|MP 4.01.16||Progesterone Therapy as a Technique to Reduce Preterm Birth in High-Risk Pregnancies|
|Original Policy Date
|Last Review Status/Date
Reviewed with literature search/10:2014
|Return to Medical Policy Index|
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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 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 had made a significant demonstrable impact on the incidence 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 was shown to have teratogenic properties, 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 Delalutin was voluntarily withdrawn from the market in 1999.
In recent years, 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 has been manufactured locally by compounding pharmacies. After an extended application process, Makena®, another injectable form of 17P was approved by the FDA in February 2011. Intravaginal progesterone gel and suppositories have also been used.
On February 3, 2011, an injectable formulation containing 17-alpha-hydroxyprogesterone caproate was approved by the FDA through the premarket approval process, as discussed above. The product is called Makena and is being marketed by K-V Pharmaceuticals. 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 use in women with multiple gestations or in women with other risk factors for preterm birth. Injectable hydroxyprogesterone caproate had previously been approved by the FDA in 1956 under the brand name Delalutin®. This product was voluntarily withdrawn from the market in 1999. As of August 2013, McGuff Pharmaceuticals is pursuing the approval of an Abbreviated New Drug Application (ANDA) for injectable hydroxyprogesterone caproate; this is a generic version of Delalutin. This product was voluntarily withdrawn from the market in 1999.
For women with a singleton pregnancy and prior history of spontaneous preterm birth before 37 weeks of gestation, the following may be considered medically necessary:
- Weekly injections of 17α-hydroxyprogesterone caproate, performed in the office setting, initiated between 16 and 20 weeks of gestation and continued until 36 weeks 6 days
- Daily vaginal progesterone between 24 and 34 weeks of gestation
For women with a singleton pregnancy and a short cervix (<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
Progesterone therapy as a technique to prevent preterm delivery is considered investigational 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 (ie, progesterone therapy in conjunction with tocolysis or following successful tocolysis);
- positive test for cervicovaginal fetal fibronectin;
- cervical cerclage; and/or
- uterine anomaly.
BlueCard/National Account Issues
State or federal mandates (e.g., FEP) may dictate that all FDA-approved devices, drugs or biologics may not be considered investigational, and thus these devices may be assessed only on the basis of their medical necessity.
This policy was originally created in 2003 and was updated regularly with searches of the MEDLINE database. The most recent literature review was performed for the period July 2012 through September 11, 2014. 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 published findings from 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. A total of 6 trials published between 2003 and 2011 provided data for the analysis of singleton pregnancies. Three of the studies used systemic progesterone (oral or intramuscular), 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 on studies evaluating twin and triplet pregnancies are discussed in the next sections on these topics.
History of Prior Spontaneous Preterm Birth
A 2013 Cochrane review by Dodd et al identified 11 trials on women with a history of previous spontaneous preterm birth; 4 used intramuscular (IM) progesterone, 5 used vaginal progesterone, and 2 used oral progesterone.(3) In a pooled analysis of data from 5 studies, the Cochrane review found that, compared with placebo, progesterone (any route) reduced the rate of preterm birth less than 34 weeks’ gestation in women with a history of prior spontaneous preterm birth (RR=0.31; 95% CI, 0.14 to 0.69). Four of the 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 history of previous preterm birth are described next.
In 2003, Meis et al published findings of a study in which 463 women were randomized to receive either weekly IM injections of 17 α-hydroxyprogesterone caproate (17P) or a placebo injection.(4) (Note: This is the trial on which FDA approval of an injectable formulation of 17P in 2011 was based). Injections began at 16 to 20 weeks of gestation and continued until 36 weeks of gestation. The frequency of delivery
before 37 weeks’ gestation, the primary outcome, was 36.3% in the progesterone group, compared with 54.9% in the placebo group. While this difference is statistically significant (p<0.001), it is important to note that 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 et al trial of 17P were published.(5) Of the 429 infants discharged alive after birth, 278 (65%) were enrolled. Loss to follow-up occurred due to the loss of centers that 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 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) found no difference in physical measures, diagnoses given by health professionals, or in the caregiver’s assessment of the health of the children.
Three randomized trials evaluated vaginal progesterone for women with singleton pregnancies in which at least 90% of the population had a history of previous preterm birth.
