The Effect of In Utero Maternal Distress on the Neurodevelopment of the Fetus
How Cortisol Plays a Major Role in Epigenetic Modification
Leslie Solomonian, BSc, ND
It has long been noted and accepted that environmental influences have a significant positive effect or negative effect on the growth and development of fetuses in utero. In addition to standard recommendations that pregnant women avoid (for example) alcohol intake, exposure to environmental chemicals, and consumption of raw animal products, clinicians must also consider the psychoneuroendocrinologic environment in which a fetus develops. Extensive animal models demonstrate that prenatal maternal stress predisposes offspring to behavioral changes that can persist into adulthood, likely mediated by changes to the hypothalamic-pituitary-adrenal (HPA) axis.1,2 Although clinical studies are limited, this effect can be seen in human infants as well, presenting significant implications in the realm of development and mental health.
The term fetal programming was coined by Barker3 to reflect the concept that the prenatal environment prepares a fetus for life outside of the womb. During critical periods of development, when the fetus is particularly plastic, an environmental stimulus has the capacity to confer changes that have persisting effects. Barker performed most of his research on the influence of undernutrition in utero on the development of chronic diseases later in life such as cardiovascular disease, diabetes mellitus, and hypertension. The same principle may be applied to the modification of neuroanatomy and neurochemistry in response to prenatal stress, predisposing children to maladaptive mental health patterns.4,5
Rutherford et al6 showed that piglets whose mothers experienced high levels of “social stress” during pregnancy demonstrated a heightened arousal and decreased tolerance to pain. They demonstrated that exposure to higher levels of stress or maternal cortisol mid-gestation induces an adaptive advantage for offspring born into a potentially adverse environment by hardwiring them to a state of hyperarousal and increased sensitivity. The modification of gene expression in utero in response to stressors can be seen as adaptive, allowing the adjustment of phenotype to environmental pressures.6 However, if the environmental conditions are not as anticipated, programming of the fetus to a stressful environment is not adaptive and may be harmful, predisposing the unborn child to neurodevelopmental detriment.1,7 Children who are exposed to prenatal maternal anxiety, depression, or stress seem to be more likely to struggle with several challenges, including anxiety, symptoms of attention-deficit/hyperactivity disorder, reduced cognitive capacity,1,2 maternally perceived “negative temperament,”8 autism, schizophrenia,9 and learning delay.1 Some studies8,10 looked at the outcomes in young infants, while other investigations observed the effects in children up 10 years old.10 The effect of such in utero stress may in fact be lifelong. The young adult children of women who experienced severe stress during pregnancy demonstrated statistically significant changes in cortisol secretion in response to a standardized social stress test, as well as corticotropin stimulation, compared with an age-matched control group.11
While these links have been observed, it remains unclear precisely what mechanism accounts for the outcome. It is likely that dysregulation of the HPA axis has a significant role in this intergenerational transfer of hyperarousal. Researchers observed elevated levels of cortisol in amniotic fluid prenatally and umbilical cord blood at birth in infants exposed to maternal distress.10,12 Cortisol, then, may have a role in the epigenetic modification of phenotype. Exposure to maternal glucocorticoids (which freely cross the placenta) may modify gene expression in the fetal central nervous system. In fact, increased maternal cortisol seems to alter the expression of the placental barrier enzyme that metabolizes cortisol, increasing fetal exposure via decreased breakdown.9 Exposure to third-trimester maternal depression (a condition that is often characterized by elevated cortisol and HPA hyperreactivity) seems to modify the methylation of a critical glucocorticoid receptor gene in newborns, potentially downregulating its expression in the hippocampus and HPA axis.13,14 These changes in gene expression may interfere with the development and regulation of the HPA axis during a critical period of plasticity.14 The effects on the brain include reduced hippocampal volume,2,12 as well as hyperarousal and impaired negative feedback regulation of the HPA axis.15
It is important to note that prenatal cortisol levels are not directly correlated to women’s subjective ratings of prenatal stress. Both seem to relate to cognitive development, suggesting that each is an independent predictor.2 Other evidence concurs that perceived maternal distress during pregnancy (independent of objective assessment of an anxiety disorder or elevated cortisol) is associated with the aforementioned consequences.16,17 The effect seems greatest when the fetus is exposed in the third trimester,8,13,15 which is a critical period for specific limbic system development,15 reinforcing the fetal programming theory by Barker.3 Maternal distress also causes elevation of free corticotropin-releasing hormone; this (possibly instead of or in addition to elevated maternal cortisol) may mediate behavioral and temperament changes in infants through influence on the amygdala and hippocampus.16 These are critical structures of the limbic system and possible mediators of behavioral changes seen in infancy and childhood. Elevated corticotropin-releasing hormone is associated with preterm delivery and with small size for gestational age,7,14 which are also independent risk factors for neurodevelopmental conditions, including attention-deficit/hyperactivity disorder and schizophrenia.16 In boys, elevated exposure to testosterone in utero may mediate the increased responsiveness of the amygdala, enhancing fear reactivity in childhood.5 This hormone may also interact with cortisol and contribute to the development of autism, language delays, and aggression.
