This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Recent evidence indicates that the human fetus is exposed to profound influences that have permanent implications for health (Barker, 1998; Nathanielsz, 1999). Maternal stress initiates a cascade of events that alter normal developmental processes in the human fetus. Human fetuses exposed to elevated stress signals have impaired learning in utero (Sandman et al., 1999a; 1999b) and are at three-fold increased risk for preterm birth and low birth weight (Wadhwa et al., 1993; 1998). Moreover, as many as one-half of the infants born early or small, have motor, sensory, or cognitive handicaps (McCarton et al., 1996). The primary aim of this five-year proposal is to determine the influence of prenatal maternal stress and maternal neuroendocrine responses on fetal behavior and to assess the relationship between fetal behavior and infant development in a multiethnic sample of 200 women.
The specific aims are to: (a) Identify the primary stress factors that influence fetal behavior. Stress will be measured (interviews and questionnaires) five times during pregnancy. Fetal behavior and development will be quantified by conventional measures of fetal growth and by measures of fetal behavioral state, movement (at rest and challenge), reactivity and habituation of fetal heart rate (FHR). (b) Determine the influence of maternal stress-related (HPA) axis activity and disregulation on fetal and infant behavior and infant HPA activity. Because maternal stress alters peptide receptors and brain peptide levels in the fetal rat brain (Takahashi et al., 1992; Poland et al., 1999; Insel et al., 1990; Sanchez et al., 1993; Fride et al., 1985) and because it influences human fetal behavior and birth outcomes, maternal peptide levels will be assayed from blood obtained at each prenatal and postnatal visit. The influence of maternal stress peptides on infant behavior and HPA activity will be determined at three, six, twelve, and twenty-four months. (c) Describe the relationshipo between fetal behavior and infant behavior. A sensitive measure of fetal CNS activity (habituation) will be integrated with contemporary measures of fetal behavior at rest and after challenge, to describe fetal maturation. These measures will be entered into models to predict infant neuromotor development. Infant behavior will be assessed with the Bayley Scales of Development, the Neuromotor Status Examination, and by basal and circadian measures of hypothalamic-pituitary-adrenal (HPA) activity. (d) To identify variability in genes involved in the regulation of the HPA pathway that links stress, parturition, and development. This project is designed to identify maternal stressful conditions that are harmful to the fetus by examination of the timing and duration of stress, by investigation of biological mechanisms related to prenatal stress, specifically the HPA and placental axis and by longitudinal studies of developmental consequences of prenatal stress in the infant. The central objective of this project is to characterize maternal stress conditions over the course of the pregnancy. References Barker DJP. (1998) Mothers, Babies, and Health Later in Life (Second edition). Edinburgh: Churchill Livingstone. Fride E, et al. (1985) Prenatal stress impairs maternal behavior in a conflict situation and reduces hippocampal benzodiaxepine receptors. Life Science, 36, 2103-9. Insel T, Kinsley CH, Mann PE, et al. (1990) Prenatal stress has long-term effects on brain opiate receptors. Brain Research, 551, 93-7. McCarton CM, Wallace IF, Divon M, Vaughan HG. (1996) Cognitive and neurological development of the premature, small for gestational age infant through age 6: Comparison by birth weight and gestational age. Pediatrics, 98, 1167-78. Nathanielsz PW. (1999) Life in the Womb: The Origin of Health and Disease. Ithaca, NY: Promethean Press. Poland RE. (1999) Brain N-acetyl aspartate concentration measured by H MRS are reduced in adult male rats subjected to perinatal stress: preliminary observations and bypothetical implications for neurodevelopmental disorders. Journal of Psychiatric Research, 33, 41-51. Sanchez MD, et al. (1993) The B-endorphin response to prenatal stress during postnatal development in the rat. Developmental Brain Research, 74, 142-5. Sandman CA, Wadhwa P, Chicz-DeMet A, et al. (1999a) Maternal corticotropin-releasing hormone and habituation in the human fetus. Developmental Psychobiology, 34, 163-73. Sandman CA, Wadhwa P, Glynn L, et al. (1999b) Corticotrophin-releasing hormone (CRH) and fetal responses in human pregnancy. New York Academy of Sciences Annals, 897, 66-75. Takahashi LK, Turner JG, Kalin NH. (1992) Prenatal stress alters brain catecholaminergic activity and potentiates stress-induced behavior in adult rats. Brain Research, 574, 131-7. Wadhwa P, Sandman C, Porto M, et al. (1993) The association between prenatal stress and infant birth weight and gestational age at birth: A prospective investigation. American Journal of Obstetrics and Gynecology, 69, 858-65. Wadhwa P, Porto M, Garite TJ, et al. (1998) Maternal Corticotropin-releasing hormone levels in early third trimester predict length of gestation in human pregnancy. American Journal of Obstetrics & Gynecology, 179, 1079-85.
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