The Meis Trial (Progesterone for Preterm Birth, Part I)

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One of the hottest controversies in OB in the last several years has been about the role of progesterone for treating preterm birth. We covered these trials very briefly in our episode on preterm birth prevention. Today, let’s dive deeper and start with part I - talking through the Meis Trial.

Next week, we’ll talk in depth about the PROLONG trial and some takeaways for your practice.

Background: 

  • Titles 

    • The Meis Trial - Prevention of Recurrent Preterm Delivery by 17 Alpha-Hydroxyprogesterone Caproate 

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

  • Who wrote the papers and where were they published? 

    • Meis: Dr. Paul Meis!  - Done with the NICHHD as part of the MFMU 

      • Published in the NEJM! Very fancy - published 2003 

    • PROLONG: Done by Dr. Sean Blackwell (was a president of SMFM!) and a bunch of people who are active in SMFM like Dr. Cynthia Gyamfi-Bannerman, Dr. Brenna Hughes, Dr. Judette Louis 

      • Published in American Journal Perinatology in 2020; which is a good journal but… nowhere near the impact factor of NEJM lol 

  • Who funded the studies? 

    • Meis: NICHD

    • PROLONG: AMAG Pharmaceuticals (those that make Makena) 

  • Why were the studies done? 

    • The initial study (Meis) was done to try and decrease preterm delivery (leading cause of infant mortality and morbidity in the US!). There had been small trials with prophylactic treatment with progestational compounds that had shown promise, but not all of them had positive results 

      • Had been a meta-analysis restricted to 17-OHP that showed a reduction in preterm delivery 

    • The second study was done after the first study was stopped early because it was thought to be unethical to continue recruitment given the robustness of evidence (spoilers, sorry) 

      • The FDA granted conditional approval for 17-OHP for commercial use in 2011 under the provision that another well-conducted randomized controlled trial was done 

      • This was a confirmatory trial for 17-OHP, and the FDA also required a long-term infant follow-up study 

  • Question to answer: Does the use of weekly 17-OHP in pregnancy decrease the risk of preterm birth? 

The MEIS Trial

Methods

  • Done at 19 participating centers, primary USA based 

  • Eligibility criteria

    • History of spontaneous preterm delivery in previous pregnancy between 20w-36w6d 

    • Current pregnancy between 15w0d-20w3d gestation 

    • Ultrasound between 14w0d-20w6d to confirm duration of gestation and to identify any major fetal anomalies 

  • Exclusion criteria 

    • Multifetal gestation

    • Known fetal anomaly 

    • Progesterone or heparin treatment during current pregnancy 

    • Current or planned cerclage 

    • Hypertension requiring medication

    • Seizure disorder 

    • Plan to deliver somewhere other than the 19 participating center 

  • Intervention 

    • Patients that consented were randomized to either IM study drug (17 OHP) or castor oil (omg - need to talk about this after!)

      • Had to be given first dose between 16w0d-20w6d; if they did not return before 20w6d, could not participate

      •  Weekly injections until 36 weeks 

  • Outcomes 

    • Date of delivery, birth weight, neonatal course - to assess for preterm delivery!  

  • Statistics 

    • Power calculation: 

      • Estimated 37% of patients in placebo group would have a preterm delivery 

      • Sample size calculation of 500 women, with 334 in progesterone group and 166 in placebo to find a reduction of 33% in rate of preterm delivery 

    • At second interim analysis, when 463 patients had undergone randomization, outcome data was available for 351 patients

      • The boundary (p=0.015) for test of significance had been crossed for preterm delivery, and enrollment was halted 

Results

  • Timeline: 

    • Started in April 1998, but ultimately stopped in February 1999 because the FDA ordered the company that supplied to the active drug to shut down and mandated a total recall of the company’s drugs because of poor quality control and documentation 

      • 150 patients had been enrolled 

    • The study was then restarted with a new drug company. The 150 women previously with other med were not included in the study data analyses 

    • New Timeline: 

      • September 1999 - February 2002 

  • Patient Demographics 

    • 1039 eligible, 463 eligible women gave their consent  

      • 310 in progesterone group 

      • 153 in placebo group 

    • Patients were similar in mean duration of previous gestational age (that qualified them for the study), mean gestational age at time of randomization, race, marital status, BMI, smoking, education level, etc. 

      • Of note, interestingly, approximately 60% of those in the study identified as non-Hispanic black (compare to PROLONG, which has very different demographics) 

      • Prepregnancy BMI 26 

    • But, women in the placebo group had more previous preterm deliveries (1.6 vs. 1.4, p=0.007) 

    • 91.5% of women were compliant with their injections (meaning they didn’t go more than 10 days without an injection) 

    • 50% reported at least one adverse effect 

      • Most common: 34.2% reported soreness at sight of injection; 14% reported swelling, 11% itching, 6.7% bruising 

      • More women with progesterone had swelling or a lump at injection sight 

  • Primary outcome 

    • Preterm delivery

      • Data was available for 459/463 women

      • Delivery before 37 weeks was reduced, 36.3% for 17-OHP group, 54.9% for placebo group (wtf, that’s super high) RR 0.66, 95% CI 0.54-0.81 

        • Spontaneous PTL was 29.4% vs. 45.1% respectively 

      • Findings were similar for black vs nonblack women 

      • Even more interesting, significant for delivery before 35 and 32 weeks gestation

        • Delivery before 35 weeks: 20.6% vs. 30.7%, RR 0.67, 95% CI 0.48-0.93 

        • Delivery before 32 weeks: 11.4% vs 19.6%, RR 0.58, 95% CI 0.37-0.91

    • Other things were not different: hospital visit for PTL, tocolytic therapy, corticosteroid use, CS, chorio 

  • Secondary outcome 

    • Fetal and neonatal outcomes 

      • No difference in fetal death, antepartum or intrapartum 

      • There was a significant difference in birthweight

        • <2500g was 27.2% vs. 41.1%, RR 0.66 (95% CI 0.51-0.87)  

      • Also difference in supplemental oxygen use (14.9% in 17OHP vs. 23.8% in placebo) 

      • And lastly, difference in IVH (1.3% vs 5.2%) 

    • No difference in neonatal death, TTN, RDS, bronchopulmonary dysplasia, vent support, NEC, retinopathy, etc. 

Conclusions 

  • Authors concluded: treatment with 17OHP weekly from 16-20 weeks to 36 weeks of gestation reduced preterm delivery at 37, 35, and 32 weeks in patients with history of sPTB

    • But … they also did say that there was an overall very high rate of preterm delivery (50% in placebo vs. 36% for 17OHP)

    • Next week, we’ll contrast with PROLONG!