key: cord-1022858-7lpe8wa6
authors: Fitzgerald, Eamon; Hor, Kahyee; Drake, Amanda J.
title: Maternal influences on fetal brain development: the role of nutrition, infection and stress, and the potential for intergenerational consequences
date: 2020-09-10
journal: Early Hum Dev
DOI: 10.1016/j.earlhumdev.2020.105190
sha: 4cfd0f18abb068d32add77e118cb87e1e64f0267
doc_id: 1022858
cord_uid: 7lpe8wa6

An optimal early life environment is crucial for ensuring ideal neurodevelopmental outcomes. Brain development consists of a finely tuned series of spatially and temporally constrained events, which may be affected by exposure to a sub-optimal intra-uterine environment. Evidence suggests brain development may be particularly vulnerable to factors such as maternal nutrition, infection and stress during pregnancy. In this review, we discuss how maternal factors such as these can affect brain development and outcome in offspring, and we also identify evidence which suggests that the outcome can, in many cases, be stratified by socio-economic status (SES), with individuals in lower brackets typically having a worse outcome. We consider the relevant epidemiological evidence and draw parallels to mechanisms suggested by preclinical work where appropriate. We also discuss possible transgenerational effects of these maternal factors and the potential mechanisms involved. We conclude that modifiable factors such as maternal nutrition, infection and stress are important contributors to atypical brain development and that SES also likely has a key role.

which may associate with deficiencies in specific nutrients, has also been associated with effects on the response to stress in young adulthood 15 . Studies in animal models aimed at delineating the long-term consequences of in utero undernutrition have demonstrated adverse effects on neurodevelopment. For example in mice, exposure to a low protein diet during gestation affects neural progenitor populations at several points during embryogenesis in both the cortex and the ganglionic eminence, and in adulthood these mice display deficiencies in short term memory 16 .

In 2017 62% of women in England were overweight and of these, 30% were obese 17these figures include women of childbearing age. Maternal obesity during pregnancy is associated with increased adiposity and cardiometabolic risk factors in adult offspring 18 . Maternal obesity is also associated with impaired neurodevelopment and executive functioning 19, 20 and with adverse neuropsychiatric outcomes in children 20 , including Attention Deficit Hyperactivity Disorder (ADHD) 21 and Autism Spectrum Disorder (ASD) 22, 23 . Studies in mouse models of maternal obesity suggest that there are adverse effects on brain development and behaviour 24, 25 and in non-human primates, exposure to a high fat diet during pregnancy is associated with an increase in offspring anxiety-like and repetitive behaviours 26 . Some of these effects may be mediated by epigenetic alterations, for example in mice, exposure to excess dietary ω-6 poly-unsaturated fatty acids (used to model a western high fat diet) has been associated with altered DNA methylation and chromatin architecture in the offspring cortex 27 .

Population data from England and Wales in 2014 indicated that 5% of pregnant women had diabetes 28 , of which 87.5% had gestational diabetes (GDM). GDM is a condition which arises during pregnancy, typically resolves postnatally and is closely associated with BMI 28,29 . Diabetes during pregnancy is associated with a range of fetal effects across various organ systems, including an increased incidence of neural tube defects 30, 31 . In mice, hyperglycaemia during pregnancy is associated with disrupted neurogenesis in the embryo 32 and with apoptosis in epithelial cells within the neural tube 33 , and additionally affects social behaviours in adulthood 34 .

Some of the effects of maternal obesity on the offspring may be mediated by the associated increase in inflammation. Higher levels of maternal inflammation during pregnancy are associated with an increased risk of neurodevelopmental delay during childhood and mediate the effect of prenatal environmental adversity on child neurodevelopmental delay 35 . Exposure to maternal obesity during the antenatal period may result in the fetus being more susceptible to other insults such as infection or inflammation; for example, in mice, high fat diet-induced diabetes during pregnancy can potentiate the transcriptional response to a subsequent inflammatory stimulus in the fetal brain 36 . This is in line with the multi-hit J o u r n a l P r e -p r o o f Journal Pre-proof hypothesis which is commonly cited for schizophrenia but may have relevance to other neurological disorders 37 .

