This document addresses the use of intramuscular injections of 17-alpha hydroxyprogesterone caproate or progesterone vaginal suppositories for the prevention of preterm birth in individuals at high-risk for preterm delivery.

 Medically Necessary:

Weekly injections of 17 alpha-hydroxyprogesterone caproate between 16 and 36 weeks of gestation are considered medically necessary in pregnant women with a singleton pregnancy with a prior history of a preterm delivery before 37 weeks gestation due to spontaneous preterm labor or premature rupture of membranes, and the absence of preterm labor within the current pregnancy.

Daily vaginal progesterone suppositories between 24 and 34 weeks gestation are considered medically necessary in pregnant women with a prior history of preterm delivery before 37 weeks gestation.

Not Medically Necessary: 

Progesterone therapy as a technique to prevent preterm labor is considered not medically necessary in other pregnant women who do not meet the above criteria, or those with other risk factors for preterm delivery, including, but not limited, to: multiple gestations, short cervical length, prior cervical cerclage, a uterine anomaly, or positive tests for cervicovaginal fetal fibronectin.

Injections of 17 alpha-hydroxyprogesterone caproate in a home setting by or through a licensed home health agency are considered not medically necessary, except when criteria for home health services are met. (See CG-MED-23 - Home Health.)

The following codes for treatments and procedures applicable to this document are included below for informational purposes.  Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy.  Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

Future ICD-10 coding (effective 10/01/2013)
A draft of ICD-10 Coding related to this document, as it might look today, is available for reference and comments at: Appendix 1: Future ICD-10 coding

Preterm labor and delivery is a major determinant of neonatal morbidity and mortality; in the United States the rate of preterm birth is 12%.  A variety of diagnostic and prophylactic measures have been investigated, including home uterine activity monitoring, subcutaneous terbutaline tocolytic therapy, and routine culture and antibiotic treatment of subclinical bacterial vaginosus.  To date, none of the above has made a significant demonstrable impact on the incidence of preterm delivery.  In the past, intramuscular injections of 17 alpha hydroxyprogesterone, (i.e., Delalutin) were used routinely to prevent premature labor.  However, the drug was shown to have teratogenic properties, and the FDA labeled the drug as Category D, (i.e., studies have demonstrated fetal risk, but use of the drug may outweigh the potential risk).  Delalutin is no longer marketed.  Most recently, there has been renewed research interest in intramuscular injections of 17 alpha-hydroxyprogesterone caproate (17P) during the second trimester when the teratogenic risk is minimized.  17P is a weakly acting, naturally occurring, progesterone metabolite, which, when coupled with caproate dextran, works as a long acting progestin, when administered intramuscularly. 

To date, 17P (17 alpha-hydroxyprogesterone caproate) has not been commercially available, but manufactured locally by compounding pharmacies.  On February 3, 2011 K-V Pharmaceutical Company (St. Louis, MO) announced FDA approval for Makena^™ (formerly known as Gestiva^™), subject to additional post-approval studies to be conducted regarding clinical outcomes benefit.  Makena is the first synthetic progestin approved by the FDA and commercially available to reduce the risk of preterm birth. Makena was launched on March 14, 2011 and will be available through a limited distribution network.  According to the FDA labeling, Makena (hydroxyprogesterone caproate injection) is "A progestin indicated to reduce the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth, (which is defined as delivery before 37 weeks of pregnancy).  The effectiveness of Makena is based on improvement in the proportion of women who delivered at less than 37 weeks of gestation. There are no controlled trials demonstrating a direct clinical benefit, such as improvement in neonatal mortality and morbidity.

Limitation of use: While there are many risk factors for preterm birth, the safety and efficacy of Makena has been demonstrated only in women with a prior spontaneous singleton preterm birth. It is not intended for use in women with multiple gestations or other risk factors for preterm birth." It is also not intended for use to stop active preterm labor. (FDA, 2011)

Contraindications to use of Makena include:

• Current or history of thrombosis or thromboembolic disorders;
• Known or suspected breast cancer, other hormone-sensitive cancer, or history of these conditions;
• Undiagnosed abnormal vaginal bleeding unrelated to pregnancy;
• Cholestatic jaundice of pregnancy;
• Liver tumors, benign or malignant, or active liver disease;
• Uncontrolled hypertension.

