Predictors of response to 17-alpha hydroxyprogesterone caproate for prevention of recurrent spontaneous preterm birth

Abstract

Background Prematurity is the leading cause of neonatal morbidity and mortality amongst non-anomalous neonates in the United States. Intramuscular 17-alpha hydroxyprogesterone caproate (17OHP-C) injections reduce the risk of recurrent prematurity by approximately one third. Unfortunately, prophylactic 17OHP-C is not always effective, and one-third of high-risk women will have a recurrent PTB despite 17OHP-C therapy. The reasons for this variability in response are unknown. Previous investigators have examined the influence of a variety of factors on 17OHP-C response, but have analyzed data used a fixed outcome of ‘term’ delivery to define progesterone response. Objective We hypothesized that the demographics, history, and pregnancy course among women who deliver at a similar gestational age with 17-alpha hydroxyprogesterone caproate (17OHP-C) for recurrent spontaneous preterm birth (SPTB) prevention differs when compared to those women who deliver later with 17OHP-C, and that these associations could be refined by using a contemporary definition of 17OHP-C ‘responder.’ Study Design This was a planned secondary analysis of a prospective, multi-center, longitudinal study of women with ≥ 1 prior documented singleton SPTB <37 weeks gestation. Data were collected at 3 pre-specified gestational age epochs during pregnancy. All women included in this analysis received 17OHP-C during the studied pregnancy. We classified women as a 17OHP-C responder or non-responder by calculating the difference in delivery gestational age between the 17OHP-C treated pregnancy and her earliest SPTB. Responders were defined as those with pregnancy extending ≥3 weeks later with 17OHP-C compared to the delivery gestational age of their earliest prior SPTB. Data were analyzed using chi-square, t-test, and logistic regression. Results 155 women met inclusion criteria. The 118 responders delivered later on average (37.7 weeks) than the 37 non-responders (33.5 weeks), p<0.001. Among responders, 32% (38/118) had a recurrent SPTB. Demographics (age, race/ethnicity, education, and parity) were similar between groups. In the regression model, the gestational age of the prior SPTB (OR 0.68, 95% CI 0.56–0.82, p<0.001), vaginal bleeding/abruption in the current pregnancy (OR 0.24, 95% CI 0.06–0.88, p=0.031), and first-degree family history of SPTB (OR 0.37, 95% CI 0.15–0.88, p=0.024) were associated with response to 17OHP-C. Because women with a penultimate preterm pregnancy were more likely to be 17OHP-C non-responders, we performed an additional limited analysis examining only the 130 women whose penultimate pregnancy was preterm. In regression models, the results were similar to those in the main cohort. Conclusions Several historical and current pregnancy characteristics define women at risk for recurrent PTB at a similar gestational age despite 17OHP-C therapy. These data should be prospectively studied in larger cohorts and combined with genetic and environmental data to identify women most likely to benefit from this intervention.

Nonresponse to 17-alpha hydroxyprogesterone caproate for recurrent spontaneous preterm birth prevention: clinical prediction and generation of a risk scoring system

“…10 Our prior study included 155 women; 37 (24%) were classified as non-responders, which is similar to the 21% non-responder rate in the current study. In that study, we also identified the gestational age of the earliest previous spontaneous PTB, significant vaginal bleeding or abruption, first-degree family history of SPTB, and preterm birth of the penultimate pregnancy as risk factors for reduced response to 17OHP-C. 10 We have confirmed these results in the current study. We were unable to evaluate family history in the current report, as this information was not collected as part of the original RCT.…”

“…8,10 To review, the difference between the earliest delivery gestational age and the delivery gestational age with 17OHP-C was calculated, and termed the ‘17OHP-C effect.’ Women with a 17OHP-C effect of ≥3 weeks (i.e., the individual’s pregnancy or pregnancies treated with 17OHP-C delivered at least 3 weeks later compared to the gestational age of the earliest PTB without 17OHP-C treatment) were considered 17OHP-C responders; this designation was made in part by using data originally published by Bloom, et al which showed that 70% of women with recurrent PTB will experience recurrence within 2 weeks of their initial PTB. 15 Women with a negative overall 17OHP-C effect and those with an overall 17OHP-C effect of <3 weeks were classified as non-responders.…”

“…These data add to a growing body of literature suggesting that women who experience a recurrent PTB or recurrent PTB at a similar gestational age while receiving 17OHP-C have distinctly different clinical and biologic characteristics than those who receive 17OHP-C and deliver at term. 8,10,11,18 …”

“…Limited genetic studies have found associations between genetic variation in the progesterone receptor and nitric oxide genes and clinical response to 17OHP-C. 8,9 Other studies have focused on clinical factors in attempts to define the population of women most likely to respond to treatment, finding that those with a family history of PTB and those who experienced bleeding or abruption in the current pregnancy were less likely to respond to 17-OHPC, and those who had a prior spontaneous PTB <34 weeks were more likely to deliver at term with 17-OHPC. 10,11 …”

Smoking, 17 Alpha-Hydroxyprogesterone Caproate, and Preterm Birth

“…For example, we and others have demonstrated that maternal genotype, 9 number of prior PTBs, 10,11 prior PTB due to preterm premature rupture of membranes (PPROM), 12,13 and maternal weight/obesity 14,15 are significant modifiers of the effectiveness of fixed-dose 17OHP-C treatment. It is thus important to understand how other recognized PTB risk factors, such as smoking, might impact the effectiveness of 17OHP-C treatment.…”