Discussion
We found that young adults who were born preterm had higher levels of cardiometabolic risk factors and were 2.5 to 4 times more likely to meet the criteria of metabolic syndrome than were their peers who were born at full term. They also had higher levels of emerging cardiometabolic risk factors, which suggests that a range of pathophysiological pathways might jointly underlie these associations. Although the results of previous studies have suggested that those born smallest and most immature have elevated cardiometabolic risk factors, our study shows that these risk factors and the full-blown metabolic syndrome are also present in the much larger group of people who were born less preterm.
Obesity, Body Composition, and Insulin Resistance
A key component underlying many characteristics of metabolic syndrome is obesity, particularly abdominal obesity. We found higher rates of obesity and more central body fat in adults who were born preterm. This differs from the situation in adults who were born severely preterm, who tend to be shorter and have a lower BMI as a result of lower lean body mass and similar fat percentages compared with those born at term. Additionally, in a recent meta-analysis in which they compared 412 adults who born preterm with 538 controls, Parkinson et al. determined that there were no differences in fat percentages; again, this is likely a result of the cases having been born severely preterm, as the mean gestational age of those who were born preterm was 30.6 weeks. Consistent with a previous study in adults with very low birth weight, we found higher fasting and 2-hour insulin concentrations among the preterm groups, although the differences in the present study were smaller. A conclusion from these findings is that although the large group of adults who were born less preterm had adverse metabolic characteristics associated with impaired glucose regulation similar to those of adults who were born severely preterm, a main contributing factor to impaired glucose regulation for adults born less preterm might be increased body fat with ectopic distribution, which includes increased hepatic fat accumulation; whereas for the smallest preterm individuals, a main contributing factor to impaired glucose regulation may be low muscle mass.
Our subjects were relatively young. As expected, few of them fulfilled the criteria for type 2 diabetes mellitus or impaired glucose tolerance. Studies in older adults have suggested that higher rates of type 2 diabetes mellitus occur in adults who were born preterm; however, such studies are based on national registers or self-reporting and, thus, involve a degree of uncertainty. Our study, on the other hand, presents direct evidence that abnormal metabolic characteristics are already present in young adult life.
Blood Pressure
Our findings are consistent with a dose-response relationship between a shorter length of gestation and higher blood pressure, a finding that has been supported by population-based studies as well as studies of adults who were born preterm with a very low birth weight. High blood pressure is strongly associated with cardiovascular mortality and, globally, is a leading risk factor of death and disease. Small differences can be important; for example, although we found a difference of 2.5 mm Hg in diastolic blood pressure between the early preterm group and controls, a difference of 2 mm Hg is associated with a 15% reduction in the risk of stroke.
Lipid Profile
Previous findings that concern the association between preterm birth and serum lipid levels in adulthood have been inconsistent. We found that women who were born early preterm had lower levels of HDL-C and its precursor apolipoprotein A1 than did women who were born at term. The difference of 11.4% that we found in HDL-C level corresponds to approximately 0.21 mmol/L. A reduction of 0.26 mmol/L has been associated with a 10% increase in the risk of coronary heart disease.
Other Biochemical Markers of Metabolic Syndrome
In addition to the established components of metabolic syndrome, we found alterations in a wide range of biomarkers that reflect different underlying pathophysiological pathways. These include uric acid, the concentrations of which were more than 20% higher in both the early and late preterm groups than in the controls. Levels of liver transaminases were also higher in adults who were born preterm, to such an extent that participants with a moderate or high fatty liver index (a proposed marker of nonalcoholic fatty liver disease) were almost exclusively born preterm. We are unaware of any previous reports on uric acid or liver enzymes in adults who were born preterm. Uric acid stimulates oxidative stress, endothelial dysfunction, inflammation, and vasoconstriction and is a strong predictor of type 2 diabetes mellitus and cardiovascular disease, independent of other metabolic syndrome components. Liver transaminases and nonalcoholic fatty liver disease also predict these disorders, although the literature is less consistent with regard to the extent that they are independent indicators of pathology rather than general markers of metabolic syndrome.
Limitations and Strengths of the Study
The main strength of the present study is the study population, which was chosen to include the whole range of preterm births in a specific geographic area. Another strength is the comprehensive measurements of conventional and emerging cardiometabolic risk factors. As to limitations, participation bias cannot be excluded, although a detailed nonparticipant analysis did not raise any concern for such bias. In particular, in the proportion of participants who had undergone an examination at 16 years of age, there was no indication that participants who were born preterm and who had elevated cardiometabolic risk factors during the study period would have been overrepresented in the preterm groups. Although we adjusted for several key confounders, residual confounding remains a possibility. In addition, collider stratification bias is possible after adjustment for intermediate factors, such as BMI, physical activity level, and smoking status, in the regression models; this is unlikely to have any significant effect, as these adjustments had a negligible effect on the results. There was some difference in the proportion of the late preterm and control groups recruited through the NFBC or FMBR; therefore, we adjusted for the recruitment cohort. We had no data to distinguish between spontaneous and medically indicated preterm birth. Instead, we relied on proxy measures, such as being small for gestational age or maternal hypertension in pregnancy, that, nevertheless, are likely to cover a major proportion of indicated preterm deliveries. Moreover, although we had sufficient power for most outcomes, power was limited for more rare outcomes, such as moderate or high fatty liver index.
Conclusions
We found that young adults who were born preterm had elevated levels of conventional and emerging cardiometabolic risk factors associated with metabolic syndrome, as well as a 2.5 to 4 times greater risk of full-blown syndrome than those born at term. These risks were also present in the large group of young adults who were born late preterm, which is consistent with a dose-response relationship between the degree of prematurity and metabolic syndrome. Our results call for the targeted promotion of a healthy lifestyle and vigilance in the early detection of metabolic syndrome in the over 10% of people born preterm.