Substantial empirical evidence in humans and animals suggests that exposure to excess stress during a mother’s pregnancy and her child’s period of intrauterine life has the potential to impact the fetus and placental functioning with adverse consequences for pregnancy course, birth outcomes, and subsequent newborn, infant, and child neurodevelopmental and physical health trajectories (Dunkel Schetter & Glynn, 2011; Dunkel Schetter, 2011; Entringer, Buss, & Wadhwa, 2015; Wadhwa, Entringer, & Buss, 2011). Although much of the earlier work in this area was limited by many conceptual and methodological problems, over the last two decades, larger, better-designed prospective, population-based human studies, as well as mechanistic ones focused on brain development and epigenetics, have provided further evidence in support of what is known as the prenatal programming hypothesis or fetal origins of adult disease hypothesis.

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There is tremendous heterogeneity in methodology and measurement of maternal stress and related constructs. Human studies of pre-pregnancy and perinatal stress have used measures of major life event stress, catastrophic community-wide disasters, chronic stress, financial strain, relationship conflicts, daily hassles, perceived stress, and pregnancy-specific measures of stress and anxiety. Although significant associations have been reported with various components or dimensions of psychological stress, it does not appear possible to draw any firm conclusions regarding which of these stress measures “best” predict pregnancy, birth, and offspring health and disease risk-related outcomes. However, considerable evidence points to pregnancy specific stress and anxiety as the best predictor when various stress measures are compared (Alderdice, Lynn, & Lobel, 2012; Buss, Davis, Hobel, & Sandman, 2011; Dunkel Schetter, 2011). Different dimensions of psychological stress are not necessarily independent of one other but tend to co-occur; their effects on physiology, behavior, and health are partly shared and are also modified by other individual difference and situational factors; and their effects are context-dependent and may interact with other processes such as diet/nutrition, physical activity, and sleep (Wadhwa et al., 2011). We, therefore, refer to the other toolboxes for recommendations of more general stress measures for each of the above-listed domains that also can be used in the context of human pregnancy and also suggest the use of a pregnancy specific distress and pregnancy anxiety questionnaires provided in Guardino & Dunkel Schetter (2014).

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More on pregnancy-specific distress: it is important to highlight certain features specific to the state of pregnancy and embryonic/fetal development that may have a bearing on studies of stress-related outcomes. First, pregnancy-specific issues and stressors are not be adequately captured by measures that have been developed and validated in non-pregnant individuals. Pregnancy is associated with major and progressive alterations in maternal biological processes as well as psychological characteristics, including but not limited to changes in neural, endocrine, immune and vascular processes (see e.g., Mastorakos & Ilias, 2003), and shifts in identity, re-engagement with childhood memories, and activation of attachment schemas. Pregnancy also appears to be associated with alterations in maternal biological responses to exogenous or endogenous challenges, including stressors (de Weerth & Buitelaar, 2005; Entringer et al., 2010; Glynn, Wadhwa, Dunkel-Schetter, Chicz-Demet, & Sandman, 2001; Schulte, Weisner, & Allolio, 1990). The physiological and psychological condition in which a woman enters pregnancy (i.e., preconceptional characteristics) appears to exert an important influence on the nature and magnitude of these above-listed pregnancy-induced alterations in biology and psychology (Buss, Entringer, Moog, Toepfer, Fair, Simhan, Heim & Wadhwa, 2017).

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For these reasons, we recommend that studies of stress in the context of pregnancy and fetal development should include a measure of pregnancy-specific stress (e.g., Carmona Monge, Penacoba-Puente, Marin Morales, & Carretero Abellan, 2012; Guardino & Dunkel Schetter, 2014; Yali & Lobel, 1999) and of stress during or even prior to the pre- and periconceptional period. Furthermore, we recommend that the study design should incorporate prospective and serial assessments of stress across early, mid and late gestation to model and detect the effects of change across gestation.

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In terms of assessing aspects of maternal-placental-fetal stress biology during pregnancy, in addition to collecting stress-related biomarkers such as those related to glucocorticoid activity and pro-inflammatory state, it may be important to assess concentrations of placental corticotrophin-releasing hormone (CRH). In primates, but not other mammals, the placenta synthesizes and releases CRH in large amounts into the fetal and maternal circulations. CRH derived from the placenta is thought to play a crucial role in the regulation of fetal maturation and timing of delivery, and CRH has also been implicated in the control of fetal-placental blood flow (Smith & Nicholson, 2007). In contrast to the inhibitory influence on hypothalamic CRH production, cortisol stimulates placental CRH production (Cheng et al., 2000) and this positive feedback loop results in a progressive amplification of CRH and cortisol production over the course of gestation (Lowry, 1993). Placental CRH can be analyzed in maternal blood samples (Florio et al., 2004).

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Author(s) and Reviewer(s):

Prepared by Sonja Entringer, PhD, Claudia Buss, PhD, and Pathik Wadhwa, MD, MPH. Reviewed by several members of the Network. If you have any comments on these measures, email sonja.entringer@charite.de. Version date: September 2018.