A large multinational study (including sites in the United States) was published in 2007 by O’Brien et al.(6) 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 women (93%) showed no difference between the active and control groups for rate of preterm birth at 37 weeks or less (42% vs 41%), rate of preterm birth at 32 weeks or less (10% vs 11%), mean gestational age at delivery (36.6 weeks vs 36.6 weeksall respectively), or any 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 either daily progesterone or placebo suppositories.(7) Inclusion criteria included either 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 study including 100 women with singleton pregnancies and a history of prior spontaneous preterm birth.(8) 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 rate 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 et al study, which had negative findings, used vaginal gel while the Da Fonseca and Majhi et al studies, both of which had positive findings, used suppositories (in the Majhi study, capsules were used).
IM Versus Vaginal Progesterone
An unblinded RCT, published in 2012 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 history of preterm birth.(9) 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 deliveries before 34 weeks in the vaginal progesterone group (17%) and 64 deliveries before 34 weeks in the IM progesterone group (26%). 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; there was a significantly higher rate in the IM progesterone group (n=64 [26%]) than the vaginal progesterone group (n=39 [15%]) (p=0.006). A significantly higher rate of adverse effects were reported by patients in the IM progesterone group (n=35 [14%]) than the vaginal progesterone group (n=19 [8%]) (p=0.017).
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.
Short Cervical Length
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, ie, participants did not have a history of prior preterm birth.(10) The study was conducted at 14 centers in the United States. 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 women in the 17P group (25%) and 80 women in the placebo group (24%). 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 an interim analysis by an independent data and safety monitoring board determined that there was an extremely low probability of finding a significant difference between groups if enrollment continued and
therefore the trial was halted early.
Another RCT, published in 2010 by Berghella et al, included a planned secondary analysis of preterm birth in women with a short cervical length (<25 mm at 16-22 weeks of gestation) and history of prior preterm birth.(11) The study was primarily intended to evaluate the efficacy of cerclage, but study participants were stratified at randomization to use or not use 17P, so the additional impact of 17P on outcomes could be examined. The 17P group did not have lower preterm birth rates, either in the group assigned to cerclage or the group assigned to no cerclage. However, in the no cerclage group, perinatal death occurred in 2 (4%) cases in the group that used 17P, and 23 (23%) cases in the group that did not use 17P; this difference was statistically significant (p=0.003). Moreover, birth before 24 weeks occurred in 1 (2%) pregnancy in the 17P group and 20 (20%) in the no 17P group (p=0.002). A limitation of this analysis is that the number of women who used 17P and did not receive cerclage was small. Moreover, all women in the study had a history of previous spontaneous preterm birth, so the study does not provide data on the efficacy of 17P for women with a short cervical length but without a prior preterm birth.
Several RCTs and a 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 to placebo or no treatment in asymptomatic pregnant women with a sonographic short cervix (cervical length 25 mm or less) in the mid-trimester.(12) A total of 5 RCTs were included in the meta-analysis. Two of the trials, Hassan et al (2011)(13) and Fonseca et al (2007)(14) limited enrollment to women with a short cervix (defined as 15 mm or less in 1 study and 10-20mm 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 of the studies were double-blind 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 5 studies found that treatment with vaginal progesterone was associated with a statistically significant reduction in the risk of preterm birth before 33 weeks of gestation compared with placebo (12.4% vs 22.0%, respectively; RR=0.58; 95% CI, 0.42 to 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 to 0.92).
The Romero et al study also examined the preterm birth outcome for other time periods. In the analysis of all available data, rates of preterm birth before 35, 34, 30, and 28 weeks of gestation were significantly lower in the group receiving vaginal progesterone compared with placebo. The outcome of preterm birth before 36 weeks of gestation was marginally significant, and there was not a significant difference
between groups in the rate of preterm birth before 37 weeks of gestation (37% in the treatment group, 43% in the placebo group).
Two RCTs focused on the evaluation of vaginal progesterone for preventing preterm birth in women with short cervical length; several other RCTs on vaginal progesterone have reported data on this group of women. 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 a singleton pregnancy and no prior history of preterm birth. There is insufficient evidence from 2 RCTs that injectable progesterone is effective for preventing preterm birth in women with short cervical length.