Interpersonal Stress and Relationships
The effect of prenatal maternal stress may extend beyond neurological development and affect the immune system as well. The tendency to atopy and IgE-mediated allergies begins to develop in utero. Prenatal stress, and in fact lifelong maternal stress, and disruption of the HPA axis may upregulate maternal and placental helper T cell subtype 2 cytokine tendency and delay helper T cell subtype 1 response maturation, resulting in elevated IgE and risk of atopy at birth.18,19 Again, this could be viewed as an adaptive response to an anticipated environmental challenge that ultimately is maladaptive.
These outcomes seem to be independent of postnatal stress.1 However, when parents who experience anxiety and hyperarousal of the HPA axis during gestation continue the pattern of hyperarousal postpartum, parenting practices are also affected. For example, parents who are anxious and hyperaroused tend to be less sensitive and responsive to their children’s communication, in turn leading to insecure attachment and hyperarousal among the children.2,9 However, consistent evidence indicates that positive child-rearing and attachment behaviors by the caregivers postpartum can moderate these outcomes, reversing the effects of prenatal cortisol exposure.2,18 So, while prenatal stress can be exacerbated by poor postnatal attachment practices, effective caregiving (by the biological parent or a foster) can moderate the effect of prenatal cortisol exposure on brain and HPA axis development.2 It was demonstrated that biobehavioral regulation in infants who were exposed to stress in utero but whose mothers were sensitive parents was indistinguishable from that in infants without in utero stress exposure.10
The greatest effect on fetal neurodevelopment seems to be interpersonal stress, especially that in the relationship with the partner.1,18 These findings highlight the importance of questioning and counseling preconception and during gestation with respect to stress and relationships. They also reinforce the need for early postnatal intervention in promoting infant-parent attachment. Because detrimental effects of the prenatal environment can be moderated by a positive postnatal bonding between parent and child, efforts to enhance attachment are prudent, especially if a woman self-reports distress during her pregnancy. For example, effective continuity of care and strong breastfeeding counseling have been shown to enhance a mother’s self-esteem, feelings of warmth toward her infant, and the ability to provide effective nurturing.20 In addition to recommendations given regarding folic acid intake and blood glucose regulation in pregnancy, efforts should be made to universally screen for and counsel on effective management of stress during pregnancy.
Leslie Solomonian, BSc, ND is a naturopathic physician in Toronto, Ontario, Canada, and an assistant professor at Canadian College of Naturopathic Medicine (Toronto), where she provides instruction in pediatrics, philosophy, and clinical medicine. Dr Solomonian is experienced in working with young families. She strongly believes that the well-being of the child is influenced by the well-being of the family, the community, and the environment. She sees healthy children as the key to a healthy future.
Talge NM, Neal C, Glover V; Early Stress, Translational Research and Prevention Science Network: Fetal and Neonatal Experience on Child and Adolescent Mental Health. Antenatal maternal stress and long-term effects on child neurodevelopment: how and why?
J Child Psychol Psychiatry. 2007;48(3-4):245-261.
