The placenta is the nutritive organ for the human fetus. It plays multiple roles in protecting the pregnancy from pathogens, producing the right endocrine milieu, supplying nutrients, and removing wastes. A more interesting role for this organ is the regulation of maternal mood and behavior, thus impacting neonatal well-being.
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There is some evidence that the placenta is the mechanistic link between prenatal stress in the mother and poor infant outcomes. Both animal and human studies have shown the close relationship of prenatal stress with poor placental function.
Background
Pregnancy induces many physical and biochemical changes in the woman. Moreover, she becomes more susceptible to mental ill-health, ranging from depression to stress or postnatal psychosis. UK mothers have a 20% incidence of prenatal or postnatal mood disorders, making it among the commonest illnesses associated with pregnancy.
Mental health is also linked to increased maternal mortality within pregnancy and the first year after delivery. The maternal stress suffered during pregnancy also leaves the mother and child at increased risk of behavioral and metabolic issues.
For one, the mother's emotional ill-health leaves its imprint on fetal health. Several studies show that fetal development is programmed by prenatal maternal stress, such that babies born to mothers in the top 15% of pregnant women with anxiety or depression are at twice the risk of mental ill-health themselves. Yet, genes also play a role, such as the brain‐derived neurotrophic factor (BDNF) and catechol‐O‐methyltransferase (COMT), which interact with environmental factors.
Secondly, the placenta must be in top form to protect the fetus against some forms of prenatal stress. The stress hormone, cortisol, is released by the mother in such situations, but the placental enzyme 11β‐hydroxysteroid dehydrogenase 2 (HSD11B2) converts it to its inactive form cortisone, protecting the fetus.
However, glucocorticoids produced in the mother or administered to her can affect the functioning of the placenta, including its vital functions like vascularization, nutrient transport, and apoptosis. Maternal catecholamines, also released during stress, can also affect the fetus via their effects on placental functioning. This, in turn, leads to poor outcomes in the children.
Thirdly, the placenta regulates and optimizes fetal growth while helping maintain maternal health.
Epigenetic Changes and Placental Changes
Maternal stress may mediate adverse placental changes via epigenetic changes in the placenta. This refers to changes in chromatin structure by adding or removing methylation tags to DNA and histones in a heritable manner.
Since the prenatal period is one in which the epigenome changes rapidly, and since maternal stress can cause such changes to occur, the risk is obvious. Animal experiments have shown such stress-related changes in the placenta, including methylation in the HSD11B2 promoter region and the ‐linked‐N‐acetylglucosamine transferase (OGT) gene.
Some of these epigenetic changes are sex-specific. Thus, anxiety in the mother during pregnancy can cause increased methylation of HSD11B2, but depression is linked to increased NR3C1 and BDNF promoter region methylation in the placenta. Again, chronic stress and trauma were linked to higher methylation of DNA in several genes implicated in regulating the hypothalamopituitary axis (HPA), including CRH, CRHBP NR3C1, and FKBP5.
Such patterns may affect function in the offspring. Earlier animal research demonstrates that stress in early life can imprint the epigenome of the offspring. This is seen following prenatal stress, separation from the mother, or maternal neglect. In humans, a marker of such stress, following maternal anxiety or depression, is CpG methylation at NR3C1 in umbilical blood.
Conversely, NR3C1, CRH, and BDNF CpG methylation is seen following exposure to war or chronic stress. Violence between partners is also linked to these changes, as is pre-eclampsia, indicating a potentially higher vulnerability of the DNA at these sites to epigenetic changes due to stress.
With BDNF being among genes that are key to brain development, its epigenetic modification may cause higher susceptibility to mental ill-health in later life.
Does the Placenta Affect Maternal Mood?
Only a few researchers have looked at how the placenta is implicated in maternal mood disorders. It is known that pregnancy hormones like pituitary prolactin and placental lactogens form one group by function. As pregnancy progresses, human placental lactogen (hPL) is secreted by the placental syncytiotrophoblast into the maternal bloodstream to substitute for prolactin.
Thus, hPL becomes the primary lactogenic hormone in pregnancy. Many studies have shown that prolactin and the prolactin receptor, which also functions as the hPL receptor, are involved in initiating maternal behaviors among rodents. The prolactin-prolactin receptor combination also stimulates neurogenesis in the mother.
