Several preclinical studies provide mechanistic insights into how prenatal nutrition affects neurodevelopment, pain modulation, and stress response.

Sullivan et al. (22) demonstrated that maternal high-fat diet (HFD) in rodents increased inflammatory cytokines and altered brain reward circuits (nucleus accumbens, ventral tegmental area, prefrontal cortex) through hypomethylation of opioid gene promoters, predisposing offspring to obesity and stress dysregulation. Limitations of this study regards animal models, which may not fully capture the complexity of human diets and genetic backgrounds, so the results cannot be directly extrapolated to humans.

Maldonado-Ruiz et al. (23) showed that in mice, HFD-induced maternal immune activation (diet-induced MIA) determines a chronic pro-inflammatory profile during fetal development, leading to hyperactivation of microglia The cross-talk between the immune system and CNS induces epigenetic modifications on immune cells in offspring, such as DNA hypermethylation and aberrant expression of proinflammatory genes in the CNS, responsible for micro- and macrostructural defects in several brain regions, leading to neurodevelopmental abnormalities. But rodent immune responses differ from humans, so these findings require validation in clinical studies.

D’Ornelas et al. (24) found that in rats, fish oil supplementation reduced inflammatory pain either when consumed during adult life or during prenatal development. Unfortunately, controlled dietary conditions in animal models may not reflect real-world human nutritional variability.

Król et al. (25) demonstrated that chronic prenatal alcohol exposure (PAE) in rats reduced nociceptive sensitivity to mechanical and thermal stimuli in early postnatal life. But alcohol exposure patterns in animals may not replicate human drinking behaviors during pregnancy.

Gerasimova et al. (26) showed that in rats, hyperhomocysteinemia increased susceptibility to cortical spreading depression associated with photophobia, mechanical allodynia, and anxiety-related behaviors. But elevated homocysteine was experimentally induced, so translational relevance to naturally occurring human metabolic disorders remains uncertain.

These animal studies highlight potential mechanisms (epigenetic reprogramming, inflammatory pathways, neurotransmitter regulation), but their external validity is limited by species differences and controlled experimental conditions.

Human studies and reviews provide epidemiological and mechanistic evidence on the role of maternal nutrition in prenatal neurodevelopment and pain regulation.

Bekdash (21) realized a review emphasizing how maternal intake of methyl-donor micronutrients (folic acid, B6, B12, choline) influences epigenetic regulation and brain development. Especially about vitamin B6, which plays an important role as a coenzyme in the metabolism of amino acids, carbohydrates, and fats, and it is important for the correct development and maintenance of the CNS and immune system. Moreover, it is essential for serotonin synthesis and is involved in the regulation of mood, sleep, appetite, memory, and concentration skills. It plays a key role in regulating methylation mechanisms, influencing gene expression, and various pathways involved in neurodevelopment and neurological functions. This study, as a narrative review, relies on secondary data without new experimental evidence.

Debnath et al. (27) wrote a review on fetal programming of schizophrenia, analysing the link between maternal undernutrition and HPA axis disregulation and glucocorticoid receptor expression: maternal undernutrition seems to determine epigenetic changes in the fetal brain related to an increased expression of genes coding for the glucocorticoid and proopiomelanocortin receptor at the level of the fetal hypothalamus, leading to increased activity of the HPA axis. Moreover, this study analysed how vitamin D can regulate gene expression, influencing brain development. Currently, the recommended intake during pregnancy is 600 UL/day. Prenatal vitamin D deficiency causes brain development abnormalities and alterations of neuronal differentiation, neurotransmission, various pathways, and calcium homeostasis, as well as post-translational modifications, underscoring the role of this vitamin in epigenetic regulation. Choline also has an important role in neurodevelopment, being implicated in adaptive modulation of cognitive functions. Therefore, maternal choline deficiency alters neurogenesis and angiogenesis in the fetal hippocampus. In fact, according to some studies, oral integration of choline in the second trimester and after birth seems to be associated with better sensorial gating. Limitations of this review regards the mechanistic hypotheses largely based on animal data and indirect human evidence.

Godfrey et al. (28) showed that maternal obesity during pregnancy could induce immune-inflammatory modifications, altering fetal neuronal pathways involved in neurodevelopment, leading to alteration of HPA activity, and epigenetic changes of neurotransmitter pathway in offspring. Among the various mechanisms, there is an increased expression of glucocorticoid receptors at the hippocampal level with changes in HPA axis activity and an increased expression of fetal cytokines, such as IL-6, leading to inflammation and neuroendocrine alterations. Moreover, epigenetic changes intervene in the dopamine and serotonin pathways. This review is based on observational human data, so causality is difficult to establish.

Cömert et al. (29) showed, through a clinical study, that pregnant obesity can also affect a newborn’s microbiota. Meconium samples of infants born to mothers who were obese pre-pregnancy showed an altered microbiota, with fewer Firmicutes and increased Proteobacteria, compared with those of infants born to mothers with normal pre-pregnancy BMI. Limitations of this article is the small-scale study; moreover, microbiome is influenced by multiple postnatal factors.

