progesteron efect at preterm

17OHPC:

An Opportunity to Prevent

Preterm Birth

DEFINITIONS & BACKGROUND OF

THE PROBLEM

Ashlesha K. Dayal, MD, FACOG

Associate Professor of Obstetrics & Gynecology,

and Womens Health

Medical Director, Labor & Delivery

Albert Einstein College of Medicine / Montefiore Medical Center

Bronx, NY

CONFLICT OF INTEREST

DISCLOSURE STATEMENT

I have no significant financial interest with any commercial or corporate enterprise.

I shall not discuss any off-label usage of any FDA-approved medications or other products.

Definitions

Preterm birth a live birth before 37 completed weeks gestation.

late preterm (34-36 6/7 w)

early preterm (31-33 6/7 w)

very early preterm (28-30 6/7 w)

extreme preterm birth (

Overview of the Problem: US

11.72% of deliveries in the US are preterm (480,000 births/yr)1

85% of all perinatal morbidity & mortality

2nd leading cause of perinatal mortality (1st among African Americans)

20% of preterm births are indicated performed for maternal & fetal indications

Source(s): Hamilton BE, Martin JA, Ventura SJ. National Vital Statistics Reports Web Release;

Vol 61, no. 5: National Center for Health Statistics; 2012

Arias E, McDorman MF, Strobino DM, Guyer B. Annual summary of vital statistics 2002.

Pediatrics, 2003: 112, 1215.

Overview of the Problem: US

Source(s): National Center for Health Statistics, final natality data.

http//www.marchofdimes.com/peristats

March of Dimes, 2012 Premature Birth Report Card,

http://www.marchofdimes.com/peristats/pdflib/998/US.pdf

Cost of Preterm Birth

In 2005, the annual societal economic cost (medical, educational, and lost productivity) associated with preterm birth in the United States was at least $26.2

billion.

The average cost per infant was $51,600.

Source(s): National Center for Health Statistics, final natality data.

Institute of Medicine. 2006. Preterm Birth: Causes,Consequences, and Prevention.

National Academy Press, Washington, DC

Preterm Birth in New York State

According to the March of Dimes, the preliminary 2011 preterm birth rate for New York State was 10.9%.

Source(s): New York State Department of Health. Vital Statistics, Table 11a: Live Births by

Birthweight and Resident County 2010.

http://www.health.ny.gov/statistics/vital_statistics/2010/table11a.htm

March of Dimes, 2012 New York State Premature Birth Report Card,

http://www.marchofdimes.com/peristats/pdflib/998/NY.pdf

Preterm Birth in New York State

In 2010, 1 in 9 babies were born preterm in New York State (11.5%; 28, 124)

Of nearly 243,000 live births in NYS in 2010, 8.2% were considered LBW (

Magnitude of the Problem

In an average week in New York State, 4,771 babies are born.

541 babies are born preterm

94 are born very preterm

386 born low birthweight (

Risk Factors for Preterm Birth

Women at greatest risk:

History of preterm delivery

Maternal weight < 50 kg

African American race

Bleeding

Sexually transmitted disease during the pregnancy

Multiple gestation

Tobacco use

Progesterone Action in

Normal Pregnancy

May suppress maternal immunity and prevent rejection of fetal cells

Myometrial quiescence

suppresses contractile genes

promotes relaxation systems

suppresses cytokines, prostaglandins, & response to oxytocin

prevents formation of gap junctions

Summary

One of the goals of prenatal care is to prevent the neonatal complications of preterm birth.

17OHPC, when properly used, may help accomplish this goal.

