Reply
2017; Elsevier BV; Volume: 218; Issue: 3 Linguagem: Inglês
10.1016/j.ajog.2017.11.582
ISSN1097-6868
AutoresDavid B. Nelson, Donald D. McIntire, Kenneth J. Leveno,
Tópico(s)Ectopic Pregnancy Diagnosis and Management
ResumoThis letter-to-the-editor is the third inquiry from Dr Zelig regarding our report on 17-alpha hydroxyprogesterone caproate (17-OHPC).1Nelson D.B. McIntire D.D. McDonald J. Gard J. Turrichi P. Leveno K.J. 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 There were 2 earlier personal communications; we begin our response by summarizing these earlier queries. Dr Zelig questioned our study on the grounds that we used historical controls. Dr Zelig’s concern was that changes in practice patterns in pregnancies that were complicated by preterm premature ruptured membranes (PPROM) could have skewed our results. Specifically, he discussed management of PPROM between 34 and 35 weeks gestation. We responded, “We are of the view that your query is appropriate. Indeed, as a result of your query, we have reviewed reports on progesterone efficacy — and could not find commentary on management of ruptured membranes between 34 and 35 weeks. Clearly stimulation of labor at 34–35 weeks would artificially increase the rate of births less than 35 weeks which could potentially diminish the effectiveness of 17-OHPC. A long-standing practice at Parkland Hospital, in place long before our prospective observational trial of 17-OHPC, was to deliver women with ruptured membranes beyond 34 weeks. However, we do provide expectant management before 34 weeks and have done so for more than 30 years. Of the 106 women with recurrent preterm births less than 35 weeks and receiving 17-OHPC, there were a total of 3 women who had ruptured membranes between 34 and 35 weeks and who received oxytocin stimulation. Removing these 3 women from our analysis would have no significant effect on our results. Specifically, before removing these three women the rate of recurrence was 24.7% compared to 24% after removing the 3 women with stimulated labor.” Dr Zelig pursued his previous line of questioning regarding management of PPROM and the use of a historical control cohort in the context of “indicated” births. In our response, we reiterated our management practices described in response to his first query. We then reviewed our use of a historical control group using our preexisting obstetrics database for women with previous preterm births for the years 1988–2011.1Nelson D.B. McIntire D.D. McDonald J. Gard J. Turrichi P. Leveno K.J. 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 During this time period, a total of 5787 women had at least 2 deliveries at Parkland, at least 1 of which was ≤35 weeks gestation. This cohort of women then served as a pool from which to identify case control women (3 to 1, controls to 17-OHPC treated women). We matched for recurrence patterns of previous preterm birth number and sequence (6 individual patterns), race, and body mass index ≥30 kg/m2. This was an assiduous effort to account for the specific preterm birth pattern because, in our opinion, it is the most powerful risk factor for recurrence.2Nelson D.B. McIntire D.D. Leveno K.J. Reply.Am J Obstet Gynecol. 2017; ([Epub ahead of print])https://doi.org/10.1016/j.ajog.2017.09.019Abstract Full Text Full Text PDF Scopus (1) Google Scholar We then explained to Dr Zelig that there were no significant differences in the rates of spontaneous preterm deliveries, PPROM, and indicated births at ≤35 weeks gestation comparing the 1290 matched cases with the 430 women who were treated with 17-OHPC. We have already responded to Dr Zelig twice in personal communications that the scenario he portrays of expectant management until 36 weeks gestation for PPROM was not the practice at Parkland. This is explicitly stated in the 17th edition of Williams Obstetrics published in 1984 and follows in editions thereafter.3Pritchard J.A. MacDonald P.C. Gant N.F. Williams Obstetrics. 17th ed. Appleton & Lange, East Norwalk (CT)1985Google Scholar To be clear, the management of PPROM has been consistent during the years of this study and continues to be the current practice at Parkland. Drs Zelig and Dexter then pivot to improvements in neonatal care between 1988 and 2016 and imply that this could confound our 17-OHPC results. True, neonatal outcomes have greatly improved, but the rate of preterm birth discouragingly has remained little changed. To be explicit, the focus of our report was recurrent preterm birth—not neonatal care. Drs Zelig and Dexter then again attempt to disparage our study — now challenging the assignment of gestational age. Their inference is that gestational age assignment “… cannot be considered to be nearly as accurate…” which therefore confounds our results. The assignment of gestational age assigned to each pregnancy entered into the Parkland Obstetric Database, beginning in 1988 and continuing today, was the best obstetric estimate that was used during management in labor and delivery. Assignment of gestational age is protocol defined and begins with last menstrual period and includes pregnancy landmarks to include fundal height.4Jimenez J.M. Tyson J.E. Reisch J.S. Clinical measures of gestational age in normal pregnancies.Obstet Gynecol. 