Maternal behaviour, interpersonal stress and psychosocial trauma
Maternal behaviour during early periods of life can alter the epigenetic state of the fetal DNA. Studies in mouse models have shown that infants rats whose mother had a high frequency of “licking, grooming and arched-back nursing” are able to better react to stress . Maternal care during infancy regulates the development of neural systems mediating the expression of fearfulness in the rat. In fact, it has been showed an increased hippocampal expression of the glucocorticoid receptor mRNA and protein, a decreased hypothalamic corticotropin release factor and reduced hypothalamic-pituitary-adrenal response to stress in pups born from mothers with licking, grooming and arched-back nursing behaviour [60, 61].
Maternal stress and maternal-placental-fetal biological mediators of stress can affect fetal development. In fact it has been showed that exposure to maternal psychosocial stress during intrauterine life is associated with significantly shorter leukocyte telomere length in young adulthood, a predictor of age related disease onset and mortality . This provides a biological basis for speculation about the effects of early occurrence of poverty and how exposure to abuse, family conflict, emotional neglect and severe discipline could lead to individual differences in the nervous and endocrine response to stress and increase susceptibility to common adult disorders such as depression, anxiety, drug abuse or chronic diseases like diabetes, cardiovascular disease and obesity.
Moreover, stress during pregnancy is associated with the risk of delivering a preterm baby or a child small for gestational age [63, 64] and it contributes to less control of the parasympathetic system on heart rate, with a low heart rate variability in response to stressful stimuli . In a study it has been shown that prenatal anxiety and stress predicted a substantial amount of variance in infant diseases and antibiotic use and precisely 9.3% for respiratory, 10.7% for general, 8.9% for skin, and 7.6% antibiotic use . Moreover, maternal stress during pregnancy alters the cytokine response of the innate and adaptive immune system. If on the one hand high levels of IL-8 and TNF-α in response to microbial stimuli are observed, on the other, there is a reduction in levels of IFN-γ with an increase in IL-13. This generates an obvious imbalance of the immune response in favour of Th2 lymphocytes and susceptibility to allergic diseases [67, 68]. An association between prenatal stress and immune function in human adults has been documented. Peripheral blood mononuclear cells from healthy young women whose mothers experienced major negative life events during their pregnancy (Prenatal Stress, PS group), and from a female comparison group, were stimulated with phytohemagglutinin (PHA), and subsequent cytokine production was measured. A bias for T-helper 2 (Th2) cytokine production due to an overproduction of IL-4 relative to IFN-gamma after PHA stimulation was observed in PS subjects. In addition, IL-6 and IL-10 were also significantly elevated suggesting a direct association between prenatal stress exposure and alterations in immune parameters in adult women . In fact, children whose mothers experienced interpersonal violence and trauma during pregnancy have twice the risk of developing asthma during their childhood .
Exposure to maternal stress also affects the child’s cognitive performance such as language, comprehension and reasoning, all of them principally realized in the prefrontal cortex. This brain region is known to develop later in term of myelination and synaptic density. Because of its protracted development and the expression of glucocorticoid receptors, the prefrontal cortex may be prone to early insults. Since children exposed to high levels of hydrocortisone have longer time reactions, this could provide support for an association between prenatal stress exposure and the potential modulatory effect of cortisol on the working memory performance, which may reflect compromised development of the prefrontal cortex .
Finally, prenatal stress increases the future risk of insulin resistance, with higher levels of insulin and C-peptide than in controls as well as a lipid profile compatible with the development of metabolic syndrome .
Smoking in pregnancy
Cigarette smoke contains more than 4000 compounds, including polycyclic aromatic hydrocarbons such as arilamine and N-nitrosamines. The ability of the individual to convert these substances into less toxic compounds is important to minimize their adverse effects. This is made possible by enzymes that allow the metabolism and detoxification of these substances. Enzymes such as CYP1A1 and glutathione-S-transferase (GSTT1), important for the detoxification of the compounds, are involved in this process. Polymorphisms of these genes have been associated with a reduction in birth weight of between 250 g and 600 g , with a higher risk of delivering a baby of low birth weight (< 2500gr) (RR = 1.32) or small for gestational age (RR = 1.21) , and a linear dose–response relationship between exposure and second trimester femur growth was observed with almost 1 cm lower femur growth for the highest versus the lowest tertile of exposure . However, the side effects of smoking may be reversible in early pregnancy because women who quit smoking before the 15th week of gestation have a lesser probability of having a premature baby or one small for gestational age, which is not different from that of non-smoking women, 4% and 10%, respectively. Conversely, if a woman continues to smoke, the incidence of preterm birth is around 10% and the risk of having a baby small for gestational age raises at 17% . Furthermore, children exposed to cigarette smoke continue to have respiratory problems during childhood, with twice the risk (RR = 2.18) of having lower values of FEV1. In a systematic review and meta-analysis it has been shown that exposure to pre- or postnatal passive smoke exposure was associated with a 30% to 70% increased risk of incident wheezing (strongest effect from postnatal maternal smoking on wheeze in children aged ≤ 2 years, OR = 1.70) and a 21% to 85% increase in incident asthma (strongest effect from prenatal maternal smoking on asthma in children aged ≤ 2 years, OR = 1.85) . Maternal smoking during pregnancy leads to abnormal lung function in infancy that tracks through to later childhood and continues into adult life. This is associated with transient wheezing illnesses through early childhood and increases the risk of chronic obstructive pulmonary disease in the elderly . Also passive exposure of pregnant women to ETS may lead to asthma in their offspring: passive exposure to ETS, mainly during the third trimester of pregnancy, was significantly associated with asthma- and allergy-related symptoms after adjusting for several confounders in a multivariate analysis (current wheeze: OR = 1.42, pruritic rash ever: OR = 1.45). As a consequence public health policies should be oriented not only towards smoking cessation, but also reinforce elimination of ETS exposure of pregnant women . In brief, exposure to passive smoking increases the incidence of wheeze and asthma in children and young people by at least 20%. Preventing parental smoking is crucially important to the prevention of asthma. Nicotine, in fact, causes higher placental vascular resistance, decreases blood flow in the uterus, and increases the concentration of carboxyhaemoglobin, all factors responsible for chronic hypoxia and reduced fetal development . In addition, children of smoking mothers have a higher risk (RR = 1.5) of being overweight or obese [81, 82] because nicotine withdrawal promotes overeating and weight gain, and on the other, children born from smoking mother tend to get less exercise and have a lower quality diet .
