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Fetal growth is closely linked to the placental circulation. At mid-gestation 30% of the combined fetal cardiac output is directed to the placenta, a fraction that declines to 20% near term1. During placental compromise this decline is augmented and appears at earlier stages of pregnancy1, 2. The fetus adapts to such constraints by diverting an increased fraction of the umbilical return from the liver to ensure oxygen delivery to the heart and brain through the ductus venosus3. However, it has become increasingly clear that the fetal liver is an important determinant of fetal growth. In the human fetus, the liver receives 75–80% of the umbilical flow4, and in fetal lambs the umbilical venous (UV) perfusion of the liver regulates hepatocyte proliferation and production of insulin-like growth factors 1 and 2. In turn, this stimulates proliferation and growth in the rest of the fetal body5, 6. Studies of UV distribution in physiologic pregnancies and intrauterine growth restriction3, 7, 8 support the assumption that these mechanisms also operate in human fetuses. Data also suggest that the UV perfusion of the liver determines fat accretion with postnatal consequences9 while the arterial circulation of the fetal liver and gut is more a marker of auto-regulation10–12 and compensatory responses to placental compromise and fetal growth restriction13. The umbilicocaval pressure gradient (which is the same as the portocaval pressure gradient) drives venous liver perfusion. In this study we utilized measurements of the peak systolic blood velocity in the portocaval shunt ductus venosus as a direct representation of this pressure gradient14–17. Accordingly, we here hypothesize that nutritional availability and macrosomic growth are reflected in venous return from the placenta and its distributional pattern rather than in arterial flow velocities and impedance.
The aim of the present study was to carry out a longitudinal assessment of the venous and arterial hemodynamic development of macrosomic fetuses during the second half of pregnancy.
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Of the 58 participants, 29 gave birth to a large neonate with birth weight ≥ 90th centile according to Norwegian standards adjusted for gestational age and sex20. These 29 participants had 111 sessions of examinations and the corresponding number of data sets were included in the analysis and compared with the reference population. In the study population 1/29, 3/29, 20/29 and 5/29 participants had two, three, four and five sets of examinations, respectively. Characteristics of the study and reference populations are given in Table 1. All the women were Caucasian and only one was a smoker. There were four operative deliveries; two emergency Cesarean sections (one for threatening asphyxia and one for obstructed labor) and one elective Cesarean section (because of obstetric history). One forceps delivery was performed because of obstructed second stage of labor. None of the neonates had an Apgar score of < 7 at 5 min.
Table 1. Characteristics of the study population and the reference population
|Characteristic||Study population (n = 29)||Reference population (n = 161)||P|
|Maternal age at inclusion (years)||31 (22–42)||29 (20–40)||< 0.05*|
|Parity||2 (1–7)||1 (0–5)||< 0.0001†‡|
|Body mass index at first visit (kg/m2)||25.2 (20.1–45.8)||22.9 (18.1–40.8)||< 0.05*|
|Maternal height (cm)||170 (160–186)||167 (150–183)||NS*|
|Maternal weight gain (kg)||15.2 (0–26.5)||14 (0–55)||NS*|
|Gestational age at delivery (weeks)||41 (38.1–43.0)||40.4 (35.4–42.6)||< 0.05*|
|Birth weight (g)||4550 (4035–5210)||3700 (2260–4980)||< 0.05*|
Reasons for missing measurements were suboptimal visualization due to maternal adiposity, unfavorable fetal position, fetal movements and time constraints (Table 2). UV flow and UV distribution to the right liver lobe (assessed by TAMXV in the left portal vein) were higher during the second half of pregnancy in the fetuses that became macrosomic (Figures 1a and c and Table 2). Even more striking was the finding that the UV return was approximately 35% higher when normalized for estimated fetal weight (mL/min/kg; Figure 1b, Table 2). Ductus venosus peak systolic velocity—reflecting umbilicocaval perfusion pressure—was marginally higher in the macrosomic fetuses (Figure 2 and Table 2), whereas the arterial flow velocities were all significantly increased except for that of the hepatic artery (Table 2). Arterial impedance (as reflected by PI) was unaltered in all vessels except for the umbilical artery, where it was significantly lower in the study population.
Figure 1. Umbilical venous (UV) blood flow (a), normalized UV blood flow (b), and distribution of UV blood to the right liver lobe expressed by left portal vein time-averaged maximum velocity (TAMXV) (c) in macrosomic fetuses (_____) and in the reference population (). Non-overlapping 95% CI for the means (thin lines) indicates significant differences. Z-score statistics: P < 0.0001 for all variables.
