It’s Déjà vu All Over Again’ *
Abstract & Commentary
Synopsis: Weekly injections of alpha-hydroxyprogesterone caproate resulted in a substantial reduction in the rate of recurrent preterm delivery among women who were at particularly high risk for preterm delivery and reduced the likelihood of several complications in their infants.
Source: Meis PF, et al. N Engl J Med. 2003;348(24): 2379-2385.
The National Institutes of Health (NIH) supported perinatal network recently conducted a study that was published in the New England Journal of Medicine this summer. It was a randomized control trial (RCT) to evaluate the ability of intramuscular progesterone to prolong pregnancy in patients at historical risk of preterm delivery.
Four hundred sixty-three women with a history of prior preterm birth (PTB) were randomized in 19 centers to have either weekly injections of 17 alpha-hydroxyprogesterone caproate (310) or an inert oil as placebo (153). The progesterone group had significantly lower rates of PTB before 37 weeks (36% vs 59%), before 35 weeks (20.6% vs 30.7%), and before 32 weeks (11.4% vs 19.6%). Compared with placebo, the progesterone group had significantly lower risk of necrotizing enterocolitis, interventricular hemorrhage, and need for oxygen in their infants compared with those given placebo in the same weekly regimen after 20 weeks.
Comment by John C. Hobbins, MD
Off and on progesterone has been used in pregnancy in various ways through the years with enough supporting reports to suggest it could be the obstetricians’ "magic bullet." Our colleagues in reproductive endocrinology have distributed it to far more patients in early pregnancy than could possibly have a true luteal phase defect, and as far back as 1960 Fritz Fuchs suggested its use to prevent preterm labor.1
There is certainly enough compelling evidence from basic investigations to suggest the possibility of its efficacy in prolonging pregnancy. In vitro progesterone prepared uterine muscle will not contract when stimulated electronically. Also, progesterone suppresses the action of estrogen (which at least indirectly stimulates contractions) by inhibiting replacement of estrogen receptors, and it also suppresses the contractile effect on the myometrium of prostaglandin F2-alpha. In nonhuman primates and in sheep, progesterone levels decrease prior to labor and it has been shown that there is a drop in progesterone receptors during labor.
It seems that the intramuscular delivery of progesterone (which at face value would not seem to be able, by weekly injections, to get to the myometrial cells in high enough quantity to work) is not the only route that is effective. For example, in a report in February 2003, a Brazilian group reported similar impressive results in pregnancy prolongation with daily application of progesterone vaginal suppositories.2 These investigators also found that patients on progesterone had fewer uterine contractions during periodic assessment with a tocodynamometer than those using placebos.
In general, studies assessing the ability of various tocolytics to stop labor have suffered from the inclusion of patients not in true labor—not so with the above New England Journal of Medicine and Brazilian studies, which had quite high rates of PTB in the placebo groups (54.9% and 28.5%, respectively). In fact, the rate in the New England Journal of Medicine study was unusually high for a mixed group of patients with only a history of at least one PTB. Nevertheless, these studies have to get our attention.
* — Quote attributed to Yogi Berra
Dr. Hobbins is Professor and Chief of Obstetrics, University of Colorado Health Sciences Center, Denver.
1. Fuchs F, Stakeman G. Am J Obstet Gynecol. 1960; 79:172.
2. da Fonseca EB, et al. Am J Obstet Gynecol. 2003; 188(2):419-424.