Subject:
Progesterone Therapy as a Technique to Reduce Preterm Delivery in High Risk Pregnancies
Description:
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IMPORTANT NOTE:
The purpose of this policy is to provide general information applicable to the administration of health benefits that Horizon Blue Cross Blue Shield of New Jersey and Horizon Healthcare of New Jersey, Inc. (collectively “Horizon BCBSNJ”) insures or administers. If the member’s contract benefits differ from the medical policy, the contract prevails. Although a service, supply or procedure may be medically necessary, it may be subject to limitations and/or exclusions under a member’s benefit plan. If a service, supply or procedure is not covered and the member proceeds to obtain the service, supply or procedure, the member may be responsible for the cost. Decisions regarding treatment and treatment plans are the responsibility of the physician. This policy is not intended to direct the course of clinical care a physician provides to a member, and it does not replace a physician’s independent professional clinical judgment or duty to exercise special knowledge and skill in the treatment of Horizon BCBSNJ members. Horizon BCBSNJ is not responsible for, does not provide, and does not hold itself out as a provider of medical care. The physician remains responsible for the quality and type of health care services provided to a Horizon BCBSNJ member.
Horizon BCBSNJ medical policies do not constitute medical advice, authorization, certification, approval, explanation of benefits, offer of coverage, contract or guarantee of payment.
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Preterm labor and delivery is a major determinant of neonatal morbidity and mortality; in the United States the rate of preterm birth is 12%. A variety of diagnostic and prophylactic measures have been investigated but none had made significant demonstrable impact on the incidence of preterm delivery. In the past, intramuscular injections of 17 alpha hydroxyprogesterone (i.e., Delalutin) were used routinely to prevent premature labor. However, the drug was shown to have teratogenic properties and the Food and Drug Administration (FDA) labeled it as Category D (i.e., studies have demonstrated fetal risk, but that the use of the drug may outweigh the potential risk). Delalutin is no longer marketed. Most recently, there has been renewed research interest in intramuscular injection of 17 alpha-hydroxyprogesterone caproate (17P). 17P is a weakly acting naturally occurring progesterone metabolite, which when coupled with caproate dextran works as a long acting progestin when administered intramuscularly. 17P is not commercially available, but can be prepared locally by compounding pharmacies. Intravaginal progesterone suppositories have also been investigated.
Hydroxyprogesterone caproate injection (Makena™) was FDA approved on February 3, 2011 to reduce the risk of preterm birth in women with a singleton pregnancy and a history of singleton spontaneous preterm birth. Hydroxyprogesterone caproate is a synthetic progestin hormone and the mechanism by which it works to reduce the risk of recurrent preterm birth is unknown. Progesterone is necessary to maintain pregnancy throughout gestation and it works to relax smooth muscle in the uterus, block uterine contractility, and inhibit myometrial gap junctions that propagate uncoordinated uterine muscle activity leading to labor.
Preterm delivery (before 37 weeks of gestation) is a major cause of infant mortality. The rate of preterm delivery is 12% in the United States and there is currently no effective and reproducible method demonstrated to prevent it. Women at greatest risk for preterm delivery include those with prior preterm delivery, multiple gestation, short cervical length, weight < 50 kg, bleeding, and those of African American race. Infants born prematurely are at increased risk of developing intraventricular hemorrhage, respiratory distress syndrome, periventricular leukomalacia, necrotizing enterocolitis, apnea, jaundice, anemia, and infections.
A multicenter, randomized, double-blind, vehicle (placebo)-controlled study was conducted in 463 pregnant women to assess the safety and efficacy of hydroxyprogesterone caproate in the risk of preterm delivery before 37 weeks of gestation. Pregnant women with a documented history of spontaneous preterm delivery who were at 15 to 20 weeks 3 days of gestation were included. Patients were excluded if they had multifetal gestation, known fetal anomaly, progesterone or heparin treatment during current pregnancy, current or planned cervical cerclage, hypertension requiring medication, a seizure disorder, or a plan to deliver elsewhere. Patients were randomized to receive 250 mg of 17 alpha-hydroxyprogesterone caproate (17P) injected weekly or inert oil placebo injected weekly until delivery or until 36 weeks of gestation (whichever occurred first). The primary endpoint was preterm delivery before 37 weeks of gestation. Baseline characteristics were similar between the groups. The results showed that the incidence of preterm delivery before 37 weeks of gestation was 36.3% in the 17P group and 54.9% in the placebo group (relative risk 0.66 (95% CI, 0.54 to 0.81). The risk of delivery at less than 35 weeks of gestation and at less than 32 weeks of gestation was also significantly reduced in the 17P group compared with placebo.