Children exposed to tobacco smoke during pregnancy also have a higher risk of poor neurodevelopmental outcome . In a prospective follow-up study of infants with a birth weight ≤ 1500 g or a gestational age < 32 weeks, the brain was imaged by serial brain ultrasound examinations until discharge and magnetic resonance imaging at term age and it has been found that the frontal lobe (P = 0.01) and the cerebellar (P = 0.03) volumes were significantly smaller in the exposed than in the unexposed infants . This is consistent with reports showing an association between prenatal smoking exposure and impairments in frontal lobe and cerebellar functions such as emotion, impulse control, and attention. Effectively, these children have a more than doubled risk of developing attention deficit disorder and hyperactivity disorder (ADHD) (RR = 2.5) [84, 85] compared to babies born to non-smoking mothers. Genes relating to the dopaminergic pathways are the focus of most genetic studies of AHD. The gene for the dopamine transporter (DAT) is of particular interest because is the site of action of psychostimulants. It has been shown that homozygosis for this gene and exposure to cigarette smoke during pregnancy increase the risk of developing ADHD and determine a poor response to psychostimulants . This risk is approximately three times greater when the gene for the dopamine transporter DAT1 and subtype D4 for the dopamine receptor DRD4 is inherited (RR = 2.9 and RR = 3, respectively) but inheriting both alleles increases by 9-fold the risk of ADHD (RR = 9) .
The role of the home
The home is the place where children spend most of their time, estimated at 15 hours out of 24 . Given the stable increase in the incidence of asthma among children, it is important to pay attention and implement environmental measures in the home to help prevent it. Contact with synthetic textiles should be avoided in the first ages of life: during the first months of life sleeping in synthetic sleeping bags increases by more than 4 times the risk (RR = 4.33) of wheezing at the age of seven years . Furthermore, the use of synthetic pillows doubles the risk (RR = 2.5) of wheezing and the risk rises to more than five times (RR = 5.2) when both synthetic pillows and blankets are used . Synthetic materials, in fact, have a structure that allows the accumulation of high concentrations of dust mite allergen (Der p1), even 15 times higher compared to cotton fabrics . Furthermore, synthetic pillows contain significantly more pet allergens than feather pillows, supporting the view that tightly woven encasements surrounding feather pillows act as a barrier for allergens .
In addition, chemicals used for cleaning are responsible for increasing domestic pollution and more than doubling the risk of wheeze (RR = 2.3),  and they cause a decrease in FEV1 and FEF25-75. This derives from both a detrimental effect on the development of airways in the prenatal period (epigenetic effect?) but also from the effects in the post-natal period. In particular, this association was noted for the use of cleaning sprays  that contain active ingredients such as alcohol, ammonia, chlorine, glycol and glycol-ethylene, sodium hydroxide (caustic soda), acrylic polymers and terpenes . When sprayed on surfaces to be cleaned, these compounds enter easily into the airways, irritating them .
