BlueCross and BlueShield of Montana Medical Policy/Codes
Progesterone Therapy as a Technique to Reduce Preterm Delivery in High-Risk Pregnancies
Chapter: Drugs - Medical Benefit
Current Effective Date: July 18, 2013
Original Effective Date: March 18, 2012
Publish Date: April 18, 2013
Revised Dates: November 08, 2012; April 17, 2013
Description

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 these have 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 (causing abnormal prenatal development), and the U.S. Food and Drug Administration (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 was pulled from the market by its manufacturer and is no longer available. Most recently, there has been renewed research interest in intramuscular injection of 17 alpha-hydroxyprogesterone caproate (17P). 17P is a weakly acting, naturally occurring progesterone metabolite, which when coupled with caproate dextran works as a long-acting progestin when administered intramuscularly. 17P is now commercially available as Makena™, (K-V Pharmaceutical Company, St. Louis, MO.) but is also manufactured locally by compounding pharmacies. Intravaginal progesterone suppositories have also been investigated.

On February 3, 2011, Makena™, hydroxyprogesterone caproate injection for intramuscular use, was approved by the FDA through the premarket approval (PMA) process. The product, formerly called Gestiva, is indicated to reduce preterm birth in women with a singleton pregnancy that have a history of singleton spontaneous preterm birth. Makena is not intended for use in women with multiple gestations or in women with other risk factors for preterm birth

March 31, 2011 the Food and Drug Administration announced that in order to support access to this important drug, at this time the 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.

The use of progesterone suppositories during pregnancy for the prevention of preterm birth in high-risk women is currently under investigation. Progesterone suppositories are usually compounded by individual pharmacists and consist of progesterone suspended in a cocoa butter type base. Upon insertion, the warmth of the body causes the suppository to melt and release the progesterone.

Policy

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply.  If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Medically Necessary

BCBSMT may consider the following medically necessary:

  • Weekly injections of 17 alpha-hydroxyprogesterone caproate between 16 and 36 weeks of gestation may be considered medically necessary in pregnant women with a prior history of a preterm delivery before 37 weeks gestation.
  • Daily vaginal progesterone suppositories between 24 and 34 weeks gestation in pregnant women with a prior history of preterm delivery before 37 weeks gestation.

Investigational

BCBSMT considers progesterone therapy as a technique to prevent preterm labor experimental, investigational and unproven in pregnant women with other risk factors for preterm delivery, including, but not limited to multiple gestations, short cervical length, or positive tests for cervicovaginal fetal fibronectin.

Policy Guidelines

Compounding of 17-alpha hydroxyprogesterone is considered integral to the injections and therefore not separately reimbursable.

Dosages are usually in the 250mg to 500mg dosage once a week. Compounders should be submitting the closest sized vial National Drug Code (NDC) number (1 gm – 5gm) depending on availability. NDC lists are subject to change based on the availability of product.

Rationale

This policy is based on an analysis of two recently published randomized trials of progestational compounds as a technique to prevent recurrent spontaneous abortion. Meis and colleagues focused on the use of weekly intramuscular injections of 17 alpha-hydroxyprogesterone caproate, while da Fonseca and colleagues focused on the role of vaginal suppositories of progesterone. 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’ gestation. The limitation in this outcome is that as delivery approaches 37 weeks, the associated morbidity and mortality decline. Delivery prior to 34 weeks is more predictably associated with neonatal morbidity and mortality.

Intramuscular 17 alpha-hydroxyprogesterone caproate (17P)

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:

Outcomes of Pregnancy

Intervention Group (%)

Placebo Group (%

p value

Delivery before 37 wks

36.4

54.9

<0.001

Delivery before 35 wks

20.6

30.7

0.02

Delivery before 32 wks

11.4

19.6

0.02

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 patients 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 patients. 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 uncertainly as to whether the results of this study can be extrapolated to other populations. Finally, as suggested by a letter to the editor, 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. A 1990 meta-analysis also supported the hypothesis that 17P does reduce the occurrence of preterm delivery.

