What is the efficacy of progesterone therapy to reduce preterm labor?

Updated: May 04, 2021
  • Author: Michael G Ross, MD, MPH; Chief Editor: Carl V Smith, MD  more...
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Recent studies support the use of progesterone supplementation to reduce preterm birth in patients at high risk for recurrent preterm delivery (ie, prior preterm birth < 37 weeks' gestation, short cervical length). Weekly injections of 17 alpha-hydroxyprogesterone caproate resulted in a substantial reduction in the rate of recurrent preterm delivery among women who were at high risk for preterm delivery and reduced the likelihood of several complications in their infants. [16] In addition, prophylactic vaginal progesterone reduced the frequency of uterine contractions and the rate of preterm delivery in women at high risk for prematurity. [17]

In October 2008, the American College of Obstetricians and Gynecologists issued a Committee Opinion stating that progesterone supplementation for the prevention of recurrent preterm birth should be offered to women with a singleton pregnancy and a prior spontaneous preterm birth due to spontaneous preterm labor or premature rupture of membranes. Progesterone supplementation for asymptomatic women with an incidentally identified very short cervical length (< 15 mm) may be considered. [18]

On February 4, 2011, the US Food and Drug Administration (FDA) approved 17-hydroxyprogesterone (Makena) to reduce risk of preterm delivery before 37 weeks’ gestation in women with singleton pregnancy and a history of at least one spontaneous preterm birth. 17-Hydroxyprogesterone is not intended for use in women with multiple gestations or other risk factors (eg, short cervical length) for preterm birth.

The dose is 250 mg (1 mL) intramuscularly in the hip every week until 37 weeks’ gestation or delivery, whichever occurs first. Initiate between 16 weeks’ gestation and before 21 weeks’ gestation (ie, 20 wk and 6 d). In 2018, Makena was approved with a subcutaneous injector, though there are no bioequivalence or efficacy studies comparing intramuscular vs subcutaneous 17- hydroxyprogesterone caproate. 

The FDA reviewed data from a multicenter, randomized, double-blind clinical trial. The study included 463 women who were pregnant with a single fetus and had a history for preterm delivery. Rates of delivery before 37 weeks' gestation were 37% in women randomized to 17-hydroxyprogesterone and 55% in controls.

A separate study evaluated children born to mothers enrolled in the controlled trial. In this study, children aged 2.5-5 years reached similar developmental targets, regardless of the mother’s treatment. The confirmatory study that is ongoing will be followed by a similar infant follow-up study to be completed about 2018.

A multicenter, randomized placebo-controlled study demonstrated that intravaginal progesterone gel effectively prevented preterm delivery in patients with a short cervix (10-20 mm). Vaginal progesterone was associated with a significant reduction in rate of preterm birth before 28, 33, and 35 weeks’ gestation; infant respiratory distress syndrome; and neonatal morbidity and mortality. Currently, applications for FDA approval are in process. Of note, the predicted clinical impact of treatment of all patients with short cervix is greater than among patients with prior spontaneous preterm birth. [19]

The EPPPIC Meta-Analysis of the effects of vaginal progesterone, intramuscular 17-hydroxyprogesterone caproate (17-OHPC), and oral progesterone found evidence for a reduction in the risk of preterm birth with progesterone treatment (preterm birth less than 34 weeks of gestation: vaginal progesterone, nine trials, 3769 women, relative risk [RR], 0.78, 95% CI, 0.68-0.90; 17-OHPC, five trials, 3053 women, RR, 0.83, 95% CI, 0.68-1.01). The impact of 17-OHPC compared with placebo did not reach statistical significance. The most consistent evidence is for the beneficial effect of vaginal progesterone for women with a short cervix. As controversy continues regarding the benefit of 17-OHPC in pregnant patients with prior spontaneous preterm birth, patients with a singleton pregnancy and a prior spontaneous preterm birth should be offered progesterone supplementation (either vaginal or intramuscular) in the context of a shared decision-making process with the patient, which incorporates both the available evidence and the patient’s preferences.

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