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Effect of maternal lipid profile, C-peptide, insulin, and HBA1c levels during late pregnancy on large-for-gestational age newborns
Ruo-Lin Hou, Huan-Huan Zhou, Xiao-Yang Chen, Xiu-Min Wang, Jie Shao, Zheng-Yan Zhao
Hangzhou, China
Author Affiliations: Department of Children's Health Care (Hou RL, Zhou HH, Chen XY, Shao J, Zhao ZY), Department of Endocrinology (Wang XM), Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
Corresponding Author: Zheng-Yan Zhao, Department of Children's Health Care, Children's Hospital, Zhejiang University School of Medicine, 57 Zhugan Xiang, Hangzhou 310003, China (Tel: 86-571-87061007 ext 12435; Fax: 86-571-87078641; Email: zhaozy@zju.edu.cn)
doi: 10.1007/s12519-014-0488-7
Background: Large-for-gestational age (LGA) newborns can increase the risk of metabolic syndrome. Previous studies have shown that the levels of maternal blood lipids, connecting peptide (C-peptide), insulin and glycosylated hemoglobin (HbA1c) were significantly different between LGA and appropriate-for-gestational age (AGA) newborns. This study aimed to determine the effect of the levels of maternal lipids, C-peptide, insulin, and HbA1c during late pregnancy on LGA newborns.
Methods: This study comprised 2790 non-diabetic women in late pregnancy. Among their newborns, 2236 (80.1%) newborns were AGA, and 554 (19.9%) newborns were LGA. Maternal and neonatal characteristics were obtained from questionnaires and their case records. The levels of maternal fasting serum apolipoprotein A1 (ApoA1), triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), C-peptide, insulin and blood HbA1c were measured. The chi-square and Mann-Whitney U test were used to analyze categorical variables and continuous variables between the AGA and LGA groups, respectively. Binary logistic regression analysis was made to determine the independent risk factors for LGA newborns.
Results: Maternal TG, C-peptide, insulin and HbA1c levels were significantly higher in the LGA group than in the AGA group (P<0.05). The LGA group had significantly lower levels of maternal TC, HDL-C and LDL-C than the AGA group (P<0.05). After adjustment for confounding variables, including maternal age, pre-pregnancy body mass index, education, smoking, annual household income, amniotic fluid volume, gestational hypertension, newborn gender and gestational age at blood collection, high maternal TG levels remained significantly associated with LGA newborns (P<0.05).
Conclusion: High maternal TG level during late pregnancy is significantly associated with LGA newborns.
Key words: large-for-gestational-age newborns; late pregnancy; maternal lipid profile; triglyceride
World J Pediatr 2014;10(2):175-181
Introduction
Fetal growth and development is determined by a combination of genetic and environmental factors. As environmental factors, maternal nutritional status and metabolism are critical to fetal growth. Adverse intrauterine environment could lead to abnormal birth weight. There are increasing evidences indicating that large-for-gestational age (LGA) is associated with metabolic syndrome (MS), such as cardiovascular disease and type 2 diabetes mellitus.[1,2] The prevalence of MS is particularly high in the obese pediatric population born with LGA.[3,4] Maternal lipids increase during gestation compared with pre-pregnancy.[5-9] Hyperlipidemia during pregnancy can result in fetal overgrowth. Low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A1 (ApoA1) in the LGA group are significantly lower than in the appropriate-for-gestational age (AGA) group. Maternal triglyceride (TG) levels during pregnancy are positively associated with birth weight, which result in a higher occurrence of LGA infants.[10-13] Previous studies[14,15] have suggested that cord connecting peptide (C-peptide) levels are positively correlated with birth weight. C-peptide and insulin levels are higher in the LGA group than in the AGA group.[15,16] Maternal lipids metabolism is important and complex in the process of fetal development. However, the effect of maternal lipids metabolism on fetal development has not been fully elucidated yet. It is well-known that gestational diabetes can significantly affect maternal lipids levels and cause adverse birth weight outcomes.[10,17-20] Studies[14-16] on the relationship between C-peptide levels and birth weight were mostly carried out in cord blood. And few studies have eliminated the effect of confounding variables that may affect fetal growth and birth weight. To our knowledge, studies of the relationship between maternal blood markers in late pregnancy and LGA newborns rarely focused on maternal lipids, C-peptide, insulin and glycosylated hemoglobin (HbA1c). Therefore, the present study aimed to determine the effect of the levels of maternal lipids, C-peptide, insulin and HbA1c during late pregnancy on LGA newborns in the non-diabetic population, independent of other confounding variables.
