Gestational Hormone Concentrations Are Associated With Timing of Delivery in a Fetal Sex-Dependent Manner

Background Early delivery remains a significant public health problem that has long-lasting impacts on mother and child. Understanding biological mechanisms underlying timing of labor, including endocrine disruption, can inform prevention efforts. Methods Gestational hormones were measured among 976 women in PROTECT, a longitudinal birth cohort in Puerto Rico. We evaluated associations between hormone concentrations at 18 and 26 weeks gestation and gestational age at birth, while assessing effect modification by fetal sex. Exploratory analyses assessed binary outcomes of overall preterm birth (PTB, <37 weeks gestation) and the spontaneous PTB subtype, defined as preterm premature rupture of membranes, spontaneous preterm labor, or both. Multivariable logistic and linear regressions were fit using visit-specific hormone concentrations, and fetal sex-specific effects were estimated using interaction terms. Main outcome models were adjusted for maternal age, education, marital status, alcohol consumption, environmental tobacco smoke exposure, and pre-pregnancy body mass index (BMI). Exploratory models adjusted for maternal age and education. Results We observed reduced gestational age at birth with higher circulating CRH (β: -2.73 days, 95% CI: -4.97, -0.42), progesterone (β: -4.90 days, 95% CI: -7.07, -2.73), and fT4 concentrations (β: -2.73 days, 95% CI: -4.76, -0.70) at 18 weeks specifically among male fetuses. Greater odds of overall and spontaneous PTB were observed among males with higher CRH, estriol, progesterone, total triiodothyronine (T3), and free thyroxine (fT4) concentrations. Greater odds of PTB among females was observed with higher testosterone concentrations. Conclusions Various associations between hormones and timing of delivery were modified by fetal sex and timing of hormone measurement. Future studies are needed to understand differential mechanisms involved with timing of labor between fetal sexes.

[1]  A. Alshawabkeh,et al.  Environmental phthalate exposure and preterm birth in the PROTECT birth cohort. , 2019, Environment international.

[2]  A. Alshawabkeh,et al.  Associations of Phthalates and Phthalate Replacements With CRH and Other Hormones Among Pregnant Women in Puerto Rico , 2019, Journal of the Endocrine Society.

[3]  I. Novak,et al.  Early Diagnosis and Treatment of Cerebral Palsy in Children with a History of Preterm Birth. , 2018, Clinics in perinatology.

[4]  M. Zimmerman,et al.  Oxidative Stress and Preterm Birth: An Integrative Review , 2018, Biological research for nursing.

[5]  J. Allen,et al.  The association between serum progesterone level and preterm delivery , 2018, International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics.

[6]  Benjamin Thompson,et al.  The effects of preterm birth on visual development , 2018, Clinical & experimental optometry.

[7]  V. Luyckx.  Preterm Birth and its Impact on Renal Health. , 2017, Seminars in nephrology.

[8]  T. Zima,et al.  Thyroid in pregnancy: From physiology to screening , 2017, Critical reviews in clinical laboratory sciences.

[9]  J. Meeker,et al.  Longitudinal Profiles of Thyroid Hormone Parameters in Pregnancy and Associations with Preterm Birth , 2017, PloS one.

[10]  H. Tiemeier,et al.  Maternal total T4 during the first half of pregnancy: physiologic aspects and the risk of adverse outcomes in comparison with free T4 , 2016, Clinical endocrinology.

[11]  G. D. Di Renzo,et al.  Progesterone in normal and pathological pregnancy , 2016, Hormone molecular biology and clinical investigation.

[12]  H. Abdul-Khaliq,et al.  Preterm Birth Is Associated with Altered Myocardial Function in Infancy. , 2016, Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography.

[13]  J. Meeker,et al.  Associations between Repeated Measures of Maternal Urinary Phthalate Metabolites and Thyroid Hormone Parameters during Pregnancy , 2016, Environmental health perspectives.

[14]  D. Currò,et al.  Thyroid Hormones, Oxidative Stress, and Inflammation , 2016, Mediators of inflammation.

[15]  E. Ferrazzi,et al.  Inflammation and preterm birth , 2016, Journal of leukocyte biology.

[16]  W. J. Boscardin,et al.  Fetal sex differences in human chorionic gonadotropin fluctuate by maternal race, age, weight and by gestational age , 2015, Journal of Developmental Origins of Health and Disease.

[17]  F. Azizi,et al.  Thyroid dysfunction and pregnancy outcomes , 2015, Iranian journal of reproductive medicine.

[18]  A. Forhead,et al.  Thyroid hormones in fetal growth and prepartum maturation. , 2014, The Journal of endocrinology.

[19]  Michael C. Byrns.  Regulation of progesterone signaling during pregnancy: Implications for the use of progestins for the prevention of preterm birth , 2014, The Journal of Steroid Biochemistry and Molecular Biology.

[20]  P. Mendola,et al.  Thyroid diseases and adverse pregnancy outcomes in a contemporary US cohort. , 2013, The Journal of clinical endocrinology and metabolism.

[21]  J. DiPietro,et al.  Sex-specific associations of maternal prenatal testosterone levels with birth weight and weight gain in infancy , 2013, Journal of Developmental Origins of Health and Disease.