In humans, both prolactin and hPL may inhibit pregnancy behaviors related to anxiety. Women with postnatal depression often have low serum prolactin levels, but high prolactin is associated with less anxiety during the gestational period. Similarly, low hPL, already linked to fetal growth restriction, could also be involved in mood abnormalities and adverse maternal outcomes.
Imprinted Genes and Placental Function
Imprinted genes may contribute to this process. Such genes are expressed from only one of the two parental alleles due to the epigenetic tags in the germline. These genes modulate several processes, including fetal growth, placental development, adult behavior, and metabolic processes.
With a multiplicity of functions and the ability of epigenetic changes to achieve a wide range of effects, scientists postulate that imprinted genes help program the fetus for adverse outcomes of pregnancy. Some imprinted genes have been found to be abnormally expressed in the placenta in infants with altered neurobehavioral development.
Again, imprinted genes are important in regulating endocrine cell types that are found in the rodent placenta. The placenta is an important source of lactogenic hormones. This may indicate that these genes could be abnormally expressed to partly cause abnormal maternal behavior in rodents via the altered exposure of the maternal brain to hPL and other placental hormones that are central to such behavior.
If this linkage between placental endocrine expression and imprinted genes is conserved, it would help explain why low birth weight occurs in many pregnancies with depressed or anxious mothers – mood disorders. Cord blood DNA has shown that imprinted genes carry epigenetic changes associated with maternal depression and/or stress in pregnancy.
Both cord blood DNA and placental DNA have demonstrated such methylation changes. These could be not simply the result of exposure to prenatal stress, as is widely assumed, but the origin of maternal mood abnormalities via alterations in placental endocrine function.
More recent studies have shown that prenatal depressive symptoms and clinical depression are closely related to the expression of an imprinted gene and its regulated product, placental lactogen. A very recent study indicates the potential for imprinted genes to affect the neural transcription profile during pregnancy, and the rodent's maternal behavior after birth, suggesting a causal role.
One study showed that the expression of the placental paternally expressed gene 3 (PEG3) gene was significantly lower in depressed mothers, even after adjusting for low birth weight and term of pregnancy. This was associated with a markedly lower hPL expression as well.
The PEG3 gene is an imprinted gene that regulates fetal growth and placental development and behavior and metabolism in mice. Its reduction in association with the observed decrease in hPL levels may mean that anomalous expression of these genes drives impaired psychological adaptation to pregnancy in these women.
The effect was demonstrated to be more severe in male placentas, supporting the further premise that these changes may perhaps also affect the infant outcome. Moreover, there is early evidence that women who bear boys may be at greater risk of postpartum depression than girls.
Such results may eventually explain why maternal depression accompanies low birth weight and adverse infant outcomes, helping to understand both the causes and effects of maternal depression in pregnancy.
What Are the Implications?
The placenta is important in achieving a healthy pregnancy, but it bears the marks of any prenatal stress. Epigenetic changes may drive the altered epigenomic pattern that leads to adverse neurological and development outcomes in the affected children, leading to mental and metabolic disorders in adult life.
Impaired placental function is also implicated in maternal mood abnormalities in pregnancy or the early postpartum period because of the lower levels of hPL and other lactogenic hormones. Several women with prenatal depression, anxiety, or stress go unrecognized because of the poor awareness of this complication and link.
One researcher points out that reduced expression of genes like PEG3 and hPL may drive prenatal depression. Still, the reverse may also be true because this gene responds to maternal diet and other environmental factors in mice. A possible solution is suggested:
A suboptimal maternal environment, which may include maternal prenatal stress, could misprogramme placental expression of PEG3, which in turn may alter placental signalling via hPL, thereby further contributing to the depressed mood."
If these findings are confirmed, future studies may help determine the utility of measuring hPL expression, for instance, in the maternal serum, as a biomarker for an increased risk of depression.
Improving maternal mood and thus supporting the development of infants' brains is a powerful capability.
The provision of better emotional care for all pregnant women and enhanced identification and support for women at particularly high risk of maternal mood disorders will help not only them, but also their children, and potentially subsequent generations."
References
- Yarmolinsky, R. (2016). Maternal Stress Alters Placenta, Slows Fetal Neurobehavioral Development. Retrieved from: Maternal Stress Alters Placenta, Slows Fetal Neurobehavioral Development. Accessed on October 29, 2021.
- Janssen, A. B. et al. (2016). Maternal Prenatal Depression Is Associated with Decreased Placental Expression of The Imprinted Gene PEG3. Psychological Medicine. https://dx.doi.org/10.1017%2FS0033291716001598. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5080674/
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