Association of cord blood betatrophin with birth weight and fetal insulin sensitivity in term newborns

To the Editor: The developmental origins of health and disease theory underscores the profound influence of early-life exposures on long-term health trajectories. Substantial evidence has established links between intrauterine growth restriction and subsequent metabolic disorders,[1] in later life. Previous studies have revealed low birth weight as an independent risk factor for cardiomentabolic diseases.[2,3] During fetal development, adipokines are secreted by fetal adipocytes and the human placenta. Betatrophin, primarily produced by adipose tissue and the liver, plays an important role in glucose homeostasis and lipid metabolism. In pregnancy, maternal betatrophin levels increase and appear to be modulated by nutritional status.[4] However, the relationship between umbilical cord blood betatrophin levels and birth weight variations in term newborns remains poorly characterized. Therefore, this study aimed to investigate cord blood betatrophin levels in neonates with variable birth weights and to analyze their associations with neonatal anthropometric measures and fetal insulin sensitivity at birth. In this study, 188 mother–infant pairs with full-term pregnancies were consecutively recruited from the Department of Gynecology and Obstetrics at Peking Union Medical College Hospital. Written informed consent was obtained from all participating women for themselves and their newborns. The study protocal was approved by the Ethics Committee of the Institutional Review Board at Peking Union Medical College Hospital (No. S-002). Newborns were classified into three groups according to birth weight: normal birth weight (NBW, n = 102), defined as birth weight ≥3000 g and <4000 g; lower birth weight (low BW, n = 58), defined as birth weight <3000 g; and high birth weight (HBW, n = 28), defined as birth weight ≥4000 g. The cut-off value for Low BW was set at 3000 g based on our previous finding that birth weight of <3000 g is an independent risk factor of impaired glucose regulation and diabetes mellitus later in life.[3] Two trained research nurses and assistants collected umbilical cord blood samples and relavant clinical data. Maternal variables included age, pre-pregnancy weight, pre-pregnancy body mass index (BMI), gestational weight gain, and gestational BMI increment. Neonatal variables included sex, gestational age, head circumference, body length, placental weight, birth weight, and ponderal index. Data were presented as mean ± standard deviation for continuous variables and n for frequency variables. Skewed distributions were natural logarithmically transformed for analysis. Analysis of variance (ANOVA) followed by multiple comparison tests was used to assess differences in continuous variables across groups. Pearson correlation analysis was used to assess associations between continuous variables. Linear regression analyses were performed with adjustments to explore relationships between umbilical cord blood hormones and fetal insulin sensitivity. Binary logistic regression models estimated odds ratios (ORs) for birth weight. P value <0.05 was considered statistically significant. All analyses were performed with SPSS 20.0 (SPSS, Inc., Chicago, IL, USA). The birth weights of NBW, low BW, and HBW groups were 3429.79 ± 239.13 g, 2787.76 ± 208.03 g, and 4267.32 ± 215.64 g, respectively. Compared with mothers of newborns in the NBW group, those in the low BW group had significantly lower pre-pregnancy weight (54.05 ± 7.71 kg vs. 56.67 ± 7.99 kg, P <0.05). In contrast, mothers of newborns in the HBW group exhibited higher pre-pregnancy weight (61.43 ± 7.24 kg vs. 56.67 ± 7.99 kg, P <0.05) and BMI (23.28 ± 2.49 kg vs. 21.38 ± 2.79 kg/m2, P <0.05), along with greater gestational weight gain (19.58 ± 4.60 kg vs. 16.28 ± 4.39 kg, P <0.05) and gestational BMI increment (6.87 ± 2.59 kg vs. 6.13 ± 1.61 kg/m2, P <0.05). Newborns in the low BW group had significantly lower head circumference (32.90 ± 1.15 kg vs. 34.58 ± 1.01 cm, P <0.01), body length (47.84 ± 2.23 kg vs. 49.81 ± 1.26 cm, P <0.001), placental weight (545.30 ± 83.66 kg vs. 667.39 ± 109.53 g, P <0.001), and ponderal index (25.71 ± 2.65 kg vs. 27.77 ± 1.93 kg/m3, P <0.001), while those in the HBW group showed significantly greater body length (51.89 ± 1.39 kg vs. 49.81 ± 1.26 cm, P <0.001), placental weight (843.15 ± 139.22 kg vs. 667.39 ± 109.53 g, P <0.001), and ponderal index (30.53 ± 2.46 kg vs. 27.77 ± 1.93 kg/m3, P <0.001). Umbilical cord blood levels of glucose, insulin, insulin-like growth factor 1 (IGF-1), leptin, and betatrophin were measured in duplicate in a blinded manner. The glucose-to-insulin ratio in cord blood was employed as the primary indicator of fetal insulin sensitivity. Both cord blood insulin and IGF-1 levels were lower in the low BW group (both P <0.001) and higher in the HBW group (P <0.001 for IGF-1 and P <0.05 for insulin). Leptin, a well-characterized adipokine, was significantly reduced in the low BW group (6.82 ± 4.76 ng/mL vs. 9.33 ± 5.30 ng/mL, P <0.001) and elevated in the HBW group (15.18 ± 7.40 ng/mL vs. 9.33 ± 5.30 ng/mL, P <0.001). Notably, betatrophin, a nutritionally regulated adipokine abundant in cord blood, was significantly higher in newborns with a birth weight <3000 g (1147.57 ± 1019.03 pg/mL vs. 764.72 ± 468.80 pg/mL, P <0.05), though no significant difference was observed between the HBW group and controls (P >0.05). The glucose-to-insulin ratio, reflecting fetal insulin sensitivity, was increased in the low BW group (8.92 ± 6.11 vs. 6.98 ± 3.27, P <0.05) but decreased in the HBW group (3.37 ± 2.77 vs. 6.98 ± 3.27, P <0.05) , suggesting enhanced insulin sensitivity in low BW newborns and reduced sensitivity in those with HBW. Pearson correlation analysis indicated that umbilical cord blood insulin