Fetal hemodynamic development in ... - Wiley Online Library

Ultrasound Obstet Gynecol 2011; 38: 303–308 Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.9046

Fetal hemodynamic development in macrosomic growth C. EBBING, S. RASMUSSEN and T. KISERUD Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway and Department of Clinical Medicine, University of Bergen, Norway

K E Y W O R D S: blood flow; circulation; Doppler; fetus; growth; liver; macrosomia

ABSTRACT

INTRODUCTION

Objective To determine the venous and arterial hemodynamics underlying macrosomic fetal growth.

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

Methods Fifty-eight healthy women who previously had given birth to a large neonate were included in a prospective longitudinal study. Of these, 29 gave birth to neonates with birth weight ≥ 90th percentile and were included in the statistical analysis. Umbilical vein blood flow and Doppler measurements of the ductus venosus, left portal vein and the hepatic, splenic, superior mesenteric, cerebral and umbilical arteries were repeated at 3–5 examinations during the second half of pregnancy and compared with the corresponding reference values. Ultrasound biometry was used to estimate fetal weight. Results Umbilical blood flow increased faster in macrosomic fetuses, showed less blunting near term and was also significantly higher when normalized for estimated fetal weight (P < 0.0001). The portocaval perfusion pressure of the liver (expressed by the ductus venosus systolic blood velocity) and the left portal vein blood velocity (expressing umbilical venous distribution to the right liver lobe) were significantly higher. Systolic velocity was higher in the splenic, superior mesenteric, cerebral and umbilical arteries, while the pulsatility index was unaltered in the cerebral, hepatic, splenic and mesenteric arteries, but lower in the umbilical artery. Conclusions There is an augmented umbilical flow in macrosomic fetuses particularly near term, also when normalized for estimated fetal weight, providing increased liver perfusion, including the right liver lobe. Signs of increased vascular cross section and flow are also seen on the arterial side but not expressed in the pulsatility index of organs with prominent auto-regulation (i.e. brain, liver, spleen and gut). Copyright  2011 ISUOG. Published by John Wiley & Sons, Ltd.

Correspondence to: Dr C. Ebbing, Department of Obstetrics and Gynecology, Haukeland University Hospital, N-5021 Bergen, Norway (e-mail: [email protected]) Accepted: 21 April 2011

Copyright  2011 ISUOG. Published by John Wiley & Sons, Ltd.

ORIGINAL PAPER

Ebbing et al.

304

hemodynamic development of macrosomic fetuses during the second half of pregnancy.

METHODS Subjects For this prospective longitudinal study 58 healthy, nondiabetic pregnant women who had previously given birth to a large neonate (birth weight ≥ 4200 g) were recruited. The Regional Committee for Medical Research Ethics approved the study protocol (REK Vest no 203.03), and all participants gave prior written consent. Gestational age was determined by fetal head circumference at the routine ultrasound scan at 17–20 weeks’ gestation18 or firsttrimester measurement of crown–rump length19 . Twin pregnancies and those with chromosomal aberrations, malformations or maternal diabetes were excluded from the study. Birth weight, placental weight, sex, gestational age at and mode of delivery and 5-min Apgar score were noted. Birth weight ≥ 90th centile according to Norwegian sex-specific standards20 was considered eligible for inclusion in the analysis. The reference population consisted of 161 women with low-risk pregnancies included in a longitudinal study. Their population characteristics21 and Doppler reference ranges10 – 12,21 have been described previously.

