Pending Policies - Prescription Drugs


Progesterone Therapy as a Technique to Reduce Preterm Delivery in High-Risk Pregnancies

Number:RX501.062

Effective Date:11-15-2018

Coverage:

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Medical policies are a set of written guidelines that support current standards of practice. They are based on current peer-reviewed scientific literature. A requested therapy must be proven effective for the relevant diagnosis or procedure. For drug therapy, the proposed dose, frequency and duration of therapy must be consistent with recommendations in at least one authoritative source. This medical policy is supported by FDA-approved labeling and nationally recognized authoritative references. These references include, but are not limited to: MCG care guidelines, DrugDex (IIb strength of recommendation or higher), NCCN Guidelines (IIb level of evidence or higher), NCCN Compendia (IIb level of evidence or higher), professional society guidelines, and CMS coverage policy.

For women with a singleton pregnancy and prior history of spontaneous preterm birth before 37 weeks’ gestation, the following may be considered medically necessary:

Weekly injections of 17α-hydroxyprogesterone caproate, initiated between 16 and 20 weeks of gestation and continued until 36 weeks 6 days; or

Daily vaginal progesterone between 24 and 34 weeks of gestation.

For women with a singleton pregnancy and a short cervix (less than 20 mm), the following may be considered medically necessary:

Daily vaginal progesterone initiated between 20 and 23 weeks 6 days of gestation and continued until 36 weeks 6 days.

NOTE: Measurements of cervical length may require an additional ultrasound that takes place between 19 and 23 weeks 6 days of gestation.

Progesterone therapy as a technique to prevent preterm delivery is considered experimental, investigational and/or unproven in pregnant women with other risk factors for preterm delivery, including but not limited to:

Twin or multiple gestation;

Prior episode of preterm labor in current pregnancy (i.e., progesterone therapy in conjunction with tocolysis or following successful tocolysis);

Positive test for cervicovaginal fetal fibronectin;

Cervical cerclage; and/or

Uterine anomaly.

Intramuscular injection of 17α-hydroxyprogesterone caproate is considered experimental, investigational and/or unproven in pregnant women for all other indications, including but not limited to initiation at < 16 weeks or ≥ 21 weeks of gestation.

Description:

Preterm birth is the leading cause of neonatal morbidity and mortality, and effective primary preventive interventions have remained elusive. In recent years, there has been renewed interest in the use of progesterone (injectable and intravaginal formulations) to prevent preterm birth.

Background

Preterm labor and delivery are major determinants of neonatal morbidity and mortality. In the U.S., the rate of preterm birth is 12%. A variety of diagnostic and prophylactic measures to prevent preterm labor and delivery have been investigated, including home uterine activity monitoring, subcutaneous terbutaline tocolytic therapy, and routine culture and antibiotic treatment of subclinical bacterial vaginosis. To date, none of these therapies has made a significant demonstrable impact on the incidence rate of preterm delivery. In the past, intramuscular (IM) injections of hydroxyprogesterone caproate (i.e., Delalutin) were used routinely to prevent premature labor. However, the drug has teratogenic properties, and the U.S. Food and Drug Administration (FDA) labeled it category D (i.e., studies have demonstrated fetal risk, but use of the drug may outweigh the potential risk). Delalutin was voluntarily withdrawn from the market in 1999.

Recently, there has been renewed research interest in IM injection of 17α-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 has been manufactured locally by compounding pharmacies. After an extended application process, Makena®, another injectable form of 17P, was approved by FDA in 2011. Intravaginal progesterone gel and suppositories have also been used.

Regulatory Status

On February 3, 2011, Makena® (K-V Pharmaceuticals), an injectable formulation containing 17P, was approved by the FDA through the premarket approval process. It is indicated to reduce preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth. Makena® is not intended for women with multiple gestations or women with other risk factors for preterm birth. Injectable hydroxyprogesterone caproate had previously been approved by FDA in 1956 under the brand name Delalutin®. This product was voluntarily withdrawn from the market in 1999.

On March 31, 2011, the FDA 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. However, this FDA position has been superseded by their announcement in June 2012 regarding the active ingredient in Makena® - 17P. The current FDA position does not consider compounding large volumes of copies, or what are essentially copies, of any approved commercially-available drug to fall within the scope of traditional pharmacy practice. One factor that the agency considers in determining whether a drug may be compounded is whether the prescribing provider has determined that a compounded product is necessary for the individual patient and would provide a significant difference for the patient as compared to the FDA-approved commercially available drug product.

Rationale:

This policy was originally created in 2006 and based on U.S. Food and Drug Administration approved label indications. It has been routinely updated with searches of the MedLine database. The most recent literature search was performed through July 13, 2017. Following is a summary of the key literature to date.

Overall Effectiveness of Progesterone for Reducing Preterm Birth in High-Risk Pregnancies

Several systematic reviews and meta-analyses summarizing data on progesterone therapy to reduce preterm birth in high-risk pregnancies have been published. (1-3) In 2012, Sotiriadis et al. conducted a meta-analysis of randomized controlled trials (RCTs) comparing progesterone and placebo in women at high risk of preterm birth due to a history of preterm birth, short cervix during the second trimester, or multiple pregnancies. (1) The analysis focused on neonatal and perinatal mortality rates; studies that did not report these outcomes were excluded. Neonatal mortality was defined as the number of deaths from birth to 28 days. Perinatal mortality was defined as deaths that occurred at less than 28 days of age plus fetal deaths that had a stated or presumed period of gestation of 20 weeks or more. Findings were reported separately for singleton, twin, and triplet gestations. Six trials published between 2003 and 2011 provided data for the analysis of singleton pregnancies. Three used systemic progesterone (oral or intramuscular [IM]) and 3 used vaginal progesterone. A pooled analysis of data from the studies on singleton pregnancies found a significantly lower risk of neonatal death in the group receiving progesterone versus placebo (relative risk [RR], 0.49; 95% confidence interval [CI], 0.29 to 0.82). No significant difference between groups was found for the outcome of perinatal death. A significant benefit for progesterone was also found for a composite adverse outcomes variable (RR=0.58; 95% CI, 0.37 to 0.89). The analyses of studies evaluating twin and triplet pregnancies are discussed in the next sections on these topics.

