Clinical Review

Can progesterone prevent prematurity—dependably?

OBG Manag. 2009 November;21(11):53-61

References

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3. da Fonseca EB, Bittar RE, Carvalho MH, Zugaib M. Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study. Am J Obstet Gynecol. 2003;188:419-424.

4. O’Brien JM, Adair CD, Lewis DF, et al. Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol. 2007;30:687-696.

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14. Fonseca EB, Celik E, Parra M, Singh M, Nicolaides KH. Fetal Medicine Foundation Second Trimester Screening Group. Progesterone and the risk of preterm birth among women with a short cervix. N Engl J Med. 2007;357:462-469.

15. Thornton JG. Progesterone and preterm labor—still no definite answers. N Engl J Med. 2007;357:499-501.

16. Iams JD, Goldenberg RL, Meis PJ, et al. The length of the cervix and the risk of spontaneous premature delivery. National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network. N Engl J Med. 1996;334:567-572.

17. DeFranco EA, O’Brien JM, Adair CD, et al. Vaginal progesterone is associated with a decrease in risk for early preterm birth and improved 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.

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The trials involved three different formulations of progesterone:

intramuscular injection of 250 mg of 17α-hydroxyprogesterone caproate
100-mg vaginal suppository of progesterone
90 mg of vaginal progesterone gel (Prochieve 8% / Crinone 8%).

Two of the trials found a significantly lower rate of preterm birth among women randomized to progesterone. The third found no difference between the progesterone and placebo groups.

Meta-analyses of all studies, including these three, found that the risk of recurrent preterm birth can be reduced by as much as 40% to 55% and low birth weight by 50% using progesterone.^5,6

TABLE 1

A woman who gives birth prematurely once likely will the next time

Source	Gestational age at first delivery	Relative risk of recurrent preterm birth (95% confidence interval)
Maternal–Fetal Medicine Units Network³⁰		2.5 (1.9–3.2)
Missouri database, 1989–1997³¹		3.6 (3.2–4.0)
University of Texas Southwestern Medical Center, 1988–1999³²		5.9 (4.5–7.0)
Denmark, 1982–1987³³	32–36 weeks	4.8 (3.9–6.0)
Denmark, 1982–1987,³³ Maternal–Fetal Medicine Units Network³⁰		6.0 (4.1–8.8)
Maternal–Fetal Medicine Units Network³⁰		10.6 (2.9–38.3)

Details of the trials

Meis and colleagues conducted a multicenter trial of 463 pregnant women who had a documented history of spontaneous preterm delivery.² Starting between 16 and 20 weeks’ gestation, participants were randomized in a 2:1 ratio to weekly injection of 250 mg of 17α-hydroxyprogesterone caproate or an inert oil placebo, with injections continuing until delivery or 36 weeks’ gestation.

Among the findings:

Treatment with progesterone significantly reduced the risk of delivery at less than 37 weeks’ gestation, with an incidence of 36.3% in the progesterone group versus 54.9% in the placebo group (relative risk [RR], 0.66; 95% confidence interval [CI], 0.54–0.81).
Progesterone reduced the risk of delivery at less than 35 weeks’ gestation, with an incidence of 20.6% in the progesterone group versus 30.7% in the placebo group (RR, 0.67; 95% CI, 0.48–0.93).
Progesterone reduced the risk of delivery at less than 32 weeks’ gestation, with an incidence of 11.4% in the progesterone group versus 19.6% in the placebo group (RR, 0.58; 95% CI, 0.37–0.91).
Progesterone was effective in African Americans and non–African Americans.
Infants of women treated with progesterone had significantly lower rates of necrotizing enterocolitis and intraventricular hemorrhage and less need for supplemental oxygen.

In a trial by da Fonseca and colleagues, 142 high-risk women who were pregnant with a singleton fetus were given a 100-mg vaginal suppository of progesterone or placebo daily (at night) between 24 and 34 weeks of gestation.³ Preterm birth occurred in 13.8% of the women treated with progesterone versus 28.5% of women in the placebo group (P<.05 more women were delivered before weeks gestation in the placebo group than progesterone>

O’Brien and associates studied 659 pregnant women who had a history of spontaneous preterm birth.⁴ Participants were randomly assigned to receive daily treatment with progesterone vaginal gel or placebo, starting between 18 and 22.9 weeks’ gestation and continuing until delivery, 37 weeks’ gestation, or premature rupture of membranes. The gel was administered in the morning.

In this trial, progesterone did not decrease the rate of preterm birth at 32 weeks’ gestation or less (10% in the progesterone group versus 11.3% in the placebo group; odds ratio, 0.9; 95% CI, 0.52–1.56).

It is unclear whether the formulation, timing, or dosage was responsible for the different outcomes in these trials ( TABLE 2) .

TABLE 2

5 Progesterone formulations have been tested for the prevention of preterm birth

Formulation	Dosage	Administration	Dosing schedule	Gestational age at initiation	Gestational age at completion
17α-Hydroxyprogesterone caproate²	250 mg	Intramuscular	Weekly	16.0–20.0 weeks	36.9 weeks
Progesterone³	100 mg	Vaginal suppository	Daily at bedtime	24 weeks	34 weeks
Progesterone¹⁴	200 mg	Vaginal suppository	Daily at bedtime	24 weeks	34 weeks
Prochieve 8%/Crinone 8%⁴	90 mg	Vaginal suppository bioadhesive formulation/gel	Every morning	18.0–22.9 weeks	37 weeks
Progesterone¹⁹	400 mg	Vaginal suppository	Daily	After arrest of preterm labor	Delivery

In this population, the number needed to treat is low

At least five strong meta-analyses have explored the prevention of recurrent preterm birth.^1,7-10 These analyses demonstrate that progesterone supplementation significantly reduces the incidence of low birth weight and preterm birth. In some cases, it also reduces the rate of respiratory distress syndrome and intraventricular hemorrhage.

Based on these data, Petrini and associates calculated that, if all pregnant women who had a history of spontaneous preterm birth had been offered progesterone in 2002, 10,000 preterm births could have been prevented.¹¹

The number needed to treat (NNT) to avoid one preterm birth was eight for 17α-hydroxyprogesterone caproate and 10 using another progesterone formulation. The NNT to prevent low birth weight was 12.

To put these figures in context, consider the use of low-dose aspirin to prevent stroke, which has a NNT of 102, and the use of a β-blocker to prevent cardiac death in patients who have suffered a myocardial infarction, which carries a NNT of 42.