- Email: [email protected]
Transplacental passage of iohexol
placental passage of iohexol 9n, MD, Richard If/..Katzberg, MD, and Michael P. Sherman, MD
We describe the appearance of an iodinated, low molecular weight radiographic contrast agent, iohexol, in the intestines of twin neonates after administration to a pregnant mother during angiography. Nonionic contrast agents cross the human placenta and enter the fetus in significant concentrations and in this case facilitated identification of an omphalomesenteric duct cyst in one twin. ( J Pediatr 2000;136:548-9)
Use of low molecular weight, watersoluble, extracellular contrast media for conventional radiographic and magnetic resonance imaging has become widespread in clinical medicine. Although generally well tolerated, little is known about placental transfer of these agents to the human. Detectable concentrations of an ionic agent, diatrizoate, in the placenta and human fetus in early pregnancy have been demonstrated,1 as has transplacental passage of the magnetic resonance agent gadolinium-DTPA throughout pregnancy in nonhuman primatesJ No reports have demonstrated placental transfer of nonionic compounds in common use. We report the radiog r a p h i c appearance of the nonionic water-soluble contrast agent iohexol (Omnipaque) in the intestinal lumens of twin fetuses after the intravenous
From the Division of Neonato/ogy, Departmentof Pediatrics and the Department of Diagnostic Radiology, University of CaliforniaDavis Medical Cente~ Sacramento,California.
Submitted for publication July 27, 1999; accepted Nov 15, 1999. Reprint requests: Anita J. Moon, MD, c/o Division of NeonatoloKv, TB 193, UC Davis School of Medicine, Davis, CA 95616. Copyright © 2000 by Mosby, Inc. 0022-3476/2000/$12.00 + 0 9•22/104525 doi: 10.1067/mpd.2000.104525 548
administration of the agent to the pregnant mother for angiography. Incidental was the diagnosis of a rare developmental abnormality of the gastrointestinal tract, an omphalomesenteric duct cyst, in one twin.
REPORT OF CASES Twins weighing 1125 g and 915 g, respectively, were delivered at 28 weeks' estimated gestational age to a 22-year-old w o m a n 1 week after the onset of preterm labor. Renal and liver function test results were normal. Two clays before delivery she had chest pain and required supplemental oxygen. A scintigraphic pulmonary perfusionventilation scan suggested pulmonary embolus. The next day pulmonary angiography performed with 160 cc Omnipaque-350 (iohexol 550 mgI/mL) showed no evidence of pulmonary embolus. Seventeen hours later tocolysis failed, and twin male infants were born. Amniotic fluid was clear. Physical examination of twin "A" revealed a gestational age of 28 weeks and no physical abnormalities. On several radiographs obtained in the first days of life, intraluminal gastrointestinal opacification was seen, consistent with the presence of contrast material. The material disappeared from the abdominal
radiographs with the establishment of a normal, regular stooling pattern. Examination of twin "B" was remarkable for a 1-cm firm immobile dark red mass within the substance of the Wharton's jelly 1 cm above the abdominal skin margin. A similar cystic structure had been noted on prenatal ultrasonography as early as 13 weeks' gestation. As with twin "A," areas of increased contrast in the small bowel were seen on radiographic examination (Figure, A). As the material cleared from the intestine, the area corresponding to the umbilical stump and associated cystic structure became increasingly radio-opaque (Figure, B). A diagnosis of omphalomesenteric duct cyst was made. No specific therapy was given. The cystic structure was no longer evident on physical examination at discharge.
