Prenatal prevention of psychiatric illness and childhood development population‐wide
Authors: Robert Freedman, Sharon K. Hunter, Amanda J. Law, M. Camille Hoffman
Journal: World Psychiatry (2021)

Fusar-Poli et al1 comprehensively describe a series of developmental steps that lead to psychosis and related psychiatric illnesses. This perspective is especially relevant when considering prenatal intervention. Several pillars of evidence support the notion that the prenatal period is the first developmental step towards psychosis. The first pillar is the epidemiological ev­idence derived from case-control studies that point to maternal adversities, such as prenatal starvation and infection, as risk factors for later psychosis. The second pillar is the molecular evidence that a substantial group of genes associated with psychosis is expressed more robustly in the fetal brain before birth than in the brain after birth2. The third pillar is given by post-mortem findings from psychotic individuals that provide information about the maturation of excitatory and inhibitory neurotransmission that normally occurs during gestation. In the brain of persons with schizophrenia, the normal pre-term maturation of glutamate receptors – from lower affinity, slower acting NMDA-type to higher affinity, fast acting kainate type – is incomplete3. The maturation of the chloride transporters that support GABA's inhibitory function from the less effective embryonic NKCC1 to the more effective mature KCCN2 is also incomplete4. These failures in gestational maturation are thus apparently irreversible over an individual's life span. Furthermore, the likely functional result, brains that process information more slowly and less efficiently, is consistent with schizophrenia patients' life-long deficits, including their well-documented deficit in processing speed. The ability of neurocognitive and ­pharmacological interventions to ameliorate this deficit in patients after birth is limited. Prevention after birth is important, as outlined by Fusar-Poli et al, but it is ­hampered by the need to compensate for failures in development before birth that are generally not reversible. Despite the evidence supporting the po­tential value of prenatal intervention, its effectiveness for the prevention of psychosis is difficult to ascertain, because of its remoteness from the diagnostic emergence of psychosis in adulthood. An obvious remote aspect is temporal. The results of prenatal interventions instituted today cannot be judged until decades later, when the clinicians and investigators who designed and delivered the intervention may be long forgotten. A second remote aspect is the absence of a nosological link of the early childhood effects of prenatal intervention to psychosis. Because few babies in prenatal intervention studies are destined to develop schizophrenia, the outcome for most babies will be more general improvement in their behavior and cognition. No test in early childhood identifies babies who would have developed schizophrenia, had the intervention not occurred. In our work, as cited in Fusar-Poli et al's review, we observed a decreased prevalence of a physiological dysfunction in newborns of mothers who received phosphatidylcholine supplements compared to placebo. Phosphatidylcholine is the dietary source of the choline needed to activate fetal alpha 7-nicotinic acetylcholine receptors. The receptor's gene CHRNA7 is associated with schizophrenia and related psychiatric illnesses, and is expressed more robustly in fetal brain than after birth2. Alpha 7-nicotinic receptor activation is a critical mechanism in the maturation of both glutamate receptors and GABA-related chloride transporters5. The physiological dysfunction, a partial failure in inhibition of the cerebral evoked response to repeated auditory stimuli that occurs in many people with schizophrenia, indicates that these neurotransmitter mechanisms are not functioning optimally6. We observed normal inhibition of the evoked response more frequently among the newborns in the phosphatidylcholine-supplemented group than in the placebo group. Fusar-Poli et al note that the positive effects of phosphatidylcholine on ­physiological dysfunctions found in schizophrenia and related mental illness are surrogate markers for prevention of psychosis. As childhood progresses, children whose mothers received phosphatidylcholine supplementation also have positive behavioral effects associated with their positive physiological response as newborns. These children have decreased problems with attention and social withdrawal, compared to children whose mothers received placebo6. Conversely, increased problems with attention and social withdrawal are rated retrospectively in children who later have developed schizophrenia, compared to those who did not7. Prenatal phosphatidylcholine supplementation appears to help children avoid a developmental pathway that is typical of many individuals who later develop schizophrenia as adults. Improvement in attention and social function in early childhood is not prevention of mental illness, but neither is it merely a surrogate marker. Children with better attention and social behavior are benefitted in their future success in school, regardless of whether they were destined to become psychotic. Based on the low frequency of psychosis, these more general effects of phosphatidylcholine supplementation may be as important for population well-being as any specific effect on psychosis. If preventive efforts in psychiatry are exclusively focused on prevention of mental illness, we may overlook broader benefits. Unique aspects of psychotic illnesses, including the psychotic break in late adolescence, certainly merit investigation. However, individuals who do not convert to psychosis, the majority of patients in prodromal or attenuated symptom status, have problems with attention and other cognitive deficits that are similar to those who do convert to psychosis. These cognitive deficits are disabling regardless of whether an individual becomes psychotic or not8. Neuropsychological studies in schizophrenia patients find that attention and learning, rather than psychotic symptoms, are the major contributor to most patients' adverse outcomes. Current genome-wide association studies, which now identify hundreds of genes in association with schizophrenia as well as with developmental problems, support the thesis that much of the molecular pathology of schizophrenia resides in general brain development that underlies social behavior, attention, and other brain functions. These clinical and genetic findings suggest a broadened reconceptualization of schizophrenia as a general alteration of neu­rodevelopmental processes, rather than the outcome of a psychosis-specific pathogenesis. This reconceptualization is congruent with a common characteristic of population-wide primary prevention: beneficial effects on development that extend broadly beyond a narrow disease target. Folic acid, for example, has positive effects on cognition and behavior, in addition to its targeted use to prevent spina bifida and facial clefts. Vitamin D, included in prenatal vitamins to support bone development, appears to be helpful in the prevention of autism spectrum disorder and schizophrenia. Thus, folic acid, vitamin D, and now choline, along with other primary interventions to protect the uterine environment as part of good obstetrical care, have broad beneficial effects for the offspring, in addition to the possible prevention of later psychiatric illness. An example is the significant protective effects of prenatal choline on the development of attention in offspring of women who contract respiratory viruses in gestation9. These findings can provide guidance for treatment of pregnant women in the COVID-19 pandemic, so that their children might not add another stone to the pillar of evidence link­ing prenatal infection to schizophrenia. Most beneficial effects will appear in early childhood, long before preventive effects for psychosis and other psychiatric illnesses can be definitely ascertained. If expectant families are to see the benefit of improved childhood behavior and cognition with the eventual possible prevention of psychosis, psychiatry cannot be the only discipline to promulgate these prenatal interventions. Prenatal nutrients such as choline that have early beneficial childhood effects require widespread acceptance by obstetricians and maternal-fetal medicine specialists, family medicine physicians, midwives and pediatricians. Working relationships with obstetricians for the assessment of perinatal depression is a model for what needs to happen to allow choline and other prenatal primary preventive interventions to become truly population-wide.