Disagreement
Some have argued that vaginal progesterone should be offered to women with a history of prior spontaneous preterm birth, but the largest study to look at this application – a randomized multinational trial reported by John M. O’Brien, MD, and his colleagues in 2007 – found that use of the compound did not reduce the frequency of recurrent preterm birth at or before 32 weeks. Others have argued that vaginal progesterone is of benefit in this group of women based on a combination of multiple subgroup analyses. There is disagreement between ACOG and SMFM on this issue. ACOG supports the use of vaginal progesterone for women with a prior preterm birth but the SMFM strongly rejects this treatment and only endorses 17-OHPC for this indication.
Unresolved
The value of vaginal progesterone supplementation in reducing preterm births in women with twin gestations is under continuing investigation, including a study of women with twin gestation and a short cervix. This MFMU Network randomized trial, now underway, is evaluating the effectiveness of vaginal progesterone or pessary, compared with placebo, in preventing early preterm birth in women carrying twins who have a cervical length less than 30 mm.
Another question about the use of progesterone concerns the woman who delivered preterm during a twin gestation and is now pregnant with a singleton gestation. Should anything be offered to her? This is a question that has not yet been addressed in the literature.
What does seem clear is that spontaneous preterm birth is a multifactorial condition with numerous causes, and quite possibly an interaction between genetics, maternal characteristics, and the environment surrounding each pregnancy (Semin Perinatol. 2016;40[5]:273-80). Certainly, there are different pathways and mechanisms at play in patients who deliver at 35-36 weeks, for instance, compared with those who deliver at 25-26 weeks.
We recently obtained cervical fluid from pregnant women with prior preterm births and analyzed the samples for concentrations of cytokines and matrix metalloproteinases. Women with a prior early preterm delivery at less than 26 weeks had elevations in five cervical cytokines – an inflammatory signature, in essence – while those whose prior preterm birth occurred at a later gestational age had no elevations of these cytokines (Am J Perinatol. 2017 Nov 15. doi: 10.1055/s-0037-1608631).
Hopefully, we soon will be able to identify subpopulations of pregnant women who will benefit more from progesterone supplementation. More research needs to be done at a granular level, with more narrowly defined populations – and with consideration of various pharmacologic, genetic and environmental factors – in order to develop a more specific treatment approach. In the meantime, it is important to appreciate the unknowns that underlie the highly variable clinical responses and outcomes seen in our clinical trials.
Dr. Caritis is professor of obstetrics, gynecology, and reproductive sciences at Magee-Womens Hospital, University of Pittsburgh. He has no disclosures relevant to this Master Class.