I read with interest the article of Durnwald et al. Contrary to our prospective evaluations, in a retrospective analysis they found that 17-alpha-hydroxyprogesterone (17P) caproate did not affect cervical length in the women who were enrolled in a preterm prevention clinic.

Apart from population differences (>50% black race and >50% overweight women), the big difference between the studies was the inclusion criteria. They observed asymptomatic women who were at risk because of their obstetric history, whereas we enrolled symptomatic women who had overcome an episode of preterm labor. The main biologic difference was the length of the cervix, which was within normal ranges in their study; it was ≤25 mm in >50% of the women who were enrolled in our small trial. This last finding means that, at random assignment, our patients experienced a local activation of inflammatory pathways, which was supported by cervical secretions of proinflammatory interleukins. This was not surprising because the cervical inflammatory activation of women in preterm labor had been discovered long ago and later was confirmed in several reports. Hence, it would be of interest to know whether Durnwald et al could find a subpopulation of their patients with a shortened cervix and then evaluate cervical changes that occurred in the no-treatment and 17P caproate–treated groups.

Although we know little about the mechanisms that allow spontaneous preterm delivery (infection and inflammatory response remain a milestone), we ignore the mode of action by which 17P caproate exerts its therapeutic role. The drug is neither hydrolyzed in vitro nor in vivo; it does not affect circulating steroid concentrations (personal observation), and it is unable to inhibit uterine contractility either in vivo or in vitro “as apex.” Likely, a still unknown metabolite seems to be responsible for the pharmacologic actions of the drug. I suggest that some antiinflammatory properties are responsible for the tertiary prevention of cervical inflammation in symptomatic women with shortened cervix when the syndrome of preterm delivery has started. This would explain the reason that 17P caproate attenuated cervical shortening, namely in patients with shortest cervix. On the other hand, other mechanisms of action have to be hypothesized to explain the effectiveness of secondary prophylaxis of preterm delivery that is demonstrated in asymptomatic women who are at risk for recurrence because of their obstetric history.