The FASEB Journal. 2020;34:12481–12491. wileyonlinelibrary.com/journal/fsb2
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12481R E S E A R C H A R T I C L E
The impact of umbilical vein blood flow and glucose
concentration on blood flow distribution to the fetal liver and systemic organs in healthy pregnancies
Gun Lisbet Opheim
1,2,3| Ane Moe Holme
4| Maia Blomhoff Holm
4|
Trond Melbye Michelsen
2,3,4| Saba Muneer Zahid
1,3| Marie Cecilie Paasche Roland
2,4|
Tore Henriksen
3,4| Guttorm Haugen
1,3This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology
Abbreviations: AC, abdominal circumference; BW, birth weight; DV, ductus venosus; FL, femur length; HC, head circumference; MCA, middle cerebral artery; PI, pulsatility index; ppBMI, pre-pregnancy body mass index; TAMX, time average maximum velocity; UA, umbilical artery; UV, umbilical vein.
1Department of Fetal Medicine, Oslo University Hospital-Rikshospitalet, Oslo, Norway
2Norwegian Advisory Unit on Women's Health, Oslo University Hospital- Rikshospitalet, Oslo, Norway
3Institute of Clinical Medicine, University of Oslo, Oslo, Norway
4Department of Obstetrics, Oslo University Hospital-Rikshospitalet, Oslo, Norway Correspondence
Gun Lisbet Opheim, Department of Fetal Medicine, Oslo University Hospital- Rikshospitalet, Sognsvannsveien 20, PO Box 4950 Nydalen, Oslo N-0424, Norway Email: [email protected]
Funding information
The Norwegian National Advisory Unit on Women's Health (to GLO, TMM, and MPR) and the South-Eastern Norway Regional Health Authority (to AMH, MBH, and TMM) provided financial support to conduct the research. The funders had no involvement in the study design, data collection, analyses, or interpretation.
Furthermore, they were not involved in the writing or the decision to publish this paper
Abstract
Glucose is a major energy substrate for the fetus, including liver, heart, and brain me- tabolism. The umbilical vein (UV) blood flow supplies the fetal liver directly from the placenta, whereas a fraction is shunted via ductus venosus (DV) to the fetal systemic circulation bypassing the fetal liver. We hypothesized UV glucose concentration to be a major regulator of the distribution of glucose supply between the fetal liver and DV, and explored the influence of maternal metabolic status on this distribution.
We included 124 healthy women with normal singleton pregnancies, scheduled for elective cesarean section. UV and DV blood flow measurements were performed by Doppler ultrasound immediately before, and blood samples were obtained during surgery. UV blood flow was significantly correlated with DV blood flow, liver blood flow, and the DV shunting fraction, while UV glucose concentration was not. For normal-weight mothers, the maternal-fetal glucose gradient was positively correlated with DV shunting fraction, and negatively with liver blood flow. For the fetuses of the overweight mothers no such correlation was found. This indicates that within the normal physiological range the human fetus makes adaptations of blood flow to ensure individual needs related to the offered maternal energy supply.
K E Y W O R D S
fetal glucose supply, fetal liver blood flow, fetal-maternal glucose gradient, maternal nutritional status
1 | INTRODUCTION
The fetal liver plays a central role in fetal energy homeosta- sis and growth through its metabolism of energy-providing nutrients, including synthesis of lipids and storage of gly- cogen, and as a source of various fetal growth factors.1,2 Macronutrients and oxygen from the placenta reach the fetus and the fetal liver through the umbilical vein (UV), which supplies the left liver lobe before dividing into the ductus ve- nosus (DV) and the left portal vein (Figure 1). In the fetus the left portal vein, as well as the portal vein, supplies the right liver lobe, while DV shunts the blood directly from the UV to the systemic circulation through the inferior caval vein and right atrium, thus bypassing the fetal liver. After reaching the right atrium, most of the blood from DV flows through the foramen ovale to the left side of the heart to supply vital fetal organs like the heart and brain. Accordingly, the venous in- tersection where the incoming blood from the UV is divided to supply the right liver lobe or bypass the liver through DV is of particular interest in studying the fetal distribution of incoming energy providing nutrients.
There are reasons to believe that distribution of umbilical blood through the liver is part of the mechanisms regulat- ing fetal energy metabolism, and thereby fetal development.
This is supported by positive correlations between liver blood flow, growth, and fat accretion in the third trimester in human ultrasound based studies.3,4 It has further been suggested that the fetal intrauterine nutritional environment provided by the materno-placental unit may influence fetal liver blood flow, and thus affect fetal growth and fat deposition. Haugen et al described a “liver sparing” response, where fetuses with under- or malnourished mothers tended to prioritize blood flow to the liver in gestational week 36, probably to optimize fat accumulation before birth.5 In a recent publication from our group, fetuses increased their liver flow after a maternal
meal in week 36, a response which significantly differed be- tween normal-weight and overweight mothers.6
Glucose is the main energy providing nutrient in fetal life, with increasing demands with gestational age. Fetal uptake, distribution, and metabolism of glucose are fundamental for fetal growth, and play a particular role in fetal cerebral and cardiac metabolism.7,8 Under normal physiological condi- tions the fetus appears to have no significant gluconeogene- sis, and is dependent on glucose provided by maternal energy intake.9 The transfer of glucose from the maternal to the fetal circulation is driven by a transplacental gradient and facili- tated by carrier proteins.10
Godfrey et al hypothesized that “the balance between fetal nutrient demand and materno-placental nutrient supply may alter the distribution of umbilical venous (UV) blood flow, with implications for fetal body composition”.3 In a recent publication we demonstrated that fetal glucose consumption (μmol·min−1) correlated with birth weight, also when fetal glucose consumption was normalized for birth weight.11 It is well established that maternal glucose levels are strongly pos- itively correlated with UV glucose levels,11 and we could fur- ther demonstrate that umbilical glucose concentrations were correlated to fetal glucose consumption.12 It is reasonable to assume there are mechanisms that prevent large variations in systemic (extra-hepatic) fetal blood glucose concentrations because both hyper- and hypoglycemia is deleterious.
