Emily S Barrett1,2, Wendy Vitek2, Omar Mbowe3, Sally W Thurston3, Richard S Legro4, Ruben Alvero5, Valerie Baker6, G Wright Bates7, Peter Casson8, Christos Coutifaris9, Esther Eisenberg10, Karl Hansen11, Stephen Krawetz12, Randal Robinson13, Mitchell Rosen14, Rebecca Usadi15, Heping Zhang16, Nanette Santoro17, Michael Diamond18. 1. Department of Epidemiology, Environmental and Occupational Health Sciences Institute, Rutgers School of Public Health, 170 Frelinghuysen Road, Piscataway, NJ, USA. 2. Department of Obstetrics and Gynecology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY, USA. 3. Department of Biostatistics and Computational Biology, University of Rochester School of Medicine and Dentistry, 265 Crittenden Avenue, Rochester, NY, USA. 4. Department of Obstetrics and Gynecology, Penn State University College of Medicine, 500 University Drive, Hershey, PA, USA. 5. Department of Obstetrics and Gynecology, Warren Alpert School of Medicine, Brown University, 90 Plain Street, Providence, RI, USA. 6. Department of Obstetrics and Gynecology, Stanford University School of Medicine, 1195 West Fremont Avenue, Sunnyvale, CA, USA. 7. Department of Obstetrics and Gynecology, University of Alabama at Birmingham, 619 19th Street South, Birmingham, AL, USA. 8. Department of Obstetrics and Gynecology, University of Vermont, 111 Colchester Avenue, Burlington, VT, USA. 9. Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, 3701 Market Street, Philadelphia, PA, USA. 10. Fertility and Infertility Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, 6710B Rockledge Drive, Bethesda, MD, USA. 11. Department of Obstetrics and Gynecology, University of Oklahoma College of Medicine, 825 NE 10th Street, Oklahoma City, OK, USA. 12. Department of Obstetrics and Gynecology, Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, 275 E. Hancock, Detroit, MI, USA. 13. Department of Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, 8300 Floyd Curl Drive, San Antonio, TX, USA. 14. Department of Reproductive Endocrinology and Infertility, University of California, 550 16th Street, San Francisco, CA, USA. 15. Carolinas Health Care System, 1025 Morehead Medical Drive, Charlotte, NC, USA. 16. Yale School of Public Health, 300 George Street, New Haven, CT, USA. 17. Department of Obstetrics and Gynecology, University of Colorado, 12631 E 17th Avenue, Aurora, CO, USA. 18. Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA, USA.
Abstract
STUDY QUESTION: Among infertile women undergoing ovarian stimulation, is allostatic load (AL), a measure of chronic physiological stress, associated with subsequent fertility and pregnancy outcomes? SUMMARY ANSWER: AL at baseline was not associated with conception, spontaneous abortion or live birth, however, it was significantly associated with increased odds of pre-eclampsia and preterm birth among women who had a live birth in the study. WHAT IS KNOWN ALREADY: Several studies have linked AL during pregnancy to adverse outcomes including preterm birth and pre-eclampsia, hypothesizing that it may contribute to well-documented disparities in pregnancy and birth outcomes. However, AL biomarkers change over the course of pregnancy, raising questions as to whether gestational AL assessment is a valid measure of cumulative physiologic stress starting long before pregnancy. To better understand how AL may impact reproductive outcomes, AL measurement in the non-pregnant state (i.e. prior to conception) is needed. STUDY DESIGN, SIZE, DURATION: A secondary data analysis based on data from 836 women who participated in Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS), a multi-center, randomized clinical trial of ovarian stimulation conducted from 2011 to 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: Ovulatory women with unexplained infertility (ages 18-40) were enrolled and at baseline, biological and anthropometric measures were collected. AL scores were calculated as a composite of the following baseline variables determined a priori: BMI, waist-to-hip ratio, systolic blood pressure, diastolic blood pressure, dehydroepiandrosterone sulfate, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, C-reactive protein and HOMA score. Participants received ovarian stimulation for up to four cycles and if they conceived, were followed throughout pregnancy. We fit multi-variable logistic