Pregnant women are more susceptible to infection and display an increased inflammatory response to some pathogens, but the mechanisms behind this are largely unknown 38, 39 . Maternal viral infections during pregnancy may increase the risk of psychiatric disease in the offspring, with the time of infection being particularly important. For instance, a large Danish study found a significant association between maternal hospitalisation for influenza during the first trimester and ASD in her offspring 40 40 and in a large American study, there was a marked increase in psychiatric disorders in the adult offspring of mothers who experienced a bacterial infection during pregnancy 48 . This was dependent on the severity of infection and a higher incidence was seen in males 48 .

stereotyped, repetitive behaviors during childhood 52, 53 . In rodents, maternal immune activation with Poly I:C results in altered social interaction, communication and repetitive behaviours in adult offspring 54 .

One potential mechanism which might mediate this is through maternal cytokine release; in mouse models, maternal interleukin (IL-)6 has been shown to mediate the effects of Poly I:C on fetal neurodevelopment 55 . A separate study indicated the maternal production of IL-17A in response to Poly I:C was involved in the pathogenesis of offspring neurodevelopmental disorders 56 . This leads to a hypothesised model in which maternal IL-6 is stimulated by a viral infection, which in turn activates TH17 cells to produce IL17A, which crosses the placenta to affect offspring neurodevelopment. Models of bacterial infection during pregnancy in rodents have also given important insights into atypical neurodevelopment induced by infection. Prenatal LPS in rodents results in an increase in repetitive behaviours 57 , reduced social interaction 58 , anxiety like behaviour 59 and spatial memory defects 60 in adult offspring. In rats, prenatal LPS is associated with an altered lipid profile in 8 week old offspring 61 and alterations in dopaminergic signalling 62 , which has been hypothesised to be central in the aetiology of schizophrenia 63 .

Stress can be broadly described as an imbalance between the environment and an individual's perception of their resources to cope with that environment. Maternal stress can occur as a result of a diverse range of environmental perturbations and crucially, the experience of stress is highly individually specific.

Therefore there are many domains of stress which can be associated with pregnancy 64 . While stress during pregnancy affects women worldwide, pregnancy-related stress in lower and middle income countries appears to be associated with a greater risk of adverse outcome in offspring 65 .

Offspring exposed to high levels of prenatal maternal stress or anxiety are at a higher risk of developing depression 66 , ASD 67 , schizophrenia 68 and ADHD 69 as well as various emotional and behavioural problems 70 ; with the timing of stress and the sex of the fetus playing important roles in the outcome of these studies. There is also evidence to suggest that maternal antenatal depression and socioeconomic status can interact with a polygenic score for major depressive disorder to modulate risk 71 . Moreover, good maternal mental health during pregnancy is positively associated with cognitive abilities in the offspring at 2 years of age 72 . There are many factors that need to be accounted for in these studies. For instance some traditional metrics to assess stress may not be validated for use in pregnancy 64 . Further, studies typically focus on periods of increased stress and neglect, but fail to measure positive or uplifting experiences which may counterbalance these 73 . The questionnaires used to measure stress during pregnancy may also be sensitive to underlying personality traits, perhaps underscored by the substantial J o u r n a l P r e -p r o o f heritable component of stress as measured by these methods 74 . Moreover, stress experienced during pregnancy tends to continue during postnatal life, making assigning the importance of pre-and postnatal stress in mediating outcomes difficult 75, 76 . To address this, some studies have focussed on the effects of short-lasting large-scale environmental perturbations during pregnancy. For example, stress associated with experiencing an earthquake during the first trimester has been associated with a shorter length of gestation 77 . There is also evidence for effects on neurodevelopmental outcome, as offspring born to mothers who were pregnant during the 1998 ice storm crisis in Quebec had lower cognitive and language abilities at 5.5 years of age when compared to control infants from pregnancies outwith this period 78 .

