Jogc-jan-08.vp

SOGC TECHNICAL UPDATE
SOGC TECHNICAL UPDATE
The Use of Progesterone for Prevention of
Preterm Birth
represents an abstraction of the evidence rather than a This technical update has been reviewed by the Maternal Fetal methodological review. The level of evidence and quality of Medicine Committee and approved by the Executive of the Society recommendations are described using the criteria and of Obstetricians and Gynaecologists of Canada.
classifications of the Canadian Task Force on Preventive HealthCare (Table 1).
PRINCIPAL AUTHORS
Values: This update is the consensus of the Maternal Fetal Medicine
Committee of the Society of Obstetricians and Gynaecologists of Benefits, Harms, and Costs: Counselling the patient at increased
risk for PTL should include consideration of the potential benefits MATERNAL FETAL MEDICINE COMMITTEE
of progesterone use and our lack of/limited knowledge of many neonatal outcomes and optimal dosing.
Sponsor: Society of Obstetricians and Gynaecologists of Canada.
Recommendations
1. Women at risk for PTL should be encouraged to participate in studies on the role of progesterone in reducing the risks of pretermlabour. (I-A) Savas Michael Menticoglou, MD, Winnipeg MB 2. Women should be informed about the lack of available data for many neonatal outcome variables and about the lack of Lynn Carole Murphy-Kaulbeck, MD, Allison NB comparative data on dosing and route of administration. Women with short cervix should be informed of the single large RCTshowing the benefit of progesterone in preventing PTL. (I-A) 3. Women and their caregivers should be aware that a previous preterm labour and/or short cervix (< 15 mm at 22–26 weeks’ gestation) on transvaginal ultrasound could be used as anindication for progesterone therapy. The therapy should be startedafter 20 weeks’ gestation and stopped when the risk of prematurityis low. (I-A) 4. On the basis of the data from the RCTs and meta-analysis, it is Abstract
recommended that in cases where the clinician and the patienthave opted for the use of progesterone the following dosages Objective: To introduce new information on the use of progesterone
to prevent premature labour and to provide guidance to obstetrical • For prevention of PTL in women with history of previous PTL: caregivers who counsel women on the merits of this choice 17 alpha- hydroxyprogesterone 250 mg IM weekly (IB) or Options: This discussion is limited to progesterone therapy for
progesterone 100 mg daily vaginally. (I-A) prevention of preterm labour (PTL) in women at increased risk of PTL.
• For prevention of PTL in women with short cervix of < 15 mm Evidence: A search of both Medline and the Cochrane Library
detected on transvaginal uktrasound at 22–26 weeks identified the most relevant medical evidence. This document progesterone 200 mg daily vaginally. (I-A) Key Words: Preterm labour, progesterone, short cervix, prematurity
This technical update reflects emerging clinical and scientific advances as of the date issued and is subject to change. The
information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can
dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
JANUARY JOGC JANVIER 2008 l
SOGC TECHNICAL UPDATE
Table 1. Key to evidence statements and grading of recommendations, using the ranking of the
Canadian Task Force on Preventive Health Care
Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive II-2: Evidence from well-designed cohort (prospective or C. The existing evidence is conflicting and does not allow to retrospective) or case-control studies, preferably from more make a recommendation for or against use of the clinical preventive action; however, other factors may influencedecision-making II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in D. There is fair evidence to recommend against the clinical uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this E. There is good evidence to recommend against the clinical III: Opinions of respected authorities, based on clinical There is insufficient evidence (in quantity or quality) to make experience, descriptive studies, or reports of expert a recommendation; however, other factors may influence *The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Forceon Preventive Health Care.30†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the The CanadianTask Force on Preventive Health Care.30 INTRODUCTION
is more complex than in other animals and that progester- Preterm birth remains a major clinical problem. Preva- one may have a more limited role than in animal models.6 lence in Canada increased from 6.3% of live births in Recently several studies on the use of progesterone to pre- 1981–1983 to 6.6% in 1991 and 7.6% in 2000,1,2 although a vent preterm labour have been published. The purpose of large portion of this increase is related to multiple pregnan- this paper is to evaluate the information in these studies and cies. There are very few interventions that improve the outline the current role for the use of progesterone for this prognosis of preterm labour. The use of antenatal corticosteroids was shown consistently to have such aneffect,3 but most studies on tocolysis, with the exception of DATA ON PROGESTERONE AND PRETERM LABOUR
one recent paper on nitroglycerin,4 had very limited clinical Many studies have examined the use of progesterone for use. Almost 50 years ago, Csapo et al.5 promoted the pro- prevention of preterm labour. Mackenzie et al.7 found 735 gesterone see-saw theory, which is that high progesterone such studies, but only three were appropriate for inclusion levels prevent uterine contractions and low levels facilitate in their meta-analysis on therapy in the second trimester, such contractions. This is one reason for the use of proges- which showed that the use of progestins in women at risk terone therapy in early pregnancy and the use of RU486, a for preterm labour reduced its occurrence by 43% (RR 0.57 progesterone antagonist, to induce abortions. It seems that [0.36–0.90]). Similar reduction of preterm births prior to 35 the hormonal control of contractions and labour in humans weeks (33%) and 32 weeks (42%) was found. Two othermeta-analyses by Sanchez Ramos et al.8 and Dodd et al.9were completed recently. Dodd et al. concluded thatwomen who received progesterone were statistically signifi- ABBREVIATIONS
cantly less likely to give birth before 37 weeks (RR 0.58;95% CI 0.48–0.70), to have an infant with birth weight of American College of Obstetricians and Gynecologists > 2.5 kg (RR 0.62; 95% CI 0.49–0.78), or to have an infant diagnosed with intraventricular hemorrhage (RR 0.25; 95% CI 0.08–0.82). Their analysis showed no apparent benefit to early start of the progesterone administration or in the use of higher doses. Sanchez-Ramos et al. selected 10 papers for l JANUARY JOGC JANVIER 2008
The Use of Progesterone for Prevention of Preterm Birth Table 2. Study characteristics (adapted from Dodd et al.9)
analysis, and their results were similar to those of the two 3. Neonatal Outcome
other meta-analyses. The characteristics of these studies The use of progesterone contributes to a significant reduc- and more recent RCTs are outlined in Table 2.
