Progesterone and preterm birth prevention: translating clinical trials data into clinical practice

www.AJOG.org
Progesterone and preterm birth prevention: translating
clinical trials data into clinical practice
Society for Maternal-Fetal Medicine Publications Committee, with the assistance of Vincenzo Berghella, MD
OBJECTIVE: We sought to provide evidence-based guidelines for using progestogens for
the prevention of preterm birth (PTB).
use in possible clinical scenarios. Other METHODS:
Relevant documents, in particular randomized trials, were identified using PubMed (US National Library of Medicine, 1983 through February 2012) publications, written in English, which evaluate the effectiveness of progestogens for prevention of PTB. Progesto- gens evaluated were, in particular, vaginal progesterone and 17-alpha-hydroxy-progesterone caproate. Additionally, the Cochrane Library, organizational guidelines, and studies identified dressed separately. The effects of inter- through review of the above were utilized to identify relevant articles. Data were evaluated according to population studied, with separate analyses for singleton vs multiple gestations, by the population studied, and in partic- prior PTB, or short transvaginal ultrasound cervical length (CL), and combinations of these factors. Consistent with US Preventive Task Force suggestions, references were evaluated for quality based on the highest level of evidence, and recommendations were graded.
RESULTS AND RECOMMENDATIONS:
Summary of randomized studies indicates that in women with singleton gestations, no prior PTB, and short CL Յ20 mm at Յ24 weeks, vaginal tiple gestations), prior PTB (vs not), and progesterone, either 90-mg gel or 200-mg suppository, is associated with reduction in PTB and perinatal morbidity and mortality, and can be offered in these cases. The issue of universal CL screening of singleton gestations without prior PTB for the prevention of PTB remains an object of debate. CL screening in singleton gestations without prior PTB cannot yet be universally mandated. Nonetheless, implementation of such a screening strategy can be viewed as rea-sonable, and can be considered by individual practitioners, following strict guidelines. In sin- What are the mechanism of action
gleton gestations with prior PTB 20-36 6/7 weeks, 17-alpha-hydroxy-progesterone caproate and safety data of progestogens?
250 mg intramuscularly weekly, preferably starting at 16-20 weeks until 36 weeks, is recom- (Levels II and III)
mended. In these women with prior PTB, if the transvaginal ultrasound CL shortens to Ͻ25 mm at Ͻ24 weeks, cervical cerclage may be offered. Progestogens have not been associated with prevention of PTB in women who have in the current pregnancy multiple gestations, preterm review, and are discussed only briefly.
labor, or preterm premature rupture of membranes. There is insufficient evidence to recom- mend the use of progestogens in women with any of these risk factors, with or without a short CL.
progestogens in preventing PTB is un-known, several possibilities have been Key words: 17-alpha-hydroxy-progesterone caproate, cervical length, preterm birth, prior preterm birth, progestogens, vaginal progesterone evidence seems to favor 2 mechanisms:an antiinflammatory effect that counter-acts the inflammatory process leading to Introduction
PTB, and a local increase in progesterone in gestational tissues that counteracts the From the Society for Maternal-Fetal Medicine Publications Committee with the assistance of Vincenzo Berghella, MD, Division of Maternal- inally or orally for prevention of preterm Fetal Medicine, Department of Obstetrics and term “progestogens” includes both vag- Thomas Jefferson University, Philadelphia, PA.
at a mean of 4 years, of 278 children ran- The authors report no conflict of interest.
portant information, the scope of this ar- Reprints not available from the authors.
376 American Journal of Obstetrics & Gynecology MAY 2012
www.AJOG.org
What is the evidence and
recommendation for use
of progestogens for prevention
Proposed mechanisms of action reported
of PTB in singleton gestations
for progestogens to prevent preterm
with no prior PTB, with unknown
Stimulate transcription of ZEB1 and ZEB2, which inhibit connexin 43 (gap-junction protein CL? (Levels I and III)
that helps synchronize contractile activity) and oxytocin-receptor gene Decrease prostaglandin synthesis, infection-mediated cytokine production (antiinflammatory Changes in PR-A and PR-B expression (decreased PR-A/PR-B ratio keeps uterus quiescent) PRs, when stimulated by progesterone, help selected gene promotion, or prevent binding of Interfere with cortisol-mediated regulation of placental gene expression Vaginal progesterone
Reduce cervical stromal degradation in cervix Alter barrier to ascending inflammation/infection in cervix nal progesterone in this population.
