Introduction

The time period surrounding pregnancy are highly important for the promotion of brain health across the lifespan. Evidence suggests that the most sensitive windows for nutrition is in late foetal and early postnatal life, with greater acceptance that the success of postnatal nutritional is dependent on
optimising foetal nutritional status prior to birth. The first 1,000 days, defined by prenatal life (280 days) followed by the first 2 years of child’s life (720 days), is an intense stage of growth and development,
characterised by a distinguished growth and development of the brain.

It is a crucial phase, known as time-window, and where early stimuli (e.g., maternal
diet, breastfeeding or children nutrition) may program adverse health outcomes, either physical or mental, in later life. Recent scientific evidence has identified that parental health and nutrition status at the time of conception may be related to the development of several preventable non‐communicable diseases in the offspring, among them neurological disorders .

What is happening in the brain during pregnancy?

In-utero is a critical brain developmental period once gene–environment
interactions influence the maternal-placental-foetal triads, resulting in both short- and long-term outcomes on brain health .
Many factors influence offspring neuro functional and structural outcomes, but nutrition has particular importance. All nutrients are essential to neuroplasticity, however the role of glucose, fats (including long-chain
polyunsaturated fatty acids), protein, iron, zinc, iodine, copper, folate and choline
have been highlighted in several studies.

Macro and micronutrients affect neurodevelopmental processes during pregnancy, all of which proceeding at a rapid pace between 22-42 weeks’ post-conception. Therefore, adequate maternal
nutritional status is recognised as extremely relevant to proper foetal development. At 25 weeks post-conceptional age, the human brain is about the size of a coffee bean. By 40 weeks, the resembles a walnut, and assumes an appearance far more similar to an adult brain. This considerable morphological change in external structure is paralleled by extensive internal growth and differentiation. While the rapidly growing foetal brain exhibits far more ability to adapt and change than the adult brain, it is also highly vulnerable to injury.

Key Risk Factors

Key risk factors during this stage include nutritional and other lifestyle considerations, such as smoking, as well as socio-economic status and levels of stress.

Nutritional Risk Factors

Unfortunately, many women of reproductive age will not be nutritionally-
prepared for pregnancy, both in high, middle and low income countries. Micronutrient
supplementation beginning in pregnancy can correct key maternal nutrient deficiencies, but such approaches can sometimes be ‘too little, too late’ to fundamentally improve child health outcomes.

Folate and B12 Insufficiency

Since approximately a third of fertile couples having regular unprotected sex will conceive within one month, optimising folic acid supplementation should coincide with the decision to become pregnant. A minimum of 4-6 weeks of folic acid supplementation is required to reach adequate levels for brain development to and three weeks after conception (to help prevent neural tube defects). This overlapping time frame emphasises the importance of preventing folic acid deficiency even prior to conception.

Nutrients which support brain development during gestational period are folic acid
and B12. Optimal maternal status of folic acid contributes to neural tube closure, which occurs within the first 28 days after conception, reducing risk of neural tube defects, such as spina bifida. In addition, there is evidence strongly supporting a relationship between low maternal vitamin B12 levels and increased risk of neural tube defects, which acts both independently and in synergy with folate,
preventing malformation in the neural tube.

A large Norwegian prospective pregnancy cohort has shown that maternal
supplementation of folic acid in the beginning of pregnancy was also linked with lower risk of severe language delay in children at age 3 years. Additionally, there is evidence showing that babies of mothers deficient in vitamin B12 and folate during pregnancy have an increased risk of neural
tube defects and neurodevelopmental disorders, such as smaller brain volumes in childhood, poorer cognitive development, attention deficit hyperactivity Disorder (ADHD) and, autism. Lastly, studies have also shown that offspring whose mothers were supplemented with vitamin B12 performed higher in
neurodevelopmental tests (BSID-III test) in domains such as cognition and language at 24–42 months of age.

Although there is growing evidence on the role of preconception nutrition for
improved birth outcomes and the benefits of periconceptional folic acid for preventing neural
tube defects, less is known about the impact on intellectual functioning in early childhood and beyond and more research is required. Maternal pre-pregnancy BMI has, however, been negatively associated with children’s cognitive performance, even after adjusting for socio-demographic
confounders and children’s BMI, and this relationship appears to become stronger as
children get older.

Iodine Deficiency

Furthermore, a positive association has also been identified between iodine
status before conception and child IQ, supporting its link to poorer cognitive function
reported in other studies. However, unexpectedly there was a
lack of association to measures of executive function. Although deficiencies are
always best avoided, further data are required to establish the public health
importance of low preconception iodine status.