Fetal glucose supply is defined as a product of two param- eters; UV blood flow and UV glucose concentration. Earlier studies have implied that maternal glucose and food intake6,13 and maternal nutritional status (fat percentage and BMI)5 in- fluence blood flow to the fetal liver vs systemic circulation.
On this background we hypothesized that the distribution of blood flow between DV and the liver relates to the concentra- tion of glucose in the UV. Furthermore, we hypothesized that maternal ppBMI would influence the distribution of blood flow between DV and the liver.
To test this hypothesis in the human, we measured UV glucose concentration, UV-, and DV blood flow, and calcu- lated the mass of glucose supplied to the fetus through the UV and its distribution between DV and the fetal liver.
Finally, we determined how fetal liver- and DV flow dis- tribution was related to markers of fetal well-being, that is, cerebral and umbilical blood flow resistance and fetal body proportions.
2 | MATERIALS AND METHODS 2.1 | Participants
This cross-sectional in vivo study is a sub cohort of 179 healthy women with uncomplicated pregnancies scheduled for elective cesarean section.12 Indications for cesarean
FIGURE 1 Venous fetal liver blood flow
section were maternal request, previous traumatic delivery, or mechanical disproportion, more than one prior cesarean section, previous myomectomy, breech presentation, and maternal request or disadvantageous pelvic measurements, previous vaginal surgery, and rupture of the anal sphincter with sequela. Exclusion criteria were preexisting comor- bidity, medication, and pregnancy complications, such as pre-eclampsia, known intrauterine growth restriction, and di- abetes treated with medications. Women who went into labor before their scheduled cesarean section were also excluded.
Our sub cohort included 124 women in which we collected both blood samples of the umbilical cord and fetal ultrasound examination including liver blood flow measurements for further analyses. BMI was recorded in first trimester and calculated based on the self-reported pre-pregnancy weight and height. Women were categorized as normal-weight if ppBMI < 25 kg/m2 and overweight if ppBMI > 25 kg/m2. We did not have any information on the nutritional habits or nutritional composition of the participants in our study.
2.1.1 | Ultrasonographic examination
The ultrasound examination was performed in the morning (06:30 to 07:30 am) of the planned cesarean section. The par- ticipants had been instructed not to eat after 2 am, and were thus in a fasting state One clinician (GH) performed all ex- aminations, each lasting no more than 40 minutes. The same equipment was used for all participants (Acuson Sequoia 512; Mountain View, CA, USA) with a curved transducer (frequency 2-6 MHz). Fetal biometric measurements in- cluded abdominal circumference (AC), head circumference (HC), and femur length (FL). We applied fetal biometric measurements using Norwegian growth curves.14 Internal vessel diameter (D) and time-average maximum velocity (TAMX) were measured in the straight portion of the intra- abdominal UV and the inlet of DV.15 The vessel diameters (DUV, DDV) were measured and calculated as the mean of five to 10 repeated measurements, as described by Kiserud et al.16
TAMX is the average of all the maximum velocities rep- resented during one heart cycle in vessels with pulsatile flow or during a certain time-period in vessels with non-pulsating flow.17 In DV, TAMX was calculated as the mean value of the measurements in three consecutive heart cycles. In the UV, TAMX was measured during a period of 3-5 seconds.
All measurements were performed during fetal quies- cence.16 The insonation angle was corrected for and always kept as low as possible and always <30̊. Middle cerebral ar- tery (MCA) Doppler velocity waveforms were sampled from the proximal part of the MCA, near the circle of Willis,18 and for the umbilical artery (UA) measurements Doppler traces were sampled in a free-floating loop. Pulsatility index (PI) was calculated as the mean of three heart cycles.
2.1.2 | Blood flow (Q) calculations
where h = spatial coefficient for the blood flow velocity profile.
As shown in the equation for liver blood flow (QLiver), we have defined liver blood flow exclusively as blood derived from the UV. The hepatic artery and the portal vein also sup- ply the liver to some extent, but the contribution is smaller and the blood from these vessels is low in oxygen and nutrient content.19,20 We used 0.5 and 0.7 as the spatial coefficients for the blood velocity profile in the UV and DV, respectively.
This coefficient is calculated as; mean velocity/maximum ve- locity. For the UV the velocity profile has a more parabolic profile than the more blunted DV, which results in a lower h in the wide UV than in the narrow inlet of DV.21
2.1.3 | Blood sampling
Cesarean section was performed under spinal anesthesia.
Women were in a fasting state and did not receive intravenous glucose infusion during the surgery. We did not register indi- vidually the exact time of the last meal before surgery, but the median (10th-90th percentile) duration of fasting from 2 am until surgery start was 8 hours and 15 minutes (7-10 hours 30 minutes). During surgery, blood samples were obtained from the maternal antecubital vein, radial artery and from the UA and UV immediately after delivery of the baby, but before the umbilical cord was clamped.22 The sampling pro- cedure took 2-4 minutes. Glucose, insulin, and triglycerides were measured by an accredited laboratory (Department of Medical Biochemistry, Oslo University Hospital) using the hexokinase/glucose-6-phosphate dehydrogenase enzymatic in vitro test (Roche, Mannheim, Germany).