Several systematic reviews 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.(1,3,15) In 2014, Schuit et al published an individual patient data meta-analysis evaluating the effectiveness of progesterone for improving the perinatal outcome in twin pregnancies.(15) The investigators identified 13 trials with a total of 3668 women; 7 used vaginal progesterone and 6 used intramuscular 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 and less than 24 weeks’ 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 also 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 also the study with the longest follow-up, was published in 2011 by Rode et al (the PREDICT trial).(16) The study 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 weeks of gestation up until 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 rate of preterm delivery before 22, 28, 32, or 37 weeks of gestation. Rates of neonatal outcomes eg, birthweight, neonatal death, perinatal complications, also did not differ significantly between groups. The investigators conducted follow-ups 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 parentadministered
Numerous RCTs and several meta-analyses have consistently found that progesterone is not associated with decreased rates of preterm delivery and other perinatal outcomes in pregnant women with twins.
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 of the trials evaluated IM injections of 17P. Caritis et al randomized healthy women with triplets to receive weekly IM injections of either 17P or placebo starting at 16 to 20 weeks and ending at delivery or 35 weeks of gestation.(17) 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). The other trial was published in 2010 by Combs et al.(18) A total of 81 women were included, 56 assigned to receive IM injections of 17P and 25 to placebo. Treatment started at 16 to 22 weeks’ gestational age and continued until 34 weeks. There was not a significant difference in the mean gestational age at delivery (31.9 in the 17P group, 31.8 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).
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.
Preterm Rupture of the Membranes
In 2010, Briery et al published a study including women with singleton pregnancies diagnosed with preterm rupture of the membranes (PPROM) at 20 to 30 weeks of gestation.(19) They were randomized to receive weekly injections of 17P (n=33) or placebo (n=36). Two women did not finish the study; however, data were analyzed on an intention-to-treat basis. There was no significant difference between groups in the gestational age at delivery (mean of 27.3 weeks in the progesterone group and 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
The single published RCT identified did not find that outcomes were improved in women with singleton pregnancies experiencing PPROM who received progesterone versus placebo.
Prior Episode of Preterm Labor in Current Pregnancy
The 2013 Cochrane review by Dodd et al identified 6 small RCTs in women who received progesterone therapy following successful tocolysis; 4 trials used IM progesterone and 2 used vaginal suppositories.(3) For most outcomes, data were not available from enough studies for meaningful pooled analyses. Pooled analyses were conducted for the outcomes of respiratory distress syndrome in neonates and neonatal
sepsis, and progesterone did not result in significantly reduced rates of either of these.
Representative RCTs, by route of administration, are described next.
Two RCTs were identified, 1 of which was placebo controlled. A 2014 RCT by Biery et al included 45 women pregnant with singletons who had experienced successful tocolysis.(20) Women were randomized to receive IM progesterone or placebo; treatment continued until either preterm labor recurred or 36 weeks’ gestation was reached. The primary study outcome was preterm delivery before 37 weeks, and there were a number of secondary outcomes. The study originally aimed to enroll 80 women, but only 45 were randomized before the study was terminated for administrative reasons. Preterm delivery before 37 weeks occurred in 19 of 22 women (86.4%) in the progesterone group and 22 of 23 (95.7%) in the placebo group; the difference between groups was not statistically significant (p=0.346). Among secondary outcomes, at the p less than 0.05 level, there was a significantly lower rate of preterm delivery before 34 weeks in the progesterone group compared with the placebo group (63.6% and 91.3%, respectively, p=0.035). Groups did not differ significantly in gestational age at delivery or the number of days from treatment initiation until delivery. Because the enrollment target was not achieved, the study may have been underpowered on the primary outcome; however, the rate of preterm birth before 37 weeks was high in both groups.