Regarding the continued availability of 17 alpha-hydroxyprogesterone caproate from compounding pharmacies, the FDA issued a statement on March 30, 2011, as follows:

The FDA understands that the manufacturer of Makena, KV Pharmaceuticals, has sent letters to pharmacists indicating that FDA will no longer exercise enforcement discretion with regard to compounded versions of Makena. This is not correct.  In order to support access to this important drug, at this time and under this unique situation, FDA does not intend to take enforcement action against pharmacies that compound hydroxyprogesterone caproate based on a valid prescription for an individually identified patient unless the compounded products are unsafe, of substandard quality, or are not being compounded in accordance with appropriate standards for compounding sterile products. As always, FDA may at any time revisit a decision to exercise enforcement discretion (FDA, 2011).

This clinical guideline is largely based on an analysis of two randomized trials of progestational compounds, as a technique to prevent preterm delivery in high-risk women.  Meis and colleagues focused on the use of weekly intramuscular injections of 17 alpha-hydroxyprogesterone caproate – 17P (Meis, 2003), while da Fonseca and colleagues focused on the role of vaginal suppositories of progesterone (da Fonseca, 2003).  A variety of outcomes can be considered.  Ideally one would like to examine the outcomes of greatest clinical significance, i.e., perinatal morbidity, (as evidenced by days in the Neonatal Intensive Care Unit) or perinatal mortality.  However, the following studies focused on the associated outcome of rates of preterm delivery, defined as birth prior to 37 weeks.  The limitation in this outcome is that as delivery approaches 37 weeks, the associated morbidity and mortality declines.  Delivery prior to 34 weeks is more predictably associated with neonatal morbidity and mortality. 

In the Meis study, 463 women with a history of a prior preterm delivery were randomized in a 2:1 ratio to receive either weekly intramuscular injections of 17P or a placebo injection, which consisted of castor oil (the same vehicle as used in the 17P injection).  Injections began at 16 to 20 weeks of gestation and continued until 36 weeks of gestation.  The primary outcome was preterm delivery before 37 weeks of gestation, although delivery rates before 35 and 32 weeks were also reported.  These data are summarized in the table below:

The frequency of delivery before 37 weeks gestation was 36.3% in the progesterone group, as compared with 54.9% in the placebo group.  While this difference is statistically significant, it is important to note that the rate of preterm delivery in the placebo group (54.9%) is exceptionally high.  For example, in calculating the required number of individuals needed to demonstrate a difference between the control and treatment group, (i.e., the power of the study), the investigators assumed that the preterm delivery rate in the control group would be 37%, based on the results of other studies.  Therefore, the statistical significance of the difference in preterm delivery in the two groups may be related primarily to the unexpected high incidence of preterm delivery in the control group, rather than any treatment effect of 17P.  The authors acknowledge the high incidence of preterm delivery in the control group and suggest that this rate may be related to the overall high risk in the enrolled participants.  For example, the mean gestational age of the prior preterm delivery in the placebo group was 31 weeks ± 4.2 weeks.  As noted by the authors, the risk of preterm delivery increases with a decreasing gestational age of the prior preterm delivery.  However, the standard deviation of 4.2 weeks suggests that the study included subjects with a prior preterm delivery at a gestational age of as low as 27 weeks ranging up to 35 weeks.  The distribution of the gestational ages is not provided.  At the very least, the high rate of preterm delivery creates uncertainty, as to whether the results of this study can be extrapolated to other populations (Greene, 2003).  Finally, as suggested in a letter to the editor (Brancazio, 2003), it is possible that the castor oil placebo somehow contributed to the high rate of preterm delivery, and the lower rate in the intervention group, (which is similar to the anticipated rate), reflects a protective effect of 17P.

Prior randomized studies have also suggested that 17P is associated with a decreased incidence of preterm delivery.  In a 1985 trial of 80 women considered at high risk, Yemini reported a preterm delivery rate of 37.8% in the control group, compared to 16.1% in the treated group (Yemini, 1985).  A 1990 meta-analysis also supported the hypothesis that 17P does reduce the occurrence of preterm delivery (Keirse, 1990).

