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Abstract

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).1US Food and Drug Administration. [email protected]: FDA Approved Drug Products. Available at: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=021945. Accessed March 29, 2018.Google Scholar Before attempting to answer this question, we feel it is important to survey the 17OHP-C evidence. The reported beneficial effects of 17OHP-C have been limited to women with current singleton pregnancies as prophylaxis in multifetal gestations and nulliparous women with a sonographic short cervix has not resulted in lowered preterm birth rates.2Caritis S.N. Rouse D.J. Peaceman A.M. et al.Prevention of preterm birth in triplets using 17 alpha-hydroxyprogesterone caproate: a randomized controlled trial.Obstet Gynecol. 2009; 113: 285-292Crossref PubMed Scopus (103) Google Scholar, 3Rouse D.J. Caritis S.N. Peaceman A.M. et al.A trial of 17 alpha-hydroxyprogesterone caproate to prevent prematurity in twins.N Engl J Med. 2007; 357: 454-461Crossref PubMed Scopus (311) Google Scholar, 4Grobman W.A. Thom E.A. Spong C.Y. et al.17 Alpha-hydroxyprogesterone caproate to prevent prematurity in nulliparas with cervical length less than 30 mm.Am J Obstet Gynecol. 2012; 207: 390.e1-390.e8Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar Accordingly, both the American College of Obstetricians and Gynecologists (ACOG) and the SMFM have legitimized the use of 17OHP-C for prevention of preterm birth in women with singleton pregnancies and a history of preterm birth.5American College of Obstetrics and GynecologistsPrediction and prevention of preterm birth. Practice bulletin no. 130.Obstet Gynecol. 2012; 120: 964-973Crossref PubMed Scopus (200) Google Scholar, 6Society for Maternal-Fetal Medicine (SMFM) Publications CommitteeThe 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-B13Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar These statements, however, hinge upon the results of a single trial—the 2003 publication by Meis and colleagues.7Meis P.J. Klebanoff M. Thom E. et al.Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate.N Engl J Med. 2003; 348: 2379-2385Crossref PubMed Scopus (1267) Google Scholar For more than a decade, the Meis et al7Meis P.J. Klebanoff M. Thom E. et al.Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate.N Engl J Med. 2003; 348: 2379-2385Crossref PubMed Scopus (1267) Google Scholar study has been challenged because of the unexpectedly high preterm delivery rate in the placebo group.8Romero R. Stanczyk F.Z. Progesterone is not the same as 17α-hydroxyprogesterone caproate: implications for obstetrical practice.Am J Obstet Gynecol. 2013; 208: 421-426Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar Specifically, 55% of the placebo group delivered preterm rather than the expected 36%. An explanation offered for such a high rate of preterm birth in the control group was asymmetry in risk of recurrence. Moreover, the mechanism of action remains unknown, and the pharmacological properties have yet to be established. Indeed, recent data presented at the SMFM 38th Annual Pregnancy Meeting further questions 17OHP-C efficacy wherein—similar to our published results—drug levels of 17OHP-C were not associated with reduced rates of preterm birth.9Downes K.L. Raman V. Caritis S. et al.Recurrent spontaneous preterm birth risk is not associated with 17-alpha hydroxyprogesterone caproate.Am J Obstet Gynecol. 2018; 218: S422-S423Google Scholar And ultimately, reports of clinical effectiveness have yet to be replicated. Consequently, we emphasize our experience with 17OHP-C.10Nelson D.B. McIntire D.D. 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.e1-600.e9Abstract Full Text Full Text PDF Scopus (62) Google Scholar Specifically, we performed a prospective observation study of 430 women treated with 17OHP-C. These women were compared to 1290 untreated women matched for obesity (body mass index ≥30 kg/m2), race/ethnicity, and individual-specific preterm birth history—using both the number and sequence of prior preterm births. As shown in the Figure, 17OHP-C was ineffective in reducing the rate of recurrent births ≤35 weeks. Furthermore, 17OHP-C was associated with an increased rate of gestational diabetes (13.4% 17OHP-C treated vs 8% controls; P = .001). Blood levels of 17OHP-C at 24 and 32 weeks in women receiving 17OHP-C were also not different between those delivering ≤35 and >35 weeks. In principle, our findings diametrically oppose the findings from the Meis et al7Meis P.J. Klebanoff M. Thom E. et al.Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate.N Engl J Med. 2003; 348: 2379-2385Crossref PubMed Scopus (1267) Google Scholar study. Thus, based upon concerns with the Meis et al7Meis P.J. Klebanoff M. Thom E. et al.Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate.N Engl J Med. 2003; 348: 2379-2385Crossref PubMed Scopus (1267) Google Scholar trial and our own data, we and others believe that the evidence to support the use of 17OHP-C to prevent recurrent preterm birth is problematic.11Young D. Clinical trials and tribulations: 17OHPC and preventing recurrent preterm birth.Am J Obstet Gynecol. 