EPPPIC Meta-analysis Results: Progestogens for Preterm Birth Prevention

PURPOSE:

• The EPPPIC group (Lancet, 2021) report on their systematic review of RCTs comparing vaginal progesterone, intramuscular 17-hydroxyprogesterone caproate (17-OHPC), or oral progesterone for prevention of preterm birth

METHODS:

• Systematic review and meta-analysis
  • Funded by Patient-Centered Outcomes Research Institute (PCORI)
  • Evaluating Progestogens for Preventing Preterm birth International Collaborative (EPPPIC)
• Study selection
  • Published and unpublished RCTs
  • Trials that assessed vaginal progesterone, IM 17-OHPC or oral progesterone with control, or with each other
  • Participants: Asymptomatic women at risk of preterm birth
  • Individual participant data were requested from investigators of eligible trials
  • Primary data collection before July 30, 2016, (12 months before data collection began), and July 30, 2019
  • Exclusion: Trials of progestogen to prevent early miscarriage or immediatelythreatened preterm birth
• Outcomes
  • Preterm birth | Early preterm birth | Mid-trimester birth
  • Adverse neonatal sequelae (composite of serious neonatal complications and individually)
  • Adverse maternal outcomes were investigated as a composite and individually

RESULTS:

• Individual participant data available for 31 trials | 11,644 women and 16,185 offspring

Singleton

• Risk factors and indications for treatment
  • Previous spontaneous preterm birth
  • Short cervix (≤25 mm)
• Preterm birth <34 weeks was reduced in women receiving progestogen
  • Vaginal progesterone: Relative risk (RR) 0.78 (95% CI, 0.68 to 0.90; 9 trials)
  • 17-OHPC: RR 0.83 (95% CI, 0.68 to 1.01; 5 trials)
  • Oral progesterone: RR 0.60 (95% CI, 0.40 to 0.90; 2 trials)  
• Other outcomes “were consistently favourable, but less certain”
• Subpopulation analysis suggests benefit was greatest for those with short cervix

Multifetal Pregnancies

• Generally, no additional risk factors
• Preterm birth <34 was was not reduced in women receiving progestogen
  • Vaginal progesterone (twins): RR 1.10 (95% CI, 0.84 to 1.20; 8 trials)
  • 17-OHPC (twins or triplets): RR 1.04 (95% CI, 0.92 to 1.18; 8 trials)
• PPROM <34 weeks was higher with 17-OHPC
  • RR 1.59 (95% CI, 1.15 to 2.22
• Evidence for other outcomes (risks or benefits) was not seen for vaginal progesterone or 17-OHPC

CONCLUSION:

• Preterm birth <34 weeks was reduced with vaginal progesterone and 17-OHPC in high risk pregnancies
• Absolute risk reduction is greater for women with a short cervix
• Evidence in this study did not support use of oral progesterone or treatment for unselected multifetal pregnancy
• An editorial suggests
  • This current meta-analysis supports “the use of either 17-OHPC or vaginal progesterone to prolonged pregnancy, even with the inclusion of the negative findings from PROLONG”
  • There are other trials currently underway and therefore this study should be considered a ‘living’ meta-analysis
• The EPPPIC authors conclude

Evidence of benefit in reducing preterm birth before 34 weeks was more certain for vaginal progesterone, but there was no clear evidence that either vaginal progesterone or 17-OHPC was superior

A consistent direction of benefit was noted for other birth and neonatal outcomes, including preterm birth before 28 weeks, preterm birth before 37 weeks, perinatal mortality, and composite serious neonatal complications 

Response from SMFM and ACOG:

SMFM

• EPPPIC reinforces current SMFM guidelines
• Singleton pregnancy and a short cervix (<25 mm) without a history of a prior spontaneous preterm birth
  • Offer vaginal progesterone
• Singleton gestation and a history of prior spontaneous preterm birth between 20 weeks and 36w6d
  • SMFM recommends “consideration of the use of 17-OHPC”