A 2016 meta-analysis by Ahn et al. focused on the outcome of neonatal mortality. (4) Twenty-two RCTs that included pregnant women treated with progesterone and that reported neonatal death met eligibility criteria. Neonatal death was defined as mortality within 1 month of delivery. Four pooled analyses were conducted: women with singleton pregnancies treated with vaginal progesterone or IM progesterone and women with multiple pregnancies treated with vaginal progesterone or IM progesterone. None of the meta-analyses found a significantly increased risk of neonatal death associated with progesterone administration versus placebo. For example, for women with singleton pregnancies treated with IM progesterone versus placebo (6 studies), the relative risk of neonatal death was 0.60 (95% CI, 0.33 to 1.09).

In 2016, Norman et al. published a large multicenter double-blind RCT (the OPPTIMUM study) evaluating outcomes in women pregnant with singletons who had 1 of a number of risk factors for preterm birth. (5) The study included 1228 women assigned to receive vaginal progesterone 200 mg daily (n=618) or placebo (n=610). Risk factors included history of preterm birth, cervical length of 25 mm or less at any time between 18 and 24 weeks of gestation, preterm premature fetal membrane rupture (PPROM), and/or history of a cervical procedure to treat abnormal smears. The study had 3 primary outcomes:

1. Fetal death or delivery before 34 weeks;

2. Neonatal morbidity or death; and

3. Cognitive score at 22 to 26 months of age, assessed using the Bayley-III instrument.

In unadjusted analyses, the progesterone group (7%) had a significantly lower rate of neonatal morbidity or death than the placebo group (10%; p=0.02) and there were no significant between-group differences for the other 2 outcomes. When analyses were adjusted for multiple primary outcomes, none of the 3 outcomes differed significantly between groups. The trial did not find a significant benefit of progesterone on the composite outcome of fetal death or preterm delivery before 34 weeks in this mixed population. However, rate of preterm delivery before 37 or 34 weeks (the primary outcome in many other RCTs) was not the sole outcome in this trial.

Singleton Pregnancy and Prior Spontaneous Preterm Birth

A 2013 Cochrane review by Dodd et al. identified 11 trials on women with a previous spontaneous preterm birth; 4 used IM progesterone, 5 used vaginal progesterone, and 2 used oral progesterone. (3) In a pooled analysis of data from 5 studies, the reviewers found that, compared with placebo, progesterone (any route) reduced the rate of preterm birth less than 34 weeks of gestation in women with a history of spontaneous preterm birth (RR=0.31; 95% CI, 0.14 to 0.69). Four of the 5 studies used vaginal progesterone and 1 used an oral formulation. Moreover, when data from 10 studies were pooled, there was a statistically significant difference in the rate of preterm birth less than 37 weeks (RR=0.55; 95% CI, 0.42 to 0.74). For the outcome preterm birth before 37 weeks, progesterone was significantly better than placebo among subsets of studies that used IM injections (n=4) and vaginal preparations (n=5).

Key RCTs focusing on women with singleton pregnancies and a previous preterm birth are described next.

IM Progesterone

In 2003, Meis et al. published findings for 463 women randomized to receive weekly IM injections of 17α-hydroxyprogesterone caproate (17P) or a placebo injection. (6) (NOTE: This is the trial on which U.S. Food and Drug Administration [FDA] based its approval of an injectable formulation of 17P in 2011.) Injections began at 16 to 20 weeks of gestation and continued until 36 weeks of gestation. The frequency of delivery before 37 weeks of gestation (the primary outcome) was 36.3% in the progesterone group compared with 54.9% in the placebo group. While this difference was statistically significant (p<0.001), the rate of preterm delivery in the placebo group (54.9%) was exceptionally high. The frequency of delivery before 35 weeks was 20.6% in the progesterone group and 30.7% in the placebo group; this difference was also statistically significant (p<0.02).

In 2007, follow-up data on children born during the Meis trial of 17P were published. (7) Of the 429 infants discharged alive after birth, 278 (65%) were enrolled. Loss to follow-up occurred due to the loss of centers no longer in the network (n=81) and parents or guardians who could not be contacted (n=55) or who declined to participate (n=15). There was a 2:1 treatment ratio in the original study, resulting in the follow-up of 194 children from the 17P group and 84 from the control group. An average 48 months of follow-up (range, <36-60 months) found no difference in physical measures, diagnoses given by health professionals, or in caregivers’ assessments of child health.

Vaginal Progesterone

Three randomized trials evaluated vaginal progesterone for women with singleton pregnancies in which at least 90% of the population had a previous preterm birth.

A large multinational study (including sites in the U.S.) was published in 2007 by O’Brien et al. (8) The study randomized 659 women with a singleton pregnancy to once-daily treatment with progesterone vaginal gel or placebo between 18 and 37 weeks of gestation. Results from 611 (93%) women showed no difference between the active and control groups for rates of preterm birth at 37 weeks or less (42% versus 41%), rates of preterm birth at 32 weeks or less (10% versus 11%), or mean gestational age at delivery (36.6 weeks versus 36.6 weeks), all respectively. The same held for the other maternal or neonatal outcome measures. Compliance and adverse events were similar for the 2 groups.

In 2003, da Fonseca et al. in Brazil reported the results of a trial that randomized 157 women with singleton pregnancies considered at high risk for preterm delivery to receive daily progesterone or placebo suppositories. (9) Inclusion criteria were a prior spontaneous preterm birth or other risk factors. A total of 142 (90%) of 157 patients completed the study. Of these, 133 (93.7%) had a previous preterm birth, 5 (3.5%) had uterine malformation, and 4 (2.8%) had an incompetent cervix. The mean gestational age of the prior preterm birth was 33 weeks. The rate of delivery before 37 weeks was 13.8% in the intervention group and 28.5% in the control group. This difference was statistically significant (p<0.03). The rate of delivery before 34 weeks was 2.8% in the intervention group and 18.6% in the placebo group; this was also statistically significant in favor of the progesterone treatment group (p<0.002).

