Betaine in Infants Born Small-for-Gestational-Age

doi:10.21203/rs.3.rs-3137452/v1

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Betaine in Infants Born Small-for-Gestational-Age

https://doi.org/10.21203/rs.3.rs-3137452/v1

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Aim

Betaine can promote methylation as a methyl donor and play an important role in the regulation of lipid metabolism, and may affect infant birth weight. The aim of this study is to assess whether betaine is associated with poor fetal growth.

Methods

A total of 141 mother–infant pairs were enrolled in the study. According to gestational age and birth weight, the mother–infant pairs were divided into small-for-gestational-age and appropriate-for-gestational-age group. Cord plasma concentrations of betaine and lipid (triglyceride, low density lipoprotein, high density lipoprotein and total cholesterol) were measured.

Results

Cord plasma betaine concentrations were higher in small-for-gestational-age (4.37 ± 0.98l ng/ml, P = 0.016) relative to appropriate-for-gestational-age (3.98 ± 0.86 ng/ml) newborns, and were not correlated to lipid levels (all P > 0.2). Adjusting for maternal and neonatal characteristics, birth weight (β = -70.32, p = 0.016) and birth length (β = -0.298, p = 0.029) were negatively correlated with the levels of betaine. Higher betaine concentrations were associated with increased risks of small-for-gestational-age (OR = 1.798, P = 0.008).

Conclusions

This study demonstrate that elevated concentration of betaine in cord blood is associated with higher risk of small-for-gestational-age and this association is independent of lipid levels. The dysregulation of betaine in infants may be a risk factor for fetal growth.

betaine

small-for-gestational-age

umbilical cord blood

birth weight.

Birth weight is of importance due to its relation to fetal health, and it’s also a predictor of the subsequent development of the child. Small-for-gestational-age is usually defined as a birth weight below the 10th percentile for gestational age and sex-specific^[1]. Previous studies have identified small-for-gestational-age as risk factors for features of developing metabolic disease later in life, including obesity, insulin resistance, glucose intolerance, cardiovascular disease, and dyslipidemia^[2-4]^. Recent meta-analysis revealed that compared with children or adolescents born appropriate-for-gestational-age, those born small-for-gestational-age had 2.33-fold higher risk of type 2 diabetes mellitus (95% confidence interval [CI]: 1.05–5.17)^[5]. Given the early life is a critical window to prevent the metabolic diseases, it is important of reveal possible risk factors for small-for-gestational-age.

Betaine, known as trimethylglycine, can promote methylation as a methyl donor and has been proven to play a role in improving lipid metabolism disorders^[6]. Betaine alleviated the high fat diet induced disruption of hepatic lipid and iron homeostasis in mice^[7]. Betaine supplementation reversed the reduction in expression of proteins related to lipid metabolism in mice induced by a high-fat diet^[8], and enhanced lipid metabolism and improve insulin resistance^[9]. Human studies demonstrated that a higher level of serum betaine was associated with significant lower body fat and inversely associated with low lean mass mainly in men^{[10, 11]}.

Both insulin resistance and lipid metabolism are relevant for fetal growth, suggesting that betaine may be implicated in abnormal fetal growth. Animal experiments reported maternal betaine supplementation affected fetal growth and lipid metabolism in high-fat fed mice^{[12, 13]}. In humans, the evidence of an association of maternal prenatal betaine concentrations with offspring anthropometric measures at birth is limited and conflicting. Moreover, data are scarce concerning whether cord blood betaine is associated with fetal growth. The aim of the present study was to evaluate whether cord blood betaine concentration is associated with poor fetal growth.

2.1Study Population and Data collection

141 pairs of mother–infant were recruited from the department of obstetrics of our hospital between June 2021 and December 2021. According to gestational age (GA) and birth weight, 62 small-for-gestational-age (SGA, <10th percentile) and 79 appropriate-for-gestational-age (AGA, between 10 and 90th percentile) were selected as the study subjects. Inclusion criteria were singleton pregnancy, live, term birth (37–42 weeks), aged 18–42 years, no self-reported smoking and drinking history. Women with pregnancy complications, such as gestational hypertension, preeclampsia, asthma, cancer, or psychiatric illness were excluded. Informed written consent was obtained. This study was approved by the Ethics Committee in our hospital.