ACOG

• ACOG notes that while 17-OHPC didn’t quite reach significance, the authors did not see a clear difference between route of administration, nor indication for treatment
• ACOG states

Patients with a singleton pregnancy and a prior spontaneous preterm birth should be offered progesterone supplementation (either vaginal or intramuscular) in the context of a shared-decision making process with the patient incorporating the available evidence and the patient’s preferences

With regard to multiple gestations, the Evaluating Progestogens for Preventing Preterm Birth International Collaborative (EPPPIC) findings support the current recommendation that progesterone supplementation is not indicated for the indication of multiple gestation alone as there is no evidence of benefit

Response from FDA:

• The FDA has responded to EPPPIC and has not altered the recommendation to withdraw approval from Makena
• The FDA states

The EPPPIC meta-analysis grouped together HPC trials of patients with differences in their risk profiles, including combining women with a prior PTB and those without a prior PTB, and women with and without a short cervix

Because of this grouping, the meta-analysis does not provide relevant information regarding Makena’s effectiveness for its approved use. CDER continues to conclude the available data have not shown Makena is effective for reducing morbidity or mortality in newborns or for the prevention of recurrent PTB in women with a prior spontaneous PTB 

Learn More – Primary Sources:

Evaluating Progestogens for Preventing Preterm birth International Collaborative (EPPPIC): meta-analysis of individual participant data from randomised controlled trials

Lancet Editorial: Role of progestogens in women at risk for spontaneous preterm birth: the final word?

SMFM Statement: Response to EPPPIC and considerations of the use of progestogens for the prevention of preterm birth

ACOG Clinical Guidance for the Integration of the Findings of the EPPPIC Meta-Analysis: Evaluating Progestogens for Preventing Preterm Birth International Collaborative

FDA: CDER perspective on recently published results of EPPPIC meta-analysis

FDA, SMFM and ACOG Respond to PROLONG Study Results: Does IM 17-OHPC Impact Preterm Delivery?

This entry has been updated with the latest FDA proposed decision and a summary of the review by Sibai et al. (Obstet Gynecol, 2020)

SUMMARY:

The authors of the PROLONG trial (Progestin’s Role in Optimizing Neonatal Gestation) reported on the use of 17α-hydroxyprogesterone caproate (17-OHPC) for the treatment of preterm birth (PTB)

In this study population, 250 mg 17-OHPC did not decrease recurrent PTB and was not associated with increased fetal/early infant death

On October 29, 2019, the FDA advisory committee recommended that the drug be withdrawn from the market (9 to 7 vote). On October 5, 2020, the Center for Drug Evaluation and Research (CDER) proposed that Makena be withdrawn from the market. The CDER proposal announcement further states

Makena and its approved generic equivalents will remain on the market until the manufacturers decide to remove the drugs or the FDA Commissioner mandates their removal

If AMAG Pharmaceuticals requests a hearing, the FDA Commissioner will determine whether to hold a public hearing and, following such hearing, decide whether to withdraw approval of Makena and its approved generic equivalents

In the interim, we recommend that health care professionals discuss Makena’s benefits, risks and uncertainties with their patients to decide whether to use Makena while a final decision is being made about the drug’s marketing status

We intend to hold a meeting with experts in obstetrics, neonatal care, and clinical trial design to discuss how to facilitate development of effective and safe therapies to treat preterm birth

Background to PROLONG Trial

• A previous study, on behalf of the NICHD, demonstrated success of IM 17-OHPC in preventing PTB (see ‘Learn More – Primary Sources)
  • Meis et al. (NEJM, 2003): 250 mg IM 17-OHPC reduced recurrent preterm birth (PTB) in women with a prior spontaneous PTB (SPTB)
    • Relative risk [RR] 0.66 (95% CI, 0.54–0.81)
• The current PROLONG study was a ‘confirmatory trial’, performed with FDA input as a requirement for the FDA accelerated approval pathway