In 2009, Majhi et al. in India published a trial of 100 women with singleton pregnancies and a history of spontaneous preterm birth. (10) Women were randomized to receive micronized natural progesterone intravaginally via capsules (n=50) or no treatment (n=50). All participants were included in the analysis; there was no loss to follow-up. Six (6%) of 50 patients in the progesterone group and 19 (38%) of 50 patients in the control group had a preterm birth before 37 weeks; this difference was statistically significant (p=0.003). The difference in the rates of preterm birth before 34 weeks-2 (4%) in the progesterone group and 3 (6%) in the control group-was not statistically significant (p=0.64), but this analysis may have been underpowered.

An unresolved issue is whether efficacy differs by the type of formulation of the intravaginal progesterone. The O’Brien study, which had negative findings, used vaginal gel while the da Fonseca and Majhi studies, both of which had positive findings, used suppositories or capsules.

IM Progesterone Versus Vaginal Progesterone

Several RCTs have compared the safety and efficacy of IM and vaginal progesterone for reducing the preterm birth rate in singleton pregnancies. The trials are described next.

A 2016 trial by Elimian et al. included 174 women with singleton pregnancies between 16 and 20 weeks 6 days of gestation with a history of preterm delivery. (11) Patients were randomized to weekly IM injections of hydroxyprogesterone caproate 250 mg (n=82) or vaginal micronized progesterone 100 mg daily (n=92). The study analysis was per protocol; 145 (83%) of 174 women completed the study. Among study completers, the primary outcome (the proportion of women who delivered before 37 weeks) was met by 43.9% in the IM progesterone group and by 37.9% in the vaginal progesterone group (p=0.50). Moreover, there were no statistically significant differences in secondary outcomes (e.g., the proportion of women who delivered before 34 weeks or before 28 weeks).

An unblinded RCT, published in 2013 by Mahar et al., compared the safety and efficacy of vaginal and IM progesterone for reducing the rate of preterm birth in women with singleton pregnancies and a prior preterm birth. (12) The study was conducted at a single center in Saudi Arabia and no industry support was reported. Participants were at a gestational age between 14 and 18 weeks, and the primary efficacy outcome was delivery before 34 weeks of gestation. A total of 518 women were randomized to receive IM progesterone (n=256) or vaginal progesterone gel (n=262). A total of 16 participants were lost to follow-up. There were 42 (16%) deliveries before 34 weeks in the vaginal progesterone group and 64 (25%) deliveries before 34 weeks in the IM progesterone group. The difference between groups was statistically significant, favoring the vaginal progesterone group (odds ratio [OR], 0.58; 95% CI, 0.37 to 0.89). Secondary maternal outcomes, including admission for threatened preterm labor, premature rupture of membranes, and use of tocolytic therapy, did not differ significantly between groups. Most secondary neonatal outcomes, including rates of neonatal death, respiratory distress syndrome, and sepsis, did not differ significantly between groups. The exception was admission to the neonatal intensive care unit, which was significantly higher in the IM progesterone group (n=64 [26%]) than in the vaginal progesterone group (n=39 [15%]; p=0.006). A significantly higher rate of adverse effects was also reported by patients in the IM progesterone group (n=35 [14%]) than in the vaginal progesterone group (n=19 [8%]; p=0.017).

Section Summary: Singleton Pregnancy and Prior Spontaneous Preterm Birth

A Cochrane review of RCTs found that progesterone (all routes of administration combined) reduced the rate of preterm birth in women with singleton pregnancies and a history of preterm birth. There is evidence from RCTs that both IM and vaginal progesterone are effective and neither route of administration is clearly superior.

Singleton Pregnancy and Short Cervical Length

IM Progesterone

A 2012 double-blind RCT by Grobman et al. evaluated the efficacy of IM 17P for preventing preterm birth in women with short cervical length and who were nulliparous (i.e., participants did not have a history of preterm birth). (13) The study was conducted at 14 centers in the U.S. Short cervix was defined as less than 30 mm between 16 weeks 0 days and 22 weeks 3 days. A total of 657 women were randomized to weekly injections of 17P (n=327) or placebo injections (n=330). No participants were lost to follow-up. The primary outcome (preterm birth before 37 weeks) occurred in 82 (25%) women in the 17P group and in 80 (24%) women in the placebo group. The difference between groups was not statistically significant (RR=1.03; 95% CI, 0.79 to 1.35). Other outcomes, including delivery before 35 weeks, gestational age at delivery, hospital visits for preterm labor, and adverse effects, also did not differ significantly between groups. The investigators initially planned to enroll 500 women in each group, but, based on interim analysis by an independent data and safety monitoring board that determined there was an extremely low probability of finding a significant difference between groups if enrollment continued, the trial was halted early.

Vaginal Progesterone

Several RCTs and a systematic review and meta-analysis of RCTs have been published. In 2012, Romero et al. published a meta-analysis of individual patient data from RCTs comparing vaginal progesterone with placebo or no treatment in asymptomatic pregnant women with a sonographically confirmed short cervix (≤25 mm) in the mid-trimester. (14) Five RCTs were included in the meta-analysis. Two of the trials, Hassan et al. (2011) (15) and Fonseca et al. (2007), (16) limited enrollment to women with a short cervix (defined as ≤15 mm in 1 study and 10-20 mm in the other) and the remaining studies included women with a wider range of risk factors but reported results separately for women with a short cervix. All studies were double-blind and placebo-controlled. The studies included data on 775 women; 723 (93%) had singleton pregnancies and 52 (7%) had twin pregnancies.