Reduce contraction frequency in myometrium Attenuate response to hemorrhage/inflammation in decidua Alter estrogen synthesis in fetal membranes/placenta .
PR, progesterone receptor; ZEB1, zinc finger E-box binding homeobox protein 1; ZEB2, zinc finger E-box binding homeoboxprotein 2.
What is the evidence and
SMFM. Progesterone and preterm birth prevention. Am J Obstet Gynecol 2012. recommendation for use
of progestogens for prevention
of PTB in singleton gestations
with no prior PTB, but short
CL? (Levels I, II, and III)
stated that “it had become impractical, It is particularly important to assess the Vaginal progesterone
was associated with similar incidences of PTB Ͻ35 weeks (13.5% vs 16.1%; P ϭ at 24 weeks until 34 weeks was associated gel daily started at 20-23 6/7 weeks until rollment was statistically very unlikely to 34%; relative risk [RR], 0.56; 95% confi- dence interval [CI], 0.36 – 0.86), but no 0.92), and a 43% significant reduction in Յ15 mm in the population screened for significant benefit of progesterone in MAY 2012 American Journal of Obstetrics & Gynecology
www.AJOG.org
result in a reduction of 95,920 PTBs Ͻ37 ● The available trials have addressed ef- was actually cost-saving (almost $13 bil- rolled patients in 44 centers in 10 coun- tions (eg, the cost of vaginal progester- States, 46% of total), and the ethnic dis- is based on cost-effectiveness analyses.
resulted in Ͼ$12 million saved, 424 quality-
adjusted life-years gained, and 22 neona- did not meet the statistical significance screened compared with no screening.
issue of robustness in efficacy in the US wide range of possible values (eg, the cost screening), universal screening was cost- effectiveness analysis initially addressed Ͻ33 weeks is approximately 604, if all tween 1.6-2.5 mm did not change their ite perinatal morbidity and mortality.
gleton gestations, with no prior PTB, and Յ20 mm is identified at Յ24 weeks, vag- inal progesterone can be offered for pre- evidence that any of the vaginal prepara- ating universal CL screening in singleton tions or doses are superior, as they have ity, and other factors may influence pre- policy of universal screening for short cer- 378 American Journal of Obstetrics & Gynecology MAY 2012
www.AJOG.org
TABLE 2
Cervical length as screening test in singleton gestations
TVU CL screening test criteria
Characteristic of screening test
Comments
TVU fulfills criteria
PTB: no. 1 cause of perinatal mortality and morbidity in developed countries; associated with 1 million deaths annually worldwide 12% in United States, about 10% worldwide Disease natural history is known/recognizable First cervical changes associated with later PTB occur at internal os, and can only be detected early by ultrasound TVU is safe even in women with 99% of women would Screening has reasonable cutoff identified 20 mm is 5th percentile, 25 mm is 10th percentile in general US Ͻ10% intraobserver and interobserver variability Yes; extremelyimportant to controlquality of TVU CL Better than manual examination; predictive in all populations Intervention, cost-effectiveness, and feasibility Two positive randomized trials both reported that using vaginal progesterone for short TVU CL is effective in preventing Screening and treating abnormals is cost- Facilities for screening are readily available All pregnancies are offered ultrasound for fetal anatomy screening Facilities for treatment are readily available Vaginal progesterone is easily administered as outpatient .
CL, cervical length; PPROM, preterm premature rupture of membranes; PTB, preterm birth; TVU, transvaginal ultrasound.
