The Pros (and Cons) of Progesterone

An overview (& friendly debate) on the use of 17OHP

for prevention of preterm birthin at-risk pregnant women.

M. Sean Esplin, MD Brett D. Einerson, MD

Wait… …I thought there was clear guidance.

“A woman with a singleton gestation and a prior spontaneous preterm singleton birth

should be offered progesterone supplementation starting at 16–24 weeks of gestation

to reduce the risk of recurrent spontaneous preterm birth”

-ACOG Practice Bulletin No 130 (reaffirmed 2018)

https://www.npr.org/sections/health-shots/2020/01/24/798731110/drug-to-prevent-premature-birth-divides-doctors-insurers-and-fda-experts

Oct 29, 2019An advisory committee votes 9-7 to recommend that the FDA withdraw Makena (17-OHP) from the market.

"Now it is clear [17OHP] is not effective.”

--Cathryn Donaldson a spokesperson for America's Health Insurance Plans

In 2020

How did we get here?

What is the latest evidence?

What is the right thing for my patients?

OutlineTHE PROBLEM AND THE HISTORY

THE NEWEST DATA

THE DEBATESPro: Sean Esplin, MDCon: Brett Einerson, MD

REASONABLE APPROACHES FOR PRACTICE

ObjectivesTHE PROBLEM AND THE HISTORY• Describe the importance of preterm birth prevention.• Understand the rationale for 17OHP treatment guidelines.THE NEWEST DATA• Describe the key findings of the PROLONG Trial and

responses by the FDA, ACOG, and SMFM.THE DEBATES• Understand arguments for and against the ongoing use of

17OHPREASONABLE APPROACHES• Decide on a reasonable approach for your practice.

Definitions for this presentation

• Preterm birth / PTB: birth at less than 37 weeks

• 17P / 17OHP / 17OHPC / ”progesterone” / Makena: intramuscular injection of 17α-hydroxyprogesterone caproate

THE PROBLEM& THE HISTORY

The Problem(things you know)

•Preterm birth is common

•Preterm birth is morbid

•Preterm birth is inequitable

•Preterm birth is costly

•Preterm birth is difficult to prevent

The QuestionCould progesterone supplementation help?

Why Would Progesterone Work?

•Progesterone decreases the inflammatory response

•Potent smooth muscle relaxant• Blocks the effect of prostaglandin-F2α and oxytocin

•Some suggest there is a decrease in the progesterone to estrogen ratio at time of delivery

Actions of Progesterone on the Myometrium

•Decreases conduction of contractions• Increases threshold for stimulation•Decreases spontaneous activity•Decreases number of oxytocin receptors

•Prevents formation of gap junctions

Confusion About Progesterone

•Does not work on all patients• Only prevents one third of recurrent SPTB

•Not all studies demonstrate benefit• Indication creep – who is really a candidate

• Twins• History of PPROM, Abruption, twin SPTB

•Multiple options for treatment• Vag P versus 17 OHCP

•Optimal timing for treatment

ProgesteroneThe new (old) option

• Meta-analysis (1990) 7 randomized controlled trials (1964-1985)

• Only 17 alpha Hydroxyprogesterone caproate (17 OHPC)• Women enrolled for either risk of recurrent SAB or previous

PTB

Keirse MJ. BJOG 1990 Feb;97(2):149

ProgesteroneThe new (old) option

• Meta-analysis (1990) 7 randomized controlled trials (1964-1985)

• Reduction in rates of preterm birth. Odds ratio was 0.50, 95% CI: 0.30-0.85

• Reduction in rates of low birthweight, Odds ratio was 0.46, 95% CI: 0.27-0.80

• No difference in neonatal morbidity and mortality

Keirse MJ. BJOG 1990 Feb;97(2):149

Meis Trial 2003• Prospective, placebo-controlled, multicenter trial

to test the effectiveness of 17P as compared with placebo in the prevention of recurrent preterm delivery

• 9/1999 to 2/2002• 19 participating centers• Randomized to weekly injections in 2:1 ratio

• 250 mg 17 P• Placebo

• Primary Outcome• Preterm delivery before 37 weeks of gestation

Meis Trial 2003• Inclusion criteria

• a history of spontaneous preterm delivery < 37 weeks• current pregnancy between 15 weeks and 20 weeks 3

days • Exclusion criteria

• Multifetal gestation• Known fetal anomaly • Progesterone or heparin treatment during the current

pregnancy• Current or planned cervical cerclage • Hypertension requiring medication • Seizure disorder

Progesterone Therapy• Meta-analysis of randomized trials

• 7 trials of 17OHP to prevent recurrent PTB• Use 17 OHP 250 mg im weekly beginning at 16-20 weeks• Risk for PTB < 37 wks - 1020 women enrolled