Bergman K, Sarkar P, Glover V, O’Connor TG. Maternal prenatal cortisol and infant cognitive development: moderation by infant-mother attachment. Biol Psychiatry. 2010;67(11):1026-1032.
Barker DJ. In utero programming of chronic disease. Clin Sci. 1998;95:115-128.
Clark PM. Programming of the hypothalamo-pituitary-adrenal axis and the fetal origins of adult disease hypothesis. Eur J Pediatr. 1998;157(suppl 1):S7-S10.
Bergman K, Glover V, Sarkar P, Abbott DH, O’Connor TG. In utero cortisol and testosterone exposure and fear reactivity in infancy. Horm Behav. 2010;57(3):306-312.
Rutherford KM, Robson SK, Donald RD, et al. Pre-natal stress amplifies the immediate behavioural responses to acute pain in piglets. Biol Lett. 2009;5(4):452-454.
Endara SM, Ryan MA, Sevick CJ, Conlin AM, Macera CA, Smith TC. Does acute maternal stress in pregnancy affect infant health outcomes? examination of a large cohort of infants born after the terrorist attacks of September 11, 2001. BMC Public Health. 2009,9:e252. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2728717/?tool=pubmed. Accessed July 26, 2012.
Davis EP, Glynn LM, Schetter CD, Hobel C, Chicz-Demet A, Sandman CA. Prenatal exposure to maternal depression and cortisol influences infant temperament. J Am Acad Child Adolesc Psychiatry. 2007;46(6):737-746.
O’Donnell K, O’Connor TG, Glover V. Prenatal stress and neurodevelopment of the child: focus on the HPA axis and role of the placenta. Dev Neurosci. 2009;31(4):285-292.
Kaplan LA, Evans L, Monk C. Effects of mothers’ prenatal psychiatric status and postnatal caregiving on infant biobehavioral regulation: can prenatal programming be modified? Early Hum Dev. 2008;84(4):249-256.
Entringer S, Kumsta R, Hellhammer DH, Wadhwa PD, Wüst S. Prenatal exposure to maternal psychosocial stress and HPA axis regulation in young adults. Horm Behav. 2009;55(2):292-298.
Sarkar P, Bergman K, O’Connor TG, Glover V. Maternal antenatal anxiety and amniotic fluid cortisol and testosterone: possible implications for foetal programming. J Neuroendocrinol. 2008;20(4):489-496.
Oberlander TF, Weinberg J, Papsdorf M, Grunau R, Misri S, Devlin AM. Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses. Epigenetics. 2008;3(2):97-106.
Weinstock M. The potential influence of maternal stress hormones on development and mental health of the offspring. Brain Behav Immun. 2005;19(4):296-308.
Huizink AC, Bartels M, Rose RJ, Pulkkinen L, Eriksson CJ, Kaprio J. Chernobyl exposure as stressor during pregnancy and hormone levels in adolescent offspring. J Epidemiol Community Health. 2008;62(4):e5. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2562331/?tool=pubmed. Accessed July 26, 2012.
Martini J, Knappe S, Beesdo-Baum K, Lieb R, Wittchen HU. Anxiety disorders before birth and self-perceived distress during pregnancy: associations with maternal depression and obstetric, neonatal and early childhood outcomes. Early Hum Dev. 2010;86(5):305-310.
Glover V, O’Connor T. Effects of antenatal stress and anxiety: implications for development and psychiatry. Br J Psychiatry. 2002;180:389-391.
Sternthal MJ, Enlow MB, Cohen S, et al. Maternal interpersonal trauma and cord blood IgE levels in an inner-city cohort: a life-course perspective. J Allergy Clin Immunol. 2009;124(5):954-960.
Wright RJ, Visness CM, Calatroni A, et al. Prenatal maternal stress and cord blood innate and adaptive cytokine responses in an inner-city cohort. Am J Respir Crit Care Med. 2010;182(1):25-33.
Ekström A, Nissen E. A mother’s feelings for her infant are strengthened by excellent breastfeeding counseling and continuity of care. Pediatrics. 2006;118(2):e309-e314. http://pediatrics.aappublications.org/content/118/2/e309.long. Accessed July 26, 2012.