Compliance with the intervention was defined as the ratio of the number of injections received to the number expected per protocol (number of whole weeks from randomization to delivery, or to 34 weeks 6 days gestation, whichever was first). Compliance was 95.6% in the 17-OHPC group and 97.0% in the placebo group (P=.08).
The rate of the primary outcome (delivery or fetal death before 35 weeks) did not differ between groups occurring in 83% (59 of 71) of pregnancies in the 17-OHPC group, and in 84% (53 of 63) in the placebo group, relative risk (RR) 1.0, 95% confidence interval (CI) 0.9–1.1 (Table 2). Results were similar when adjusted by race. Mean gestational age at delivery did not differ between groups, nor did the proportion of deliveries occurring before 32 or 28 weeks. Table 2 also compares each of the components of the primary outcome in the two treatment groups. The rates of spontaneous (48% and 43%) and indicated (35% and 41%) preterm births were similar in the 17-OHPC and in the placebo groups, respectively. There were seven fetal losses from the time of randomization to 34 6/7 weeks, one in the 17-OHPC group and six in the placebo group. There were no fetal losses after 35 weeks. The fetal death in the 17-OHPC group was associated with multiple malformations. The six fetal losses in the placebo group occurred in three pregnancies; in one, delivery occurred at 23 weeks secondary to preeclampsia and preterm labor and all three fetuses died during labor. In the other two pregnancies, the deaths were unexplained and the remaining fetuses survived. Figure 2 depicts the proportion of randomly assigned participants who remained undelivered and with three living fetuses according to the gestational age and treatment group. The two groups were similar (P=.743). Table 3 summarizes selected maternal outcomes and interventions; there were no significant differences between the two groups.
The rate of the serious adverse composite neonatal outcome (neonatal death, severe retinopathy of prematurity, respiratory distress syndrome, early onset neonatal culture-proven sepsis, necrotizing enterocolitis stage II or III, bronchopulmonary dysplasia, intraventricular hemorrhage grade III or IV, or periventricular leukomalacia) was 37% in the 17-OHPC group compared with 34% in the placebo group, RR 1.1, 95% CI 0.7–1.7 (Table 4). Table 4 also summarizes selected neonatal outcomes according to treatment group. There were five neonatal deaths among four of the pregnancies treated with 17-OHPC. These newborns were delivered at 24 (two neonates), 25, 30, and 32 weeks. All died due to complications of prematurity. The pregnancy delivered at 24 weeks was the same pregnancy with the fetal demise associated with multiple anomalies. There were two neonatal deaths in the placebo group in two separate pregnancies. Both infants were delivered at 25 weeks and died of complications of prematurity. Likewise, the rates of individual outcomes were similar in the two treatment groups (Table 4). There was a greater proportion of infants in the 17-OHPC group with a birth weight less than 1,500 g; the difference was statistically significant (43% compared with 25%, RR 1.7, 95% CI 1.1–2.7). However, there was no overall difference in birth weight (as a continuous variable, P=.142) or in the proportion of neonates with a birth weight of less than 2,500 g (RR 0.9, 95% CI 0.9–1.0).
Adverse effects were common in both groups (69% and 65% in the 17-OHPC and placebo group, respectively, RR 1.1, 95% CI 0.8–1.3), but were generally mild and, in the majority (64%) of women who experienced them were limited to pain, swelling, bruising, itching, or redness at the injection site. Three women (two in the 17-OHPC group and one in the placebo, P=.55) experienced adverse effects so severe that the injections were not continued. These adverse effects included constitutional symptoms and elevated liver enzymes (placebo participant) and intense injection site reactions (two 17-OHPC participants).
This randomized, placebo-controlled trial has demonstrated that 17-OHPC does not reduce the rate of preterm birth in women with triplet gestation. This lack of benefit occurred regardless of conception method. Combined with our companion study with twins,4 the findings of this study help to clarify further those conditions where 17-OHPC should be considered. Although, 17-OHPC reduces the rate of preterm birth in women with a singleton gestation who had a prior preterm birth, this treatment is ineffective in reducing the rate of prematurity in multifetal gestation. The mechanism of action of 17-OHPC in reducing preterm birth rates in singleton gestation is unclear. Consequently, explanations for why this therapy proved ineffective in multifetal gestations must remain speculative. We undertook this study because we hypothesized that 17-OHPC might affect a proposed mechanism for preterm parturition in multiples, that of uterine stretch. The degree of uterine stretch is greater in multiple than in singleton gestation, and it is well-documented that uterine stretch induces transcription of several contraction-associated proteins.10 These proteins, including oxytocin receptors, gap junctions (connexin 43), and cyclooxygenase (COX), characterize an activated myometrium. Progesterone inhibits formation of these contraction-associated proteins.11 Older studies in humans and animals suggest that 17-OHPC is more potent and has a longer lasting progestational effect than progesterone.12,13 This led us to postulate that 17-OHPC might suppress expression of those contraction-associated proteins better than endogenous progesterone and therefore might reduce the rate of preterm delivery among women with multifetal gestation.