Progesterone Vaginal Suppository

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 patients. Inclusion criteria included either a prior history of preterm birth, prophylactic cervical cerclage, or a uterine malformation. In addition, the mean gestational age of the prior preterm birth (33 weeks) was greater than the Meis trial, suggesting that; overall, this population of patients was at lower risk for preterm birth. The following pregnancy outcomes were reported.

Pregnancy outcome

Placebo (%)

Intervention (%)

p value

Delivery before 37 weeks

28.5

13.8

0.03

Delivery before 34 weeks

18.6

2.8

0.002

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.

Additional Information

In November 2003, the American College of Obstetricians and Gynecologists (ACOG) issued a committee opinion on the use of progesterone to reduce preterm birth, which included a review of the Meis and da Fonseca studies. The ACOG document states, “… [the results of these two studies] support the hypothesis that progesterone supplementation reduces preterm birth in a select very high-risk group of patients. 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 patients 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.”

Rouse et al. randomized 661 women with twin gestations to weekly (from 16 to 35 weeks gestation) intramuscular injections of 17P or placebo. No differences were observed in the occurrence of delivery or fetal death before 35 weeks (42% vs. 37%) or in serious adverse fetal or neonatal events (20% vs. 18%). The use of vaginal progesterone in women at high risk of pre-term delivery due to short cervical length was also reported. One study 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. Preterm delivery (<34 gestational weeks) occurred in 24 (19%) women in the progesterone group and 43 (34%) in the control group. Composite measures of neonatal therapy (25% vs. 33%) and morbidity (8% vs. 14%) were not significantly reduced. Secondary analysis from the O’Brien Randomized control trial - fetal (RCTF) described above described the effect of vaginal progesterone in women with short cervical length. A significant group difference was found in the two groups of women (n=46) who had a cervical length < 28 mm. For the 19 women who had received vaginal progesterone there were no (0%) preterm births, while the group of 27 women who had received placebo had eight (30%) preterm births at 32 weeks or less. There was no difference in the average gestational age at birth (36 vs. 35 weeks). This study is limited by the small number of subjects and the exploratory post-hoc analysis; further study in this population is needed.

Also reported was follow-up of children born during the Meis et al. trial of 17P. Of the 429 infants discharged alive after birth, 278 (65%) were enrolled. Loss to follow-up occurred due to the loss of centers who were no longer in the network (n=81), and parents or guardians who were not able to be contacted (n=55) or who declined to participate (n=15). There was a 2:1 treatment ratio in the original study, resulting in follow-up of 194 children from the 17P group and 84 from the control group. An average 48 months follow-up (from < 36 to 60 months) found no differences in physical measures, diagnoses given by health professionals, or in the caregiver’s assessment of the health of the children. This follow-up is encouraging, but uncertainty regarding long-term complications from prenatal progesterone exposure will remain until longer follow-up becomes available.

Questions remain about the most effective dose and mode of administration of progesterone in women with a prior history of preterm delivery, and additional study is needed to evaluate the effect of progesterone in women with other risk factors for preterm delivery. Reconsideration of the policy statements awaits results from ongoing randomized controlled trials (RCTs), which have a combined expected enrollment of over 5,000 women with high-risk pregnancy.

2011 Update

Tita et al. conducted a systematic review of RCTs and meta-analyses of RCTs that evaluated the use of progesterone for the prevention of preterm birth. The focus was on the pharmacologic aspects of progesterone and risk factor-specific outcomes. A total of 17 relevant reports were identified: eight individual RCTs, six meta-analyses, and three national guidelines. The following key pharmacologic aspects of progesterone were identified: 1) natural progesterone is almost exclusively delivered vaginally; 2) doses ranged from 90 to 400 mg/day, initiated variably at 18 to 25 weeks; 3) compared to intramuscular routes of administration, vaginal has better bioavailability; and 4) synthetic progesterone (17-alpha-hydroxyprogesterone) was given exclusively by the intramuscular route in variable doses (25 to 100 mg) once weekly to thrice weekly. The authors concluded that “…the reviewed data strongly suggest that prophylactic use of progesterone leads to significant reductions in measures of preterm birth and low birth weight. The data also suggest, but less conclusively, that progesterone may confer neonatal morbidity and mortality benefit. However, the benefit of progesterone may vary by risk group, route of administration, and dose. “