Clinical trials and research

supporting 17OHPC for prevention

of recurrent preterm birth

Ashley S. Roman, MD, MPH, FACOG

Assistant Clinical Professor of Obstetrics and Gynecology

New York University School of Medicine

New York, NY

Overview

A review of significant trials and research on 17OHPC

Increasing evidence that progestin supplementation reduces the rate of preterm birth in high-risk women

Different formulations and delivery mechanisms of progestins exist

Focus on 17OHPC for the prevention of spontaneous preterm birth

17OHPC for prevention of

recurrent spontaneous preterm

birth in women with a prior

spontaneous singleton

preterm birth

Early Data

1970: First randomized controlled trial on 17P for preventing preterm birth in high risk women

Subsequent evidence on benefits was conflicting

Resulted in limited 17OHPC use in clinical practice

1990: Meta-analysis of 7 placebo-controlled trials involving 17OHPC

17OHPC associated with 15-70% reduction in occurrence of preterm birth, but no significant reduction in perinatal mortality or morbidity

Source(s): Papiernik E. Double blind study of an agent to prevent pre-term delivery among

women at increased risk. In: Edition Schering, Serie IV, fiche 3. 1970;65-8.

Keirse MJ. Progestogen administration in pregnancy may prevent preterm delivery. Br J

Obstet Gynaecol 1990;97:149-54.

463 patients with a prior spontaneous preterm birth of a singleton gestation were randomized to weekly 17OHPC or a placebo at 16-20 weeks gestation until 37 weeks

Prior SPTB was defined as PTB due to PTL or PPROM resulting in delivery between 20 and 36 6/7 weeks gestation

Primary outcome: risk of spontaneous preterm birth prior to 37 weeks

NICHD-MFMU Trial on 17OHPC

Source: Meis PJ, Klebanoff M, Thom E, et al. Prevention of recurrent preterm delivery by

17 alpha-hydroxyprogesterone caproate. N Engl J Med 2003; 348:2379.

NICHD-MFMU Trial on 17OHPC:

Risk of Spontaneous Preterm Birth

Source(s): Meis PJ, Klebanoff M, Thom E, et al. Prevention of recurrent preterm delivery

by 17 alpha-hydroxyprogesterone caproate. N Engl J Med 2003; 348:2379.


Certain complications or events associated with pregnancy occurred more often in women who received 17 OHPC

compared to women who did not (but none reached statistical significance), including:

Miscarriage

Stillbirth

Hospital admission for preterm labor

Source(s): Meis PJ, Klebanoff M, Thom E, et al. Prevention of recurrent preterm delivery by


Observational data of 17OHPC in >5,400 women with a history of a prior spontaneous preterm birth demonstrated similar rates of PTB as in NICHD-treated group trial

Risk of SPTB < 37 weeks was 28.3%



17OHPC in Actual Clinical Practice

Source(s): Sibai BH, Istwan NB, Palmer B, Stanziano GJ. Pregnancy outcomes of women

receiving compounded 17 alpha-hydroxyprogesterone caproate for prophylactic prevention

of preterm birth 2004-2011. Am J Perinatol 2012; 29:635-642.

Meta-analyses of Progestogens

for Preventing Recurrent PTB

Meta-analyses of RCTs: decreased risk of PTB in women with a history of prior PTB treated with any progestogen during pregnancy

22% reduction in the risk of recurrent PTB with any form of progestogen

A significant reduction in risk of perinatal death of 42% (RR 0.58, interval 0.68-0.88)

Source(s): Likis FE, Velez Edwards DR, Andrews JC, et al. Progestogens for preterm birth

prevention: a systematic review and meta-analysis. Obstet Gynecol 2012;120:897-907.

Estimated Effect on US PTB Rate

In 2002, approximately 30,000 recurrent PTBs occurred

If 17OHPC were administered to all 30,000:

Nearly 10,000 SPTBs would have been prevented

The overall US preterm birth rate reduced from 12.1% to 11.8% (a 2% reduction)

U.S. annual net savings of $452 million for initial medical costs and $2 billion over the lifetime of affected infants

Source(s): 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;

105:267.

Bailit JL, Berkowitz R, Thorp JM, et al. Use of progesterone to prevent preterm birth in a tertiary

care center. Journal of Reproductive Medicine, 2007: 42(4); 280-84.

Optimal Timing and Duration of

Therapy

Initiation of treatment: between 16 0/7 and 20 6/7 weeks

But, 17OHPC still appears to be associated with a reduced risk of recurrent PTB if started as late as

17OHPC for prevention of

spontaneous preterm birth in

other high risk populations

17OHPC: NOT for Short Cervix

One trial evaluated 17OHPC in nulliparous women with cervical length < 30mm (650 patients).