SMFM. Progesterone and preterm birth prevention. Am J Obstet Gynecol 2012. singleton gestation without prior SPTB.
singleton gestations does fulfill many cri- ● If an approach of universal screening is to ● There may be lack of availability of this ● There is level-1 evidence of prevention of PTB and neonatal benefits based on treat- ● This strategy is not only beneficial in MAY 2012 American Journal of Obstetrics & Gynecology
www.AJOG.org
Oral progesterone
tance to society, but also cost-effective, ● TVU CL is a safe, acceptable, reproduc- sociated with significantly reduced rates potentially widespread availability.
nents of universal screening raise valid issues.
CL screening in singleton gestations without 95% CI, 0.54 – 0.81), PTB Ͻ37 and Ͻ32 sally. Nonetheless, implementation of such a ciated with trend (but no significant dif- screening strategy should be viewed as rea- sonable, and can be considered by individual weeks (26% vs 57%; P ϭ .15) and venti- practitioners. Third-party payers should not lator use (0% vs 21%; P ϭ .07) compared deny reimbursements for this screening.
Practitioners who decide to implement uni- for 17P to be started Ͻ21 weeks, benefi- progesterone, based on the 2 largest tri- Therefore, 17P 250 mg IM weeklystarting at 16-20 weeks until 36 weeks ● Randomized trials and cost-effective- Vaginal progesterone
20-36 6/7 weeks. In cases in which 17P is weeks was associated with significant re- What is the evidence and
Յ20 mm at Ͻ24 weeks. Clinicians weeks (RR, 0.48; 95% CI, 0.25–0.96) and recommendation for use of
Ͻ34weeks,aswellasreductionincontrac- progestogens for prevention of PTB in
singleton gestations with prior PTB,
and short CL? (Levels I, II, and III)
ued until 37 0/7 weeks was not associated with significantly different rates of PTBϽ What is the evidence and
recommendation for use of
screened for this trial were excluded be- progestogens for prevention of PTB
in singleton gestations with prior
PTB, and unknown or normal CL?
Effect of progesterone on CL
(Levels I, II, and III)
tistically significant decrease in PTB Ͻ24 receiving cerclage in a secondary analysis Ͼ1 prior spontaneous abortion, 17P 250 was associated with significant reduction 17P were noted primarily for womenmg IM weekly started as soon as prena- 380 American Journal of Obstetrics & Gynecology MAY 2012
www.AJOG.org
received neither 17P nor cerclage, 25% if Algorithm for use of progestogens in prevention of PTB in clinical care
they received cerclage, 21% if they re-ceived 17P, and 17% if they receivedWhile these results were not sta- tistically significant, they suggest thatfurther research is needed to evaluate therelationship and possible cumulativebeneficial effect of progesterone andcerclage.
In a randomized trial that did not recruit the planned sample size, 17P had similareffects compared to cerclage in preventingPTB in women with a TVU CL Ͻ25 mm, but cerclage was more beneficial in women with CL Ͻ15 While cerclage seemsto be more efficacious (lower RRs) for CLon the lower end of the proges-terone seems to be most efficacious for Vaginal progesterone
In a secondary analysis of an eval-
uating just the 46 singleton gestations
TVU CL Ͻ28 mm at 18-22 6/7 weeks,vaginal progesterone 90-mg gel dailystarted at 18-23 6/7 weeks until 37 weekswas associated with significant decreasesin the rates of both PTB Ͻ32 weeks and If TVU CL screening is performed; b17P 250 mg intramuscularly every week from 16-20 weeks to 36 weeks; ceg, daily 200-mg suppository or 90-mg gel from time of diagnosis of short CL to 36 weeks.
CL, cervical length; PTB, preterm birth; 17P, 17-alpha-hydroxy-progesterone caproate; TVU, transvaginal ultrasound.