Da Fonseca and colleagues reported on the results of a trial that randomized 142 women considered at high risk for preterm delivery to receive either daily progesterone or placebo suppositories.  While the Meis study included only women with a prior history of preterm delivery, this study included a broader range of subjects.  Inclusion criteria included either a prior history of preterm birth, prophylactic cervical cerclage or a uterine malformation.  Additionally, the mean gestational age of the prior preterm birth (33 weeks) was greater than the Meis trial, suggesting that, overall, this population of study subjects was at lower risk for preterm birth.  The following pregnancy outcomes were reported:

As part of the design of the trial, the authors estimated that the overall incidence of preterm delivery was 25%, and therefore, the 28.5% incidence of preterm delivery in the placebo group was in the expected range, unlike the Meis trial (da Fonseca, 2003). In the da Fonseca (2003) randomized controlled trial, preterm birth occurred in 13.8% of the progesterone group and in 28.5% of the placebo group, which was statistically significant. Also in the placebo group, 18.5% of women delivered before 34 weeks, as compared with only 2.7% in the active treatment group (also significant). However, of the 142 high-risk subjects entered into this trial, only four subjects had an incompetent cervix requiring cerclage, and only five subjects had a uterine malformation. As a result, it is difficult to extrapolate the overall conclusion of efficacy for progesterone vaginal suppository therapy in these two small groups. Since that time, no other published studies have focused specifically on the high-risk variables of either cervical cerclage or uterine anomaly. As a result, the current evidence supporting the effectiveness of progesterone in reducing preterm birth in women with either of these conditions remains insufficient.

In 2007, da Fonseca reported on the use of vaginal progesterone in women at high risk of pre-term delivery due to short cervical length.  This study, which was sponsored by the Fetal Medicine Foundation, randomized 250 women with a cervical length of 15 mm or less to nightly (between 24 and 34 weeks of gestation) vaginal progesterone or placebo capsules. Although vaginal progesterone therapy was associated with a reduction of 44% in the rate of preterm birth, questions remained regarding fetal outcomes; composite measures of neonatal therapy (25% vs. 33%) and morbidity (8% vs. 14%) were not significantly reduced.  Two publications of the same systematic reviews were published in 2009 which suggest that vaginal progesterone therapy may benefit a select group of women with short cervical length, and they advocate for routine screening of cervical length in the mid trimester, although this strategy is not currently recommended by the American College of Obstetrics and Gynecology (ACOG) (daFonseca, 2009a; daFonseca, 2009b). 

Another systematic review also attempted to assess the benefits and harms of progesterone administration for the prevention of preterm birth in women and their infants.  Eleven randomized controlled trials (2,425 women and 3,187 infants) were included. For women with a history of spontaneous preterm birth, progesterone was associated with a significant reduction in preterm birth before 34 weeks (one study, 142 women, RR 0.15, 95% confidence interval [CI] 0.04-0.64, number needed to treat 7, 95% CI 4-17), but no statistically significant differences were identified for the outcome of perinatal death. For women with a short cervix identified on ultrasound, progesterone was not associated with a significant difference in perinatal death (one study, 274 participants, RR 0.38, 95% CI 0.10-1.40), but there was a significant reduction in preterm birth before 34 weeks (one study, 250 women, RR 0.58, 95% CI 0.38-0.87, number needed to treat 7, 95% CI 4-25).  The authors concluded that progesterone is associated with some beneficial effects in pregnancy outcome for some women at increased risk of preterm birth (Dodd, 2008). 