Data was collected from the hospital’s electronic information system, including socio-demographic information, maternal pre-pregnancy Body Mass Index (BMI), gestational weight gain, delivery and neonatal outcomes (including GA, newborn gender). Measurements of infant BW and birth length were obtained immediately after birth. Birth weights were categorized into SGA (< 10th percentile) and AGA (10-90th percentile) for the same gestational age by sex according to the Chinese neonatal birth weight curve^[14]. Neonatal umbilical cord blood was collected at delivery. Samples were immediately delivered to the hospital laboratory and centrifuged, frozen at −80°C until assays.

2.2 Cord blood betaine measurement

The betaine concentration in serum was measured by high-performance liquid chromatography tandem-mass spectrometry (HPLCMS/MS) using a Waters UPLC Xevo TQS (Waters Corporation, Milford, MA, USA). Briefly, the samples were thawed at room temperature for 30 min. First, QCs, standards, and plasma samples (5μl) were added into the micro-centrifuge tube. Precipitant with isotopic IS in a 12:1 (v/v) mixture of acetonitrile: water (180μl) was added to the tube to precipitate protein. Then the tube was resealed, mixed vigorously and centrifuged at 19000g for 5 min at 4℃. Finally, the supernatant (100μl) was extracted into a 96-wells plate for HPLCMS/MS analysis. The betaine in serum was separated by HPLC on a Shimadzu Waters BEH C18μm 1.7 2.1*50mm column and quantitated by MS. All procedures were performed in a dark room to protect the samples from light.

2.3 Biochemical Assays

Plasma levels of triglyceride(TG), low density lipoprotein(LDL), high density lipoprotein(HDL) and total cholesterol(TC) were determined using commercially available assays on an automatic biochemical analyzer (BS-240 VET, Mindray Medical, Shenzhen, China) using reagent from Mindray Medical company and was analyzed according to the manufacturer procedure.

2.4 Statistical Analysis

All analyses were performed using SPSS version 25.0. Data are presented as mean ± standard deviation (SD) for continuous variables, medians and interquartile range for skewed distributions, and counts (percentages) for categorical variables. Comparisons of the demographic characteristics, clinical features, and laboratory results among subjects in the SGA and AGA group and were performed using independent samples t-tests. Pearson partial correlation coefficients were calculated to evaluate the associations of cord blood betaine with lipid levels adjusted for confounders. Multivariate linear regression models were used to estimate the association of cord blood betaine concentrations and lipid levels with birth weight and birth length. Multinomial logistic regression models were fitted to assess the associations of cord blood betaine and lipid levels with SGA adjusted for maternal and neonatal characteristics. The confounders considered were maternal age, pre-pregnancy BMI (in kilograms per square meter), mode of delivery, GA, and sex of the infants. A p-value <0.05 was considered statistically significant.

3.1 Baseline Characteristics of the Mother–Infant Pairs

Table1 shows baseline characteristics for SGA and AGA. A total of 141 mother–infant pairs were enrolled in this study, including 62 in the SGA group and 79 in the AGA group. Statistically significant differences were found in maternal age, delivery mode, birth weight and birth length between the two groups. No significant differences were observed for gender, gestational age, pre-pregnancy maternal body mass index and weight gain during pregnancy. Women with SGA babies were more likely to deliver spontaneously, and have smaller age than AGA groups.

3.2 Comparisons of betaine and lipid levels in the two Groups

Statistically significant differences were found in the cord blood concentrations of betaine and TG between the two groups; however, no significant differences were observed in LDL, HDL and TC. The concentrations of betaine and TG in the SGA group were significantly higher than those in the AGA group. (Table 2).

3.3 Partial correlations between betaine and lipid levels

The partial correlation coefficients between lipid levels and the cord blood concentrations of betaine are shown in Table 3. After adjusting for GA, sex, mother’s age, delivery mode, pre-pregnancy BMI, and weight gain during pregnancy, cord blood betaine was not correlated with LDL, HDL, TC and TG (all P > 0.2, Table 3).

