title: 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 remains a leading cause of neonatal morbidity and mortality among nonanomalous neonates in the United States. Spontaneous preterm birth tends to recur at similar gestational ages. Intramuscular 17-alpha hydroxyprogesterone caproate reduces the risk of recurrent spontaneous preterm birth. Unfortunately, one-third of high-risk women will have a recurrent spontaneous preterm birth despite 17-alpha hydroxyprogesterone caproate therapy; the reasons for this variability in response are unknown.
  
  
  OBJECTIVE
  We hypothesized that clinical factors among women treated with 17-alpha hydroxyprogesterone caproate who suffer recurrent spontaneous preterm birth at a similar gestational age differ from women who deliver later, and that these associations could be used to generate a clinical scoring system to predict 17-alpha hydroxyprogesterone caproate response.
  
  
  METHODS
  Secondary analysis of a prospective, multicenter, randomized controlled trial enrolling women with ≥1 previous singleton spontaneous preterm birth <37 weeks' gestation. Participants received daily omega-3 supplementation or placebo for the prevention of recurrent preterm birth; all were provided 17-alpha hydroxyprogesterone caproate. Women were classified as a 17-alpha hydroxyprogesterone caproate responder or nonresponder by calculating the difference in delivery gestational age between the 17-alpha hydroxyprogesterone caproate-treated pregnancy and her earliest previous spontaneous preterm birth. Responders were women with pregnancy extending ≥3 weeks later compared with the delivery gestational age of their earliest previous preterm birth; nonresponders delivered earlier or within 3 weeks of the gestational age of their earliest previous preterm birth. A risk score for nonresponse to 17-alpha hydroxyprogesterone caproate was generated from regression models via the use of clinical predictors and was validated in an independent population. Data were analyzed with multivariable logistic regression.
  
  
  RESULTS
  A total of 754 women met inclusion criteria; 159 (21%) were nonresponders. Responders delivered later on average (37.7±2.5 weeks) than nonresponders (31.5±5.3 weeks), P<.001. Among responders, 27% had a recurrent spontaneous preterm birth (vs 100% of nonresponders). Demographic characteristics were similar between responders and nonresponders. In a multivariable logistic regression model, independent risk factors for nonresponse to 17-alpha hydroxyprogesterone caproate were each additional week of gestation of the earliest previous preterm birth (odds ratio, 1.23; 95% confidence interval, 1.17-1.30, P<.001), placental abruption or significant vaginal bleeding (odds ratio, 5.60; 95% confidence interval, 2.46-12.71, P<.001), gonorrhea and/or chlamydia in the current pregnancy (odds ratio, 3.59; 95% confidence interval, 1.36-9.48, P=.010), carriage of a male fetus (odds ratio, 1.51; 95% confidence interval, 1.02-2.24, P=.040), and a penultimate preterm birth (odds ratio, 2.10; 95% confidence interval, 1.03-4.25, P=.041). These clinical factors were used to generate a risk score for nonresponse to 17-alpha hydroxyprogesterone caproate as follows: black +1, male fetus +1, penultimate preterm birth +2, gonorrhea/chlamydia +4, placental abruption +5, earliest previous preterm birth was 32-36 weeks +5. A total risk score >6 was 78% sensitive and 60% specific for predicting nonresponse to 17-alpha hydroxyprogesterone caproate (area under the curve=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 area under the curve of 0.66.
  
  
  CONCLUSIONS
  Several clinical characteristics define women at risk for recurrent preterm birth at a similar gestational age despite 17-alpha hydroxyprogesterone caproate therapy and can be used to generate a clinical risk predictor score. These data should be refined and confirmed in other cohorts, and women at high risk for nonresponse should be targets for novel therapeutic intervention studies.
authors.affiliation: Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, University of North Carolina-Chapel Hill, Chapel Hill, NC; Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, University of Utah School of Medicine, Salt Lake City, UT. Electronic address: tmanuck@med.unc.edu.
authors.forename: Tracy A
authors.initials: TA
authors.lastname: Manuck
authors.affiliation: Division of Epidemiology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Stoddard
authors.affiliation: Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina-Chapel Hill, Chapel Hill, NC.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Fry
authors.affiliation: Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, University of Utah School of Medicine, Salt Lake City, UT; Intermountain Healthcare Women and Newborns Clinical Program, Salt Lake City, UT.
authors.forename: M Sean
authors.initials: MS
authors.lastname: Esplin
authors.affiliation: Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, University of Utah School of Medicine, Salt Lake City, UT; Intermountain Healthcare Women and Newborns Clinical Program, Salt Lake City, UT.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Varner
mesh_terms: D000077713:17 alpha-Hydroxyprogesterone Caproate; D000328:Adult; D003661:Decision Support Techniques; D004334:Drug Administration Schedule; D004965:Estrogen Antagonists / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D006908:Hydroxyprogesterones / Q000627:therapeutic use*; D007273:Injections, Intramuscular; D016015:Logistic Models; D008297:Male; D011247:Pregnancy; D047928:Premature Birth / Q000209:etiology / Q000517:prevention & control*; D011446:Prospective Studies; D012008:Recurrence; D018570:Risk Assessment; D012307:Risk Factors; D017211:Treatment Failure
chemical_list: D004965:Estrogen Antagonists; D006908:Hydroxyprogesterones; D000077713:17 alpha-Hydroxyprogesterone Caproate
keywords: progesterone supplementation; recurrent preterm birth; risk prediction; spontaneous preterm labor