DISCUSSION Studies of low molecular weight, water-soluble contrast agents in pregnancy have been limited, and effects on the fetus are largely unknown. Ionic agents have previously been shown to cross the placenta and enter the fetus in primates 2 and in humans. 1 Nonionic water-soluble compounds did not cross the placenta in several animal models. Several nonionic agents were shown in the 18-day pregnant rat to be rapidly cleared by the maternal kidneys with no clear passage across the placenta and no retention in the fetal tissues. 3 No measurable levels of iobitridol or iohexol were detected in the amniotic fluid or in fetal plasma at 15, 30, 60, and 180 minutes and at 24 hours after maternal injection of 300 mgI/kg in the 21-day
THE JOURNAL OF PEDIATRICS VOLUME 136, NUMBER 4
pregnant rabbit. The dose was similar to that used clinically for angiography. 4 The agent administered in this case, iohexol, is nonionic. More than 90% of the injected dose will be excreted by the kidney within the first 24 hours, with peak urine concentrations in the first hour. The compound is poorly absorbed from the gastrointestinal tract, with only 0.1% to 0.5% of an oral close subsequently detectable in the urine (Omnipaque package insert). In pregnancy, renal clearance is similar to that of the nonpregnant state, 105 to 178 mL/min X 1.Z3 mY.s These twins were born 17 hours after administration of iohexol to the mother. We propose several mechanisms to explain the contrast material in the bowels of the twins. First, the compounds may have crossed the placenta by simple diffusion. The agent may then have diffused into the amniotic fluid to be swallowed by the fetus. Second, the iohexol may have passed into the fetal circulation by the umbilical vein, as has been previously reported for gadolinium. It would then be rapidly excreted by the fetal kidney into the amniotic fluid and subsequently swallowed. Alternately, it may have been excreted by the liver into the small bowel and concentrated by gut absorption of other ingested fluids. These explanations, however, remain speculative. What is clearly apparent is that the administration of a routine close of iohexol for angiography in a pregnant w o m a n resulted in radiographically detectable amounts of this agent in her fetuses, an unexpected finding based on the negative studies previously reported in animalsl No adverse effects of the ioxehol were evident in either twin. It is reassuring that a related compound, iomeprol, caused no reproductive, developmental, or genetic toxicity in an animal model. 6 Nevertheless, the potential hazards of fetal exposure to these agents should be further investigated and taken into
MOON, KATZBERG,AND SHERMAN
Figure.
Twin "B" at I day (A) and 8 days (B) of life, Contrast material can be appreciated in the
early radiograph (A) in the intestinal lumen.Thereafter(B), there is passage of the contrast agent into the umbilical area (whi~earrows) in a distribution consistent with the mass found on physical examination within the umbilical cord and diagnosed as an omphalomesenteric duct cyst,
consideration when these agents are used in pregnancy. The presence of contrast material in the bowel of twin "B" was, in fact, fortuitous. Cysts of the umbilical cord are rare, and the differential diagnosis includes teratoma, hemangioma, urachal remnants, and omphalomesenteric (vitelline) remnants. Passage of the contrast material into the umbilical mass established continuity, with the small bowel identifying the structure as an omphalomesenteric duct cyst. The omphalomesenteric duct is a communication between the developing embryonic gut and the yolk sac. Remnants of this structure, usually obliterated by the seventh week of gestation, include Meckel's diverticulum, bands, and umbilical sinus, polyp, fistula, and cyst. Provided there is no active drainage, opinion regarding treatment of such cysts varies, and m a n y advocate observation. 7 The potential for volvulus or intussusception exists, however; thus it has been suggested that early excision of the omphalomesenteric duct remnant be performed. 8 This case indicates the potential for a role for intravenous contrast agents during pregnancy in the diagnostic evaluation of developmental abnormalities of the gastrointestinal tract.
REFERENCES 1. Dean PB. Fetal uptake of an intravascular radiologic contrast medium. Rofo. Fortschritte auf dem Gebiete der Rontgenstrahlen und der Nuklearmedizin 1977;127:267-70. 2. Panigel M, Wolf G, Zeleznick A. Magnetic resonance imaging of the placenta in rhesus monkeys, Macaca mulatta. J Med Primatol 1988; 17:3-18. 5. Tauber U, Meutzel W, Schulze PE. Whole body autoradiographic distribution studies on nonionic x-ray contrast agents in pregnant rats. Fortschritte auf dem Gebiete der Rontgenstrahlen und der Nuklearmedizin. Erganzungsband 1989;128:215-9. 4. Bourrinet P, Dencausse A, Havard E Violas X, Bonnemain B. Transplacental passage and milk excretion of iobitridol. Invest Radiol 1995;30:156-8. 5. Olofsson P, Krutzaen E, Nilsson-Ehle R Iohexol clearance for assessment of glomerular filtration rate in diabetic pregnancy. Eur J Obstet Gynecot Reprod Biol 1996;64:63-7. 6. Morisetti A, Tirone P, Luzzani E de Haeen C. Toxicological safety assessment of iomeprol, a new x-ray contrast agent. Eur J Radiol 1994;18 (Suppl 1):$21-31. 7. Heifetz SA, Rueda-Pedraza ME. Omphalomesenteric duct cysts of the umbilical cord. Pediatr Pathol 1983;1: 325-35. 8. Quarantillo EP Jr. Cyst of the omphalomesenteric duct presenting as an acute abdominal condition. Am J Surg 1967; 114:465-6.
