Progesteron Efect at preterm
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Transcript of Progesteron Efect at preterm
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17OHPC:
An Opportunity to Prevent
Preterm Birth
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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
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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.
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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 (
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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.
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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
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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
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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
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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 (
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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 (
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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
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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
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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.
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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
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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.
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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
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17OHPC for prevention of
recurrent spontaneous preterm
birth in women with a prior
spontaneous singleton
preterm birth
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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.
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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.
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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.
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NICHD-MFMU Trial on 17OHPC
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NICHD-MFMU Trial on 17OHPC
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
17 alpha-hydroxyprogesterone caproate. N Engl J Med 2003; 348:2379.
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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%
Risk of SPTB < 35 weeks was 13.8%
Risk of SPTB < 32 weeks was 6.1%
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.
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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.
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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.
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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
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17OHPC for prevention of
spontaneous preterm birth in
other high risk populations
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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
17 alpha-hydroxyprogesterone caproate. N Engl J Med 2003; 348:2379.
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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)
Source(s): Likis FE, Velez Edwards DR, Andrews JC, et al. Progestogens for preterm birth
prevention: a systematic review and meta-analysis. Obstetrics and Gynecology,
2012;120:897-907.
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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
Source(s): Likis FE, Velez Edwards DR, Andrews JC, et al. Progestogens for preterm birth
prevention: a systematic review and meta-analysis. Obstetrics and Gynecology,
2012;120:897-907.
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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.
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Established safety for 17OHPC
in FDA Category B
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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
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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
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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.
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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
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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.
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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.
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Asymptomatic Screening for
PTB with Biomarkers in Patients
Treated with 17OHPC17OHPC17OHPC17OHPC Retrospective Cohort (n=176 patients)
67 pts (38.1%) had a short CL (
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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?
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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
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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
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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
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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
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Source(s): Iams, Identification of Candidates for Progesterone, Obstet Gynecol, 2014.
Conclusions
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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
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CONFLICT OF INTEREST
DISCLOSURE STATEMENT
.
I have the following relationship with the
industry relative to the topic being discussed:
Speaker for Lumara Health
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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
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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
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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.
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Develop/Implement Protocols
Ordering
Medication storage
Administration
Coding/Billing
Patient education
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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
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Compounded 17OHPC
Ordered from compounding pharmacies
Ordering process may vary
Preservative-free option may be a concern
Waiver form may be required
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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
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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
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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
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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.