Class 15, 1st year Introdução à Medicina II 28th May 2010 Mestrado Integrado em Medicina Progesterone supplementation can prevent preterm birth in women with short cervical length in second trimester pregnancy Intervention Outcome Population Class 15, 1st year Introdução à Medicina II 28th May 2010

Summary Background Motivations Aims Methodology Results Conclusions Preterm Birth Second trimester pregnancy Cervix Progesterone Motivations Aims Methodology Results Conclusions References

1. Background Preterm birth (PTB): Cervix: Second trimester pregnancy 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 falar sobre os aspectos iniciais introdutórios: _ the problem: PTB _ defined as… _ considered one of the main problems that lead to perinatal morbidity and mortality. _iIt has increased in the last years (due to the delayed child bearing and the growing frequency of multifetal pregnancies from assisted reproductive technology) _one of the possible causes: short cervix _defined as… in second trimester _ why? The cervix is involved in the maintenance of pregnancy: _ the endocervix produces a mucus, which forms a mucus plug _ the cervix remains closed through the most part of the pregnancy, assuring a sterile and safe environment for the baby. (Until the end of pregnancy, where it shortens and starts to open) A short cervix gradually opens due to the pressure caused by the increasing weight of the, becoming thinner and widener and ultimately causing an early delivery (PTB) _possible treatment: progesterone _can act as an antagonist of oxytocin (which has a major role in the delivery, stimulating contractions associated with labor), inhibiting its effects, causing the uterine muscles to relax and contract less. _ there are still controversies about its efects [1 ] How HY,et al, 2009 [2] Lee HJ, et al,, 2009 [3] Grimes-Dennis J, et al, 2007

Summary Background Motivations Aims Methodology Results Conclusions References

2. Motivations Lee HJ, MD, PhD et. al, Management of Pregnancies With Cervical Shortening: A Very Short Cervix Is a Very Big Problem, 2009 How HY, Sibai BM, Progesterone for the prevention of preterm birth: indications, when to initiate, efficacy and safety,2009

Summary Background Motivations Aims Methodology Results Conclusions 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

Summary Background Motivations Aims 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 Results Conclusions References

4. Methodology 4.1. Selection criteria Type of study: Systematic Review 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) We will only include articles that report the association between the use of progesterone supplementation and the prevention of PTB in a population of women with short cervix in second trimester pregnancy The quality of the articles, if too low, will also be na exclusion factor Search in: PubMed, ISI Web of Knowledge, SCOPUS, Cochrane database of SR

4. Methodology 4.2. 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 Outcome Population We used some mesh terms (in bold), wildcards(*) and many synonyms. We didn’t limit these searches to clinical trials nor to a specific date and we also chose not to use search filters in most of them. Instead we decided to make more sensitive searches in order to obtain a higher number of articles which we will then analyze.

4. Methodology 4.3. Articles’ selection Pubmed U ISI Web U Scopus U Cochrane 202 Articles #1 #4 #3 #2 DECISION 16 Articles 7 Included articles Primary selection: Title Abstract Second selection: Full article After having collected all of the articles, we eliminated the duplicated ones and end up with 202 articles. The articles were submitted to 2 selections: _1st: they were distributed by 4 groups of 2 elements who independently analyzed the title and the abstract and decided if the article should be included or excluded. We formed another group of 3 elements which intervened when the 2 reviewers had different opinions. This last group was formed by 3 elements that reached a final decision. _2nd : similar. However we analyzed the full article. The exclusion reasons were registered 14 articles weren’t available: we contacted the respective authors via e-mail asking the full text article. We are still waiting for the answers We send e-mails to some of the responsible of ongoing clinical trials in order to obtain more informations

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 The articles were randomly distributed to groups of 2 elements who read them and reach to a consensus about their quality, classifying them according to… The quality of the articles was assessed using an established list16, which we find to be similar to the Consort list, having in addition a quantitative scale from 0 to 100 to classify the article, which made comparisons between articles easier and more efficient. Each article was analyzed by 2 elements independently. We didn’t exclude any article since all of them fulfilled our criteria (the score was superior to 60 points, the lowest score was 70,5).

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 ultrasonography Cervical lenght <=15mm Cervical lenght <28mm Cervical length<25mm Participants 250 women (cervical length<15mm): Vaginal progesterone group: 125 Placebo group: 125 46 women (cervical lenght <28mm) Vaginal progesterone group:19 Placebo group:27 Women with prior preterm birth, 152 received cerclage 148 did not receive cerclage Intervention Vaginal progesterone: 200mg capsules Placebo: 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

4. Methodology 4.5. Data extration Articles Facchinetti et al, 2007 Keeler et al, 2009 Short cervix assessment and definition Transvaginal ultrasound CL<=25 mm CL<25 mm Participants Women with singleton pregnancy, who were hospitalized for preterm labor 30 women received 17P 30 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) Aqui só aparecem 5 artigos porque os outros 2 são complementos. Por isso não valia a pena referir É preciso dizer isto (oralmente)…

4. Methodology 4.6. Data management Review Manager 5 SPSS statistics 18

4. Methodology 4.7. 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. Methodology 4.7. Data analysis Homogeneous Heterogeneous Metanalysis Subgroups Statistical Analysis of Data

Summary Background Motivations Aims Methodology Results Conclusions References

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

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

Summary Background Motivations Aims Methodology Preliminary results Conclusions 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.