The Barker hypothesis of fetal origins of disease, derived from observational epidemiological studies first introduced in the 1970s by Forsdahl in Norway1, has been modified by the realization that the early influences on cardiovascular development that may be recognized in the fetus, for example in the setting of placental insufficiency or volume loading, may not end at the time of delivery. An individual's adaptive responses are further amplified throughout infancy and childhood by environmental factors and their responses to them2, 3. The hypothesis is now more broadly referred to as the ‘developmental origins of health and disease’ or ‘DOHaD’4. Studies have been replicated in diverse populations and a further layer of sophistication, that of epigenetics, incorporated that explains why some individuals exposed to similar stimuli show a more or less extreme response through individual variations in DNA methylation5. Fetal adaptation is primarily an in-utero survival strategy and sets up an individual's predictive adaptive responses which may be at odds with the postnatal environment. For example, if animal evidence can be extrapolated to the human5–7, obesity and Type 2 diabetes may become more prevalent in individuals who have not achieved their growth potential in utero.
Observational evidence of functional vascular alteration in adults
The original Barker hypothesis was based on observations from large cohorts of adults in whom careful birth records had been made. One of the earliest reports described discordant iliac arterial compliance in children whose birth records showed they had a two-vessel cord8. This supported earlier postmortem evidence from children, dying accidentally, who were known to have had a two-vessel cord9. Berry and colleagues reported that the common iliac artery perfusing the placenta was large and elastic but where umbilical arterial flow was absent the artery was small and muscular8. These two studies support the theory that flow determines vascular growth in the fetal cardiovascular system and that a reduction in flow alters later vascular behavior. The underlying mechanism is likely to involve altered endothelial function that cannot as yet be assessed in fetal life. The determinants of disordered endothelial function are now recognized in childhood and underline the importance of, for example, public health strategies to reduce risk in early life from passive smoking and early therapeutic strategies to reduce cholesterol levels and blood pressure10–12.
Programming of endothelial function in fetal life may be inferred from observational studies in individuals with coarctation of the aorta (CoA). Abnormalities of vascular function were found in the pre-coarctation site in a cohort of young adults who had undergone coarctation repair in the neonatal period13. Alteration of endothelium-dependent and -independent function was not present in the post-coarctation site (left arm or legs) and did not depend on timing of surgery, suggesting that there were adverse effects of fetal and neonatal arch obstruction persisting in young adulthood despite adequate surgical repair and the findings of a normal blood pressure on exercise testing. Long-term follow-up of a larger cohort of young adults that had undergone CoA repair (including these individuals) has confirmed that persistent alteration in conduit artery function and arterial stiffness are common and are, in some, accompanied by elevated blood pressure and augmented left ventricular mass in later years14.
Fetal evidence for vascular programming
Twin-to-twin transfusion syndrome (TTTS) is a naturally occurring phenomenon in genetically identical monochorionic diamniotic or monoamniotic twin pregnancies. The vascular stimuli experienced by twins differ significantly and thus they provide an interesting model to study postnatal vascular outcomes. The majority of individuals surviving TTTS appear to have normal cardiac function. However, arterial stiffness is altered in childhood in those who have undergone this disease process compared with uncomplicated monochorionic diamniotic (MCDA) pregnancies15. While MCDA control fetuses showed similar arterial stiffness in childhood, a significant intertwin difference in arterial stiffness was measured in those with TTTS. More intriguing was that the pattern of intertwin discordance differed depending on fetal therapy: those that had undergone serial aminoreduction showed increased arterial stiffness in the smaller of the twins while those that had undergone laser photocoagulation of the placental anastomoses generally showed increased stiffness in the larger, recipient twin, resembling the pattern seen in dichorionic diamniotic pregnancies where the larger of the twins had the higher brachial artery pulsed wave velocity in childhood. These studies suggest that fetal programming occurs in utero and may be altered by fetal therapy16.