PROLONG Methods

• Double-blind randomized controlled trial (RCT)
• Participants
  • ≥18 years
  • Singleton pregnancy
  • Currently 16w0d to 20w6d
  • Previous history of singleton SPTB (birth between 20w0d and 36w6d following preterm labor or PROM)
• Groups (IM injection 1 in upper outer quadrant of the gluteus maximus) weekly until delivery or 36 weeks
  • 17-OHPC (250 mg)
  • Placebo
• Stratified by
  • Study site
  • GA at randomization
• Primary outcomes
  • PTB < 35 weeks
  • Composite neonatal morbidity and mortality index

PROLONG Results

• PTB < 35w0d (p=0.72)
  • 17-OHPC: 11.0%
  • Placebo: 11.5%
  • Relative risk (RR) 0.95 (95% CI, 0.71–1.26)
• Neonatal composite index (p=0.73)
  • 17-OHPC 5.6%
  • Placebo 5.0%
  • RR 1.12 (95% CI, 0.70–1.66)
  • Note: No differences seen in any of the individual components that were part of the composite index

KEY POINTS:

SMFM Response

SMFM has responded to the PROLONG trial results and makes the following substantive points comparing current data to Meis et. al. study

• Difference in population when analyzing Meis et al., vs PROLONG
  • Higher rate of black women: 59% vs 7%
  • Smoking (tobacco): >20% vs 8%
  • >1 prior PTB: 32% vs 12%
  • Additional PTB risk factors aside from prior history: 91% vs 48%
• Difference in results may be a result of high vs average risk but “population differences do not completely explain the discrepancy” due to complexity of PTB
• Concerns related to 17-OHPC include
  • Healthcare costs
  • Injection-site pain
  • Additional patient visits
• Additional research required to (1) determine long-term maternal and neonatal side effects (2) “identify populations in which administration of 17-OHPC may provide needed benefit in the reduction of recurrent sPTB”
• SMFM states that

…it is reasonable for providers to use 17-OHPC in women with a profile more representative of the very high-risk population reported in the Meis trial. For all women at risk of recurrent sPTB, the risk/benefit discussion should incorporate a shared decision-making approach, taking into account the lack of short-term safety concerns but uncertainty regarding benefit

ACOG Response

ACOG has likewise responded to the PROLONG trial with a Practice Advisory | Guidance remains unchanged following the FDA decision

• Similar to SMFM, ACOG notes that while eligibility criteria were similar between the Meis trial and PROLONG, the populations are different and preterm birth rate in the current study is approximately 50% lower than the earlier study
• The study authors acknowledge that
  • PROLONG may be underpowered for the population under study
  • Selection bias may have played a role, as women at higher risk would not have agreed to possibility of receiving placebo
• Additional studies, including a meta-analysis, are planned
• ACOG Guidance (Practice Bulletin 130) states

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, regardless of transvaginal ultrasound cervical length, to reduce the risk of recurrent spontaneous preterm birth

• The Practice Advisory response to the PROLONG trial states that ACOG

is not changing our clinical recommendations at this time and continues to recommend offering hydroxyprogesterone caproate as outlined in Practice Bulletin # 130

Sibai et al. Obstet Gynecol, 2020

Meis Trial

• Well designed and conducted
• Highly statistically significant results
  • Prespecified criterion threshold of alpha=0.015 was met regarding benefit of 17-OHPC
  • Preterm birth <37 weeks: Relative risk (RR) 0.66 (95% CI, 0.54 to 0.81; P<.001)
  • Preterm births <35 weeks: RR 0.67 (95% CI, 0.48 to 0.93)
  • Preterm birth <32 weeks: RR 0.58 (95% CI, 0.37–0.91)
• Subgroup analysis: Number of prior preterm birth | Race | Marital status | Smoking or substance use
  • Confirmed generalizability