2.1.4 | Calculations of glucose supply, gradient, and consumption
We combined blood flow (Q) calculations with glucose con- centration (G) measurements, using the following formulas:
Q=h×[D 2 ]
2×𝜋× TAMX
Qliver=QUV−QDV
DV shunting fraction (%) =QDV∕QUV×100.
Umbilical vein glucose supply =QUV× [G]UV
2.1.5 | Ethical approval
The study was approved by the Institutional Review Board (number 2012-5678) and the Regional Committee of Medical and Health Research Ethics, Southern Norway (reference number 2419/2011) and followed the standards laid out in the Helsinki Declaration. Participants gave written informed consent.
2.1.6 | Statistics
All data can be accessed through Norwegian Centre for Research data (NSD), https://doi.org/10.18712/ NSD-NSD27 80-V1
We applied birth weight z-scores using Norwegian birth weight curves.23 Descriptive data are presented as median values with percentiles (10th-90th) and frequencies with percentages. We employed Mann-Whitney U tests to analyze group differences between independent samples. Correlations were determined by Spearman's rank correlation. All statisti- cal tests were two-sided, and we considered P < .05 to indi- cate statistical significance. Data were analyzed using SPSS version 23.0 (SPSS Inc, Chicago, IL, USA).
3 | RESULTS
Maternal, fetal, and neonatal characteristics as well as glu- cose concentration, gradients, and consumption measure- ments for the total group (n = 124) and, thereafter, for the normal-weight (n = 91) and the overweight (n = 33) groups with the associated p-value are presented in Table 1.
The study group consisted of presumably healthy mothers scheduled for elective cesarean section. There were no neo- nates with Apgar score <7 after 5 minutes in the total group, which was expected in this low risk population delivered by elective cesareans.
Diameter and velocity measures and calculations of blood flow in the UV and DV are shown in Table 2 together with the estimated glucose mass supply and distribution to the fetal liver.
The median (10-90 percentile) DV shunting fraction was 29.8 (13.5-48.2) %.
The blood flow in UV was significantly correlated with DV blood flow, liver blood flow, and the DV shunting frac- tion, while the glucose concentration in UV was not. UV glu- cose supply was positively correlated with both DV- and liver blood flow adjusted for BW, and negatively correlated with DV shunting fraction (Table 3).
Fetal glucose consumption was positively correlated with liver blood flow, and the maternal-fetal glucose gradient was positively correlated with DV shunting fraction. We used fetal factors; fetal cerebral and umbilical pulsatility indices as a sub- stitute for flow distribution and placental capacity, respectively, and fetal HC/AC ratio as a variable to describe the degree of asymmetrical growth. The calculated correlations between DV- and liver flow adjusted for BW, DV shunting fraction (%) and these markers of fetal well-being are listed in Table 4.
3.1 | Maternal ppBMI groups
In order to assess the influence of maternal ppBMI on fetal liver flow and distribution through DV, ppBMI was dichoto- mized at 25 kg/m2. The mothers in the overweight group had significantly higher fasting glucose, insulin, and triglyceride levels compared to the normal-weight group (Table 1). The fetuses in the overweight group had significantly higher birth weight z-score and subcutaneous fat mass (measured by cali- per) compared to the normal-weight group (Table 1).
The fetal glucose consumption was positively correlated with fetal liver flow for both groups, rs = .333, P = .002 for the normal-weight and rs = .436, P = .01 for the overweight group. For the fetuses in the normal-weight group there was a positive correlation with glucose consumption and DV flow, rs = .310, P = .003, but no correlation with shunting fraction, rs = −.028, P = .80. The opposite was the case for the fe- tuses in the overweight group, where there was no significant correlation with DV flow, rs = −.293, P = .10, but a nega- tive correlation with shunting fraction, rs = −.481, P = .005 (Figure 2).
The fetuses of the normal-weight mothers showed a neg- ative correlation between the maternal-fetal glucose gradient and the fetal liver flow; rs = −.290, P = .008, and a corre- sponding positive correlation between the gradient and the DV shunting fraction; rs = .319, P = .003. In the overweight group we found no correlations for the same parameters, rs = .087, P = .62, and rs = −.097, P = .65, respectively (Figure 3).
4 | DISCUSSION
The results do not support our hypothesis of a relation be- tween incoming glucose concentrations in the UV and the distribution of glucose between the liver and the systemic Fetal liver glucose supply =(
QUV−QDV)
× [G]UV Ductus venosus glucose supply =QDV× [G]UV Maternal−fetal glucose gradient = [G]radial artery− [G]UA
Fetal glucose consumption =(
[G]UV− [G]UA)
×QUV
TABLE 1 Maternal and neonatal clinical characteristics, ultrasonographic, and glucose measurements Total group n = 124 Maternal normal-weight
group n = 91 Maternal overweight group
n = 33 Mann-
Whitney U test Median (10th-90th
percentile) n (%) Median (10th-90th
percentile) n (%) Median (10th-90th percentile)
n (%) P value*
Maternal characteristics
Maternal age, years 35 (30-41) 34 (30-41) 36 (30-42) 0.37
Pre-pregnancy body mass
index 22.3 (19.5-28.4) 21.8 (19.3-23.9) 28.0 (25.6-35.8)
Systolic blood pressure 1.