Ultrasound measurements The participants were scheduled for four examinations at 3–5-week intervals during the second half of pregnancy. During each 1-hour session the participants were examined using a 2–5-, 2–7- or 4–8-MHz transabdominal transducer (Voluson 730 Expert, GE Medical Systems, Kretz Ultrasound, Zipf, Austria) with the high-pass filter set to 70 Hz. The women were examined for no more than 60 min in a semi-recumbent position with a pillow underneath the knees. We videotaped one typical examination session and timed the use of different ultrasound modes. Pulsed Doppler time constituted 11%, color Doppler 40% and grayscale ultrasound 33% of the total examination time, the remaining 16% being frozen-image time. The mechanical and thermal indices were for the most part kept at < 1.1 and < 0.9, respectively, but occasionally reached 1.9 and 1.5. Blood flow velocities, peak systolic velocity and timeaveraged maximum velocity (TAMXV) were measured using Doppler ultrasound in the middle cerebral, umbilical, hepatic, splenic and superior mesenteric arteries, the intra-abdominal umbilical and left portal veins and the ductus venosus. Fetal weight was estimated from biometry of the head, abdominal circumference and femur length22 . Blood-flow velocities in the study group were measured using the same techniques as in the reference studies10 – 12 . Briefly, the umbilical artery was assessed in a free-floating loop of the umbilical cord and the middle cerebral artery at the proximal


part of the vessel23 . The hepatic artery was insonated in an axial or sagittal view of the fetal abdomen and flow velocity assessed close to the ductus venosus10 . The splenic artery was identified in an axial view at its origin from the celiac artery in front of the aorta and posterior to the stomach24 . The superior mesenteric artery was identified as the second of the anterior unpaired arteries from the abdominal aorta, and again the sample volume was placed at the proximal part of the vessel25 . UV flow was estimated from repeated measurements (at least three) of the inner diameter and flow velocity in the intraabdominal umbilical vein26 . Prenatally, the left portal vein connects the umbilical vein to the portal circulation. We utilized blood velocity in the left portal vein as a direct reflection of the UV distribution to the right liver lobe27 . The Doppler insonation was aligned to the left portal vein with a small sample volume placed between the ductus venosus inlet and the junction with the main portal stem in order to measure the TAMXV28 . The ductus venosus blood velocity (reflecting the portocaval pressure gradient17 ) was assessed in a sagittal or oblique section of the fetal abdomen15 . We determined flow velocity (in the veins for 2–4 s and in the arteries for at least three heart cycles) and pulsatility index (PI) during fetal quiescence over at least three uniform cardiac cycles.

Statistical analysis Standard deviation scores were calculated based on power-transformed mean and SD values for the reference population and then modeled against gestational age by multilevel regression. Multilevel t-test was used to assess differences. Lack of overlap of the 95% CI of means was considered a significant difference. Otherwise, P ≤ 0.05 was regarded as statistically significant. Statistical analysis was carried out using the Statistical Package for the Social Sciences (SPSS Inc., Chicago, IL, USA) and the MLWin program (MLWin; Centre for Multilevel Modelling, University of Bristol, UK).

RESULTS 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.

Ultrasound Obstet Gynecol 2011; 38: 303–308.

Hemodynamics in fetal macrosomia

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Table 1 Characteristics of the study population and the reference population

Characteristic Maternal age at inclusion (years) Parity Body mass index at first visit (kg/m2 ) Maternal height (cm) Maternal weight gain (kg) Gestational age at delivery (weeks) Birth weight (g) Male gender

Study population (n = 29)

Reference population (n = 161)

P

31 (22–42) 2 (1–7) 25.2 (20.1–45.8) 170 (160–186) 15.2 (0–26.5) 41 (38.1–43.0) 4550 (4035–5210) 31

29 (20–40) 1 (0–5) 22.9 (18.1–40.8) 167 (150–183) 14 (0–55) 40.4 (35.4–42.6) 3700 (2260–4980) 50.3

< 0.05* < 0.0001†‡ < 0.05* NS* NS* < 0.05* < 0.05* 0.056†

Data expressed as median (range) or %. *Mann–Whitney U-test. †Pearson chi-square test. ‡Parity grouped as 0, 1 and 2+ for statistical analysis. (a) UV blood flow (mL/min)

400


350 300 250 200 150 100 50 0 20

(b)

140 120

DISCUSSION

25

30 35 Gestational age (weeks)

40

25


40

25


40

100 80 60 40 20 0 20

(c)

18

Left portal vein TAMXV (cm/s)

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 .