A small, placebo-controlled RCT in women with a short cervical length (≤30 mm) and no prior preterm birth did not find a statistically significant benefit for vaginal progesterone in preventing preterm birth. (17) In this 2015 trial by van Os et al., the rate of preterm birth at 32 weeks was 2% in the progesterone group and 8% in the control group (RR=0.33; 95% CI, 0.04 to 3.0) and at 34 weeks it was 7.0% and 10.0%, respectively (RR=1.2; 95% CI, 0.39 to 3.5). The trial may have been underpowered; enrollment was stopped early due to an unexpectedly low number of women with a short cervix.

IM Progesterone Versus Vaginal Progesterone

In 2015, Bafgi et al. published an RCT that included 78 women with singleton pregnancies who had either a short cervix (<25 mm) or a history of preterm delivery. (18) Randomization was done separately for the 2 subgroups. Women were assigned to weekly IM injections of 17P 250 mg or vaginal progesterone 200 mg daily. The primary outcomes were rate of preterm delivery (<37 weeks) and mean gestational age at the time of delivery. Follow-up data were available for all participants. There were no significant differences between groups on either of the primary outcome measures. In the overall study population, the rate of preterm delivery was 33.3% in the vaginal progesterone group and 30.7% in the vaginal progesterone group (p=0.088). Mean (SD) gestational age at delivery was 37.1 (2.2) weeks in the vaginal progesterone group and 36.8 (2.8) weeks in the IM progesterone group (p=0.765). In an analysis of the subgroup with a short cervix, mean age at delivery was 38.0 (1.43) years in the vaginal progesterone group and 37.6 (1.6) years in the IM progesterone group. The difference between groups was not statistically significant. However, the study was not powered to find differences at the subgroup level, which limits conclusions about use of IM progesterone in women with a short cervix.

Section Summary: Singleton Pregnancy and Short Cervical Length

Three RCTs have evaluated vaginal progesterone for preventing preterm birth in women with short cervical length. A recent meta-analysis of data from 5 RCTs found that vaginal progesterone significantly reduced the rate of preterm delivery in women with a short cervical length. In addition, there was benefit in the subgroup of women with singleton pregnancies and no prior preterm birth. One placebo-controlled RCT that assessed whether injectable progesterone is effective for preventing preterm birth in women with short cervical length was unpowered. Another RCT that compared injectable and vaginal progesterone and included women with a short cervix was also not powered to detect differences in the short cervix subgroup. Thus conclusions cannot be drawn about the comparability of the 2 delivery systems.

Twin Gestations

Several systematic reviews and meta-analyses of RCTs have not found that progesterone administration significantly reduces the rate of preterm birth or improves other health outcomes in patients with twin pregnancies. (1, 3, 19) In 2015, Schuit et al. published an individual patient data meta-analysis evaluating the effectiveness of progesterone for improving perinatal outcomes in twin pregnancies. (19) The investigators identified 13 trials (total N=3668 women); 7 trials used vaginal progesterone and 6 used IM 17P. Twelve studies were placebo-controlled and the thirteenth compared progesterone with no treatment. Studies enrolled twin pregnancies at a gestational age of at least 16 weeks but less than 24 weeks of gestation. The primary outcome of the meta-analysis was a composite of perinatal mortality and severe neonatal morbidity. Among the studies on 17P, the primary outcome occurred in 423 (20%) of the children in the 17P group and 318 (17%) in the control group; the difference was not statistically significant (RR=1.2; 95% CI, 0.87 to 1.5). Rates of the primary outcome in studies on vaginal progesterone were 219 (13%) in the active treatment group and 201 (13%) in the control group. As with 17P, rates did not differ significantly between groups (RR=0.96; 95% CI, 0.83 to 1.1).

The 2013 Cochrane review (previously described) (3) pooled data from 5 trials of vaginal progesterone and found no significant benefit over placebo on the rate of preterm birth at less than 34 weeks of gestation (RR=0.92; 95% CI, 0.69 to 1.23). Moreover, a pooled analysis of 7 trials (6 were limited to twins and 1 included other multiples) did not find that progesterone significantly reduced the rate of preterm birth less than 37 weeks (RR=1.04; 95% CI, 0.95 to 1.14). There was also no difference in the rate of perinatal death (RR=0.93; 95% CI, 0.45 to 1.94; 7 trials, 5 limited to twin pregnancies).

The largest RCT on twin pregnancies published to date, and with the longest follow-up, was published in 2011 by Rode et al. (the PREDICT trial). (20) It was conducted in Denmark and Austria. A total of 667 pregnant women with twins were randomized to receive vaginal progesterone or placebo. Treatment was initiated between 20 and 24 weeks of gestation and continued until either 34 weeks of gestation, rupture of the membranes, or delivery. The primary outcome (delivery before 34 weeks of gestation) did not differ significantly between groups. Preterm delivery before 34 weeks occurred in 51 (15.3%) of 334 women in the treatment group and 63 (18.5%) of 341 women in the control group (OR=0.8; 85% CI, 0.5 to 1.2). Similarly, there were no significant differences between groups in the rates of preterm delivery before 22, 28, 32, or 37 weeks of gestation. Rates of neonatal outcomes (e.g., birthweight, neonatal death, perinatal complications) also did not differ significantly between groups. The investigators conducted follow-ups at 6 and 18 months after birth. They did not find significant differences between groups on children’s scores on the Ages and Stages Questionnaire, a parent-administered instrument.

