Clinical UM Guideline
|Subject:||Progesterone Therapy as a Technique to Prevent Preterm Delivery in High-Risk Women|
|Guideline #:||CG-DRUG-19||Current Effective Date:||11/23/2015|
|Status:||Revised||Last Review Date:||11/05/2015|
This document addresses the use of intramuscular injections of 17-alpha hydroxyprogesterone caproate or vaginal progesterone for the prevention of preterm birth in individuals at high-risk for preterm delivery.
Not Medically Necessary:
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.
|99506||Home visit for intramuscular injections|
|J1725||Injection, hydroxyprogesterone caproate, 1 mg [Makena]|
|J3490||Unclassified drugs [when specified as injectable 17-alpha hydroxyprogesterone caproate]|
|J7999||Compounded drug, not otherwise classified [when specified as a compounded progesterone product] [Note: code will be effective for dates of service on or after 01/01/2016]|
|Q9977||Compounded drug, not otherwise classified [when specified as a compounded progesterone product] [Note: code will be deleted effective 12/31/2015]|
|No specific code for progesterone suppositories|
|No specific code for vaginal gel [Crinone, Prochieve]|
|S9560||Home injectable therapy; hormonal therapy (e.g., Leuprolide, Goserelin), including administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment, per diem [when specified as progesterone therapy]|
|O09.211-O09.219||Supervision of pregnancy with history of pre-term labor [includes codes O09.211, O09.212, O09.213, O09.219]|
|O09.291-O09.299||Supervision of pregnancy with other poor reproductive or obstetric history [includes codes O09.291, O09.292, O09.293, O09.299]|
|O26.872-O26.879||Other specified pregnancy related conditions, cervical shortening [vaginal gel]|
Preterm labor and delivery is a major cause of neonatal morbidity and mortality; in the United States the rate of preterm birth is 11.4% (CDC, 2015). Although a variety of diagnostic and prophylactic measures have been investigated, tto date, none have significantly impacted the incidence of preterm delivery. In the past, intramuscular injections (IM) of 17 alpha-hydroxyprogesterone, (that is, Delalutin) were used to prevent the onset of premature labor. However, the drug was subsequently found to have teratogenic properties, and the FDA gave the drug a Category D pregnancy status meaning, studies demonstrated fetal risk, but use of the drug may outweigh the potential risk. Delalutin is no longer on the market. Research interest was renewed in a similar drug known as 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 and is also administered IM.
On February 3, 2011 K-V Pharmaceutical Company (St. Louis, MO) announced approval of the only U.S. Food and Drug Administration (FDA) approved form of 17P to date, known as Makena™ (formerly known as Gestiva. Makena is the only synthetic progestin approved by the FDA and commercially available to reduce the risk of preterm birth. According to the FDA label, 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" 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.
The FDA (2011) states:
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.
Contraindications to use of Makena include:
In 2012, the FDA issued a statement regarding compounded versions of hydroxyprogesterone caproate (the active ingredient in Makena). The FDA announced that it had completed its on-site review of compounded samples and summarized their findings as follows:
Although the analysis of this limited sample of compounded hydroxyprogesterone caproate products and active pharmaceutical ingredients (APIs) did not identify any major safety problems, approved drug products, such as Makena, provide a greater assurance of safety and effectiveness than do compounded products.
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 IM 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, a study would examine the outcomes of greatest clinical significance, such as 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 (FDA pivotal trial), 463 women with a history of a prior preterm delivery were randomized in a 2:1 ratio to receive either weekly IM 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:
|Outcomes of Pregnancy|
Intervention Group (%)
Placebo Group (%)
|Delivery before 37 weeks|
|Delivery before 35 weeks|
|Delivery before 32 weeks|
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.
Several studies have investigated the effect of vaginal progesterone on the incidence of preterm birth. da Fonseca and colleagues (2003) reported on the results of a trial that randomized 142 women considered at high risk for preterm delivery to receive either daily vaginal progesterone or placebo suppositories. This study included a broad range of subjects including a prior history of preterm birth, prophylactic cervical cerclage or a uterine malformation. The mean gestational age of the prior preterm birth was 33 weeks. The following pregnancy outcomes were reported:
|Delivery before 37 weeks|
|Delivery before 34 weeks|
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 (da Fonseca, 2003). Preterm birth occurred in 13.8% of the progesterone group and in 28.5% of the placebo group, which was statistically significant (P<0.05). Also in the placebo group, 18.5% of women delivered before 34 weeks, as compared with only 2.7% in the active treatment group (P<0.05). However, of the 142 high-risk subjects entered into this trial, only 4 subjects had an incompetent cervix requiring cerclage, and only 5 women 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.