trimester (mmHg) 110 (95-124) 110 (95-124) 110 (100-125) 0.34
Diastolic blood pressure 1.
trimester (mmHg) 70 (60-80) 70 (58-80) 70 (60-79) 0.29
Maternal fasting glucose
(radial artery), mmol/L 4.50 (4.03-5.15) 4.44 (4.03-5.10) 4.63 (4.27-5.30) 0.02
Maternal fasting insulin
(antecubital vein), mmol/L 50.9 (25.5-93.9) 47.0 (22.5-89.5) 66.0 (28.4-133.8) 0.007 Maternal fasting triglycerides
(antecubital vein), mmol/L 2.23 (1.54-3.22) 2.16 (1.45-2.99) 2.43 (1.88-4.35) 0.005
Higher education (>12 years) 105 (84.7) 81 (89.0) 24 (72.7) 0.03
Nulliparous 31 (25.0) 23 (25.3) 8 (24.2) 0.91
Fetal and neonatal characteristics
Gestational age, weeks + days 39+2 (38+5-39+6) 39+2 (38+3-40+1) 39+2 (38+5-39+6) 0.84 Head circumference (HC),
mm 339 (325-354) 339 (325-355) 340 (327-353) 0.67
Abdominal circumference
(AC), mm 356 (327-385) 355 (322-385) 364 (335-387) 0.08
HC/AC ratio 0.95 (0.89-1.04) 0.96 (0.90-1.04) 0.94 (0.87-1.02) 0.06
Fetal glucose (umbilical
vein), mmol/L 3.79 (3.30-4.35) 3.77 (3.27-4.32) 3.94 (3.33-4.46) 0.02
Fetal glucose (umbilical
artery), mmol/L 3.27 (2.77-3.89) 3.21 (2.69-3.88) 3.55 (2.87-3.93) 0.01
Middle cerebral artery
pulsatility index, MCA - PI 1.6 (1.1-2.0) 1.6 (1.1-2.0) 1.6 (1.1-2.0) 0.10
Umbilical artery pulsatility
index, UA - PI 0.78 (0.61-1.05) 0.78 (0.61-1.01) 0.76 (0.59-1.18) 0.80
Placental weight, g 614 (452-779) 613 (402-730) 630 (489-830) 0.08
Birth weight, g 3495 (2900-4143) 3445 (2846-4092) 3662 (3193-4257) 0.01
Birth weight z-score −0.11 (−1.27-1.21) −0.23 (−1.49-1.03) 0.25 (−0.81-1.84) 0.02
Subscapular skinfold
thickness, mm 4.6 (3.4-6.2) 4.4 (3.4-6.1) 5.2 (3.8-7.3) 0.02
Gender (males) 72 (58) 53 (58) 19 (57) 0.95
Glucose gradients and consumption Maternal-fetal glucose
gradient (mmol/L) 1.20 (0.74-1.76) 1.22 (0.77-1.74) 1.18 (0.58-1.92) 0.52
Fetal glucose consumption
(µmol/min) 96.8 (10.2-217.0) 95.5 (15.4-206.6) 98.6 (−27.6-263.4) 0.87
*P value corresponds to the comparison between the normal-weight and the overweight maternal groups.
circulation (DV) in a low risk healthy study group toward term. The distribution of umbilical glucose was, however, largely dependent on the UV blood flow. Approximately 30% of the UV blood flow and fetal glucose supply by- passed the fetal liver through DV. Importantly, this propor- tion ranged from 14% to 48% (10-90 percentile), indicating a
large variation between different individuals. Whether the in- dividual variation is caused by instant regulations at the time of sampling or as a result of a longer developmental vascular adjustment, or both, cannot be determined.
Although we did not find a direct link between variation in UV glucose levels (within a fasting range) and distribution
Umbilical vein Ductus venosus Liver Median (10th-90th
percentile) Median (10th-90th
percentile) Median (10th-90th percentile) Diameter (mm) 6.27 (4.92-7.24) 1.72 (1.19-2.25)
TAMX (m/s) 21.3 (16.7-29.6) 57.7 (47.2-69.1) Calculated blood flow
(mL/min) 196.2 (117.2-305.9) 58.9 (26.0-95.2) 134.8 (65.8-238.9) Glucose supply (µmol/
min) 742.5 (421.3-1257.8) 218.1 (102.2-359.4) 500.8 (252.9-984.1) Glucose supply
adjusted for fetal weight (µmol/min/kg)
208.5 (132.1-338.3) 62.5 (28.8-97.8) 140.6 (78.9-259.5)
Abbreviation: TAMX, time average maximum velocity.
TABLE 2 Diameter and velocity measures in the umbilical vein (UV) and ductus venosus (DV) and calculated blood flow and glucose supply in the UV, DV, and to the fetal liver
DV flow/BW
(mL/min/kg) DV shunting
fraction (%) Liver flow/BW (mL/min/kg) UV flow (mL/min) rs = 0.208 rs = −0.450 rs = 0.829
P = 0.02 P < 0.001 P < 0.001 UV glucose concentration
(mmol/L) rs = 0.029 rs = −0.033 rs = 0.053
P = 0.75 P = 0.71 P = 0.56
UV glucose supply (µmol/min)
rs = 0.198 rs = −0.426 rs = 0.770 P = 0.03 P < 0.001 P < 0.001 Abbreviations: BW, birth weight; DV, ductus venosus; rs, Spearmans rank correlation coefficient; UV, umbilical vein.