• RR = 0.58, 95% CI = 0.48-0.70• Risk for infant with birth weight of < or =2.5 kg - 872 infants

• RR = 0.62, 95% CI = 0.49-0.78• Risk of an infant diagnosed with intraventricular

hemorrhage -458 infants • RR = 0.25, 95% CI = 0.08-0.82

Dodd JM Cochrane Database Syst Rev 2006:1

Timeline2003Meis (MFMU) trial stopped early for huge benefit

2008 ACOG/SMFM jointly endorse progesterone

2011U.S. FDA grants conditional approval

2016-nowBranded Makena gains market dominance over compounded 17OHP

2011• FDA “Accelerated approval” for Makena

(based on Meis)

• Indication: To reduce PTB in women with singleton who have a history of sPTB

• Dose: 250 mg once per weekbeginning 16w0d – 20w6duntil 37w or birth

• Approval provisional until confirmatory trial complete

THE NEWESTDATA

“The Confirmatory Trial”

Progestin’s Role in Optimizing Neonatal Gestation (PROLONG)

PROLONG (2019)Question(s):Does 17P reduce recurrent PTB and neonatal morbidity(and not increase fetal/infant death) in women with a prior spontaneous PTB with a singleton?

Design:International, multicenter RCT2:1 ratio 17P vs placeboIndustry sponsored

Primary Outcomes:PTB <35 wkNeonatal Composite*

*neonatal death, gr 3 or 4 IVH, RDS, BPD, necrotizing enterocolitis, sepsis

PROLONG

11.0%

5.6%

11.5%

5.0%

PTB <35w0d Neonatal composite

17OHP Placebo

RR: 0.95 (95% CI 0.71 – 1.26) RR: 1.12 (95% CI 0.68 – 1.61)

PROLONG…did not ”confirm” the benefit of 17OHP.

…was hampered by low event rates.

…is difficult to harmonize with current practice.

PROLONGFDA response

Expert Advisory Panel to FDA

Vote 13-3:There is not “substantial evidence of effectiveness of Makena in reducing the risk” of recurrent PTB

Vote 9-7: Recommend* that FDA withdraw provisional approval of Makena

*Non-binding

PROLONGACOG response

“not changing our recommendations at this time”

“we will continue to monitor this topic,evaluate additional literatureand any further analyses…”

“…will issue updated clinical guidanceas appropriate”

Practice Advisory. Oct 25, 2019ACOG Statement on 17OHP. Oct 25, 2019

PROLONGSMFM response

“differences in the study populationsmay partially explain the differences in response”

“SMFM believes that it is reasonablefor providers to use 17-OHPC in women [more similar to] the Meis trial”

“…shared decision making…”

SMFM Statement. Oct 25, 2019

THE DEBATES

Debate Q1

Q1. Which trial is more pertinent to my practice?

Q1. ResponsePro

The U.S. trial is more pertinent to U.S. practice.

Meis et al (2003): Still the largest U.S. trial

Meis 310 US women got 17OHPPROLONG 256 US women got 17OHP

PROLONG

Meta-analysis of US women likely to show benefit

Q1. ResponseCon

PROLONG is just as pertinent to the U.S.

Meis vs “U.S.” PROLONG•Nearly identical protocols•Nearly identical inclusion criteria•Nearly identical enrollment numbers

“U.S.” PROLONGMore pertinent than Meis?

• More modernenrollment end date 2018 (vs 2002)

• More representative of ‘real’ U.S practiceIdaho Falls – Tacoma – Louisville – Racine – Etc.(vs Ivory Tower)

Another big U.S. studyNelson et al. AJOG 2017Pre-post comparison of 17OHP useSetting: multi-cultural DallasEligible if prior PTB <35wk

16.8%

25.0%

PTB <35 weeks

Pre 17OHP(before 2012)17OHP(2012-2016)

No 17PN=430

17P

Q1(b). ResponsePro

The PROLONG study population was too low-risk

by comparison

SMFM: “substantial differences in the populations studied likely account for the different baseline rates of recurrent PTB and potentially explain some of the contrasting results”

Different Risk

5.2%11.5%

21.9%19.6%

30.7%

54.9%

PTB <32 PTB <35 PTB <37

PROLONG (Placebo)Meis (Placebo)

Different Patients

PROLONG MeisCaucasian / White 87% 24%African Am. / Black 7% 59%>1 prior PTB 13% 32%Body mass index (BMI) 23 26Education (yrs) 13 11Smoking 8% 20%

Q1(b). ResponseCon

The PROLONG study represents moderate-risk

women

PROLONG was not “low risk”SMFM: “population differences do not completely explain the discrepancy in PTB”• Inclusion and exclusions criteria almost identical• All had h/o prior PTB• Still a lot of PTB

in the U.S. group33.2%

28.2%

36.3%

54.9%

PTB <37 17OHP PTB <37 Placebo

PROLONG (U.S.)Meis

Debate Question 2

Q2. For whom should 17OHP be indicated?

