Introduction
Human telomeres are nucleoprotein structures consisting of the repeating nucleotide sequence 5'-TTAGGG-3', along with protein complexes, that interact with the DNA. They are located at the end of eucaryotic chromosomes, and their main role is to maintain the stability of chromosomes and their protection from degradation throughout enzymatic decay (1). Telomeres have been found to be at their maximum length after birth and as cells divide over time, they gradually get shorter due to incomplete synthesis of DNA. After 40-60 cell divisions, they reach a critically short length known as Hayflick's limit, that triggers cellular senescence and apoptosis (2,3). To avoid the shortening of telomeres, human somatic cells produce the enzyme telomerase, which adds nucleotides at the 3' end of the telomeres, and thus the telomeres can maintain their length. This enzyme is active in numerous somatic tissues during fetal and early neonatal development, but its activity gradually decreases with age, resulting in inactivation in the somatic cells of adults (4).
Telomere length (TL) is a biomarker of cellular aging and genomic stability, and is influenced by genetic, environmental, and physiological factors. TL is known to be partially inherited and may reflect maternal health and stress exposures. Preterm birth has been associated with adverse intrauterine environments, including inflammation, oxidative stress, and maternal metabolic conditions, all of which may affect telomere dynamics (4). Investigating the correlation of TL between mothers and their neonates, especially comparing full-term and preterm births, may provide insight into how maternal health and gestational age influence early-life biological aging.
TL can differ significantly among individuals of the same age, and this variability is noticeable from birth. During in utero development, the fetus undergoes crucial phases of cellular growth, differentiation, and maturation, that cause modifications in telomere dynamics (5). These alterations can have far-reaching consequences for an individual's health and susceptibility to diseases throughout their life (6). Emerging research suggests that TL in neonates can also impact the development of age-related diseases. Shorter telomeres have been associated with increased risks of cardiovascular diseases, cancer, neurodegenerative disorders, and other chronic conditions (7-10). Therefore, it is highly probable that the TL of an individual as they age is significantly shaped by their TL at birth and the subsequent attrition of telomeres during early life (11).
The typical duration of a human pregnancy is usually between 37 to 42 gestational weeks, during which the developing fetus undergoes cell differentiation and organ maturation, essential for successful survival outside the womb. In this case, the TL that neonates are born with has been estimated to be 9 to 12,5 kilobases (12). When the gestation period is disrupted and childbirth occurs before 37 weeks, childbirth is characterized as premature (13). Preterm birth is a multifactorial phenomenon that, according to the WHO, ranged from 4 to 16% across countries in 2020 (https://www.who.int/news-room/fact-sheets/detail/preterm-birth). It is more prevalent among male infants, with ~55% of preterm births occurring in boys (14), and mortality rates are also higher among premature boys compared with premature girls (15). Multiple pregnancies, obesity, gestational diabetes mellitus (GDM), alcohol use during pregnancy, and smoking are main maternal factors that appear to affect preterm birth, and studies have indicated that these factors can also affect embryonic TL throughout pregnancy (16-20). Previous research has revealed that higher maternal pre-pregnancy body mass index (BMI) is associated with shorter in both mothers and their infants, indicating increased oxidative stress and accelerated cellular aging (11).
The purpose of the present study was to investigate the correlation between neonatal TL and that of their mothers, and to examine potential differences between preterm and full-term neonates. Additionally, associations between maternal characteristics, medical history, and pregnancy-related events with neonatal TL was assessed.
Discussion
The present study highlighted a weak to moderate, positive and statistically significant correlation between maternal and neonatal TL, irrespective of full-term or preterm pregnancy. Some maternal features, particularly BMI before pregnancy, appeared to be the determinant factor in maternal TL. Additionally, grouping cases into preterm or full-term neonates influenced some of the findings; however, no statistically significant associations were observed between neonatal TL and maternal characteristics, medical history, and pregnancy details (Fig. 2).
The mean maternal TL in the present study fell within the reference range of 7 to 9 kilobases for women in their 30s (22), consistent with the mean maternal age in our sample. For neonates, the TL was predicted to fall within 8 to 11 kilobases (22). Most of the neonates examined were preterm and the slightly higher mean TL, supports a previous observation that preterm neonates tend to have longer telomeres than those born at term (23).
A study involving 319 mother-newborn pairs found a significant positive association between maternal and newborn TLs (β=0.31; P#x003C;0.001), indicating that maternal TL is a predictor of neonatal TL (24). Research has shown that preterm infants have significantly longer telomeres than their term-born counterparts. Specifically, TL was negatively correlated with gestational age and birth weight in preterm infants (25). In a cohort of African American women, shorter maternal peripheral blood TL was associated with an increased risk of preterm birth. Notably, for every 10-unit decrease in the telomere-to-single-copy gene (T/S) ratio, the odds of preterm birth increased by a factor of 2.664(26).
Previous studies did not directly correlate maternal BMI with the TL of neonates, in contrast to most previous studies (11,27). Indeed, prior research has identified a negative correlation between maternal BMI and neonatal TL (11). At the molecular level, elevated maternal BMI may promote oxidative stress and inflammation in the fetal environment, which could contribute to telomere shortening during prenatal development (28-30). Additionally, neonatal telomere shortening was more likely to occur in infants born to mothers with higher anxiety scores, elevated fasting blood glucose levels, lower levels of plasma insulin-like growth factor-binding protein 3 (IGFBP-3) and vitamin B12, and who actively smoke status pregnancy (27). However, there are studies which support that a high maternal pre-pregnancy BMI is associated with shorter maternal TL and TL in infants, indicating increased oxidative stress and accelerated cellular aging (31,32).