SMFM. Progesterone and preterm birth prevention. Am J Obstet Gynecol 2012. 50%; odds ratio [OR], 3.11; 95% CI,1.13– 8.53) and Ͻ34 weeks (5.4% vs26.5%; OR, 6.30; 95% CI, 1.25–31.70) clage offers an additive effect in reducing 0.55– 0.89) and a 36% reduction in com- starting at 16 weeks, as described above.
gested, so that cerclage can be offered for ton gestation and prior SPTB, there is in- sufficient evidence to assess efficacy of a ized trials did not receive 17P, there is insufficient evidence to determine if the therefore it is reasonable to continue 17P cerclage was associated with a significant MAY 2012 American Journal of Obstetrics & Gynecology
www.AJOG.org
port the use of any type of progestogen for Current Society for Maternal-Fetal Medicine recommendations
regarding use of progestogens for prevention of preterm birth
Population
Recommendation regarding use of progestogens
experts have suggested the use of 17P starting but there is insufficient evidence to make this 17P 250 mg IM weekly from 16-20 wk until 36 wk suppository daily from diagnosis of short CL until 36 What is the evidence and
recommendation for use of
progestogens for prevention of PTB
in multiple gestations, and short CL?
(Levels I and III)
17P, 17-alpha-hydroxy-progesterone caproate; CL, cervical length; IM, intramuscularly; PPROM, preterm premature ruptureof membranes; PTL, preterm labor; SPTB, spontaneous preterm birth; TVU, transvaginal ultrasound.
In a secondary analysis of a trial involv- SMFM. Progesterone and preterm birth prevention. Am J Obstet Gynecol 2012. ing women with DC twin gestation, 52women, of whom 18.5% had prior PTB,were identified to have a TVU CL of Յ35 until 36 weeks, and to offer cervical cer- of 17P in triplet gestations. In a total of What is the evidence and
recommendation for use of
progestogens for prevention of PTB in
PTB Ͻ35 weeks (64% vs 46%; P ϭ .18) multiple gestations, and unknown or
normal CL? (Levels I and III)
on incidence of PTB or perinatalmorbidity and mortality compared to Vaginal progesterone
In a secondary analysis of a trial involv- Vaginal progesterone
In 500 women with twin gestation, vaginal progesterone 90 mg daily starting at 24 weeks and continued for at least 10 weeks was not associated with significant effects in inci- tation, vaginal progesterone 200-mg pessar- mortality in a National Institute of Child ies starting at 20-24 weeks until 34 weeks werenotassociatedwithsignificanteffectson incidences of PTB or perinatal complications and Ͻ30 weeks, as well as similar rates of 1.46), but a significant reduction in com- 95% CI, 1.16 –10.46) but not Ͻ34 weeks dence to assess the effect of progestogens fect of vaginal progesterone on triplet gesta- 382 American Journal of Obstetrics & Gynecology MAY 2012
www.AJOG.org
What is the evidence and
What is the evidence and
Level I evidence,
recommendation for use of
recommendation for use of
level A recommendation
progestogens for prevention of PTB in
progestogens for prevention of PTB in
2. In women with singleton gestations, no preterm labor? (Levels I, II, and III)
preterm premature rupture of
Primary tocolysis
membranes? (Levels I and III)
orally once was associated with a significant no PTB or neonatal outcomes were reported 250 mg IM is associated with no effect on Level I and level III evidence,
interval to delivery, gestational age at de- level B recommendation
3. The issue of universal TVU CL screening Adjunctive tocolysis
of singleton gestations without prior PTB Vaginal progesterone
ject of debate. CL screening in singleton nal progesterone in this population.
dence to assess effect of progesterone in implementation of such a screening strat- has been receiving 17P for prior SPTB, in be considered by individual practitioners.
was associated with similar rates of PTB, the absence of evidence to the contrary, it is but with lower total dose of ritodrine ad- Conclusions
Maintenance tocolysis
Assessment of efficacy of progestogens for 17P. In 60 women with singleton ges- prevention of PTB should be done separately should follow strict guidelines. Practitio- tation still pregnant after successful to- for each type of progestogens, with vaginal vaginal progesterone, either 90-mg gel or varies also depending on each different risk factor. In addition, dose, gestational age at Ͻ37 weeks (but not 35 weeks) and of initiation and termination, compliance, andrisk of cervical shortening compared to other issues are factors that influence efficacy Level I and level III evidence,
of progestogens for prevention of PTB.