Methods
Study population
Pregnant women during 28-37 weeks' gestation were enrolled into this study. Before enrollment, written informed consent was signed. These women were asked to complete a questionnaire with items of maternal age, height, pre-pregnancy weight, smoking, maternal education level and annual household income. Information about diabetes, abnormal glucose tolerance, gestational hypertension and amniotic fluid were collected. At the same time, overnight fasting blood was collected. The women were followed up from enrollment to delivery, and data on gestational age, Apgar score and birth weight were recorded by the doctor upon delivery. Inclusion criteria of pregnant women were as follows: pregnancy at 28-37 weeks' gestation, conceiving naturally and singleton pregnancy. Exclusion criteria of pregnant women were as follows: diabetes, abnormal glucose tolerance, chromosomal abnormality, inherited metabolic diseases, thyroid disease, and risk for fetal chromosomal abnormality. Inclusion criterion of newborns was full term birth. Exclusion criteria of newborns included inherited metabolic diseases, congenital abnormalities and congenital heart diseases. In 3111 women enrolled, 127 pregnant women were diagnosed with abnormal glucose tolerance, and 22 with diabetes. In their newborns, there were 83 SGA, 2236 AGA, 554 LGA, 82 preterm and 7 post-term. The present study aimed to investigate the effect of blood markers on LGA newborns; therefore, the SGA newborns were also excluded. Based on the criteria above, 2790 women were finally included. This study was approved by the Ethics Committee of the hospital.
Biochemical analyses
Venous blood after overnight fasting was taken from the women, put in a separation tube and then centrifuged. Serum was collected and assayed for ApoA1, C-peptide, HbA1c, insulin, total cholesterol (TC), HDL-C, LDL-C and TG according to the protocols. Blood collected with a sodium fluoride anticoagulant tube was used for HBA1c measurement. ApoA1 and HbA1c levels were measured with an immunoturbidimetry method,[21] with reference values (from nonpregnant individuals) of 1.00-2.25 g/L and 4.0%-6.3%, respectively. C-peptide and insulin levels were measured using an electrochemiluminescence method,[22,23] with reference values (from nonpregnant individuals) of 0.370-1.470 nmol/L and 4.50-16.15 mIU/L, respectively. TC, HDL-C, and LDL-C levels were measured by enzymatic colorimetric assay, with reference values (from nonpregnant individuals) of 3.10-6.00 mmol/L, 0.80-1.80 mmol/L and 1.40-4.90 mmol/L, respectively. TG levels were measured by the colorimetric assay, with reference values (from nonpregnant individuals) of 0.56-1.70 mmol/L.
Definitions
Newborns were defined as LGA when their birth weights were above the 90th percentile for gestational age. Newborns were defined as AGA when their birth weights were at or above the 10th percentile, but below the 90th percentile for gestational age in accordance with Neonatal Birth Weight for Gestational Age and Percentile in 15 Cities in China.[24]
Body mass index (BMI) (kg/m2) was calculated by pre-pregnancy weight/height2 based on pre-pregnancy weight and maternal height. The levels of maternal ApoA1, C-peptide, insulin, and HbA1c were classified according to references from the protocols. Classification of maternal serum lipids was based on the Chinese Guidelines on Prevention and Treatment of Dyslipidemia in Adults.[25] Maternal smoking was classified as current smoking or quitting time <1 year, quitting time ≥1 year, never smoking, or <100 cigarettes consumed. Polyhydramnios was defined as the maximum depth of amniotic fluid ≥8.0 cm or an amniotic fluid index of ≥20 cm. Oligohydramnios was defined as the maximum depth of the amniotic fluid ≤3.0 cm or amniotic fluid index of ≤5.0 cm.
