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Echogenic bowel in intrauterine growth restriction fetuses: does this jeopardize the gut?
Echogenic Bowel in Intrauterine Growth Restriction Fetuses: Does This Jeopardize the Gut? Reuwen Achiron, MD, Rami Mazkereth, MD, Raoul Orvieto, MD, Jacob Kuint, MD, Shlomo Lipitz, MD, and Zeev Rotstein, MD OBJECTIVE: To investigate the association between intrauterine growth restriction (IUGR) fetuses with echogenic bowel and high resistance in the umbilical artery and increased risk of developing neonatal necrotizing enterocolitis. METHODS: We analyzed two groups: group 1, singleton IUGR fetuses with echogenic bowel or reversed diastolic flow in the umbilical artery, and group 2, neonates who were diagnosed as having neonatal necrotizing enterocolitis. In group 1, the pulsatility index of the superior mesenteric artery and celiac trunk were determined. In group 2, a retrospective analysis was carried out from the medical records of the neonates. RESULTS: Fifteen fetuses with echogenic bowel and severe IUGR were evaluated by Doppler studies, and 21 neonates with neonatal necrotizing enterocolitis were reviewed. In group 1, none of the IUGR fetuses developed neonatal necrotizing enterocolitis, whereas in group 2, only one neonate was defined as IUGR. The mean gestational age at delivery did not differ statistically between the two groups (28.8 ⴞ 2.3 weeks versus 30.1 ⴞ 3.3 weeks), whereas the mean birth weight was significantly lower in the first group (700 ⴞ 200 g versus 1431 ⴞ 466 g in the second group, P < .001). The mean pulsatility index ⴞ standard deviation in the superior mesenteric artery and celiac trunk of the IUGR fetuses were 1.5 ⴞ 0.14 and 1.2 ⴞ 0.17, respectively, both being found significantly lower than those of normal, appropriate controls (1.9 ⴞ 0.15 and 1.7 ⴞ 0.1, respectively, P < .005). CONCLUSION: Fetal echogenic bowel in IUGR fetuses is not associated with development of neonatal necrotizing enterocolitis. In these fetuses, vasodilatation in the superior mesenteric artery and celiac trunk have been demonstrated. (Obstet Gynecol 2002;100:120 –5. © 2002 by The American College of Obstetricians and Gynecologists.)
From the Department of Obstetrics and Gynecology, Neonatal Intensive Care Unit, and Department of Biostatistics, The Chaim Sheba Medical Center, Tel Hashomer, Israel; Department of Obstetrics and Gynecology, Rabin Medical Center, Petah Tikva, Israel; and Sacker School of Medicine, Tel Aviv University, Tel Aviv, Israel.
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Intrauterine growth restriction (IUGR) has been reported to be associated with postnatal intestinal disturbances.1 Hackett et al2 found an increased risk for neonatal necrotizing enterocolitis IUGR fetuses when abnormal flow in the fetal aorta appeared on Doppler examination. This observation was further supported by Malcolm et al,3 who noted a close association between absence or reversed end-diastolic flow velocities in the umbilical artery and development of neonatal necrotizing enterocolitis in morphologically normal IUGR fetuses. Furthermore, it has been reported that fetal hyperechogenic bowel, although it may reflect a normal variant,4 is associated with IUGR and increased, adverse prenatal outcome.5 Because gut dysfunction was noted in fetuses with echogenic bowel, it was speculated by Ewer et al6 that this unusual antenatal bowel appearance is a reflection of intrauterine gut ischemia. Although studies on gut perfusion in neonates with neonatal necrotizing enterocolitis have been reported, and have shown abnormal flow velocities in the superior mesenteric artery,7,8 limited information exists in the literature concerning gut perfusion in normal and abnormal fetal conditions.9,10 The present study was therefore conducted to: 1) investigate the association between IUGR and risk of neonatal necrotizing enterocolitis development, and 2) determine fetal gut perfusion in IUGR fetuses with echogenic bowel and increased resistance in the umbilical artery. MATERIALS AND METHODS The study population was divided into two groups. Group 1 (15 fetuses) comprised singleton pregnancies with echogenic bowel and IUGR who were referred to our ultrasound unit between January 1, 1990, and December 31, 1999. Group 2 (21 neonates) comprised all neonates diagnosed as having neonatal necrotizing enterocolitis during the same period. In group 1, IUGR was defined as estimated fetal weight below the third percentile according to the Warsof chart.11 Only fetuses with bowel echogenicity (Figure 1) similar to or greater
VOL. 100, NO. 1, JULY 2002 © 2002 by The American College of Obstetricians and Gynecologists. Published by Elsevier Science Inc.