levels were positively correlated with neonatal body length (r = 0.203, P <0.01), placental weight (r = 0.254, P <0.001), birth weight (r = 0.301, P <0.001), and the ponderal index (r = 0.177, P <0.01). Similarly, umbilical cord blood leptin levels showed positive associations with maternal gestational BMI gain (r = 0.213, P <0.01), as well as with several anthropometric parameters of term newborns: gestational age (r = 0.217, P <0.001), head circumference (r = 0.163, P <0.001), body length (r = 0.300, P <0.001), placental weight (r = 0.293, P <0.001), birth weight (r = 0.413, P <0.001), and ponderal index (r = 0.246, P <0.001). In contrast, betatrophin levels exhibited no significant correlation with clinical characteristics of either mothers or newborns (all P >0.05). Additionally, umbilical cord blood insulin levels were positively correlated with both IGF-1 (r = 0.269, P <0.001) and leptin levels (r = 0.270, P <0.001), and leptin levels were also positively correlated with IGF-1 (r = 0.244, P <0.001). No significant correlations were observed between cord blood betatrophin and other parameters measured in umbilical cord blood (all P >0.05). Furthermore, cord blood insulin (r = –0.864, P <0.001) and leptin (r = −0.321, P <0.001) concentrations were negatively correlated with the glucose-to-insulin ratio. To further explore the relationship between umbilical cord blood leptin levels and fetal insulin sensitivity, linear regression analyses were conducted with adjustments for pre-pregnancy BMI, gestational BMI increase, birth weight, and the natural log-transformed (ln) values of IGF-1, leptin, and betatrophin concentrations. The results showed that umbilical cord blood leptin level (β = −1.585; P <0.05) was an independent predictor of fetal insulin sensitivity, as assessed by the glucose-to-insulin ratio. Given that cord blood betatrophin levels were significantly elevated in term newborns with low BW, binary logistic regression analysis was further performed in term newborns with birth weight <3000 g and controls. The analysis revealed that each unit increase in ln–betatrophin was associated with a twofold higher risk of low BW (odds ratio: 2.123; 95% confidence interval: 1.045–4.310). These findings suggest that umbilical cord blood betatrophin levels is independently associated with the risk of low BW. Thus, in this cross-sectional study of 188 mother–infant, we demonstrated that elevated cord blood betatrophin levels are associated with lower birth weight in term newborns. Furthermore, we identified distinct roles for cord blood adipokine, leptin, but not betatrophin, was positively correlated with maternal gestational weight gain and key neonatal growth parameters. Notably, leptin levels were also inversely associated with fetal insulin sensitivity, as indicated by the glucose-to-insulin ratio. These findings provide new insights into the relationships between cord blood parameters, birth outcomes, and fetal metabolic regulation in term newborns. [Supplementary Figure 1, https://links.lww.com/CM9/C725] The level of leptin, a well-established adipokine in umbilical cord blood, was positively correlated with maternal gestational weight gain and neonatal growth parameters, which is consistent with the findings of previous studies.[5] Our study revealed significantly elevated cord blood betatrophin levels in term newborns with low BW. In addition, our study further demonstrated that cord blood leptin levels are negatively correlated with fetal insulin sensitivity. The negative association between levels of cord blood leptin and fetal insulin sensitivity may be partly explained by the amount of adipose tissue in newborns. However, no correlation was found between cord blood betatrophin levels and fetal insulin sensitivity. Similarly, Pérez-López et al[6] reported there was no difference in cord blood betatrophin between gestational diabetes mellitus and controls. This study explored the relationships between umbilical cord blood betatrophin levels and anthropometric parameters in term neonates with variable birth weights. However, several limitations still exist, including the small sample size. In addition, this was a cross-sectional study, which does not allow inference of causality between umbilical cord blood betatrophin levels and poor long-term outcomes because of the lack of long-term follow-up. Moreover, the molecular mechanisms underlying the effects of umbilical cord blood betatrophin concentration on low BW require further investigation. Nevertheless, our present study is novel because it provides an important basis for further studies on umbilical cord blood betatrophin in term newborns with low BW. In conclusion, our study demonstrated that umbilical cord blood leptin and betatrophin are significantly associated with anthropometric parameters and fetal insulin sensitivity in term neonates. However, high-quality, large-scale clinical studies and further preclinical experiments are urgently needed to clarify the underlying mechanisms involved. Funding This work was supported by the grants from National Natural Science Foundation of China (Nos. 82170854, 81870579, 81870545, 81570715, and 82571043), Noncommunicable Chronic Diseases-National Science and Technology Major Project (Nos. 2024ZD0530200 and 2024ZD0530204), Beijing Nova Program (Nos. Z201100006820117 and 20220484181), Beijing Natural Science Foundation (Nos. 7202163, 7202163, and 7214258), Beijing Municipal Science and Technology Commission (No. Z201100005520011), National High Level Hospital Clinical Research Funding (Nos. 2022-PUMCH-C-019 and 2022-PUMCH-B-121), Peking University Clinical Scientist Training Program (No. BMU2023PYJH022), National Key Research and Development Program of China (No. 2018YFC2001100), and CAMS Innovation Fund for Medical Sciences (Nos. CIFMS2021-1-I2M-002 and CIFMS2017-I2M-1-008). Conflicts of interest None.