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17-alpha Hydroxyprogesterone caproate did not reduce the rate of recurrent preterm birth in a prospective cohort study

Published:February 19, 2017DOI:https://doi.org/10.1016/j.ajog.2017.02.025

      Background

      17-alpha Hydroxyprogesterone caproate for prevention of recurrent preterm birth is recommended for use in the United States.

      Objective

      We sought to assess the clinical effectiveness of 17-alpha hydroxyprogesterone caproate to prevent recurrent preterm birth ≤35 weeks compared to similar births in our obstetric population prior to the implementation of 17-alpha hydroxyprogesterone caproate.

      Study Design

      This was a prospective cohort study of 17-alpha hydroxyprogesterone caproate in our obstetric population. The primary outcome was the recurrence of birth ≤35 weeks for the entire study cohort compared to a historical referent rate of 16.8% of recurrent preterm birth in our population. There were 3 secondary outcomes. First, did 17-alpha hydroxyprogesterone caproate modify a woman’s history of preterm birth when taking into account her prior number and sequence of preterm and term births? Second, was recurrence of preterm birth related to 17-alpha hydroxyprogesterone caproate plasma concentration? Third, was duration of pregnancy modified by 17-alpha hydroxyprogesterone caproate treatment compared to a prior preterm birth?

      Results

      From January 2012 through March 2016, 430 consecutive women with prior births ≤35 weeks were treated with 17-alpha hydroxyprogesterone caproate. Nearly two thirds of the women (N = 267) began injections ≤18 weeks and 394 (92%) received a scheduled weekly injection within 10 days of reaching 35 weeks or delivery. The overall rate of recurrent preterm birth was 25% (N = 106) for the entire cohort compared to the 16.8% expected rate (P = 1.0). The 3 secondary outcomes were also negative. First, 17-alpha hydroxyprogesterone caproate did not significantly reduce the rates of recurrence regardless of prior preterm birth number or sequence. Second, plasma concentrations of 17-alpha hydroxyprogesterone caproate were not different (P = .17 at 24 weeks; P = .38 at 32 weeks) between women delivered ≤35 weeks and those delivered later in pregnancy. Third, the mean (±SD) interval in weeks of recurrent preterm birth before 17-alpha hydroxyprogesterone caproate use was 0.4 ± 5.3 weeks and the interval of recurrent preterm birth after 17-alpha hydroxyprogesterone caproate treatment was 0.1 ± 4.7 weeks (P = .63). A side effect of weekly 17-alpha hydroxyprogesterone caproate injections was an increase in gestational diabetes. Specifically, the rate of gestational diabetes was 13.4% in 17-alpha hydroxyprogesterone caproate–treated women compared to 8% in case-matched controls (P = .001).

      Conclusion

      17-alpha Hydroxyprogesterone caproate was ineffective for prevention of recurrent preterm birth and was associated with an increased rate of gestational diabetes.

      Key words

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      Linked Article

      • Reply
        American Journal of Obstetrics & GynecologyVol. 218Issue 2
        • Preview
          Clearly, Drs Hauspurg, Venkataraman, and Caritis disagree with our findings. Their criticism challenges our methodology, and we respect their opportunity to criticize our work in the Journal in the form of Letters to the Editor. We, however, are also grateful for the opportunity to respond.
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      • Do maternal obesity or smoking explain the lack of effectiveness of 17-alpha hydroxyprogesterone caproate?
        American Journal of Obstetrics & GynecologyVol. 217Issue 5
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          We thank Nelson et al1 for their recent study showing lack of efficacy of 17-alpha hydroxyprogesterone caproate (17OHP-C) for the prevention of recurrent preterm birth in their population. The adoption of 17OHP-C into widespread clinical practice based primarily on a single trial2 is somewhat unusual, and further validation is certainly warranted. Like these authors, we anxiously await the results of the PROLONG trial.
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      • Reply
        American Journal of Obstetrics & GynecologyVol. 217Issue 5
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          Drs Heyborne and Allshouse have written regarding our recent publication1 in which we describe the ineffectiveness of 17-alpha hydroxyprogesterone caproate (17OHP-C) to prevent recurrent preterm birth. These investigators previously hypothesized, using secondary analysis of the Maternal-Fetal Medicine Units Network trial by Meis et al,2 that maternal smoking increased the effectiveness of 17OHP-C whereas larger maternal habitus decreased effectiveness.3,4
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      • Response to 17-alpha hydroxyprogesterone caproate
        American Journal of Obstetrics & GynecologyVol. 219Issue 2
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          Dr David B. Nelson and colleagues1 recently reported the results of a prospective cohort study concluding that 17-alpha hydroxyprogesterone caproate (17OHP-C) was ineffective for prevention of recurrent preterm birth and was associated with an increased risk of gestational diabetes.
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        American Journal of Obstetrics & GynecologyVol. 218Issue 3
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          This letter-to-the-editor is the third inquiry from Dr Zelig regarding our report on 17-alpha hydroxyprogesterone caproate (17-OHPC).1 There were 2 earlier personal communications; we begin our response by summarizing these earlier queries.
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      • Reply
        American Journal of Obstetrics & GynecologyVol. 219Issue 2
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          Dr Vadnais and Ms Frappaolo ask an important question. They ask that because professional organizations, such as the Society for Maternal-Fetal Medicine (SMFM), have legitimized the use of 17-alpha hydroxyprogesterone caproate (17OHP-C) for prevention of recurrent preterm birth, what is a provider to do given the published results of our study? This question is timely given the recent US Food and Drug Administration approval of the Makena auto-injector (AMAG Pharmaceuticals, 2018).1
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