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

Abstract

Background Spontaneous preterm birth (SPTB) remains a leading cause of neonatal morbidity and mortality amongst non-anomalous neonates in the United States. SPTB tends to recur at similar gestational ages. Intramuscular 17-alpha hydroxyprogesterone caproate (17OHP-C) reduces the risk of recurrent SPTB. Unfortunately, one-third of high-risk women will have a recurrent SPTB despite 17OHP-C therapy; the reasons for this variability in response are unknown. Objective We hypothesized that clinical factors among women treated with 17OHP-C who suffer recurrent SPTB at a similar gestational age differ from women who deliver later, that these associations could be used to generate a clinical scoring system to predict 17OHP-C response. Study Design Secondary analysis of a prospective, multi-center, randomized controlled trial enrolling women with ≥1 prior singleton SPTB <37 weeks gestation. Participants received daily omega-3 supplementation or placebo for recurrent PTB prevention; all were provided 17OHP-C. Women were classified 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 prior SPTB. Responders were women with pregnancy extending ≥3 weeks later compared to the delivery gestational age of their earliest prior PTB; non-responders delivered earlier or within 3 weeks of the gestational age of their earliest prior PTB. A risk score for non-response to 17OHP-C was generated from regression models using clinical predictors, and was validated in an independent population. Data were analyzed with multivariable logistic regression. Results 754 women met inclusion criteria; 159 (21%) were non-responders. Responders delivered later on average (37.7 +/− 2.5 weeks) than non-responders (31.5 +/− 5.3 weeks), p<0.001. Among responders, 27% had a recurrent SPTB (vs. 100% of non-responders). Demographic characteristics were similar between responders and non-responders. In a multivariable logistic regression model, independent risk factors for non-response to 17OHP-C were each additional week of gestation of the earliest prior PTB (OR 1.23, 95% CI 1.17–1.30, p<0.001), placental abruption or significant vaginal bleeding (OR 5.60, 95% CI 2.46–12.71, p<0.001), gonorrhea and/or chlamydia in the current pregnancy (OR 3.59, 95% CI 1.36–9.48, p=0.010), carriage of a male fetus (OR 1.51, 95% CI 1.02–2.24, p=0.040), and a penultimate PTB (OR 2.10, 95% CI 1.03–4.25, p=0.041). These clinical factors were used to generate a risk score for non-response to 17OHP-C as follows: Black +1, male fetus +1, penultimate PTB +2, gonorrhea/chlamydia +4, placental abruption +5, earliest prior PTB was 32–36 weeks +5. A total risk score >6 was 78% sensitive and 60% specific for predicting non-response to 17OHP-C (AUC=0.69). This scoring system was validated in an independent population of 287 women; in the validation set, a total risk score >6 performed similarly with a 65% sensitivity, 67% specificity and AUC of 0.66. Conclusions Several clinical ch...

Low Birth Weight and Adverse Perinatal Outcomes

“…In addition to this, women with early 17-alpha hydroxyprogesterone caproate initiation also had lower rates of major neonatal morbidity than those with later 17-alpha hydroxyprogesterone caproate initiation [73]. The effectiveness of 17-hydroxyprogesterone caproate is reduced as the gestational age increased; nonresponders increased as evidenced by a study done by Manuck and his collaborator's [75]. Consideration of the factors that increased nonresponse for the hormone should be considered during initiation, mainly placental abruption or significant Low Birth Weight and Adverse Perinatal Outcomes DOI: http://dx.doi.org /10.5772/intechopen.89049 vaginal bleeding, gonorrhea and/or chlamydia in the current pregnancy carriage of a male fetus.…”

“…Consideration of the factors that increased nonresponse for the hormone should be considered during initiation, mainly placental abruption or significant Low Birth Weight and Adverse Perinatal Outcomes DOI: http://dx.doi.org /10.5772/intechopen.89049 vaginal bleeding, gonorrhea and/or chlamydia in the current pregnancy carriage of a male fetus. For thus, a clinical prediction score is needed before prescribing the hormone [75].…”

Predictors of Early Preterm Birth Despite Vaginal Progesterone Therapy in Singletons with Short Cervix

“…Manuck et al addressed this issue in women with a prior PTB treated with intramuscular progesterone. 27 As we strive to improve the personalization of medicine, it is critical to identify individual factors that may impact response to therapy and allow us to target a subgroup of women that may benefit from studies on adjunctive interventions.…”

Driving Factors of Preterm Birth Risk in Adolescents

“…The natality file includes data on parental demographics, medical and obstetric characteristics, complications, and neonatal status at birth. Maternal age was categorized into young adolescent (< 16 years), older adolescent (16)(17)(18)(19).9 years), and adult (!20 years) was used as the referent group. PTB was defined as delivery < 37 weeks of gestation.…”

“…The increased risk associated with carrying a male fetus has been previously reported [16][17][18] and may be a risk factor for nonresponsiveness to PTB prevention with 17-hydroxyprogesterone caproate. 19…”