level A and B recommendations
Therefore, singleton vs multiple gestation, 4. In singleton gestations with prior SPTB still pregnant after successful tocolysis for history (eg, prior PTB), short TVU CL (and degree of) or not, asymptomatic vs PTL and at 24-31 6/7 weeks until 36 weeks was as- PPROM, etc, are all factors that should be considered, as progestogens have different Ͻ37, Ͻ34, and Ͻ32 weeks, and of perina- effects in populations with any one (or com- bination of) risk factor. Several metaanalyses Level I, level II, and level III evidence,
not evaluate these studies according to the Vaginal progesterone. In 70 women with level B recommendation
singleton gestation still pregnant after suc- soon become out of date because of publica- cessful tocolysis for PTL, vaginal progester- with prevention of PTB in multiple gesta- one 400 mg daily until delivery was associ- ated with longer latency until delivery, later RECOMMENDATIONS
gestational age at delivery (PTB was not re- Level I and level III evidence,
risk factors, with or without a short CL.
level A recommendation
1. There is insufficient evidence to recom- evaluate the risks and benefits of this in- MAY 2012 American Journal of Obstetrics & Gynecology
www.AJOG.org
REFERENCES
Quality of evidence
1. Csapo A, Goodall M. Excitability, length ten-
sion relation and kinetics of uterine muscle con- 15. Sfakianaki AK, Norwitz ER. Mechanisms of
traction in relation to hormonal status. J Physiol progesterone action in inhibiting prematurity. J Matern Fetal Neonatal Med 2006;19:763-72.
2. Keirse MJNC. Progestogen administration
in pregnancy may prevent preterm delivery.
16. O’Brien JM, DeFranco EA, Adair CD, et al.
Effect of progesterone on cervical shortening in women at risk for preterm birth: secondaryanalysis from a multinational, randomized, 3. American College of Obstetricians and Gy-
double-blind, placebo-controlled trial. Ultra- necologists. Use of progesterone to reduce preterm birth: ACOG committee opinion no.
II-1 Well-designed controlled trial without
17. Zakar T, Hertelendy F. Progesterone with-
drawal: key to parturition. Am J Obstet Gynecol II-2 Well-designed cohort or case-control
4. Dodd JM, Flenady V, Cincotta R, Crowther
CA. Prenatal administration of progesterone 18. Resseguie LJ, Hick JF, Bruen JA, Noller
for preventing preterm birth in women consid- II-3 Multiple time series with or without
KL, O’Fallon WM, Kurland LT. Congenital ered to be at risk of preterm birth. Cochrane utero to progestins, Olmsted County, Minne- sota, 1936-1974. Fertil Steril 1985;43:514-9.
5. Kilpatrick SJ, for the Society for Maternal-
Fetal Medicine. Progesterone for the prevention 19. Northen AT, Norman GS, Anderson K, et
al, for the National Institute of Child Health Recommendations were graded in
6. Meis PJ, Klebanoff M, Thom E, et al. Preven-
Fetal Medicine Units (MFMU) Network. Fol- the following categories:
tion of recurrent preterm delivery by 17 alpha- low-up of children exposed in utero to 17 hydroxyprogesterone caproate. N Engl J Med 7. O’Brien JM, Adair CD, Lewis DF, et al. Pro-
gesterone vaginal gel for the reduction of recur- 20. Hauth JC, Gilstrap LC III, Brekken AL,
rent preterm birth: primary results from a ran- Hauth JM. The effect of 17 alpha-hydroxypro- domized, double-blind, placebo-controlled trial.
The recommendation is based on limited or gesterone caproate on pregnancy outcome in Ultrasound Obstet Gynecol 2007;30:687-96.
an active-duty military population. Am J Obstet 8. Berghella V, Rafael TJ, Szychowski JM,
21. Grobman WA; for the Eunice Kennedy
Rust OA, Owen J. Cerclage for short cervix on Shriver National Institute of Health and Human Development. Randomized controlled trial of progesterone treatment for preterm birth pre- vention in nulliparous women with cervical length less than 30mm. Am J Obstet Gynecol 9. Renthal NE, Chen NN, Williams KC, et al.
miR-200 family and targets, ZEB1 and ZEB2, 22. Keeler SM, Kiefer D, Rochon M, Quinones JN,
for Maternal–Fetal Medicine with the as- modulate uterine quiescence and contractility Novetsky AP, Rust O. A randomized trial of cerclage during pregnancy and labor. Proc Natl Acad vs 17 ␣-hydroxyprogesterone caproate for treat- Sci U S A 2010;107:20828-33. Level II-2.
ment of short cervix. J Perinat Med 2009;37:473-9.