0029-7844/02/$22.00 PII S0029-7844(02)02038-0
Figure 1. Transverse fetal sonographic view at 26 weeks’ gestation demonstrating an echogenic bowel (EB). SP ⫽ spine. Achiron. IUGR and Splanchnic Doppler Studies. Obstet Gynecol 2002.
than the surrounding bone (grades 2 and 3), according to the definition of Nyberg et al,12 were included in the study. All patients were scanned by one operator (RA), who measured the umbilical artery systolic-diastolic ratio, superior mesenteric artery, and celiac trunk pulsatility index (PI). All had undergone detailed comprehensive obstetric and neonatal follow-up. Fetal blood flow velocity waveforms were investigated by means of combined color-coded Doppler and two-dimensional realtime ultrasound, carrier frequency 5–7 mHz, high-pass filter 100 mHz (Synergy Diasonics, Haifa, Israel; GE Logic 700, Milwaukee, WI). For the superior mesenteric artery and celiac trunk, the fetus was scanned longitudi-
nally. A left parasaggital view of the fetal abdomen was obtained, and the superior mesenteric artery and celiac trunk were identified on color Doppler as they arose caudally from the aorta to the diaphragm (Figure 2). The first vessel emerging from the aorta below the diaphragm is the celiac trunk, and the second is the superior mesenteric artery. A 2-mm sample volume was placed at the celiac trunk and superior mesenteric artery, and velocity waveforms were recorded from three consecutive cardiac cycles (Figure 3). The PI (PI ⫽ [peak systolic velocity ⫺ maximum diastolic velocity]/mean maximum velocity)13 was automatically calculated with the software included in the ultrasound system. An average of three
Figure 2. Longitudinal view of the fetal abdomen demonstrating, with color Doppler (red), the origin of the superior mesenteric artery (SMA) and celiac trunk (CT) (arrow head). Note: legs are to the right, the heart to the left. The CT is located cephally to the origin of the SMA. AO ⫽ aorta; UV ⫽ umbilical vein. Achiron. IUGR and Splanchnic Doppler Studies. Obstet Gynecol 2002.
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Figure 3. Small for gestational age fetus with echogenic bowel. The Doppler gate is positioned in the superior mesenteric artery and shows a low pulsatility index (PI) of 1.65, which results from low impedance to flow during diastole. Note the echogenic bowel (arrow heads). Achiron. IUGR and Splanchnic Doppler Studies. Obstet Gynecol 2002.
waveforms was analyzed. Care was taken to include only measurements obtained at an angle between 0° and 30° during fetal apnea. The PI values obtained in this study group were compared with the PI of normal appropriate for gestational age (AGA) fetuses. Reference ranges of the normal PI in the AGA fetuses were constructed from measurements taken during routine normal fetal examination in our laboratory. The methodology of superior mesenteric artery nomograms was previously published.9 Similarly, the celiac trunk PI was measured in 96 normal AGA fetuses from 14 to 37 weeks’ gestation (unpublished data, R. Achiron et al, 1998). Group 2 consisted of all neonates who were diagnosed with neonatal necrotizing enterocolitis during the same period in the intensive neonatal care unit of The Chaim Sheba Medical Center. A retrospective review of all their detailed medical information was recorded and evaluated. The staging of necrotizing enterocolitis was performed in accordance with the modified Bell staging criteria.14 Only neonates with proven necrotizing enterocolitis, Stage II and above, were included in the study. All demographic and clinical variables are presented as mean ⫾ standard deviation. Student t test was performed for comparison among the PI in group 1, whereas a nonparametric Wilcoxon test was performed in group 2; P ⬍ .05 was considered statistically significant. RESULTS During the 10-year period between 1990 and 2000, we evaluated 15 IUGR fetuses (group 1) with echogenic
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bowel and abnormal velocities in the umbilical artery, and 21 fetuses (group 2) with proven neonatal necrotizing enterocolitis were collected from our neonatal database. The mean gestational age of both groups at delivery did not differ significantly (28.8 ⫾ 2.3 weeks in group 1, compared with 30.1 ⫾ 3.3 weeks in group 2, P ⫽ .231). However, the mean birth weight in group 1 was significantly lower (700 ⫾ 200 g compared with 1431 ⫾ 466 g in group 2, P ⬍ .001) (Table 1). All 15 fetuses in group 1 had severe IUGR, with fetal weight below the third percentile. Umbilical artery Doppler in all these cases showed high diastolic impedance expressed by absence or reversed diastolic flow. Adequate velocity waveforms were obtained in the superior mesenteric artery and celiac trunk in all cases. The mean PI ⫾ standard deviation in the superior mesenteric artery (Figure 3) and celiac trunk in these 15 cases (Table 2) was 1.5 ⫾ 0.14
Table 1. Demographic Data in Fetuses With Intrauterine Growth Restriction and Echogenic Bowel (Group 1) and Neonates With Necrotizing Enterocolitis (Group 2)
Mean maternal age (y) Mean delivery gestational age (wk) Mean birth weight (g) Primiparity (%) No. (%) of maternal diseases
Group 1 (n ⫽ 15)
Group 2 (n ⫽ 21)
25.2 (5.1) 28.8 ⫾ 2.3
27.3 (5.2) 30.1 ⫾ 3.4
700 ⫾ 200 10 (66) 12 (80)
1431 ⫾ 466* 12 (57) 1 (5)†
Values are mean ⫾ standard deviation. * P ⬍ .05. † P ⬍ .01.