Caritis et al. performed an RCT in 14 centers to assess whether 17 alpha-hydroxyprogesterone caproate reduces the rate of preterm birth in women carrying triplets. This study was not included in the systematic review by Tita et al. Healthy women with triplets (n=134) were randomly assigned to weekly intramuscular injections of either 250 mg of 17 alpha-hydroxyprogesterone caproate or matching placebo, starting at 16 to 20 weeks and ending at delivery or 35 weeks of gestation. The primary study outcome was delivery or fetal loss before 35 weeks. A total of 134 women were randomized with 71 assigned to 17 alpha-hydroxyprogesterone caproate and 63 to placebo; none were lost to follow-up. Baseline demographic data were similar in the two groups. The proportion of women experiencing the primary outcome (a composite of delivery or fetal loss before 35 weeks) was similar in the two treatment groups: 83% of pregnancies in the 17 alpha-hydroxyprogesterone caproate group and 84% in the placebo group (relative risk 1.0). The lack of benefit of 17 alpha-hydroxyprogesterone caproate was evident regardless of the conception method or whether a gestational age cutoff for delivery was set at 32 or 28 weeks. The authors concluded that treatment with 17 alpha-hydroxyprogesterone caproate did not reduce the rate of preterm birth in women with triplet gestations.

A review by O’Brien and Lewis revealed recent findings regarding progestin therapy from both clinical and laboratory data considers unresolved issues for use of these agents. The authors concluded that “…the prophylactic administration of progestins showed greatest promise to prevent preterm birth with a large multicenter study by Meis et al. Despite remarkable advances in our understanding of this hormone's [progesterone] mechanism of action, its roles in human pregnancy maintenance and parturition are not fully appreciated. Proper scientific hypothesis testing of progestins to prevent preterm birth has been limited because of the issues that can plague interventional trials in obstetrics, including patient selection, choice of outcome and power. Finally, the safety of progestin administration is a legitimate concern and justifies the need for further investigation of safety issues.”

Given these ongoing concerns, data from the da Fonseca et al. study was re-evaluated. While this is the only RCT to date assessing the utility of progestin for the prevention of preterm birth that included patients with cervical cerclage (n=4) and uterine malformation (n=5), as these numbers indicate there were very few patients with these conditions in that study. Thus, given these small subgroups in light of ongoing concerns and the 2008 ACOG recommendations, the reevaluation concludes that the evidence is insufficient for use of progestin therapy to prevent preterm birth in patients with cervical cerclage or uterine anomaly.

Available evidence is sufficient regarding intramuscular use of synthetic progesterone (17-alpha hydroxyprogesterone) and vaginal use of natural progesterone to prevent preterm birth for women with a singleton pregnancy with a prior history of spontaneous preterm birth before 37 weeks’ gestation. The available literature regarding progesterone therapy to prevent preterm delivery in pregnant women with other risk factors, but without a prior history of spontaneous preterm birth; multiple gestations, short cervical length, positive tests for cervicovaginal fetal fibronectin, cervical cerclage, or uterine anomaly are inadequate to draw clinical conclusions. This therapy is investigational in women with these risk factors given the insufficient evidence to evaluate the impact on net health outcome.

In November 2003, the American College of Obstetricians and Gynecologists (ACOG) issued a committee opinion on the use of progesterone to reduce preterm birth, which included a review of the Meis and da Fonseca studies. The ACOG document states, “… [the results of these two studies] support the hypothesis that progesterone supplementation reduces preterm birth in a select very high-risk group of patients.”

In October 2008, the ACOG issued a committee opinion, Use of Progesterone to Reduce Preterm Birth. This document replaces the committee opinion of November 2003. The document states that ”…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. 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 has not been studied as a supplemental treatment to cervical cerclage for suspected cervical insufficiency, as a preventive agent for asymptomatic women with positive cervico-vaginal fetal fibronectin screen result, as a tocolytic agent, or as a therapeutic agent after tocolysis, and it should not be used at this time for these indications alone.”