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Table 2. Flow parameters of the macrosomic fetuses compared with the reference population10
| ||Study population||Reference population|| |
|Parameter||Mean ± SE (95% CI)||n||Mean ± SE (95% CI)||n||P*|
|UV flow (mL/min)||1.21 ± 0.11 (0.99 to 1.43)||92||0 ± 0.05 (−0.09 to 0.09)||525||< 0.0001|
|UV flow normalized (mL/min/kg)||0.85 ± 0.11 (0.64 to 1.06)||90||0 ± 0.05 (−0.09 to 0.09)||511||< 0.0001|
|LPV-TAMXV (cm/s)||0.75 ± 0.12 (0.52 to 0.98)||71||− 0.02 ± 0.06 (−0.14 to 0.1)||272||< 0.0001|
|DV-PSV (cm/s)||0.26 ± 0.1 (0.06 to 0.46)||96||0 ± 0.04 (−0.08 to 0.09)||550||0.019|
|HA-PSV (cm/s)||− 0.17 ± 0.14 (−0.45 to 0.1)||55||0.01 ± 0.08 (−0.15 to 0.17)||162||0.265|
|HA-PI||0.08 ± 0.13 (−0.18 to 0.33)||55||− 0.01 ± 0.08 (−0.16 to 0.14)||162||0.57|
|SMA-PSV (cm/s)||0.35 ± 0.1 (0.15 to 0.55)||95||0 ± 0.04 (−0.08 to 0.08)||543||0.002|
|SMA-PI||0.02 ± 0.1 (−0.17 to 0.21)||95||− 0.01 ± 0.04 (−0.09 to 0.08)||543||0.8|
|SA-PSV (cm/s)||0.29 ± 0.11 (0.08 to 0.5)||92||0.02 ± 0.05 (−0.07 to 0.11)||489||0.019|
|SA-PI||0.12 ± 0.1 (−0.08 to 0.31)||94||− 0.02 ± 0.05 (−0.11 to 0.07)||489||0.2|
|MCA-PSV (cm/s)||0.38 ± 0.11 (0.17 to 0.58)||95||0.03 ± 0.04 (−0.06 to 0.12)||524||< 0.0001|
|MCA-PI||0.18 ± 0.1 (−0.02 to 0.38)||95||0 ± 0.04 (−0.08 to 0.09)||519||0.094|
|UA-PSV (cm/s)||0.33 ± 0.1 (0.14 to 0.53)||101||− 0.03 ± 0.04 (−0.11 to 0.06)||562||0.001|
|UA-PI||− 0.49 ± 0.1 (−0.68 to − 0.29)||101||0.01 ± 0.04 (−0.07 to 0.09)||562||< 0.0001|
The birth weight to placenta weight ratio was the same in the study and the reference group, mean 5.3 (95% CI, 5.1–5.5) vs. 5.3 (95% CI, 4.9–5.6), respectively.
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In this study of healthy non-diabetic women with fetuses that became macrosomic, we found notably higher UV flow, higher venous perfusion pressure of the fetal liver and enhanced umbilical blood distribution to the right liver lobe during the second half of pregnancy compared with a reference population. The augmented umbilical flow was also substantial when normalized for estimated fetal weight. In low-risk pregnancies fetal growth is undiminished during the last weeks of pregnancy29, suggesting a continued increase in nutrient availability that is not correspondingly supported by the UV flow, which had a reduced increment near term (Figure 1a)4, 30. Interestingly, in the macrosomic fetuses, in addition to having higher UV flow per kg than expected, the UV flow also continued to increase during the last weeks of pregnancy, supporting the concept that the hemodynamic effect of umbilical liver perfusion is a determinant of growth in its own right. The concept is supported by experimental studies in sheep and a recent similar study of macrosomic fetuses5, 6, 31.
Increased TAMXV in the left portal vein has been shown to correlate well with increased distribution of UV blood to the right liver lobe27. In contrast, in intrauterine growth restriction, the UV supply to the liver and the right liver lobe is reduced3, 8, 13, 26, and in extreme cases of placental compromise the right liver lobe receives exclusively portal venous and no UV blood8. Our finding of increased UV hepatic perfusion pressure and high umbilical blood-flow velocity directed to the right liver lobe is in line with another study of macrosomic growth31 showing an increased UV liver supply, including the right liver. Such changes may be related to lasting metabolic and homeostatic patterns, since to be born large for gestational age is a risk factor for developing obesity and related diseases later in life32–34. Our study population had a higher body mass index than did controls, which is a known risk factor for increased birth weight, but no relationship was demonstrated between maternal weight gain and birth weight35, possibly due to small sample size.
In pregnancies complicated by diabetes, altered maternal substrate levels and placental nutrient transport and metabolism are thought to be major factors underlying excessive fetal growth36. In such pregnancies the placental weight to birth weight ratio was high37. In our study the women were non-diabetic and the relationship between birth weight and placental weight was normal, suggesting that abnormal placental metabolism and transport were not the primary cause of extreme growth in our study population.
An increased flow velocity in all arteries except the hepatic artery reflects increased volume flow and organ size38. Increased flow velocity in the splenic and superior mesenteric arteries is in agreement with increased portal return from the splanchnic organs in macrosomic fetuses31. However, hepatic artery flow velocity and PI did not differ from those of the reference population, although we expected the liver to be larger in the macrosomic fetuses. This fits with the assumption that the hepatic artery buffer response (HABR) was not activated in macrosomic fetuses. The HABR is known in postnatal life as a powerful auto-regulatory system that is activated when portal sinusoid perfusion is reduced39. The mechanism has also been shown to operate during prenatal life, a period when portal liver perfusion is dominated by the umbilical flow10–12. We observed signs of increased portal perfusion pressure and flow in the macrosomic fetuses (Figures 1 and 2 and Table 2), supporting our assumption that the hepatic artery parameters reflect auto-regulatory status rather than actual liver size. A similar pattern of unaltered PI was seen for the spleen, gut and brain.
The combination of increased flow velocity and reduced PI in the umbilical arteries supplying the placenta with blood from the fetus, and increased UV return to the fetus implies augmented placental perfusion in the macrosomic fetuses during the second half of pregnancy. This is in keeping with the concept that in these fetuses less of the cardiac output is recycled within the fetal body and more is directed to the placenta31, and in contrast to fetal growth restriction where more of the combined cardiac output is recycled1.
In conclusion, our study shows that non-diabetic macrosomic growth is associated with augmented hemodynamics, particularly on the venous side, with a maintained increase in flow until term, while the arterial side mainly reflects the fact that auto-regulatory systems are not activated. In addition to supporting the concept that UV perfusion of the liver is a growth-driving mechanism in its own right, we believe that our data will be useful for future studies of abnormal excessive fetal growth such as in diabetic pregnancies.