Exposto et al. (30) analysed pre-natal nutrition as risk factor for painful temporomandibular disorders and headaches in young adults: they conducted a prospective longitudinal cohort study, analysing survey data from the Danish National Birth Cohort (DNBC), including prenatal nutritional information assessed using a healthy eating index (HEI) derived from a food frequency questionnaire collected between 1996 and 2002 and offspring’s p-TMD and headache status at age 18–23 years, assessed in 2021. In conclusion, they found that offspring of mothers with higher HEI scores, corresponding to healthier dietary choices during pregnancy, had significantly lower odds of headaches, but they did not find a significant link with painful temporomandibular disorders in young adulthood. Lower maternal intake of saturated fatty acids and red meat were associated with decreased odds of reporting headaches later in life. It’s an observational design, in which self-reported dietary intake is subject to recall bias; moreover, it cannot infer causality.

Our previous study (1) is a review highlighting the roles of the main nutrients (omega-3 s, folate, vitamin D, B6, B12, and choline), but also dietary patterns, in neurodevelopment, analysing the association between prenatal nutritional factors and neurodevelopmental disorders. We studied the role of omega-3 fatty acids in the CNS, as components of neuronal membrane and of myelin sheet, influencing neurotransmitter function, signal transduction, but also neurogenesis, synaptogenesis, and myelination, improving cognitive functions. Moreover, folates play a role in many metabolic reactions and pathways, but also neurogenesis, neuronal proliferation, migration, differentiation, vesicular transport, apoptosis, synaptogenesis, and myelination. It’s a review, that relies on secondary data without new experimental evidence.

Zinkow et al. (31) produced a review describing how omega-3 fatty acids modulate the gut–brain axis, HPA axis activity, and inflammation. Especially EPA and DHA, have been shown to regulate the HPA axis by reducing excessive cortisol production, associated with stress responses and mental health disorders. Omega-3 fatty acids have anti-inflammatory properties by altering eicosanoid production, reducing proinflammatory cytokines, and promoting anti-inflammatory mediators. Additionally, omega-3 fatty acids, particularly DHA, can influence the composition and function of the gut microbiota, promoting beneficial bacterial populations’ abundance and gut microbiome diversity, which contribute to gut health and improve systemic immunity. At the same time, gut microbiota can affect the absorption and metabolism of these fatty acids. Fish oil, for instance, reduces the growth of Enterobacteria while increasing that of Bifidobacteria. These actions help preserve the integrity of cellular barriers like the intestinal and blood–brain barriers. This review integrates preclinical and clinical data, but specific causal pathways remain unclear in humans.

Delarue et al. (32) showed, through a small human trial, that fish oil prevents stress-induced adrenal activation: they found that low plasma levels of omega-3 fatty acids are correlated with higher CRH and plasma concentration of cortisol, while omega-3 fatty acid supplementation may decrease CRH expression and corticosterone secretion. Unfortunately, it’s about a limited sample, with short-term intervention and an uncertain generalizability to pregnant populations.

Mocking et al. (33) demonstrated, through a clinical study, the link between HPA-axis dysregulation and altered fatty acid metabolism in recurrent depression, showing that omega-3 fatty acid supplementation may decrease CRH expression and corticosterone secretion. It’s an observational design and cannot establish directionality.

Nieminen et al. (34) found that omega-3 fatty acids correlate with plasma neuroactive steroids in patients with alcoholism and depression: particularly, excessive stress response and HPA hyperactivity may be linked to higher concentrations of brain and plasma neuroactive steroids (NASs), and be related to lower plasma levels of omega-3 fatty acids This study is based on small clinical cohort and comorbidities may confound associations.

Menni et al. (35) showed, through an observational study in women, that omega-3 intake correlates with gut microbiome diversity: particularly DHA, can influence the composition and function of the gut microbiota, promoting beneficial bacterial populations’ abundance and gut microbiome diversity, which contribute to gut health and improve systemic immunity. But it’s about a cross-sectional design and causality cannot be established.

Li et al. (36) produced a systematic review showing the association between prenatal nutrition and neurodevelopmental disorders. Especially, they highlighted that a decreased folate intake provokes incorrect DNA methylation, leading to an alteration of brain development. Limitations are related to heterogeneity of included studies; moreover, some data is based on self-reported dietary intake.

Berti et al. (37) highlighted, through a review, the importance of micronutrient supplementation in pregnancy, recommending periconceptional and prenatal supplementation of folic acid in the prevention of neural tube defects, reminding that data recommend a periconceptional supplementation of 400 mg/day. Moreover, they found an association between deficiency of vitamin B12 during pregnancy (values below 200 pg./mL) and irritability, reduced brain growth, and increased risk of neural tube defects. Unfortunately, some recommendations derived from population-level data, with evidence gaps.

Georgieff et al. (38) emphasized, through a review, the importance of vitamin B12 and other nutrients for brain myelination and development. Particularly, vitamin B12 acts as an enzyme and as a cofactor and is essential for the metabolism of fats and proteins, for haemoglobin synthesis, and contributes to DNA methylation. This review is mainly a conceptual synthesis, with limited longitudinal human trials.