Overall Nutritional Status

Additional recent data shows that weekly preconception supplementation of
multiple micronutrients improved certain domains of intellectual functioning at age 6
to 7 years compared with folic acid alone . The impact of
supplementation on child intellectual functioning was also magnified among children
whose mothers consumed supplements at least 6 months before conception.
Moreover, this effect was greatest among children born into families with the lowest
household socioeconomic status. These findings suggest the scope for
preconception micronutrient interventions to have long-term benefits for cognition,
particularly for these members of the community.

The effects of proper nutritional status are believed to influence
brain health even before the 1000 days, during the periconceptional period. Studies have shown that maternal supplementation of folic acid, iron and vitamin B12 at preconception period enhances vitamin stores during the early neurodevelopmental period, and has proven to have a major preventive effect in
neurodevelopmental disorders. Findings from the Dutch Famine studies revealed that children whose
mothers were exposed to severe famine within one month before to two months after
conception, had higher risk of neural tube defects, depressive symptoms,
schizoid personality at age 18 and schizophrenia in adulthood.
Therefore, considering the particular strong evidence on the benefits of folic
acid on reducing risk of neuro congenital birth defects, it is recommended that individuals of childbearing age take a folic acid supplement, preferably 5–6 months before conceiving.

Caffeine
Caffeine is the most widely consumed psychoactive substance, including
throughout pregnancy. It is a potent neuromodulator that easily crosses the placental barrier and therefore it is linked to impaired neurodevelopment during childhood. Caffeine-related threats to foetal neurocognitive development have been greatly explored through animal and human-models.
Although there are still some incongruences about the maternal caffeine intake effect on offspring brain outcomes, several publications advert for the caffeine-related alterations in brain microstructures, risk of changes in hippocampus and prefrontal cortex, leading to long-term alterations in memory and learning. Studies also showed an increased risk of a range of behavioural and psychiatric disorders and higher neuronal network excitability, associated with increased susceptibility to seizures.

Notably, the British Medical Journal has recently suggested that caffeine should be avoided completely whilst trying to conceive and during pregnancy, as it may increase incidences of miscarriage, stillbirth and adverse pregnancy outcomes, based on findings from observational studies.

Maternal Gut Health
Maternal gut microbiota has been associated with abnormalities in the brain
function and behaviour of offspring—often in response to factors like infection, high-
fat diet or stress during pregnancy. Interactions between gut microbiota and intestinal
mucosa cells influence the immunological tolerance and production of pro- and anti-inflammatory substances (e.g., cytokines). Previous studies in mice have observed
that changes in the gut microbiota, may alter levels of brain-inflammatory factors in
the cortex and hippocampus, interfering in the brain plasticity.

Imbalances in the Ratio of Omega 3: Omega 6
Animal research reveals that a maternal diets rich in omega-6 fats (and low in
omega-3) impairs the neuronal layer formation in the offspring’s neocortex, and also provides compelling evidence that these diets can have long- lasting effects on the offspring’s mental state and abnormal levels of anxiety in adulthood. More recent research has indicated that when pregnant females consume
diets high in polyunsaturated omega-6 fatty acids, the produced excess of
endocannabinoids overloads the corresponding cannabinoid receptors in the foetal
brain. The consequence of this is that healthy brain development is impaired by
disrupting and limiting neuronal signalling. In line with this, evidence shows that a good balance of omega-6 and omega-3 fatty acids is known to improve the development of brain functions. Omega-3
supplementation during either pregnancy or infancy has actually been found to
improve child neurodevelopment, indicating the importance of sufficient
polyunsaturated fatty acid intake by pregnant women and young children.

Medical guidelines highlight maternal food intake during pregnancy as a major
factor for child development, with a near-equivalent ratio of omega-3 and omega-6
PUFAs recommended as dietary optimum to satisfy basic metabolic demands and to prevent adverse neurological outcomes. However, the evolution of human diets led to preferences towards
polyunsaturated fatty acid (PUFA) content with ‘Western’ diets enriched in omega-6
PUFAs, making this ratio largely skewed.Moreover, a series of human longitudinal studies identify optimal fatty acid composition in maternal diet during pregnancy as a means to reduce the risk of
childhood diabetes, hypertension and obesity, all conditions known to interact with quality of life and mental health.