Several more recent RCTs, published in 2014 and 2015, also found that progesterone did not reduce the rate of preterm birth in twin gestations. A study by Awwad et al. included 293 women and used IM progesterone (21) and the study by Brizot et al. enrolled 390 women and used vaginal progesterone. (22) A trial by Winer et al. used IM progesterone but was stopped early after enrolling 105 women because interim analysis demonstrated lack of efficacy of progesterone at prolonging pregnancy. (23)

A 2016 study by El-refaie et al. focused on women pregnant with twins who had a short cervix (20-25 mm) and used a higher dose of progesterone (400 mg) than used in previous studies. (24) The trial included 322 women randomized to vaginal progesterone 400 mg daily (n=125) or to a no treatment control group (n=125). The rate of preterm labor before 34 weeks was 35.3% in the progesterone group and 52.8% in the control group (p=0.010). (The authors appeared to use the terms preterm labor and preterm birth synonymously.) The rate of preterm labor before 32 weeks also significantly favored the progesterone group, but the rates of preterm labor before 28 weeks were similar in both groups. Mean gestational age at delivery was significantly longer in the progesterone group (34.3 weeks) than in the control group (33.4 weeks; p=0.007). This is the first published RCT evaluating progesterone to prevent preterm birth in women pregnant with twins who have a short cervix and it also used a higher dose of progesterone than previous studies. Additional studies in this population, including at least 1 using a high dose of vaginal progesterone, are underway.

Section Summary: Twin Gestations

Numerous RCTs and several meta-analyses have consistently found that progesterone is not associated with decreased rates of preterm delivery and other perinatal outcomes (e.g., perinatal death) in women pregnant with twins. A 2016 RCT found that a high dose of vaginal progesterone was associated with a lower rate of preterm labor than no treatment in patients with twin pregnancies and a short cervix. Additional studies:

1. Replicating these findings in women with both twin pregnancy and; short cervix and

2. Confirming the optimal dose of vaginal progesterone are needed.

Triplet Gestations

The 2012 Sotiriadis meta-analysis (1) identified 2 trials on progesterone in women with triplet gestations. Pooled analyses of data from these 2 studies did not find any statistically significant differences in outcomes between women receiving progesterone or placebo.

Both trials evaluated IM injections of 17P. Caritis et al. randomized healthy women with triplets to receive weekly IM injections of 17P or placebo starting at 16 to 20 weeks and ending at delivery or 35 weeks of gestation. (25) The primary study outcome was delivery or fetal loss before 35 weeks. A total of 134 women were randomized, with 71 assigned to 17P and 63 to placebo; none were lost to follow-up. The proportion of women experiencing the primary outcome (a composite of delivery or fetal loss before 35 weeks) was similar in the 2 treatment groups: 83% of pregnancies in the 17P group and 84% in the placebo group (RR=1.0). In the other trial, by Combs et al., which included 81 women, 56 were assigned to receive IM injections of 17P and 25 to placebo. (26) Treatment started at 16 to 22 weeks of gestational age and continued until 34 weeks. There was no significant difference in the mean gestational age at delivery (31.9 weeks in the 17P group versus 31.8 weeks in the placebo group, p=0.36). However, there were 13 mid-trimester fetal losses in the 17P group and none in the placebo group (p<0.02).

Section Summary: Triplet Gestations

Two RCTs and a meta-analysis of data from these 2 trials did not find that progesterone is associated with improved outcomes in women pregnant with triplets.

Singleton Pregnancy and Preterm Premature Rupture of the Membranes (PPROM)

In 2011, Briery et al. published a study including women with singleton pregnancies diagnosed with PPROM at 20 to 30 weeks of gestation. (27) They were randomized to receive weekly injections of 17P (n=33) or placebo (n=36). Two women did not finish the study, though data were analyzed on an intention-to-treat basis. There was no significant difference between groups in the gestational age at delivery (mean, 27.3 weeks in the progesterone group versus 29.5 weeks in the placebo group; p=0.15). Neonatal outcomes, including birth weight, length of stay in the neonatal intensive care unit, and neonatal morbidity and mortality, also did not differ significantly between groups. For example, mean birth weight was 1216 grams in the progesterone group and 1396 grams in the placebo group (p=0.15).

Section Summary: Singleton Pregnancy and Preterm Premature Rupture of the Membranes

The single published RCT identified did not find improved outcomes in women with singleton pregnancies experiencing PPROM who received progesterone versus placebo.

Singleton Pregnancy and Prior Episode of Preterm Labor in Current Pregnancy

IM Progesterone

A 2015 systematic review and meta-analysis by Saccone et al. selected RCTs that included women with single gestations who had successfully arrested preterm labor who were assigned to maintenance tocolysis with IM progesterone or a control intervention. (28) Five RCTs (total N=426 women) met the inclusion criteria; 4 trials used a no treatment control and 1 used placebo. Only 1 trial was conducted in the U.S. A meta-analysis of data from 3 trials (n=293 women) did not find a significant difference between groups in the primary outcome (preterm birth before 37 weeks). Pooled rates were 42% in the progesterone group and 51% in the control group (RR=0.78; 95% CI, 0.50 to 1.22). Pooled rates of preterm birth before 34 weeks of gestation also did not differ significantly between groups (RR=0.60; 95% CI, 0.28 to 1.12). Findings on secondary outcomes were mixed. Several secondary outcomes favored the progesterone group, including having a higher mean birthweight and a later gestational age at delivery. Secondary outcomes with similar rates between groups included the incidence of recurrent preterm labor, neonatal death, and neonatal sepsis.

Vaginal Progesterone

A 2015 systematic review and meta-analysis by Suhag et al. searched for RCTs that included women with single gestations who had successfully arrested preterm labor and who were assigned to maintenance tocolysis with vaginal progesterone or a control intervention. (29) Five RCTs (total N=441 women) met the inclusion criteria; 3 trials used a no treatment control and 2 used placebos. All trials were conducted outside of the U.S. A meta-analysis of data from 3 trials (n=296 women) found a statistically significant difference between groups in the primary outcome (preterm birth before 37 weeks). Pooled rates were 62% in the progesterone group and 86% in the control group (RR=0.71; 95% CI, 0.57 to 1.90). A meta-analysis of 2 trials did not find a significant difference in the rates of preterm birth before 34 weeks (RR=0.75; 95% CI, 0.36 to 1.57). Findings were mixed on other secondary outcomes. The authors noted the general poor quality of the trials (e.g., lack of blinding).