Prolong Trial

• Population studied was very different from that of the Meis trial (non-US)
• Trial is underpowered based on observed event rates
  • For 90% power, PROLONG required 3,600 women for preterm birth <35 weeks and 6,000 women for neonatal composite outcome
• PROLONG not powered for subgroup analysis, but Meis et al. did look at US subgroup and found that while not statistically significant
  • Direction and magnitude of effect <32 weeks and neonatal composite index were similar to the Meis trial

Authors’ Conclusion

We assert PROLONG was underpowered, based on substantially lower observed preterm birth rates than anticipated, and therefore was a false-negative study, rather than the Meis trial being a false-positive study

Careful assessment of these two trials is critical as removal of 17α-hydroxyprogesterone caproate from the U.S. marketplace may have substantial effects on public health

Learn More – Primary Sources:

17-OHPC to Prevent Recurrent Preterm Birth in Singleton Gestations (PROLONG Study): A Multicenter, International, Randomized Double-Blind Trial

Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. (NEJM, 2003)

SMFM Statement: Use of 17-alpha hydroxyprogesterone caproate for prevention of recurrent preterm birth

ACOG Practice Advisory: Clinical guidance for integration of the findings of the PROLONG study: Progestin’s Role in Optimizing Neonatal Gestation

ACOG Statement on FDA Proposal to Withdraw 17p Hydroxyprogesterone Caproate

ACOG Practice Bulletin 130: Prediction and Prevention of Preterm Birth

Meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee Meeting Announcement: MAKENA supplemental new drug application

FDA (October 2020): CDER proposes withdrawal of approval for Makena

Re-examining the Meis Trial for Evidence of False-Positive Results (Sibai et al. Obstetrics & Gynecology, 2020)

Does Use of Progestogen Prolong Labor in PPROM Pregnancies?

BACKGROUND AND PURPOSE: 

• Progestogen use appears to prolong pregnancy in women with previous spontaneous preterm birth and short cervical length 
• Quist-Nelson et al. (AJOG, 2018) sought to determine whether progestogen use in singleton pregnancies prolongs pregnancy after preterm prelabor rupture of membranes (PPROM)

METHODS: 

• Systematic review and meta-analysis  
  • Database search of RCTs 
  • Singleton gestations deliveries following PPROM  
• PPROM: Defined <37 weeks 
• Patients had received  
  • Progestogens (17 alpha-hydoxyprogesterone caproate or natural progesterone) 
  • Matched placebo or no treatment 
• Primary outcome:  Time from randomization until delivery (latency) 
• Secondary outcomes 
  • Preterm birth at <37, <34, <32, and <28 weeks | Mean gestational age at delivery | Mode of delivery | Endometritis, chorioamnionitis | Neonatal outcomes, such as birthweight, RDS, IVH etc.  
  • Outcomes stratified by progestogen and route of administration

RESULTS: 

• Six RCTs were included | Totaling 545 participants 
• Mean gestational age at time randomization 
  • 17-α hydroxyprogesterone caproate group: 26.9 weeks  
  • Control group: 27.3 weeks  
• 17-α Hydroxyprogesterone caproate administration was not found to prolong the latency period between randomization and delivery  
  • Mean difference, 0.11 days (95% CI, –3.30 to 3.53) 
• There were no differences in  
  • Mean gestational age at delivery 
  • Mode of delivery 
  • Maternal or neonatal outcomes 
• No difference in latency for those women who received rectal progesterone 
  • Mean difference, 4.00 days (95% CI, –0.72 to 8.72) 

CONCLUSION: 

• Progestogen administration was not found to prolong time to labor in pregnancies with PPROM

Learn More – Primary Sources: 

Progestogens in singleton gestations with preterm prelabor rupture of membranes: a systematic review and metaanalysis of randomized controlled trials

Cervical Cerclage – Professional Recommendations

CLINICAL ACTIONS:

ACOG defines cervical insufficiency as “the inability of the uterine cervix to retain a pregnancy in the absence of the signs and symptoms of clinical contractions, or labor, or both in the second trimester.” In addition, ACOG separates out indication for cerclage in to 3 categories

