Obesity during pregnancy is a rising public health concern rapidly increasing worldwide ^[1][2][3][1,2,3]. Excessive maternal weight gain during pregnancy is consistently associated with many adverse impacts, including neurocognitive outcomes in the offspring ^[1][4][1,4]. Recently, the effect of obesity in pregnancy on maternal and fetal health has been reviewed ^[5][6][5,6]. The adverse effect of maternal obesity on the fetal programming of adult diseases extends beyond non-communicable diseases to brain diseases ^[7][8][7,8]. Obesity and a high-fat diet predispose offspring to adverse cardiometabolic and neurodevelopmental outcomes [9]. In addition, maternal high-fat intake during pregnancy was associated with an elevated risk of neuropsychiatric disorders such as hyperactivity/attention-deficit disorder/anxiety and depressive-like behaviours later in life in offspring ^{[10][11][12][13][14][15][16][17][18]}[10,11,12,13,14,15,16,17,18]. Both obesity and a high-fat diet can impact maternal lipid metabolic state and gut microbial composition and affect offspring’s metabolic health and brain development ^[19][20][19,20]. Available data from extensive epidemiologic studies indicate an association between maternal obesity and adverse neurodevelopmental outcomes in human offspring. Maternal diet, adiposity, peripheral inflammation, and gut microbiota are the potential mechanisms for underlying changes in offspring brains and behaviour ^{[20][21][22][23]}[20,21,22,23].

The diversity of intestinal microbiota during pregnancy has emerged as an essential factor as their metabolites can affect the host’s health in multiple ways, from lipid metabolism to brain development and function. The microbiota-gut axis can regulate maternal obesity, diet, lifestyle and physical activity. Gut microbiota produces neurotransmitters and neuromodulators (e.g., serotonin, GABA, SCFAs and their metabolites) and their derivatives in the circulation. These bioactive factors are transported to the brain via blood vessels after crossing the BBB and modulate the neonate’s cognitive development and brain-mediated performance activities. A steady-state microbiota of the mother is determined by several extrinsic (environment, geography, lifestyle) and intrinsic (genetics, mode of delivery, eating habits, age, infection, stress, medication) factors. While one-third of the gut microbial composition is common in most individuals, the remaining two-thirds are specific to the individual [24]. Despite these, not much data is available on maternal obesity during pregnancy and the modulation of gut microbial composition and diversity on the brain development of the offspring.

2. Impacts of Obesity on Maternal Endocrine Factors and Fetal Brain Development

In pregnancy, the maternal metabolism changes dramatically to support fetal growth and meet maternal additional energy requirements. However, maternal obesity in pregnancy increases maternal complications and enhances the risk of developing obesity, cardiovascular disease, diabetes, and cognitive dysfunction in offspring in adult life ^[25][26][25,26]. Obesity-induced metaflammation results in aberrant changes at the cellular and humoral levels that contribute to pregnancy complications. However, the physiological inflammatory process favours implantation, placental development, and parturition [27]. Complex interactions mediate adverse effects of obesity between metabolic, inflammatory, and oxidative stress homeostasis. Obesity in pregnancy is associated with elevated levels of pro-inflammatory cytokines such as interleukin 6 (IL-6), IL-1β, IL-8, and monocyte chemotactic protein-1 (MCP-1) in both the placenta and in maternal plasma ^[28][29][28,29]. The maternal obesity-induced swing toward a pro-inflammatory state can affect the neurometabolic state of the fetus. Obesity-induced changes in maternal hormone levels can affect gene expression involved in fetal brain growth and development ^[30][31][30,31]. Obese pregnant women possess an increased risk of developing thyroid dysfunction during gestation. Maternal hormones such as thyroid and glucocorticoids affect fetal brain development. The hormones’ effects on brain development are time- and concentration-dependent [32]. Since obesity is associated with hypothyroidism and consequently affects brain development [33]. Maternal thyroid metabolism is also disturbed by maternal iodine deficiency, environmental endocrine modifiers, and other intrinsic factors associated with thyroid diseases [34]. In early pregnancy, thyroid hormones are needed for brain developmental processes such as neuronal migration, differentiation of neurons, glial cells, neurogenesis, and synaptogenesis ^[35][36][35,36]. Thyroid hormones regulate gene expression in the cell cycle and intracellular signalling, cytoskeleton organization, extracellular matrix proteins and several cellular adhesion factors involved in neuronal migration and neurogenesis ^[35][37][35,37]. In addition, thyroid hormones are also involved in neuronal migration and neuron development by regulating reelin and neurogenin 2 genes [37]. Therefore, optimum maternal thyroid function is critically required for fetal neurodevelopment. The altered thyroid hormone levels result in severe neurological deficiency and mental disability [38]. In addition, thyroid deficiency during pregnancy may drive offspring to the later onset of neurodevelopmental disorders ^[34][39][40][34,39,40]. Several neurodevelopmental deficits are observed in offspring born from mothers with thyroid dysfunction during the first half of gestation ^[41][42][41,42]. Even babies of the mother with asymptomatic thyroid dysfunction are at increased risk of impaired brain development [43]. The adverse subclinical hypothyroidism on fetal neurocognitive development is less specific. Maternal hypothyroxinemia occurs in mild iodine deficiency and may result in neurodevelopmental problems. Corticosteroids in late gestation are indispensable for fetal brain maturation [44]. The developing brain is susceptible to corticosteroid-induced stress [45]. A study showed that prenatal maternal stress increased glucocorticoids, and a high-fat diet, increased the risk of developing obesity in offspring in later life [46]. Chronic activation of glucocorticoid receptors alters the levels of glucocorticoid in hippocampal and hypothalamic regions, thus modifying feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis [47]. Corticosteroid effects are also mediated via epigenetic changes in genes associated with synaptic plasticity [48]. Stress hormones such as catecholamines, vasopressin, and oxytocin affect fetal brain development and functionalities [49]. Chronically increased cortisol levels in maternal stress result in lower levels of maternal T4 available for the fetal brain, thus affecting fetal brain development [50]. In addition to thyroid and glucocorticoid, several other hormones play roles in fetal neurodevelopment [51]. Maternal obesity and abnormal hormone levels affect fetal programming beyond the endocrine and cardiovascular systems to the brain. Several studies showed an association between high maternal BMI and adverse neurodevelopmental functions in their progenies (Table 1).