3.4 Associations of cord blood biomarker concentrations with birth weight and birth length

The association of cord blood betaine concentrations and lipid levels with birth weight and birth length are shown in Table 4. Higher cord blood betaine concentrations were associated with lower birth weight and birth length in crude model and adjusted model. Among the lipid levels, a significant inverse association was also seen for TG with birth weight in crude model and adjusted model, but TG was not associated with birth length. None of other lipid levels was associated with birth weight and length in our study.

3.5 Associations of cord blood betaine and lipid levels with the risk of SGA

Table 5 shows the association of cord blood betaine and lipid levels with SGA risk. Higher cord blood betaine concentrations were associated with a higher odds of SGA, and the elevated risk after the adjustment remained significant for SGA (OR = 1.798, P = 0.008). Among the lipid levels, without any adjustment, higher cord plasma TG concentrations were associated with increased odds of SGA (OR = 155.807, 95% CI 7.269–3339.558). Adjusted for maternal and neonatal characteristics, the OR for SGA became low statistically significant (OR = 32.682, P = 0.038). Cord plasma LDL, HDL, TC were not associated with SGA.

Our study demonstrates the association between the levels of cord blood betaine and poor fetal growth in Chinese infants. The association is independent of lipid levels, and our data also confirmed that cord blood TG concentrations are associated with fetal growth.

In this cross-sectional sample of infants, we observed elevated cord blood betaine concentrations in infants with poor fetal growth (SGA) relative to infants with optimal fetal growth (AGA) and cord blood betaine concentrations were associated with birth weight, which is consistent with the results of previous studies. A small study reported umbilical cord blood plasma betaine levels in the SGA group were higher than those in the AGA group^[15], and another study reported that cord blood plasma betaine levels were inversely associated with birth weight^[16]. This finding suggests that there might be a role of betaine in determining the birth weight and underscores the importance of betaine nutrition in fetal growth.

As birth weight is significantly correlated with maternal betaine status, SGA infants may be born from betaine deficient mothers. Clinical studies have shown that higher maternal betaine status was generally associated with smaller infant birth size^{[17, 18]} and a higher risk of being born SGA^[18], instead, some studies reported no association between betaine and birth weight^{[16, 19]}. The reasons behind these discrepancies are might be partly due to different study participants. Unfortunately, we did not measure serum betaine levels in pregnant mothers.

Interestingly, the KOALA Birth Cohort Study has shown that maternal plasma betaine was associated with higher odds of boys being overweight between ages 6 and 8 y (OR: 1.17)^[19]. We speculate that elevated betaine concentrations in infants may play a role in early life development of the vulnerability to metabolic syndrome related disorders. Moreover, studies in adults have associated elevated circulating betaine concentrations with better body composition and fat distribution^[10]. It is unclear whether the higher cord blood betaine concentrations in SGA infants are related to their increased metabolic syndrome related disorders in childhood and adults. Long-term follow-up studies are required to address this question.

We could not determine whether the elevated betaine concentration in SGA infants is a cause or consequence of poor fetal growth. In animal studies, maternal betaine supplementation affects fetal growth and lipid metabolism in high-fat fed mice^[12], lending some support in betaine’s role in the development of fetal growth. The pathways relating betaine to fetal growth are unknown. Studies have linked betaine with lipid metabolism^{[20, 21]} and altered cord blood lipid concentrations were correlate with birth weight^{[22, 23]}, therefore, we speculate that elevated betaine concentrations can lead to lipid metabolism disorders, resulting in an increased risk of SGA. However, we found no significant association between cord blood betaine serum levels with lipid levels, suggesting it may be mediated by pathways other than lipid metabolism. Some nutrients such as dimethylglycine and homocysteine have been associated with serum betaine concentrations^[24]. It remains to be explored whether these nutrients may be related to the association between betaine and SGA.