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Table 2. Mean Pulsatility Index ⫾ Standard Deviation in the Superior Mesenteric Artery and Celiac Trunk of 15 Small for Gestational Age Fetuses With Echogenic Bowel Compared With Control Appropriate for Gestational Age Fetuses SGA SMA CT
1.5 ⫾ 0.14 1.2 ⫾ 0.17
AGA
t test 9
1.9 ⫾ 0.15 1.7 ⫾ 0.19*
P ⬍ .005 P ⬍ .005
SGA ⫽ small for gestational age; AGA ⫽ appropriate for gestational age; SMA ⫽ superior mesenteric artery; CT ⫽ celiac trunk. * Unpublished data, R. Achiron et al, 1998.
and 1.2 ⫾ 0.17, respectively. This was significantly lower than the comparable values of normal AGA fetuses (1.9 ⫾ 0.15 and 1.7 ⫾ 0.1, respectively, P ⬍ .005). None of the fetuses in group 1 developed neonatal necrotizing enterocolitis, whereas in group 2, among the 21 cases with proven neonatal necrotizing enterocolitis, only one was defined as IUGR; all others were preterm AGA. DISCUSSION In recent years, the study of human fetal circulation by Doppler ultrasonography has advanced our understanding of fetal physiology under normal and abnormal circumstances. Two aspects of our results are interesting. Firstly, we found significant vascular vasodilatation in the splanchnic circulation of IUGR fetuses with echogenic bowel, and secondly, surprisingly none of the neonates with neonatal necrotizing enterocolitis belonged to this group. Although many studies exist regarding Doppler flow velocimetry of splanchnic circulation in neonates,7,8,15–17 only a few studies were carried out during fetal life. The sparse data on splanchnic perfusion during human gestation may reflect the technical difficulties in obtaining flow velocities in small, fetal vessels. However, with the recent advent of high-resolution ultrasound machines, it is now possible to determine flow velocities in most types of fetal circulation.18 Flow studies of fetal superior mesenteric artery have been reported in the normal AGA population. It was found that apart from the early stages of gestation, a relatively stable vascular resistance in the superior mesenteric artery exists throughout gestation.9 In the present study, we demonstrated a significant drop in the PI of both superior mesenteric artery and celiac trunk when compared with normal values. Mari et al (Mari G, Abuhamad A, Uerpairojkit B, Copel J. Superior mesenteric artery velocity waveform in the appropriate and small for gestational age fetus [abstract]. Ultrasound Obstet Gynecol 1996;8 Suppl 1:99) reported a similar PI reduction in the superior mesenteric artery of nine small for
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gestational age (SGA) fetuses, compared with 57 AGA fetuses.10 However, in a later extended study of 131 AGA fetuses (Mari G, et al, Ultrasound Obstet Gynecol 1996;8 Suppl 1:99), a converse observation was reported by the same group. A linear increase of PI was demonstrated in the superior mesenteric artery with advancing gestation, and a further increase in 17 of 41 SGA fetuses.19 Our results showed that IUGR fetuses with increased resistance in the umbilical artery and echogenic bowel had a significantly decreased PI of the superior mesenteric artery and celiac trunk. This observation merits a thorough explanation because previous animal studies have shown that in utero, stress results in reduced blood flow to the splanchnic organs on behalf of the brain circulation.20,21 The above fetal adaptive mechanism to in utero stress is known as the “sparing effect” or redistribution phenomenon, also described in human gestation by Doppler ultrasonography in the spleen, adrenal, coronary, and cerebral circulation.18,22–25 Our finding of a low PI, or a sparing effect in the superior mesenteric artery and celiac trunk, although surprising, was anecdotally reported previously by Mari et al (Mari G, et al, Ultrasound Obstet Gynecol 1996;8 Suppl 1:99) and Kilavuz and Vetter (Kilavuz O, Vetter K. The liver: The 4th preferential organ of the fetus [abstract]. Ultrasound Obstet Gynecol 1999;14 Suppl 1:79), who showed a preferential flow to the fetal liver in SGA fetuses. One possible explanation to splenic artery vasodilatation was the thought that in cases with hypoxemia, mediated erythropoietin stimulation may occur in the fetal spleen.22 However, this theory is not convincing because most fetal erythropoietin is produced by the liver, and therefore a different explanation is required. We suggest that the vasodilatation in some fetal SGA organs may be the result of hemodynamic changes, rather than the cause. If we assume that the fetal arterial bed with the placenta acts as a single chamber, any increase in umbilical artery resistance should be compensated by reciprocal vasodilatation in other fetal compartments. This has been shown in the adrenal spleen, coronary brain, and liver (Kilavuz O, et al, Ultrasound Obstet Gynecol 1999;14 Suppl 1:79).18 Therefore, the present results further confirm that the sparing effect may also be observed in the superior mesenteric artery and celiac trunk. The main disadvantage of all previous experimental studies is that they have been performed on hypoxic animal models, which essentially differ from the chronic human in vivo situation. The fetal arterial blood redistribution is mediated via a complex inter-relationship between local vascular and reflex effects. It is well known that as the oxygen content of blood reduces, the fetus increases the blood flow to