A follow-up study of surviving children of mothers who participated in the previously discussed trial evaluated the safety of 17P after in utero exposure. The guardian was interviewed about the child’s general health and the children were assessed through physical examination. The children also underwent developmental screening with the Ages and Stages Questionnaire (assesses communication, gross motor, fine motor, problem solving, and personal/social domains) and gender-specific roles were assessed with the Preschool Activities Inventory (evaluations the masculinity or femininity of play activities). 278 children were available for evaluation at a mean age of 48 months. No significant differences were seen in health status or physical examination between 17P and placebo. Scores on the Preschool Activities Inventory were within normal range in both groups.
Policy:
1. Weekly intramuscular injections of 250 mg of 17 alpha-hydroxyprogesterone caproate (17P) beginning at 16 to 20 weeks gestation and continued to delivery or 36 weeks of gestation (whichever one comes first) are considered medically necessary in pregnant women with a prior history of a preterm delivery before 37 weeks gestation.
[INFORMATIONAL NOTE: ACOG's Practice Bulletin on prediction and prevention of preterm birth published in October 2012 recommends that 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.]
2. A. Intramuscular injection of Makena™ (hydroxyprogesterone caproate) injection is considered medically necessary to reduce the risk of preterm birth when ALL of the following criteria are met:
- The prescriber is a specialist in the area of the patient’s diagnosis (e.g. obstetrician-gynecologist) or has consulted with a specialist in the area of the patient’s diagnosis AND
- The treatment of should be administered by a healthcare professional AND
- Patient is a woman of at least 16 years of age with a singleton pregnancy AND
- Patient has a history of singleton spontaneous preterm birth (defined as delivery at less than 37 weeks of gestation following spontaneous preterm labor or premature rupture of membranes) AND
- Patient is not in preterm labor during the current pregnancy AND
- Patient does not have history of or current thrombosis or thromboembolic disorders; known or suspected breast cancer, other hormone-sensitive cancer, or history of these conditions; undiagnosed abnormal vaginal bleeding unrelated to pregnancy; cholestatic jaundice of pregnancy; liver tumors or active liver disease; or uncontrolled hypertension
B. When Makena™ (hydroxyprogesterone caproate) injection is considered medically necessary, patients will be eligible for therapy according to FDA dosage and administration guidelines with the approval period of 6 months:
Intramuscular administration
- 250 mg (1 mL) every 7 days beginning between 16 weeks, 0 days and 20 weeks, 6 days of gestation
- Continue therapy through 36 weeks, 6 days of gestation or until delivery (whichever occurs first)
Subcutaneous administration
· 275 mg once weekly every week by a healthcare provider beginning between 16 weeks, 0 days and 20 weeks, 6 days of gestation
· Continue therapy through 36 weeks, 6 days of gestation or until delivery (whichever occurs first)
3. Daily vaginal progesterone suppositories between 24 and 34 weeks gestation is considered medically necessary in pregnant women with a prior history of any of the following:
- preterm delivery before 37 weeks gestation;
- prior cervical cerclage;
- uterine anomaly.
4. Progesterone therapy is not considered medically necessary for endometrial cancer, dysfunctional uterine bleeding, amenorrhea, postmenopausal women, placenta previa, treatment of a short cervix.
5. Progesterone therapy as a technique to prevent preterm labor is considered investigational in pregnant women with other high-risk obstetric factors for preterm delivery including, but not limited to, multiple gestations, short cervical length, or positive tests for cervicovaginal fetal fibronectin without a prior history of preterm delivery before 37 weeks gestation.
[INFORMATIONAL NOTE: Progesterone therapy to prevent preterm birth in twin pregnancies has shown no clear benefit, but an individual participant data (IPD) meta-analysis is underway to investigate adverse perinatal outcomes in patients treated with 17-hydroxyprogesterone caproate or vaginal progesterone.]
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Horizon BCBSNJ Medical Policy Development Process:
This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.
