Articles’ selection

4.4 Quality assessment

4.5. Data extraction

4.6. Data management

4.7. Data analysis

5. Results

6. Conclusions

7. References

4. Methodology 4.1. Selection criteria

Inclusion Criteria Exclusion Criteria

Progesterone prevention of preterm birth short cervix

Type of study:

Randomized Clinical

Trials

Date:

Articles not published in the

last 10 years

Language:

Other than Portuguese,

English, French or Spanish

Quality rate (less than 60

points)

Search in: PubMed, ISI Web of Knowledge, SCOPUS, Cochrane database of SR

Type of study: Systematic Review

4. Methodology4.2. Query selection

(progesterone OR progest*) AND (cervix or cervic*) AND

(premature birth OR ((preterm OR premature) AND (birth OR

delivery OR labour)) OR prematur*) AND (pregnancy OR

pregnancy trimester, second OR midtrimester OR second

trimester OR midpregnancy)Intervention

OutcomePopulatio

n

4. Methodology4.3. Articles’ selection

Pubmed U ISI Web U Scopus U Cochrane

202 Articles

#1 #4#3#2

DECISION

16 Articles

#1 #4#3#2

DECISION

7 Included articles

Primary selection:

• Title

• Abstract

Second selection:

• Full article

4. Methodology 4.4. Quality assessment

Criteria used

extracted from

Sindhu, Carpenter et

al. 1997[6]

Numerical rate (0-

100):

To facilitate

comparisons between

studies

Article to rate

Discussion and Consensus

Rating

Reader no.1

Group no. x

Reader no.2

4. Methodology 4.4. Quality assessment

Sindhu, Carpenter et al. 1997[6]

4. Methodology 4.5. Data extration

Participants Number of participants General caracteristics:

Race

Age

Singleton or twin pregnancy

Obstetrical history

Methods How the cervical length

condiction was assessed? Main features of study :

Randomised intervention Allocation concealment

Exclusion criteria

Outcomes

Only the ones that show relation

between PTB and progesterone

supplementation

Intervention Type of progesterone Administration aspects:

Dosages Application moment Application period

4. Methodology 4.5. Data extration

Articles Fonseca EB et al, 2007

DeFranco EA et al, 2007

Berghella et al, 2010

Short cervix assessment and definition

Transvaginal ultrasonographyCervical lenght <=15mm

Transvaginal ultrasonographyCervical lenght <28mm

Transvaginal ultrasonographyCervical length<25mm

Participants 250 women (cervical length<15mm):Vaginal progesterone group: 125Placebo group: 125

46 women (cervical lenght <28mm)Vaginal progesterone group:19Placebo group:27

Women with prior preterm birth,152 received cerclage 148 did not receive cerclage

Intervention

Vaginal progesterone: 200mg capsulesPlacebo: safflower oil Daily treatment

vaginal gel (containing 90 mg of progesterone)placebo: identical bioadhesive delivery system, but without progesterone. daily treatment

17 alpha-hydroxyprogesterone dose:250mg intramusculary starting at 16 weeksand continued weekly until 36 weeks

Articles Facchinetti et al, 2007 Keeler et al, 2009

Short cervix assessment and definition

Transvaginal ultrasoundCL<=25 mm

Transvaginal ultrasoundCL<25 mm

Participants Women with singleton pregnancy, who were hospitalized for preterm labor

30 women received 17P30 women did not receive 17P

Patients (asymptomatic, singleton pregnancies) with a cervical length (N=75)

Intervention Patients who were enrolled as cases received 341 mg of 17P intramuscularly every 4 days, until gestational week 36. The remaining patients were included as control subjects and received no drugs.