Statistical analysis
Data were presented as median (interquartile range, IQR) or n (%). The Chi-square test was used to evaluate mean differences in categorical variables between the AGA and LGA groups. The Mann-Whitney U test was used to evaluate mean differences in continuous variables between the two groups. Binary logistic regression analysis was made to determine the independent risk factors for LGA newborns at term. In the model, maternal age, pre-pregnancy BMI, education level, smoking, annual household income, amniotic fluid volume, gestational hypertension, newborn sex, and gestational age at blood collection were used as confounding variables. SPSS 16.0 (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. P<0.05 was considered statistically significant.
Results
Maternal and neonatal demographic characteristics are shown in Table 1. There were 2236 (80.1%) AGA and 554 (19.9%) LGA newborns. The median maternal age was 26 years and pre-pregnancy BMI was 19.93 kg/m2. The median gestational age at blood collection and delivery was 34 and 39 weeks, respectively. The median birth weight of the neonates was 3350 g. There were no significant differences in gestational age at blood collection, maternal age, maternal smoking, maternal education, annual household income, or gestational hypertension between the LGA and AGA groups. Pre-pregnancy BMI in the LGA group was significantly higher than that in the AGA group (P<0.05). The occurrence of LGA was significantly higher in boys than in girls (P<0.05). There was significant difference in amniotic fluid volume between the two groups (P<0.05).
Data on the levels of fasting maternal lipids, C-peptide, HBA1c, and insulin are shown in Table 2. There were significantly higher levels of maternal C-peptide, HbA1c, insulin and TG in the LGA group than in the AGA group (P<0.05). The levels of maternal HDL-C, LDL-C and TC were significantly lower in the LGA group than in the AGA group (P<0.05). However, there was no significant difference in ApoA1 levels between the two groups.
After controlling maternal age, pre-pregnancy BMI, education, smoking, annual household income, amniotic fluid volume, gestational hypertension, gestational age at blood collection and newborn sex, maternal TG levels remained significantly associated with LGA newborns (Table 3). Women with TG ≥1.70 mmol/L during late pregnancy experienced an approximately 3.0-fold increase of risk of having an LGA newborn [P=0.04, adjusted odds ratio (OR)=3.037, 95% confidence interval (CI): 1.054-8.747], with TG <1.70 mmol/L as reference. In addition, women with TG ≥2.26 mmol/L experienced a 3.3-fold increase of risk of having an LGA newborn (P=0.022, adjusted OR=3.303, 95% CI: 1.177-9.27), with TG <1.70 mmol/L as reference.
Discussion
Infant development is affected by various factors including maternal BMI, maternal metabolism, gestational weeks at birth. To determine the relationship between maternal blood markers and LGA newborns, we enrolled pregnant women at 28-37 weeks' gestation in the study. We observed the effect of levels of maternal C-peptide, HbA1c, insulin, HDL-C, LDL-C, TG and TC on LGA newborns. Pregnant women who delivered LGA newborns had higher levels of C-peptide, HbA1c, insulin, and TG, and lower levels of HDL-C, LDL-C, and TC than those who delivered AGA newborns. The results in our study were consistent with those reported elsewhere,[10,11,13,15,26] showing that high levels of maternal C-peptide and TG are positively correlated with birth weight. The levels of maternal TC and LDL-C were significantly lower in LGA newborns.[27] However, conflicting results indicated that maternal TG level was similar between the LGA and AGA groups,[27] and that there were no significant differences in maternal TC, TG or HDL-C levels during early or late pregnancy.[10,13] This finding might be explained in two aspects: one was the differences in exclusion criteria and the other was that maternal blood was measured during 28-37 weeks' gestation in our study, which was different from others.
In addition, we found that the LGA group had higher pre-pregnancy BMI than the AGA group; this finding is consistent with other report.[13] The finding indicated that women with higher maternal age and pre-pregnancy BMI are more likely to give birth to LGA newborns. In addition, it was revealed that maternal obesity was also associated with inflammation of their children.[28] In the present study, the effect of amniotic fluid volume on LGA was also analyzed. Polyhydramnios resulted in the occurrence of LGA newborns, suggesting that polyhydramnios can lead to fetal overgrowth. However, the effects of maternal education, annual household income and gestational hypertension on LGA infants were not significant. Our findings suggest that boys are more likely to develop LGA than girls.