A Cochrane meta-analysis review of progestogen therapy (the British word for progesterone) for prevention of miscarriage assessed fifteen trials (of 2,118 women) that were included regardless of gravidity and number of previous miscarriages.  Results showed no statistically significant difference in the risk of miscarriage between progestogen and placebo or no treatment groups (Peto odds ratio [Peto OR] 0.98; 95% CI 0.78 to 1.24) and no statistically significant difference in the incidence of adverse effect in either mother or baby. Subgroup analysis of three of these trials, involving women who had recurrent miscarriages (three or more consecutive miscarriages), showed a statistically significant decrease in miscarriage rate in the treatment group, compared to placebo or no treatment (Peto OR 0.38; 95% CI 0.20 to 0.70).  The authors concluded, "…There seems to be evidence of benefit in women with a history of recurrent miscarriage. Treatment for these women may be warranted… Larger trials are currently underway to inform treatment for this group of women." (Haas, 2008).

In November of 2003, the American College of Obstetrics and Gynecology (ACOG) issued a committee opinion on the use of progesterone to reduce preterm birth.  This committee opinion reviewed the Meis and da Fonseca studies, discussed above.  This document states:

(The results of these two studies) support the hypothesis that progesterone supplementation reduces preterm birth in a select very high-risk group. Despite the apparent benefits of progesterone in a high-risk population, the ideal progesterone formulation is unknown. The 17P used in the (Meis) trial was specially formulated for research and is not currently commercially available on a wide scale. Whether vaginal progesterone is equally efficacious remains to be proven in a larger population. The American College of Obstetricians and Gynecologists Committee on Obstetric Practice believes that further studies are needed to evaluate the use of progesterone in those with other high-risk obstetric factors, such as multiple gestations, short cervical length, or positive test results for cervicovaginal fetal fibronectin. When progesterone is used, it is important to restrict its use to only women with a documented history of a previous spontaneous birth at less than 37 weeks of gestation, because unresolved issues remain, such as optimal route of drug delivery and long term safety of the drug (ACOG, 2003). 

In October 2008, ACOG issued an updated position paper on the use of progesterone for reduction of preterm birth which summarized the results of the clinical trials currently available and reaffirmed its view that, "Progesterone supplementation for the prevention of recurrent preterm birth should be offered to women with a singleton pregnancy and a prior spontaneous preterm birth due to spontaneous preterm labor or premature rupture of membranes.  Current evidence does not support the routine use of progesterone in women with multiple gestations.  Progesterone supplementation for asymptomatic women with an incidentally identified very short cervical length (less than 15 mm) may be considered; however, routine cervical length screening is not recommended…Recent studies support the hypothesis that progesterone supplementation reduces preterm birth in a select group of women.  Despite the apparent benefits of progesterone, the ideal progesterone formulation is unknown…Based on current knowledge, it is important to offer progesterone for pregnancy prolongation to only women with a documented history of a previous spontaneous birth at less than 37 weeks of gestation.  The ACOG Committee on Obstetric Practice and the Society for Maternal Fetal Medicine believe that further studies are needed to evaluate the optimal preparation, dosage, route of administration, and other indications for the use of progesterone for the prevention of preterm delivery."  (ACOG, 2008; ACOG update, 2009).

ACOG was a cosponsor of a report by the Institute of Medicine (IOM) entitled "Preterm Birth: Causes, Consequences, and Prevention" (IOM, 2006). In a press release, ACOG expressed particular support for the report's recommendation for an increase in federal funding for research into the causes and prevention of preterm birth (ACOG, 2006).

Gestation:  This term refers to a pregnancy and is usually given to denote the status of the pregnancy in weeks relative to the time of conception.

Preterm birth: This term refers to a live birth before 37 completed weeks of gestation.  Further definitions includes late preterm (34-36 weeks), moderately preterm (32-36 weeks) and very preterm (less than 32 weeks) (ACOG, 2009).

Spontaneous preterm birth:  Unintentional, unplanned labor before 37 completed weeks of gestation. While the cause of spontaneous preterm birth is unknown, a history of spontaneous preterm birth is one of the strongest predictors for a preterm birth in a subsequent pregnancy (ACOG, 2009).

