What is the role of hydroxyprogesterone (17-hydroxyprogesterone) in preventing preterm birth and its therapeutic use in conditions like congenital adrenal hyperplasia?

Hydroxyprogesterone Caproate: Clinical Applications and Current Status

Critical Update on Market Status

17-alpha hydroxyprogesterone caproate (17-OHPC) has been removed from the U.S. market, fundamentally changing preterm birth prevention strategies. 1

Historical Role in Preterm Birth Prevention

For Women with Prior Spontaneous Preterm Birth

Prior to market withdrawal, 17-OHPC 250 mg intramuscularly weekly from 16-20 weeks until 36 weeks was the standard of care for singleton pregnancies with prior spontaneous preterm birth between 20-36 6/7 weeks. 2, 3 This recommendation was based on:

• 34% reduction in recurrent preterm birth at <37 weeks (36.3% vs 54.9% with placebo) 3, 4
• 33% reduction at <35 weeks and 42% reduction at <32 weeks 3, 5, 4
• Significant improvements in neonatal outcomes including reduced necrotizing enterocolitis, intraventricular hemorrhage, and need for supplemental oxygen 3, 5, 4

The evidence supporting 17-OHPC came from a landmark randomized controlled trial of 463 women, which demonstrated consistent benefit across all gestational age thresholds and maternal races. 4 Long-term follow-up at 2-5 years showed no detrimental effects on child neurodevelopment. 5

For Women with Short Cervical Length (No Prior Preterm Birth)

17-OHPC was never indicated for women with short cervical length but no prior preterm birth. 2 For this population, vaginal progesterone (90-mg gel or 200-mg suppository daily) was and remains the appropriate intervention when cervical length is ≤20 mm at ≤24 weeks. 2, 6

Current Alternatives Following Market Withdrawal

Vaginal Progesterone as Alternative

Vaginal progesterone should NOT be considered an equivalent substitute for 17-OHPC in women with prior spontaneous preterm birth. 3 Multiple randomized trials demonstrate:

• No reduction in recurrent preterm birth with vaginal progesterone versus placebo in women with prior spontaneous preterm birth 3
• The O'Brien trial and OPPTIMUM study both confirmed lack of benefit 3

However, one smaller randomized trial (n=100) comparing 200 mg vaginal progesterone effervescent tablet daily versus 250 mg 17-OHPC weekly found similar preterm birth rates (20% vs 20.8%), suggesting vaginal progesterone may be a reasonable alternative in the absence of 17-OHPC. 7 This represents lower-quality evidence compared to the larger trials showing no benefit.

Current Recommendations by Clinical Scenario

For singleton pregnancies with prior spontaneous preterm birth (20-36 6/7 weeks):

• Given 17-OHPC withdrawal, vaginal progesterone may be considered as the only available option, though evidence is conflicting 3, 7
• If cervical length shortens to <25 mm at ≤24 weeks despite progesterone therapy, cervical cerclage should be offered 2

For singleton pregnancies without prior preterm birth but cervical length ≤20 mm at ≤24 weeks:

• Vaginal progesterone 90-mg gel or 200-mg suppository daily from diagnosis until 36 weeks remains the standard of care 2, 6
• This reduces preterm birth by 45% and composite neonatal morbidity/mortality by 43% 6

Populations Where Progesterone is NOT Effective

Do not use any form of progesterone for:

• Multiple gestations (twins, triplets) - no benefit regardless of prior preterm birth history or cervical length 2, 6
• Active preterm labor (tocolysis) - insufficient evidence of effectiveness 2, 6
• Preterm premature rupture of membranes (PPROM) - no demonstrated benefit 2, 6

Mechanism of Action

Progesterone maintains pregnancy through: 8

• Promotion of uterine quiescence
• Inhibition of pro-inflammatory cells
• Immunosuppressive action
• Anti-inflammatory effects counteracting processes leading to preterm birth 2

Non-Obstetric Uses

Hydroxyprogesterone has limited gynecologic applications:

• May be considered for menopausal symptom management in women with endometrial cancer history where estrogen is contraindicated 6

Key Clinical Pitfalls

• Never substitute vaginal progesterone for 17-OHPC based on strong guideline recommendations (though this is now moot given market withdrawal) 3
• Never use progesterone in multiple gestations - consistently shown to be ineffective 2, 6
• Never switch from progesterone to another formulation if cervical shortening develops - continue the same therapy and consider cerclage 2, 3
• Do not screen or treat women with normal cervical length and no prior preterm birth - no evidence of benefit 2