The role of environmental pollution
In New York City it has been shown that prenatal exposure to pollutants doubles the risk of delivering an infant small for gestational age and increases by five times the risk of preterm delivery . These effects were observed in African-American but not in Domenicans and this may reflect modification of the risk by healthful cultural practice among Domenican immigrants including diets with higher nutritional quality and greater social support. In the same environment it has been reported that infants of pregnant women exposed to high concentrations of polycyclic aromatic hydrocarbons have more than twice the risk of developing cognitive delay at age three, resulting in poor school performance and low IQ at age 5. Furthermore, forty percent of the analyzes on the DNA of white blood cells of umbilical cord blood of New York City children showed damage to the DNA reflecting transplacental exposure to traffic-related polycyclic aromatic hydrocarbons (PAHs). The increased formation of DNA adducts is associated with a possible consequent increased risk in adulthood of cancer  and of asthma . At this regard it has been shown that for concentrations of 2.41 ng/m3 of PAHs the risk of finding methylation in the DNA increases by almost 14 times (RR = 13.8) and the risk of developing asthma increases by almost four times (RR = 3.9). Concerns about pollutants were always related to elderly people and respiratory diseases, but now we start to understand that fetal tissues are exposed as well with long time persistent consequences. Based on these observations, the reduction of environmental pollutants, mostly from vehicle fuel combustion, could help reduce the incidence of several diseases.
A pregnant mother’s diet has both an immediate protective effect, and a long lasting effect on life. We have discussed the fact that exposure to pollutants like PAHs increases the risk of mutations, with DNA adduct formation and carcinogenesis. However it has been shown that antioxidants protect against damage caused by these substances. Subjects with low levels of alpha tocopherol have an almost four times higher risk (RR = 3.96) of having high levels of DNA adducts than those with high levels of antioxidants . Also fish consumption during pregnancy contributes to reduce the risk of low birth weight , preterm birth (<34 weeks), the number of low birth weight babies and the number of admissions to neonatal intensive care . Other studies demonstrated the protective role of fish against the development of atopic dermatitis at the age of one year and asthma at six years, with a decrease of 30% and 50% in the incidence of these allergic diseases, respectively .
It has been reported that women who consumed high amounts of fish during pregnancy had a lower incidence of postpartum depression during the first six months after delivery (9.67% vs. 11.19% of women with low intake), while not all authors agree on the protective role on the development of the brain and cognitive functions [92, 102]. Fish is an important source of polyunsaturated fatty acids (docosahexaenoic acid DHA-EPA-and acid-eicosaepentanoic-) and essential nutrients that are not produced by the human body, and which play a protective role in the development of the neurological, immune and cardiovascular systems. They are essential for the development of the brain and retina, tissues that have the maximum uptake of these substances during the second half of pregnancy and early in childhood. However, not all types of fish can be consumed during pregnancy, because in some kind of fish the content of mercury is higher. Salmon, shrimp and hake are recommended because they are rich in ω-3 fatty acids and low in mercury, whereas large deep-water fish like tuna, swordfish and Atlantic shark should be avoided [103, 104]. Small-sized fish, like sardines can be consumed because of their high content of selenium, an element capable of reducing the toxicity of mercury .
A pregnant mother’s diet that includes fruits and vegetables can also prevent asthma and atopic dermatitis . Furthermore, levels of maternal vitamin E affect the development of fetal biometrics (crown-rump length, femur length and biparietal diameter) and lung development: for every millimeter of increase in fetus length, there is an increase of up to 5 ml of FEV1 and 6 ml of FVC . Intake of vitamin D during pregnancy, either through the diet or through supplements, has a protective role against asthma and atopic dermatitis. High levels of maternal vitamin D can reduce the risk of asthma and wheezing in children by up to 60% [108, 109]. The average dose of vitamin D to be taken is about 600 UI/day , but many studies indicate that a higher dose of vitamin D during pregnancy and lactation, up to 1000 UI/day, is necessary to achieve a good level of vitamin D assets .
Finally, maternal cholesterol levels below the 10th percentile (<159 mg/dl) and higher than the 90th (261 mg/dl) are associated with an increased risk of preterm delivery. Children born at term to mothers with low levels of cholesterol weigh about 150 grams less than controls, and have a higher risk of microcephaly . Cholesterol Low-density lipoprotein (LDL) represents the main substrate for the synthesis of progesterone and cell membranes of the decidua, essential for proper installation and vascularization of the placenta. Alterations in placental cholesterol concentrations cause changes in placental transport functions and fetal growth retardation .
Folic acid and pregnancy
According to the U.S. Preventive Services Task Force all women of childbearing age or who are planning to become pregnant should take daily supplements of folic acid, at a dose range between 0.4 and 0.8 mg, to prevent neural tube defects. Several studies provide evidence that specific genes and DNA methylation sites are subject to change during development and during a lifetime as a direct response to nutrition. Studies of the methyl donors-folate, choline, and methionine offer the most convincing evidence of a role in mediating DNA methylation changes . Folic acid is essential for the synthesis and function of DNA and affects the embryogenesis of the nervous system . Since a requirement for folic acid intake during pregnancy was introduced, there has been a 19% reduction of neural tube defects (anencephaly and bifid spine). However, only about 35% of women of childbearing age take the minimal daily dose of folic acid, and annual consumption of folic acid is decreasing . Supplementation with acid folic decreases the incidence of the risk of preterm delivery in the period 20-28th week of gestation by 70% and by 50% during the 28-32nd week period; but has no influence on the labor thereafter. In fact, low concentrations of folic acid can alter the function of lymphocytes and neutrophils, increasing the risk of bacteriuria in pregnancy, which in turn can increase the risk of preterm delivery .