Prenatal programming – can it affect offspring mental outcomes?

11th October 2018, Dr Chee L Khoo

Epigenetics is the modification of the DNA that changes a gene’s expression without altering the nucleotide sequence. DNA methylation and histone modifications are the most commonly studied epigenetic mechanisms by which cell structure and function can be altered during embryogenesis. The in-utero environment can lead to prenatal programming by which genes are activated or deactivated. Prenatal programming is thought to be associated with many adult diseases like cardiovascular disease and metabolic disorders. Can prenatal programming affect the mental health outcomes of the offspring?

Patients often asked us about the heredity of mental illness. The concept of “three-hit hypothesis” of disease vulnerability and resilience is now evolving. Genetic predisposition is “hit 1,” the prenatal environment could be viewed as “hit 2,” altering gene expression and leading to phenotypes with differing susceptibility to later life experiences and exposures (hit 3).

A recent review of current understanding and mechanisms of prenatal programming of mental illness is most insightful. The type and timing of exposure as well as the offspring sex are critical factors to consider in evaluating the importance of prenatal programming on mental health outcomes.

Types of stress

Severe emotional distress experienced by the mother during pregnancy such as death of an older child increases the rate of serious malformations in the developing foetus. Whether maternal psychosocial stress or frank mental illness during pregnancy exerts programming effects on the developing foetus through enhanced foetal exposure to glucocorticoids, inflammation, placental modifications, suboptimal maternal health behaviours (such as poor nutritional intake and nicotine, drug, or alcohol use), or factors yet to be identified is an area of active investigation requiring a translational approach to determine mechanisms and potential interventions.

Timing of stress

Early gestational insults could impact systems such as the hypothalamic-pituitary-adrenal (HPA) axis that are critical for the modulation of circadian rhythms, physical growth, and limbic-cortical processes. In a sample of approximately three million Swedes, extreme maternal stress due to exposure to the death of a first-degree relative significantly increased the risk of infant mortality if the stress occurred in the immediate preconception period (6 to 0 months), but not if the stress occurred during pregnancy. In another study, heightened maternal anxiety during late gestation was associated with behavioural/emotional problems in the offspring during childhood.

Different effects on different sex

Male offspring exposed to maternal prenatal stress demonstrate impaired learning while female offspring perform better following exposure to maternal stress during early gestation. Male rodents are more sensitive to the effects of maternal stress-induced placental inflammation, displaying enhanced stress-induced locomotor hyperactivity when tested during adulthood. Female rodents appear to be more sensitive to the activating effects of prenatal stress on hypothalamic-pituitary-adrenal axis function. Male offspring of mothers who were stressed during pregnancy may be at relatively greater risk of attention deficit hyperactivity disorder symptoms during childhood and even schizophrenia later in life. Maternal anxiety was associated with depression in adolescent girls but not in boys. Whether these sex differences in relationship to exposure to maternal prenatal distress can be observed because the frequency of specific behavioral/psychiatric disorders varies between males and females or because maternal stress actually contributes to these epidemiologic differences is worthy of further investigation.

Neuropsychiatric conditions

A Danish registry study of 1.38 million births from 1973 to 1995 found that the risk of schizophrenia was increased in the offspring (as of 2005) of mothers who were exposed to death of a relative during the first trimester of pregnancy. Interestingly, a greater proportion of male offspring developed schizophrenia than female offspring. Exposure to bereavement stress during the second or third trimester did not substantially increase the risk for schizophrenia, suggesting that the first trimester is a particularly sensitive window for the programming effects of extreme stress, particularly among male offspring.

Adolescents whose fathers had died when they were in utero were more likely to develop symptoms of schizophrenia by the age of 15 compared to teens who lost their fathers during their first year of life. In a large cohort from Northern Finland, unwanted pregnancies were associated with a twofold increased risk of schizophrenia compared to wanted or mistimed pregnancies after controlling for socioeconomic, perinatal, and birth factors. Maternal factors such as smoking and stress during pregnancy, rather than birth complications, increased the risk of adolescent psychosis in a cohort of 963 adolescents aged 15–20 years old. These studies suggest that while birth complications and poor maternal health behaviors are higher in persons who develop schizophrenia, prenatal stress is an independent risk factor.

Foetal hypoxia, maternal infections resulting in increased levels of maternal serum IgG and IgM class immunoglobulins at delivery, maternal exposure to influenza or toxoplasmosis, and maternal malnutrition  have all been related in epidemiologic samples to increase the risk for the offspring development of psychosis, particularly schizophrenia.

Autistic Spectrum Disorder (ASD)

Human studies suggest that infection may be most important in the first trimester as ASD is more common in children whose mothers are hospitalized for viral infections in the first trimester, although this needs further study. Maternal obesity also increased the risk for ASD among 2-year-old children born at a gestational age of ≤30 weeks. A high-fat diet can increase inflammation through inducing levels of cytokines that have been associated with ASD in humans, and there is evidence that increased cytokine levels during pregnancy negatively impact neural development.

Attention Deficit Hyperactivity Disorder (ADHD)

In a retrospective case-control study, maternal stressful events during pregnancy was significantly associated with ADHD compared to an unaffected sibling, with males more likely than females to be affected. In large Danish cohort, severe bereavement stress was associated with an increased risk of ADHD. In another Danish study, boys born to mothers who experienced the unexpected death of a child or a spouse during pregnancy had a 72 % increased risk of a hospital diagnosis of ADHD or receiving ADHD medication.


Prospective data are starting to emerge, suggesting that significant depression during pregnancy is an independent risk factor for the later onset of depression in the adult human offspring. One study found that 18-year-old offspring were 1.28 times more likely to report depression for each standard deviation increase in maternal depression score.

Although somewhat inconsistent, there are compelling data which suggest that exposures to severe stressors such as loss of a first-degree relative or a spouse early in pregnancy or even immediately prior to conception increase the risk of mental illness in the offspring.

Access abstract here


Kim, D.R., Bale, T.L. & Epperson, C.N. Curr Psychiatry Rep (2015) 17: 5.