• History: ≥1 of the following
  • Second trimester pregnancy losses related to painless cervical dilation and no history of labor or abruption
  • Previous second trimester cerclage for painless cervical dilation
• Physical Examination: Also known as ‘physical examination–indicated cerclage’, ‘rescue cerclage’ and ’emergency cerclage’
  • Patient presents with painless second trimester cervical dilation
• Ultrasound: Cervical length shortening and history of preterm birth
  • Singleton pregnancy
  • Prior spontaneous preterm birth (<34 weeks)
  • Cervical length:  <25 mm (at <24 weeks)

SMFM states that cerclages are effective in woman based on the following indications:

• History indicated: 3 or more PTBs or second-trimester losses.
• Ultrasound indicated: ≥1 early PTB (defined as delivery between 17w to 33w6d), and cervical length (CL) <25 mm on transvaginal ultrasound (TVUS) before 24 weeks

Timing of Cerclage Placement

• History-indicated cerclage
  • Place between 12 and 14 weeks after confirmation of pregnancy viability
• Ultrasound or exam-indicated cerclage
  • May be placed prior to 23 weeks

Risk Factors

• Prior PTB
• Repeated cervical dilation
• Cervical procedures (including cone and LEEP)
• Cervical laceration
• Urogenital abnormalities

SYNOPSIS:

Clinically, cervical insufficiency is painless dilation and recurrent mid-trimester losses without signs of preterm labor (PTL), PPROM, or infection. Patient history may include superimposed symptoms (i.e. bleeding, pressure), therefore a judicious review of records is advised.  Those with a history of prior preterm birth can benefit from cervical length screening to appropriate guide selected patients for cerclage.

KEY POINTS:

Ultrasound Indicated Cerclage with Prior History of Preterm Birth or Second Trimester Losses (SMFM)

• CL surveillance
  • Begin at 16 weeks
  • Perform every 2 weeks
  • CL measurement 25-29 mm: Perform weekly
• Offer cerclage when
  • CL <25 mm prior to 23w0d weeks and
  • History of spontaneous PTB at 17w0d to 33w6d
• 17–alpha hydroxyprogesterone caproate (17-OHPC)
  • Note: Cerclage placement or presence should not alter recommendations
• Evidence from research studies
  • There is no difference in efficacy of McDonald versus Shirodkar techniques

Special Circumstances

• Diagnosis of cervical insufficiency is unclear
  • Consider close screening starting at 16 weeks in place of history indicated cerclage placement
• Very early losses
  • Consider beginning screening <16 weeks if there is a history of very early second trimester losses

‘Emergency’ Cerclage (Exam indicated)

• There is literature, including a meta-analysis (Obstet Gynecol, 2015), to support ’emergency’ or ‘rescue’ cerclage
  • Neonatal survival
    • Cerclage: 71% survival
    • No cerclage: 43% survival
    • Relative risk 1.65 (95% CI 1.19–2.28)
  • Prolongation of pregnancy
    • Mean difference: 33.98 days (95% CI, 17.88 to 50.08)
  • Authors note significant limitations including quality of data and only 1 RCT included

After clinical examination to rule out uterine activity, or intraamniotic infection, or both, physical examination-indicated cerclage placement (if technically feasible) in patients with singleton gestations who have cervical change of the internal os may be beneficial

SMFM Choosing Wisely Campaign

• SMFM recommends the following after cerclage placement
  • Do not perform serial cervical length measurements
  • There is no evidence that cervical length monitoring following a cerclage improves outcomes, despite cervical shortening being associated with increased risk for preterm birth

Learn More – Primary Sources:

SMFM: Cervical cerclage for the woman with prior adverse pregnancy outcome

ACOG Practice Bulletin 142: Cerclage for the Management of Cervical Insufficiency

Physical Examination–Indicated Cerclage: A Systematic Review and Meta-analysis