What is a suitable research title for evaluating the effectiveness of progesterone therapy in preventing preterm birth in high-risk pregnancies?

Research Title Suggestions for Progesterone Therapy in Preterm Birth Prevention

Based on the current evidence landscape and gaps in knowledge, here are evidence-based research title suggestions for an Obstetrician-Gynecologist:

High-Priority Research Areas

For Singleton Pregnancies with Short Cervix

"Comparative Effectiveness of Vaginal Progesterone versus 17-OHPC in Singleton Pregnancies with Mid-Trimester Short Cervical Length: A Randomized Controlled Trial"

• This addresses a critical gap since both formulations show efficacy in singleton gestations with short cervix (≤20-25 mm), but head-to-head comparisons are limited 1, 2, 3
• The EPPPIC meta-analysis demonstrated that vaginal progesterone reduced preterm birth before 34 weeks (RR 0.78) in high-risk singletons, while 17-OHPC showed similar trends (RR 0.83), but direct comparison data is lacking 3

Long-Term Childhood Outcomes

"Neurodevelopmental and Cognitive Outcomes at 5 Years in Children Exposed to Antenatal Vaginal Progesterone: A Prospective Cohort Study"

• Current guidelines acknowledge that long-term effects on child development are not well-established, with limited follow-up data 2
• This represents a significant knowledge gap given widespread progesterone use 1, 3

Twin Gestations with Short Cervix

"Vaginal Progesterone for Prevention of Preterm Birth in Twin Pregnancies with Short Cervical Length: A Multi-Center Randomized Controlled Trial"

• Evidence shows vaginal progesterone does not reduce preterm birth in unselected twin pregnancies (RR 1.01), but the subgroup with short cervix remains understudied 3, 4
• Current recommendations note this appears "promising" but requires further research 4

Alternative Research Directions

Combination Therapy

"Cervical Pessary Plus Vaginal Progesterone versus Progesterone Alone in Singleton Pregnancies with Cervical Length 15-25 mm: Impact on Neonatal Morbidity and Mortality"

• A 2022 trial showed no benefit of combination therapy on composite neonatal outcomes, but delivery before 34 weeks was reduced (aRR 0.66) 5
• This warrants investigation in more refined cervical length subgroups 5

Low-Risk Populations

"Universal Cervical Length Screening and Targeted Vaginal Progesterone in Low-Risk Nulliparous Women: A Cost-Effectiveness Analysis and Clinical Trial"

• Universal screening remains controversial and cannot be universally mandated per ACOG 1, 2
• One low-risk population study showed non-significant trends but was underpowered (only 80 participants) 6
• Cost-effectiveness modeling suggested universal screening could prevent 95,920 preterm births annually in the US and save $13 billion 1

Post-Market Surveillance

"Clinical Outcomes Following 17-OHPC Market Withdrawal: Real-World Evidence of Alternative Progesterone Strategies in Women with Prior Spontaneous Preterm Birth"

• 17-OHPC was recently removed from the market, creating an urgent clinical gap 7
• This was previously the first-line treatment for women with singleton pregnancies and prior spontaneous preterm birth 7, 2
• Comparative effectiveness of vaginal progesterone as the replacement strategy needs documentation 2

Assisted Reproductive Technology

"Vaginal Progesterone for Preterm Birth Prevention in Singleton Pregnancies Conceived by In Vitro Fertilization: A Randomized Controlled Trial"

• Current evidence suggests VP "appears promising" in ART-conceived pregnancies but further research is explicitly needed 4

Methodological Considerations

Each proposed study should prioritize:

• Composite neonatal morbidity and mortality as primary outcomes (not just preterm birth rates) 3, 5
• Adequate power calculations based on EPPPIC meta-analysis effect sizes 3
• Long-term childhood follow-up protocols 2, 8
• Maternal safety outcomes given uncertain signals about potential complications 3