Peer Reviewed Publications:

1. Brancazio LR, Murtha AP, Heine RP. Prevention of recurrent preterm delivery by 17 alpha- hydroxyprogesterone caproate. N Engl J Med. 2003; 349(11):1087-1088.
2. da Fonseca EB, Bittar RE, Carvalho MH, Zugaib M. Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study. Am J Obstet Gynecol. 2003; 188(2):419-424.
3. da Fonseca EB, Bittar RE, Damiao R, Zugaib M. Prematurity prevention: the role of progesterone. Curr Opin Obstet Gyn. 2009b; 21(2):142-147.
4. da Fonseca EB, Celik E, Parra M, et al. Fetal Medicine Foundation Second Trimester Screening Group. Progesterone and the risk of preterm birth among women with a short cervix. N Engl J Med. 2007; 357(5):462-469.
5. da Fonseca EB, Damiao R, Nicholaides K.  Prevention of preterm birth based on short cervix:  progesterone. Sem Perinatol. 2009a; 33:334-337.
6. DeFranco EA, O'Brien JM, Adair CD, et al. Vaginal progesterone is associated with a decrease in risk for early preterm birth and improved neonatal outcome in women with a short cervix: a secondary analysis from a randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol. 2007; 30(5):697-705.
7. Greene MF. Progesterone and preterm delivery - déjà vu all over again. N Engl J Med. 2003; 348(24):2453-2455.
8. Hassan SS, Romero R, Vidyadhari D, et al.  Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial.  Ultrasound Obstet Gynecol. 2011; 38:18–31.
9. Keirse MJ. Progestogen administration in pregnancy may prevent preterm delivery. Br J Obstet Gynaecol. 1990; 97(2):149-154.
10. Mackenzie R, Walker M, Armson A, et al.  Progesterone for the prevention of preterm birth among women at increased risk:  a systematic review and meta-analysis of randomized controlled trials.  Am J Obstet Gynecol. 2006; 194(5):1234-1242.
11. Norman JE, Mackenzie F, Owen P, et al.  Progesterone for the prevention of preterm birth in twin pregnancy (STOPPIT):  a randomized, double-blind, placebo-controlled study and meta-analysis.  Lancet. 2009; 373:2034-2040. 
12. O'Brien JM, Adair CD, Lewis DF et al. Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol. 2007; 30(5):687-696.
13. O'Brien JM, Lewis DF. Progestins for the prevention of spontaneous preterm birth: review and implications of recent studies. J Reprod Med. 2009; 54(2):73-87.
14. Porter TF, Scott JR. Evidence-based care of recurrent miscarriage. Best Pract Res Clin Obstet Gynaecol. 2005; 19(1):85-101.
15. Petrini JR, Callaghan WM, Klebanoff M, et al. Estimated effect of 17 alpha-hydroxyprogesterone caproate on preterm birth in the United States.  Obstet Gynecol. 2005; 105(2):267-272.  Available at:  http://mail.ny.acog.org/website/17PEffect.pdf.  Accessed on October 12, 2011.
16. Rittenberg C, Sullivan S, Istwan N, et al. Clinical characteristics of women prescribed 17 alphahydroxyprogesterone caproate in the community setting. Am J Obstet Gynecol. 2007; 197:262. e1-4.
17. Rode L, Langhoff-Roos J, Andersson C, et al.  Systematic review of progesterone for the prevention of preterm birth in singleton pregnancies.  Acta Obstet Gynecol Scand. 2009; 88(11):1180-1189.
18. Rouse DJ, Caritis SN, Peaceman AM, et al. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. A trial of 17 alpha-hydroxyprogesterone caproate to prevent prematurity in twins. N Engl J Med. 2007; 357(5):454-461.
19. Sanchez-Ramos L, Kaunitz AM, Delke I.  Progestational agents to prevent preterm birth: a meta-analysis of randomized controlled trials. Obstet Gynecol. 2005; 105(2):273-279.
20. Simhan HN, Caritis SN. Prevention of preterm delivery. N Engl J Med. 2007; 357(5):477-487.
21. Snegovskikh V, Park JS, Norwitz ER. Endocrinology of parturition.  Endocrinol Metab Clin N Am. 2006; 35:173-191.
22. Thornton JG. Progesterone and preterm labor -- Still no definite answers. N Engl J Med. 2007; 357(5):499-501.
23. Tita AT, Rouse DJ. Progesterone for preterm birth prevention: an evolving intervention. Am J Obstet Gynecol. 2009; 200(3):219-224.
24. Yemini M, Borenstein R, Dreazen E, et al. Prevention of premature labor by 17 alpha-hydroxyprogesterone caproate. Am J Obstet Gynecol. 1985; 151(5):574-577.