The lack of benefit in multifetal gestation may be due to an inadequate dose of 17-OHPC. For this study and our study in twins, we administered 250 mg intramuscularly weekly, a dose identical to that used in our study of singletons.3 We chose to use this dose because the therapeutic concentration of 17-OHPC was and is still not known. The dose selected for the study of Meis et al3 in singletons was based on prior studies14 and a meta-analysis that suggested that 250 mg 17-OHPC might be effective in reducing preterm birth rates in high-risk women.15 If the 250 mg weekly dose achieves “therapeutic” levels in only a portion of women with singleton gestation, that might explain why the success rate in a study of Meis et al3 was only 33%. In the same vein, if the dose of 250 mg 17-OHPC weekly does not achieve therapeutic levels in a substantial percentage of women with singletons, it is conceivable that concentrations in women with multifetal gestation are even lower given the physiologic changes that occur in pregnancy, which generally enhance drug metabolism or elimination. Analysis of the relationship of 17-OHPC concentration and preterm birth rates is currently under investigation in both the women with triplet or twin gestation. This exploration should address those issues related to 17-OHPC dosing and success.
Another plausible explanation for the failure of 17-OHPC to reduce the rates of preterm birth in multifetal gestation may be that myometrial stretch, the proposed mechanism of preterm birth in multiples, is not altered by 17-OHPC. To our knowledge the effect of 17-OHPC on stretch regulated contraction-associated proteins has not been evaluated.
Clearly, any attempt to define the basis of failure of 17-OHPC in reducing preterm birth rates in multiples or in any other group of patients at increased risk of preterm birth is severely constrained by our lack of understanding of how this treatment works. We have defined the pharmacokinetics of 17-OHPC in multifetal gestation and have shown that the drug has a half-life of nearly 9 days (Caritis S, Venkataramanan R. Pharmacokinetics of 17-alpha hydroxyprogesterone caproate (17-OHPC) in women with twin gestation [meeting abstract]. Annual Meeting of the Society for Gynecologic Investigation. Reno, Nevada, 2007.). The long half-life likely represents slow release from the depot injection site. The mechanism of action of 17-OHPC, however, has remained elusive. The drug is no better than progesterone in activating progesterone-responsive genes through the classic hormone–hormone receptor pathway.16 Injection of 17-OHPC does not seem to significantly alter plasma progesterone or 17-hydroxyprogesterone concentrations.17 Thus, the beneficial effect of 17-OHPC is not likely mediated by an effect on any of these hormones. Clearly, more research is required to define the mechanism of action of this drug.
The results of our study and our companion study in twins provide information on fetal safety of 17-OHPC in pregnancy. In reviewing a recent New Drug Application for 17-OHPC, the U.S. Food and Drug Administration raised concern about fetal safety because in the study of Meis et al,3 a nonsignificant increase in fetal deaths (RR 1.5, 95% CI 0.3–7.3) was seen in the 17-OHPC group.18 In our study of twins, fetal deaths were more common in the 17-OHPC group but those differences were not statistically significantly different from the placebo-treated group (RR 1.4, 95% CI 0.6–3.2). In our triplet study, only one fetal death was seen in the 17-OHPC group from the time of enrollment to the study endpoint of 35 weeks, and the fetus had multiple malformations. Six fetal deaths were seen in the placebo group. Our studies in twins and triplets collectively, therefore, provide a measure of reassurance that 17-OHPC therapy does not increase the risk of fetal demise. Furthermore, we found similar rates of small for gestational age infants in our current study among the two treatment groups.
Another issue about 17-OHPC treatment raised by the study of Meis et al3 is addressed with the current study and our companion study in twins, the effect of castor oil on preterm birth rates.4 It has been suggested that the use of castor oil in the placebo group and as a diluent for 17-OHPC might confound findings of 17-OHPC trials by actually increasing uterine contractility through the smooth muscle effects of castor oil.19 Castor oil is a gastrointestinal stimulant only when taken orally and not likely to have any effect on smooth muscle when given intramuscularly, since ricinoleic acid, the active ingredient, is formed by hydrolysis in the gut.20 Furthermore, the mean gestational ages at delivery in the 17-OHPC and placebo groups were consistent with the gestational age at delivery of triplets reported in the U.S. Natality report of 2005.21 Similar findings were seen in our study with twins.
Adverse effects were common in this study and overwhelmingly associated with injection site symptoms, such as pain, itching, and bruising. These findings were similar to those we reported in our study of twins and singletons.3,4 We also tracked serious adverse effects, including outcomes such as maternal death, unplanned hospitalization, and neonatal deaths. There were no maternal deaths reported among our study of triplets or twins. Likewise, the rates of other serious adverse outcomes in these studies were similar in the 17-OHPC and placebo groups.
The application of 17-OHPC therapy to women at risk of preterm birth is supported by our trial in singletons3 and the meta-analysis of Keirse,15 which summarized the literature on the use of 17-OHPC to prevent preterm birth in earlier studies. This treatment unfortunately has been expanded to other groups of women deemed to be at high risk for preterm birth with the expectation that the treatment will work in all high-risk groups.22 The present study and our companion study in twins clearly point out that such expectations are unfounded and that prospective randomized trials are needed before expanding use of 17-OHPC to other at-risk groups.
In summary, we have shown that 17-OHPC, as prescribed in this trial, does not reduce the rate of preterm birth in triplets, and our companion study demonstrated a lack of benefit in twins. Women with multifetal gestation should therefore not be treated with 17-OHPC as a preventive for preterm birth unless new information emerges to alter that recommendation. Treatment with 17-OHPC seems to be safe for the mother and her fetus.
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