In conclusion, this study found that elevated concentration of betaine in cord blood was associated with higher risk of SGA. Therefore, it is urgent to investigate the optimal environment in pregnancy and regulate it to reduce the risk of SGA in the future. Nonetheless, more prospective studies are warranted to illustrate such associations in different population and the mechanism between betaine and infant birth weight.

AGA, appropriate for gestational age group; BMI, Body Mass Index; BW, Birth weight; CS, cesarean section; GA, gestational age; HDL, high density lipoprotein; LBW, low birth weight; LDL, low density lipoprotein; SD, standard deviation; SGA, small for gestational age; TG, triglyceride; TC, Total cholesterol.

Statements and Declarations

Funding

This study was supported by the Chongqing medical scientific research project (Joint project of Chongqing Health Commission and Science and Technology Bureau) (2021MSXM211) and Maternal and infant nutrition and health research project(2021FY012).

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Author Contributions

Guicun Yang performed the data analysis and wrote the manuscript. Yan Zhao and Guicun Yang conceived the study. Hao Liu contributed to manuscript preparation. Nianrong Wang and Lina Si helped with data analysis. All the authors contributed to the manuscript and approved the submitted version.

Ethics statement

The parents or guardians of all patients signed a written informed consent form before they were recruited. This study was approved by the ethics committee of Chongqing Health Center for Women and Children (2021053).

Acknowledgments

We wish to thank the assistance provided by members of the Department of Children Healthcare and Neonatal Screening Center of Chongqing Health Center for Women and Children. We also thank all the mothers who provided samples.

Text

Betaine in Infants Born Small-for-Gestational-Age

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Table1- Maternal and neonatal characteristics of the mother–infant pairs in SGA and AGA group.

Maternal information	SGA（n=62）	AGA（n=79）	P-value
Maternal age (years)	28.87±3.83	30.99±3.75	0.001*
>35	4(6.4%)	7(8.9%)	0.597
Prepregnancy maternal body mass index, mean ± SD	20.31±2.52	20.89±2.60	0.191
BMI group			0.113
Underweight (<18.5)	19(30.6%)	13(16.5%)
Normal weight (18.5-24.0)	36(58.1%)	58(73.4%)
Overweight (>=24)	7(11.3%)	8(10.1%)
Weight gain during pregnancy	12.18±4.17	12.59±4.28	0.569
Neonatal information
Delivery mode (SVD/CS), n (%)	47(75.8%)/15(24.2%)	33(41.8%)/46(58.2%)	<0.001***
Gestational age (weeks)	38.85±1.06	39.14±0.86	0.351
Gender (male/female), n (%)	33(53.2%)/29(46.8%)	35(44.3%)/44(55.7%)	0.293
Birth weight (g)	2670(2480,2790)	3230(2930,3430)	<0.001***
Birth length (cm)	47.4±1.64	49.44±1.34	<0.001***

Data presented are medians, mean ± SD for continuous variables, n (%) for categorical variables, and interquartile range for skewed distributions. The p-values are from independent samples t-tests for differences in means for continuous variables or chi-square tests for differences in proportions for categorical variables groups. Values in bold are significant at p < 0.05. SGA, small-for-gestational-age (birth weight <10th percentile); AGA, appropriate-for-gestational-age (10-90th percentiles); SVD, spontaneous vaginal delivery; CS, cesarean section. *p < 0.05, ***p < 0.001.

Table2-Cord blood concentrations of betaine, choline and lipid levels in SGA and AGA infants.

	SGA (62)	AGA (84)	P-value
Betaine(ng/ml)	4.37±0.98	3.98±0.86	0.016*
LDL(mmol/L)	0.59±0.16	0.57±0.19	0.520
HDL(mmol/L)	0.83±0.26	0.89±0.22	0.136
TC(mmol/L)	1.65±0.38	1.64±0.40	0.891
TG(mmol/L)	0.34±0.13	0.26±0.12	0.001***

Data presented are mean ± SD, medians and interquartile range for skewed distributions. The p-values are from independent samples t-tests for differences in means for continuous variables. Values in bold are significant at p < 0.05. SGA, small-for-gestational-age (birth weight <10th percentile); AGA, appropriate-for-gestational-age (10-90th percentiles). TC, triglyceride; LDL, low density lipoprotein; HDL, high density lipoprotein; TC, Total cholesterol. *p < 0.05, ***p < 0.001.