Q2. ResponseCon

We don’t know which patients benefit from 17P,

so restrict use to those at highest risk.

Pay attention to the population

• Which study’s population looks most like yours?

• Use 17OHP in those with additional risk factors (besides history of preterm birth)

PROLONG MeisCaucasian / White 87% 24%African Am. / Black 7% 59%>1 prior PTB 13% 32%Body mass index (BMI) 23 26Education (yrs) 13 11Smoking 8% 20%

A proposal for 17OHP• Patient like PROLONG?

“Moderate risk”“May not benefit” Shared decisions making No strong recommendation

• Patient like Meis trial?“High risk”“Likely to benefit” Shared decision making Recommend 17OHP

Q2. ResponsePro

We don’t know which patients benefit from 17P,

so continue to use until we know!

PROLONG underpowered• Lower-than-expected event rates may explain the

“lack of benefit”

• But there still appears to be benefit in the U.S. subset

• Restricting accessbecause of uncertaintyis unwise

Risk Stratification is Hard• Not particularly data-driven (at least yet)

Detailed sub- and meta-analyses needed

• Controversial implicationsRestrict access to women based on race?

• History can be unreliable / oddWhen was your PTB? “At 6 months.”“I had 2 term births with a 33wk PPROM in between”

• High risk groups may respond differently to 17PManuck et al. Nonresponse to 17P. AJOG 2016

Debate Question 3

Q3. The benefit of 17OHP has been challenged, is there any harm?

Q3. ResponseCon

If no benefit, then any hint of harm is unacceptable.

Potential harmsNo harms have been proven, but note:

• Fetal death / stillbirth ?• Meis: 2% vs 1.3% (RR 1.5, 95% CI 0.3 – 7.3)• PROLONG: 1% vs 0.5% (RR 2.07, 95% CI 0.59 – 7.29)

• Gestational diabetes ?• Nelson: 13.4% vs 8% (p=0.001)

Safety of 17OHPSMFM:“appears to be safe, at least in the short term…”

FDA required a long-term infant follow up.

That study is ongoing.

Q3. ResponsePro

RCTs show no harm.

PROLONGNo harm with 17OHP

17OHP PlaceboComposite neonatal 5.6% 5.0%Neonatal death 0.5% 0.5%Sepsis 0.5% 0.5%Fetal / early infant death 1.7% 1.9%Miscarriage 0.5% 1.3%

GDM 3.1% 3.6%Preeclampsia 4.2% 5.2%Cesarean delivery 25.8% 24.2%

There were no statistical differences in other secondary maternal or neonatal outcomes in PROLONG

Safety of 17OHPSMFM:“appears to be safe, at least in the short term…”

See what the infant follow-up study shows

”Trend toward” harm is not harm

Debate Question 4

Q4. What about the cost?

Q4. ResponseCon

17P is expensive in the U.S. Substantial benefit should be

proven.

Cost per pregnancy

$204

$10,917

Fried et al. JAMA Int Med 2017;117:1689

Cost-Effectiveness in Question

Past cost-effectiveness analyses* are flawed• Underestimated costs of 17OHP• Overestimated benefits

*Odibo. 2006 Obstet Gynecol.; Bailit JL. AJOG 2007.

There’s a problem…

There is no

cost-effectiveness

without proven effectiveness

The insurers may decide…• In the United States, insurers make many cost-

effectiveness decisions…

• Remember:

"Now it is clear [17OHP] is not effective.”

--Cathryn Donaldson a spokesperson for America's Health Insurance Plans

Q4. ResponsePro

17P is cost-effective in the U.S.(PTB is expensive)

17OHP is Cost EffectiveIn multiple studies,across wide-ranges explored in sensitivity analyses,even assuming conservative and realisticestimates of cost savings and benefit…

17OHP likely saves money(~2 billion annually)

…why?

Bailet AJOG 2007; Odibo Obstet Gynecol 2006; Armstrong AJOG 2007

Preterm birth is expensivePrice tag for prematurity in the U.S. $26 billion*

$16.9 billion Newborn medical care$1.9 billion Maternal medical care

$611 million Early intervention services$1.1 billion Special education services$5.7 billion Lost work and pay

*in 2007, according to the IOM

REASONABLE APPROACHES

Reasonable Approaches 17OHP for Your Practice in 20201. Stay the course, for now…

2. Recommend 17OHP for your “Meistrial profile” patients

3. Recommend 17OHP for patients at highest risk

The debate reminds us…•Be wary of dogma

•Be flexible when new data emerge

•Practice shared decision making

•Medicine is still an art