A large number of studies show that low birth weight is associated with cardiovascular disease and its risk factors including raised blood pressure, glucose intolerance and the metabolic syndrome. These findings have formed the basis for the ‘fetal origins hypothesis’. This suggests that the operation of adverse influences during intrauterine life leads to permanent alterations in fetal structure and physiology which predispose to adult disease. The process is known as developmental plasticity or programming and is strongly supported by studies in experimental animals. Ongoing research is providing important insights into the underlying mechanisms. It is likely that adverse environmental factors during pregnancy are important, and that these include suboptimal nutrition of the mother. The long-term programming effects may be transduced by alterations in the set-point of key hormonal axes, especially the hypothalamic-pituitary-adrenal axis, and recent evidence suggests that epigenetic modification of gene expression may also be a key factor. Importantly, this has the potential to produce transgenerational effects.
The hypothesis has not remained unchallenged and a wide variety of criticisms have been put forward. These include accusations that the associations are weak and overestimated due to publication bias, that there are many inconsistencies between studies, that the associations are confounded by lifestyle factors, and that there has been inappropriate adjustment for adult size. Finally many studies report that the findings in singletons do not seem to be replicated in twins. While many of these issues have been resolved, some continue to form the basis of a lively dialogue and ongoing research. Nevertheless the research findings have important implications for clinical obstetric practice and maternal-fetal medicine.