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    MFM Consult: Progesterone for prevention of preterm birth

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    Q: I am caring for a woman with a prior preterm birth at 30 weeks after an episode of preterm premature rupture of the membranes (pPROM). What are the current indications for progesterone to prevent preterm birth?

    A: Although the majority of preterm births occurring before 37 weeks' gestation don't happen in women with a prior preterm birth, having had a prior spontaneous preterm birth due to preterm labor or pPROM nevertheless increases the threat of a subsequent preterm birth. In recent randomized trials, the recurrence of preterm birth dropped from 55% in women receiving a placebo to 36% in women receiving weekly intramuscular injections of 250 mg 17-alpha hydroxyprogesterone caproate (17-OHPC)1 when administered beginning in the second trimester. Similarly, preterm birth dropped from 29% in women receiving a placebo to 14% in women receiving daily 100-mg progesterone vaginal suppositories.2

    However, a third study using 90 mg of progesterone gel administered vaginally each day to women with a prior preterm delivery did not find any benefit.3 On a more positive note, no long-term adverse health outcomes in the progesterone-exposed children have been seen after 4 years of pediatric follow-up.4 Based on these results, ACOG and SMFM have recommended that progesterone be offered to pregnant women with a prior spontaneous singleton preterm delivery.5 These women should continue taking progesterone until delivery or 37 weeks. The risks of progesterone are generally minor and appear to be limited to irritation at the injection site. Currently the only recommended indication for progesterone for the prevention of preterm deliveries is in women with a singleton pregnancy and a prior spontaneous preterm delivery. The hormone has not been shown to benefit women in preterm labor, so its use for this indication is not recommended.

    What other indications for progesterone to prevent prematurity have been studied, and has it been shown to be effective?

    Progesterone for the prevention of prematurity has been studied in at least two other groups of high-risk women. Randomized trials in women with twins and triplets did not find less frequent PTB with 17-OHPC, so the drug is not recommended for these women.6,7 In a study of women found on second-trimester ultrasound to have a cervical length of 15 mm or less, those randomized to daily 200 mg of vaginal micronized progesterone capsules from 24 to 34 weeks of gestation had less frequent preterm delivery compared to those women who received placebo.8 However, at least 25% of the women in this study had risk factors for preterm delivery such as multiple gestation or prior preterm delivery. In this study, only 1.7% of all women screened had a cervix that fulfilled the study criterion of a short cervix (≤15 mm). Because of this, routine screening for a short cervix is not recommended for this indication until further studies are completed. There are no randomized trials that have compared progesterone to placebo in women with positive fetal fibronectin. As there are several ongoing randomized trials evaluating progesterone for the reduction of preterm delivery, the clinical recommendations are likely to continue to evolve over the next few years.

    What formulations are currently available, and what are the advantages and disadvantages of each?

    The two progesterone formulations that have been shown to be efficacious in the prevention of recurrent preterm birth are vaginal progesterone suppositories (100 mg daily)2 and 17-hydroxyprogesterone caproate (250 mg IM weekly).1 The study of progesterone treatment for women with a short cervical length used 200 mg daily of vaginal micronized progesterone capsules.8 These formulations are available but have not received FDA approval for prevention of preterm birth. 17-OHPC is available from some compounding pharmacies, but is not available at all pharmacies. Medicaid and some insurance companies cover it in most states. It is not yet known if there are substantial differences in mechanism and effectiveness of these two formulations. More studies are needed to determine if other formulations are effective. If these formulations are unavailable because of insurance, cost, or logistic reasons, it may be prudent to document this in the patient's medical record.

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    Sarah J. Kilpatrick, MD, PhD
    Dr. Kilpatrick is the Helping Hand Endowed Chair in the Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los ...

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