tion in low birth weight and intraventricular hemorrhage.
Reviews and meta-analysis on the topic published prior to Further data are needed to demonstrate a significant reduc- 2000 differed in methodology and inclusion criteria from tion in the following outcomes: perinatal death, respiratory one another. None of them included the latest RCTs distress syndrome, necrotizing enterocolitis, patent ductus reviewed here. Daya et al.19 looked at the use of progestins arteriosus, sepsis, and retinopathy of prematurity, as the to prevent losses in women who had recurrent losses.
current studies and the meta-analysis are underpowered to Kierse et al.20 limited their analysis to therapy with 17 alpha-hydroxyprogesterone, and the review by Goldsteinet al.21 included studies on women at low risk for PTL. The 4. Safety
studies by Daya et al. and Kierse et al. (but not the study by Progesterone has been used extensively and safely in the Goldstein et al.) showed some benefit in using progester- first trimester, when the fetus is more vulnerable for luteal one. Other publications on cervical length changes and PTL phase insufficiency and recurrent losses. To date, no data from RCTs and other studies for prevention of preterm The main results of the RCTs outlined above are provided birth indicate this therapy is not safe aside from a single retrospective study28 that showed that the incidence of ges-tational diabetes was 12.9% in women treated with 17P SUMMARY OF THE CURRENTLY AVAILABLE DATA
group (n = 557) compared with 4.9% in control subjects(n = 1524, P < 0.001; OR 2.9 [95% CI 2.1–4.1]).
1. Prevention of PTL
The summary of data presented above indicates that admin-
5. Route of Administration and Dosage
istration of progesterone in the second trimester to women There are no data comparing routes of administration or with short cervix or with a previous history of preterm dosing regimens. The meta-analysis of Dodd et al.9 did not labour may reduce their risk for preterm birth. This modi- show an added benefit of progesterone use prior to fies the sole indication of PTL outlined in the ACOG tech- 20 weeks’ gestation. A recent RCT reached the same nical bulletin of 2003.25 The ACOG guideline cautiously recommends the use of progesterone exclusively in womenwith previous preterm labour.
6. Need for Further Research
There are still large gaps in our knowledge. More data are 2. Frequency of Use
required to properly evaluate the impact on neonatal out- The frequency of progesterone use based on the ACOG comes. More information is needed on formulation (17 recommendations increased in the US from 38% in 2003 to alpha-hydroxyprogesterone vs. progesterone), route of 67% in 2005.26 In contrast, a recent Canadian study27 administration (IM vs. vaginal or oral), and the optimal dos- showed that only 7% of Canadian obstetricians were using age for progesterone use. More research is required to pro- progesterone for the prevention of PTL in 2004.
vide definitive data on the potential rare risks associated JANUARY JOGC JANVIER 2008 l
SOGC TECHNICAL UPDATE
Table 3. Outcomes of studies
RR for B-weight < 2500 gm RR for perinatal mortality Table 4. Meta-analysis of neonatal clinical outcomes from six randomized trials that
compared intramuscular progesterone with placebo
with progesterone administration. Currently, there is at least cervix (< 15 mm at 22–26 weeks’ gestation) on one RCT (The PROGRESS study) recruiting Canadian transvaginal ultrasound could be used as an indication patients at risk for PTL to evaluate vaginal administration of for prophylactic progesterone therapy. The therapy should be started after 20 weeks’ gestation and stopped Recommendations
when the risk of prematurity is low. (I-A) 1. Women at risk for PTL should be encouraged to partici- 4. On the basis of the data from the RCTs and meta- pate in studies on the role of progesterone in reducing analysis, it is recommended that in cases where the clini- cian and the patient have opted for the use of progester- 2. Women should be informed about the lack of available one the following dosages should be used: data for many neonatal outcome variables and about the • For prevention of PTL in women with history of lack of comparative data on dosing and route of adminis- previous PTL: 17 alpha-hydroxyprogesterone tration. Women with short cervix should be informed of 250 mg IM weekly (I-B) or progesterone 100 mg the single large RCT showing the benefit of progesterone • For prevention of PTL in women with short cervix 3. Women and their caregivers should be aware that a of < 15 mm detected on transvaginal ultrasound at previous spontaneous preterm labour and/or short 22–26 weeks: progesterone 200 mg daily vaginally. (I-A) l JANUARY JOGC JANVIER 2008
The Use of Progesterone for Prevention of Preterm Birth REFERENCES
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