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vital organs such as the brain, adrenal, and myocardium.21 However, local effects of changes in oxygen environment are less clearly established for other organs.26 In animal experiments, it was found that hypoxia-induced vasodilatation at the superior mesenteric artery was not adenosine mediated.27 Recently, the role of endothelium-derived nitric oxide has been established as a potent smooth muscle relaxing factor. In the fetus, endothelium-derived nitric oxide produced by umbilical vascular endothelium, and in fetal sheep in utero, is capable of modulating resting umbilical vascular tone and pulmonary artery.28 In addition, it was found that at midgestation, fetal nitric oxide plays a major role in the regulation of blood flow and vascular tone across all segments of the fetal gastrointestinal tract.29 Endothelium-derived nitric oxide, which is produced by most endothelial cells in response to hypoxemia, leads to significant smooth muscle relaxation of vascular resistance.30 In SGA fetuses, absence of or reversed diastolic flow in umbilical arteries increase the afterload, and a hypertensive state is established. This may lead to increased production of fetal endothelium-derived nitric oxide, which stimulates vascular dilatation in the superior mesenteric artery and celiac trunk, as has been described in rats.31 Our second important observation was that none of our SGA fetuses with echogenic bowel developed neonatal necrotizing enterocolitis, despite evidence of a redistribution phenomenon reflected by increased umbilical resistance. Although previous studies have indicated increased association of SGA fetuses with Doppler abnormalities in the umbilical circulation with neonatal necrotizing enterocolitis complications, we could not support this finding.2,3 The precise etiology of neonatal necrotizing enterocolitis is unknown, and it is generally accepted that the most important etiologic factor is intestinal ischemia, or hypoperfusion leading to altered mucosal integrity.32 However, in our SGA fetuses, hypoperfusion was not evident, and on the contrary showed vasodilatation. Probably, adequate bowel perfusion was maintained, and consequently none developed neonatal necrotizing enterocolitis. The retrospective analysis of all our neonatal necrotizing enterocolitis cases in the neonatal intensive care unit further supports this observation because only one of 21 neonates was SGA. We assume that the echogenic bowel during fetal life represents a hyperperfused gut, which protects the newborn from neonatal necrotizing enterocolitis complications. However, the precise etiology of this sonographic appearance was beyond the scope of the present study. We can, therefore, conclude that SGA fetuses with echogenic bowel and increased resistance in the umbilical artery may manifest a redistribution phenomenon or splanch-
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nic sparing effect, which was not found to be associated with development of neonatal necrotizing enterocolitis. REFERENCES 1. Robel-Tilling E, Vogtmann C, Faber R. Postnatal intestinal disturbances in small for gestational age premature infants after prenatal hemodynamic disturbances. Acta Pediatr 2000;89:324 –30. 2. Hackett GA, Campbell S, Gamsu H, Cohen-Overbeek T, Pearce JMF. Doppler studies in the growth retarded fetus and prediction of neonatal necrotizing enterocolitis, haemorrhage and neonatal morbidity. Br Med J 1987;294:13– 6. 3. Malcolm G, Ellwood D, Devonald K, Beilby R, Henderson-Smart D. Absent or reversed end diastolic flow velocity in the umbilical artery and necrotizing enterocolitis. Arch Dis Child 1991;66:805–7. 4. Fakhary J, Reiser M, Shapiro LR, Schechter A, Pait LP, Glennon A. Increased echogenicity in the lower fetal abdomen: A common normal variant in the second trimester. J Ultrasound Med 1986;5:489 –92. 5. Achiron R, Seidman D, Horowitz A, Mashiach S, Goldman B, Lipitz S. Hyperechogenic fetal bowel found in women with elevated serum alpha-feto protein is associated with a poor fetal prognosis. Obstet Gynecol 1996;88: 368 –71. 6. Ewer AK, McHugo J, Chapman S, Newwell SJ. Fetal echogenic gut: A marker of intrauterine gut ischemia? Arch Dis Child 1993;69:510 –3. 7. Kempley ST, Gamsu HR. Superior mesenteric artery blood flow velocity in necrotizing enterocolitis. Arch Dis Child 1992;67:793– 6. 8. Coombs RC, Morgan MEI, Durbin GM, Booth IW, McNeish AS. Abnormal gut blood flow velocities in neonates at risk of necrotizing enterocolitis. J Pediatr Gastroenterol Nutr 1992;15:13–9. 