We regarded gestational age at blood collection as a confounding variable because lipids level increased with gestational age.[1,9] After adjustment for maternal age, pre-pregnancy BMI, education, smoking, annual household income, amniotic fluid volume, gestational hypertension, newborn gender and gestational age at blood collection, TG levels remained significantly different between the LGA and AGA groups. This finding indicated that higher TG level (≥1.7 mmol/L) is an independent risk factor for LGA newborns. Similar results from other studies[13,29] also suggested that maternal fasting serum TG levels could independently predict LGA newborns. Moreover, women with a TG level higher than 2.26 mmol/L had a greater risk for giving birth to LGA newborns than those with a TG level lower than 2.26 mmol/L. Obviously, lipoprotein lipase (LPL) participates in the hydrolysis of maternal TG, and facilitates the transplacental transfer of TG-derived free fatty acid, which is important for the supply of components for fetal development. The increase of TG level may be due to decreased LPL activity and increased concentration of estrogen during late pregnancy.[30,31] The mechanism for the association between maternal TG levels and fetal growth might be enhanced insulin resistance during late pregnancy.[12,13]
However, there was no significant difference in HbA1c levels between the AGA and LGA groups in this study. This finding was not consistent with another study showing that mid-pregnancy HbA1c levels in non-diabetic women may predict neonatal birth weight, with a HbA1c cut-off level of 4.99%.[32] However, another study showed that pregnant women had lower HbA1c levels than non-pregnant women, and the change from the first to second trimester appeared to be important in predicting birth weight.[33]
After adjustment, higher BMI, time of quitting smoking ≥1 year and polyhydramnios remained as independent risk factors for LGA newborns. Women with a duration of quitting smoking ≥1 year were more likely to give birth to LGA newborns than those non-smoking women. However, other studies suggested that maternal smoking can lead to small-for-gestational age newborns and quitting smoking during the first trimester of pregnancy could result in a higher incidence of small-for-gestational age, compared with non-smoker.[34,35] The inconsistency of this finding with others might be due to the following reasons: Pregnant women in our study might obtain more nutrition during gestation, which is difficult to evaluate, and fetal growth was affected by other potential unknown factors. Additionally, oligohydramnios can be regarded as a protective factor for LGA newborns.
The present study has strengths and limitations. The strengths include a large population of non-diabetic women in late pregnancy with comprehensive information, which is useful to determine the independent risk factors for LGA newborns. Besides, the study is a prospective one and the follow-up of the population provided more information about infant development, which is important to detect the mechanism of MS development. The limitation is that some maternal demographic characteristics were self-reported from pregnant women, which may lead to bias. Moreover, although many variables were obtained in our study, we did not include other potential confounding variables (e.g., weight gain during pregnancy), which may affect birth weight.[36-38] Some unknown potential factors that might also affect fetal growth in intrauterine environment were not included in the study. Hence, further study is needed to determine these possibilities.
Our findings suggest that pre-pregnancy BMI, time of quitting smoking ≥1 year, polyhydramnios and high maternal TG levels in late pregnancy play a critical role in fetal development. These factors are independently associated with the occurrence of LGA newborns. Some interventional measures should be taken to reduce the adverse effect on fetal growth and development. Therefore, the occurrence of LGA newborns as well as the incidence of adulthood MS can be reduced.
Acknowledgments
We are grateful to all participating hospitals, obstetric clinics and the pregnant women who were involved in this study.
Funding: This study was supported by grants from the "11th Five-Year Plan" and the "12th Five-Year Plan" from the National Science and Technology Issues Research, China (2009BAI80B03, 2012BAI02B03), the Innovation Program for Early Screening and Intervention of Birth Defects, Zhejiang Province (2010R50045), and the National Key Scientific Research Projects of China (973 Program) (2012CB944900).
Ethical approval: This study was approved by Ethics Committee of Children's Hospital, Zhejiang University School of Medicine.
Competing interest: The authors declare no conflicts of interest.
Contributors: Hou RL participated in study design, data collection and analysis and wrote the draft under the supervision of Zhao ZY. Zhou HH and Chen XY participated in data collection. Wang XM, Shao J and Zhao ZY participated in study design. All authors approved the final version of the manuscript.
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Accepted after revision April 4, 2014
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