Maternal pre-pregnancy body mass index and newborn telomere length
Persons of the same age vary greatly with regards to telomere length and this variation is present from early life. The key finding of our paper is that pre-pregnancy BMI is associated with shorter newborn cord blood and placental telomeres. These associations remained unchanged after adjustments for paternal and maternal age at birth, maternal education, and newborn gender, birth weight, and gestational age. Our findings shed light on the pre-pregnancy effects of maternal BMI on the next generation. Indeed, our data showed that, for each BMI unit increase, average relative cord blood and placental telomeres were 0.50 % and 0.66 % shorter, respectively. The telomere loss in newborns of obese mothers may increase the risk for chronic diseases in adulthood. As we used a real-time PCR method we are not able to provide absolute values of telomere lengths to estimate the effects of our decline based on absolute values as measured, for instance, using terminal restriction fragments. Nevertheless, an estimation can be based on available data from mean umbilical cord blood telomere lengths (measured using TRF), leading to an estimated value of approximately 10 kb [20, 21, 52, 53], indicating a decrease of 0.50 % leads to a loss of approximately 50 bp in cord blood telomere length for each maternal BMI point increase. Based on longitudinal studies, an annual loss between 32.2 and 45.5 bp is estimated in adult leukocytes [54], indicating that each maternal pre-pregnancy BMI point increase is equivalent to a loss of 1.1 to 1.6 telomeric year equivalence in adulthood (based on telomere attrition of 32.2–45.5 bp/year). This illustrates the public health significance of our findings, as newborns from obese mothers compared with newborns from normal weight mothers were biologically approximately 12 to 17 years older, based on telomeric year equivalence in adulthood.
Longitudinal studies have shown that telomere attrition is greatest during early life. Experimental studies in zebra finches show that telomere length in early life is predictive of longevity [55]. Therefore, our results of maternal BMI on newborn telomere length comprise an important public health finding.
Epidemiologic and animal studies indicate associations between pre-pregnancy maternal obesity and cardiovascular diseases and metabolic disorders in the offspring [45, 46]. Maternal obesity during the first trimester of pregnancy has been associated with a relative risk of childhood obesity of 2.3 (95 % CI, 2.0–2.6) at the age of 4 years [43]. A suggested mechanism that could underlie these relationships is in utero fetal programming by nutritional stimuli [38]. Fetuses have to adapt to the supply of nutrients crossing the placenta, which may permanently change their physiology and metabolism.
Our findings in newborns support the association between BMI and telomere length in adulthood. Meta-analytical evidence suggests that leukocyte telomere length is inversely associated with BMI in adulthood [33]. In adult women, Valdes et al. [56] reported on the average 240 bp shorter telomeres in obese women BMI??30 compared with lean women which corresponds to a age difference of 8.8 years. The role of the enzyme telomerase in the association between increased BMI and shortened telomeres is less well understood. Epel et al. [57] described low telomerase activity with increased BMI in 62 adult healthy women, which may be an important factor for the observed shortened telomeres in relation with body weight. Whether altered telomerase activity in mothers due to increased BMI also indicates altered neonatal telomerase activity remains unclear and might be an interesting topic of research. Obesity increases systemic inflammation and generation of reactive oxygen species (ROS) in fat cells [58–60]. These high levels of ROS resulting in higher oxidative stress might explain accelerated shortening of telomeres in addition to cellular replication [61, 62]. As telomeres contain G-rich fragments that are highly sensitive to ROS, these higher levels of oxidative stress can lead to breakage of DNA and a more rapid decline in telomere length [63]. Higher maternal oxidative stress and inflammation status due to increased obesity might generate a higher inflammatory and oxidative stress intrauterine environment for the developing fetus, influencing telomere biology during the in utero life. Recent studies indeed showed that maternal obesity leads to increased oxidative stress in both mothers and newborns. Higher states of oxidative stress were observed in maternal plasma as well as in newborn plasma and placental tissue of obese mothers compared with normal weight mothers [64]. Increased levels of malondialdehyde, superoxide anion, and nitric oxide levels were observed in newborns of obese mothers [64, 65]. These higher levels of oxidative stress have been proposed to induce metabolic alterations that may act as mechanisms in fetal programming [66] and this may provide a link between maternal obesity and shortened telomere lengths in newborns.
In the ENVIRONAGE birth cohort, we observed (in unadjusted analysis), besides an association with pre-pregnancy BMI, longer cord blood and placental telomeres in female newborns compared to male newborns, that telomeres tended to be longer with increased paternal age, and that cord blood telomeres were longer in association with higher maternal education, all of which are in accordance to recent studies [28, 29, 67]. A strength of our study is the large sample size of newborns with matching cord blood and placental tissue, to study telomere length associations. We found consistent results of shorter telomere length in both newborn cord blood and placenta in association with pre-pregnancy BMI. Further, our findings are generalizable as our study population is representative for the gestational segment of the population at large (Additional file 1: Table S1). Our associations remained unchanged after adjustments for different covariates and potential cofounders and persisted across subgroups or after excluding non-European newborns, mothers with pre-pregnancy BMI less than 18.5 kg/m2, cesarean sections, and pregnancy complications, further suggesting an independent association. We need to address some limitations of this study. We do not have information on paternal BMI and recent epigenetic effects of paternal weight on newborns have been described [68, 69]. We used a real-time PCR method to determine telomere lengths, which has, in general, higher assay variability compared to the traditionally used TRF method [70, 71]. However, we participated in an inter-laboratory comparison and achieved coefficients of variation of less than 7 %. Further, we acknowledge the fact that variability within the placenta exists, and for our study the intra-placental variability for telomeres was 11 %. Recently, Factor-Litvak et al. [67] showed a strong correlation between newborn telomere length measured in cord blood and both age-adjusted paternal and maternal telomere lengths. As overweight mothers may potentially have shorter telomeres, the association between pre-pregnancy BMI and newborn telomere length might be mediated by maternal telomere lengths. This mediation could not be addressed in the ENVIRONAGE birth cohort at this moment as no data on maternal telomere lengths was available. Finally, we need to acknowledge that other potential important factors that occur during pregnancy, such as newborn telomerase activity and alteration of oxidative stress-related markers in mothers and newborns, and which might influence telomere length at birth, were not measured.