showed that low birth weight is associated with impaired endothelial function in childhood, which is an important risk factor for subsequent cardiovascular disease. The discovery that endothelial dysfunction in adults may be due to prenatal life events is of great importance since it indicates that atherosclerosis may also have its roots in prenatal events which are not genetically controlled. The authors calculated the relation between birth weight and endothelium-dependent flow-mediated dilatation (FMD) and concluded that a 1-kg difference in birth weight is equivalent to 4.5 cigarette pack-years as far as risk for subsequent vascular disease is concerned. This means that the adverse impact of reduced birth weight on vascular function across the birth weight range is as great as the effect of smoking. The correlation between reduced caloric intake during pregnancy and adverse fetal outcomes has been studied in populations in times of war and natural catastrophes. From November 1944 to May 1945, the German blockade of Western Netherlands led to what has been termed ‘The Dutch Famine or Hungerwinter’. Rations went as low as 400 calories a day, equivalent to 25% of the minimal daily requirement. At the Academic Medical Center in Amsterdam, the Dutch Famine Cohort Study was initiated; it investigates the outcomes of men and women who were born in the Wilhelmina Gasthuis in Amsterdam between November 1943 and February 1947 (www.hongerwinter.nl). Thanks to well-preserved documentation, the researchers were able to strongly corroborate the ‘Barker theory’. They found that individuals who were exposed in utero to malnutrition weighed 200-300 g less than controls and suffered later in life from a variety of diseases, including diabetes, cardiovascular disease, higher LDL/HDL ratios, obesity, coagulation disorders, hypertension, pulmonary disease, and renal disease. Ijzerman et al. [12] demonstrated in dizygotic, and hence genetically unlike twins that low birth weight was associated with insulin resistance and lower HDL levels, indicating a pathology independent of genetic factors. Intrauterine malnutrition seems to affect male and fetal fetuses differently. Sardina et al. [13] examined the central anorexigenic effects of insulin in rats. Female but not male adult rats who were exposed to intrauterine undernutrition developed in adulthood adiposity, impairment of hypothalamic insulin signaling, and loss of insulin-induced hypophagia.
It is becoming increasingly apparent that many forms of adult disease may have their roots in fetal programming and in early childhood. Obesity is one example: obesity has become a major public health problem affecting the majority of adults in the USA. Extremes of birth weight, i.e. low birth weight and increased birth weight, may cause future obesity and metabolic syndrome. It has been shown that prenatal androgen exposure of female mice causes impaired insulin secretion both as an organizational effect and as an activational effect which is based on defective islet cell function. Chronic diseases like osteoporosis, mood disorders, and psychiatric syndromes as well as polycystic ovary syndrome have been related to fetal programming. Other adult diseases such as cardiovascular disease, a variety of metabolic and endocrine pathologies, diabetes, and various other diseases may also be due to inadequate determination of set points during fetal programming. There is now preliminary evidence that eating disorders, which are more common in females that in males, are organized by low levels of prenatal testosterone and then activated by increasing estrogen levels during puberty in girls.
The Impact of Maternal Prenatal Stress on the Developing Embryo and Fetus
Four decades ago, Ward [14] reported that male rats which were exposed prenatally to stress showed low levels of male copulatory behavior but increased female lordotic sexual responses. There is a growing body of prospective data which links antenatal maternal stress with impaired, gender-specific emotional and cognitive development of offspring in childhood. Prenatal stress in pregnant animals can cause permanent impairment of neurodevelopment in offspring, including shorter attention spans, anxiety, and impaired cognitive function. Weinstock [15] showed in rats that maternal stress increases corticosteroid levels in the fetal brain and decreases testosterone levels and aromatase activity in male fetuses. Moreover, noradrenalin activity increased and dopamine activity decreased in male fetuses and levels became similar to those of female fetuses as a result of maternal stress. Male offspring had more learning deficits while female rats exhibited anxiety, depression, and an increased response of the pituitary-adrenal axis to stress. Based on rodent studies, Weinstock [15] further pointed out that maternal stress during critical periods of fetal brain development may exert long-term effects on the hypothalamus-pituitary-adrenal axis, including an impaired feedback mechanism and impairment of the circadian release of corticosteroids. This effect seems to be time sensitive and impinges on the fetal brain only during specific time windows. It has been shown that the increased incidence of schizophrenia in men whose mothers were subject to severe stress, as during the May invasion of the Netherlands in 1940, was restricted to the second trimester of pregnancy and did not occur during the first trimester of pregnancy [16]. Kashan et al. [17] studied a cohort of 1.3 million births in Denmark, which occurred between 1973 and 1995. They reported that death of a relative in the first but not in the second and third trimester of pregnancy was associated with an increased gender-specific risk for schizophrenia in offspring (adjusted RR 1.67; 95% CI 1.02-2.73). The incidence per 100,000 person-years was higher in males (55.4%) than in females (41.3%). The death of a relative occurring up to 6 months before conception had no such effect. Malaspina et al. [18] reported on a cohort of 88,829 births which occurred in Jerusalem between 1964 and 1976. They linked the data to Israels’ Psychiatric Registry and found an increased risk (RR = 2.3; 95% CI 1.1-4.7) for schizophrenia in individuals whose mothers were subject to substantial stress during the second month of pregnancy. In contrast to the report of Kashan et al. [17], they reported that the risk was higher in females (RR = 4.3; 95% CI 1.7-10.7) than in males (RR = 1.2; 95% CI 0.4-3.8). This sex preference for females is more in accord with other reports. It is noteworthy that attention deficit hyperactivity disorder (ADHD) symptoms have been observed in children and young adolescents whose mothers were suffering from increased anxiety during pregnancy and more often in males than in females. Although systems involving serotonergic and dopaminergic activity may also be involved, the most likely physiological and pathophysiological mechanisms by which maternal stress and PTSD affect offspring is the hypothalamic-pituitary-adrenal (HPA) axis. In essence, an increase in cortisol secretion in a person under stress is an adequate response as long as an intact feedback mechanism causes cortisol levels to decrease once the danger is over. However, if this feedback mechanism is impaired, adaptation to stress becomes inadequate. Steroid receptors are abundant in the hippocampus where mediation of feedback is concentrated. A reduction of steroid receptors in this area would affect an adequate feedback mechanism and could therefore interfere with adequate adaption to stress and the environment. Epigenetic processes may occur in the fetal hippocampus as a result of maternal stress which actually change the functional state of glucocorticoid receptors, cause a reduced feedback response, and consequently inadequately increase the cortisol response to stress later in life. This changed set point in the function of the HPA axis could then be one possible etiology for ADHD. Stress can, of course, not be totally avoided during pregnancy and a small to moderate stress level may actually be beneficial to the mental and physical development of offspring. This has been demonstrated by DiPietro et al. [19] who studied pregnant women who lived in a financially and emotionally stable environment but were exposed to moderately stressful situations. They reported that mild to moderate stress may enhance fetal maturation in healthy populations. Prenatal maternal stress may also lead to premature delivery and small-for-gestational-age babies. These in turn are risk factors for impaired cognitive development and may also affect neonatal neurobehavior.