TABLE 3 Correlations of fetal umbilical vein glucose concentration, blood flow, and glucose supply in the fetal liver and ductus venosus flow distribution
DV flow/BW
(mL/min/kg) DV shunting
fraction (%) Liver flow/BW (mL/min/kg) MCA-PI (n = 121) rs = 0.135 rs = −0.149 rs = 0.286
P = 0.14 P = 0.10 P = 0.001
UA-PI (n = 122) rs = −0.099 rs = 0.131 rs = −0.213
P = 0.28 P = 0.15 P = 0.02
HC/AC ratio (n = 118) rs = −0.151 rs = 0.147 rs = −0.284
P = 0.10 P = 0.11 P = 0.002
Fetal glucose consumption
(µmol/min) (n = 121) rs = 0.141 rs = −0.156 rs = 0.358
P = 0.12 P = 0.09 P < 0.001
Maternal-fetal glucose
gradient (mmol/L) (n = 111) rs = 0.061 rs = 0.192 rs = −0.178
P = 0.52 P = 0.04 P = 0.06
Abbreviations: AC, abdominal circumference; BW, birth weight; DV, ductus venosus; HC, head
circumference; MCA, middle cerebral artery; PI, pulsatility index; rs, Spearmans rank correlation coefficient;
UA, umbilical artery.
TABLE 4 Correlations of fetal glucose consumption, maternal-fetal glucose gradient, and fetal blood flow and growth pattern with fetal liver and DV flow distribution
of liver blood flow in the current study, we cannot exclude that there are glucose-related mechanisms that influence the liver/DV distribution. We did find a correlation between the maternal-fetal glucose gradient and fetal liver and DV blood flow distribution. Higher levels of circulating glucose than in the present study or changes related to maternal food intake might have a different impact. This notion is supported by our recent finding that fetal liver flow is increased after vs before a maternal meal6 as well as after an oral glucose challenge test in large fetuses.13
As stated above the UV blood flow largely influences glu- cose distribution in the fetus. The simplest model would be that increasing blood flow in the UV leads to a corresponding
rise in blood flow, and thus glucose supply, to both the liver and the systemic circulation. However, the negative correla- tion between UV blood flow and DV shunting fraction im- plies that flow distribution is regulated at this intersection.
The mechanisms regulating the flow distribution at the left portal vein-DV intersection are elusive. Our finding that UV blood flow is closely related to the liver/DV distribution may be a result of long-term vascular adaptions rather than more acute vasomotoric regulations. A long-term vascular adap- tion could involve the intrahepatic vasculature, the left portal vein-DV intersection as well as the villous vasculature. This notion could also imply that a low proportional flow to the liver in an individual reflects that the glucose supply over
FIGURE 2 Correlations between fetal liver and ductus venosus blood flow distribution and fetal glucose consumption according to maternal pre-pregnancy body mass index. Fetal glucose consumption on the x-axis vs DV- and liver flow adjusted for BW, and DV shunting fraction on the y-axis. The normal-weight maternal group (ppBMI < 25.0 kg/m2, n = 91) on the left, and the overweight maternal group (ppBMI > 25.0 kg/m2, n = 33) on the right side. BW, birth weight; DV, ductus venosus; rs, Spearmans rank correlation coefficient; UV, umbilical vein
time has been in the lower range, given that brain and heart are prioritized organs in term of energy supply. The presence of a DV “sphincter” is controversial, and more smooth mus- cle is found in the intrahepatic branches of the portal vein than in the DV isthmus.24 The degree of DV shunting may be regulated by pressure gradients provided by increased or de- creased resistance of the hepatic vascular bed. The regulatory factors that create pressure gradients are in general divided into three categories; myogenic, neural, and humoral.25-27
Stable fetal systemic blood glucose may be achieved pri- marily by flow distribution between liver and DV, but also by adjustment of liver metabolism. Animal studies indicate that
in the case of hypoglycemia the fetal liver may induce glu- coneogenesis or glycogenolysis.28 Whether this occurs in the human fetus is unknown, but it is reasonable to assume that the human fetus strives to make the most favorable use of the resources offered, trying to find the optimal balance between energy deposition (ie, prioritizing blood flow to the liver) and brain development (ie, shunting blood to the brain).3 Several human studies in low risk populations have demonstrated a positive association between fetal liver flow and fetal vari- ables such as growth, birth weight,29,30 and fat deposition.3,4
Growth restricted fetuses often display increased head-ab- domen (HC/AC) ratio as well as increased DV-shunting
FIGURE 3 Correlations between fetal liver and ductus venosus blood flow distribution and maternal-fetal glucose gradient according to maternal pre-pregnancy body mass index. The maternal-fetal glucose gradient on the x-axis vs DV- and liver flow adjusted for BW, and DV shunting fraction on the y-axis. The normal-weight maternal group (ppBMI < 25.0 kg/m2, n = 91) on the left, and the overweight maternal group (ppBMI > 25.0 kg/m2, n = 33) on the right side. BW, birth weight; DV, ductus venosus; rs, Spearmans rank correlation coefficient ; UV, umbilical vein
fraction. This is assumed to ensure oxygen and nutritional supply to vital organs as the brain and heart.30,31 In clinical practice, MCA-PI measured by Doppler ultrasound provides information about fetal adaptation to hypoxia. In the case of low fetal blood oxygen saturation, the blood flow resistance in the fetal brain is reduced32 and more blood redistributed to the fetal brain.3,33 The cerebral vasodilatation leads to cen- tralization of blood flow, so called “brain sparing,” measured as a fall in MCA-PI.33-35 Our present findings indicate that similar mechanisms may operate in healthy fetuses in terms of glucose supply. First, we found that the HC/AC ratio was negatively correlated to liver flow. Second, the UA-PI, an in- dicator of placental vascular resistance (indicating reduced placental capacity), was negatively related to liver flow.