Subsequent to the systematic review search date, Martinez de Tejada et al. published a multicenter, double-blind, placebo-controlled RCT on prevention of preterm delivery in women with a prior episode of preterm labor in the current pregnancy. (30) The trial included 385 women successfully treated with acute tocolysis between 24 and 34 weeks of gestation. The primary efficacy outcome (preterm delivery before 37 weeks of gestation) did not differ significantly between groups. Rates were 42.5% in the progesterone group and 35.5% in the placebo group (p=0.20). Secondary outcomes, including delivery before 34 weeks, delivery before 32 weeks, and neonatal outcomes, were also similar in the 2 groups.

Section Summary: Singleton Pregnancy and Prior Episode of Preterm Labor in Current Pregnancy

Meta-analyses of RCTs have not definitively found that IM progesterone or vaginal progesterone reduce the rate of preterm birth or improve other outcomes. RCTs had mixed findings and methodologic limitations (e.g., lack of blinding).

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 1.

Table 1. Summary of Key Trials

NCT Number

Trial Name

Planned Enrollment

Completion Date

Ongoing

NCT01050647

Progesterone for the Management of Preterm, Premature Rupture of the Membranes: A Randomized Controlled Trial

40

Oct 2016

NCT02697331

Evaluation of the Role of Vaginal Progesterone in Prevention of Preterm Labor in Twin Gestation with Short Cervix: Randomized Controlled Trial

120

Oct 2016

NCT02304237a

Vaginal Compared with Intramuscular Progesterone for Prevention of Preterm Birth in High Risk Pregnant Women

360

Dec 2016

NCT02329535

Comparing Double Dose of Vaginal Progesterone to no Treatment for Prevention of Preterm Birth in Twins and Short Cervix

214

Jan 2018

NCT01004029

A Phase 3B, Multi-Center, Randomized, Double-Blind Study of Hydroxyprogesterone Caproate Injection, 250 mg/mL, Versus Vehicle for the Prevention of Preterm Birth in Women with a Previous Singleton Spontaneous Preterm Delivery

1707

Nov 2018

Table Key:

NCT: National Clinical Trial.

a: Denotes industry-sponsored or cosponsored trial.

Practice Guidelines and Position Statements

American College of Obstetricians and Gynecologists (ACOG)

In May 2014, the ACOG published a Practice Bulletin on multifetal gestations that included the following statement on progesterone therapy (Replaced by Practice Bulletin Number 169 and reaffirmed 2016) (31, 32):

“Progesterone treatment does not reduce the incidence of spontaneous preterm birth in unselected women with twin or triplet gestations and, therefore, is not recommended.”

Previously, in October 2012 (Reaffirmed 2016), ACOG published a Practice Bulletin on prediction and prevention of preterm birth. (33) The bulletin included the following recommendations (level A evidence) related to progesterone therapy in women with singleton pregnancies:

“A woman with a singleton gestation and a prior spontaneous singleton birth should be offered progesterone supplementation starting at 16-24 weeks of gestation … to reduce the risk of recurrent spontaneous preterm birth.”

“Vaginal progesterone is recommended as a management option to reduce the risk of preterm birth in asymptomatic women with a singleton gestation without a prior preterm birth with an incidentally identified very short cervical length less than or equal to 20 mm before or at 24 weeks of gestation.”

Society for Maternal-Fetal Medicine (SMFM)

A 2012 clinical guideline by the SMFM included the following conclusions and recommendations (34):

1. “There is insufficient evidence to recommend the use of progestogens in singleton gestations with no prior PTB [preterm birth], and unknown CL [cervical length].”

2. “In women with singleton gestations, no prior SPTB [spontaneous preterm birth], and short TVU [transvaginal ultrasound] CL 20 mm at 24 weeks, vaginal 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.”

3. “The issue of universal TVU 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 reasonable, and can be considered by individual practitioners. Given the impact on prenatal care and potential misuse of universal screening, stretching the criteria and management beyond those tested in RCTs should be prevented. Practitioners who decide to implement universal TVU CL screening should follow strict guidelines. Practitioners who choose to screen low-risk singleton gestations may consider offering vaginal progesterone, either 90-mg gel or 200-mg suppositories, for short TVU CL 20 mm at 24 weeks.”

4. “In singleton gestations with prior SPTB 20-36 6/7 weeks, 17P 250 mg IM weekly preferably starting at 16-20 weeks until 36 weeks is recommended. In these women, if the TVU CL shortens to 25mm at 24 weeks, cervical cerclage may be offered.”

5. “Progestogens have not been associated with prevention of PTB in multiple gestations, PTL [preterm labor], or PPROM [preterm premature rupture of membranes]. There is insufficient evidence to recommend the use of progestogens in women with any of these risk factors, with or without a short CL. Some experts offer 17P to women with a prior SPTB and a current multiple gestation, but there are insufficient data to evaluate the risks and benefits of this intervention in this population.”

Summary of Evidence

For individuals who have a singleton pregnancy and prior spontaneous preterm birth before 37 weeks of gestation who receive intramuscular injections of progesterone or vaginal progesterone, the evidence includes RCTs and a meta-analysis. Relevant outcomes are overall survival, morbid events, and treatment-related morbidity. Pooled analyses of RCT data found statistically significant reductions in term birth rates with progesterone compared with placebo. Findings were similar in studies that used injectable or vaginal progesterone. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.

For individuals who have a singleton pregnancy and a short cervix (<20 mm) who receive intramuscular injections of progesterone, the evidence includes 2 RCTs. Relevant outcomes are overall survival, morbid events, and treatment-related morbidity. A placebo-controlled RCT did not find that intramuscular progesterone significantly decreased the rate of preterm birth. An RCT comparing intramuscular and vaginal progesterone did not find a significant difference in preterm delivery in the subgroup of women with a short cervix; however, the ability to draw conclusions from this trial is limited because it was not powered for a subgroup analysis. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have a singleton pregnancy and a short cervix (<20 mm) who receive vaginal progesterone, the evidence includes several RCTs and a meta-analysis of individual patient data from the RCTs. Relevant outcomes are overall survival, morbid events, and treatment-related morbidity. A meta-analysis of RCTs found that vaginal progesterone significantly reduced the rate of preterm delivery. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.