9. Achiron R, Orvieto R, Mashiach S, Lipitz S, Yagel S, Rotstein Z. Superior mesenteric artery blood flow velocimetry: Cross-sectional Doppler ultrasound study in normal fetuses. J Ultrasound Med 1998;17:769 –73. 10. Mari G, Abuhamad A, Uerpairojkit B, Martinez E, Copel J. Blood flow velocity waveforms of the abdominal arteries in the appropriate and small for gestational age fetus. Ultrasound Obstet Gynecol 1995;6:15– 8. 11. Warsof SL, Gohari P, Berkowitz RL, Hobbins JC. The estimation of fetal weight by computer assisted analysis. AJOG 1977;128:881–92. 12. Nyberg DA, Dubinsky T, Resta RG, Mahony BC, Hickok DE, Luthy DA. Echogenic fetal bowel during the second trimester: Clinical importance. Radiology 1993;188: 527–31. 13. Gosling RG, King DH. Ultrasound angiology. In: Marcus AW, Adamson L, eds. Arteries and veins. Edinburgh: Churchill Livingstone, 1975:61–98. 14. Kanto WP Jr, Hunter JE, Stoll BJ. Recognition and medi-
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cal management of necrotizing enterocolitis. Clin Perinatol 1994;2:335– 46. 15. Coombs RC, Morgan MEI, Durbin GM, Booth IW, McNeish AS. Gut blood flow velocities in the newborn: Effects of patent ductus arteriosus and parenteral indomethacin. Arch Dis Child 1990;65:1067–71. 16. Coombs RC, Morgan MEI, Durbin GM, Booth IW, McNeish AS. Doppler assessment of human neonatal gut blood flow velocities: Postnatal adaptation and response to feeds. J Pediatr Gastroenterol Nutr 1992;15:6 –12. 17. Deeg KH, Rupprecht T, Schmid E. Doppler sonographic detection of increased flow velocities in the celiac trunk and superior mesenteric artery in infants with necrotizing enterocolitis. Pediatr Radiol 1993;23:578 – 82. 18. Gembruch U. Assessment of fetal circulatory state in uteroplacental insufficiency by Doppler ultrasound: Which vessels are the most reliable? Ultrasound Obstet Gynecol 1996;8:77– 8. 19. Rhee E, Detti L, Mari G. Superior mesenteric artery flow velocity waveforms in small for gestational age fetuses. J Matern Fetal Med 1998;7:120 –3. 20. Morin FC III, Weiss KT. Response of the fetal circulation to stress. In: Polin RA, Fox WW, eds. Fetal and neonatal physiology. Philadelphia: WB Saunders, 1997:620 –9. 21. Peeters LLH, Sheldon RE, Jones MD, Makowski EL, Meschia G. Blood flow to fetal organs as a function of arterial oxygen content. Am J Obstet Gynecol 1979;135: 637– 46. 22. Mari G, Deter RL. Middle cerebral artery flow velocimetry waveforms in normal and small for gestational age fetus. Am J Obstet Gynecol 1992;166:1262–70.
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gestational age fetus. Ultrasound Obstet Gynecol 1996;8: 82– 6. Gembruch U, Baschat AA. Demonstration of fetal coronary blood flow by color coded and pulsed wave Doppler sonography: A possible indicator of severe compromise and impending demise in intrauterine growth retardation. Ultrasound Obstet Gynecol 1996;7:10 – 6. Heyman MA. Fetal and neonatal circulations. In: Moss’ heart disease in infants, children and adolescents. 4th ed. Baltimore: Williams & Wilkins, 1968:27–34. Lockhart LK, Lautt WW. Hypoxia induced vasodilatation of the feline superior mesenteric artery is not adenosine mediated. Am J Obstet Gynecol 1990;259:605–10. Chang JK, Roman C, Heyman MA. Effect of endothelium-derived relaxing factor inhibition on the umbilicalplacental circulation in fetal lambs in utero. Am J Obstet Gynecol 1992;166:727–34. Fan WQ, Smolich JJ, Wild J, Yu VY, Walker AM. Major vasodilator role for nitric oxide in the gastrointestinal circulation of the mid-gestation fetal lamb. Pediatr Res 1998;44:344 –50. Blitzer ML, Lee SD, Creager MA. Endothelium derived nitric oxide mediated hypoxic vasodilatation of resistance vessels in humans. Am J Physiol 1996;271:H1182–5. Kimura K, Nishio I. Impaired endothelium-dependent relaxation in mesenteric arteries of reduced renal mass hypertensive rats. Scand J Clin Lab Invest 1999;59: 199 –204. Pearse RG, Roberton NRC. In: Roberton NRC, ed. Textbook of neonatology. Edinburgh: Churchill Livingstone, 1986:752–5.
23. Abuhamad A, Mari G, Bodgan D, Evans AT. 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 –5.
Address reprint requests to: Reuwen Achiron, MD, Chaim Sheba Medical Center, Department of Obstetrics and Gynaecology, Tel Hashomer, 52621, Israel; E-mail: rachiron@post. tau.ac.il.
24. Mari G, Uerpairojkit B, Abuhamad Z, Copel JA. Adrenal artery velocity waveforms in the appropriate and small for
Received August 13, 2001. Received in revised form January 17, 2002. Accepted February 14, 2002.
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From the Department of Obstetrics and Gynecology, Neonatal Intensive Care Unit, and Department of Biostatistics, The Chaim Sheba Medical Center, Tel Hashomer, Israel; Department of Obstetrics and Gynecology, Rabin Medical Center, Petah Tikva, Israel; and Sacker School of Medicine, Tel Aviv University, Tel Aviv, Israel.