Third, the corresponding indicator of blood flow resistance in brain, MCA-PI, was positively correlated with liver flow.
Taken together, these findings are compatible with a notion that, even in a low risk population, slimmer fetuses with lower placental capacity (lower energy supply) prioritize blood flow to the brain and heart.3,30,36
Maternal metabolic state influences fetal growth37 and several studies have implied that alterations in liver blood flow may be part of the causal pathway. In a study of liver flow patterns in fetuses of pre-gestational diabetic mothers Lund et al found that fetuses of overweight women had a higher liver flow. Furthermore, they found that the pattern of liver flow was different between BMI groups in the di- abetic group.38 Interestingly, also in our healthy population those with ppBMI above and below 25 kg/m2 showed a di- verse pattern of fetal liver flow and shunting fraction with distinct relations to fetal glucose consumption. There was a positive correlation between fetal liver flow and fetal glucose consumption independent of maternal ppBMI. However, in the normal maternal weight group, fetal glucose consumption was positively correlated both to liver and DV-flow, whereas the shunting fraction was not. In contrast, in overweight moth- ers, blood shunted through the DV was negatively related to fetal glucose consumption. These findings suggest that in normal-weight mothers energy needed to supply the systemic circulation is well balanced with the UV supply. In over- weight mothers, however, there is a surplus supply of energy, as reflected in higher UV glucose supply, which may have resulted in a vascular adaption over time to divert more glu- cose to the liver and thereby keep the systemic glucose levels stable. In line with this observation, Kessler et al found that macrosomic fetuses continued to prioritize liver flow close to term, in contrast to normal-weight fetuses, who experienced a relative reduction in liver blood flow close to birth.29 Further underscoring the influence of maternal metabolic state, we found that the maternal-fetal glucose gradient was positively related to the proportion of blood shunted through DV and negatively related to liver flow in normal-weight women only.
In overweight mothers the energy supply, reflected in higher
UV glucose, may provide sufficient glucose to the systemic organs even in a fasting state. This notion is in line with our previous study, which revealed increased fetal liver flow as a response to a maternal meal in normal-weight as opposed to overweight women.6 Interestingly, Ikenoue et al found a sig- nificant correlation between fetal liver flow and newborn fat percentage, but in subclass analyses the relation was strength- ened in the maternal normal-weight group and disappeared in the overweight group.4 Body mass index (BMI) is often used as a proxy for body fat mass. In early pregnancy, BMI mea- sures correlate better with body fat mass than BMI measures later in pregnancy.39 Adipose tissue not only stores energy (as triglycerides), but secretes a variety of substances includ- ing hormones and inflammatory factors.40 In obese women, the physiological insulin resistance is increased across gesta- tion.41,42 It is thus of interest that our overweight population had significantly higher fasting glucose, insulin and triglycer- ide levels.
A major strength of the current work is the combi- nation of in vivo blood sampling and advanced Doppler ultrasound measurements in a substantial number of partic- ipants. A limitation is the cross-sectional study design that restricts our opportunity to draw conclusions on causality, and whether the findings are applicable at earlier gesta- tional ages. After dividing the group depending on ppBMI, the overweight maternal group counted only 33 women, which gave a low statistical power. In the calculation of blood flow, the vessel diameter is squared and any impreci- sions in the measurements would be enhanced in the final flow values. To increase the precision, a single examiner familiar with the methodology3,13,43 performed all Doppler ultrasound measurements and the mean of five to 10 re- peated diameter measurements were used.16 Our measure- ments were performed in fetal quiescence to minimize the effect of respiratory movements on the UV diameter and blood flow velocities.44 We found our measures of volume blood flow to be in line with other studies and consider the wide inter-subject variation to be physiological.6,15,43,45 Still, the methodological challenges mentioned above must be kept in mind. We did not measure hepatic arterial and portal vein blood flow. In fetal life the hepatic arteries only contribute with a minor part of the total blood supply to the fetal liver. The exact amount in human fetuses is not known, but sheep studies suggest <10%.20 Portal vein blood flow is not considered to be a source of nutrients in the fetus because of minimal nutritional uptake from the gut.29,46 Kessler et al have measured that the contribution from the portal vein accounts for 20% of the total venous blood flow to the liver near term.19
Both the ultrasound measurements and the blood sam- pling were performed in a maternal fasting state, as a con- sequence of the planned cesarean section. Consequently, all measurements are standardized concerning maternal intake
of food. However, any conclusions from the current study are limited to fasting individuals.
5 | CONCLUSION
Umbilical vein blood flow, rather than UV glucose con- centration, seems to regulate blood flow to the fetal liver vs systemic organs in healthy pregnancies at term The fetal liver may serve as a buffer against overexposure of glu- cose in order to maintain a stable systemic glucose level.
This is comparable to the liver's role in maintaining normal glucose homeostasis in born individuals.47 The heart and brain, moreover, are prioritized when the maternal-fetal gradient is high and the fetus strives for nutrition. Maternal pre-pregnancy body mass index influenced fetal handling of glucose through alterations in fetal liver blood flow distribution.
In this low risk population, leaner fetuses with higher um- bilico-placental vascular resistance, prioritized blood flow to the brain and heart. Taken together, our findings indicate that even in normal pregnancies, fetal glucose supply is regulated through subtle adjustments of blood flow related to maternal and fetal metabolic status.