10. Briery CM, Veillon EW, Klauser CK, et al.
Progesterone does not prevent preterm births 23. Fonseca EB, Celik E, Parra M, Singh M,
in women with twins. South Med J 2009;102: Nicolaides KH. Progesterone and the risk of preterm birth among women with a short cervix.
11. Briery CM, Veillon EW, Klauser CK, et al.
N Engl J Med 2007;357:462-9. Level I.
Women with preterm premature rupture of the 24. Hassan SS, Romero R, Vidyadhari D, et al,
membranes do not benefit from weekly proges- for the PREGNANT Trial. Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, ran- 12. Zakar T, Mesiano S. How does progester-
domized, double-blind, placebo-controlled trial.
one relax the uterus in pregnancy? N Engl Ultrasound Obstet Gynecol 2011;38:18-31.
13. Peltier MR, Tee SC, Smulian JC. Effect of
25. US Food and Drug Administration. Advi-
ner) have submitted a conflict of interest pathogens associated with preterm birth.
26. Romero R, Nicolaides K, Conde-Agudelo
A, et al. Vaginal progesterone in women with might be perceived as a real or potential 14. Xu H, Gonzalez JM, Ofori E, Elovitz MA. Pre-
an asymptomatic sonographic short cervix in venting cervical ripening: the primary mecha- the midtrimester decreases preterm delivery nism by which pregestational agents prevent and neonatal morbidity: a systematic review 384 American Journal of Obstetrics & Gynecology MAY 2012
www.AJOG.org
and meta-analysis of individual patient data.
droxyprogesterone caproate for prevention of one caproate to prevent prematurity in twins.
Am J Obstet Gynecol 2012;206:124.e1-19.
recurrent preterm delivery: does gestational age N Engl J Med 2007;357:454-61. Level I.
at initiation of treatment matter? Am J Obstet 53. Combs CA, Garite T, Maurel K, Das A, Porto
27. Cahill AG, Odibo AO, Caughey AB, et al.
Gynecol 2007;197:260.e1-4. Level II-2.
M; for the Obstetrix Collaborative Research Net- Universal cervical length screening and treat- 41. Rebarber A, Ferrara LA, Harley ML, et al.
work. 17-hydroxyprogesterone caproate for twin ment with vaginal progesterone to prevent pre- Increased recurrence of preterm delivery with pregnancy: a double-blind, randomized clinical term birth: a decision and economic analysis.
early cessation of 17-alpha-hydroxyprogester- trial. Am J Obstet Gynecol 2011;204:221.e1-8.
Am J Obstet Gynecol 2010;202:548.e1-8.
54. Caritis SN, Rouse DJ, Peaceman AM, et al,
28. Werner EF, Han CS, Pettker CM, et al.
42. da Fonseca EB, Bittar RE, Carvalho MH,
for the Eunice Kennedy Shriver National Insti- Universal cervical-length screening to prevent Sugaib M. Prophylactic administration of pro- tute of Child Health and Human Development preterm birth: a cost-effectiveness analysis.
gesterone by vaginal suppository to reduce the (NICHD), Maternal-Fetal Medicine Units Net- Ultrasound Obstet Gynecol 2011;38:32-7.