549
We describe the appearance of an iodinated, low molecular weight radiographic contrast agent, iohexol, in the intestines of twin neonates after administration to a pregnant mother during angiography. Nonionic contrast agents cross the human placenta and enter the fetus in significant concentrations and in this case facilitated identification of an omphalomesenteric duct cyst in one twin. ( J Pediatr 2000;136:548-9)
Use of low molecular weight, watersoluble, extracellular contrast media for conventional radiographic and magnetic resonance imaging has become widespread in clinical medicine. Although generally well tolerated, little is known about placental transfer of these agents to the human. Detectable concentrations of an ionic agent, diatrizoate, in the placenta and human fetus in early pregnancy have been demonstrated,1 as has transplacental passage of the magnetic resonance agent gadolinium-DTPA throughout pregnancy in nonhuman primatesJ No reports have demonstrated placental transfer of nonionic compounds in common use. We report the radiog r a p h i c appearance of the nonionic water-soluble contrast agent iohexol (Omnipaque) in the intestinal lumens of twin fetuses after the intravenous
From the Division of Neonato/ogy, Departmentof Pediatrics and the Department of Diagnostic Radiology, University of CaliforniaDavis Medical Cente~ Sacramento,California.
Submitted for publication July 27, 1999; accepted Nov 15, 1999. Reprint requests: Anita J. Moon, MD, c/o Division of NeonatoloKv, TB 193, UC Davis School of Medicine, Davis, CA 95616. Copyright © 2000 by Mosby, Inc. 0022-3476/2000/$12.00 + 0 9•22/104525 doi: 10.1067/mpd.2000.104525 548
administration of the agent to the pregnant mother for angiography. Incidental was the diagnosis of a rare developmental abnormality of the gastrointestinal tract, an omphalomesenteric duct cyst, in one twin.
REPORT OF CASES Twins weighing 1125 g and 915 g, respectively, were delivered at 28 weeks' estimated gestational age to a 22-year-old w o m a n 1 week after the onset of preterm labor. Renal and liver function test results were normal. Two clays before delivery she had chest pain and required supplemental oxygen. A scintigraphic pulmonary perfusionventilation scan suggested pulmonary embolus. The next day pulmonary angiography performed with 160 cc Omnipaque-350 (iohexol 550 mgI/mL) showed no evidence of pulmonary embolus. Seventeen hours later tocolysis failed, and twin male infants were born. Amniotic fluid was clear. Physical examination of twin "A" revealed a gestational age of 28 weeks and no physical abnormalities. On several radiographs obtained in the first days of life, intraluminal gastrointestinal opacification was seen, consistent with the presence of contrast material. The material disappeared from the abdominal
radiographs with the establishment of a normal, regular stooling pattern. Examination of twin "B" was remarkable for a 1-cm firm immobile dark red mass within the substance of the Wharton's jelly 1 cm above the abdominal skin margin. A similar cystic structure had been noted on prenatal ultrasonography as early as 13 weeks' gestation. As with twin "A," areas of increased contrast in the small bowel were seen on radiographic examination (Figure, A). As the material cleared from the intestine, the area corresponding to the umbilical stump and associated cystic structure became increasingly radio-opaque (Figure, B). A diagnosis of omphalomesenteric duct cyst was made. No specific therapy was given. The cystic structure was no longer evident on physical examination at discharge.