A 2012 open-label multicenter RCT by Rozenberg et al in France evaluated IM progesterone to prevent preterm delivery in 188 pregnant women after a previous episode of successful tocolysis during the same pregnancy.(21) Women had all been admitted for preterm labor with intact membranes. To be eligible for study participation, women also needed to be carrying a singleton pregnancy and to be between the 24th
and 31st weeks of gestation. Following acute tocolysis, women assigned to progesterone treatment (n=94) received injections of 17P twice a week until 36 weeks of gestation or preterm delivery. Women in the control group (n=94) received usual care. Outcome data were available for 184 (97%) of 188 participants. An intention-to-treat analysis did not find a statistically significant difference between groups in the study’s primary efficacy outcome, time to delivery (from randomization). The time to delivery was a median of 64 days in the 17P group and 67 days in the control group. Other delivery-related outcomes, ie, delivery before 32, 34, and 37 weeks of gestation, did not differ significantly between groups. In addition, fetal and neonatal outcomes, including birthweight, rate of neonatal death and rates of respiratory distress syndrome, were not different in the 17P and control groups.
A 2013 RCT by Areia et al included 52 women with singleton pregnancies who had preterm labor successfully arrested by atosiban, a tocolytic agent currently unavailable in the United States.(22) Women were randomized to receive daily vaginal progesterone (n=26) or usual care (n=26). Treatment began on the day atisoban was terminated and continued until the day of delivery. None of the patients were lost to follow-up. The primary outcome was the time until delivery (ie, the number of days to delivery following termination of atisoban treatment), and there were a number of secondary outcomes. The mean time until delivery was 55 days in the progesterone group and 38 days in the usual care group; the difference was statistically significant (p=0.02), favoring treatment. Secondary outcomes did not differ significantly between groups but the study may have been underpowered to detect clinically meaningful differences on these. For example, preterm labor recurred in 2 women (8%) in the progesterone group and 8 women (31%) in the control group, and the mean gestational age at delivery was 37.8 weeks in the progesterone group versus 36.6% in the control group (p=0.07 for each of these analyses).
A 2012 trial by Saleh Gargari et al in Iran included 72 women pregnant with singletons who had undergone successful tocolysis with magnesium sulfate for preterm labor.(23) After tocolysis, participants were randomly assigned to apply vaginal progesterone suppository until delivery or usual care. The authors stated that study personnel (other than statisticians) and participants were blinded to treatment group; however, the ability to blind a no-treatment control group may be limited. The study evaluated numerous outcomes, and there was no primary outcome specified. Two main delivery-related outcomes were reported. The mean gestational age at delivery was 36.2 weeks (SD=1.4) in the progesterone group and 34.1 (SD=1.5) in the usual care group (p=0.039). The mean length of time that delivery was postponed was 4.0 weeks (SD=1.5) in the progesterone group and 1.4 weeks (SD=0.2) in the usual care group (p=0.048). If the p value had been adjusted to account for 2 comparisons (ie, p<0.025 instead of p<0.05), it is unlikely that the differences in these outcomes would have been statistically significant. The number of neonatal deaths was 3 (4.2%) in the progesterone group and 8 (11%) in the usual care group; the difference between groups was not statistically significant (p=0.08), but the study likely was underpowered to detect differences between groups in the rate of neonatal death given the low number of deaths overall. The number of low birthweight babies was 8 (11%) in the progesterone group and 26 (36%) in the usual care group (p<0.001).
Small RCTs on progesterone therapy to prevent preterm birth after successful tocolysis have had mixed findings. Additional RCTs that have large enough sample sizes to be able to detect clinically important differences in relevant health outcomes are needed.
Ongoing and Unpublished Clinical Trials
- Confirmatory Study of 17P Versus Vehicle for the Prevention of Preterm Birth in Women With a Previous Singleton Spontaneous Preterm Delivery (NCT01004029)(24): This RCT is enrolling pregnant women with a history of previous singleton spontaneous delivery. Participants will be randomly assigned to receive injections of 17P or placebo injections. Estimated enrollment is 1707 women and the expected date of study completion is December 2016.
- Progesterone for the Management of Preterm, Premature Rupture of the Membranes: A Randomized Controlled Trial (NCT01050647)(25): This RCT is comparing 17P injections to castor oil (placebo) injections in women pregnant with singletons who are diagnosed with PPROM. Estimated enrollment is 40 women and the expected date of study completion is August 2014.
- Progesterone (17P, Makena®) for Prolongation of Pregnancy in Women With Preterm Rupture of the Membranes (PROM) (17PinPROM) (NCT01119963)(26): This double-blind study includes women with singleton pregnancies diagnosed with PPROM. They will be randomized to receive injections of 17P or castor oil (placebo) injections. The estimated enrollment is 222 women and the expected date of study of study completion is January 2015.
