Association of hyperglycaemia with the placenta of GDM-induced macrosomia with normal pre-pregnancy BMI and the proliferation of trophoblast cells

Abstract

The aim of this study was to identify the effect of hyperglycaemia on placentas of gestational diabetes mellitus (GDM) women with macrosomia and normal pre-pregnancy body mass index (BMI), and uncover the molecular mechanism of hyperglycaemia on trophoblast cells in vitro. GDM women with normal pre-pregnancy BMI were divided into GM group (macrosomia, n = 30) and GN group (normal birth weight, n = 35). The study showed GM group had more adverse pregnancy outcomes and higher levels of gestational weight gain, blood glucose and triglyceride. After adjustment for confounding factors, just the fasting plasma glucose level and HbA1c percentage were related to the incidence of GDM-induced macrosomia with normal pre-pregnancy BMI. Meanwhile, the fasting blood glucose was closely related to the placental weight and placental PCNA expression. Furthermore, the in vitro model for placenta showed that hyperglycaemia significantly promoted trophoblast cell proliferation and activated ERK1/2 phosphorylation. ERK1/2 inhibitor markedly suppressed hyperglycaemia-induced trophoblastic proliferation. The fasting plasma glucose and placenta are closely related with the development of GDM-induced macrosomia with normal pre-pregnancy BMI. The mechanism may be hyperglycaemia promotes trophoblast cell proliferation via ERK1/2 signalling. It provides scientific evidence for optimising outcomes of GDM women with normal pre-pregnancy BMI.

IMPACT STATEMENT

• What is already known on this subject? Gestational diabetes mellitus (GDM) is one of the strongest risk factors correlated with macrosomia. The hyperglycaemic intrauterine environment affects not only the foetus but also the placental development and function in humans and experimental rodents. However, placental abnormalities associated with maternal diabetes have been inconsistently reported, possibly because of population differences in pre-pregnancy weight, diabetes types, glycemic control or pregnancy complication, and the molecular mechanism of hyperglycaemia on trophoblast cells in vitro was not clearly stated.

• What do the results of this study add? This is the first study to identify the effect of hyperglycaemia on placentas of gestational diabetes mellitus (GDM) women with macrosomia and normal pre-pregnancy body mass index (BMI), and uncover the molecular mechanism of hyperglycaemia on trophoblast cells in vitro.

• What are the implications of these findings for clinical practice and/or further research? Understanding placental changes in the environment of abnormal glucose metabolism which can establish the maternal-placental-foetal interface dysfunction as a potential source of adverse pregnancy outcomes is very necessary. Our study found the fasting plasma glucose and placenta are closely related with the development of GDM-induced macrosomia with normal pre-pregnancy BMI. The mechanism may be hyperglycaemia promotes trophoblast cell proliferation via ERK1/2 signalling. It provides scientific evidence for optimising outcomes of GDM women with normal pre-pregnancy BMI, and could be used for the following studies of relationship between placenta and childhood complications.

Keywords:

• Hyperglycaemia
• placenta
• macrosomia
• gestational diabetes mellitus
• pre-pregnancy body mass index
• ERK1/2 signal pathway

Acknowledgments

The authors thank Hongbin Liu at the Second Affiliated Hospital of Nantong University for helping us reviewing placental samples in immunohistochemistry. The authors also thank Haiming Huang at the Second Affiliated Hospital of Nantong University who measured the umbilical cord diameter.

Ethical approval and consent to participate

All participants provided informed written consent, and the study protocol was by the Ethics Committee of the Second Affiliated Hospital of Nantong University.

Disclosure statement

All authors have no conflicts of interest to declare.

Additional information

Funding

This work was supported by National Natural Science Foundation of China [grant number 81501258] and Ke-Jiao-Qiang-Wei-Qing-Nian-Yi-Xue-Zhong-Dian-Ren-Cai Financial Assistance of Jiangsu Province [grant number QNRC2016414].