incidence of spontaneous preterm birth in work (MFMU). Prevention of preterm birth in women at increased risk: a randomized place- triplets using 17 alpha-hydroxyprogesterone 29. Hernandez-Andrade E, Romero R, Ahn H,
bo-controlled double-blind study. Am J Obstet caproate: a randomized controlled trial. Obstet et al. Transabdominal evaluation of uterine cer- vical length during pregnancy fails to identify a 43. Durnwald CP, Lynch CD, Walker H, Iams
55. Combs CA, Garite T, Maurel K, et al, for the
substantial number of women with a short cer- JD. The effect of treatment with 17 alpha-hy- Obstetrix Collaborative Research Network. Fail- vix. J Mat Fetal Neo Med 2012 Mar 16 [Epub ure of 17-hydroxyprogesterone to reduce neo- cervical length over time. Am J Obstet Gynecol natal morbidity or prolong triplet pregnancy: a 30. Iams JD, Goldenberg RL, Meis PJ, et al. The
double-blind, randomized clinical trial. Am J length of the cervix and the risk of spontaneous 44. Rai P, Rajaram S, Goel N, Ayalur Go-
Obstet Gynecol 2010;203:248.e1-9. Level I.
premature delivery. N Engl J Med 1996;334: palakrishnan R, Agarwal R, Mehta S. Oral mi- 56. Norman JE, Mackenzie F, Owen P, et al.
Progesterone for the prevention of preterm birth cronized progesterone for prevention of pre- 31. Rafael TJ. Short cervical length. In: Ber-
in twin pregnancy (STOPPIT): a randomized, term birth. Int J Gynaecol Obstet 2009;104: ghella V, ed. Preterm birth: prevention and man- double-blind, placebo-controlled study and agement. New York: Wiley-Blackwell; 2010.
45. Glover MM, McKenna DS, Downing CM,
et al. A randomized trial of micronized proges- 32. Carlan SJ, Richmond LB, O’Brien WF. Ran-
57. Rode L, Klein K, Nicolaides KH, Krampl-
terone for the prevention of recurrent preterm domized trial of endovaginal ultrasound in pre- Bettelheim E, Tabor A; PREDICT Group. Pre- birth. Am J Perinatol 2011;28:377-81. Level I.
term premature rupture of membranes. Obstet vention of preterm delivery in twin gestations 46. Berghella V, Figueroa D, Szychowski JM, et
(PREDICT): a multicenter, randomized, place- al, for the Vaginal Ultrasound Trial Consortium.
33. Dutta RL, Economides DL. Patient accep-
bo-controlled trial on the effect of vaginal mi- 17-alpha-hydroxyprogesterone caproate for tance of transvaginal sonography in the early cronized progesterone. Ultrasound Obstet Gy- the prevention of preterm birth in women with pregnancy unit setting. Ultrasound Obstet Gy- prior preterm birth and a short cervical length.
58. Iams JD, Berghella V. Care for women with
Am J Obstet Gynecol 2010;202:351.e1-6.
34. Lockwood CJ. The real progesterone
story. Contemp Obstet Gynecol 2011;5:10-5.
47. Owen J, Szychowski J. Can the optimal
59. Durnwald CP, Momirova V, Rouse DJ, et al,
cervical length for placing ultrasound-indicated 35. Campbell
for the Eunice Kennedy Shriver National Insti- cerclage be identified? Am J Obstet Gynecol screening and vaginal progesterone prevents tute of Child Health and Human Development early preterm births, reduces neonatal morbid- Maternal-Fetal Medicine Units Network. Sec- ity and is cost saving: doing nothing is no longer 48. Owen J, Hankins G, Iams JD, et al. Multi-
ond-trimester cervical length and risk of preterm an option. Ultrasound Obstet Gynecol 2011; center randomized trial of cerclage for preterm birth in women with twin gestations treated with birth prevention in high-risk women with short- 17-␣ hydroxyprogesterone caproate. J Matern 36. Combs CA. Vaginal progesterone for
ened midtrimester cervical length. Am J Obstet Fetal Neonatal Med 2010;23:1360-4. Level II-1.
asymptomatic cervical shortening and the case 60. Klein K, Rode L, Nicolaides KH, Krampl-
for universal screening of cervical length. Am J 49. DeFranco EA, O’Brien JM, Adair CD, et al.
Bettelheim E, Tabor A; PREDICT Group. Vagi- Obstet Gynecol 2012;206:101-3. Level III.