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Intrauterine growth restriction (IUGR) has been reported to be associated with postnatal intestinal disturbances.1 Hackett et al2 found an increased risk for neonatal necrotizing enterocolitis IUGR fetuses when abnormal flow in the fetal aorta appeared on Doppler examination. This observation was further supported by Malcolm et al,3 who noted a close association between absence or reversed end-diastolic flow velocities in the umbilical artery and development of neonatal necrotizing enterocolitis in morphologically normal IUGR fetuses. Furthermore, it has been reported that fetal hyperechogenic bowel, although it may reflect a normal variant,4 is associated with IUGR and increased, adverse prenatal outcome.5 Because gut dysfunction was noted in fetuses with echogenic bowel, it was speculated by Ewer et al6 that this unusual antenatal bowel appearance is a reflection of intrauterine gut ischemia. Although studies on gut perfusion in neonates with neonatal necrotizing enterocolitis have been reported, and have shown abnormal flow velocities in the superior mesenteric artery,7,8 limited information exists in the literature concerning gut perfusion in normal and abnormal fetal conditions.9,10 The present study was therefore conducted to: 1) investigate the association between IUGR and risk of neonatal necrotizing enterocolitis development, and 2) determine fetal gut perfusion in IUGR fetuses with echogenic bowel and increased resistance in the umbilical artery. MATERIALS AND METHODS The study population was divided into two groups. Group 1 (15 fetuses) comprised singleton pregnancies with echogenic bowel and IUGR who were referred to our ultrasound unit between January 1, 1990, and December 31, 1999. Group 2 (21 neonates) comprised all neonates diagnosed as having neonatal necrotizing enterocolitis during the same period. In group 1, IUGR was defined as estimated fetal weight below the third percentile according to the Warsof chart.11 Only fetuses with bowel echogenicity (Figure 1) similar to or greater
VOL. 100, NO. 1, JULY 2002 © 2002 by The American College of Obstetricians and Gynecologists. Published by Elsevier Science Inc.
0029-7844/02/$22.00 PII S0029-7844(02)02038-0
Figure 1. Transverse fetal sonographic view at 26 weeks’ gestation demonstrating an echogenic bowel (EB). SP ⫽ spine. Achiron. IUGR and Splanchnic Doppler Studies. Obstet Gynecol 2002.
than the surrounding bone (grades 2 and 3), according to the definition of Nyberg et al,12 were included in the study. All patients were scanned by one operator (RA), who measured the umbilical artery systolic-diastolic ratio, superior mesenteric artery, and celiac trunk pulsatility index (PI). All had undergone detailed comprehensive obstetric and neonatal follow-up. Fetal blood flow velocity waveforms were investigated by means of combined color-coded Doppler and two-dimensional realtime ultrasound, carrier frequency 5–7 mHz, high-pass filter 100 mHz (Synergy Diasonics, Haifa, Israel; GE Logic 700, Milwaukee, WI). For the superior mesenteric artery and celiac trunk, the fetus was scanned longitudi-
nally. A left parasaggital view of the fetal abdomen was obtained, and the superior mesenteric artery and celiac trunk were identified on color Doppler as they arose caudally from the aorta to the diaphragm (Figure 2). The first vessel emerging from the aorta below the diaphragm is the celiac trunk, and the second is the superior mesenteric artery. A 2-mm sample volume was placed at the celiac trunk and superior mesenteric artery, and velocity waveforms were recorded from three consecutive cardiac cycles (Figure 3). The PI (PI ⫽ [peak systolic velocity ⫺ maximum diastolic velocity]/mean maximum velocity)13 was automatically calculated with the software included in the ultrasound system. An average of three
Figure 2. Longitudinal view of the fetal abdomen demonstrating, with color Doppler (red), the origin of the superior mesenteric artery (SMA) and celiac trunk (CT) (arrow head). Note: legs are to the right, the heart to the left. The CT is located cephally to the origin of the SMA. AO ⫽ aorta; UV ⫽ umbilical vein. Achiron. IUGR and Splanchnic Doppler Studies. Obstet Gynecol 2002.
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Figure 3. Small for gestational age fetus with echogenic bowel. The Doppler gate is positioned in the superior mesenteric artery and shows a low pulsatility index (PI) of 1.65, which results from low impedance to flow during diastole. Note the echogenic bowel (arrow heads). Achiron. IUGR and Splanchnic Doppler Studies. Obstet Gynecol 2002.