Clinical Input Received From Physician Specialty Societies and Academic Medical Centers
In response to requests, input was received through physician specialty societies and academic medical centers while this policy was under review in 2009 and 2011. While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted. In 2009, the 2 physician specialty societies and 4 academic medical centers, that responded strongly, agreed with the policy statements as adopted in October of that year. There was unanimous agreement that injectable progesterone and vaginal progesterone may be considered medically necessary for women with a singleton pregnancy and a prior history of preterm delivery before 37 weeks of gestation. All but 1 response indicated there was no evidence supporting 1 mode of progesterone administration over another. The single response, from an academic medical center, that said there was a difference commented that the Meis (2003)(4) and Da Fonseca (2003)(7) studies differed, and thus one formulation may be preferred over another for a particular patient. The least agreement was regarding short cervical length as a risk factor; however, most of those providing input agreed with the current policy statement. The clinical input also raised questions about the clinical applications for cervical length measurement.
In 2011, responses were received from 1 physician specialty society and 6 academic medical centers. There was unanimous agreement among the academic medical center respondents that both weekly injections of progesterone and daily intravaginal progesterone may be considered medically necessary to prevent preterm births in singleton pregnancies when there is a prior history of spontaneous preterm birth. The physician specialty society respondent referred to their organization’s clinical guideline which states that progesterone is recommended for women with a history of prior spontaneous preterm birth and that the optimal formulation is not known. Two physician respondents commented that it may be appropriate to begin vaginal progesterone earlier in pregnancy, similar to intramuscular progesterone, which is given starting between 16 and 36 weeks of gestation. One respondent commented that, while data support the use of both IM and vaginal progesterone in women with a history of prior preterm birth, the data are stronger in support of IM progesterone.
There was near-consensus from academic medical center respondents that progesterone therapy may be considered medically necessary for women with a short cervix. The Hassan et al (2011)(13) randomized trial was not published at the time clinical input was obtained. The input did not specify timing of vaginal progesterone in women with a short cervix.
Input was also received from 4 academic medical centers on start and stop dates. All of the reviewers supported the use of different start and stop dates, rather than 1 uniform set of dates across all formulations and indications. Most reviewers agreed with all of the recommended start and stop dates as written in the policy statement. For injectable progesterone, the reviewers agreed with using the FDAapproved start and stop dates.
Summary of Evidence
There is sufficient evidence from randomized controlled trials (RCTs) and meta-analyses of RCTs that injectable and vaginal progesterone are associated with improved health outcomes in women with singleton pregnancies who have a history of prior preterm birth. In addition, there is sufficient evidence that progesterone improves health outcomes in women with singleton pregnancies and short cervical length. Thus, progesterone therapy may be considered medically necessary in the above situations for selected women who meet clinical criteria.
The evidence is insufficient that progesterone is effective for reducing preterm delivery in other situations such as women with twin or multiple gestations, women with preterm rupture of the membranes, or women with a prior episode of preterm labor in the current pregnancy (in conjunction with or following tocolysis) and thus these indications are considered investigational.
Practice Guidelines and Position Statements
In May 2014, the American College of Obstetricians and Gynecologists (ACOG) published a Practice Bulletin on multifetal gestations that included the following statement on progesterone therapy(27):
- 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, ACOG published a Practice Bulletin on prediction and prevention of preterm birth.(28) The bulletin includes the following recommendations related to progesterone therapy in women with singleton pregnancies:
- A woman with a singleton pregnancy and a prior spontaneous singleton birth should be offered progesterone supplementation starting at 16 to 24 weeks of gestation to reduce the risk of recurrent spontaneous preterm birth.
- A woman with a short cervix identified with transvaginal ultrasonography, a singleton gestation and no prior spontaneous preterm birth should be offered vaginal progesterone supplementation if cervical length is 20 mm or less before or at 24 weeks of gestation.
A 2012 clinical guideline by the Society for Maternal-Fetal Medicine included the following conclusions and recommendations(29):
“1. There is insufficient evidence to recommend the use of progestogens in singleton gestations with no prior PTB [pre-term 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 [threatened 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 [spontaneous preterm birth] and a current multiple gestation, but there are insufficient data to evaluate the risks and benefits of this intervention in this population.”
