Early observations and pilot data that first suggested a new direction
Preterm birth (<37 weeks) is the leading cause of neonatal mortality and long-term disability worldwide. The biological rationale for progesterone supplementation is compelling: progesterone maintains uterine quiescence during pregnancy, and a functional progesterone withdrawal is implicated in the onset of labor. da Fonseca and colleagues published a seminal RCT in 2003 demonstrating that vaginal progesterone (100mg daily) in women with prior preterm birth reduced recurrent preterm delivery from 28.5% to 13.8%. This initial signal generated enormous enthusiasm for a simple, inexpensive intervention to address a devastating clinical problem.
Landmark RCTs and pivotal trials that established the evidence base
The Meis trial (2003) provided the pivotal US evidence for 17-alpha hydroxyprogesterone caproate (17-OHP, intramuscular). This NICHD-sponsored RCT randomized 463 women with prior spontaneous preterm birth to weekly 17-OHP injections or placebo from 16-20 weeks through 36 weeks. 17-OHP reduced recurrent preterm birth by 34% (36.3% to 20.6%), leading to FDA approval of the branded product (Makena). Simultaneously, the Fonseca 2007 trial demonstrated that vaginal progesterone reduced preterm birth in women with short cervix (≤15mm) on transvaginal ultrasound, introducing a screen-and-treat paradigm based on cervical length rather than obstetric history alone. The PREGNANT trial (Hassan 2011) confirmed vaginal progesterone benefit for women with short cervix (10-20mm), reducing preterm birth <33 weeks by 45%.
Follow-up studies, subgroup analyses, and real-world validation
The OPPTIMUM trial (2016), a large UK RCT of 1,228 women at high risk of preterm birth, found that vaginal progesterone (200mg daily) did not significantly reduce the primary composite outcome of fetal death, preterm birth <34 weeks, or neonatal morbidity. This negative result shook confidence in progesterone's universal efficacy. Subsequently, the FDA-mandated PROLONG trial (2019) studied 17-OHP in an international replication of the Meis trial and found no reduction in recurrent preterm birth (11.0% vs 11.3% placebo), leading to an FDA advisory committee vote recommending withdrawal of Makena from the market. The FDA withdrew approval of 17-OHP in 2023, marking a dramatic reversal for what had been considered a proven therapy. Meanwhile, individual patient data meta-analyses by Romero and colleagues consistently supported vaginal progesterone specifically for women with short cervix, maintaining the cervical length-guided paradigm.
Integration into clinical practice guidelines and recommendations
Following the PROLONG results and FDA withdrawal of 17-OHP, guidelines have shifted significantly. ACOG (updated 2023) no longer recommends 17-OHP for prevention of recurrent preterm birth and instead recommends vaginal progesterone for women with short cervix (≤25mm) on transvaginal ultrasound at 16-24 weeks, regardless of obstetric history. SMFM recommends universal cervical length screening at 18-24 weeks in singleton pregnancies, with vaginal progesterone for short cervix. NICE recommends vaginal progesterone or cervical cerclage for women with short cervix and history of preterm birth. The paradigm has shifted from history-based to cervical length-guided treatment.
ACOG
Vaginal progesterone recommended for women with short cervix (≤25mm) on transvaginal ultrasound at 16-24 weeks; 17-OHP no longer recommended following PROLONG trial and FDA withdrawal
SMFM
Universal transvaginal cervical length screening at 18-24 weeks in singleton pregnancies; vaginal progesterone for cervical length ≤25mm
NICE
Offer vaginal progesterone or cervical cerclage to women with short cervix (<25mm) at 16-24 weeks and history of spontaneous preterm birth or mid-trimester loss
Now
Current standard of care and ongoing research directions
The progesterone for preterm birth story illustrates both the promise and complexity of reproductive pharmacology. After 17-OHP's dramatic rise and fall, the evidence now supports a cervical length-guided approach using vaginal progesterone. Universal transvaginal cervical length screening is increasingly recommended but not yet universally implemented due to cost and access barriers. For women with prior preterm birth and short cervix, a combination of vaginal progesterone and cervical cerclage may be considered. Research continues into other preventive strategies including cervical pessary (mixed results from PECEP, ProTwin, and C-STICH trials), omega-3 fatty acids, and personalized risk assessment using combinations of biomarkers, cervical length, and clinical history. The field is evolving toward precision prevention that targets the specific pathophysiological pathway driving each individual's preterm birth risk.
Why was Makena (17-OHP) withdrawn from the market?+
Makena was approved based on the Meis 2003 trial showing 34% reduction in recurrent preterm birth. However, the FDA-mandated PROLONG confirmatory trial (1,708 women, international) found no reduction in preterm birth with 17-OHP versus placebo. After lengthy proceedings, the FDA withdrew approval in 2023. The discrepancy between trials may relate to differences in populations, baseline risk, or the original trial being a false positive. This case highlights the importance of confirmatory trials before widespread adoption.
Does vaginal progesterone work for all women at risk of preterm birth?+
No. The strongest evidence supports vaginal progesterone specifically for women with a short cervix (≤25mm) on transvaginal ultrasound, regardless of obstetric history. Individual patient data meta-analyses show approximately 34% reduction in preterm birth <33 weeks in this group. Vaginal progesterone has not shown benefit for women with multiple gestations or for preterm birth prevention based solely on obstetric history without cervical shortening.
Should all pregnant women be screened with transvaginal cervical length measurement?+
SMFM recommends universal cervical length screening at 18-24 weeks in singleton pregnancies, as it identifies women who would benefit from vaginal progesterone. However, universal screening is not yet standard in all countries due to cost, access, and the need for trained sonographers. ACOG acknowledges cervical length screening as reasonable but has not yet mandated it as universal. Cost-effectiveness analyses generally support screening in populations with higher baseline preterm birth rates.
