In recent postings concerning postnatal trauma (e.g., circumcision) there have been some references to prenatal events as well.  Prenatal stress (PS) has been adequately demonstrated to be a behavioral teratogen, a factor, I have pointed out for years, which has not been controlled for in neurodevelopmental or twin research in schizophrenia.

Prenatal Stress and Schizophrenia
In rodents, prenatal stress (PS) is associated in the adult offspring with behavioral changes, persistent changes in HPA axis activity, as well as changes in glucocorticoid receptor density (Takahashi et al. 1992; Henry et al. 1994; Lordi et al. 2000; Szuran et al. 2000).  In non-human primates, prenatal stress results in attentional difficulties, neuromotor abnormalities, decreased locomotion, and hyperresponsiveness to stress in adult offspring (Schneider et al. 2002).  PS in primates results in increased levels of dihydroxyphenlacetic acid (DOPAC), a dopamine metabolite, in offspring suggesting increased dopamine activity.

Maccari and colleagues (1998) demonstrated a major role for maternal glucocorticoids in the developing fetal neuroaxis (dysregulating the hypothalamic-pituitary-adrenal axis, the HPA), as well as maternal behavior which served a neuroprotective role in counteracting the effects of prenatal stress.  Schneider and Moore (2000) also provided support for the hypothesis that prenatal stress in humans and animals results in dysregulation of the stress response (the HPA axis), along with alterations particularly in the dopaminergic system of the brain. They concluded that there is supporting evidence for prenatal stress to be considered a behavioral teratogen.  They noted:

“The pattern of evidence thus far is supportive of the hypothesis that prenatal stress could be a behavioral teratogen; human correlational results show negative effects of prenatal stress, experiments with both nonhuman primates and other animals show significant behavioral and physiological effects of prenatal stress that can extend into adulthood, and the animal research provides evidence regarding the physiological processes that are likely to be altered by prenatal stress” (p. 236).

Marta Weinstock (1998), in her research on prenatal stress, concluded:

“Exposure to psychological stress during gestation can induce long-lasting behavioral changes in the offspring, characterized by a decreased ability to cope with, or adapt to, stressful situations.  This is associated with dysregulation of the HPA axis [limbic-hypothalamic-pituitary-adrenal]... these modifications can affect the developing fetal brain at a critical time during development.”  In longitudinal research in humans, schizophrenia has been correlated with exposure to several forms of maternal PS, including death of the father during gestation (Huttunen & Niskanen 1978), unwanted pregnancy (Myhrman et al. 1996), exposure to wars and catastrophes, such as the 1940 invasion of Holland (van Os & Selten 1998), and the nuclear attack on Nagasaki (Koenig et al. 2002).  Elevated rates of schizophrenia are also related to maternal depression during pregnancy (Jones et al. 1998).  Depression is often associated with hypercortisolemia.

In my book-in-progress, The Schizophrenias: Brain, Mind and Culture, I noted the following in regards to the connection between PS and later rates of schizophrenia:

“The link between exposure to stress during gestation and subsequent schizophrenia was suggested by a study that prenatal death of father was associated with increased risk of schizophrenia (Kuh & Ben-Sholomo 1997).  In a population-based study on increased risk of schizophrenia, it was observed that subjects exposed during the first trimester of pregnancy to the stress of invasion by the Nazi army in the Netherlands had increased rates of schizophrenia (van Os & Selten 1998-”Prenatal exposure to maternal stress and subsequent schizophrenia”.  British Journal of Psychiatry, 172, 324-326).  An additional population-based study conducted in the Netherlands discovered a (non-significant) increased risk of developing schizophrenia in subjects prenatally exposed to the 1953 Dutch flood disaster (Selten, van der Graaf, et al 1999-”Psychotic illness after prenatal exposure to the 1953 Dutch flood disaster.” Schizophrenia Research, 35, 243-245).  Rates of schizophrenia were significantly higher in subjects whose mothers were told of their husbands’ deaths during the war between Finland and Russia while in the 2nd and 3rd trimesters as opposed to hearing the news after birth.  I wonder if the connection between maternal starvation and later development of schizophrenia made by Susser & Lin (1992-”Schizophrenia after prenatal exposure to Dutch hunger winter of 1944-1945,” Archives of General Psychiatry, 49, 983-988), could also be contributed to by the effects of maternal stress secondary to a lack of food supply .Verdoux and Sutter (2002-”Obstetrical complications, maternal psychopathology, and the risk of psychosis” ) noted: “The association between prenatal exposure to maternal stress and later schizophrenia may be mediated by the direct impact of stress, such as fetal hypoxia induced by vasoconstriction; or more indirectly, by increasing the risk of OC’s [obstetrical complications], such as prematurity, or by increasing the risk of maternal prenatal or postnatal depression” (p.108).

Brian Koehler