Government Agency, Medical Society, and Other Authoritative Publications:

1. 17 alpha-hydroxyprogesterone caproate (progesterone). In: DrugPoints^® System [Internet database]. Greenwood Village, CO: Thomson Healthcare. Updated periodically. Last updated Nov. 19, 2007. Available at: http://www.thomsonhc.com. Accessed on October 12, 2011.
2. American College of Obstetricians and Gynecologists (ACOG) Committee on Practice Bulletins. Management of preterm labor. ACOG Practice Bulletin. Clinical management guidelines for obstetrician-gynecologist. Number 43, May 2003. Obstet Gynecol. 2003; 101(5 Pt 1):1039-1047.
3. American College of Obstetrics and Gynecologist (ACOG) Committee Opinion. Use of progesterone to reduce preterm birth. Int J Gynaecol Obstet. 2004; 84(1):93-94.
4. American College of Obstetricians and Gynecologists (ACOG) [website]. ACOG News Release. ACOG Statement in Support of IOM Report, Preterm Birth: Causes, Consequences, and Prevention. July 13, 2006. Available at: http://classic.acog.org/from_home/publications/press_releases/nr07-13-06.cfm. Accessed on October 12, 2011.
5. American College of Obstetricians and Gynecologists (ACOG). ACOG Committee Opinion No. 419, 2008. Use of progesterone to prevent preterm birth. Obstet Gynecol. 2008; 112(4):963-965. (Replaces No. 291, November 2003). Available at: http://mail.ny.acog.org/website/17PCommitteeOpinion.pdf. Accessed on October 12, 2011.
6. American College of Obstetricians and Gynecologists (ACOG). Preventing preterm birth: The role of 17 alpha hydroxyprogesterone caproate. January 2009. Available at: http://mail.ny.acog.org/website/17PResourceGuide.pdf. Accessed on October 12, 2011.
7. American College of Obstetricians and Gynecologists (ACOG). Committee Opinion No. 387, 2007. Pharmaceutical Compounding. Available at: http://www.acog.org/~/media/Committee%20Opinions/Committee%20on%20Gynecologic%20Practice/co387.ashx?dmc=1&ts=20111214T0535094334. Accessed on October 12, 2011.
8. American College of Obstetricians and Gynecologists (ACOG) Women's Health Care Physicians and the Society for Maternal Fetal Medicine (SMFM). Information Update on 17a-Hydroxyprogesterone Caproate (17P) from the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine. October 13, 2011. Available at: http://www.acog.org/~/media/Announcements/20111013MakenaLtr.ashx. Accessed on December 21, 2011.
9. American College of Obstetricians and Gynecologists (ACOG) Women's Health Care Physicians and the Society for Maternal Fetal Medicine (SMFM). Letter regarding compounding 17 alpha hydroxyprogesterone caproate. April 28, 2011. Available at: https://www.smfm.org/SMFM%20Home%20Information%20Page.cfm?ht=h. Accessed on October 12, 2011.
10. Behrman RE, Butler AS, eds. Institute of Medicine of the National Academies (IOM⁾ Committee on Understanding Premature Birth and Assuring Healthy Outcomes. Preterm Birth: Causes, Consequences, and Prevention. The National Academies Press [website]. 2007. Available at: http://books.nap.edu/catalog.php?record_id=11622. Accessed on October 12, 2011.
11. Caritis SN, Rouse DJ, Peaceman AM, et al. Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). Maternal-Fetal Medicine Units Network (MFMU). Prevention of preterm birth in triplets using 17 alpha-hydroxyprogesterone caproate: a randomized controlled trial. Obstet Gynecol. 2009; 113(2 pt 1):285-292.
12. Dodd JM, Crowther CA, McPhee AJ, et al.  Progesterone after previous preterm birth for prevention of neonatal respiratory distress syndrome (PROGRESS): a randomised controlled trial. BMC Pregnancy Childbirth. 2009; 9:6.
13. Dodd JM, Flenady V, Cincotta R, Crowther CA. Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth. Cochrane Database Syst Rev. 2006; (1):CD004947.