450

Normalized UV blood flow (mL/min)/kg)

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. 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.

16 14 12 10 8 6 4 2 0 20

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 ) and in the reference (TAMXV) (c) in macrosomic fetuses ( ). Non-overlapping 95% CI for the means (thin population ( lines) indicates significant differences. Z-score statistics: P < 0.0001 for all variables. Ultrasound Obstet Gynecol 2011; 38: 303–308.

Ebbing et al.

306 Table 2 Flow parameters of the macrosomic fetuses compared with the reference population10 Study population Parameter UV flow (mL/min) UV flow normalized (mL/min/kg) LPV-TAMXV (cm/s) DV-PSV (cm/s) HA-PSV (cm/s) HA-PI SMA-PSV (cm/s) SMA-PI SA-PSV (cm/s) SA-PI MCA-PSV (cm/s) MCA-PI UA-PSV (cm/s) UA-PI

Reference population

Mean ± SE (95% CI)

n

Mean ± SE (95% CI)

n

P*

1.21 ± 0.11 (0.99 to 1.43) 0.85 ± 0.11 (0.64 to 1.06) 0.75 ± 0.12 (0.52 to 0.98) 0.26 ± 0.1 (0.06 to 0.46) −0.17 ± 0.14 (−0.45 to 0.1) 0.08 ± 0.13 (−0.18 to 0.33) 0.35 ± 0.1 (0.15 to 0.55) 0.02 ± 0.1 (−0.17 to 0.21) 0.29 ± 0.11 (0.08 to 0.5) 0.12 ± 0.1 (−0.08 to 0.31) 0.38 ± 0.11 (0.17 to 0.58) 0.18 ± 0.1 (−0.02 to 0.38) 0.33 ± 0.1 (0.14 to 0.53) −0.49 ± 0.1 (−0.68 to −0.29)

92 90 71 96 55 55 95 95 92 94 95 95 101 101

0 ± 0.05 (−0.09 to 0.09) 0 ± 0.05 (−0.09 to 0.09) −0.02 ± 0.06 (−0.14 to 0.1) 0 ± 0.04 (−0.08 to 0.09) 0.01 ± 0.08 (−0.15 to 0.17) −0.01 ± 0.08 (−0.16 to 0.14) 0 ± 0.04 (−0.08 to 0.08) −0.01 ± 0.04 (−0.09 to 0.08) 0.02 ± 0.05 (−0.07 to 0.11) −0.02 ± 0.05 (−0.11 to 0.07) 0.03 ± 0.04 (−0.06 to 0.12) 0 ± 0.04 (−0.08 to 0.09) −0.03 ± 0.04 (−0.11 to 0.06) 0.01 ± 0.04 (−0.07 to 0.09)

525 511 272 550 162 162 543 543 489 489 524 519 562 562

< 0.0001 < 0.0001 < 0.0001 0.019 0.265 0.57 0.002 0.8 0.019 0.2 < 0.0001 0.094 0.001 < 0.0001

95% CI given for the mean value. n given for number of measurements. *t-test. CI, confidence interval; DV, ductus venosus; HA, hepatic artery; LPV, left portal vein; MCA, middle cerebral artery; PI, pulsatility index; PSV, peak systolic velocity; SA, splenic artery; SE, standard error; SMA, superior mesenteric artery; TAMXV, time-averaged maximum velocity; UA, umbilical artery; UV, umbilical vein. 100

DV-PSV (cm/s)

80

60

40

20

0 20

25


40

Figure 2 Individual values of ductus venosus peak systolic velocity ) and 95% CI (DV-PSV) in macrosomic fetuses ( ) with mean ( ) of these values shown, along with the mean of the mean ( ( ), 95% CI of the mean ( ) and 5th and 95th centiles ( ) of the reference population, showing a significant difference between groups (P = 0.019).

°

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.


Hemodynamics in fetal macrosomia 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.

ACKNOWLEDGMENT C.E. was supported financially by the Western Norway Regional Health Authority (Post doctoral grant no 911581).