For individuals who are pregnant with twins who receive intramuscular injections of progesterone or vaginal progesterone, the evidence includes RCTs and systematic reviews. Relevant outcomes are overall survival, morbid events, and treatment-related morbidity. The RCTs and several meta-analyses of these studies have consistently found that progesterone is not significantly associated with decreased rates of preterm delivery or other perinatal outcomes in pregnant women with twins. One RCT found that a high dose of vaginal progesterone was associated with a lower rate of preterm delivery in women pregnant with twins who also had a short cervix; additional studies in this population are needed to confirm findings and optimal dose of medication. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who are pregnant with triplets who receive intramuscular injections of progesterone or vaginal progesterone, the evidence includes RCTs and a meta-analysis. Relevant outcomes are overall survival, morbid events, and treatment-related morbidity. Two RCTs and a meta-analysis of data from these 2 trials did not find that progesterone was associated with improved outcomes in women pregnant with triplets. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals with a singleton pregnancy and preterm premature rupture of the membranes who receive intramuscular injections of progesterone or vaginal progesterone, the evidence includes 1 RCT. Relevant outcomes are overall survival, morbid events, and treatment-related morbidity. The RCT did not find a lower rate of preterm delivery or neonatal outcomes (e.g., birthweight, neonatal mortality) in women treated with progesterone versus placebo. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals with a singleton pregnancy and prior episode of preterm labor in the current pregnancy who receive intramuscular injections of progesterone or vaginal progesterone, the evidence includes RCTs and meta-analyses. Relevant outcomes are overall survival, morbid events, and treatment-related morbidity. A meta-analysis of RCTs on intramuscular progesterone did not find significantly better outcomes compared with control interventions. A meta-analysis of RCTs on vaginal progesterone had mixed findings. The evidence is insufficient to determine the effects of the technology on health outcomes.

Contract:

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.

Coding:

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.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

99506

HCPCS Codes

J1725, J1726, J1729, Q9986, S9123, S9124, S9208

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.

A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

References:

1. Sotiriadis A, Papatheodorou S, Makrydimas G. Perinatal outcome in women treated with progesterone for the prevention of preterm birth: a meta-analysis. Ultrasound Obstet Gynecol. May 18 2012; 40(3):257-66. PMID 22611023

2. Rode L, Langhoff-Roos J, Andersson C, et al. Systematic review of progesterone for the prevention of preterm birth in singleton pregnancies. Acta Obstect Gynecol. 2009; 88(11):1180-9. PMID 19900136

3. Dodd JM, Jones L, Flenday V, et al. Prenatal administration of progesterone for preventing preterm birth. Cochrane Database Syst Rev. 2013; (1):CD004947. PMID 23903965

4. Ahn KH, Bae NY, Hong SC, et al. The safety of progestogen in the prevention of preterm birth: meta-analysis of neonatal mortality. J Perinat Med. Apr 28 2016. PMID 27124668

5. Norman JE, Marlow N, Messow CM, et al. Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomized, double-blind trial. Lancet. May 21 2016; 387(10033):2106-16. PMID 26921136

6. Meis PJ, Klebanoff M, Thom E, et al. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med. Jun 12 2003; 348(24):2379-85. PMID 12802023

7. Northen AT, Norman GS, Anderson K, 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. Obstet Gynecol. Oct 2007; 110(4): 665-72. PMID 17906021

8. 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. Oct 2007; 30(5):687-96. PMID 17899572

9. da Fonseca EB, Bittar RE, Carvalho MH, 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. Am J Obstet Gynecol. Feb 2003; 188(2):419-24. PMID 12592250

10. Majhi P, Bagga R, Kalra J, et al. Intravaginal use of natural micronized progesterone to prevent pre-term birth: a randomized trial in India. J Obstet Gynecol. Aug 2009; 29(6):493-8. PMID 19697195

11. Elimian A, Smith K, Williams M, et al. A randomized controlled trial of intramuscular versus vaginal progesterone for the prevention of recurrent preterm birth. Int J Gynaecol Obstet. Aug 2016; 134(2):169-72. PMID 27168167

12. Maher MA, Abdelaziz A, Ellaithy M, et al. Prevention of preterm birth: a randomized trial of vaginal compared with intramuscular progesterone. Acta Obstet Gynecol Scand. Feb 2013; 92(2):215-22. PMID 23016508

13. Grobman WA, Thom EA, Spong CY, et al. 17 alpha-hydroxyprogesterone caproate to prevent prematurity in nulliparas with cervical length less than 30 mm. Am J Obstet Gynecol. Nov 2012; 207(5):390 e1-8. PMID 23010094

14. Romero R, Nicolaides K, Conde-Agudelo A, et al. Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and metaanalysis of individual patient data. Am J Obstet Gynecol. Feb 2012; 206(2):124 e1-19. PMID 22284156

15. 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. Jul 2011; 38(1):18-31. PMID 21472815

16. Fonseca EB, Ceilk 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. Aug 2 2007; 357(5): 462-9. PMID 17671254

17. van Os MA, van der Ven AJ, Kleinrouweler CE, et al. Preventing preterm birth with progesterone in women with a short cervical length from a low-risk population: a multicenter double-blind placebo-controlled randomized trial. Am J Perinatol. Aug 2015; 32(10):993-1000. PMID 25738790

18. Bafghi AS, Bahrami E, Sekhavat L. Comparative study of vaginal versus intramuscular progesterone in the prevention of preterm delivery: a randomized clinical trial. Electron Physician. Oct 2015; 7(6):1301-9. PMID 26516434

19. Schuit E, Stock S, Rode L, et al. Effectiveness of progestogens to improve perinatal outcome in twin pregnancies: an individual participant data meta-analysis. BJOG. Jan 2015; 122(1):27-37. PMID 25145491