1983; 61: 438-443PubMed Google Scholar Discrepancies were checked with the use of sonography. For example, in 2008 at Parkland, 15,392 women delivered, and 18,221 obstetric ultrasound examinations were performed. The suggestion that misclassification of gestational age confounds our results does not compute. As shown in the Figure, when examined by gestational week with the use of national data, the percent agreement of the last menstrual period–based measure of gestational age compared with the best obstetric estimate with the use of sonography as needed (similar to our practice at Parkland) was virtually superimposed for each week <37 weeks gestation.5Martin J.A. Osterman M.J. Kirmeyer S.E. Gregory E.C. Measuring gestational age in vital statistics data: transitioning to the obstetric estimate.Natl Vital Stat Rep. 2015; 64: 1-20PubMed Google Scholar Indeed, the 2 gestational age estimates show essentially the same percentages of births at 37–38 weeks gestation.5Martin J.A. Osterman M.J. Kirmeyer S.E. Gregory E.C. Measuring gestational age in vital statistics data: transitioning to the obstetric estimate.Natl Vital Stat Rep. 2015; 64: 1-20PubMed Google Scholar Drs Zelig and Dexter’s open-ended assertion that gestational age assignment in our obstetric dataset “…cannot be considered to be nearly as accurate…” is not the reason 17OHP-C failed. Throughout these exchanges with Dr Zelig, the historical cohort spanning 1988–2011 is repeatedly used in a pejorative context, which includes in the title of this letter. It is disappointing that our study design is considered a “limitation” by Drs Zelig and Dexter because we believe that the use of a historical cohort is actually a major strength. In fact, our analysis depended on the use of such a historical cohort to create a pool of patients from which to match recurrent preterm births in the 3:1 matched analysis. This effort was made possible only by the use of a computerized database that has been operational at Parkland since 1988 and has been supervised directly by ≥1 of the coauthors since its inception (K.J.L., D.D.M.). To give background on the magnitude of this effort, 355,002 women delivered at our hospital from 1988 –2011, and this delivery volume served as the backdrop for our historical control. Put another way, the matched control cohort of 1290 women was made possible by the 355,002 births in our dataset. This, in turn, made possible the matching for race/ethnicity, obesity, and specific number and sequence of previous preterm birth. As we have previously emphasized, the a priori risk of a patient, and subsequent attributable benefit of 17OHP-C, can be made only when considering the individual patient risk. And because we chose a clinically meaningful outcome of prematurity defined as ≤35 weeks gestation (rather than 37 weeks gestation), accounting for these demographic features and specific prematurity risk profile of each woman was made possible only by exercising the breadth of such a dataset. To summarize, nothing we can answer apparently will satisfy — nay appease Dr Zelig. After 3 separate inquiries, he seems intent on treating patients with 17-OHPC. Such treatment is certainly his prerogative, and we are not attempting to deprive him of the opportunity to use 17OHP-C. We again refer to the commentary in our original report in which the 17OHP-C story is chronicled and in which we described the 1 randomized trial by Meis et al6Meis 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 (1266) Google Scholar that is at the foundation of Dr Zelig’s enthusiasm for 17OHP-C. Because of the asymmetric risk of preterm birth in the randomization of patients because differing histories of preterm birth, this study is clearly not without serious blemish. Should the 17OHP-C story end with this 1 trial? We think not. This is especially true, given that 17OHP-C has become a billion dollar vehicle for the pharmaceutical industry.7Fried I. Beam A.L. Kohane I.S. Palmer N.P. Utilization, cost, and outcome of branded vs compounded 17-alpha hydroxyprogesterone caproate in prevention of preterm birth.JAMA Intern Med. 2017; ([Epub ahead of print.])https://doi.org/10.1001/jamainternmed.2017.5017Crossref Scopus (11) Google Scholar The result of which is not only prescribing a potentially extremely expensive therapy but also an ineffective one. Moreover, believing that we have found an answer for the prevention of preterm birth stymies the search for another—effective—alternative. As physicians, we believe that we have a responsibility to measure the efficacy and safety of the treatments that we prescribe. For this reason, we believe that our pragmatic trial of 17OHP-C was imperative for us. We remain confident that our prospective observational trial was performed carefully and about as good as a single-center study as could be done without unblemished randomization. We are of the view that prospective observational trials have an important place in contemporary obstetrics where a single randomized trial has become a de facto, “forever more trial” as is the case with the Meis et al trial6Meis 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 (1266) Google Scholar for the past 14 years. 17-alpha Hydroxyprogesterone caproate did not reduce the rate of recurrent preterm birth in a prospective cohort studyAmerican Journal of Obstetrics & GynecologyVol. 216Issue 6Preview17-alpha Hydroxyprogesterone caproate for prevention of recurrent preterm birth is recommended for use in the United States. Full-Text PDF
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