In a prospective, randomised trial, Majhi et al in a study in India published a study of 100 pregnant women with one or more prior spontaneous pre-term birth that were randomized into two groups. In Group I, women received 100 mg natural micronized progesterone intravaginally once daily from 20-24 weeks' gestation until 36 weeks. In Group II, women did not receive progesterone. Both groups were regularly supervised until delivery. Pre-term birth (<37 and <34 weeks) and other maternal, neonatal outcomes were primary and secondary outcomes, respectively. The Chi-square test and Fisher exact tests were used to compare categorical variables. Independent sample t-test and one-way ANalysis Of Variance test (ANOVA) were used to compare continuous variables and multiple comparisons, respectively. Pre-term births <37 weeks were significantly lower in Group I (12% vs. 38%, p = 0.002), but pre-term births <34 weeks were similar. The mean birth weight of neonates born to women in Group I was significantly higher (2800 vs. 2,500 g, p =0.023). The authors concluded that intravaginal administration of 100 mg of natural micronized progesterone significantly reduced the incidence of pre-term birth <37 weeks in women with one or more prior pre-term birth. Future research is warranted to assess the long-term safety and efficacy of progesterone.

In a small study by Briery et al. women with twin gestations between 20 to 30 weeks gestation were randomized to receive weekly injections of either 250 mg 17P injection (Group I), or placebo (Group II). Thirty twin pregnancies were randomized; 16 received 17P and 14 received placebo. Demographic data as well as past history and gestational age were the same between groups. Days spent in the Neonatal Intensive Care Unit (NICU) among 17P (18.4) versus placebo (17.3, P = 0.155), neonatal death (P = 0.359) and those infants discharged with neurologic handicap (P = 0.594) were equivalent between groups (P = 0.286-0.847). The incidence of preterm labor (P = 0.980), and premature rupture of membranes (P = 0.525) were not different between groups. Among this group of twin gestations weekly 17HP injections did not reduce the incidence of preterm birth or the complications associated with prematurity.

A clinical trial is underway sponsored by the University of Oklahoma and currently recruiting participants. This study compares intramuscular injection of progesterone to vaginal progesterone in women with singleton pregnancies and a history of prior preterm birth. (NCT00579553). The estimated date of completion is August 2013.

Coding

Disclaimer for coding information on Medical Policies           

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.           

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.           