waveforms was analyzed. Care was taken to include only measurements obtained at an angle between 0° and 30° during fetal apnea. The PI values obtained in this study group were compared with the PI of normal appropriate for gestational age (AGA) fetuses. Reference ranges of the normal PI in the AGA fetuses were constructed from measurements taken during routine normal fetal examination in our laboratory. The methodology of superior mesenteric artery nomograms was previously published.9 Similarly, the celiac trunk PI was measured in 96 normal AGA fetuses from 14 to 37 weeks’ gestation (unpublished data, R. Achiron et al, 1998). Group 2 consisted of all neonates who were diagnosed with neonatal necrotizing enterocolitis during the same period in the intensive neonatal care unit of The Chaim Sheba Medical Center. A retrospective review of all their detailed medical information was recorded and evaluated. The staging of necrotizing enterocolitis was performed in accordance with the modified Bell staging criteria.14 Only neonates with proven necrotizing enterocolitis, Stage II and above, were included in the study. All demographic and clinical variables are presented as mean ⫾ standard deviation. Student t test was performed for comparison among the PI in group 1, whereas a nonparametric Wilcoxon test was performed in group 2; P ⬍ .05 was considered statistically significant. RESULTS During the 10-year period between 1990 and 2000, we evaluated 15 IUGR fetuses (group 1) with echogenic
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bowel and abnormal velocities in the umbilical artery, and 21 fetuses (group 2) with proven neonatal necrotizing enterocolitis were collected from our neonatal database. The mean gestational age of both groups at delivery did not differ significantly (28.8 ⫾ 2.3 weeks in group 1, compared with 30.1 ⫾ 3.3 weeks in group 2, P ⫽ .231). However, the mean birth weight in group 1 was significantly lower (700 ⫾ 200 g compared with 1431 ⫾ 466 g in group 2, P ⬍ .001) (Table 1). All 15 fetuses in group 1 had severe IUGR, with fetal weight below the third percentile. Umbilical artery Doppler in all these cases showed high diastolic impedance expressed by absence or reversed diastolic flow. Adequate velocity waveforms were obtained in the superior mesenteric artery and celiac trunk in all cases. The mean PI ⫾ standard deviation in the superior mesenteric artery (Figure 3) and celiac trunk in these 15 cases (Table 2) was 1.5 ⫾ 0.14
Table 1. Demographic Data in Fetuses With Intrauterine Growth Restriction and Echogenic Bowel (Group 1) and Neonates With Necrotizing Enterocolitis (Group 2)
Mean maternal age (y) Mean delivery gestational age (wk) Mean birth weight (g) Primiparity (%) No. (%) of maternal diseases
Group 1 (n ⫽ 15)
Group 2 (n ⫽ 21)
25.2 (5.1) 28.8 ⫾ 2.3
27.3 (5.2) 30.1 ⫾ 3.4
700 ⫾ 200 10 (66) 12 (80)
1431 ⫾ 466* 12 (57) 1 (5)†
Values are mean ⫾ standard deviation. * P ⬍ .05. † P ⬍ .01.
OBSTETRICS & GYNECOLOGY
Table 2. Mean Pulsatility Index ⫾ Standard Deviation in the Superior Mesenteric Artery and Celiac Trunk of 15 Small for Gestational Age Fetuses With Echogenic Bowel Compared With Control Appropriate for Gestational Age Fetuses SGA SMA CT
1.5 ⫾ 0.14 1.2 ⫾ 0.17
AGA
t test 9
1.9 ⫾ 0.15 1.7 ⫾ 0.19*
P ⬍ .005 P ⬍ .005
SGA ⫽ small for gestational age; AGA ⫽ appropriate for gestational age; SMA ⫽ superior mesenteric artery; CT ⫽ celiac trunk. * Unpublished data, R. Achiron et al, 1998.
and 1.2 ⫾ 0.17, respectively. This was significantly lower than the comparable values of normal AGA fetuses (1.9 ⫾ 0.15 and 1.7 ⫾ 0.1, respectively, P ⬍ .005). None of the fetuses in group 1 developed neonatal necrotizing enterocolitis, whereas in group 2, among the 21 cases with proven neonatal necrotizing enterocolitis, only one was defined as IUGR; all others were preterm AGA. DISCUSSION In recent years, the study of human fetal circulation by Doppler ultrasonography has advanced our understanding of fetal physiology under normal and abnormal circumstances. Two aspects of our results are interesting. Firstly, we found significant vascular vasodilatation in the splanchnic circulation of IUGR fetuses with echogenic bowel, and secondly, surprisingly none of the neonates with neonatal necrotizing enterocolitis belonged to this group. Although many studies exist regarding Doppler flow velocimetry of splanchnic circulation in neonates,7,8,15–17 only a few studies were carried out during fetal life. The sparse data on splanchnic perfusion during human gestation may reflect the technical difficulties in obtaining flow velocities in small, fetal vessels. However, with the recent advent of high-resolution ultrasound machines, it is now possible to determine flow velocities in most types of fetal circulation.18 Flow studies of fetal superior mesenteric artery have been reported in the normal AGA population. It was found that apart from the early stages of gestation, a relatively stable vascular resistance in the superior mesenteric artery exists throughout gestation.9 In the present study, we demonstrated a significant drop in the PI of both superior mesenteric artery and celiac trunk when compared with normal values. Mari et al (Mari G, Abuhamad A, Uerpairojkit B, Copel J. Superior mesenteric artery velocity waveform in the appropriate and small for gestational age fetus [abstract]. Ultrasound Obstet Gynecol 1996;8 Suppl 1:99) reported a similar PI reduction in the superior mesenteric artery of nine small for
