Maternal–Foetal Medicine
which, upon release, interact with their receptors on cells of the anterior pituitary gland leading to the secretion of adrenocorticotropic hormone (ACTH). ACTH, released into the peripheral blood stream, interacts with its own receptors on the adrenal cortex, leading to the immediate synthesis and release of the stress hormone cortisol.26 Cortisol has profound influences on the entire organism and supports the body’s adaptation to stress.27
One of cortisol’s targets is the brain
itself, ultimately ‘shutting down’ its own production. This negative feedback function is important, as prolonged high levels of cortisol can be deleterious and suppress growth and immune systems.28
The
HPA system shows both a natural variation of cortisol production across the day (circadian pattern) as well as increased release in response to stressful stimuli.
Depressed pregnant women show higher levels of prenatal cortisol than healthy women.10,13
These women are also found to have smaller
foetuses in mid pregnancy and slower foetal growth compared with non-depressed controls; subsequently, depressed pregnant women are more likely to show premature delivery and have neonates with low birth weight.10,13
Diego and colleagues explored the role of
Neonates of depressed mothers showed significantly higher morning urinary cortisol compared to those of healthy mothers within the first 24 hours of birth.13
maternal cortisol in these adverse pregnancy and foetal outcomes, and found that exposure to elevated maternal cortisol mediated 30 % of the variance of gestational age outcome and 14 % of foetal growth outcome.10
CRH plays a central role in regulating the activity of the HPA axis. Maternal psychosocial stress during pregnancy has been associated with increased placental CRH production.29
In pregnancy, placental CRH
is released into both maternal and foetal compartments and elevated levels have been associated with pre-term labour and slowed foetal growth.30,31
Wadhwa and colleagues32
Post-partum Depression Impact on Parenting
also found that infants exposed to
high levels of maternal prenatal stress and stress hormones were rated by their mothers at six weeks post-partum as temperamentally more difficult, even controlling for concurrent maternal depression and prematurity, thus suggesting adverse post-natal effects on infant development beyond negative birth outcomes.
Other researchers explored foetal stress reactivity as a marker for healthy foetal development. Increased stress reaction and increased heart rate, markers for a ‘reactive style’ foetus, are associated with poor infant outcomes.33
response threshold to stimulus and slow return to baseline after stress.33
Monk and colleagues33 investigated foetal stress reactivity
among pregnant women with and without depression exposed to a brief psychological stressor during a foetal heart rate measurement, and found that foetuses of depressed mothers had significantly greater heart rate increase during the stress task compared to foetuses of healthy mothers. Interestingly, foetal baseline heart rates did not differ by groups. Other research groups have linked foetal stress reactivity to subsequent adverse post-natal outcomes, such as inhibited temperament in infancy and propensity to stress-related psychopathology (anxiety and depression) later in life.34,35
Current research attempts to disentangle genetic and environmental contributions to foetal development. Environmental factors may lead to changes in phenotype (appearance) or gene expression via mechanisms that do not change the underlying DNA sequence/structure but lead to modifications of the activation of
26
For young infants, primary care-givers are the critical external factor shaping the development of effective biological and emotional systems.40,41
‘Reactive style’ is also linked to lower
Early care-giving creates a context in which infants develop a sense of self, a capacity for emotional and biological self-regulation and a template for future interpersonal relationships.42,43 Sensitive mothers monitor their young infants’ environments so that the social demands are developmentally appropriate and, through their own bio-psycho-social regulation, these mothers model strategies of effective self-regulation. By contrast, depressed mothers are less able to regulate their own affect when interacting with their infants than healthy mothers44
sensitive or responsive to their children’s emotional cues.45,46 meta-analysis of 46 observational studies,47
and impress as less In a
maternal post-partum
depression was associated with increased rates of less optimal parenting behaviours directed towards the infant. Depressed mothers engaged more often than healthy mothers in either intrusive parenting (e.g., “roughly pulling or poking at the infant, handling or speaking to the infant in angry manner, controlling behaviour”) or in disengaged parenting (e.g., “ignore, low responsive, few vocalisations to the infant”).47,48
The presence of post-partum
depression also alters affected mothers’ attributions of infant needs in response to an infant cry stimulus; depressed women were less likely to rate recordings of infant hunger cries as indicating a need for a care-giving response compared to healthy controls,49
suggesting
alterations in maternal perceptions and attributions as mechanism for decreased sensitivity. These cognitive patterns in depressed mothers, once established, may have trait-like characteristics and persist even during non-depressed periods, as mothers with a
EUROPEAN OBSTETRICS & GYNAECOLOGY
certain genes (e.g., silencing). DNA methylation, that is adding a methyl group to the cytosine-guanine base combination site, is one mechanism found to silence gene expression, and has been associated with environmental influences such as early care-giving. For example, Meaney and colleagues36
suggest that decreased
maternal nurturing of the rodent pup during an early sensitive period of development is causal for increased DNA methylation in the offspring. Subsequent studies have shown that increased DNA methylation can result in adverse long-term outcomes37
by silencing
the expression of genes important to adequate stress regulation. Most research on methylation thus far is based on animal work,36,38 yet there is emerging interest in replicating these results in human studies. Oberlander et al.39
investigated epigenetic phenomena in
neonates born to mothers with elevated anxiety and depression during the second and third trimesters of pregnancy. These newborns presented with higher levels of DNA methylation in white blood cells obtained from cord blood after birth.39
Subsequently, greater neonate
methylation levels predicted increased infant cortisol reactivity at three months post-partum to stress stimuli, thus highlighting the link between stress exposure, high methylation levels and child HPA stress axis hyperreactivity.39
The above studies converge to
underscore the importance of a relatively stress-protected in utero environment for a developing foetus. Increased stress levels or antenatal depression can lead to impaired foetal growth, or pre-term birth, and build the foundation for increased infant stress reactivity early in development. Future research should shed light on in utero pathways of stress transmission from mother to child, and replicate and expand prior work linking maternal cortisol, placental CRH and child DNA methylation.39
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