regression models examining AL (one-tailed and two-tailed) in relation to the following reproductive outcomes: conception, spontaneous abortion, live birth, pre-eclampsia, preterm birth and low birthweight. MAIN RESULTS AND THE ROLE OF CHANCE: Adjusting for covariates, a unit increase in two-tailed AL score was associated with 62% increased odds of pre-eclampsia (OR: 1.62, 95% CI: 1.14, 2.38) 44% increased odds of preterm birth (OR: 1.44, 95% CI: 1.02, 2.08), and 39% increased odds of low birthweight (OR: 1.39, 95% CI: 0.99, 1.97). The relationship between AL and preterm birth was mediated by pre-eclampsia (P = 0.0003). In one-tailed AL analyses, associations were similar, but slightly attenuated. AL was not associated with fertility outcomes (conception, spontaneous abortion, live birth). LIMITATIONS, REASONS FOR CAUTION: Results may not be generalizable to fertile women who conceive naturally or women with other types of infertility. Comparisons to previous, related work are difficult because variables included in AL composite measures vary across studies. AL may be indicative of overall poor health, rather than being specific to chronic physiological stress. WIDER IMPLICATIONS OF THE FINDINGS: Our results suggest that chronic physiological stress may not impact success of ovarian stimulation, however, they confirm and extend previous work suggesting that AL is associated with adverse pregnancy outcomes. Physiological dysregulation due to chronic stress has been proposed as a possible mechanism underlying disparities in birth outcomes, which are currently poorly understood. Assessing biomarkers of physiological dysregulation pre-conception or in early pregnancy, may help to identify women at risk of adverse pregnancy outcomes, particularly pre-eclampsia. STUDY FUNDING/COMPETING INTEREST(S): Support for AMIGOS was provided by: U10 HD39005, U10 HD38992, U10 HD27049, U10 HD38998, U10 HD055942, HD055944, U10 HD055936 and U10HD055925. Support for the current analysis was provided by T32ES007271, R25HD075737, P30ES001247 and P30ES005022. This research was made possible by funding by American Recovery and Reinvestment Act. The content is solely the responsibility of the authors and does not necessarily represent the official views of NICHD, NIEHS or NIH. E.B., W.V., O.M., R.A., M.R., V.B., G.W.B., C.C., E.E., S.K., R.U., P.C, H.Z., N.S. and S.T. have nothing to disclose. R.L. reported serving as a consultant to Abbvie, Bayer, Kindex, Odega, Millendo and Fractyl and serving as a site investigator and receiving grants from Ferring. K.H. reported receiving grants from Roche Diagnostics and Ferring. R.R. reported a grant from AbbVie. M.D. reported being on the Board of Directors of and a stockholder in Advanced Reproductive Care. TRIAL REGISTRATION NUMBER: Clinical Trials.gov number: NCT01044862.
STUDY QUESTION: Among infertile women undergoing ovarian stimulation, is allostatic load (AL), a measure of chronic physiological stress, associated with subsequent fertility and pregnancy outcomes? SUMMARY ANSWER: AL at baseline was not associated with conception, spontaneous abortion or live birth, however, it was significantly associated with increased odds of pre-eclampsia and preterm birth among women who had a live birth in the study. WHAT IS KNOWN ALREADY: Several studies have linked AL during pregnancy to adverse outcomes including preterm birth and pre-eclampsia, hypothesizing that it may contribute to well-documented disparities in pregnancy and birth outcomes. However, AL biomarkers change over the course of pregnancy, raising questions as to whether gestational AL assessment is a valid measure of cumulative physiologic stress starting long before pregnancy. To better understand how AL may impact reproductive outcomes, AL measurement in the non-pregnant state (i.e. prior to conception) is needed. STUDY DESIGN, SIZE, DURATION: A secondary data analysis based on data from 836 women who participated in Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS), a multi-center, randomized clinical trial of ovarian stimulation conducted from 2011 to 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: Ovulatory women with unexplained infertility (ages 18-40) were enrolled and at baseline, biological and anthropometric measures were collected. AL scores were calculated as a composite of the following baseline