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Index:
Progesterone Therapy as a Technique to Reduce Preterm Delivery in High Risk Pregnancies
17 Alpha-Hydroxyprogesterone Caproate (17P)
7P (17 Alpha-Hydroxyprogesterone Caproate)
Preterm Delivery, Progesterone Therapy for
Progesterone Vaginal Suppositories, Prevention of Preterm Delivery
Makena (Hydroxyprogesterone caproate)
Hydroxyprogesterone caproate (Makena)
References:
1. American College of Obstetricians and Gynecologists. ACOG Committee Opinion #291. Use of Progesterone to Reduce Preterm Birth. November 2003, re-affirmed July 13, 2006. (see reference # 27 for updated 2008 ACOG Committee Opinion)
2. Meis PJ, Leadoff M, Thom E, et al. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Eng J Med 2003;348:2379-85.
3. da Fonseca EB, Bitter RE, Carvalho MHB, 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 2003;188:419-24.
4. Greene MK. Progesterone and preterm delivery – Déjà vu all over again. N Eng J Med 2003;348:2453-55.
5. Brancazio LR, Murtha AP, Heine RP, et al. Prevention of recurrent preterm delivery by 17 alpha hydroxyprogesterone caproate. Letter to the Editor. N Eng J Med 2003;349:1087-88.
6. Yemini M, Borenstein R, Greazen E, et al. Prevention of premature labor by 17 alpha-hydroxyprogesterone caproate. Am J Obstet Gynecol 1985;151:574-77.
7. Keirse MJ. Progestogen administration in pregnancy may prevent preterm delivery. Br J Obstet Gynaecol 1990;97:149-54.
8. Meis PJ, Aleman A. Progesterone treatment to prevent preterm birth. Drugs 2004;64(21):2463-74.
9. Sanchez-Ramos L, Kaunitz AM, Delke I. Progestational agents to prevent preterm birth: a meta-analysis of randomized controlled trials. Obstet Gynecol 2005 Feb;105(2):273-9.
10. ECRI Institute. Health Technology Trends: Hormone therapy may reduce premature deliveries among high risk women. 06/2003.
11. Dodd JM, Flenady V et al. Prenatal administration of progesterone for preventing preterm birth. Cochrane Database of Systematic Reviews. 2006, Issue 1. ARt. No.:CD004947. DOI: 10.1002/14651858.CD004947.pub2.
12. Lamont RF, Jaggat AN. Emerging drug therapies for preventing spontaneous preterm labor and preterm birth. Expert Opin Investig Drugs. 2007 Mar;16(3):337-45.
13. Sfakianaki AK, Norwitz ER. Mechanisms of progesterone action in inhibiting prematurity. J Matern Fetal Neonatal Med. 2006 Dec;19(12):763-72.
14. Ness A, Dias T et al. Impact of the recent randomized trials on the use of progesterone to prevent preterm birth: a 2005 follow-up survey. Am J Obstet Gynecol. 2006 Oct;195(4):1174-9.
15. Odibo AO, Stamillo DM et al. 17alpha-hydroxyprogesterone caproate for the prevention of preterm delivery: A cost-effectiveness analysis. Obstet Gynecol. 2006 Sep;108(3 Pt 1):492-9.
16. Coomarasamy A, Thangaratinam S et al. Progesterone for the prevention of preterm birth: a critical evaluation of evidence. Eur J Obstet Gynecol Reprod Biol. 2006 Dec;129(2):111-8. Epub 2006 Jul3.
17. 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. 2007 Aug 2;357(5):462-9.
18. Meis PJ, Society for Maternal-Fetal Medicine. 17 hydroxyprogesterone for the prevention of preterm delivery. Obstet Gynecol 2005; 105(5 pt 1):1128-35.
19. Petrini JR, Callaghan WM, Klebanoff M et al. Estimated effect of 17 alpha-hydroxyprogesterone caproate on preterm birth in the United States. Obstet Gynecol 2005; 105(2):267-72.
20. Dodd JM, Flenady V, Cincotta R et al. Prenatal administration of progesterone for preventing preterm birth. Cochrane Database Syst Rev 2006; 25;(1):CD004947.
21. Mackenzie R, Walker M, Armson A et al. Progesterone for the prevention of preterm birth among women at increased risk: a systematic review and meta-analysis of randomized controlled trials. Am J Obstet Gynecol 2006; 194(5):1234-42.
