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
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to American Journal of Obstetrics & GynecologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Preterm birth: causes, consequences, and prevention.National Academies Press, Washington (DC)2007
- Correlation between initial neonatal and early childhood outcomes following preterm birth.Am J Obstet Gynecol. 2014; 210: 426.e1-426.e9
- National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate.N Engl J Med. 2003; 348: 2379-2385
- Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study.Am J Obstet Gynecol. 2003; 188: 419-424
- Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial.Ultrasound Gynecol. 2007; 30: 687-696
- Progesterone and the risk of preterm birth among women with a short cervix. Fetal Medicine Foundation Second Trimester Screening Group.N Engl J Med. 2007; 357: 462-469
- Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial. PREGNANT Trial.Ultrasound Obstet Gynecol. 2011; 38: 18-31
- Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and metaanalysis of individual patient data.Am J Obstet Gynecol. 2012; 206: 124.e1-124.e9
- Vaginal progesterone decreases preterm birth ≤34 weeks of gestation in women with a singleton pregnancy and a short cervix: an updated meta-analysis including data from the OPPTMUM study.Ultrasound Obstet Gynecol. 2016; 48: 308-317
FDA. FDA approves drug to reduce risk of preterm birth in at-risk pregnancy women. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm242234.htm. Accessed Feb. 4, 2011.
- Prediction and prevention of preterm birth. Practice bulletin no. 130.Obstet Gynecol. 2012; 120: 964-973
- Progesterone and preterm birth prevention: translating clinical trials data into clinical practice.Am J Obstet Gynecol. 2012; 206: 376-386
- SMFM Publications Committee. SMFM statement: the choice of progestogen for the prevention of preterm birth in women with singleton pregnancy and prior preterm birth.Am J Obstet Gynecol. 2017; 216: B11-B13
- A blueprint for the prevention of preterm birth: vaginal progesterone in women with a short cervix.J Perinat Med. 2013; 41: 27-44
Clinical Trials. Confirmatory study of 17P versus vehicle for the prevention of preterm birth in women with a previous singleton spontaneous preterm delivery (PROLONG). Available at: https://clinicaltrials.gov/ct2/show/NCT01004029. Accessed January 6, 2017.
- Randomized controlled trials and population-based observational research: partners in the evolution of medical evidence.Br J Cancer. 2014; 110: 551-555
- Real-world evidence–what is it and what can it tell us?.N Engl J Med. 2016; 375: 2293-2297
- Quality assessment of compounded 17-hydroxyprogesterone caproate.Am J Obstet Gynecol. 2014; 210: 47.e1-47.e7
- Recurrence risk for preterm delivery.Am J Obstet Gynecol. 2007; 196: 576.e1-576.e7
- Relationship between 17-alpha hydroxyprogesterone caproate concentration and spontaneous preterm birth.Am J Obstet Gynecol. 2014; 210: 128.e1-128.e6
- Predictors of response to 17-alpha hydroxyprogesterone caproate for prevention of recurrent spontaneous preterm birth.Am J Obstet Gynecol. 2016; 214: 376.e1-376.e8
- Recurrence of preterm birth in singleton and twin pregnancies.Obstet Gynecol. 2001; 98: 379-385
- Efficacy of 17alpha-hydroxyprogesterone caproate in the prevention of premature labor.N Engl J Med. 1975; 293: 675-680
- The effect of 17 alpha-hydroxyprogesterone caproate on pregnancy outcome in an active-duty military population.Am J Obstet Gynecol. 1983; 146: 187-190
- Progestogen administration in pregnancy may prevent preterm delivery.Br J Obstet Gynecol. 1990; 97: 149-154
FDA. Gestiva slides revision. Meeting of the Advisory Committee for Reproductive Health Drugs. Aug. 29, 2006. NDA 21-945, 17α-hydroxyprogesterone caproate (Gestiva). Available at: http://www.fda.gov/ohrms/dockets/ac/06/slides/2006-4227S1-02-03-FDA_Wesley_files/frame.htm. Accessed Jan. 7, 2017.