In 2011, Hassan and colleagues published results of a Phase III multi-center, randomized, double-blind, placebo-controlled trial in which intravaginal progesterone (90 mg) was administered mid-trimester to reduce the risk of preterm birth and associated neonatal complications in women with a sonographic short cervix. Asymptomatic women with a singleton pregnancy and a sonographic short cervix (10 to 20 mm) at 19 + 0/7 to 23 + 6/7 weeks of gestation were enrolled in this study. They were allocated randomly to receive vaginal progesterone gel or placebo daily starting from 20 to 23 + 6/7 weeks until 36 + 6/7 weeks, rupture of membranes or delivery, whichever occurred first. Randomization sequence was stratified by center and history of a previous preterm birth. The primary endpoint was preterm birth before 33 weeks of gestation. Analysis was by intention-to-treat. Of 465 women randomized, 7 were lost to follow-up and 458 (vaginal progesterone gel, n=235; placebo, n=223) were included in the analysis. Results showed that women allocated to receive vaginal progesterone had a lower rate of preterm birth before 33 weeks than did those allocated to placebo (8.9% (n=21) versus 16.1% (n=36); RR, 0.55; 95% CI, 0.33-0.92; P=0.02). Vaginal progesterone was also associated with a significant reduction in the rate of preterm birth before 28 weeks (5.1% versus 10.3%; RR, 0.50; 95% CI, 0.25-0.97; P=0.04), as well as the incidence of other neonatal complications and markers of mortality and morbidity, (such as respiratory distress syndrome, birth weight less than 1500 g). There were no differences in the incidence of treatment-related adverse events between the groups. The authors concluded that administration of vaginal progesterone gel to women with a sonographic short cervix in the mid-trimester is associated with a 45% reduction in the rate of preterm birth before 33 weeks of gestation and with improved neonatal outcome (Hassan, 2011).
The Hassan trial results follow earlier studies, such as that reported by daFonseca regarding 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%) which were not significantly reduced (daFonseca, 2007).
In 2012, Romero published a meta-analysis of individual data from five randomized controlled trials, in which vaginal progesterone was compared to placebo or no treatment in asymptomatic pregnant subjects with a sonographic short cervix (cervical length 25 mm or less) in the mid-trimester. All of the studies were double-blinded and placebo-controlled. The studies included data on a total of 775 women, 723 (93%) with singleton pregnancies and 52 (7%) with twin pregnancies. A pooled analysis of data from the five studies found that treatment with vaginal progesterone was associated with a statistically significant reduction in the risk of preterm birth before 33 weeks gestation, compared to placebo (12.4% vs. 22.0%, respectively; RR: 0.58, 95% CI, 0.42 -0.80). When the analysis was limited to women with a singleton birth and no history of previous preterm birth, there remained a significant benefit of progesterone treatment to reduce the rate of preterm birth before 33 weeks (RR: 0.60, 95% CI, 0.39-0.92). The outcome of preterm birth before 36 weeks gestation was marginally significant, and there was not a significant difference between groups in the rate of preterm birth before 37 weeks gestation (37% in the treatment group and 43% in the placebo group; Romero, 2012). An additional prospective cohort study provided secondary analysis of a prior study (O'Brien, 2007) of women with a short cervix (less than 28 mm) and a history of early preterm delivery, who were administered vaginal progesterone gel (90 mg); results showed a significantly reduced rate of preterm birth (before 32 weeks) compared with placebo (DeFranco, 2007).
A systematic review assessed 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, four studies were included; two used IM progesterone and two used vaginal progesterone. In this subset of the analysis, progesterone was associated with a significant reduction in preterm birth before 34 weeks (one study, 142 women, relative risk [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 progesterone therapy for prevention of miscarriage assessed 15 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 progesterone and placebo groups (Peto odds ratio [Peto OR] 0.98; 95% CI, 0.78-1.24) and no statistically significant difference in the incidence of adverse effect in either mother or baby. Subgroup analysis of four 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 (Peto OR 0.39; 95% CI, 0.210-0.72). 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, 2013). No statistically difference was found in the route of administration of progesterone (oral, IM or vaginal).