There are a number of rodent models of maternal stress during pregnancy including exposure to a lactating female, forced swimming, noise and restraint stress 79 and the first rodent experiments describing altered behaviour in the offspring of stressed mothers was published more than 60 years ago 80 . In this study the adult offspring showed increased activity in the open field (a preclinical proxy of anxiety like behaviour), a finding which has been replicated in many subsequent studies (see Weinstock 2017 for a full review 79 ). Prenatal stress in rodent models has also been shown to affect other cognitive domains in offspring, such as spatial memory 81, 82 and social behaviour 83 . To account for the effects of pre-and postnatal stress, offspring cross-fostering studies have been performed. Cross-fostering the offspring of stressed mothers onto a control non-stressed mother at birth results in no differences in anxiety or social related behaviours in stress-exposed offspring and controls, suggesting that the postnatal environment is important for some effects 84, 85 , but differences in learning memory, novel object recognition, long-term potentiation and risk of depression remain 86-88 .

Many of the effects of maternal stress on the fetus may be attributable to fetal glucocorticoid overexposure 89 . The enzyme 11β-hydroxysteroid dehydrogenase type 2 is present within the placenta and is responsible for converting active glucocorticoids in the maternal circulation (cortisol in humans, corticosterone in rodents) into an inactive form (cortisone or 11-dehydrocorticosterone). However, the enzyme has finite capacity and some active glucocorticoid may cross to the fetus, particularly in the presence of the increased maternal circulating glucocorticoid concentrations which may occur in stressful situations 90 . The administration of synthetic glucocorticoids, which bypass this enzyme, is commonplace in the management of women at risk of preterm birth and significantly improves morbidity and mortality in preterm babies 91 . However, there have been concerns about the deleterious effects of exposure to excess glucocorticoids (endogenous or exogenous) on the developing brain, with clinical studies reporting long-term effects on the function of the hypothalamic-pituitary-adrenal axis and behaviour in exposed children [92] [93] [94] [95] [96] . This is supported by data from a number of animal studies (reviewed by McGowan and J o u r n a l P r e -p r o o f Journal Pre-proof Matthews 95 ). Although evidence from both human and animal studies suggests that excess fetal exposure to glucocorticoids can have adverse consequences on the brain, the effects of pregnancy related stress cannot be entirely attributed to glucocorticoid exposure 97 . Maternal stress in rodents is also associated with an accumulation of catecholamines in the fetal circulation 98 , an increase in kynurenic acid in the placenta and fetal brain 99 , changes in oxytocin signalling 83 , and an altered maternal microbiome and associated in utero cytokine levels 100 . Finally, maternal stress may interact with other factors e.g.

infection to modulate offspring neurodevelopmental outcome. For example concurrent infection and stress during the second trimester result in a higher adolescent depression score in offspring then either alone 101 .

A growing number of studies suggest that 'programmed' effects might not be limited to the first generation offspring i.e. those directly exposed in utero, but may be transmitted to a number of 

Factors such as poor nutrition, stress and infection during pregnancy have all been associated with adverse effects on fetal neurodevelopment. One important consideration is that the long-term risks associated with exposure to an adverse intra-uterine environment are not evenly distributed across society.

Low socio-economic status (SES) is associated with an array of adverse pregnancy outcomes even in countries with established antenatal care programs 112,113 which may in part be due to a reduced awareness of service provision 114 . Women of lower SES have an increased likelihood of exposure to risk factors during pregnancy 115 and SES is independently associated with future cognition 115, 116 . In higher 117 as well as lower-and middle-income countries 118 lower SES is associated with measures of unhealthy behaviour for example poor nutrition, smoking and low levels of physical activity, including amongst women of reproductive age 119 . Increased levels of infections have been seen in pregnant women with a lower SES.

For instance, an increased presence of the infectious bacterium H. pylori 120 (which has been linked with hyperemesis gravidarum 121 ) and an increase in urinary tract infections 122 . This is important for public health policy since many of the behaviours associated with lower SES are potentially amenable to change.

For example, income supplementation, independent of a changing family dynamic or characteristic can reduce the prevalence of clinically relevant externalising behaviours in a low income population 123 .

Increasing the provision of support for families in lower socio-economic brackets may be one crucial step in mitigating some of the antenatal risk factors associated with atypical brain development. Such interventions also have the potential to improve help in future generations.

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