14. Dodd JM, Flenady VJ, Cincotta R, Crowther CA.  Progesterone for the prevention of preterm birth: a systematic review. Obstet Gynecol. 2008; 112(1):127-134.
15. Farine D, Mundle WR, Dodd J, et al. Maternal Fetal Medicine Committee of the Society of Obstetricians and Gynaecologists of Canada. The use of progesterone for prevention of preterm birth. J Obstet Gynaecol Can. 2008; 30(1):67-77.
16. Haas DM, Ramsey PS. Progestogen for preventing miscarriage. Cochrane Database Syst Rev. 2008; (2):CD003511.
17. Makena™ [Product Information], Bloomington, IN. Baxter Pharmaceutical Solutions LLC. Updated on February 3, 2011. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails. Accessed on December 20, 2011.
18. Meis PJ, Klebanoff M, Dombrowski MP, et al. Does progesterone treatment influence risk factors for recurrent preterm delivery? National Institute of Child Health and Human Development. Rockville, MD. Obstet Gynecol. 2005; 106(3):557-561.
19. Meis PJ, Klebanoff M, Thom E, et al. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. N Engl J Med. 2003; 348(24):2379-2385.
20. Norman JE, Mackenzie F, Owen P, et al. Progesterone for the prevention of preterm birth in twin pregnancy (STOPPIT): a randomised, double-blind, placebo-controlled study and meta-analysis. Lancet. 2009; 373(9680):2034-2040.
21. Northen AT, Norman GS, Anderson K et al. National Institute of Child Health and Human Development (NICHD). Maternal-Fetal Medicine Units (MFMU) Network. National Institutes of Health (NIH).  Bethesda, MD.  Follow-up of children exposed in utero to 17 alpha-hydroxyprogesterone caproate compared with placebo. Obstet Gynecol. 2007; 110(4):865-872.
22. Papatsonis D, Flenady V, Liley H. Maintenance therapy with oxytocin antagonists for inhibiting preterm birth after threatened preterm labour. Cochrane Database Syst Rev. 2009; (2):CD005938.
23. Spong CY. National Institute of Child Health and Human Development (NICHD), Pregnancy and Perinatology Branch. National Institutes of Health (NIH). Bethesda, MD. Prediction and prevention of recurrent spontaneous preterm birth. Obstet Gynecol. 2007; 110:405-415.
24. Spong CY, Meis PJ, Thom EA, et al. National Institute of Child Health and Human Development Maternal Fetal Medicine Units Network. Progesterone for prevention of recurrent preterm birth:  impact of gestational age at previous delivery. Am J Obstet Gynecol. 2005; 193(ePt2):1127-1131.
25. Su LL, Samuel M, Chong YS. Progestational agents for treating threatened or established preterm labor. Cochrane Database Syst Rev. 2010; (1):CD006770. Available at: http://onlinelibrary.wiley.com/o/cochrane/clsysrev/articles/CD006770/frame.html. Accessed on October 12, 2011.
26. United States Food and Drug Administration (FDA). Press release regarding continued access to 17 alpha-hydroxyprogesterone caproate from compounding pharmacies. March 30, 2011. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm249025.htm. Accessed on October 12, 2011.

1. Additional press release information about the FDA new approval of Makena^TM.  February 4, 2011.  Available at: http://www.prnewswire.com/news-releases/fda-approves-makena-the-first-and-only-treatment-to-reduce-the-risk-of-preterm-birth-in-women-with-a-singleton-pregnancy-who-have-a-history-of-singleton-spontaneous-preterm-birth-115271964.html.  Accessed on October 12, 2011.
2. United States Food and Drug Administration (FDA).  Additional information about approval of Makena.  February 4, 2011.  Available at:  http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm242234.htm.  Accessed on October 12, 2011.

17AHPC
Alpha Hydroxyprogesterone
Hydroxyprogesterone, 17a-
Makena^™