Fetal
programming is the process by which early environment interacts with genes to
produce an individual human constitution. It is not only of great interest to
developmental scientists but also has high media resonance due to the more and
more commonly acknowledged notion that pregnancy actually affects vulnerability
to disease later in life. First evidence came from an epidemiological study showing
that birth characteristics, like low weight and lower gestational age, were
linked to later diseases like diabetes, hypertension, but also psychopathology.
What is currently accepted, though, is that these individual characteristics at
birth are not the actual risk factors for later disease but rather is the environment
to which the mother and the fetus are exposed during pregnancy that affects
fetal development itself and in turn development later in life. There comes the
focus of this post on actual prenatal conditions that may increase the risk for
disease later in life, with a specific focus on mental health.
A key
assumption is that biological systems undergoing rapid developmental changes
are especially vulnerable to organizing and disorganizing influences. Once we
accept this key assumption, it becomes logic to consider the brain a key vulnerable
system to environmental influences, with 100 billion neurons and 100 trillion
connections resulting from a 3mm long neural tube just after conception.
Early
environment interacts with genes to eventually increase vulnerability to
disease later in life. In simple terms, genes do frame development but it is
early environment that actually sculpts it. It all starts before birth, during
pregnancy, when conditions like maternal stress, obesity, infection,
inflammation, and drug exposure, including alcohol use, might impact later
psychopathology. A way to see the effects of early environment is through the
analysis of brain alterations in newborns followed up longitudinally across several
years over development. Here, I will focus on stress and its effect on the
fetus through the mother as I think it is, together with anxiety, the disease
of the century. Many of us have experienced or currently suffer from anxiety,
and I think nobody can say not to be stressed at all nowadays. If it is the
disease of today, how much do we know about it? How can we handle it? And can
we make sure it does not become the disease of tomorrow? I will not be able to
answer all these questions here, but will try to convey the message that it can
be the disease of tomorrow with all likelihood, and we are making sure it
passes on.
Maternal
stress during pregnancy is a risk factor for children’s cognitive impairment
and behavioural issues in toddlerhood. Higher anxiety in mothers during
pregnancy was linked to lower brain matter volume in brain areas associated
with functions like language, memory and attention, and was associated to the correspondent
cognitive impairments in 7-year-olds. Similarly, prenatal maternal depression was
linked to child cortical thinning in frontal areas at 7 years of age, mediating
the association with externalizing symptoms in those children. These brain
alterations affect behaviour in different ways, both directly in the associated
function, but also indirectly by changing the way the child learns from and
adapts to the environment over development. Looking at newborns, researchers
found an association of maternal stress with small hippocampal volume, a key
region for memory. This brain alteration can affect how the child responds and
adapts to a richer and more stimulating environment over development, resulting
in different cognitive levels and behavioural profiles. Specifically, newborns
with larger hippocampus could benefit more from a stimulating environment in
relation to later cognitive function, suggesting differential susceptibility to
environmental influences over development based on prenatal environment.
Many brain
imaging studies have been conducted to investigate the association between maternal
stress, depression and anxiety and brain development in the child. These
studies identified various alterations in both anatomy and connectivity of the
brain in fetuses, children, as well as adolescents. But how does the fetus know
that mom is stressed? and how does the fetus react? First, stress is very much
personal at a behavioural level, as can be related to work, family issues, or
anything else. But for the fetus to know that mom is stressed, stress has to be
biologically based. There is no neural connection between mom and fetus and all
happens through placenta, so here comes cortisol, which is produced during
stress responses and can pass through placenta to the fetus. Cortisol is
fundamental for brain development in terms of cellular growth and functioning and
so important for the fetus to receive, just not too much. A specific enzyme is
in charge to convert cortisol from active to inactive in placenta when it
passes through, although 10 to 20% still remains active. If mom is stressed,
though, her own level of cortisol increases plus that specific enzyme is less effective,
leading to an increase in cortisol concentration in the fetus. This can lead to
alterations in brain development affecting neuronal proliferation and
differentiation, and has been linked to neurodevelopmental disorders like autism. Higher
cortisol at 15 weeks of gestation was associated to higher amygdala volume and
amygdala connectivity to somatosensory and frontal areas in baby girls, and such
larger amygdala mediated affective symptoms, in particular the increase in internalizing
behaviours at 3 years of age. It is not clear why females are more affected
here, and in fetal programming in general, but potentially supports the idea of
adaptation to higher vigilance in an environment considered to be hostile
during development.