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gestational age (SGA) fetuses, compared with 57 AGA fetuses.10 However, in a later extended study of 131 AGA fetuses (Mari G, et al, Ultrasound Obstet Gynecol 1996;8 Suppl 1:99), a converse observation was reported by the same group. A linear increase of PI was demonstrated in the superior mesenteric artery with advancing gestation, and a further increase in 17 of 41 SGA fetuses.19 Our results showed that IUGR fetuses with increased resistance in the umbilical artery and echogenic bowel had a significantly decreased PI of the superior mesenteric artery and celiac trunk. This observation merits a thorough explanation because previous animal studies have shown that in utero, stress results in reduced blood flow to the splanchnic organs on behalf of the brain circulation.20,21 The above fetal adaptive mechanism to in utero stress is known as the “sparing effect” or redistribution phenomenon, also described in human gestation by Doppler ultrasonography in the spleen, adrenal, coronary, and cerebral circulation.18,22–25 Our finding of a low PI, or a sparing effect in the superior mesenteric artery and celiac trunk, although surprising, was anecdotally reported previously by Mari et al (Mari G, et al, Ultrasound Obstet Gynecol 1996;8 Suppl 1:99) and Kilavuz and Vetter (Kilavuz O, Vetter K. The liver: The 4th preferential organ of the fetus [abstract]. Ultrasound Obstet Gynecol 1999;14 Suppl 1:79), who showed a preferential flow to the fetal liver in SGA fetuses. One possible explanation to splenic artery vasodilatation was the thought that in cases with hypoxemia, mediated erythropoietin stimulation may occur in the fetal spleen.22 However, this theory is not convincing because most fetal erythropoietin is produced by the liver, and therefore a different explanation is required. We suggest that the vasodilatation in some fetal SGA organs may be the result of hemodynamic changes, rather than the cause. If we assume that the fetal arterial bed with the placenta acts as a single chamber, any increase in umbilical artery resistance should be compensated by reciprocal vasodilatation in other fetal compartments. This has been shown in the adrenal spleen, coronary brain, and liver (Kilavuz O, et al, Ultrasound Obstet Gynecol 1999;14 Suppl 1:79).18 Therefore, the present results further confirm that the sparing effect may also be observed in the superior mesenteric artery and celiac trunk. The main disadvantage of all previous experimental studies is that they have been performed on hypoxic animal models, which essentially differ from the chronic human in vivo situation. The fetal arterial blood redistribution is mediated via a complex inter-relationship between local vascular and reflex effects. It is well known that as the oxygen content of blood reduces, the fetus increases the blood flow to
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vital organs such as the brain, adrenal, and myocardium.21 However, local effects of changes in oxygen environment are less clearly established for other organs.26 In animal experiments, it was found that hypoxia-induced vasodilatation at the superior mesenteric artery was not adenosine mediated.27 Recently, the role of endothelium-derived nitric oxide has been established as a potent smooth muscle relaxing factor. In the fetus, endothelium-derived nitric oxide produced by umbilical vascular endothelium, and in fetal sheep in utero, is capable of modulating resting umbilical vascular tone and pulmonary artery.28 In addition, it was found that at midgestation, fetal nitric oxide plays a major role in the regulation of blood flow and vascular tone across all segments of the fetal gastrointestinal tract.29 Endothelium-derived nitric oxide, which is produced by most endothelial cells in response to hypoxemia, leads to significant smooth muscle relaxation of vascular resistance.30 In SGA fetuses, absence of or reversed diastolic flow in umbilical arteries increase the afterload, and a hypertensive state is established. This may lead to increased production of fetal endothelium-derived nitric oxide, which stimulates vascular dilatation in the superior mesenteric artery and celiac trunk, as has been described in rats.31 Our second important observation was that none of our SGA fetuses with echogenic bowel developed neonatal necrotizing enterocolitis, despite evidence of a redistribution phenomenon reflected by increased umbilical resistance. Although previous studies have indicated increased association of SGA fetuses with Doppler abnormalities in the umbilical circulation with neonatal necrotizing enterocolitis complications, we could not support this finding.2,3 The precise etiology of neonatal necrotizing enterocolitis is unknown, and it is generally accepted that the most important etiologic factor is intestinal ischemia, or hypoperfusion leading to altered mucosal integrity.32 However, in our SGA fetuses, hypoperfusion was not evident, and on the contrary showed vasodilatation. Probably, adequate bowel perfusion was maintained, and consequently none developed neonatal necrotizing enterocolitis. The retrospective analysis of all our neonatal necrotizing enterocolitis cases in the neonatal intensive care unit further supports this observation because only one of 21 neonates was SGA. We assume that the echogenic bowel during fetal life represents a hyperperfused gut, which protects the newborn from neonatal necrotizing enterocolitis complications. However, the precise etiology of this sonographic appearance was beyond the scope of the present study. We can, therefore, conclude that SGA fetuses with echogenic bowel and increased resistance in the umbilical artery may manifest a redistribution phenomenon or splanch-
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Address reprint requests to: Reuwen Achiron, MD, Chaim Sheba Medical Center, Department of Obstetrics and Gynaecology, Tel Hashomer, 52621, Israel; E-mail: rachiron@post. tau.ac.il.
24. Mari G, Uerpairojkit B, Abuhamad Z, Copel JA. Adrenal artery velocity waveforms in the appropriate and small for
Received August 13, 2001. Received in revised form January 17, 2002. Accepted February 14, 2002.
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