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References:

Alderdice, F., Lynn, F., & Lobel, M. (2012). A review and psychometric evaluation of pregnancy-specific stress measures. J Psychosom Obstet Gynaecol, 33(2), 62-77. doi:10.3109/0167482X.2012.673040

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Buss, C., Davis, E. P., Hobel, C. J., & Sandman, C. A. (2011). Maternal pregnancy-specific anxiety is associated with child executive function at 6-9 years age. Stress, 14(6), 665-676. doi:10.3109/10253890.2011.623250

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Buss, C., Entringer, S., Moog, N.K., Toepfer, P., Fair, D.A., Simhan, H.N., Heim, C.M., Wadhwa, P.D. J Am Acad Child Adolesc Psychiatry. 2017 May;56(5):373-382. doi: 10.1016/j.jaac.2017.03.001.

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Carmona Monge, F. J., Penacoba-Puente, C., Marin Morales, D., & Carretero Abellan, I. (2012). Factor structure, validity and reliability of the Spanish version of the Cambridge Worry Scale. Midwifery, 28(1), 112-119. doi:10.1016/j.midw.2010.11.006

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Cheng, Y. H., Nicholson, R. C., King, B., Chan, E. C., Fitter, J. T., & Smith, R. (2000). Corticotropin-releasing hormone gene expression in primary placental cells is modulated by cyclic adenosine 3',5'-monophosphate. J Clin Endocrinol Metab, 85(3), 1239-1244.

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de Weerth, C., & Buitelaar, J. K. (2005). Physiological stress reactivity in human pregnancy--a review. Neurosci Biobehav Rev, 29(2), 295-312.

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Dunkel Schetter, C., & Glynn, L. M. (2011). Stress in pregnancy: Empirical evidence and theoretical issues to guide interdisciplinary research. In R. J. Contrada & A. Baum (Eds.), The handbook of stress science: Biology, psychology, and health (pp. 321-347). New York, NY, US: Springer Publishing Co.

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Dukel Schetter, C. (2011). Psychological science on pregnancy: Stress processes, biopsychosocial models, and emerging research issues. Annu Rev Psychol, 62, 531-538.

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Entringer, S., Buss, C., Shirtcliff, E. A., Cammack, A. L., Yim, I. S., Chicz-DeMet, A., . . . Wadhwa, P. D. (2010). Attenuation of maternal psychophysiological stress responses and the maternal cortisol awakening response over the course of human pregnancy. Stress, 13(3), 258-268. doi:10.3109/10253890903349501

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Entringer, S., Buss, C., & Wadhwa, P. D. (2015). Prenatal stress, development, health and disease risk: A psychobiological perspective-2015 Curt Richter Award Paper. Psychoneuroendocrinology, 62, 366-375. doi:10.1016/j.psyneuen.2015.08.019

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Florio, P., Imperatore, A., Sanseverino, F., Torricelli, M., Reis, F. M., Lowry, P. J., & Petraglia, F. (2004). The measurement of maternal plasma corticotropin-releasing factor (CRF) and CRF-binding protein improves the early prediction of preeclampsia. J Clin Endocrinol Metab, 89(9), 4673-4677.

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Guardino, C.M. & Dunkel Schetter, C. (March, 2014). Understanding Pregnancy Anxiety: Concepts, Correlates, and Consequences. Zero to Three.

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Glynn, L. M., Wadhwa, P. D., Dunkel-Schetter, C., Chicz-Demet, A., & Sandman, C. A. (2001). When stress happens matters: effects of earthquake timing on stress responsivity in pregnancy. Am J Obstet Gynecol, 184(4), 637-642.

Lowry, P. J. (1993). Corticotropin-releasing factor and its binding protein in human plasma. Ciba Found Symp, 172, 108-115; discussion 115-128.

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Mastorakos, G., & Ilias, I. (2003). Maternal and fetal hypothalamic-pituitary-adrenal axes during pregnancy and postpartum. Ann N Y Acad Sci, 997, 136-149.

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Monk, C., Spicer, J., Champagne, F.A. (2012). Linking prenatal maternal adversity to developmental outcomes in infants: The role of epigenetic pathways. Development and Psychopathology, 24(4), 1361-1376.

Schulte, H. M., Weisner, D., & Allolio, B. (1990). The corticotrophin releasing hormone test in late pregnancy: lack of adrenocorticotrophin and cortisol response. Clin Endocrinol (Oxf), 33(1), 99-106.

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Smith, R., & Nicholson, R. C. (2007). Corticotrophin releasing hormone and the timing of birth. Front Biosci, 12, 912-918.

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Wadhwa, P. D., Entringer, S., & Buss, C. (2011). The contribution of maternal stress to preterm birth: Issues and considerations. Clinics in Perinatology, 38 351–384.

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Yali, A. M., & Lobel, M. (1999). Coping and distress in pregnancy: an investigation of medically high risk women. J Psychosom Obstet Gynaecol, 20(1), 39-52.