ACKNOWLEDGMENTS
We thank Øystein Horgmo, Oslo University Hospital, for preparing Figures 1-3, and Manuela Zucknick for statistical help.
DISCLOSURE
The authors have nothing to disclose.
AUTHOR CONTRIBUTIONS
G.L. Opheim analyzed data; G.L. Opheim, A.M. Holme, M.B. Holm, T.M. Michelsen, S.M. Zahid, M.C.P. Roland, T. Henriksen, and G. Haugen wrote the paper; A.M. Holme, T.M. Michelsen, M.B. Holm, M.C. Paasche Roland, T. Henriksen, and G. Haugen designed research; A.M.
Holme, M.B. Holm, T.M. Michelsen, M.C.P. Roland, T.
Henriksen, and G. Haugen performed research.
REFERENCES
1. Tchirikov M, Kertschanska S, Sturenberg HJ, Schroder HJ. Liver blood perfusion as a possible instrument for fetal growth regula- tion. Placenta. 2002;23(Suppl A):S153-S158.
2. Sjogren K, Liu J-L, Blad K, et al. Liver-derived insulin-like growth factor I (IGF-I) is the principal source of IGF-I in blood but is not required for postnatal body growth in mice. Proc Natl Acad Sci USA. 1999;96(12):7088-7092.
3. Godfrey KM, Haugen G, Kiserud T, et al. Fetal liver blood flow distribution: role in human developmental strategy to prioritize fat deposition versus brain development. PLoS One. 2012;7(8):e41759.
4. Ikenoue S, Waffarn F, Ohashi M, et al. Prospective association of fetal liver blood flow at 30 weeks gestation with newborn adipos- ity. Am J Obstet Gynecol. 2017;217(2):204.e1-204.e8.
5. Haugen G, Hanson M, Kiserud T, Crozier S, Inskip H, Godfrey KM. Fetal liver-sparing cardiovascular adaptations linked to moth- er's slimness and diet. Circ Res. 2005;96(1):12-14.
6. Opheim GL, Henriksen T, Haugen G. The effect of a maternal meal on fetal liver blood flow. PLoS One. 2019;14(6):e0216176.
7. du Plessis AJ. Cerebral blood flow and metabolism in the develop- ing fetus. Clin Perinatol. 2009;36(3):531-548.
8. Battaglia FC, Meschia G. Principal substrates of fetal metabolism.
Physiol Rev. 1978;58(2):499-527.
9. Kalhan S, Parimi P. Gluconeogenesis in the fetus and neonate.
Semin Perinatol. 2000;24(2):94-106.
10. Hay WW Jr. Energy and substrate requirements of the placenta and fetus. Proc Nutr Soc. 1991;50(2):321-336.
11. Holme AM, Roland MC, Lorentzen B, Michelsen TM, Henriksen T. Placental glucose transfer: a human in vivo study. PLoS One.
2015;10(2):e0117084.
12. Michelsen TM, Holme AM, Holm MB, et al. Uteroplacental glucose uptake and fetal glucose consumption: a quantita- tive study in human pregnancies. J Clin Endocrinol Metab.
2019;104(3):873-882.
13. Haugen G, Bollerslev J, Henriksen T. Human fetoplacen- tal and fetal liver blood flow after maternal glucose loading: a cross-sectional observational study. Acta Obstet Gynecol Scand.
2014;93(8):778-785.
14. Johnsen SL, Wilsgaard T, Rasmussen S, Sollien R, Kiserud T.
Longitudinal reference charts for growth of the fetal head, abdo- men and femur. Eur J Obstet Gynecol Reprod Biol. 2006;127(2):
172-185.
15. Kiserud T, Rasmussen S, Skulstad S. Blood flow and the degree of shunting through the ductus venosus in the human fetus. Am J Obstet Gynecol. 2000;182(1 Pt 1):147-153.
16. Kiserud T, Rasmussen S. How repeat measurements affect the mean diameter of the umbilical vein and the ductus venosus.
Ultrasound Obstet Gynecol. 1998;11(6):419-425.
17. Kiserud T, Hellevik LR, Eik-Nes SH, Angelsen BA, Blaas HG.
Estimation of the pressure gradient across the fetal ductus ve- nosus based on Doppler velocimetry. Ultrasound Med Biol.
1994;20(3):225-232.
18. Ebbing C, Rasmussen S, Kiserud T. Middle cerebral artery blood flow velocities and pulsatility index and the cerebroplacental pulsatility ratio: longitudinal reference ranges and terms for se- rial measurements. Ultrasound Obstet Gynecol. 2007;30(3):
287-296.
19. Kessler J, Rasmussen S, Kiserud T. The fetal portal vein: normal blood flow development during the second half of human preg- nancy. Ultrasound Obstet Gynecol. 2007;30(1):52-60.
20. Edelstone DI, Rudolph AM, Heymann MA. Liver and duc- tus venosus blood flows in fetal lambs in utero. Circ Res.
1978;42(3):426-433.
21. Kiserud T, Hellevik LR, Hanson MA. Blood velocity profile in the ductus venosus inlet expressed by the mean/maximum velocity ratio. Ultrasound Med Biol. 1998;24(9):1301-1306.
22. Holme AM, Holm MB, Roland MCP, et al. The 4-vessel sampling approach to integrative studies of human placental physiology in vivo. J Vis Exp. 2017;126.
23. Skjaerven R, Gjessing HK, Bakketeig LS. New standards for birth weight by gestational age using family data. Am J Obstet Gynecol.
2000;183(3):689-696.