22. Spong CY, Meis PJ, Thom EA et al. National Institute of Child Health and Human Development Maternal Fetal Medicine Units Network. Progesterone for prevention of recurrent preterm birth: impact of gestational age at previous delivery. Am J Obstet Gynecol 2005; 193(3 pt 2):1127-31.
23. 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.
24. Rouse DJ, Caritis SN, Peaceman AM et al.; National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. A trial of 17 alpha-hydroxyprogesterone caproate to prevent prematurity in twins. N Engl J Med 2007; 357(5):454-61.
25. DeFranco EA, O'Brien JM, Adair CD et al. Vaginal progesterone is associated with a decrease in risk for early preterm birth and improved neonatal outcome in women with a short cervix: a secondary analysis from a randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol 2007; 30(5):697-705.
26. Northen AT, Norman GS, Anderson K et al.; National Institute of Child Health and Human Development Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network. Follow-up of children exposed in utero to 17 alpha-hydroxyprogesterone caproate compared with placebo. Obstet Gynecol 2007; 110(4):865-72.
27. Society for Maternal Fetal Medicine Publications Committee. ACOG Committee Opinion number 419 October 2008 (replaces no. 291, November 2003). Use of Progesterone to reduce preterm birth. Obstet Gynecol. 2008 Oct;112(4):963-5.
28. Makena™ (hydroxyprogesterone caproate) injection Prescribing Information. February 2018.
29. Makena™ (hydroxyprogesterone caproate) injection Company Dossier. Baxter Pharmaceutical Solutions LLC. Bloomington, IN.
30. 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.
31. Northern AT, Norman GS, Anderson K, et al. Follow-up of Children Exposed In Utero to 17 -Hydroxyprogesterone Caproate Compared With Placebo. Obstet & Gynecol 2007;110:865-72.
32. ACOG Committee Opinion Number 419 October 2008 (replaces no. 291, November 2003). "Use of Progesterone to Reduce Preterm Birth," Obstet Gynecol 2008;112(4):963-65.
33. Schuit E, Stock S, Groenwold RH, et al. Progestogens to prevent preterm birth in twin pregnancies: an individual participant data meta-analysis of randomized trials. BMC Pregnancy Childbirth. 2012 Mar 15;12(1):13. [Epub ahead of print]
34. Gold Standard, Inc. Hydroxyprogesterone. Clinical Pharmacology [database online]. Available at: http://www.clinicalpharmacology.com. Accessed: April 15, 2015.
35. Reifenstein EC Jr: The treatment of advanced endometrial cancer with hydroxyprogesterone caproate. Gynecol Oncol 1974; 2:377-414.
36. Reifenstein EC Jr: Hydroxyprogesterone caproate therapy in advanced endometrial cancer. Cancer 1971; 27:485-502.
37. Kohorn EI: Gestagens and endometrial carcinoma. Gynecol Oncol 1976; 4:398-411.
38. Vergote I, Kjorstad K, & Abeler V er al: A randomized trial of adjuvant progestagen in early endometrial cancer. Cancer 1989; 64:1011-1016.
39. Podratz KC, O'Brien PC, Malkasian GD, et al: Effects of progestational agents in treatment of endometrial carcinoma. Obstet Gynecol 1985; 66:106-110.
40. Agostini R, Casini ML, Costabile L, et al. Efficacy and safety of 17 α-hydroxyprogesterone caproate in hormone replacement therapy. Gynecol Endocrinol. 2005 Nov;21(5):265-7.
41. MICROMEDEX® 2.0 (Healthcare Series). DRUGDEX® Evaluations. Hydroxyprogesterone caproate. Available at: http://www.thomsonhc.com. Accessed April 15, 2015.
42. Lacny J. Cyclic Progestational Therapy of Amenorrhea. Canad. Med. Ass. J. May 19, 1962, vol. 86.
43. 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
44. Clinicaltrials.gov Makena. Available at https://clinicaltrials.gov/ct2/results?cond=&term=makena&cntry=&state=&city=&dist=
45. AMAG reports on FDA advisory committee meeting for MAKENA® (HYDROXYPROGESTERONE CAPROATE INJECTION). October 29, 2019. Available at: https://www.amagpharma.com/news/amag-reports-on-fda-advisory-committee-meeting-for-makena-hydroxyprogesterone-caproate-injection/
Codes:
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CPT*
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J1726
J1729
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