variables determined a priori: BMI, waist-to-hip ratio, systolic blood pressure, diastolic blood pressure, dehydroepiandrosterone sulfate, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, C-reactive protein and HOMA score. Participants received ovarian stimulation for up to four cycles and if they conceived, were followed throughout pregnancy. We fit multi-variable logistic regression models examining AL (one-tailed and two-tailed) in relation to the following reproductive outcomes: conception, spontaneous abortion, live birth, pre-eclampsia, preterm birth and low birthweight. MAIN RESULTS AND THE ROLE OF CHANCE: Adjusting for covariates, a unit increase in two-tailed AL score was associated with 62% increased odds of pre-eclampsia (OR: 1.62, 95% CI: 1.14, 2.38) 44% increased odds of preterm birth (OR: 1.44, 95% CI: 1.02, 2.08), and 39% increased odds of low birthweight (OR: 1.39, 95% CI: 0.99, 1.97). The relationship between AL and preterm birth was mediated by pre-eclampsia (P = 0.0003). In one-tailed AL analyses, associations were similar, but slightly attenuated. AL was not associated with fertility outcomes (conception, spontaneous abortion, live birth). LIMITATIONS, REASONS FOR CAUTION: Results may not be generalizable to fertile women who conceive naturally or women with other types of infertility. Comparisons to previous, related work are difficult because variables included in AL composite measures vary across studies. AL may be indicative of overall poor health, rather than being specific to chronic physiological stress. WIDER IMPLICATIONS OF THE FINDINGS: Our results suggest that chronic physiological stress may not impact success of ovarian stimulation, however, they confirm and extend previous work suggesting that AL is associated with adverse pregnancy outcomes. Physiological dysregulation due to chronic stress has been proposed as a possible mechanism underlying disparities in birth outcomes, which are currently poorly understood. Assessing biomarkers of physiological dysregulation pre-conception or in early pregnancy, may help to identify women at risk of adverse pregnancy outcomes, particularly pre-eclampsia. STUDY FUNDING/COMPETING INTEREST(S): Support for AMIGOS was provided by: U10 HD39005, U10 HD38992, U10 HD27049, U10 HD38998, U10 HD055942, HD055944, U10 HD055936 and U10HD055925. Support for the current analysis was provided by T32ES007271, R25HD075737, P30ES001247 and P30ES005022. This research was made possible by funding by American Recovery and Reinvestment Act. The content is solely the responsibility of the authors and does not necessarily represent the official views of NICHD, NIEHS or NIH. E.B., W.V., O.M., R.A., M.R., V.B., G.W.B., C.C., E.E., S.K., R.U., P.C, H.Z., N.S. and S.T. have nothing to disclose. R.L. reported serving as a consultant to Abbvie, Bayer, Kindex, Odega, Millendo and Fractyl and serving as a site investigator and receiving grants from Ferring. K.H. reported receiving grants from Roche Diagnostics and Ferring. R.R. reported a grant from AbbVie. M.D. reported being on the Board of Directors of and a stockholder in Advanced Reproductive Care. TRIAL REGISTRATION NUMBER: Clinical Trials.gov number: NCT01044862.
Authors: Claudia Holzman; Janet Eyster; Mary Kleyn; Lynne C Messer; Jay S Kaufman; Barbara A Laraia; Patricia O'Campo; Jessica G Burke; Jennifer Culhane; Irma T Elo Journal: Am J Public Health Date: 2009-08-20 Impact factor: 9.308
Authors: Michael P Diamond; Mohamed Mitwally; Robert Casper; Joel Ager; Richard S Legro; Robert Brzyski; Peter Casson; Esther Eisenberg; Heping Zhang Journal: Contemp Clin Trials Date: 2011-07-20 Impact factor: 2.226
Authors: Kate Walsh; Clare A McCormack; Rachel Webster; Anita Pinto; Seonjoo Lee; Tianshu Feng; H Sloan Krakovsky; Sinclaire M O'Grady; Benjamin Tycko; Frances A Champagne; Elizabeth A Werner; Grace Liu; Catherine Monk Journal: Proc Natl Acad Sci U S A Date: 2019-10-14 Impact factor: 11.205
Authors: Margareta D Pisarska; Jessica L Chan; Kate Lawrenson; Tania L Gonzalez; Erica T Wang Journal: J Clin Endocrinol Metab Date: 2019-06-01 Impact factor: 5.958
Authors: Chauntelle Jack-Roberts; Patricia Maples; Betul Kalkan; Kaydine Edwards; Ella Gilboa; Ikhtiyor Djuraev; Shuli Zou; Lori Hoepner; Lawrence Fordjour; Wen-Ching Lee; John Kral; Mudar Dalloul; Xinyin Jiang Journal: BMJ Open Diabetes Res Care Date: 2020-10