Table3- Pearson partial correlation coefficients of cord blood betaine and choline with lipid levels.

	betaine
	r	p-value
LDL (mmol/L)	0.042	0.628
HDL (mmol/L)	-0.050	0.567
TC (mmol/L)	-0.022	0.802
TG (mmol/L)	0.062	0.472

Partial correlation analysis was used with adjustments for maternal age, mode of delivery, gestational age, sex, pre-pregnancy BMI and weight gain during pregnancy. TC, triglyceride; LDL, low density lipoprotein; HDL, high density lipoprotein; TC, Total cholesterol. r, partial correlation coefficient; P values in bold, p < 0.05.

Table 4-Associations of cord blood biomarker concentrations with birth weight and birth length* (β-Coefficients and 95 % confidence intervals)

	Birth weight		Birth length
	β (95%CI)	P	β (95%CI)	P
Betaine (ng/ml)
Model 1	-95.03(-165.97, -24.08)	0.009	-0.421(-0.735, -0.107)	0.009
Model 2	-70.32(-127.09, -13.56)	0.016	-0.298(-0.566, -0.030)	0.029
LDL (mmol/L)
Model 1	-197.687 (-582.050, 186.676)	0.311	-0.652(-2.355, 1.051)	0.451
Model 2	35.016(-285.358, 355.390)	0.829	0.335(-1.123, 1.792)	0.651
HDL (mmol/L)
Model 1	277.657(-0.855, 556.168)	0.051	0.779(-0.463, 2.022)	0.217
Model 2	187.932.576(-44.945, 420.809)	0.113	0.286(-0.783, 1.355)	0.598
TC (mmol/L)
Model 1	20.825(-153.702, 195.352)	0.814	-0.086(-0.858, 0.686)	0.826
Model 2	57.656(-87.836, 203.184)	0.435	-0.003(-0.166, 0.661)	0.993
TG (mmol/L)
Model 1	-942.969(-1453.269, -432.669)	0.001	-1.765(-4.109, 0.580)	0.139
Model 2	-765.212(-1215.554, -314.870)	0.001	-1.221(-3.345,0.903)	0.258

Model 1: crude models. Model 2: adjusted for maternal age, mode of delivery, gestational age, sex, pre-pregnancy BMI, and weight gain during pregnancy. TC, triglyceride; LDL, low density lipoprotein; HDL, high density lipoprotein; TC, Total cholesterol. P values in bold, p < 0.05.

Table 5- Associations of cord blood betaine and lipid levels (LDL, HDL, TC, TG) with the risk of SGA.

	Crude OR (95% CI)	P	Adjusted OR (95% CI)	P
Betaine	1.576(1.080, 2.298)	0.018	1.798(1.164, 2.775)	0.008
LDL	1.872(0.281, 12.482)	0.517	1.206(0.145, 10.048)	0.863
HDL	0.335(0.079, 1.416)	0.175	0.269(0.054, 1.335)	0.096
TC	1.062(0.451, 2.504)	0.890	0.839(0.321, 2.191)	0.720
TG	155.807(7.269, 3339.558)	0.001	32.682(1.207, 884.977)	0.038

The odds ratio per SD increase in each biomarker from multinomial logistic regression models adjusted for maternal age, mode of delivery, gestational age, sex, pre-pregnancy BMI, and weight gain during pregnancy. TC, triglyceride; LDL, low density lipoprotein; HDL, high density lipoprotein; TC, Total cholesterol. P values in bold, p < 0.05.

No competing interests reported.

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Betaine in Infants Born Small-for-Gestational-Age

Status:

Version 1

Abstract

Aim

Methods

Results

Conclusions

1. Introduction

2. Methods

3. Results

Discussion

Abbreviations

Declarations

References

Tables

Additional Declarations

Status:

Version 1