The lack of association between maternal BMI and neonatal TL contrasts with previous studies (11,27), potentially due to the BMI distribution in this cohort, which consisted primarily of normal-weight participants. Additionally, the variability in qPCR protocols, along with factors such as maternal stress, smoking, or nutrition, which can modulate TL independently of BMI, may confound results. Furthermore, limited statistical power and sample size may lack the statistical power to detect subtle associations (33,34).
Pre-pregnancy maternal BMI was not correlated with neonatal TL as expected but has been found to be related to preterm birth, and the present study aligns with this indication (P=0.017) (Fig. 1). Preterm deliveries resulting from premature labor with cervical dilation or early rupture of membranes are categorized as ‘spontaneous’, while those that are induced or carried out via cesarean section, due to maternal or fetal health concerns, are termed ‘indicated’ preterm births. In the present study, the type of preterm delivery was not provided. Most mothers who participated were categorized as οverweight (BMI between 25 and 30; mean BMI, 26) prior to pregnancy, which could also justify why a significant correlation with neonatal TL was not observed. However, the sample did include individuals from both the underweight and overweight categories, with BMIs ranging from 18.1 to 45.6. Previous studies have found that maternal overweight is more commonly associated with medically indicated preterm births, whereas maternal underweight tends to slightly increase the risk of spontaneous preterm labor (35). The exact mechanisms by which abnormal maternal BMI affects neonatal TL are not fully understood, although these effects may be linked to chronic inflammation and oxidative stress during fetal development (30). Moving forward, this research is planned to be expanded by categorizing participants into different BMI groups. Through this approach, further exploration into how maternal BMI may influence preterm deliveries is expected to be conducted, possibly revealing novel insights into its effects on fetal genotypic outcomes.
When mothers were examined separately, a moderate negative correlation between pre-pregnancy maternal BMI and maternal TL was observed (P=0.037). Previous research has examined the correlation between maternal BMI and TL. For instance, adult women with a BMI exceeding 30 kg/m2, had telomeres that were on average, 240 base pairs shorter compared with women with a BMI below 20 kg/m2, and this difference was equivalent to an aging effect of ~8.8 years (36).
Finally, no evidence of a the relationship between maternal pregnancy complications and neonatal TL was revealed in the present study. This finding appears to be consistent with recent data showing that maternal stress does not exert a significant effect on infant TL of infants as determined by qPCR analysis (37). Currently, the results of the present study appear to contradict previous findings supporting that maternal pregnancy complications can contribute to neonatal telomere shortening (5,24,38-40). The discrepancies among studies can be attributed to the small sample size in previous studies. Indeed, numerous detrimental variables (such as oxidative stress, inflammation, and other genetic/epigenetic, immunological, physiological, lifestyle, and environmental factors, including nutrition) have been shown to result in an advanced aging trajectory and exacerbate placental dysfunction, given that TL reflects the cumulative impact of stressors (41,42). In addition, several pregnancy complications, such as GDM, intrauterine growth restriction, hypertensive disorders and preeclampsia, have been demonstrated to be associated with prematurity and neonatal telomere alterations while still in utero (43,44). In the majority of studies, GDM has been associated with reduced neonatal telomeres (45-49), although some other studies have found similar TLs (43,44,50) or even longer ones in newborns compared with those from mothers without GDM (51). Cardiovascular conditions such as hypertension and preeclampsia have also been associated with shorter telomeres in previous research, although the mechanisms remain unclear (52). The small sample size in the present study limited the ability to assess how pregnancy complications and lifestyle factors (such as alcohol consumption and smoking) affect neonatal TL, and future studies with larger participant pools are required to address these gaps.
Even though a correlation between maternal and neonatal TL was identified in the present study, it has several limitations. Initially, qPCR was used to evaluate relatively average TL, although this technique has been considered more variable than the classically used terminal restriction fragment analysis (53,54). Secondly, evaluating TL in neonates represents only a snapshot of aging at birth, as limited data are available on TL in embryos during pregnancy and childhood.
Indeed, the qPCR method was used to assess maternal and neonatal TL, as only 200 µl of neonatal blood, obtained from the complete blood count, was available for analysis. The collected blood from preterm or full-term neonates was of invaluable and utmost importance since neonate samples are unique, especially that of preterm neonates. It is worth noting that the acquisition of increased blood amounts can result in the reduction of neonatal hematocrit (55). However, the present study did not detect TL differences across chromosomes at a single-cell level, which can be accomplished through metaphase Q-FISH (56,57). The Q-FISH technique can provide an overall analysis of TL distributions, providing measurements for extremely short or extremely long telomeres at the chromosome level (57). Despite this limitation, the present study provides unique insight into the average TL of maternal and full-term or preterm neonates. A limitation was also noted due to the small sample size, which affects the statistical power of sample. However, numerous studies have confirmed the reproducibility of the qPCR method in neonatal samples (58-60).
Another challenge of the study was the limited sample size. In most cases, there was also an insufficient number of participants diagnosed with some of the examined disorders within the timeframe of sample collection. Due to the shortcoming of the sample size, a general overview of neonatal TL in relation to maternal characteristics could not be provided. Therefore, future studies with a more substantial and diverse participant pool are encouraged to validate and strengthen the conclusions derived from the present research.
In conclusion, the present study revealed a weak to moderate, positive and statistically significant correlation between maternal and neonatal TL, regardless of pregnancy duration. No significant differences were observed between maternal TL and maternal habits, medical history, or gestational history. However, maternal BMI before pregnancy appears to have a decisive impact on determining maternal TL. Future studies with a larger sample size and the inclusion of additional parameters, such as socioeconomic status, maternal stress levels, and environmental exposures, are recommended to further clarify these associations.