- Progesterone is not the same as 17α-hydroxyprogesterone caproate: implications for obstetrical practice.Am J Obstet Gynecol. 2013; 208: 421-426
- Prevention of preterm birth with vaginal progesterone or 17-alpha-hydroxyprogesterone caproate: a critical examination of efficacy and safety.Am J Obstet Gynecol. 2016; 214: 45-56
- Progesterone and preterm: seventy years of “déjà vu” or “still to be seen”?.Birth. 2004; 31: 230-235
- Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate.N Engl J Med. 2003; 349: 1087-1088
- 17 alpha-Hydroxyprogesterone caproate vehicle, castor oil, enhances the contractile effect of oxytocin in human myometrium in pregnancy.Am J Obstet Gynecol. 2010; 202: 453.e1-453.e4
- Gestational diabetes: detection, management, and implications.Clin Diab. 1998; 16: 4-11
- Increased incidence of gestational diabetes in women receiving prophylactic 17α-hydroxyprogesterone caproate for prevention of recurrent preterm delivery.Diabetes Care. 2007; 30: 2277-2280
- The effect of progesterone on the human uterus.Proc Natl Acad Sci U S A. 1965; 54: 1069-1076
- Gap junctions and myometrial steroid hormone receptors in pregnant and postpartum rats: a possible cellular basis for the progesterone withdrawal hypothesis.Am J Obstet Gynecol. 1985; 151: 805-812
- Myometrial progesterone responsiveness and the control of human parturition.J Soc Gynecol Investig. 2004; 11: 193-202
- How does progesterone relax the uterus in pregnancy?.N Engl J Med. 2011; 364: 972-973
- Use of progesterone and progestin analogs for inhibition of preterm birth and other uterine contractility disorders.Facts Views Vis Obgyn. 2012; 4: 237-244
- Suppression of interleukin 8 production by progesterone in rabbit uterine cervix.Biochem J. 1994; 301: 183-186
- Hormonal regulation of matrix metalloproteinase 9/gelatinase B gene expression in rabbit uterine cervical fibroblasts.Biol Reprod. 1997; 56: 575-580
- Medroxyprogesterone acetate modulates remodeling, immune cell census, and nerve fibers in the cervix of a mouse model for inflammation-induced preterm birth.Reprod Sci. 2009; 16: 257-264
- Anti-inflammatory effect of proteoglycan and progesterone on human uterine cervical fibroblasts.Life Sci. 2012; 90: 484-488
- Vaginal progesterone, but not 17α-hydroxyprogesterone caproate, has anti-inflammatory effects at the murine maternal-fetal interface.Am J Obstet Gynecol. 2015; 213: 846.e1-846.e19
- Prevention of preterm birth by progestational agents: what are the molecular mechanisms?.Am J Obstet Gynecol. 2013; 208: 223.e1-223.e7
- The use of progestational agents for preterm birth: lessons from a mouse model.Am J Obstet Gynecol. 2006; 195: 1004-1010
- Progesterone receptor polymorphisms and clinical response to 17-alpha-hydroxyprogesterone caproate.Am J Obstet Gynecol. 2011; 205: 135.e1-135.e9
- Pharacogenomics of 17-alpha hydroxyprogesterone caproate for recurrent preterm birth prevention.Am J Obstet Gynecol. 2014; 210: 321.e1-321.e21
- Unjustified increase in cost of care resulting from US Food and Drug Administration approval of Makena (17α-hydroxyprogesterone caproate).Obstet Gynecol. 2011; 117: 1408-1412
- Estimated effect of 17 alpha-hydroxyprogesterone caproate on preterm birth in the United States.Obstet Gynecol. 2005; 105: 267-272
- Design of randomized controlled trials.Circulation. 2007; 115: 1164-1169
Clinical Trials. FAQ: clinical trial phases. Available at: https://www.nlm.nih.gov/services/ctphases.html. Accessed January 8, 2017.