24. Tchirikov M, Schroder HJ, Hecher K. Ductus venosus shunting in the fetal venous circulation: regulatory mechanisms, diagnostic
methods and medical importance. Ultrasound Obstet Gynecol.
2006;27(4):452-461.
25. Poisson J, Lemoinne S, Boulanger C, et al. Liver sinusoidal en- dothelial cells: physiology and role in liver diseases. J Hepatol.
2017;66(1):212-227.
26. Mizuno K, Ueno Y. Autonomic nervous system and the liver.
Hepatol Res. 2017;47(2):160-165.
27. Brown JM, Scarlett JM, Schwartz MW. Rethinking the role of the brain in glucose homeostasis and diabetes pathogenesis. J Clin Investig. 2019;129(8):3035-3037.
28. Houin SS, Rozance PJ, Brown LD, Hay WW Jr, Wilkening RB, Thorn SR. Coordinated changes in hepatic amino acid metabo- lism and endocrine signals support hepatic glucose production during fetal hypoglycemia. Am J Physiol Endocrinol Metab.
2015;308(4):E306-E314.
29. Kessler J, Rasmussen S, Godfrey K, Hanson M, Kiserud T. Venous liver blood flow and regulation of human fetal growth: evidence from macrosomic fetuses. Am J Obstet Gynecol. 2011;204(5): 429.
e1-429.e7.
30. Kiserud T, Kessler J, Ebbing C, Rasmussen S. Ductus veno- sus shunting in growth-restricted fetuses and the effect of um- bilical circulatory compromise. Ultrasound Obstet Gynecol.
2006;28(2):143-149.
31. Kessler J, Rasmussen S, Godfrey K, Hanson M, Kiserud T. Fetal growth restriction is associated with prioritization of umbilical blood flow to the left hepatic lobe at the expense of the right lobe.
Pediatr Res. 2009;66(1):113-117.
32. Chiba Y, Murakami M. Cerebral blood flow dynamics in fetus. No to Hattatsu Brain Develop. 1992;24(2):136-139.
33. Wladimiroff JW, Tonge HM, Stewart PA. Doppler ultrasound as- sessment of cerebral blood flow in the human fetus. Br J Obstet Gynaecol. 1986;93(5):471-475.
34. Mari G, Moise KJ Jr, Deter RL, Kirshon B, Carpenter RJ Jr, Huhta JC. Doppler assessment of the pulsatility index in the ce- rebral circulation of the human fetus. Am J Obstet Gynecol.
1989;160(3):698-703.
35. Wladimiroff JW, van den Wijngaard JA, Degani S, Noordam MJ, van Eyck J, Tonge HM. Cerebral and umbilical arterial blood flow velocity waveforms in normal and growth-retarded pregnancies.
Obstet Gynecol. 1987;69(5):705-709.
36. Bellotti M, Pennati G, De Gasperi C, Bozzo M, Battaglia FC, Ferrazzi E. Simultaneous measurements of umbilical venous, fetal hepatic, and ductus venosus blood flow in growth-restricted human fetuses. Am J Obstet Gynecol. 2004;190(5):1347-1358.
37. Roland MCP, Friis CM, Voldner N, et al. Fetal growth versus birth- weight: the role of placenta versus other determinants. PLoS One.
2012;7(6):e39324.
38. Lund A. Maternal Diabetes Mellitus and Fetal Venous Liver Flow—A Longitudinally Study [Medicine]. Bergen: University of Bergen; 2019.
39. Sewell MF, Huston-Presley L, Amini SB, Catalano PM. Body mass index: a true indicator of body fat in obese gravidas. J Reprod Med. 2007;52(10):907-911.
40. Shoelson SE, Herrero L, Naaz A. Obesity, inflammation, and insu- lin resistance. Gastroenterology. 2007;132(6):2169-2180.
41. Catalano PM, Presley L, Minium J, Hauguel-de MS. Fetuses of obese mothers develop insulin resistance in utero. Diabetes Care.
2009;32(6):1076-1080.
42. Catalano PM, Shankar K. Obesity and pregnancy: mechanisms of short term and long term adverse consequences for mother and child. BMJ. 2017;356:j1-j.
43. Haugen G, Kiserud T, Godfrey K, Crozier S, Hanson M. Portal and umbilical venous blood supply to the liver in the human fetus near term. Ultrasound Obstet Gynecol. 2004;24(6):599-605.
44. Nyberg MK, Johnsen SL, Rasmussen S, Kiserud T. Fetal breath- ing is associated with increased umbilical blood flow. Ultrasound Obstet Gynecol. 2010;36(6):718-723.
45. Acharya G, Wilsgaard T, Berntsen GKR, Maltau JM, Kiserud T. Reference ranges for serial measurements of umbilical artery Doppler indices in the second half of pregnancy. Am J Obstet Gynecol. 2005;192(3):937-944.
46. Ebbing C, Rasmussen S, Kiserud T. Fetal hemodynamic de- velopment in macrosomic growth. Ultrasound Obstet Gynecol.
2011;38(3):303-308.
47. Petersen MC, Vatner DF, Shulman GI. Regulation of hepatic glucose metabolism in health and disease. Nat Rev Endocrinol.
2017;13(10):572-587.
How to cite this article: Opheim GL, Moe Holme A, Blomhoff Holm M, et al. The impact of umbilical vein blood flow and glucose concentration on blood flow distribution to the fetal liver and systemic organs in healthy pregnancies. The FASEB Journal. 2020;34:
12481–12491. https://doi.org/10.1096/fj.20200 0766R