In 2012, a previously published clinical guideline was reaffirmed by the Society for Maternal Fetal Medicine (SMFM), in which the following recommendations were made:
Also in 2012, ACOG issued a practice bulletin No. 130 entitled, Prediction and Prevention of Preterm Birth. The following recommendations were made regarding progesterone therapy:
Level A: (based on good and consistent scientific evidence)
Level B: (based on limited or inconsistent scientific evidence)
In 2014, a separate ACOG practice bulletin (No. 144) was issued on Multifetal Gestations that included the following statement on progesterone therapy:
According to Truven Health Analytics DrugPoints® compendia, progesterone gel formulations, which include crinone® (Watson Pharma, Inc., Parsippany, NJ), prochieve® (Actavis Pharma, U.S.A.) and other brand names, have a Class 2A recommendation for the off-label indication of prevention of preterm birth of newborn due to presence of a short cervix (Evidence level: Category B [evidence favors efficacy]). This recommendation was largely based on the results of the previously described Phase III trial by Hassan and colleagues (2011).
Gestation period: The time in which a fetus develops, beginning with fertilization and ending with birth (usually denoted in weeks).
Preterm birth: A live birth before 37 completed weeks of gestation. Further definitions include, moderately preterm (32 to <37 weeks), very preterm (28 to <32 weeks) and extremely preterm (<28 weeks).
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.
Teratogenic: Able to disturb the development of an embryo or fetus; may cause a birth defect or pregnancy termination.
Peer Reviewed Publications:
Government Agency, Medical Society, and Other Authoritative Publications:
|Websites for Additional Information|
The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.
|Revised||11/05/2015||Medical Policy & Technology Assessment Committee (MPTAC) review. Reformatted criteria and amended indications for vaginal progesterone. Updated Background/Overview and Reference sections. Updated Coding section to note 01/01/2016 HCPCS changes; also removed ICD-9 codes.|
|07/01/2015||Updated Coding section with 07/01/2015 HCPCS changes.|
|04/01/2015||Updated Coding section; added HCPCS code S9560.|
|Revised||11/13/2014||MPTAC review. The medically necessary criteria have been expanded to include use of daily progesterone vaginal gel when other criteria are met. The Coding, Discussion and References sections were updated.|
|Reviewed||11/14/2013||MPTAC review. Discussion section and References were updated.|
|Reviewed||11/08/2012||MPTAC review. Discussion section and References were updated.|
|Reviewed||11/17/2011||MPTAC review. References were updated. Updated Coding section with 01/01/2012 HCPCS changes; removed Q2042 deleted 12/31/2011.|
|Revised||05/19/2011||MPTAC review. The position statement for injectable 17 alpha-hydroxyprogesterone caproate was clarified to state that 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 are criteria for medical necessity (taken from the 2009 updated ACOG statement). The Discussion section and References were updated. Updated Coding section with 07/01/2011 HCPCS changes.|
|Reviewed||02/17/2011||MPTAC review. Information about the newly FDA approved drug, Makena, and updated 2009 ACOG information was added to the Discussion section. The Definitions and References were also updated.|
|Revised||11/18/2010||MPTAC review. The note on pg. 1 regarding home injections has been replaced with a new not medically necessary statement as follows: Injections of 17 alpha-hydroxyprogesterone caproate in a home setting by or through a licensed home health agency are not medically necessary, except when criteria for home health services are met. (See CG-MED-23 - Home Health.) References and Coding were updated.|
|Revised||02/25/2010||MPTAC review. The position statement regarding use of daily vaginal progesterone suppositories has been revised to no longer consider history of prior cervical cerclage or uterine anomaly as medically necessary indications for treatment. These indications are now considered not medically necessary. The Discussion section, References and coding were updated.|
|Reviewed||02/26/2009||MPTAC review. Singleton pregnancy was added to the medically necessary criteria for clarification consistent with the updated 2008 ACOG position paper. Removed the section on Place of Service. References were updated.|
|Reviewed||02/21/2008||MPTAC review. References were updated.|
|New||03/08/2007||MPTAC review. Initial guideline development. Transferred content from DRUG.00025 Progesterone Therapy as a Technique to Prevent Preterm Delivery in High-Risk Women to new clinical UM guideline. Not Medically Necessary indications in new guideline previously considered Investigational/Not Medically Necessary in prior document. Coding and References were updated.|
Last Review Date
|DRUG.00025||17-Alpha Hydroxyprogesterone Caproate for the Prevention of Preterm Delivery|
|WellPoint Health Networks, Inc.|
|8.09.02||Progesterone Therapy as a Technique to Prevent Preterm Delivery in High Risk Women|