Both GDM and abnormal growth patterns have been associated with long-term adverse outcomes on offspring and changes in the lipoprotein composition have been proposed as potential markers of cardiovascular diseases later in life. In this study, taking advantage of a thorough lipoprotein profiling by using 1H-NMR, we show for the first time that GDM modifies the umbilical cord blood lipoprotein profile in AGA neonates. In particular, GDM alters IDL-lipoproteins, triglyceride content in LDL, and medium-size VLDL-P and LDL-P in those children. By contrast, GDM offspring belonging to the LGA and SGA groups have a lipoprotein profile more similar to controls. Besides, we found that cord blood small LDL-P, known to be associated with atherosclerosis development, have a predictive value for later obesity in the offspring.
Both under and overnutrition in utero affects the lipoprotein profile of neonates.4–7 SGA neonates are reported to exhibit higher cord blood triglyceride concentrations,(6, 9, 27) higher VLDL and IDL concentrations, and lower HDL concentrations when compared with equivalent AGA neonates.(10) Some of these findings have also been reported in fetal macrosomia(6, 8) and GDM pregnancies.(28) However, standard lipid profiling have failed to identify differences between offspring born to healthy pregnant and GDM mothers.(29) Nonetheless, a more extensive characterization of lipoproteins, as have been stated in other metabolic disorders such as diabetic dyslipidemia,(17) could provide more accurate information on the regulation of lipoprotein metabolism in fetal life and its potential implications for metabolism in later life. Thus, using 1H-NMR-based cord blood lipoprotein profiling we detected differences according to fetal growth categories in GDM women, revealing a disturbed cholesterol and triglyceride metabolism even in AGA neonates. This pattern may denote an excessive transfer of triglycerides to LDL, and the further increased cholesterol-poor LDL particles in the liver.(30) Furthermore, nutritional factors and dysfunctional HDL lipoproteins,(31) found in cord blood of infants of GDM mothers,(15) may induce an abnormal hepatic lipase activation also increasing IDL half-life. This scenario is similar to the dyslipidemia associated with diabetes and insulin-resistant states, where an increased generation of IDL, small and dense LDL particles, and triglyceride-enriched HDL particles is observed,(30) and which has been related to an increased atherogenic risk. These findings lead us to hypothesize that postnatal insulin resistance, which has been described in offspring of GDM women, may be programmed in utero and would be present even in AGA neonates, suggesting that a good glycemic control during pregnancy is not enough to prevent long term complications, as has been previously reported.(32, 33)
When analysing the lipoprotein profile according to birth-weight categories (Table 4), most of the differences observed in the whole group were replicated both, in GDM and controls separately (Tables 5 and 6). These findings may support an effect of fetal growth accretion instead of the glucose status. In this context, it must be remarked that the evidence of cord blood lipoprotein as biomarkers of later cardiovascular disease as it happens in adult life, is scarce. However, we tend to extrapolate what we observe in adult life to fetal life, despite it may have different interpretation. In fact, differences in lipoprotein composition between adults and fetuses has been described (excess apoE is found on fetal HDL particles which are large in size with absence of paroxonase I(34, 35), suggesting that these particles do not have anti-oxidant capacity; small LDL poorer in lipids content(36), etc.), highlighting the need to better understanding of how lipid metabolism in utero relates to lipid metabolism in adults and in turn, how these metabolic changes in fetus impacts on adult cardiovascular health.
Previous studies exploring the potential relationship between prenatal lipid metabolism and adverse metabolic outcomes in offspring have generated inconsistent results.(37–42) Following other reports,(43, 44) we confirm that GDM, pre-pregnancy BMI, and GWG during pregnancy are all associated with offspring obesity in early life. Furthermore, we found that small LDL-P in cord blood were associated with early obesity, even after controlling for confounding factors. These findings support the notion that disturbances in the lipoprotein metabolism at birth may have lasting effects independently of birth weight or maternal metabolic status.
There is evidence that an altered fetal lipoprotein profile is associated with aorta intima thickness in SGA and LGA neonates,(8, 27) indicating a potentially increased atherosclerotic risk, already at birth. We are aware that our results cannot establish a direct link between the 1H-NMR-assessed lipoprotein profile, observed in GDM-AGA newborns, with an increased atherogenic risk but, however, it offers new clues to understand the high metabolic and cardiovascular risk in the offspring of GDM pregnant women.(45) Long-term studies are guaranteed to confirm whether cord blood 1H-NMR-based lipoprotein profiling can be implemented as a useful biomarker of later metabolic diseases beyond two years of age.
One of the main limitations in observational studies is the inability to attribute causation between the observed associations. However, we have considered many confounding variables to mitigate bias in the analysis. Thus, the main prenatal factors were addressed, and the groups were comparable for maternal BMI and birth-weight categories. Otherwise, to reach a sufficient sample size in the three birth-weight categories, the SGA and LGA groups were overrepresented, and further population-based studies are needed to determine the role of lipoprotein composition and subfractions in the pathogenesis of metabolic diseases in offspring.
The strengths of this study include a longitudinal birth cohort with almost complete maternal data that establish a temporal relationship between the outcome and the exposure to GDM. The novelty of the lipoprotein assessment, which allows us to identify different fetal metabolic behaviors, is also a big asset in the experimental methods.