- The environment and disease: association or causation?.Proc R Soc Med. 1965; 58: 295-300
- Exposure-wide epidemiology: revisiting Bradford Hill.Stat Med. 2016; 35: 1749-1762
- Beyond the randomized clinical trial: the role of effectiveness studies in evaluating cardiovascular therapies.Circulation. 2008; 118: 1294-1303
- A population-based, multifaceted strategy to implement antenatal corticosteroid treatment versus standard care for the reduction of neonatal mortality due to preterm birth in low-income and middle-income countries: the ACT cluster-randomized trial.Lancet. 2015; 385: 629-639
- Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth.Cochrane Database Syst Rev. 2006; 3: CD004454
SMFM Newsroom. Physicians weigh in on study in The Lancet on use of antenatal corticosteroids in prevention of pre-term birth. Available at: http://www.smfmnewsroom.org/2014/10/physicians-weigh-in-on-study-in-the-lancet-on-use-of-antenatal-corticosteroids-in-prevention-of-pre-term-birth/. Accessed January 8, 2016.
Mcclure E, Goldenberg R, Swanson D, et al. Routine antenatal ultrasound in low/middle income countries: a cluster randomized trial. Abstract no. 3. Presented at: Society for Maternal-Fetal Medicine 37th Annual Meeting–The Pregnancy Meeting; Jan. 23-28, 2017; Las Vegas, NV.
Article info
Publication history
Published online: February 19, 2017
Accepted:
February 13,
2017
Received in revised form:
February 10,
2017
Received:
January 10,
2017
Footnotes
A portion of this study was sponsored by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number UL1TR001105. Additionally, members of this research team (Drs Nelson, McIntire, and Leveno) were supported by the Parkland Hospital Obstetric Research Center.
The authors report no conflict of interest.
Cite this article as: Nelson DB, McIntire DD, McDonald J, et al. 17-alpha Hydroxyprogesterone caproate did not reduce the rate of recurrent preterm birth in a prospective cohort study. Am J Obstet Gynecol 2017;216:600.e1-9.
Identification
Copyright
© 2017 Elsevier Inc. All rights reserved.
ScienceDirect
Access this article on ScienceDirectLinked Article
- ReplyAmerican Journal of Obstetrics & GynecologyVol. 218Issue 2
- Do maternal obesity or smoking explain the lack of effectiveness of 17-alpha hydroxyprogesterone caproate?American Journal of Obstetrics & GynecologyVol. 217Issue 5
- PreviewWe 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.
- Full-Text
- Preview
- ReplyAmerican Journal of Obstetrics & GynecologyVol. 217Issue 5
- PreviewDrs 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
- Full-Text
- Preview
- Response to 17-alpha hydroxyprogesterone caproateAmerican Journal of Obstetrics & GynecologyVol. 219Issue 2
- ReplyAmerican Journal of Obstetrics & GynecologyVol. 218Issue 3
- ReplyAmerican Journal of Obstetrics & GynecologyVol. 219Issue 2
- PreviewDr 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
- Full-Text
- Preview
- Clinical trials and tribulations: 17OHPC and preventing recurrent preterm birthAmerican Journal of Obstetrics & GynecologyVol. 216Issue 6
- PreviewIn this issue of the Journal, Nelson et al1 report a prospective cohort of 430 consecutive women pregnant with a single fetus who had a history of 1 or more prior singleton spontaneous preterm births (ssPTBs). The women all received intramuscular(IM) 17-alpha hydroxyprogesterone caproate (17OHPC) prophylaxis without a lowering in the preterm birth (PTB) recurrence rate. The investigators were surprised by this in light of the specific recommendation of the Society of Maternal-Fetal Medicine (SMFM)2 for use of 17OHPC for this indication, first in 2012, but just reaffirmed3 in 2017.
- Full-Text
- Preview