Lifestyle Risk Factors

Smoking tobacco
Intrauterine tobacco exposure, including passive smoking, are linked with
several negative nicotine, carbon monoxide and other toxin-related effects.
The mechanisms by which prenatal exposures influence early neurodevelopment and neurobehavioural dysfunction are numerous, highly interrelated and not completely understood. However, it is well established that the negative effects of tobacco are dose and duration-responded, particularly disrupting the neurological route of neurotransmitters, acetylcholine and dopamine . Continued exposure to smoking toxins throughout pregnancy may influence offspring neurodevelopment, coursing with foetal developmental brain vulnerability, increased risk of neuropsychiatric disease, such as autism, schizophrenia, depression, anxiety, attention and hyperactivity disorders. Moreover, evidence has shown that nicotine intake during the second trimester of pregnancy affects the dopaminergic neurological system, making the foetal brain more susceptible to nicotine and developing ADHD symptoms not just in a foetus but, persisting later into adolescence.

Alcohol consumption
Alcohol is teratogenic to the foetus and can be harmful to babies’ brains even
in small amounts. Higher foetal sensitivity to the alcohol effects has been recognised
at a very early pregnancy stage (between the second and tenth week of pregnancy),
a period when many women do not know yet to be pregnant. Pregnant women’s alcohol consumption may cause the Foetal Alcohol Syndrome, which is a disease entity characterised by neurobehavioral abnormalities, several brain damages and body structure changes.

Stress During Pregnancy

Maternal psychological and social stress during pregnancy may adversely
affect child mental and physical health-related outcomes. It is important to note that whilst adverse
intrauterine exposure may not, per se, ’cause’ disease, it may determine propensity
for disease(s) in later life by shaping phenotypic responsivity to disease-related risk
conditions. Evidence has suggested an association between
prenatal stress exposure and subsequent shorter telomere length. With telomere
length acting as a biomarker of cellular integrity and ageing, this research exposed
an important biological pathway underlying the developmental origins of adult health
and disease risk.

Accumulating evidence also suggests a bidirectional interaction between
nutrition and stress, which means that nutritional manipulations may interfere on
cortisol-mediated inflammatory process, but also, feeding behaviour and food choice are highly correlated to high calorie, ultimately linked to metabolic fate of food in target tissues. Foetus developing in a pro-inflammatory milieu is significantly more susceptible to subsequently developing various neurodevelopmental disorders. This increased susceptibility is assumed to be a
consequence of specific alterations in brain anatomy and connectivity that result from
excessive exposure of the foetal brain to pro-inflammatory cytokines.

Higher maternal cortisol concentration (one of the primary biomarkers of physiological stress) in early
gestation was associated with higher prevalence of child affective problems, while pregnancy anxiety at 19 weeks gestation was associated with several brain anatomic change.
Evidence also shows that maternal pre-pregnancy BMI, but not weight gain during
pregnancy, is associated with a 2.8-fold increase in the prevalence of ADHD
among children of obese, compared to those of non-obese mothers.
Taken together, the findings support the notion that pre-conceptional and
prenatal conditions may impact child brain development, with significant offspring
brain alterations being associated with variation in environmental conditions during
gestation.

Barriers/challenges to achieving optimal neurological health & strategies
Recognising maternal nutrient needs and how genetic and lifestyle factors impact
metabolism, is the best way to empower actions to improve nutritional approaches to
prenatal care. There remain many challenges in understanding the
complex interplay of maternal-placental-foetal conditions and injury on early
neurodevelopment, as well as potential overlapping mechanisms of brain harm. However, antepartum, peripartum, neonatal, and early childhood have been already been indicated to be highly important sensitive windows and integrated stages to promote brain health. As children grow, deficits in socio-emotional function and intellectual abilities become
increasingly apparents, especially regarding social judgement, antisocial behaviour,
interpersonal skills, and academic achievements. Early stimuli such as post and prenatal maternal nutrition may increase the risk of adverse health
outcomes, either physical or mental, in later life. Due to foetal neuroplasticity even a small increase in developmental risk associated with prenatal exposure may be sufficient to move significant numbers of children into the developmentally delayed range of functioning.

Despite being recognised as extremely relevant to proper foetal neurodevelopment,
the low adherence to nutritional recommendations is a global issue. Multiple sociocultural factors such as income, education, cultural traditions, food availability and affordability, individual beliefs and preferences, social, geographical, and environmental aspects influence maternal choices both, post conception and during gestation. Moreover, social-economic stressors along with
environmental stressors exacerbates pre-existing disparities and maternal health
conditions. Optimal nutrition during pregnancy requires a multi-faceted approach including
effective strategies to determine nutrient status, address key nutrient gaps, and gain a
deeper understanding of maternal nutrient interactions on foetal and childhood brain
development.

Nutritional Interventions

Table 1 below lists some key nutrients for preconception and pregnancy, with their functions and food sources.

Researched by: Dr Natalia Medeiros and Hazel de Maeijer

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