Maternal diabetes mellitus and fetal venous liver flow – a longitudinal study
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Background: Despite adequate glycemic control, the risks of perinatal complications and fetal macrosomia are increased in pregnancies with pregestational diabetes (PGDM). Maternal overweight, obesity and excess gestational weight gain add significantly to the risk of large for gestational age offspring in PGDM pregnancies. Umbilical perfusion of the fetal liver has a key role in regulating fetal growth. We hypothesized that PGDM alters umbilical venous distribution and fetal liver blood flow depending on maternal anthropometry and glycemic control. Aims: The aims were to study a population with PGDM to 1) Compare the longitudinal development of the venous liver flow with a low-risk population 2) Assess the relation between maternal HbA1C and fetal venous liver flow 3) Explore the influence of maternal body mass index (BMI) and weekly gestational weight gain (GWG) on the venous liver flow 4) Test if fetal flow was related to birthweight differently in PGDM compared with the reference population. Materials and methods: In a prospective longitudinal observational study, 49 women with PGDM underwent monthly ultrasound examinations in gestational weeks 20 – 36. The time average maximum blood velocity was measured by Doppler in the umbilical vein (UV), ductus venosus (DV), left portal vein (LPV) and portal vein (PV). The inner vessel diameter was measured in UV, DV and PV, and the blood flow was calculated. Flow was normalized for estimated fetal weight. Mean and percentile curves were modelled by multilevel regression and compared with reference curves from a low-risk population (n=160). In addition, differences between mean fetal flow z -scores in the PGDM and low-risk populations were tested by independent sample t-test. HbA1C was measured in the first trimester and the relation to fetal venous flow was assessed by multilevel regression. Pre-pregnancy BMI and weekly GWG were calculated from self-reported prepregnancy weight and maternal height, and the last maternal weight that was measured before delivery. ANOVA was used to test fetal flow differences between the BMI and GWG categories, and to test differences between birthweight in fetal flow categories. The impact of BMI and weekly GWG on the fetal flow variables was investigated by log-likelihood statistics. Results: Compared with the reference, UV flow, LPV velocity, umbilical venous liver flow and total venous liver flow were larger, and the DV flow was smaller in PGDM pregnancies. In the PGDM population birthweights were high and when normalized for estimated fetal weight the UV and total venous liver flow were smaller than the reference values. The most prominent deviations from the reference curves were seen after 30 weeks of gestation and near term. DV shunting and PV fraction of total venous liver flow were negatively, and LPV velocity positively related to first trimester HbA1C. There was a graded positive association between UV flow, umbilical venous liver flow, total venous liver flow, LPV velocity and birthweight, and this effect was more pronounced in PGDM pregnancies than in the low-risk reference population. BMI and GWG modified venous liver flow to a larger extent in PGDM pregnancies than in the reference population. Overweight women with PGDM had the highest umbilical venous liver flow, total venous liver flow and LPV velocity, while PV fraction was lower. Those with excessive GWG had the largest UV flow, umbilical venous liver flow and LPV velocity, and lower PV fraction, compared with the other GWG categories. Conclusion: This study provides new insight to the fetal development and the physiological mechanisms contributing to increased risks in PGDM pregnancies. UV flow to the liver was prioritized at the expense of DV shunting. Reduced DV shunting could increase neonatal risks by inhibiting fetal compensatory responses to hypoxia near term and during labour. Increased distribution of UV blood to the liver contributed to larger birthweight in PGDM pregnancies, and maternal glycemic control influences the distribution of fetal liver flow. After 30 gestational weeks however, the blunted development of the umbilical venous liver flow caused an increasing mismatch between fetal growth and venous blood supply in the third trimester. The modification of fetal flow and birthweight by BMI and GWG was larger in PGDM pregnancies than in the reference population. Our study supports the concept that fetal liver perfusion is an important regulator of fetal growth. We found this mechanism to be augmented in PGDM pregnancies.
Består avPaper I: Lund A, Ebbing C, Rasmussen S, Kiserud T, Kessler J. Maternal diabetes alters the development of ductus venosus shunting in the fetus. Acta obstetricia et gynecologica Scandinavica. 2018;97(8):1032-1040. The article is available in the main thesis. The article is also available at: https://doi.org/10.1111/aogs.13363
Paper II: Lund A, Ebbing C, Rasmussen S, Kiserud T, Hanson M, Kessler J. Altered development of fetal liver perfusion in pregnancies with pregestaional diabetes. PLOS ONE. 2019; 14(3):e0211788. The article is available at: http://hdl.handle.net/1956/22205
Paper III: Lund A, Ebbing C, Rasmussen S, Qvigstad E, Kiserud T, Kessler J. Maternal body mass and gestational weight gain are associated with augmented fetal liver blood flow and birthweight in pregnancies with pregestational diabetes. The article is not available in BORA.