Source(s): Grobman WA, Thom EA, Spong SY, Iams, JD, et al. 17 alpha-

hydroxyprogesterone caproate to prevent prematurity in nulliparas with cervical length less

than 30 mm. American Journal of Obstetrics and Gynecology, 2012: 207:390.e1-8.

Meis PJ, Klebanoff M, Thom E, et al. Prevention of recurrent preterm delivery by 17 alpha-

hydroxyprogesterone caproate. N Engl J Med 2003; 348:2379.

Source(s): Meis PJ, Klebanoff M, Thom E, et al. Prevention of recurrent preterm delivery by


17OHPC: NOT for Multiple

Gestations 7 RCTs have evaluated the effect of 17OHPC on risk of

PTB in multiple gestations

2012 meta-analysis of progestogens for the prevention of PTB in multiple gestations

No benefit for the prevention of spontaneous PTB < 35 weeks (RR 1.02; 95% CI 0.87-1.17)

No benefit for the prevention of neonatal mortality (RR 0.85; 95% CI 0.51-1.24)


prevention: a systematic review and meta-analysis. Obstetrics and Gynecology,

2012;120:897-907.

17OHPC for Treatment of

Arrested PTL?

Limited evidence has found an association between progestogen treatment and a lower risk of preterm birth and neonatal mortality.

Further research needed


prevention: a systematic review and meta-analysis. Obstetrics and Gynecology,

2012;120:897-907.

17OHPC for Treatment of PPROM

17OHPC has also been studied for prolonging gestation in women with PPROM.

A randomized controlled trial of 69 patients with PPROM found no benefit to 17OHPC in extending gestation when compared with the placebo.

NO BENEFIT

Source(s): Briery CM, Veillon EW, Klauser CK, et al. Progesterone does not prevent preterm

birth in women with twins. South Med J 2009;102:900-4.

Established safety for 17OHPC

in FDA Category B

Safety of 17OHPC in Pregnancy

7 observational studies examining total number of pregnancies

Newborns

No adverse effect

Multiple reviews and expert opinion have concluded no safety concerns

Summary

17OHPC reduces the risk of recurrent spontaneous preterm birth in women with a history of prior spontaneous singleton preterm birth, including PPROM and PTL.

Physicians should be able to prescribe 17 OHPC based on accepted medical indications after discussion with the patient.*

Current evidence does not support the use of 17OHPC for reducing the risk of preterm birth in other high risk populations.

* Source: ACOG & SMFM, Information update on 17 hydroxyprogesterone caproate from

The American College of Obstetricians and Gynecologists and The Society for Maternal-

Fetal Medicine. October 13, 2011

Summary

For women with arrested preterm labor, limited evidence has found an association between 17OHPC treatment and a lower risk of preterm birth and neonatal mortality. However, due to the small size of these trials, 17OHPC is not currently recommended for this indication.

17OHPC has not been associated with short-term or long-term adverse outcomes in offspring exposed to 17OHPC in utero.

Fetal Fibronectin & Cervical

Cerclage in Patients on 17OHPC

Peter S. Bernstein, MD, MPH, FACOG

Professor of Clinical Obstetrics & Gynecology & Womens Health

Albert Einstein College of Medicine / Montefiore Medical Center

Bronx, NY

ACOG Guidance

Methods not recommended as screening strategies

Fetal fibronectin

Bacterial vaginosis testing

Home uterine activity monitoring

Interventional studies based on use of these tests for screening asymptomatic women have not demonstrated improved perinatal outcome

Source: The American College of Obstetricians and Gynecologists. Prediction and Prevention

of Preterm Birth, Practice Bulletin #130, October 2012.

Asymptomatic Screening for

PTB with Biomarkers in Patients

Treated with 17OHPC17OHPC17OHPC17OHPC Retrospective Cohort (n=176 patients)

67 pts (38.1%) had a short CL (

What to do with patients on

17OHPC who develop a short

cervix?

Women with a prior spontaneous PTB and singleton gestation may be monitored safely with transvaginalultrasonographic cervical length measurements.

