This is the first report of the relationship between plasma 17-OHPC concentrations and gestational age at delivery.7
The current study provides considerable insight into the drug’s impact on selected markers of preterm birth and on endogenous hormones. The most intriguing findings of this study relate to the relationship of 17-OHPC and gestational age at delivery particularly with evidence of early systemic inflammation in women receiving 17-OHPC. Adjusting for 17-OHPC in the proportional hazards regression, as well as race/ethnicity, BMI and gestational age at blood draw, CRP did not show a significant relationship with gestational age at delivery (p=0.06). In addition, we could not demonstrate a relationship between 17-OHPC and CRP concentrations suggesting that the negative relationship between gestational age at delivery and 17-OHPC concentrations may not be primarily attributable to an effect of the elevated CRP. Labor and parturition are recognized as inflammatory states; therefore, it is possible that the elevated CRP concentrations represent a concomitantly activated parturitional process rather than an antecedent cause of the parturitional process. Although CRP was significantly higher in the 17-OHPC treated group compared with the placebo group was significantly higher in the 17-OHPC treated group compared with the placebo group at 24–28 weeks, by 32–35 weeks the CRP concentrations were similar in the two groups. The apparent negative association of 17-OHPC concentration and gestational age at delivery was not associated with significant difference in gestational age at delivery in parent study or in the ancillary study reported here 2
. In the parent study, delivery or fetal death before 35 weeks occurred in 41.5% of pregnancies in the 17-OHPC group and 37.3% of those in the placebo group (relative risk, 1.1; 95% confidence interval [CI], 0.9 to 1.3). Yet, among these same subjects we were able to demonstrate a highly significant negative relationship between 17-OHPC concentrations and gestational age at delivery. A similar relationship is seen between 17-OHPC and progesterone concentrations. Although mean progesterone concentrations did not differ significantly between treatment groups a very strong relationship was seen between 17-OHPC and progesterone concentrations. These observations suggest that the negative association between 17-OHPC concentration and gestational age at delivery may impact a limited subset of subjects with twin gestation. For example, women with specific progesterone receptor (PR) genotype polymorphisms may be at particular risk. Manuck et al9
reported that certain PR single nucleotide polymorphisms (SNPs) were associated with higher risk of preterm birth in response to 17-OHPC. Whether PR SNPs were responsible for the inverse relationship between 17-OHPC concentration and gestational age at delivery noted in this study is unknown as we did not determine PR polymorphisms in this group.
The inverse relationship between 17-OHPC concentration and gestational age at delivery and the elevated CRP in the 17-OHPC group in twins should not be extrapolated to singleton gestations since the drug concentration and pregnancy outcome relationships may be different. Clearly additional pharmacologic data may help to define the relationship between progesterone supplementation and pregnancy outcome in twins. Whether these relationships have applicability to singleton gestation is unknown.
We also found several interesting and perhaps clinically relevant associations with 17-OHPC use. First we found a very strong relationship between 17-OHPC and progesterone concentrations even though plasma progesterone concentrations were, overall, not significantly different between the two treatment groups. This can be explained by the fact that several factors affect progesterone concentrations and the impact of 17-OHPC on plasma progesterone concentration is relatively small compared with these other factors. In human liver microsomes, progesterone competes with metabolism of 17-OHPC.10
Progesterone and 17-OHPC are both metabolized by CYP 3A4 and it is likely that the increase in progesterone concentrations is due to some degree of inhibition with the metabolizing enzyme.11
In monkeys, 17-OHPC clearly increases progesterone concentrations12
but in human studies, including the current one, median values are increased with 17-OHPC treatment but only modestly.13,14
Whether the increase in progesterone concentrations has a benefit on pregnancy outcome cannot be determined at this time. The fact that progesterone supplementation seems to reduce preterm birth in certain subsets of at-risk women suggests that an increase in progesterone concentrations is central to any beneficial effect of progestin supplementation. Plasma progesterone concentrations do not reflect tissue concentrations of progesterone thus the positive impact of 17-OHPC on progesterone concentration may be much greater at the tissue level than at the plasma level and may account for any benefit attributable to this therapy.
The strength of the relationship between CRH and 17-OHPC concentration is relatively modest and, in fact, 17-OHPC is positively not negatively associated with CRH concentration. It is important to evaluate the relationship between CRH and 17-OHPC because CRH increases in both term and preterm births weeks prior to delivery. Since 17-OHPC is positively related to CRH concentration, this could imply a potential adverse effect of 17-OHPC treatment. Although the dose relationship is weak, it is possible that 17-OHPC has a clinically relevant impact on CRH and gestational age at delivery. In fact, we have previously demonstrated that although BMI has a very modest relationship (r= −0.28 to −0.34) to 17-OHPC concentration, when BMI is modeled against plasma 17-OHPC concentrations, it has a very dramatic effect on plasma concentrations 15
. Clearly additional data are required to reach any meaningful conclusion about this intriguing relationship especially in singleton gestation.
In conclusion, we have demonstrated, for the first time, the relationship between 17-OHPC concentration and gestational age at delivery in women with twin gestation. This may define more clearly the potential risks and benefits of this therapy. We have demonstrated that among women with twin gestation higher plasma concentrations of 17-OHPC are associated with a shorter gestational age at delivery than lower concentrations of 17-OHPC. Women receiving 17-OHPC have higher CRP values than women receiving placebo but no dose relationship between CRP and 17-OHPC is apparent. We have also demonstrated a strong dose-relationship between 17-OHPC and progesterone and a modest but significant relationship between 17-OHPC and CRH especially the rate of rise of CRH. The findings above apply to women with twin gestation and cannot be assumed to pertain in women with singleton gestation. More research is required to define the mechanism of action of 17-OHPC and to optimize the dose of 17-OHPC especially in singleton gestation where efficacy has been demonstrated. An urgent need exists to identify subsets of women who may most benefit from this therapy and to define those who might be harmed by this therapy.