Discussion
This study indicates that some of the changes in cardiac geometry and function previously described in children and adolescents born SGA are present in adults. When indexed to BSA, those in the SGA cohort consistently exhibited slightly greater LV systolic and diastolic dimensions and RV base-to-apex length. This indicates that SGA adults have slightly larger hearts relative to their BSA, as compared with adults born AGA. Indeed, in females born SGA, their OR for having a dilated indexed LVED dimension was 3.1 (95% CI 1.2 to 7.9). Our data were indexed to BSA as there is extensive evidence that cardiac dimensions are dependent on age, sex and BSA.13 ,15 ,16 A sensitivity analysis indexing to height rather than BSA also demonstrated subtly increased LV dimension in those born SGA; however, several parameters did not reach statistical significance.
Furthermore, SGA participants had a trend towards lower LV stroke volumes (74.5 mL vs 78.8 mL, p<0.01; indexed 39.5 mL/m2 SGA vs 40 mL/m2 AGA, p=0.51) as compared to their average birth size contemporaries. This reduction in stroke volume has been noted in childhood, but this is the first time there is some evidence that it may persist, albeit to a smaller extent, into adulthood.7 It is accompanied by no significant change in heart rate, but a trend towards reduced overall cardiac output (5 L/min SGA vs 5.2 L/min AGA, p=0.06). Importantly, while significant differences in both cardiac geometry and systolic function were noted in this study between those born SGA and those born AGA, all mean values were still within normal adult ranges.13
While these changes were statistically significant, they are unlikely to be clinically relevant, given their very small magnitude. This is particularly true when we note that there are considerably less marked differences than were seen in childhood (approximately 2% vs 10% mean differences).7 The lesser differences in cardiac parameters in adulthood between the SGA and AGA groups, compared with the differences seen in childhood, might suggest progressive adaptation over time. Interestingly, those born SGA demonstrated a systolic blood pressure 1 mm Hg greater than those born AGA (119.1 mm Hg vs 118.1 mm Hg, p=0.05). Whilst this result was statistically significant, we are not able to quantify the clinical relevance or implications of this difference due to our small sample size.
Unfortunately, this study was not sufficiently powered to determine if there was a subgroup of severe SGA in whom there were more marked changes in cardiac structure and function. An analysis of IQR for all echocardiographic parameters, however, did not demonstrate significantly larger IQRs in the SGA group than was seen in the AGA group (see online supplementary tables S1–S3).
The association between low birth weight and increased risk of cardiovascular disease in adulthood has been well established over decades. Barker et al2 reviewed birth weights from men born during 1911–1930 and documented that those with the lowest weights at birth and 1 year had the highest death rates from ischaemic heart disease. Despite knowledge of this correlation, the underlying pathological processes have been more difficult to elucidate.17
There are numerous theories that have been identified as potential mechanisms for this association. ‘Small baby syndrome’, where low birth weight/fetal malnutrition is associated with endothelial dysfunction and subsequent increased risk of premature hypertension, stroke and coronary artery disease, is supported by numerous international studies, including the Cardiovascular Risk in Young Finns Study, based on carotid intima-media thickness, brachial flow-mediated dilation and cardiovascular risk factors.3 ,5 ,6 ,17 ,18
Our study sought to probe one of the other main theories that have been hypothesised to be mechanistic in this process, that growth restriction in utero might be associated with persistent significant changes in cardiac structure into adult life.7 Indeed, there is good evidence that intrauterine growth restriction and hypoxia results in a dilated cardiomyopathic process in utero in the developing fetus, both in humans and in animal models.8 ,19 There are also haemodynamic data in the newborn period that SGA babies have relative cardiac hypertrophy and elevated brain natriuretic peptide levels, possibly indicative of increased cardiac workload and ventricular dysfunction.20 Population studies have also indicated that birth weight independently correlates with LV mass in adolescence.9 Our data, however, indicated that, in proportion to body size, the left (and possibly right) ventricle was very subtly dilated in adults who were born SGA, as distinct from previous studies in childhood that showed a more globular heart with increased transverse diameters and reduced longitudinal lengths.7 This is supported by the lack of difference in the sphericity index, a marker of a globular heart, between the SGA and AGA groups in our study. A proposed mechanism for this change in cardiac structure is altered loading conditions in utero. Increased placental vascular resistance leads to hypoxia and undernutrition, with a subsequent increase in afterload, decrease in arterial compliance, and resultant increased wall stress.7 Supporting this, fetal growth restriction has been proven to be associated with higher placental resistance indices in vivo.19 ,21 These maladaptive changes may lead to a more inefficient heart in childhood, with reduced stroke volumes and resultant reliance on relative sinus tachycardia in order to maintain cardiac output. These changes, however, attenuate over time. We demonstrated that by adulthood there was only an approximate 5% decrease in LV stroke volume (compared to approximately 20% in childhood),7 with no significant change in the heart rate, cardiac output or LV diastolic function.
In our study, we defined AGA as the 50th–90th centile of birth weight. A sensitivity analysis comparing SGA babies with AGA babies, where that was defined as 10th–90th centile birth weight, resulted in no statistically significant changes in the results obtained. Further, we performed another sensitivity analysis where echocardiographic measures were indexed to current height (significantly different between the 2 cohorts) rather than BSA. This demonstrated slightly greater LV dimensions in the SGA group (although only LVEDD reached statistical significance), but no difference in RV dimensions.
The strengths of this study include the large sample size, comprehensive information on birth weight and birth length, and the extensive available information on potential confounding factors such as socioeconomic status and physical activity levels. The standardised method used for obtaining transthoracic data is also noteworthy, reducing potential variations in results depending on individual sonographer techniques.
Our study also has limitations. As distinct from previous studies,7 we did not use prenatal Doppler to classify SGA into severe and mild. Thus, it is possible that a milder SGA cohort could be partially responsible for the attenuation in cardiac structural and functional changes that we had noted in adulthood, as compared to other studies performed in childhood such as that by Crispi et al7 Furthermore, cardiac MRI may be a more sensitive way to measure ventricular volumes and mass than transthoracic echocardiography.22 Lewandowski et al have shown (using cardiac MRI) that individuals born preterm exhibit unique LV geometry and function in adulthood, specifically increased LV and RV mass, smaller LV and RV volumes, and reduced LV and RV systolic and diastolic function. They have not, however, been able to determine if there are any structural and functional changes in those born at term but SGA, due to the study size and power.23 ,24