Oral Progesterone Indications in Pregnancy
Oral progesterone 400 mg daily can be used for preventing preterm birth in singleton pregnancies with short cervical length (≤20 mm at 18-24 weeks), though vaginal progesterone remains the preferred route due to stronger evidence. 1
Primary Indication: Short Cervical Length Without Prior Preterm Birth
For women with singleton pregnancies who have no history of prior spontaneous preterm birth but are found to have a cervical length ≤20 mm on transvaginal ultrasound at approximately 24 weeks, oral progesterone 400 mg daily represents an acceptable option, though the American College of Obstetricians and Gynecologists notes that vaginal administration (90-mg gel or 200-mg suppository daily) has more robust evidence for efficacy. 1, 2
Supporting Evidence for Oral Formulation
A randomized controlled trial of 212 women with prior spontaneous preterm birth demonstrated that oral micronized progesterone 100 mg every 6 hours (400 mg total daily) reduced the relative risk of spontaneous preterm delivery by 30% (RR 0.7,95% CI 0.54-0.92), with a number-needed-to-treat of only 5 to prevent one preterm birth. 3
Another trial of 150 high-risk women showed oral micronized progesterone 100 mg twice daily significantly reduced preterm birth rates (39.2% vs 59.5%, P=0.002) and improved neonatal outcomes including birth weight and NICU admissions. 4
Critical Distinction: NOT for Prior Spontaneous Preterm Birth
Women with a history of prior spontaneous preterm birth should receive 17-alpha-hydroxyprogesterone caproate (17P) 250 mg intramuscularly weekly—NOT oral progesterone—starting at 16-20 weeks and continuing until 36 weeks. 5, 2 This recommendation is based on the landmark Meis trial showing a 34% reduction in recurrent preterm birth with 17P. 5, 2 Vaginal progesterone and oral progesterone should not be substituted for 17P in this population, as direct comparison trials demonstrate 17P superiority. 5, 2
Populations Where Oral Progesterone Should NOT Be Used
The following clinical scenarios have no proven benefit from progesterone therapy of any formulation:
- Multiple gestations (twins, triplets) regardless of cervical length or prior history 5, 1, 2
- Active preterm labor with contractions 5, 1, 2
- Preterm premature rupture of membranes (PPROM) 5, 1, 2
- Singleton pregnancies without risk factors (no prior preterm birth and normal cervical length) 5, 2
Common Pitfall to Avoid
Do not use oral progesterone as primary prevention in women with prior spontaneous preterm birth—this population requires 17P intramuscularly, which is not interchangeable with oral or vaginal formulations. 1, 2 The Society for Maternal-Fetal Medicine explicitly recommends against substituting vaginal progesterone for 17P in women with prior spontaneous preterm birth, even if cervical length shortens during pregnancy. 5
Dosing and Duration
When oral progesterone is indicated, the typical regimen is 400 mg daily (given as 100 mg every 6 hours or 200 mg twice daily), starting from diagnosis of short cervical length and continuing until 34-37 weeks of gestation or delivery. 1, 6, 3, 4
Safety Profile
Oral progesterone is associated with mild maternal side effects including dizziness (29% vs 10% placebo), somnolence (42% vs 20%), and vaginal dryness (21% vs 9%), but these are generally well-tolerated. 3 Long-term follow-up studies show no adverse effects on child development, physical examination, or performance, and no short-term safety concerns have been identified in large trials. 1
The Cervical Length Screening Debate
While the American College of Obstetricians and Gynecologists acknowledges that universal cervical length screening in singleton pregnancies without prior preterm birth cannot yet be universally mandated, implementation of such screening can be viewed as reasonable and may be considered by individual practitioners following strict guidelines. 5 This is relevant because identifying short cervical length is the gateway to progesterone therapy in this population.