In October 2012, ACOG published a Practice Bulletin on prediction and prevention of preterm birth.(28) The bulletin includes the following recommendations related to progesterone therapy:
- A woman with a singleton pregnancy and a prior spontaneous singleton birth should be offered progesterone supplementation starting at 16 to 24 weeks of gestation to reduce the risk of recurrent spontaneous preterm birth.
- A woman with a short cervix identified with transvaginal ultrasonography, a singleton gestation and no prior spontaneous preterm birth should be offered vaginal progesterone supplementation if cervical length is 20 mm or less before or at 24 weeks of gestation.
- Progesterone supplementation is not recommended to reduce preterm birth in women with twin or triplet gestations.
U.S. Preventive Services Task Force Recommendations
The U.S. Preventive Services Task Force has not addressed progesterone for preventing preterm birth.
Medicare National Coverage
There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.
- 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 2012; 40(3):257-66.
- Rode L, Langhoff-Roos J, Andersson C et al. Systematic review of progesterone for the prevention of preterm birth in singleton pregnancies. Acta Obstet Gynecol Scand 2009; 88(11):1180-9.
- Dodd JM, Flenady V, Cincotta R et al. Prenatal administration of progesterone for preventing preterm birth. Cochrane Database Syst Rev 2006; (1):CD004947.
- Meis PJ, Klebanoff M, Thom E et al. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med 2003; 348(24):2379-85.
- Northen AT, Norman GS, Anderson K et al. Follow-up of children exposed in utero to 17 alpha-hydroxyprogesterone caproate compared with placebo. Obstet Gynecol 2007; 110(4):865-72.
- O'Brien JM, Adair CD, Lewis DF et al. Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol 2007; 30(5):687-96.
- 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):419-424. PMID 12592250
- Majhi P, Bagga R, Kalra J, et al. Intravaginal use of natural micronised progesterone to prevent pre-term birth: a randomised trial in India. J Obstet Gynaecol. Aug 2009;29(6):493-498. PMID 19697195
- 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):215-222. PMID 23016508
- 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 e391-398. PMID 23010094
- Berghella V, Figueroa D, Szychowski JM, 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. Apr 2010;202(4):351 e351-356. PMID 20350641
- 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 e121-119. PMID 22284156
- 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
- Fonseca EB, Celik E, Parra M, et al. Progesterone and the risk of preterm birth among women with a short cervix. N Engl J Med. Aug 2 2007;357(5):462-469. PMID 17671254
- 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. Aug 22 2014. PMID 25145491
- 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):272-280. PMID 21739497
- Caritis SN, Rouse DJ, Peaceman AM, et al. Prevention of preterm birth in triplets using 17 alphahydroxyprogesterone caproate: a randomized controlled trial. Obstet Gynecol. Feb 2009;113(2 Pt 1):285-292. PMID 19155896
- 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 e241-249.PMID 20816146
- 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 e51-55. PMID 20869038
- Briery CM, Klauser CK, Martin RW, et al. The use of 17-hydroxy progesterone in women with arrested preterm labor: a randomized clinical trial. J Matern Fetal Neonatal Med. Mar 10 2014. PMID 24512252
- Rozenberg P, Chauveaud A, Deruelle P, et al. Prevention of preterm delivery after successful tocolysis in preterm labor by 17 alpha-hydroxyprogesterone caproate: a randomized controlled trial. Am J Obstet Gynecol. Mar 2012;206(3):206 e201-209. PMID 22381603
- Areia A, Fonseca E, Moura P. Progesterone use after successful treatment of threatened pre-term delivery. J Obstet Gynaecol. Oct 2013;33(7):678-681. PMID 24127952
- Saleh Gargari S, Habibolahi M, Zonobi Z, et al. Outcome of vaginal progesterone as a tocolytic agent: randomized clinical trial. ISRN Obstet Gynecol. 2012;2012:607906. PMID 22685670
- Sponsored by KV Pharmaceuticals. Confirmatory Study of 17P Versus Vehicle for the Prevention of Preterm Birth in Women With a Previous Singleton Spontaneous Preterm Delivery (NCT01004029).www.clinicaltrials.gov. Accessed June, 2014.
