Special Feature

Progesterone and the Prevention of Preterm Labor

Abstract & Commentary

By John C. Hobbins, MD, Professor and Chief of Obstetrics, University of Colorado Health Sciences Center, Denver, is Associate Editor for OB/GYN Clinical Alert.

Dr. Hobbins reports no financial relationship to this field of study.

Progesterone in Patients With a History of Preterm Labor (PTL)

Years ago investigators attempted to use a form of progesterone—delalutin—to prevent PTL. However, since there was no real proof of its benefit, progesterone was relegated to the "been there, done that" bin for many years until the concept was resurrected in the seminal paper published in 2003 by Meis et al.1 In this collaborative, randomized study of 463 women, undertaken by the NICHD perinatal network, the investigators found that weekly intramuscular injections of 17 alpha-hydroxyprogesterone caproate (17P) diminished the rate of preterm birth (PTB) by 40%. This, and another study from Brazil in patients with a history of PTB showing similar results with vaginal progesterone, stimulated a flurry of new studies, each addressing the permutations of progesterone as a uterine quieting agent.

Progesterone in Patients With Short Cervical Length (CL)

Ever since Iams et al2 demonstrated the relationship between short CL and PTB, many papers have emerged showing that CL's, obtained by transvaginal ultrasound between 20 and 24 weeks, can give the clinician a reasonable idea of who is at the greatest risk for repeat PTB and, just as importantly, who is at the least risk. It was a logical next step for investigators to fold CL into their preterm treatment protocols as a criterion for entry. For example, in one recent randomized trial, Fonseca et al3 showed that patients with CL's < 1.6 cm who were given daily progesterone vaginal suppositories had a PTL rate (at < 33 weeks) of 19% vs 34% in those given placebos, which translated into a reduced risk of about 50%.

In another randomized study from Italy,4 the investigators found that daily administration of vaginal progesterone diminished the rate of incremental cervical shortening in patients initially admitted in preterm labor for tocolysis and later followed up with serial CL's.

The last two enlightening papers5,6 were published back-to-back in the October 2007 issue of Ultrasound Obstet Gynecol by a multinational group of investigators. Six hundred and fifty-nine (659) patients with a history of having had spontaneous PTL ending in delivery prior to 36 weeks were randomized to having daily progesterone gel inserted vaginally (332) or placebo (327), starting from 18 to 20 weeks. Using the endpoint of delivery prior to 33 weeks, there were no statistically significant differences in outcomes between the placebo group (11.3%) and the progesterone group (10%). However, the most interesting finding emerged from a secondary analysis of data from a subset of patients in the same study with CL of <2.8 cm. In this group of patients whose CLs were performed at the time of entry, there was a significant difference in PTB before 33 weeks (0% in the progesterone group and 29.6 % in the placebo group). This would suggest that CL is a more powerful predictor of PTB, and a much better indicator of whom to treat with progesterone (than using history alone).

Commentary

Many years ago, it was noted that progesterone-primed in vitro uterine muscle would not contract when subjected to electrical stimulation. Also, based on earlier studies in the sheep model demonstrating a drop in progesterone levels prior to labor, the concept of a "progesterone block" emerged in which progesterone was cast in the role of protector against preterm labor. Unfortunately, there had to be more to the story since, later, progesterone levels were not found to be decreased prior to labor in humans. However, corticotropin-releasing hormone (CRH) was noted to be elevated in pre-laboring patients. So progesterone's role had to be more subtle, and, therefore, investigation was then channeled to address its ability to bind to progesterone receptors, or to stimulate enhanced gene expression, or, alternatively, to compete with CRH for glucocorticoid receptors (thereby elevating circulating CRH levels). With this in mind, a study7 surfaced last month in which both natural progesterone and 17P were found to be weak binders to progesterone and glucocorticoid receptors and poor activators of gene expression. Therefore, it seems that investigators will have to search further to find how these agents work.

In the meantime, whatever mechanism is involved, the studies with 17P and vaginal progesterone have now clearly shown that either can diminish the potential for preterm birth, especially in those with a combination of a history of prior preterm birth and a short cervix. Also, a recent study8 has shown that even if 17P is given later in pregnancy (21-27 weeks) than is generally recommended, there seems to be similar benefit.

For reference, the weekly dosage of 17 alpha-hydroxyprogesterone in the Meis study was 250 mg and vaginal capsules of 200 mg of progesterone were used in the Fonseca study. In the DeFranco paper, 90 mg of progesterone gel was delivered daily with a vaginal applicator.

Key Points

  1. Randomized trials show that both weekly intramuscular 17P and daily vaginal progesterone can diminish the rate of PTB in those with a history of PTB together with a short CL.
  2. One randomized trial shows a decrease in PTB with 17P in patients with a history of PTB alone.
  3. Another (non-randomized) study suggests the benefit of 17P, even when initiated late, at 21 to 27 weeks.
  4. As yet, no study has addressed the benefit of either 17P or vaginal progesterone in those with an inadvertent finding of a short CL alone.
  5. One study has shown no benefit from 17P in multiple gestations.9

References

  1. Meis PJ, et al. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med. 2003;348:2379-2385.
  2. Iams JD, et al. The length of the cervix and the risk of spontaneous preterm delivery. N Engl J Med. 1996; 334:567-572.
  3. Fonseca EB, et al. Progesterone and the risk of preterm birth among women with a short cervix. N Engl J Med. 2007;357:462-469.
  4. Facchinetti F, et al. Cervical length changes during preterm cervical ripening: effects of 17-alpha-hydroxyprogesterone caproate. Am J Obstet Gynecol. 2007; 196:453.e1-453.e4.
  5. O'Brien JM, et al. Progesterone vaginal gel for reduction of recurrent preterm birth: primary results from a randomized double-blind placebo controlled trial. Ultrasound Obstet Gynecol. 2007;30:687-696.
  6. DeFranco EA, et al. Vaginal progesterone is associated with a decrease in risk for early preterm birth and improve neonatal outcome in women with a short cervix: a secondary analysis from a randomized double-blind placebo-controlled trial. Ultrasound Obstet Gynecol. 2007;30:697-705.
  7. Attardi BJ, et al. Comparison of progesterone and glucocorticoid receptor binding and stimulation of gene expression by progesterone, 17 alpha hydroxyprogesterone caproate, and related progestins. Am J Obstet Gynecol. 2007;197:599.e1-599-e7.
  8. How HY, et al. Prophylaxis with 17 alpha-hydroxyprogesterone caproate for prevention of recurrent preterm delivery: does gestational age at initiation of treatment matter? Am J Obstet Gynecol. 197:260.e1-260.e4.
  9. Caritis S, et al. A randomized controlled trial of 17-hydroxyprogesterone caproate (17-OHPC) for the prevention of preterm birth in twins. Am J Obstet Gynecol. 2006; 195 (Suppl 1): S2.