DISCUSSION Studies of low molecular weight, water-soluble contrast agents in pregnancy have been limited, and effects on the fetus are largely unknown. Ionic agents have previously been shown to cross the placenta and enter the fetus in primates 2 and in humans. 1 Nonionic water-soluble compounds did not cross the placenta in several animal models. Several nonionic agents were shown in the 18-day pregnant rat to be rapidly cleared by the maternal kidneys with no clear passage across the placenta and no retention in the fetal tissues. 3 No measurable levels of iobitridol or iohexol were detected in the amniotic fluid or in fetal plasma at 15, 30, 60, and 180 minutes and at 24 hours after maternal injection of 300 mgI/kg in the 21-day
THE JOURNAL OF PEDIATRICS VOLUME 136, NUMBER 4
pregnant rabbit. The dose was similar to that used clinically for angiography. 4 The agent administered in this case, iohexol, is nonionic. More than 90% of the injected dose will be excreted by the kidney within the first 24 hours, with peak urine concentrations in the first hour. The compound is poorly absorbed from the gastrointestinal tract, with only 0.1% to 0.5% of an oral close subsequently detectable in the urine (Omnipaque package insert). In pregnancy, renal clearance is similar to that of the nonpregnant state, 105 to 178 mL/min X 1.Z3 mY.s These twins were born 17 hours after administration of iohexol to the mother. We propose several mechanisms to explain the contrast material in the bowels of the twins. First, the compounds may have crossed the placenta by simple diffusion. The agent may then have diffused into the amniotic fluid to be swallowed by the fetus. Second, the iohexol may have passed into the fetal circulation by the umbilical vein, as has been previously reported for gadolinium. It would then be rapidly excreted by the fetal kidney into the amniotic fluid and subsequently swallowed. Alternately, it may have been excreted by the liver into the small bowel and concentrated by gut absorption of other ingested fluids. These explanations, however, remain speculative. What is clearly apparent is that the administration of a routine close of iohexol for angiography in a pregnant w o m a n resulted in radiographically detectable amounts of this agent in her fetuses, an unexpected finding based on the negative studies previously reported in animalsl No adverse effects of the ioxehol were evident in either twin. It is reassuring that a related compound, iomeprol, caused no reproductive, developmental, or genetic toxicity in an animal model. 6 Nevertheless, the potential hazards of fetal exposure to these agents should be further investigated and taken into
MOON, KATZBERG,AND SHERMAN
Figure.
Twin "B" at I day (A) and 8 days (B) of life, Contrast material can be appreciated in the
early radiograph (A) in the intestinal lumen.Thereafter(B), there is passage of the contrast agent into the umbilical area (whi~earrows) in a distribution consistent with the mass found on physical examination within the umbilical cord and diagnosed as an omphalomesenteric duct cyst,
consideration when these agents are used in pregnancy. The presence of contrast material in the bowel of twin "B" was, in fact, fortuitous. Cysts of the umbilical cord are rare, and the differential diagnosis includes teratoma, hemangioma, urachal remnants, and omphalomesenteric (vitelline) remnants. Passage of the contrast material into the umbilical mass established continuity, with the small bowel identifying the structure as an omphalomesenteric duct cyst. The omphalomesenteric duct is a communication between the developing embryonic gut and the yolk sac. Remnants of this structure, usually obliterated by the seventh week of gestation, include Meckel's diverticulum, bands, and umbilical sinus, polyp, fistula, and cyst. Provided there is no active drainage, opinion regarding treatment of such cysts varies, and m a n y advocate observation. 7 The potential for volvulus or intussusception exists, however; thus it has been suggested that early excision of the omphalomesenteric duct remnant be performed. 8 This case indicates the potential for a role for intravenous contrast agents during pregnancy in the diagnostic evaluation of developmental abnormalities of the gastrointestinal tract.
REFERENCES 1. Dean PB. Fetal uptake of an intravascular radiologic contrast medium. Rofo. Fortschritte auf dem Gebiete der Rontgenstrahlen und der Nuklearmedizin 1977;127:267-70. 2. Panigel M, Wolf G, Zeleznick A. Magnetic resonance imaging of the placenta in rhesus monkeys, Macaca mulatta. J Med Primatol 1988; 17:3-18. 5. Tauber U, Meutzel W, Schulze PE. Whole body autoradiographic distribution studies on nonionic x-ray contrast agents in pregnant rats. Fortschritte auf dem Gebiete der Rontgenstrahlen und der Nuklearmedizin. Erganzungsband 1989;128:215-9. 4. Bourrinet P, Dencausse A, Havard E Violas X, Bonnemain B. Transplacental passage and milk excretion of iobitridol. Invest Radiol 1995;30:156-8. 5. Olofsson P, Krutzaen E, Nilsson-Ehle R Iohexol clearance for assessment of glomerular filtration rate in diabetic pregnancy. Eur J Obstet Gynecot Reprod Biol 1996;64:63-7. 6. Morisetti A, Tirone P, Luzzani E de Haeen C. Toxicological safety assessment of iomeprol, a new x-ray contrast agent. Eur J Radiol 1994;18 (Suppl 1):$21-31. 7. Heifetz SA, Rueda-Pedraza ME. Omphalomesenteric duct cysts of the umbilical cord. Pediatr Pathol 1983;1: 325-35. 8. Quarantillo EP Jr. Cyst of the omphalomesenteric duct presenting as an acute abdominal condition. Am J Surg 1967; 114:465-6.
549