In 2003, the Eunice Kennedy Shriver National Institute of Child Health and Human Development’s Maternal-Fetal Medicine Units (MFMU) Network reported on a placebo-controlled randomized study of 17–alpha hydroxyprogesterone caproate (17-OHPC) in women with a history of spontaneous preterm delivery. The study demonstrated a 33% reduction in recurrent preterm birth after weekly treatment with 17-OHPC, which was initiated at 16-20 weeks of gestation.
This landmark study, led by Paul Meis, MD, validated what had been suggested in an earlier meta-analysis (1990) by Mark Keirse, MD – and it quickly altered clinical practice. It set into motion a string of studies on the use of 17-OHPC and other progestational compounds in women with a variety of conditions associated with an increased risk for preterm birth.
Dr. Steve Caritis
It is not surprising, then, that the literature has become muddied and full of contradictory findings since publication of the Meis study and the initial studies on vaginal progesterone in women with a midtrimester short cervix. Further confounding our ability to judge a treatment’s effectiveness is the fact that spontaneous preterm birth is increasingly understood to be a multifactorial, highly heterogeneous condition. We cannot, with a broad stroke, say that all women with a prior preterm birth, for instance, will respond to progestogens in a similar manner or are at the same level of risk of recurrent spontaneous preterm birth (sPTB).
The number of large, randomized clinical trials evaluating progestins is actually quite small but opinions abound about the data from these studies. Below, I have categorized these treatments according to my view at this time of the currently available data.
Consensus
One area in which there is agreement concerns the use of 17-OHPC intramuscular injections in multifetal gestations. Two randomized clinical trials undertaken by the MFMU Network – one in twins and one in triplets – concluded that 17-OHPC is ineffective in reducing the rate of preterm birth. Moreover, in another, more recent MFMU Network study, there was a negative linear relationship between concentrations of 17-OHPC and gestational age at delivery. Women with twin gestations who had higher concentrations of 17-OHPC delivered at earlier gestational ages than women with lower concentrations (Am J Obstet Gynecol. 2012;207[5]:396.e1-8).
Other investigators have similarly shown in clinical trials that the preterm birth rate actually seems to be worsened in multifetal gestations when 17-OHPC is used. There is now widespread agreement that the compound should not be used in these patients.
In addition, an MFMU Network study led by William A. Grobman, MD, demonstrated that 17-OHPC (250-mg injections) does not provide any benefit to nulliparous women with a sonographic cervical length less than 30 mm (Am J Obstet Gynecol. 2012;207[5]:390.e1-8). Other studies utilizing higher doses of 17-OHPC similarly found no benefit. There is also agreement that 17-OHPC has no benefit in treating women with preterm premature rupture of the membranes, preterm labor, or as a maintenance treatment after an episode of preterm labor.
General agreement without consensus
There is general agreement that women with a singleton gestation and a prior spontaneous preterm birth should be offered 17-OHPC, and that women with a singleton gestation and a midtrimester shortened cervical length should be offered vaginal progesterone and not 17-OHPC. However, even in these populations, there are questions about efficacy, dosing, and other issues.
In the Meis study (N Engl J Med. 2003;348:2379-85), treatment with 17-OHPC in women with a singleton gestation and a prior preterm delivery significantly reduced the risk of another preterm birth at less than 37 weeks’ gestation (36.3% in the progesterone group vs. 54.9% in the placebo group; relative risk, 0.66), at less than 35 weeks’ gestation (RR, 0.67), and at less than 32 weeks’ gestation (RR, 0.58). The exceptionally high rate of preterm delivery in the placebo group, however, prompted other investigators to express concern in published correspondence that the study was potentially flawed.
We reported an inverse relationship between 17-OHPC concentration and spontaneous preterm birth as part of a study conducted with the MFMU Network and the Obstetrical-Fetal Pharmacology Research Units Network. All women in the study had singleton gestations and received 250 mg weekly 17-OHPC (the broader study was designed to evaluate the benefit of omega-3 supplementation). We measured plasma concentrations of 17-OHPC and found that women with concentrations in the lowest quartile had a significantly higher risk of preterm birth and delivered at significantly earlier gestational ages than did women in the second through fourth quartiles (Am J Obstet Gynecol. 2014;210[2]:128.e1-6).
Other studies/abstracts similarly evaluating the relationship between 17-OHPC concentrations and preterm birth have reported mixed results, with both validation and refutation of our findings.
Research underway may help settle the controversy. In an ongoing, open-label pharmacology study being conducted by the Obstetrical-Fetal Pharmacology Research Units Network, women with singleton pregnancies and a history of prior preterm birth are being randomly assigned to receive either 250 mg (the empirically chosen, currently recommended dose) or 500 mg 17-OHPC. A relationship between the plasma concentration of 17-OHPC at 26-30 weeks’ gestation and the incidence of preterm birth would offer proof of efficacy and could help elucidate the therapeutic dosing; if there is no relationship, we revert to the question of whether the agent really works. Based on current evidence, both the Society for Maternal-Fetal Medicine (SMFM) and the American College of Obstetricians and Gynecologists (ACOG) support the use of 17-OHPC for prevention of sPTB in women with a prior sPTB.
Questions about vaginal progesterone have also been somewhat unsettled. Eduardo B. Fonseca, MD, reported in 2007 that asymptomatic women with a short cervix (defined as 15 mm or less) who were randomized to receive vaginal progesterone at a median of 22 weeks’ gestation had a significantly lower rate of preterm birth before 34 weeks’ gestation than those who received placebo (RR, 0.56; N Engl J Med. 2007;357[5]:462-9). Research that followed offered mixed conclusions, with a study by Sonia S. Hassan, MD, showing benefit and a study by Jane E. Norman, MD, showing no benefit. Notably, in 2012, the Food and Drug Administration voted against approval of a sustained-release progesterone vaginal gel, citing research results that were not sufficiently compelling.
Still, vaginal progesterone has been endorsed by both ACOG and by the SMFM for women with a short cervical length in the midtrimester. This is supported by a new review and meta-analysis of individual patient data by Roberto Romero, MD, in which vaginal progesterone was found to significantly decrease the risk of preterm birth in singleton gestations with a midtrimester cervical length of 25 mm or less. The reduction occurred over a wide range of gestational ages, including at less than 33 weeks of gestation (RR, 0.62; Am J Obstet Gynecol. 2018 Feb;218[2]:161-80).