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

Rationale for Benefit Administration
 
ICD-9 Codes

99.24, 99.29, V23.41, V28.82

ICD-10 Codes
O09.211-O09.219
Procedural Codes: 96372, J1725, J3490, S9123, S9124, S9208, S9542, S9560, S9810
References
  1. Meis, P.J., Klebanoff, M., et al. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. New England Journal of Medicine (2003) 348(24):2379-85.
  2. da Fonseca, E.B., Bittar, R.E., et al. 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. American Journal of Obstetrics and Gynecology (2003) 188(2):419-24.
  3. Meis, P. J. 17-hydroxyprogesterone for the prevention of preterm delivery. Obstetrics and Gynecology (2005) 105: 1128-35.
  4. Sanchez-Ramos, L., Kaunitz, A.M., et al. Progestational agents to prevent preterm birth: a meta-analysis of randomized controlled trials. Obstetrics and Gynecology (2005) 105: 273-9.
  5. Dodd, J.M., Flenady, V., et al. Prenatal administration of progesterone for preventing preterm birth. Cochrane Database Syst Rev (2006) (1):CD004947.
  6. O'Brien, J.M., Adair, C.D., 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):687-96.
  7. Rouse, D.J., Cartis, S.N., et al. A trial of 17 alpha-hydro-hydroprogesterone caproate to prevent prematurity in twins. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. New England Journal of Medicine (2007) 357(5): 454-61.
  8. Northern, A.T., Norman, G.S., et al. National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine (MFMU) Network. Follow-up of children exposed in utero to 17 alpha-hydroxyprogesterone caproate compared with placebo. Obstetrics and Gynecology (2007) 110(4): 665-72.
  9. Fonseca, E.B., Ceilk, E., et al. Fetal Medicine Foundation Second Trimester Screening Group. Progesterone and the risk of preterm birth among women with a short cervix. New England Journal of Medicine (2007) 357(5): 462-9.
  10. DeFranco, E.A., O’Brien, J.M., 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 Obstetrics and Gynecology (2007) 30(5): 697-705.
  11. American College of Obstetricians and Gynecologists’ Committee on Obstetric Practice and the Society for Maternal Fetal Medicine. Use of Progesterone to Reduce Preterm Birth. ACOG Committee Opinion Number 419 (replaces No. 291, November 2003). Obstet Gynecol (2008) 112(4):963-5.
  12. Majhi, P., Bagga, R., et al. Intravaginal use of natural micronized progesterone to prevent pre-term birth: a randomized trial in India. J Obstet Gynecol (2009) 29(6):493-8.
  13. Tita, A.T., and D.J. Rouse. Progesterone for preterm birth prevention: an evolving intervention. Am J Obstet Gynecol (2009) 200(3):219-24.
  14. Progesterone Therapy as a Technique to Reduce Preterm Birth in High-Risk Pregnancies. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2009 October) OB/GYN Reproduction 4.01.16.
  15. Caritis, S.N., Rouse, D.J., 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):285-92.
  16. Norman, J.E., Mackenzie, F., 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(9680):2034-40.
  17. O'Brien, J.M., and D.F. Lewis. Progestins for the prevention of spontaneous preterm birth: review and implications of recent studies. J Reprod Med (2009) 54(2):73-87.
  18. Rode, L., Langhoff-Roos, J., et al. Systematic review of progesterone for the prevention of preterm birth in singleton pregnancies. Acta Obstect Gynecol (2009) 88(11):1180-9.
  19. Dodd, J.M., and C.A. Crowther. The role of progesterone in prevention of preterm birth. Int J Womens Health (2010) 1:73-84.
  20. Berghella, V., Figueroa, D., et al. 17-alpha-hydroxyprogesterone caproate for the prevention of preterm birth in women with prior preterm birth and a short cervical length. Am J Obstet Gynecol (2010) 202(4):351, e1-6.
  21. Briery, C.M., Veillon, E.W., et al. Women with premature rupture of the membranes do not benefit from weekly progesterone. Am J Obstet Gynecol (2011) 204(1):54.e1-5.
  22. FDA—Food and Drug Administration Statement Makena™. Highlights of prescribing information. (2011 3 February).  http://www.fda.gov  (accessed 2011 April 6).
  23. FDA—Food and Drug Administration Statement on Makena™. Press Announcement. (2011 3 February) http://www.fda.gov (accessed 2011 April 6).
  24. FDA—Food and Drug Administration Statement on Makena™ and Compounding Pharmacies. Press Announcement. (2011 30 March). http://www.fda.gov (accessed 2011 April 6).
History
January 2012 New policy with HCPCS code Q2042 added
November 2012 Policy reviewed with literature search through July 2012. Investigational statement reformatted to bulleted list to improve readability. Added bullet point to investigational statement, “prior episode of preterm labor in current pregnancy (i.e. progesterone therapy in conjunction with tocolysis or following successful tocolysis).” References 1, 10, 11, 15, 16, 20, 22, 23, 25-27 added; other references renumbered or removed.
April 2013 Changed title from "Progesterone Therapy as a Technique to Reduce Preterm Birth in High-Risk Pregnancies" to "Progesterone Therapy as a Technique to Reduce Preterm Delivery in High-Risk Pregnancies".  Coverage for women with a singleton pregnancy and a short cervix (less than 20 mm) changed from Medically Necessary to Investigational.  Added codes S9123, S9124, S9542, S9560, S9810, and J3490.  Removed codes 99506 and Q2042.
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Progesterone Therapy as a Technique to Reduce Preterm Delivery in High-Risk Pregnancies