title: 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 death among nonanomalous neonates in the United States. Intramuscular 17-alpha hydroxyprogesterone caproate injections reduce the risk of recurrent prematurity by approximately one third. Unfortunately, prophylactic 17-alpha hydroxyprogesterone caproate is not always effective, and one-third of high-risk women will have a recurrent preterm birth, despite 17-alpha hydroxyprogesterone caproate therapy. The reasons for this variability in response are unknown. Previous investigators have examined the influence of a variety of factors on 17-alpha hydroxyprogesterone caproate response but have analyzed data that 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 for recurrent spontaneous preterm birth prevention differs when compared with those women who deliver later with 17-alpha hydroxyprogesterone caproate and that these associations could be refined by the use of a contemporary definition of 17-alpha hydroxyprogesterone caproate "responder."
  
  
  METHODS
  This was a planned secondary analysis of a prospective, multicenter, longitudinal study of women with ≥1 previous documented singleton spontaneous preterm birth at <37 weeks gestation. Data were collected at 3 prespecified gestational age epochs during pregnancy. All women who were included in this analysis received 17-alpha hydroxyprogesterone caproate during the studied pregnancy. We classified women 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 spontaneous preterm birth. Responders were defined as those with pregnancy that extended ≥3 weeks later with 17-alpha hydroxyprogesterone caproate, compared with the delivery gestational age of their earliest previous spontaneous preterm birth. Data were analyzed with the use of chi-square test, t-test, and logistic regression.
  
  
  RESULTS
  One hundred fifty-five women met the inclusion criteria. The 118 responders delivered later on average (37.7 weeks gestation) than the 37 nonresponders (33.5 weeks gestation; P < .001). Among responders, 32% (38/118 women) had a recurrent spontaneous preterm birth. Demographics (age, race/ethnicity, education, and parity) were similar between groups. In the regression model, the gestational age of the previous spontaneous preterm birth (odds ratio, 0.68; 95% confidence interval, 0.56-0.82; P < .001), vaginal bleeding/abruption in the current pregnancy (odds ratio, 0.24; 95% confidence interval, 0.06-0.88; P = .031), and first-degree family history of spontaneous preterm birth (odds ratio, 0.37; 95% confidence interval, 0.15-0.88; P = .024) were associated with response to 17-alpha hydroxyprogesterone caproate. Because women with a penultimate preterm pregnancy were more likely to be 17-alpha hydroxyprogesterone caproate nonresponders, 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 historic and current pregnancy characteristics define women who are at risk for recurrent preterm birth at a similar gestational age, despite 17-alpha hydroxyprogesterone caproate therapy. These data should be studied prospectively in larger cohorts and combined with genetic and environmental data to identify women who are most likely to benefit from this intervention.
authors.affiliation: Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, University of Utah School of Medicine, Salt Lake City, UT; Intermountain Healthcare Department of Maternal Fetal Medicine, Salt Lake City, UT. Electronic address: tmanuck@med.unc.edu.
authors.forename: Tracy A
authors.initials: TA
authors.lastname: Manuck
authors.affiliation: Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, University of Utah School of Medicine, Salt Lake City, UT; Intermountain Healthcare Department of Maternal Fetal Medicine, 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, and Center for Women's Reproductive Health, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Joseph
authors.initials: J
authors.lastname: Biggio
authors.affiliation: Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of Texas Medical Branch, Galveston, TX.
authors.forename: Radek
authors.initials: R
authors.lastname: Bukowski
authors.affiliation: Department of Obstetrics and Gynecology, University of Pennsylvania School of Medicine, Philadelphia, PA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Parry
authors.affiliation: Collaborative Center for Statistics in Science, Yale University School of Public Health, New Haven, CT.
authors.forename: Heping
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Collaborative Center for Statistics in Science, Yale University School of Public Health, New Haven, CT.
authors.forename: Hao
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, University of Utah School of Medicine, Salt Lake City, UT; Intermountain Healthcare Department of Maternal Fetal Medicine, Salt Lake City, UT.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Varner
authors.affiliation: Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, and Center for Women's Reproductive Health, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: William
authors.initials: W
authors.lastname: Andrews
authors.affiliation: Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of Texas Medical Branch, Galveston, TX.
authors.forename: George
authors.initials: G
authors.lastname: Saade
authors.affiliation: Magee-Womens Research Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: Yoel
authors.initials: Y
authors.lastname: Sadovsky
authors.affiliation: Pregnancy and Perinatology Branch, Center for Developmental Biology and Perinatal Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD.
authors.forename: Uma M
authors.initials: UM
authors.lastname: Reddy
authors.affiliation: Pregnancy and Perinatology Branch, Center for Developmental Biology and Perinatal Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD.
authors.forename: John
authors.initials: J
authors.lastname: Ilekis
mesh_terms: D000077713:17 alpha-Hydroxyprogesterone Caproate; D000037:Abruptio Placentae / Q000453:epidemiology; D000328:Adult; D004965:Estrogen Antagonists / Q000627:therapeutic use*; D005260:Female; D005865:Gestational Age; D006801:Humans; D006908:Hydroxyprogesterones / Q000627:therapeutic use*; D008137:Longitudinal Studies; D011247:Pregnancy; D018566:Pregnancy, High-Risk; D047928:Premature Birth / Q000235:genetics / Q000517:prevention & control*; D011446:Prospective Studies; D012008:Recurrence; D012307:Risk Factors; D017211:Treatment Failure; D014592:Uterine Hemorrhage / Q000453:epidemiology; D055815:Young Adult
chemical_list: D004965:Estrogen Antagonists; D006908:Hydroxyprogesterones; D000077713:17 alpha-Hydroxyprogesterone Caproate
keywords: decidual hemorrhage; progesterone; recurrent preterm birth; spontaneous preterm labor