Background: Exposure to prenatal stress is associated with later adverse health and adjustment outcomes. This is generally presumed to arise through early environmentally mediated programming effects on the foetus. However, associations could arise through factors that influence mothers' characteristics and behaviour during pregnancy which are inherited by offspring.Method: A ‘prenatal cross-fostering’ design where pregnant mothers are related or unrelated to their child as a result of in vitro fertilization (IVF) was used to disentangle maternally inherited and environmental influences. If links between prenatal stress and offspring outcome are environmental, association should be observed in unrelated as well as related mother–child pairs. Offspring birth weight and gestational age as well as mental health were the outcomes assessed.Results: Associations between prenatal stress and offspring birth weight, gestational age and antisocial behaviour were seen in both related and unrelated mother–offspring pairs, consistent with there being environmental links. The association between prenatal stress and offspring anxiety in related and unrelated groups appeared to be due to current maternal anxiety/depression rather than prenatal stress. In contrast, the link between prenatal stress and offspring attention deficit hyperactivity disorder was only present in related mother–offspring pairs and therefore was attributable to inherited factors.Conclusions: Genetically informative designs can be helpful in testing whether inherited factors contribute to the association between environmental risk factors and health outcomes. These results suggest that associations between prenatal stress and offspring outcomes could arise from inherited factors and post-natal environmental factors in addition to causal prenatal risk effects.

The 600-kilobase (kb) break points 4 and 5 (BP4-BP5) 16p11.2 deletion and duplications (chr16; 29.6-30.2 megabase) are among the most frequent genetic causes of autism spectrum disorder (ASD), schizophrenia, and other neurodevelopmental disorders.^1-5 These reciprocal copy number variants (CNVs) are associated with mirror phenotypes of obesity and being underweight and with increased and decreased global and regional brain volumes in deletion and duplication carriers, respectively.^6-8 Previous studies^5,9 have demonstrated that ASD is diagnosed in approximately 18% of deletion carriers and that this CNV affects global cognition by shifting the IQ approximately 2 SDs without altering the variance. To our knowledge, such studies have not been conducted for the reciprocal duplication. Akin to duplications of other genomic regions, case series^10-18 have reported variable expressivity and suggested incomplete penetrance; however, incomplete penetrance was recently ruled out after recalling carriers identified in unselected populations.¹⁹ This phenotypic variability and the limited available data underscore the need to systematically characterize the clinical impact of the duplication with standardized assessments in large numbers of carriers.

It is widely considered that exposure to maternal cigarette smoking in pregnancy has risk effects on offspring attention-deficit/hyperactivity disorder (ADHD). This view is supported by consistent observations of association. It is, however, impossible to be certain of adequate control for confounding factors with observational designs. We use a novel "natural experiment" design that separates prenatal environmental from alternative inherited effects. The design is based on offspring conceived with Assisted Reproductive Technologies recruited from 20 fertility clinics in the United Kingdom and United States who were: 1) genetically unrelated, and 2) related to the woman who underwent the pregnancy. If maternal smoking in pregnancy has true risk effects, association will be observed with ADHD regardless of whether mother and offspring are related or unrelated. Data were obtained from 815 families of children ages 4 years-11 years with parent questionnaires and antenatal records. Birth weight was used as a comparison outcome. The key outcome considered was child ADHD symptoms. Association between smoking in pregnancy and lower birth weight was found in unrelated and related mother-offspring pairs, consistent with a true risk effect. However, for ADHD symptoms, the magnitude of association was significantly higher in the related pairs (beta = .102, p < .02) than in the unrelated pairs (beta= -.052, p > .10), suggesting inherited effects. Our findings highlight the need to test causal hypotheses with genetically sensitive designs. Inherited confounds are not necessarily removed by statistical controls. The previously observed association between maternal smoking in pregnancy and ADHD might represent an inherited effect.