Long-term effects of growth restriction
The major question is whether observations in fetal life and in childhood are likely to have long-lasting effects on future health. Vascular studies of those born small for gestational age or growth restricted suggest this may be so. They suggest that the perturbation is more complex than first thought from the earliest examination of the developing cardiovascular system. Doppler ultrasound has been used since the 1970s to characterize umbilical cord flow and placental resistance and establish the ‘cardioplacental’ relationship. However, technological advances now allow us to examine the further the effects of placental dysfunction on the development of fetal conduit arteries and peripheral vascular beds17, 18. In addition to the reduction in size and altered function of the circulation in the fetus, a variety of complex and interacting mechanisms, including alteration of myocyte function, baroreceptor control and the composition of vascular elements of the aortic wall, all contribute to what is thought to play an important role in the development of hypertension in later life through abnormalities of ventricular vascular coupling as the heart attempts to match its workload to the varying circulatory afterload in the growth restricted fetus19. It appears that failure to achieve growth potential is the important stimulus for altered vascular behavior as one study of arterial stiffness in school children described altered arterial stiffness only in those born small for their gestational age, but not if born preterm but appropriately grown20. Moreover the effects are manifest by altered reactivity in the microcirculation and conduit arteries as increased carotid artery stiffness has been measured in young children following growth restriction21.
There are now cohort studies of young adults who were monitored in fetal life using Doppler ultrasound because they were thought to be small-for-gestational age. These have shown that the reduced descending aortic volume blood flow recorded before delivery has had a long-term influence on vascular size in adulthood, the poorly perfused fetal aorta leading to an aorta that was smaller in adult life than that of size-matched controls. These young adults also demonstrated an increased resting heart rate, suggesting altered sympathetic balance22. Adults who were growth-restricted fetuses have altered development of their peripheral vascular beds, including the retina23, that is known to be associated with increased cardiovascular mortality24. A reduced number of glomeruli have been reported in IUGR fetuses as well as in the donor twin of TTTS pregnancies. This has implications for the function of many homeostatic mechanisms, including the renin–angiotensin system (RAS), and may exert long-term influences on blood pressure modulation25. Power Doppler and fractional moving blood volume (FMBV) allow us to observe the vascularity of peripheral beds and may provide a reproducible measure of organ perfusion that could aid in the assessment of the growth-restricted fetus in future years18, 26–29.
Future directions in research
Non-invasive assessment of endothelial function is now a routine part of the assessment of adult cardiovascular health and plays an important role in the management of hypertension, atherogenesis, Type 2 diabetes, coronary heart disease and in the metabolic syndrome30, 31. Passive smoking is known to alter endothelial function in children and in non-smoking bar workers and the results of these and similar studies have been powerful influences in forming the current no-smoking legislation in public places10. As yet there is no good method of assessment of endothelial function in the fetus but wall-tracking devices have measured a reduction in the relative pulse diameter of the fetal aorta in response to maternal smoking as well as in fetuses with growth restriction19, 32.
Follow-up studies of young adults who were growth restricted in utero have shown that, despite catch-up of somatic growth, they do not achieve the same arterial growth as individuals that were normally grown22. It is likely that this is caused by a combination of responses, for example altered endothelial function combined with altered arterial wall composition, such as a reduction in elastin deposition that usually occurs during the third trimester and first months of postnatal life and suffers as a result of nutritional restriction imposed at this time33.
We have limited tools to measure vascular function in the fetus and small baby in early postnatal life and many studies have been unable to detect differences in vascular behavior from normal in the first months after delivery34. Indeed functional abnormalities may be unmasked only by a provocation test such as a tilt test to test baroreceptor function35 or examination of the microvascular responses in skin tested with the local application of acetylcholine (inducing endothelium-dependent vasodilatation) and nitroglycerin (endothelium-independent vasodilatation), where local perfusion changes can be measured using laser Doppler21. Careful serial examination of high-risk pregnancies will allow us to monitor these early responses, but to understand the long-term influences of in-utero pathophysiology will require coordinated longitudinal follow-up of sufficiently large well-phenotyped cohorts to test out these responses.