REFERENCES 1. Kiserud T, Ebbing C, Kessler J, Rasmussen S. Fetal cardiac output, distribution to the placenta and impact of placental compromise. Ultrasound Obstet Gynecol 2006; 28: 126–136. 2. Rizzo G, Capponi A, Cavicchioni O, Vendola M, Arduini D. Low cardiac output to the placenta: an early hemodynamic adaptive mechanism in intrauterine growth restriction. Ultrasound Obstet Gynecol 2008; 32: 155–159. 3. Kiserud T, Kessler J, Ebbing C, Rasmussen S. Ductus venosus shunting in growth-restricted fetuses and the effect of umbilical circulatory compromise. Ultrasound Obstet Gynecol 2006; 28: 143–149. 4. 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: 147–153. ¨ ¨ 5. Tchirikov M, Kertschanska S, Sturenberg HJ, Schroder HJ. Liver blood perfusion as a possible instrument for fetal growth regulation. Placenta 2002; 23 (Suppl A): S153–S158. ¨ 6. Tchirikov M, Kertschanska S, Schroder HJ. Obstruction of ductus venosus stimulates cell proliferation in organs of fetal sheep. Placenta 2001; 22: 24–31. 7. 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: 1347–1358. 8. 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: 113–117. 9. Haugen G, Harvey N, Cooper C, Crozier S, Hanson M, Inskip H, Kiserud T, Godfrey K. Human neonatal body composition is related to umbilical venous and fetal liver blood flows independently of placental size. Pediatr Res 2005; 58: 1123. 10. Ebbing C, Rasmussen S, Godfrey KM, Hanson MA, Kiserud T. Hepatic artery hemodynamics suggest operation of a buffer response in the human fetus. Reprod Sci 2008; 15: 166–178.


307 11. Ebbing C, Rasmussen S, Godfrey KM, Hanson MA, Kiserud T. Fetal celiac and splenic artery flow velocity and pulsatility index: longitudinal reference ranges and evidence for vasodilation at a low portocaval pressure gradient. Ultrasound Obstet Gynecol 2008; 32: 663–672. 12. Ebbing C, Rasmussen S, Godfrey KM, Hanson MA, Kiserud T. Fetal superior mesenteric artery: longitudinal reference ranges and evidence of regulatory link to portal liver circulation. Early Hum Dev 2009; 85: 207–213. 13. Ebbing C, Rasmussen S, Godfrey KM, Hanson MA, Kiserud T. Redistribution pattern of fetal liver circulation in intrauterine growth restriction. Acta Obstet Gynecol Scand 2009; 88: 1118–1123. ¨ 14. Schroder HJ, Tchirikov M, Rybakowski C. Pressure pulses and flow velocities in central veins of the anesthetized sheep fetus. Am J Physiol Heart Circ Physiol 2003; 284: H1205–H1211. 15. Kiserud T, Eik-Nes SH, Blaas HGK, Hellevik LR. Ultrasonographic velocimetry of the fetal ductus venosus. Lancet 1991; 338: 1412–1414. 16. Kiserud T, Hellevik LR, Eik-Nes SH, Angelsen BAJ, Blaas HG. Estimation of the pressure gradient across the fetal ductus venosus based on Doppler velocimetry. Ultrasound Med Biol 1994; 20: 225–232. 17. Hellevik LR, Kiserud T, Irgens F, Ytrehus T, Eik-Nes SH. Simulation of pressure drop and energy dissipation for blood flow in a human fetal bifurcation. J Biomech Eng 1998; 120: 455–462. 18. Johnsen SL, Rasmussen S, Sollien R, Kiserud T. Fetal age assessment based on ultrasound head biometry and the effect of maternal and fetal factors. Acta Obstet Gynecol Scand 2004; 83: 716–723. 19. Robinson HP, Fleming JEE. A critical evaluation of sonar ‘‘crown–rump length’’ measurements. Br J Obstet Gynaecol 1975; 82: 702–710. 20. Skjaerven R, Gjessing HK, Bakketeig LS. Birthweight by gestational age in Norway. Acta Obstet Gynecol Scand 2000; 79: 440–449. 21. 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 serial measurements. Ultrasound Obstet Gynecol 2007; 30: 287–296. 22. Combs CA, Jaekle RK, Rosenn B, Pope M, Miodovnik M, Siddiqi TA. Sonographic estimation of fetal weight based on a model of fetal volume. Obstet Gynecol 1993; 82: 365–370. 23. Mari G, Abuhamad AZ, Cosmi E, Segata M, Altaye M, Akiyama M. Middle cerebral artery peak systolic velocity: technique and variability. J Ultrasound Med 2005; 24: 425–430. 24. Abuhamad AZ, Mari G, Bogdan D, Evans AT 3rd . Doppler flow velocimetry of the splenic artery in the human fetus: is it a marker of chronic hypoxia? Am J Obstet Gynecol 1995; 172: 820–825. 25. Mari G, Abuhamad AZ, Uerpairojkit B, Martinez E, Copel JA. Blood-flow velocity wave-forms of the abdominal arteries in appropriate-for-gestational-age and small-for-gestational-age fetuses. Ultrasound Obstet Gynecol 1995; 6: 15–18. 26. Kiserud T, Eik-Nes SH, Blaas HG, Hellevik LR, Simensen B. Ductus venosus blood velocity and the umbilical circulation in the seriously growth-retarded fetus. Ultrasound Obstet Gynecol 1994; 4: 109–114. 27. Kessler J, Rasmussen S, Kiserud T. The left portal vein as an indicator of watershed in the fetal circulation: development during the second half of pregnancy and a suggested method of evaluation. Ultrasound Obstet Gynecol 2007; 30: 757–764. 28. Kiserud T, Kilavuz O, Hellevik LR. Venous pulsation in the fetal left portal branch: the effect of pulse and flow direction. Ultrasound Obstet Gynecol 2003; 21: 359–364. 29. Johnsen SL, Rasmussen S, Wilsgaard T, Sollien R, Kiserud T. Longitudinal reference ranges for estimated fetal weight. Acta Obstet Gynecol Scand 2006; 85: 286–297.


