The synthetic progestin 17-hydroxyprogesterone caproate (17-OHP-C) and natural progesterone differ remarkably in their structure and relative affinity for progesterone receptors (the binding affinity of 17OHP-C is only 26-30% of the binding affinity of progesterone). Furthermore, the synthetic is not metabolized into a naturally occurring compound. This varied biochemistry may elicit varied responses, which have been observed in laboratory experiments (some of which are negative regarding exposure to the synthetic). Combs et al describe a randomized controlled trial that adds further suspicion regarding the safety of 17-OHP-C because fetal death caused by midtrimester loss was significantly more common with this treatment.

That death is the safety outcome that is significantly different between groups is alarming, especially for an intervention that is considered to be prophylactic therapeutic. Combs et al highlight a Food and Drug Administration evaluation that identified the same safety signal. Metaanalysis has also raised concern for an association between 17-OHP-C and second-trimester miscarriage. Therefore, biologic plausibility for harm exists, given the relative differences in binding affinity for progesterone receptors, and suspicion for harm related to the synthetic is present from human data and experimentation.

Progesterone has not been associated with death, and efficacy for the prevention of preterm birth has been observed in randomized controlled trials. Hence, several essential questions arise for the specialty of obstetrics:

• 1
  

  Will proven rare adverse events regarding fetal outcomes be treated in a similar manner to rare adverse events that are observed in adults? If so, could much publicized warnings lead to distrust for American College of Obstetricians and Gynecologist–supported treatments and undermine our specialty’s goal for the prevention of preterm birth?

  
  
• 2
  

  In the absence of Food and Drug Administration approval of either medication for this indication, what entity will best evaluate the risk/benefit ratio for these medications and suggest the safest course for the practice of obstetrics?

  
  
• 3
  

  How much evidence for harm is necessary before alternative therapies are more definitively supported for prophylactic treatments?

  
  
• 4
  

  Should progesterone be identified as the safest treatment option, based in part on anthropologic evidence regarding biologic selection that this particular compound is ubiquitous throughout the class Mammalia and that no synthetic could potentially be safer to stimulate progesterone receptors to enhance reproductive functions than progesterone?

Finally, do the authors suggest the American College of Obstetricians and Gynecologists Obstetric Practice Committee, Agency for Healthcare Research and Quality, both, or neither should comment on the safest practice for preterm birth prevention with these agents; or should those leaders wait to opine, despite the potential for a starker action/reaction from regulators at the FDA, the legal system, and the public if their findings are ultimately validated?