2017; 216: 543-546Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar It is because of these issues that we feel the need to underscore the consequences of organizations legitimizing use of 17OHP-C and the associated high costs of health care in the United States.12Bloom S.L. Leveno K.J. Unproven technologies in maternal-fetal medicine and the high cost of US health care.JAMA. 2017; 317: 1025-1026Crossref PubMed Scopus (8) Google Scholar For example, a recent report by Fried and colleagues13Fried I. Beam A.L. Kohane I.S. et al.Utilization, cost, and outcome of branded vs compounded 17-alpha hydroxyprogesterone caproate in prevention of preterm birth.JAMA Intern Med. 2017; 177: 1689-1690Crossref PubMed Scopus (11) Google Scholar found that the branded drug cost of 17OHP-C was 5200% more than the equivalent compounded drug ($10,917 vs $206). In the case of 17OHP-C, this has translated to enormous revenue for the pharmaceutical industry. Indeed, the manufacturer, AMAG Pharmaceuticals, reported that the Makena revenues grew to nearly $400 million in 2017.14AMAG Pharmaceuticals. AMAG Pharmaceuticals Announces FDA Approval of Makena® (hydroxyprogesterone caproate injection) Subcutaneous Auto-Injector to Reduce the Risk of Preterm Birth in Certain At-Risk Women. Available at: https://www.amagpharma.com/news/amag-pharmaceuticals-announces-fda-approval-of-makena-hydroxyprogesterone-caproate-injection-subcutaneous-auto-injector-to-reduce-the-risk-of-preterm-birth-in-certain-at-risk-women/. Accessed March 29, 2018.Google Scholar Ultimately, the financial consequences of such conduct can be found in the national health care expenditures shared by all in the United States.15Papanicolas I. Woskie L.R. Jha A.K. Health care spending in the United States and other high-income countries.JAMA. 2018; 319: 1024-1039Crossref PubMed Scopus (766) Google Scholar Indeed, the United States spends twice as much per capita on health care but performs less well on many health outcomes compared to other high-income countries.15Papanicolas I. Woskie L.R. Jha A.K. Health care spending in the United States and other high-income countries.JAMA. 2018; 319: 1024-1039Crossref PubMed Scopus (766) Google Scholar, 16Emanuel E.J. The real cost of the US health care system.JAMA. 2018; 319: 983-985Crossref PubMed Scopus (39) Google Scholar, 17Parente S.T. Factors contributing to higher health care spending in the United States compared with other high-income countries.JAMA. 2018; 319: 988-990Crossref PubMed Scopus (8) Google Scholar Drug prices are a major driver to this cost.16Emanuel E.J. The real cost of the US health care system.JAMA. 2018; 319: 983-985Crossref PubMed Scopus (39) Google Scholar For example, Papanicolas and associates15Papanicolas I. Woskie L.R. Jha A.K. Health care spending in the United States and other high-income countries.JAMA. 2018; 319: 1024-1039Crossref PubMed Scopus (766) Google Scholar recently reported that the total US pharmaceutical expenditures are $1443 per capita compared to mean $749 of the 11 other high-income countries examined. This finding is consistent with the US Department of Health and Human Services that showed that 16.7% of total personal health care spending ($457 billion in 2015) was attributed to pharmaceuticals.18Office of Assistant Secretary for Policy and Evaluation, Department of Health and Human Services. Observations on trends in prescription drug spending. Available at: https://aspe.hhs.gov/pdf-report/observations-trends-prescription-drug-spending. Accessed March 29, 2018.Google Scholar No other category of spending accounts for as much of the cost difference than pharmaceuticals.16Emanuel E.J. The real cost of the US health care system.JAMA. 2018; 319: 983-985Crossref PubMed Scopus (39) Google Scholar And so, the question remains, to 17OHP-C or not to 17OHP-C? What is the cost in doing so? And, what is the standard of care? A disclaimer within the SMFM publication regarding choice of progestogens states that it “is neither designed nor intended to establish an exclusive standard of perinatal care.”6Society for Maternal-Fetal Medicine (SMFM) Publications CommitteeThe 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-B13Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar Similarly, the ACOG practice bulletin states, “these guidelines should not be construed as dictating an exclusive course of treatment or procedure.”5American College of Obstetrics and GynecologistsPrediction and prevention of preterm birth. Practice bulletin no. 130.Obstet Gynecol. 2012; 120: 964-973Crossref PubMed Scopus (200) Google Scholar The reality is that de facto these statements do become the standard of care; ergo, the question asked by Dr Vadnais and Ms Frappaolo. We answer with a question of our own. What is the purpose of publication? We believe that the purpose of peer-reviewed publications in the medical literature is to share experiences—not dictate practice. We do not suggest that we have the final answer. Therefore, we cannot take the position of an ideal course or define the standard of care. Put another way, we are not attempting to make a pronouncement. We feel it is incumbent upon the reader of the medical literature to decide whether to use, or not to use, 17OHP-C. Our purpose beginning with the original article and in all subsequent responses in letters to the editor have been an attempt to report our experience such that the reader can make a decision based on as many experiences as currently available.10Nelson D.B. McIntire D.D. 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.e1-600.e9Abstract Full Text Full Text PDF Scopus (62) Google Scholar, 19Nelson D.B. McIntire D.D. Leveno K.J. Reply.Am J Obstet Gynecol. 2018; 218: 360-362Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar, 20Nelson D.B. McIntire D.D. Leveno K.J. Reply.Am J Obstet Gynecol. 2018; 218: 261-262Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar, 21Nelson D.B. McIntire D.D. Leveno K.J. Reply.Am J Obstet Gynecol. 2017; 217: 621-622Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar Response to 17-alpha hydroxyprogesterone caproateAmerican Journal of Obstetrics & GynecologyVol. 219Issue 2PreviewDr 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. Full-Text PDF