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.
The Pregnant Woman as an Information Source for the Growing Fetus
One important aspect of intrauterine programming may be the fetal response to signals conveyed by the pregnant women to her unborn child by which she ‘describes’ to her/him the outside world into which it is going to be born. Based on this information, the growing fetus prepares his/her physiological adaptation in order to cope with the outside world. This preparation for the postnatal world may cause what Gluckman and Hanson [1] have termed a ‘predictive adaptive response’ (PAR) and may have a profound impact on future health and disease. Obviously, genetic changes as a result of Darwinian selection could not occur rapidly enough to prepare the unborn for the specific environment into which it is going to be born, but epigenetic mechanisms can. Thus, adaptive changes in very early developmental stages in a single generation can equip the newborn with appropriate tools to meet ‘anticipated’ changes. If the newborn indeed faces the expected challenges, he will be well equipped. If, however, the environment has changed, his adaptive tools may be inadequate and he will actually be at a disadvantage. For example, maternal stress during pregnancy, which may lead subsequently to increased vigilance and higher awareness of potential threats in offspring, may be adequate if the new world is indeed full of danger. However, if the newborn is born into a quiet and protected world, his adaptive measures may be ill placed and his high vigilance and suspicion of his surroundings combined with rapid shifts of attention may express itself as attention disorders and even paranoia. Another example relates to the use of food: Desai et al. [20] restricted pregnant rams in food intake. This may have conveyed a signal to the fetuses about restricted postnatal food availability. When the newborns were given food ad libitum, they overate and developed obesity. When, however, intrauterine food restriction persisted after birth, the offspring developed like controls which were not food restricted before or after birth. Here is an interesting example of how external signals about the anticipated environment into which the fetus is going to be born are conveyed by the pregnant female to the developing fetus. Lee and Zucker [21] showed that the length of days during gestation of voles affects the coat at birth. Voles born in the autumn have thicker coats than those born in the spring and are better prepared for the winter period. Obviously, the thicker coat does not confer any immediate survival advantage but is advantageous for the growing pup.
Intrauterine Environment and IQ
The long standing and sometimes fierce ‘nature-versus-nurture’ controversy has often focused on the heritability of IQ, a fertile ground for infamous racist theories and ideologies. In order to arrive at meaningful and scientifically sound results, studies cannot be based on genetics only but need to take into account the different environments in which a human being and his/her IQ develop. Home, social groups, and educational frameworks are such environments, but so is the uterus. Devlin et al. [22] published a meta-analysis of 212 IQ studies which included over 50,000 twins. They reported that IQ is positively related to birth weight, normalized for gestational age, indicating that maternal nutrition may affect the IQ of the child. Moreover, they summarized literature reports indicating that IQ may also be increased by certain dietary supplements used by pregnant women and lowered by consumption of alcohol, drugs, and tobacco during pregnancy. Thus, the intrauterine environment affects the IQ in addition to the postnatal environment. The authors estimated, based on their studies, that the total effect of genes on IQ is less than 50%. Moreover, the fetal environment alone accounts for 20% of the covariance between twins and 5% between siblings born from the same mother at different times. The fluidity of the relative impact of the environment and genetics on IQ levels has been emphasized by Turkheimer et al. [23] who showed in close to 60,000 children that the relative contribution of the environment and genetics to future IQ levels is closely related to the socioeconomic status of the family. The lower the status, the higher the impact of the environment, and vice versa. According to this body of data it seems that in the low socioeconomic bracket virtually all of the variance of IQ is related to the pre-and postnatal environment while in the highest socioeconomic environment most of the IQ can be attributed to genetics.
Intrauterine Environment and Its Influence on Subsequent Sexuality
The development and determination of human sexual orientation is a complex and multicausal process and the ‘nurture-nature controversy’ has not spared human sexuality. For decades or even centuries, homosexuality has been regarded as an ‘acquired disease’. The notion was that homosexuality is either a voluntary deviation from ‘normalcy’ and therefore punishable by society or a disease and therefore amenable to treatment. Psychoanalysis as a treatment mode for homosexuality was developed by Sigmund Freud and advocated by psychologists and psychoanalytics until the 70s of the last century. This was based on the theory that the rejection of a dominant and overpowering father could cause homosexuality in his son. This ‘disease’ theory has been refuted only recently and the ‘nature’ origin of male homosexuality has gained ground. Numerous studies indicate that homosexuality, both in men and in women, may be familial, with genetic transmission accounting for a large proportion of the variance in sexual orientation. However, there may also be epigenetic events during fetal programming which are involved in the development of sexual orientation. Blanchard and Ellis [24] have suggested that the increased odds of homosexuality in later born males are related to the number of earlier born biological brothers and may be linked to a progressive immunization of some mothers to Y-linked minor histocompatibility antigens (H-Y antigens). It has been estimated that one in seven American male homosexuals is gay because of older brothers.
Fetal Programming as a‘Species Survival’Strategy
In a different dimension, fetal programming may also prepare the species for survival. In times of population stress such as famine, natural disasters such as after the Kobe earthquake, or man-made disasters, a reduction in the human sex ratio has been observed. Trivers and Willard [