Thus, early
life stress caused by conditions like maternal stress during pregnancy acts on
alterations of the endocrine system (cortisol), which acts as mediator for
altered brain development eventually leading to altered cognitive and affective
processes and overall mental health issues. Of note, cortisol is needed for fetal
development anyway. It is not a toxic substance or so, but it’s just the
concentration levels to be altered in response to adverse environment during
pregnancy. From an evolutionary point of view, the resulting behavioural
characteristics can be also thought as adaptation to the early disruptive
environment. An example? Anxiety can be seen as increased vigilance which can
be protective in a dangerous environment. Thus, we should keep in mind that all
this is the result of adaptive mechanisms to change in concentrations of
biological substances that are supposed to be there to prepare the fetus to the
external world.
Other
gestational conditions, including obesity and prenatal inflammation, have been
shown to be risk factors for various neurodevelopmental disorders, including
autism and schizophrenia. A key substance that increases in concentration
levels in response to stress or depression is interleukin 6, involved in
inflammatory processes. In stressed moms, it can pass through placenta directly
or stimulate placental cytokine production resulting in release of inflammatory
cytokines like interleukine 6 in the fetal compartment, where they reach the
fetus brain. Interleukin-6 has also been associated to higher amygdala volume and
more connectivity to brain areas involved in learning and memory in baby boys
as well as girls. These brain alterations during the first year of life can eventually
lead to alterations in cognition and general functioning, as indicated by cognitive
impairments at age 1 lower intelligence at age 4. Thus, immune activation and inflammation
of moms during pregnancy affect their own children’s behaviour in toddlerhood
by acting on connectivity between their salience and attentional brain networks
as newborns. Researchers have also found that antibodies to this interleukin-6
can block the effects of maternal inflammation on offspring stress reactivity,
social deficits and learning impairments.
Finally, it
is important to include in this framework some considerations on mom’s past
experiences that might affect her behaviour during pregnancy and beyond that.
It is, in fact, possible that not only what mom experiences during pregnancy
affects the child’s development but also what she experienced before, as a
child herself, like childhood trauma. We know that childhood trauma is a risk
factor for psychiatric disorders as well as or other biological alterations
like obesity, altered response to stress and higher levels of inflammation. A mom
brings along her own physiological alterations during pregnancy, which in turn
affect the child’s development. The sad cycle of childhood trauma can be set in
motion by changing the parenting behaviour of a mom or dad (see neglect or
abuse), leading to further trauma in the child that may result in developmental
conditions like autism. Even if the cycle is broken and the child is not directly
exposed to trauma, the package of childhood trauma that mom brings along can
have an intergenerational effect on the child, for instance through
physiological alterations (like stress response, inflammation and obesity) or
behavioural alterations (like drug and alcohol abuse, depression, anxiety and
altered parenting style in general).
To
conclude, I showed you the tip of the iceberg of something as fascinating and complex
as fetal programming. I focused on the stress-related part of this topic due to
the high pertinence in our lives as we are living in such a frenetic society. We
are all stressed out, with a long list of consequences for ourselves and our
offspring. But how could we not in crazy times like these when we just needed a
pandemic to make things even worse? This is not something easy to solve, but it
would be useful to acknowledge the issue, raise awareness and try to do what we
can to improve things a bit, like a change of view on current lifestyle and
priorities.
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