- Sponsored by Stanford University. Progesterone for the Management of Preterm, Premature Rupture of the Membranes: A Randomized Controlled Trial (NCT01050647). www.clinicaltrials.gov. Accessed June, 2014.
- Sponsored by Obstetrix Medical Group. Progesterone (17P, Makena®) for Prolongation of Pregnancy in Women With Preterm Rupture of the Membranes (PROM) (17PinPROM) (NCT01119963). www.clinicaltrials.gov. Accessed June, 2014.
- American College of Obstetricians and Gynecologists (ACOG). Multifetal gestations: twin, triplet, and higherorder multifetal pregnancies (ACOG Practice Bulletin No. 144). www.guideline.gov. Accessed September, 2014.
- Committee on Practice Bulletins-The American College of Obstetricians and Gynecologists. Practice bulletin no. 130: prediction and prevention of preterm birth. Obstet Gynecol. Oct 2012;120(4):964-973. PMID 22996126
- Progesterone and preterm birth prevention: translating clinical trials data into clinical practice. Am J Obstet Gynecol. May 2012;206(5):376-386. PMID 22542113
|CPT||96372||Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular|
|99506||Home visit for intramuscular injections|
|ICD-9 Diagnosis||V23.41||Pregnancy with history of preterm labor|
|HCPCS||J1725||Injection, hydroxyprogesterone caproate, 1 mg|
|Q2042||Injection, hydroxyprogesterone caproate, 1 mg|
|S9208||Home management of preterm labor, including administrative services, professional pharmacy services, care coordination, and all necessary supplies or equipment (drugs and nursing visits coded separately), per diem (Do not use this code with any home infusion per diem code)|
|ICD-10-CM (effective 10/1/15)||O09.211-O09.219||Supervision of pregnancy with history of pre-term labor, code range|
|ICD-10-PCS (effective 10/1/15)||ICD-10-PCS codes are only used for inpatient services. There is no specific ICD-10-PCS code for this procedure.|
|Type of Service||Obstetrics/Gynecology|
17 Alpha-Hydroxyprogesterone Caproate, Prevention of Preterm Delivery
Preterm Delivery, Progesterone
Progesterone Vaginal Suppositories, Prevention of Preterm Delivery
|12/17/03||Add to OB/Gyn Reproduction section||New policy|
|11/09/04||Replace policy||Policy discussed; policy statement unchanged|
|09/27/05||Replace policy||Policy updated with literature search; policy statement unchanged. Reference numbers 7 through 9 added. No further scheduled review|
|12/14/05||Replace policy-coding update only||CPT and HCPCS coding updated|
|12/12/06||Replace policy||Policy updated with literature search; reference numbers 10-12 added; policy statement unchanged|
|04/09/08||Replace policy||Policy updated with literature search; reference numbers 13-17 added; policy statements unchanged|
|10/06/09||Replace policy||Policy reviewed with literature search from March 2008 through May 2009; clinical input reviewed; the policy statement has been revised to clarify the medically necessary use applies to women with a singleton pregnancy; prior history of cervical cerclage, and/or uterine anomaly changed to investigational; reference numbers 18-22 added|
|04/14/11||Replace policy||Policy reviewed with literature search through December 2010. Rationale extensively re-written. References 2, 4, 9, 10 and 13 added; other references renumbered or removed. No change to policy statements. ICD-10 codes added to policy|
|07/14/11||Replace policy||Policy reviewed with literature search through April 2011. References 12 and 20 added. Use of vaginal progesterone to treat women with singleton pregnancies and short cervical length added as medically necessary. Minor edits were made to the investigational statement to be consistent with this change. Additional clinical input obtained. Start and stop dates of injectable progesterone changed to be consistent with label of FDA-approved product. Policy reformatted to improve readability.|
|11/10/11||Replace policy -coding update only||HCPCS code J1725 added to policy|
|09/13/12||Replace policy||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.|
|9/12/13||Replace policy||Policy reviewed with literature search through July 22, 2013. No change to policy statements. References 9, 11, 18-20, 24, 27-29 and 32 added; other references renumbered or removed.|
|10/09/14||Replace policy||Policy reviewed with literature review through September 11, 2014. No change to policy statements. References 3, 15, 20, 22, and 27 added.|