Prado and Dewey (39), analysed choline’s role in neurodevelopment and epigenetic modulation. Choline plays a role in various pathways, including the synthesis of phospholipids and neurotransmitters. It acts as a methyl group donor, leading to epigenetic modifications in the fetal brain and placenta through mechanisms of DNA methylation; moreover, it is involved in the proliferation of stem cells and transmembrane signalling during neurogenesis. This review is based primarily on preclinical evidence, with scarce human intervention studies.

Together, human studies support the importance of balanced maternal nutrition (especially omega-3 fatty acids, B vitamins, choline, and vitamin D) in regulating stress response, pain sensitivity, and neurodevelopment, though limitations (observational designs, self-reporting, and heterogeneous methods) restrict firm causal conclusions.

Palmer et al. (40) investigated food restriction during lactation in rodents, showing alteration in brain structures such as hippocampus, striatum, hypothalamus, and cortex, which are critical areas for external information processing and stress responses. This study is conducted in rodents, thus results may not fully translate to humans. Moreover, the restricted diet model may not represent the complexity of human nutritional deficiencies.

McMillen et al. (41) reported that maternal overnutrition during lactation in sheep can predispose offspring to altered energy balance and metabolic syndrome. This study focused on sheep, which may not perfectly replicate human metabolic development; moreover, long-term neurobehavioral effects were not extensively studied.

Bouret et al. (42) found that postnatal overfeeding in rodents can affect synaptic plasticity of specific neuronal pathways involved in metabolic regulation and stress response. Unfortunately, rodent neurodevelopment occurs at a different pace compared to humans, limiting extrapolation.

Walker (43) explored how macronutrients (carbohydrates, fats, proteins) affect neonatal brain development and stress responses in rodents, reporting that sucrose ingestion reduced stress and pain responses, while fats influenced HPA axis regulation and neuroplasticity. Carbohydrate ingestion affects several neuropeptides and neurotransmitter system, including neuropeptide Y (NPY), serotonin, dopamine, norepinephrine and the release of endogenous opioids (EOP). Increased carbohydrate intake might subserve functions related to coping with pain and making cognitive memories. Indeed, sucrose has often been associated with opiate-like effects in the brain. Sucrose ingestion induces changes in several neuropeptide and neurotransmitters systems in the CNS mainly via the activation of vagal afferents and other afferents to the nucleus of the tractus solitarius (NTS) and catecholaminergic cell groups in the medulla and locus coeruleus. Inputs are relayed to regions that are critical for the regulation of the HPA axis such as the paraventricular nucleus (PVN), amygdala and BNST. Some of the resulting effects of sucrose ingestion include a reduction in stress responses and pain and an increase in cognitive appraisal and reward value of the stimuli associated with sucrose ingestion. Also, fat ingestion plays a role in regulation of the HPA axis and stress responses. The production of free fatty acids (FFA) from triglycerides affects several organs including a stimulation or inhibition of the adrenal glucocorticoid production in rodents and humans, respectively. In rodents, FFA are suggested to stimulate CRF production. FFA also affect liver production of corticosterone binding globulin (CBG), insulin secretion from the pancreas and adipose tissue growth and release of leptin, cytokines, etc. Leptin has been shown to inhibit adrenal glucocorticoid production and hypothalamic CRF synthesis, while cytokines such as IL-1beta have the opposite effect to stimulate the HPA axis. Fat can also alter the expression of several hypothalamic neuropeptides that impact on CRF synthesis and secretion. The consequences of feeding on a high fat diet on neuroplasticity and cognition are thought to be mediated by changes in free radical production, and synthesis of BDNF, CREB, etc. Moreover, high intake of fat in neonates insures that short-term energy requirement are met in cases of hypoglycemia. This study is mainly based on animal models, moreover, sucrose effects may differ in humans (in infants lactose is the main component of milk and is not associated with the typical analgesic effect demonstrated by sucrose ingestion).

Soares et al. (44) analysed the facilitating effect of the lipids from goat milk and conjugated linoleic acid during lactation on an excitability-related phenomenon in the brain such as cortical spreading depression (CSD) in rodents, associated with migraine and epilepsy, linking maternal diet to increased susceptibility to migraine-like phenomena in offspring. Unfortunately, experimental diet models may not reflect typical human nutrition; moreover, the association with migraine-like states remains indirect.

Yam et al. (43), dedicated some parts of the review, analysing how free fatty acids and dietary fats influence HPA axis regulation in both rodents and humans, finding that FFAs modulate adrenal glucocorticoid production differently in rodents (stimulation) and humans (inhibition). But human evidence remains largely correlative and based on biochemical observations rather than controlled dietary trials.

Galland (45) reviewed the role of intestinal microbiota integrity in pain and migraine, suggesting that pro-inflammatory substances related to increased intestinal permeability may reach the trigeminovascular system and trigger migraine-like attacks in human, highlighting diet-microbiota interactions. Other studies suggested a link between migraine and various inflammatory diseases, such gastrointestinal disorders, or increased intestinal permeability (46, 47). As a narrative review, Walker’s study does not establish causality, moreover, data on dietary interventions remain limited and heterogeneous.