McDonald cerclage (N=42) or weekly intramuscular injections of 17OHP-C (N=37)

4. Methodology 4.5. Data extration

4. Methodology4.6. Data management

Review Manager 5

SPSS statistics 18

4. Methodology4.7. Data analysis

Based on tables and forest plot

Relative risk as effect measure

95% Confidence interval as dispersion measure

Statistical method:

Inverse variance

Heterogeneity:

Observed using Chi-Square test

4. Methodology4.7. Data analysis

Homogeneous

Heterogeneous

Metanalysis

Subgroups

Statistical Analysis of Data

Summary

1. Background

2. Motivations

3. Aims

4. Methodology

5. Results

6. Conclusions

7. References

5. Results

Study or Subgroup

Am J Obstet Gynecol 2010 (1)N. Eng. Med 2007 (2)Obstet Gynecology 2007 (3)

Total (95% CI)

Total eventsHeterogeneity: Chi² = 1.94, df = 2 (P = 0.38); I² = 0%Test for overall effect: Z = 2.53 (P = 0.01)

Events

20268

54

Total

5212519

196

Events

444516

105

Total

10012527

252

Weight

41.4%40.3%18.4%

100.0%

IV, Fixed, 95% CI

0.87 [0.58, 1.32]0.58 [0.38, 0.87]0.71 [0.38, 1.31]

0.71 [0.55, 0.93]

Progesterone Placebo Risk Ratio

(1) Intramuscular 17-alpha-hydroxyprogesterone caproate - 250mg; Spontaneous delivery <35 weeks(2) Vaginal Progesterone - 200mg; Spontaneous delivery at <34 weeks(3) Vaginal progesterone - 90mg; Spontaneous delivery at <37 weeks.

Risk RatioIV, Fixed, 95% CI

0.2 0.5 1 2 5Favours progesterone Favours placebo

Heterogeneity condition wasn’t verified. So, we will perform a metanalysis

5. Results

Study or Subgroup

Am J Obstet Gynecol 2010 (1)J Perinat. Med 2009 (2)

Total (95% CI)

Total eventsHeterogeneity: Chi² = 0.00, df = 1 (P = 0.98); I² = 0%Test for overall effect: Z = 0.87 (P = 0.39)

Events

2022

42

Total

5237

89

Events

3422

56

Total

10142

143

Weight

44.4%55.6%

100.0%

IV, Fixed, 95% CI

1.14 [0.74, 1.77]1.14 [0.77, 1.68]

1.14 [0.85, 1.53]

Progesterone Cerclage Risk Ratio

(1) Intramuscular 17-alpha-hydroxyprogesterone caproate - 250mg; Spontaneous delivery <35 weeks(2) Intramuscular 17-alpha-hydroxyprogesterone caproate - 250mg; McDonald cerclage; Spontaneous birth <35 weeks

Risk RatioIV, Fixed, 95% CI

0.2 0.5 1 2 5Favours progesterone Favours cerclage

Heterogeneity condition wasn’t verified. So, we will perform a metanalysis

Summary

1. Background

2. Motivations

3. Aims

4. Methodology

5. Preliminary results

6. Conclusions

7. References

6. Conclusions

The analysis of these articles suggests that

progesterone might prevent preterm birth in

women with short cervix on second

trimester. However, there is no evidence that it

has a higher effect on the prevention of PTB than

cerclage.

7. References [1] How HY, Sibai BM. Progesterone for the prevention of preterm

birth: indications, when to initiate, efficacy and safety. Ther Clin Risk Manag. 2009 Feb;5(1):55-64.

[2] Lee HJ, Park TC, Norwitz ER. Management of Pregnancies With Cervical Shortening: A Very Short Cervix Is a Very Big Problem. Rev Obstet Gynecol.2009 Spring;2(2):107-15.

[3] Grimes-Dennis J, Berghella V. Cervical length and prediction of preterm delivery. Curr Opin Obstet Gynecol. 2007 Apr ;19(2):191-5.

[4] Denney JM, Culane JF, Goldenberg RL. Prevention of preterm birth. Womens Health (Lond Engl). 2008 Nov;4(6):625-38

[5] Thornton JG. Progesterone and preterm labor--still no definite answers. N Engl J Med. 2007 Aug 2;357(5):499-501.

[6] Sindhu, F., L. Carpenter, et al. (1997). "Development of a tool to rate the quality assessment of randomized controlled trials using a Delphi technique." Journal of Advanced Nursing 25: 1262-1268.