Pregnancy is a complex condition. Prenatal stress is one of many factors that can affect the dynamic link between mother and child, with significant impact on fetal development. Maternal stress during pregnancy may profoundly affect the fetus, with lifelong implications to the child’s wellness. 
Challenges in maternal fetal research leave us with a limited understanding of the mechanisms of this issue. However, there are studies that shed some light on the processes and implications of prenatal stress on the fetus. Multiple studies have shown that prenatal stress can have a profound effect on fetal HPA axis development. As there are no direct neural links between the fetus and the mother, maternal stress shapes HPA axis development and function through physiological signals. [1, 2, 3, 4, 6, 9, 11]
Research has shown that adrenocorticotropic hormone (ACTH) is released in the fetus in response to stress.  Additionally, glucocorticoids may pass through the placenta to the fetus with postnatal effects, including birth weight, brain development, and HPA axis function.  Catecholamines also play a role; studies have also shown that catecholamines released in response to the mother’s psychological stress affect the fetus by decreasing uterine blood flow. 
Methylation and Maternal Stress
Studies have also shown that prenatal stress affects fetal development through epigenetic changes in HPA axis genes. DNA methylation is an epigenetic mechanism in which a methyl group (CH3) is added to DNA, altering gene function. Modifications of genes such as NR3C1 have been shown in children whose mothers experienced chronic and traumatic stress while pregnant. [4, 7] Dysregulated HPA axis function has been found in those who experience traumatic stress; this may be characterized by either high or low cortisol levels. The glucocorticoid receptor gene, NR3C1, is an important marker for HPA axis function. We know that decreased methylation of NR3C1 is associated with less circulating cortisol. NR3C1 methylation abnormality is also associated with early life stress and stress reactivity. [10, 12]
One study explored how mothers exposed to genocide while pregnant can pass on PTSD to their child. Exposed mothers and their children had lower cortisol and glucocorticoid receptor levels and higher mineralocorticoid receptor levels than non-exposed mothers and children. The exposed group also had higher methylation of the NR3C1 exon 1F, and increased methylation of CpGs in the NR3C2 coding sequence than non-exposed groups. This supports the idea that prenatal stress affects fetal development through epigenetic changes of HPA axis genes. [7 ]
Another study found that both chronic stress and war trauma had extensive effects on gene methylation of the HPA axis. Significant effects were found at transcription factor binding sites in all tested genes, including CRH, CRHBP, NR3C1, and FKBP5. Methylation in NR3C1 and CRH CpG cites was linked with abnormal birth weight. Exposure to chronic or war-related stress also influenced the mother and fetus differently, showing that the effects of stress are different at various stages of life. 
The time periods most susceptible to prenatal maternal stress are yet to be confirmed. Some feel that adverse health outcomes may be more likely during early pregnancy, when the expression of glucocorticoid receptors in the fetus is limited. [8, 9] Other research has shown that acute maternal stress later in pregnancy may have a greater effect on the fetus than chronic prenatal stress. 
It is important to understand that the effects of maternal stress can have permanent implications to the infant later in life due to the modified HPA axis and brain activity. [2, 4, 9] Stress during pregnancy is associated with a higher risk for altered physiological, emotional, and behavioral development as well as affective disorders in children. [2, 6, 8]
More Research Needed
There is still a need for more research into the mechanisms of how maternal stress affects the fetus. However, the implication is clear: prenatal maternal stress may alter the development of the fetus, including HPA axis changes that can manifest as functional, behavioral, and emotional issues for the child later in life. Significant changes have been noted with both chronic and acute stress in various stages of pregnancy. It is essential to monitor stress and HPA axis function in pregnant women. Having a window into HPA axis function may allow for implementation of appropriate interventions and/or lifestyle changes that can ensure better quality of life for the parent and the child.
1. DiPietro, J. A. (2012). Maternal stress in pregnancy: considerations for fetal development. Journal of Adolescent Health, 51(2), S3-S8.
2. Emack, J., & Matthews, S. G. (2011). Effects of chronic maternal stress on hypothalamo–pituitary–adrenal (HPA) function and behavior: no reversal by environmental enrichment. Hormones and behavior, 60(5), 589-598.
3. Fink, N. S., Urech, C., Berger, C. T., Hoesli, I., Holzgreve, W., Bitzer, J., & Alder, J. (2010). Maternal laboratory stress influences fetal neurobehavior: cortisol does not provide all answers. The Journal of Maternal-Fetal & Neonatal Medicine, 23(6), 488-500.
4. Kertes, D. A., Kamin, H. S., Hughes, D. A., Rodney, N. C., Bhatt, S., & Mulligan, C. J. (2016). Prenatal maternal stress predicts methylation of genes regulating the hypothalamic–pituitary–adrenocortical system in mothers and newborns in the Democratic Republic of Congo. Child development, 87(1), 61-72.
5. Kosinska-Kaczynska, K., Bartkowiak, R., Kaczynski, B., Szymusik, I., & Wielgos, M. (2012). Autonomous adrenocorticotropin reaction to stress stimuli in human fetus. Early human development, 88(4), 197-201.
6. Levendosky, A. A., Bogat, G. A., Lonstein, J. S., Martinez-Torteya, C., Muzik, M., Granger, D. A., & Von Eye, A. (2016). Infant adrenocortical reactivity and behavioral functioning: relation to early exposure to maternal intimate partner violence. Stress, 19(1), 37-44.
7. Perroud, N., Rutembesa, E., Paoloni-Giacobino, A., Mutabaruka, J., Mutesa, L., Stenz, L., … & Karege, F. (2014). The Tutsi genocide and transgenerational transmission of maternal stress: epigenetics and biology of the HPA axis. The World Journal of Biological Psychiatry, 15(4), 334-345.
8. Rakers, F., Bischoff, S., Schiffner, R., Haase, M., Rupprecht, S., Kiehntopf, M., … & Nathanielsz, P. W. (2015). Role of catecholamines in maternal-fetal stress transfer in sheep. American journal of obstetrics and gynecology, 213(5), 684-e1.
9. Rakers, F., Frauendorf, V., Rupprecht, S., Schiffner, R., Bischoff, S. J., Kiehntopf, M., … & Schwab, M. (2013). Effects of early-and late-gestational maternal stress and synthetic glucocorticoid on development of the fetal hypothalamus–pituitary–adrenal axis in sheep. Stress, 16(1), 122-129.
10. Schechter, D. S., Moser, D. A., Paoloni-Giacobino, A., Stenz, L., Gex-Fabry, M., Aue, T., … & Sancho Rossignol, A. (2015). Methylation of NR3C1 is related to maternal PTSD, parenting stress and maternal medial prefrontal cortical activity in response to child separation among mothers with histories of violence exposure. Frontiers in psychology, 6, 690.
11. Tollenaar, M. S., Beijers, R., Jansen, J., Riksen-Walraven, J. M. A., & De Weerth, C. (2011). Maternal prenatal stress and cortisol reactivity to stressors in human infants. Stress, 14(1), 53-65.
12. Palma-Gudiel, H., Córdova-Palomera, A., Leza, J. C., & Fañanás, L. (2015). Glucocorticoid receptor gene (NR3C1) methylation processes as mediators of early adversity in stress-related disorders causality: a critical review. Neuroscience & Biobehavioral Reviews, 55, 520-535.