But what should we do with women with a history of PTB already on 17OHPC and who develop shortened cervical length? Consider cerclage? Continue 17OHPC? Switch to vaginal progesterone?

17OHPC and Women Who

Already Have a Cerclage

Retrospective cohort of singleton gestations with a history indicated cerclage and a prior SPTB +/- 17OHPC Treating with 17OHPC showed no difference in rates of

recurrent SPTD at

Cerclage for Women Already on

17OHPC

Prospective RCT of singleton gestation and CL < 25mm between 16-22 6/7 weeks evaluated the efficacy of cerclage (use of 17OHPC was at provider discretion) 148 were randomized to an Ultrasound Indicated

Cerclage UIC decreased SPTB the use of 17P had no effect on PTB

17OHPC with Cerclage

Limitations of these trials

Retrospective nature of some of the trials

Lack of randomization in the larger studies

Sample size is insufficient for a definite conclusions in the prospective trial

17OHPC and a Short Cervix:

Conclusions Patients with previous spontaneous PTB should be

offered 17OHPC starting at 16-20w.

Serial vaginal scanning for cervical length may identify patients receiving 17OHPC who have a short cervix.

A cerclage may be of benefit for those patients with a CL

Source(s): Iams, Identification of Candidates for Progesterone, Obstet Gynecol, 2014.

Conclusions

PROTOCOL FOR IN-OFFICE USE

OF 17OHPC

TO REDUCE PRETERM BIRTH

David L. Gandell, MD, FACOG

Clinical Professor of Obstetrics and Gynecology

Strong Memorial Hospital

University of Rochester

Rochester, NY



.

I have the following relationship with the

industry relative to the topic being discussed:

Speaker for Lumara Health

Hydroxyprogesterone

Caproate/17OHPC/Makena

Originally marketed as Delalutin 1956 - 1999

Only available to physicians as a compounded product from 2003-11

Preparation was used in 2003 Meis trial, not a compounded product, but met FDA criteria for quality

February 2011 Makena approved by the FDA

Makena vs. Compounded

17OHPC

Makena is the FDA-approved version of hydroxyprogesterone caproate

17OHPC is still available from some compounding pharmacies and has sometimes been prescribed due to cost or coverage issues

FDA 2012: Should healthcare practitioners

prescribe and patients take the FDA-

approved product rather than the

compounded product?

If there is an FDA-approved drug that is medically appropriate for a patient, the FDA-approved product should be prescribed and used

Makena was approved based on an affirmative showing of safety and efficacy

Compounded drugsQlack an FDA finding of manufacturing quality

Source: FDA, Questions & Answers, June 29, 2012.

Develop/Implement Protocols

Ordering

Medication storage

Administration

Coding/Billing

Patient education

Ordering/Billing Guidelines

Detailed guidelines available

Reimbursement is based on acquisition cost

Many insurers cover Makena and compounded 17OHPC covered

Specific J codes should be used

Compounded 17OHPC

Ordered from compounding pharmacies

Ordering process may vary

Preservative-free option may be a concern

Waiver form may be required

Medication Storage

Shelf life (longer for Makena than compounded product)

Be aware of expiration date

Store at room temperature no refrigeration needed

Do not use if cloudy or particulate

Protocol for Use

Office vs. home administration

Dealing with missed doses

Not particularly painful; analgesia can be used

Specific injection instructions:

- Clean vial top and administration site

- Draw up 1 ml (250mg), 18 G, 3cc syringe

- Give with 21 G needle

Possible side effects pain, swelling, itching

Helping Patients Understand

17OHPC17OHPC17OHPC17OHPC Identify patient candidates early in their care

Document patient counseling regarding preterm labor and:

While 17OHPC reduces the risk of preterm birth, it does not guarantee that the patient won't deliver preterm

Further research is being done to determine whether there is an increased risk of miscarriage, stillbirth, preeclampsia or other complications from 17OHPC

Treat preterm labor per routine

Web resources: www.acog.org

Summary

The use of hydroxyprogesterone caproate to reduce the risk of preterm birth in high risk patients is an important and valuable tool,

and following these suggestions should help make the process straightforward for

patients and their care givers.

progesteron efect at preterm

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