[22]  A. Alshawabkeh,et al.  Distribution, variability, and predictors of urinary concentrations of phenols and parabens among pregnant women in Puerto Rico. , 2013, Environmental science & technology.

[23]  J. Newnham,et al.  Fetal sex and preterm birth. , 2013, Placenta.

[24]  Johannes W. Dietrich,et al.  TSH and Thyrotropic Agonists: Key Actors in Thyroid Homeostasis , 2012, Journal of thyroid research.

[25]  Ann-Beth Moller,et al.  National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications , 2012, The Lancet.

[26]  M. Lehtinen,et al.  Determinants of Maternal Sex Steroids During the First Half of Pregnancy , 2011, Obstetrics and gynecology.

[27]  T. Szemeš,et al.  Testosterone and estradiol in maternal plasma and their relation to fetal sex , 2010, Prenatal diagnosis.

[28]  A. Leviton,et al.  American Journal of Epidemiology Original Contribution Pregnancy Disorders That Lead to Delivery before the 28th Week of Gestation: an Epidemiologic Approach to Classification , 2022 .

[29]  G. Saade,et al.  The Effect of Acculturation on Progesterone/Estriol Ratios and Preterm Birth in Hispanics , 2008, Obstetrics and gynecology.

[30]  S. Mesiano,et al.  Steroid hormone control of myometrial contractility and parturition. , 2007, Seminars in cell & developmental biology.

[31]  E. Norwitz,et al.  Endocrinology of parturition. , 2006, Endocrinology and metabolism clinics of North America.

[32]  J. Buitelaar,et al.  Maternal Serum Steroid Levels Are Unrelated to Fetal Sex: A Study in Twin Pregnancies , 2005, Twin Research and Human Genetics.

[33]  P. Yen,et al.  Physiological and molecular basis of thyroid hormone action. , 2001, Physiological reviews.

[34]  S. Lye,et al.  Endocrine and paracrine regulation of birth at term and preterm. , 2000, Endocrine reviews.

[35]  M. Mitchell,et al.  Maternal thyroid deficiency and pregnancy complications: implications for population screening , 2000, Journal of medical screening.

[36]  R. Smith,et al.  Corticotropin-releasing hormone directly and preferentially stimulates dehydroepiandrosterone sulfate secretion by human fetal adrenal cortical cells. , 1998, The Journal of clinical endocrinology and metabolism.

[37]  T. Li,et al.  Serum androgen levels in women who have recurrent miscarriages and their correlation with markers of endometrial function. , 1998, Fertility and sterility.

[38]  M. Mclean,et al.  A placental clock controlling the length of human pregnancy , 1995, Nature Medicine.

[39]  H. Mcgarrigle,et al.  Lack of normal increase in saliva estriol/progesterone ratio in women with labor induced at 42 weeks' gestation. , 1992, American journal of obstetrics and gynecology.

[40]  J. Pedersen,et al.  Secretory endometrial protein PP14 in women with early pregnancy bleeding. , 1991, Human reproduction.

[41]  P. Meulenberg,et al.  Maternal testosterone and fetal sex , 1991, The Journal of Steroid Biochemistry and Molecular Biology.

[42]  R. Romero,et al.  Evidence for a local change in the progesterone/estrogen ratio in human parturition at term. , 1988, American journal of obstetrics and gynecology.

[43]  C. Wolfe,et al.  Plasma corticotropin-releasing hormone concentrations during pregnancy and parturition. , 1987, The Journal of clinical endocrinology and metabolism.

[44]  H. Mcgarrigle,et al.  Increased saliva oestriol to progesterone ratio before preterm delivery: a possible predictor for preterm labor? , 1987, British medical journal.

[45]  P. Eneroth,et al.  Fetal sex dependent hormone levels in early pregnant women with elevated maternal serum α‐fetoprotein , 1983, International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics.

[46]  B. Runnebaum,et al.  Maternal peripheral testosterone levels during the first half of pregnancy. , 1978, American journal of obstetrics and gynecology.

[47]  S. Takagi,et al.  Sex differences in fetal gonadotropins and androgens. , 1977, Journal of steroid biochemistry.

[48]  J. Goldberg.  Committee Opinion No 700: Methods for Estimating the Due Date. , 2017, Obstetrics and gynecology.

[49]  D. Grammatopoulos.  The role of CRH receptors and their agonists in myometrial contractility and quiescence during pregnancy and labour. , 2007, Frontiers in bioscience : a journal and virtual library.

[50]  Roger Smith,et al.  Corticotrophin releasing hormone and the timing of birth. , 2007, Frontiers in bioscience : a journal and virtual library.

[51]  O. Levalle,et al.  Overt and subclinical hypothyroidism complicating pregnancy. , 2002, Thyroid : official journal of the American Thyroid Association.

[52]  A. Baron,et al.  Fetal Gender Differences in Preterm Birth: Findings in a North American Cohort , 1992, American journal of perinatology.

[53]  J. Darne,et al.  Increased saliva oestriol toprogesterone ratio before idiopathic pretermdelivery: a possible predictor forpretermlabour? , 1987 .