Objective
Experimental studies show that fetal liver venous perfusion is a determinant for growth in utero. Here we explore the relationship between fetal venous blood flow to the liver and macrosomia.
Study Design
From diameter and blood flow velocity measurements, we derived liver venous blood flow in a longitudinal ultrasound study of 25 macrosomic fetuses of nondiabetic mothers during the second half of pregnancy.
Results
Compared with appropriately growing fetuses, macrosomic fetuses directed more umbilical blood to the liver tissue, with correspondingly less contribution from the portal circulation when normalized for fetal weight. Whereas total venous liver blood flow showed no late gestation rise in the reference population, it continued to increase in macrosomic fetuses and was accompanied by greater fetal weight.
Conclusion
The direct relationship between venous liver blood flow and macrosomia in the fetus supports the concept that intrauterine growth is linked to the amount and distributional pattern of venous liver perfusion.
Infant size at birth is influenced by a variety of genetic, endocrine, and metabolic factors through gestation. In addition, maternal body composition, diet, and insulin sensitivity influence growth in utero. Studies in humans have shown an association between size at birth and cord blood levels of insulin, insulin-like growth factors (IGF I and II), and their binding proteins and suggest that maternal nutritional status influences growth factor levels in the fetus. IGFs are considered important endocrine mediators of fetal growth and are synthesized, to a large degree, in the fetal liver. IGF secretion is not only dependent on fetal glucose metabolism but also on the venous perfusion of the fetal liver. In fetal sheep, experimentally increased venous liver blood flow produces an increase in IGF secretion; reduced venous blood supply is accompanied by lower IGF levels. These data support the concept that fetal venous liver perfusion plays a part in the regulation of fetal growth.
In normal human pregnancies, total venous liver blood flow increases during the second half of gestation. Although dominated by umbilical blood, the fraction of portal blood that contributes to total venous liver blood flow increases from 12% at mid gestation to 20% close to term. Venous liver perfusion is influenced by maternal diet, body composition, and weight gain with a redistribution pattern that favors the left liver lobe. We have shown that growth-restricted fetuses have venous hypoperfusion in relation to appropriately grown fetuses, although this is compensated partly by increased portal and hepatic artery blood flow. However, research on the relationship between circulatory adaptations and fetal growth has focused mainly on restricted nutrient supply and placental insufficiency that is associated with reduced fetal growth. Apart from a few cross-sectional studies on umbilical blood flow in diabetic pregnancies, there is little information about circulatory adaptations in macrosomic or large-for-gestational-age fetuses. Studies in such fetuses are of interest because they allow the examination of whether such increased growth exceeds the capacity of the fetal circulation, as might be expected if growth were driven primarily by nutrient levels, or whether the increased growth is accompanied by greater venous liver blood flow, as might be expected if venous liver blood flow lies on the causal pathway regulating growth.
The aim of the present study was to use serial measurements of the components of hepatic venous perfusion in macrosomic fetuses of nondiabetic mothers to determine whether a relationship exists between liver perfusion and fetal growth under the conditions of increased fetal growth.
Materials and Methods
The study protocol was approved by the local research ethics committee (reference code: REK-Vest 04/3837) and participants were recruited after written informed consent.
Healthy women who previously had delivered children with a birthweight of ≥4200 g (corresponding to 90th percentile of the reference population ) were invited to the study. Women with a history of gestational diabetes or diabetes mellitus, fetal malformations or chromosomal abnormalities, and twin pregnancies were excluded. Gestational age was determined by ultrasound scanning in the second trimester. A total of 39 participants were examined longitudinally at 4-week intervals during the second half of pregnancy. At delivery, sex and birthweight were noted.
A Sonos 7500 ultrasound machine (Phillips, Seattle, WA) with a 3.5 MHz (2-6 MHz) curved linear transducer that included color Doppler (2.5 MHz) and pulsed Doppler (3 MHz) facilities was used for the study. The high-pass filter was set at 50 Hz. Vessel diameter and blood flow velocities were measured at the intraabdominal portion of the umbilical vein, inlet of the ductus venosus, left portal vein, and main portal stem ( Figure 1 ). The measurement techniques and calculation of volume blood flow (Q) are described elsewhere.
The total venous blood supply of the liver (Q liver ) was calculated in the following manner: Q liver = Q umbilical vein − Q ductus venosus + Q portal vein . The venous blood flow to the left liver lobe (Q left liver ) was calculated in the following manner: Q left liver = Q umbilical vein − (Q ductus venosus + Q left portal vein ); venous blood flow to the right lobe (Q right liver ) was calculated in the following manner: Q right liver = Q portal vein + Q left portal vein . The umbilical and portal fraction of the total venous liver supply was calculated in the following manner: (Q umbilical vein − Q ductus venosus ) × 100%/Q liver and Q portal vein × 100%/Q liver , respectively. Blood flow to the right and left lobes relative to the total venous liver blood flow was calculated in the following manner: Q left liver × 100%/Q liver and Q right liver × 100%/Q liver , respectively. The blood flow was also normalized for estimated fetal weight and sex. Statistical analysis was performed with Statistical Package for the Social Sciences software (SPSS Inc, Chicago, IL). Multilevel modeling was used to construct mean curves for each variable by gestational age with the MlWin program (MlWin; Centre for Multilevel Modeling, University of Bristol, Bristol, UK) following the principles described previously. Data from the study population were compared with a reference population of 160 appropriately growing fetuses with the use of the mean curves and the corresponding CIs. Nonoverlapping 95% confidence intervals (CIs) of the means indicate a significant difference between the reference and study population. In addition, the level of significance was estimated with the use of z -score statistics and t test scores.
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