Correspondence
Progesterone and Preterm Birth
N Engl J Med 2007; 357:2306-2307November 29, 2007
- Article
To the Editor:
The reports by Fonseca et al. and Rouse et al. (Aug. 2 issue)1,2 raise important issues regarding the efficacy and safety of progestins for the prevention of preterm birth. An essential difference between the two study designs is that the study by Fonseca et al. evaluated progesterone administration for a defined pathologic condition, premature cervical shortening, and the the study by Rouse et al. assessed treatment for a risk factor, twin pregnancy.
Rouse et al. observed an increase in deliveries that occurred before 28 weeks of gestation and a nonsignificant increase in newborns with birth weights below 1500 g (relative risk, 2.0; 95% confidence interval [CI], 1.0 to 3.9) after exposure to 17 alpha-hydroxyprogesterone caproate (17P), raising a safety concern. The Food and Drug Administration has previously identified a safety signal for early pregnancy loss with early exposure to 17P.3 Other randomized, blinded, placebo-controlled trials in which 17P was used at less than 20 weeks of gestation have also noted similar nonsignificant increases in miscarriage.4,5 Use of this synthetic agent earlier in pregnancy should therefore be carefully reconsidered, especially since the natural hormone has been found to be safe and efficacious.1 In addition, the lack of benefit and possibility of harm observed with active treatment in the trial by Rouse et al. suggests that future trials might best be focused on women with objective findings suggesting pathophysiology predisposing them to preterm delivery.
5 ReferencesJohn M. O'Brien, M.D.
Central Baptist Hospital, Lexington, KY 40503
jobrien@bhsi.com 1
Fonseca EB ,Celik E ,Parra M , et al. Progesterone and the risk of preterm birth among women with a short cervix. N Engl J Med 2007;357:462-469
Full Text | Web of Science | Medline2
Rouse DJ ,Caritis SN ,Peaceman AM , et al. A trial of 17 alpha-hydroxyprogesterone caproate to prevent prematurity in twins. N Engl J Med 2007;357:454-461
Full Text | Web of Science | Medline3
17-Alpha hydroxyprogesterone caproate for prevention of preterm birth: overview of FDA background document. Rockville, MD: Food and Drug Administration. (Accessed November 9, 2007, at http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4227B1-02-01-FDA-Background.pdf.)
4
Yemini M ,Borenstein R ,Dreazen E , et al. Prevention of premature labor by 17 alpha-hydroxyprogesterone caproate. Am J Obstet Gynecol 1985;151:574-577
Web of Science | Medline5
Johnson JWC ,Austin KL ,Jones GS ,Davis GH ,King TM . Efficacy of 17 alpha-hydroxyprogesterone caproate in the prevention of premature labor. N Engl J Med 1975;293:675-680
Full Text | Web of Science | Medline
To the Editor:
Fonseca et al. showed that spontaneous delivery at less than 34 weeks of gestation was less frequent with progesterone than with placebo in women with a short cervix, with no improvement in neonatal morbidity. The authors suggest a role for routine cervical ultrasound screening and prophylactic progesterone administration.
The number needed to treat to prevent one early birth is only 6.6 (95% CI, 3.8 to 22.8). However, given the low prevalence of a short cervix (1.5%) among low-risk women, the number needed to scan is 650 (95% CI, 379 to 2248).
Authorities in the United Kingdom recommend abdominal scans for structural anomalies between 18 and 20 weeks of gestation.1 Routine vaginal scanning at a later gestational age would have a considerable impact on the provision of services.
Prolonging gestation does not necessarily translate into improved neonatal outcomes. The divergent Kaplan–Meier curves suggest that progesterone is most beneficial after 30 weeks, when the benefit of prolonging pregnancy is less certain. Routine vaginal scanning at later gestational ages is not yet justified.
1 ReferencesManju Chandiramani, M.B., Ch.B., B.Sc.
Rachel Tribe, Ph.D., B.Sc.
Andrew Shennan, M.D.
King's College London, London SE1 7EH, United Kingdom
manju.chandiramani@kcl. ac. uk Author/Editor Response
In England, pregnant women used to undergo one routine ultrasound examination at 16 to 20 weeks of gestation. Now they are offered one scan at 11 weeks to 13 weeks 6 days for pregnancy dating and early diagnosis of major chromosomal and other fetal abnormalities and another scan at 20 to 24 weeks for examination of the fetal anatomy and growth. Measurement of cervical length, which takes about 5 minutes to perform, does not require an additional hospital visit; it can be carried out at the time of the second scan.
In our study, the benefit of progesterone in prolonging pregnancy was apparent from the commencement of drug administration. In the Kaplan–Meier analysis, the survival curves for progesterone and placebo were not divergent but approximately parallel, and there was no significant variation in the hazard ratio over the period from commencement of progesterone administration to the end of the 33rd completed week. Progesterone was also associated with a nonsignificant reduction in neonatal morbidity (8.1% vs. 13.8%; relative risk, 0.59; 95% CI, 0.26 to 1.25).
We agree with the comments of O'Brien.
Kypros H. Nicolaides, M.D.
Ebru Celik, M.D.
Eduardo B. Fonseca, M.D.
King's College Hospital, London SE5 8RX, United Kingdom
kypros@fetalmedicine.com Author/Editor Response
We take issue with some of O'Brien's assertions. First, one1 of the two reports he cites as noting an increased rate of miscarriage did not in fact provide data on miscarriage. Second, in our study, miscarriage occurred less frequently with 17P — in two versus four pregnancies (relative risk, 0.5, 95% confidence interval, 0.07 to 2.8) — although the difference was not statistically significant. Third, the distinction between “findings suggesting pathophysiology” and a “risk factor” seems as much philosophical as biologic. In our trial, the rate of delivery before 28 weeks of gestation was 7%, and the rate of birth weight below 1500 g was 11.3%, 11 and 10 times the national rates2 for singletons, respectively. These rates are inarguably pathologic. Fourth, though 17P was ineffective in twin pregnancies, we believe it would be ill-advised to abandon a pharmacologic intervention that has been clearly shown to decrease the risk of recurrent preterm birth1,3 without demonstrable harm1,3,4 on the dubious grounds of a “safety signal” or a “natural” versus “synthetic” construct.
4 ReferencesDwight J. Rouse, M.D.
University of Alabama at Birmingham, Birmingham, AL 35249
drouse@uab.edu Elizabeth A. Thom, Ph.D.
George Washington University Biostatistics Center, Rockville, MD 20852Catherine Y. Spong, M.D.
National Institute of Child Health and Human Development, Bethesda, MD 20892for the NICHD Maternal Fetal Medicine Units Network
1
Johnson JWC ,Austin KL ,Jones GS ,Davis GH ,King TM . Efficacy of 17 alpha-hydroxyprogesterone caproate in the prevention of premature labor. N Engl J Med 1975;293:675-680
Full Text | Web of Science | Medline2
Martin JA, Hamilton BE, Sutton PD, et al. Births: final data for 2004. National vital statistics reports. Vol. 55. No. 1. Hyattsville, MD: National Center for Health Statistics, 2006.
3
Meis PJ ,Klebanoff M ,Thom E , et al. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med 2003;348:2379-2385[Erratum, N Engl J Med 2003;349:1299.]
Full Text | Web of Science | Medline4
Northen AT ,Norman GS ,Anderson K , et al. Follow-up of children exposed in utero to 17 alpha-hydroxyprogesterone caproate compared with placebo. Obstet Gynecol 2007;110:865-872
CrossRef | Web of Science | Medline