Vaginal progesterone is associated with a de- nal micronized progesterone and risk of pre- 37. Johnson JW, Austin KL, Jones GS, Davis
crease in risk for early preterm birth and im- term delivery in high-risk twin pregnancies: GH, King TM. Efficacy of 17alpha-hydroxy- secondary analysis of a placebo-controlled ran- progesterone caproate in the prevention of short cervix: a secondary analysis from a ran- domized trial and meta-analysis. Ultrasound domized, double-blind, placebo-controlled trial.
Obstet Gynecol 2011;38:281-7. Level II-1.
Obstet Gynecol 2007;30:697-705. Level II-1.
61. Erny R, Pigne A, Prouvost C, et al. The ef-
38. Petrini JR, Callaghan WM, Klebanoff M, et
50. Cetingoz E, Cam C, Sakalli M, et al. Proges-
fects of oral administration of progesterone for al. Estimated effect of 17 alpha-hydroxyproges- terone effects on preterm birth in high-risk preg- premature labor. Am J Obstet Gynecol 1986; terone caproate on preterm birth in the United nancies: a randomized placebo-controlled trial.
States. Obstet Gynecol 2005;105:267-72.
Arch Gynecol Obstet 2011;283:423-9. Level I.
62. Noblot G, Audra P, Dargent D, Faguer B,
51. Hartikainen-Sorri AL, Kauppila A, Tuimala
Mellier G. The use of micronized progesterone 39. González-Quintero VH, Istwan NB, Rhea
R. Inefficacy of 17 a-hydroxyprogesterone in the treatment of menace of preterm delivery.
DJ, Smarkusky L, Hoffman MC, Stanziano GJ.
caproate in the prevention of prematurity in Eur J Obstet Gynecol Reprod Biol 1991;40: Gestational age at initiation of 17-hydroxypro- gesterone caproate (17P) and recurrent pre- 63. Facchinetti F, Paganelli S, Comitini G, Dante
term delivery. J Matern Fetal Neonatal Med 52. Rouse DJ, Caritis SN, Peaceman AM, et al;
G, Volpe A. Cervical length changes during pre- National Institute of Child Health and Human term cervical ripening: effects of 17-␣-hydroxy- 40. How HY, Barton JR, Istwan NB, Rhea DJ,
Development Maternal-Fetal Medicine Units progesterone caproate. Am J Obstet Gynecol Stanziano GJ. Prophylaxis with 17 alpha-hy- Network. A trial of 17 alpha-hydroxyprogester- MAY 2012 American Journal of Obstetrics & Gynecology
www.AJOG.org
64. Rozenberg P, Chauveaud A, Deruelle P, et
lished preterm labor. Cochrane Database Syst al. Prevention of preterm delivery after success- ful tocolysis in preterm labor by 17 alpha-hy- 67. MacKenzie R, Walker M, Armson A, Han-
evolve, and individual circumstances will nah ME. Progesterone for the prevention of pre- vary. This opinion reflects information avail- controlled trial. Am J Obstet Gynecol 2012; term birth among women at increased risk: a able at the time of its submission for publi- systematic review and meta-analysis of ran- cation and is neither designed nor intended 65. Borna S, Sahabi N. Progesterone for main-
domized controlled trials. Am J Obstet Gynecol to establish an exclusive standard of peri- tenance tocolytic therapy after threatened pre- term labor: a randomized controlled trial. Aust N 68. Sanchez-Ramos L, Kaunitz AM, Delke I.
natal care. This publication is not expected Z J Obstet Gynaecol 2008;48:58-63. Level I.
Progestational agents to prevent preterm birth: to reflect the opinions of all members of the 66. Su LL, Samuel M, Chong YS. Progesta-
a meta-analysis of randomized controlled trials.
Society for Maternal–Fetal Medicine.
tional agents for treating threatened or estab- Obstet Gynecol 2005;105:273-9. Level I.
386 American Journal of Obstetrics & Gynecology MAY 2012

Source: http://www.mfmsm.com/media_pages/MFM_Progesterone_and_preterm_birth_prevention.pdf