Ebbing et al.

308 30. Acharya G, Wilsgaard T, Berntsen GKR, Maltau JM, Kiserud T. Reference ranges for umbilical vein blood flow in the second half of pregnancy based on longitudinal data. Prenat Diagn 2005; 25: 99–111. 31. 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: 429.e1–7. 32. Eriksson J, Fors´en T, Tuomilehto J, Osmond C, Barker D. Size at birth, childhood growth and obesity in adult life. Int J Obes Relat Metab Disord 2001; 25: 735–740. 33. Oken E, Gillman MW. Fetal origins of obesity. Obes Res 2003; 11: 496–506. 34. Ong KK, Dunger DB. Birth weight, infant growth and insulin resistance. Eur J Endocrinol 2004; 151 (Suppl 3): U131–U139. 35. Ludwig DS, Currie J. The association between pregnancy weight


36.

37.

38.

39.

gain and birthweight: a within-family comparison. Lancet 2010; 376: 984–990. Jansson T, Cetin I, Powell TL, Desoye G, Radaelli T, Ericsson A, Sibley CP. Placental transport and metabolism in fetal overgrowth – a workshop report. Placenta 2006; 27 (Suppl A): S109–S113. Lao TT, Lee CP, Wong WM. Placental weight to birthweight ratio is increased in mild gestational glucose intolerance. Placenta 1997; 18: 227–230. Acharya G, Wilsgaard T, Berntsen GKR, Maltau JM, Kiserud T. Doppler-derived umbilical artery absolute velocities and their relationship to fetoplacental volume blood flow: a longitudinal study. Ultrasound Obstet Gynecol 2005; 25: 444–453. Lautt WW. The 1995 Ciba-Geigy Award Lecture. Intrinsic regulation of hepatic blood flow. Can J Physiol Pharmacol 1996; 74: 223–233.