20. Rode L, Klein K, Nicolaides KH, et al. Prevention of preterm delivery in twin gestations (PREDICT): a multicenter, randomized, placebo-controlled trial on the effect of vaginal micronized progesterone. Ultrasound Obstet Gynecol. Sep 2011; 38(3):272-80. PMID 21739497

21. Awwad J, Usta IM, Ghazeeri G, et al. A randomized controlled double-blind clinical trial of 17-hydroxyprogesterone caproate for the prevention of preterm birth in twin gestation (PROGESTWIN): evidence for reduced neonatal morbidity. BJOG. Jan 2015; 122(1):71-9. PMID 25163819

22. Brizot ML, Hernandez W, Liao AW, et al. Vaginal progesterone for the prevention of preterm birth in twin gestations: a randomized placebo-controlled double-blind study. Am J Obstet Gynecol. Jul 2015; 213(1):82, e81-9. PMID 25731690

23. Winer N, Bretelle F, Senat MV, et al. 17 alpha-hydroxyprogesterone caproate does not prolong pregnancy or reduce the rate of preterm birth in women at high risk for preterm delivery and a short cervix: a randomized controlled trial. Am J Obstet Gynecol. Apr 2015; 212(4):485 e481-5, e410. PMID 25448515

24. El-refaie W, Abdelhafez MS, Badawy A. Vaginal progesterone for prevention of preterm labor in asymptomatic twin pregnancies with sonographic short cervix: a randomized clinical trial of efficacy and safety. Arch Gynecol Obstet. Jan 2016; 293(1):61-67. PMID 26044148

25. 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. Feb 2009; 113(2 pt 1):285-92. PMID 19155896

26. Combs CA, Garite T, Maurel K, et al. Failure of 17-hydroxyprogesterone to reduce neonatal morbidity or prolong triplet pregnancy: a double-blind, randomized clinical trial. Am J Obstet Gynecol. Sep 2010; 203(3):248 e1-9. PMID 20816146

27. Briery CM, Veillon EW, Klauser CK, et al. Women with preterm premature rupture of the membranes do not benefit from weekly progesterone. Am J Obstet Gynecol. Jan 2011; 204(1):54 e1-5. PMID 20869038

28. Saccone G, Suhag A, Berghella V. 17-alpha-hydroxyprogesterone caproate for maintenance tocolysis: a systematic review and metaanalysis of randomized trials. Am J Obstet Gynecol. Jul 2015; 213(1):16-22. PMID 25659469

29. Suhag A, Saccone G, Berghella V. Vaginal progesterone for maintenance tocolysis: a systematic review and metaanalysis of randomized trials. Am J Obstet Gynecol. Oct 2015; 213(4):479-487. PMID 25797233

30. Martinez de Tejada B, Karolinski A, Ocampo MC, et al. Prevention of preterm delivery with vaginal progesterone in women with preterm labour (4P): randomised double-blind placebo-controlled trial. BJOG. Jan 2015; 122(1):80-91. PMID 25209926

31. Committee on Practice Bulletins-The American College of Obstetricians and Gynecologists. Practice Bulletin No. 144: Multifetal gestations: Twin, Triplet, and Higher-order Multifetal Pregnancies. Obstet Gynecol. May 2014; 123(5):1118-32. PMID 24785876

32. Committee on Practice Bulletins-The American College of Obstetricians and Gynecologists. Practice Bulletin No. 169: Multifetal gestations: Twin, Triplet, and Higher-order Multifetal Pregnancies (Replaces Practice Bulletin No. 144, May 2014) (Reaffirmed 2016). Obstet Gynecol. Oct 2016. Available at <https://www.acog.org> (accessed - 2017 July 13).

33. Committee on Practice Bulletins-The American College of Obstetricians and Gynecologists. Practice Bulletin No. 130: Prediction and Prevention of Preterm Birth (2012) (Reaffirmed 2016). Obstet Gynecol 2012; 120(4):964-73.

34. Society for Maternal-Fetal Medicine Publications Committee, and V. Berghella. Progesterone and preterm birth prevention: translating clinical trials data into clinical practice. Am J Obstet Gynecol. May 2012; 206(5):376-86. PMID 22542113

35. Progesterone Therapy as a Technique to Reduce Preterm Birth in High-Risk Pregnancies. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2016 August) OB/GYN Reproduction 4.01.16.

Policy History:

DateReason
11/15/2018 Reviewed. No changes.
12/15/2017 Document updated with literature review. The following addition was made to coverage: Intramuscular injection of 17α-hydroxyprogesterone caproate is considered experimental, investigational and/or unproven in pregnant women for all other indications, including but not limited to initiation at < 16 weeks or ≥21 weeks of gestation.
11/1/2016 Document updated with literature review. Coverage unchanged.
5/15/2015 Reviewed. No changes.
8/1/2014 Document updated with literature review. The following coverage statement was added: For women with a singleton pregnancy and a short cervix (less than 20 mm), the following may be considered medically necessary: Daily vaginal progesterone initiated between 20 and 23 weeks 6 days of gestation and continued until 36 weeks 6 days. The following indications were added to the experimental, investigational, and/or unproven coverage statement: 1) Twin gestation; 2) Prior episode of preterm labor in current pregnancy (i.e., progesterone therapy in conjunction with tocolysis or following successful tocolysis); 3) Cervical cerclage; and/or 4) Uterine anomaly. Rationale substantially revised. CPT/HCPCS code(s) updated.
3/1/2013 CPT/HCPCS code(s) updated
7/15/2011 Document reviewed with literature search. Coverage statement is unchanged. Makena™, hydroxyprogesterone caproate injection for intramuscular use, was approved by the FDA and has been added to the document. Rationale updated. CPT/HCPCS codes updated.
4/1/2011 Coverage changed to remove requirement for administration of 17 alpha-hydroxyprogesterone caproate or vaginal suppositories in the home setting unless a person is home-bound and unable to receive the services elsewhere.
5/1/2008 Revised/updated entire document. This policy is no longer scheduled for routine literature review and update.
8/1/2006 New medical document

Archived Document(s):

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