Induction of Fetal Diuresis with Intraamniotic Furosemide Injection Reduces Intestinal Damage in a Rat Model of Gastroschisis

Abstract

Background/Purpose: Contact with amniotic fluid causes intestinal damage (ID) in fetuses with gastroschisis. Intraamniotic meconium has been shown to be responsible for ID, and ID has been shown to correlate with intraamniotic meconium concentrations. ID can be prevented by lowering the intraamniotic meconium concentration. A new method to lower intraamniotic meconium concentration might consist in the induction of fetal diuresis with intraamniotic diuretic injection. This hypothesis was tested in a rat model.

Materials and Method: There were 4 experimental groups.

Control group: Rat fetuses without any manipulation. Fetuses were harvested by cesarean section for examination at E21.5 (Term).

Sham group: On E18.5, the hind limb of the rat fetuses were exteriorized by hysterotomy and replaced in the uterus.

Gastroschisis group: Gastroschisis was surgically created in rat fetuses on E18.5, under a dissection microscope (16×).

Gastroschisis+furosemide group: After surgical creation of gastroschisis on E18.5, intraamniotic furosemide (5 mg/kg) was administered to the fetuses on E20. All fetuses were harvested on E21.5.

Results: There was no significant difference between intestinal serosal thicknesses of the control and sham groups. The serosal thickness was significantly higher in the gastroschisis group compared to the control group. In the gastroschisis+furosemide group, the intestinal serosal thickness was found significantly decreased compared with the gastroschisis group.

Conclusion: Intraamniotic furosemide injection caused a substantial decrease in ID encountered in gastroschisis. The induction of fetal diuresis with intraamniotic furosemide injection seems promising as a prenatal treatment modality.

gastroschisis - amniotic fluid - intestinal damage - intraamniotic furosemide injection - prenatal treatment

References

• 1 Haller JA, Kehrer BH, Shaker JI. et al . Studies of the pathophysiology of gastroschisis in fetal sheep.  J Pediatr Surg. 1974;  9 627-632
• 2 Klück P, Tibboel D, van der Kamp AWM. et al . The effect of fetal urine on the development of bowel in gastroschisis.  J Pediatr Surg. 1983;  18 47-50
• 3 Tibboel D, Klück P, van der Kamp AWM. et al . The development of the characteristic anomalies found in gastroschisis: experimental and clinical data.  Z Kinderchir. 1985;  40 355-360
• 4 Tibboel D, Vermey-Keers C, Klück P. et al . The natural history of gastroschisis during fetal life: development of the fibrous coating on bowel loops.  Teratology. 1986;  33 267-272
• 5 Tibboel D, Raine P, McNee M. et al . Development aspects of gastroschisis.  J Pediatr Surg. 1986;  21 865-869
• 6 Albert A, Julia MV, Morales L. et al . Gastroschisis in the partially extraamniotic fetus: Experimental study.  J Pediatr Surg. 1993;  28 656-659
• 7 Bealer JF, Graf J, Bruch SW. et al . Gatroschisis increases small bowel nitric oxide synthase activity.  J Pediatr Surg. 1996;  31 1043-1046
• 8 Aktuğ T, Hosgör M, Akgür FM. et al . End results of experimental gastroschisis created by abdominal wall defect versus umbilical cord defect.  Pediatr Surg Int. 1997;  12 583-586
• 9 Heffez DS, Aryanpur J, Hutchins GM. et al . The paralysis associated with myelomeningocele: Clinical and experimental data implicating a preventable spinal cord injury.  Neurosurgery. 1990;  26 987-992
• 10 Olguner M, Akgür FM, Özdemir T. et al . Amniotic fluid exchange for the prevention of neural tissue damage in myelomeningocele: An alternative minimally invasive method to open in utero surgery.  Pediatr Neurosurg. 2000;  33 252-256
• 11 Akgür FM, Özdemir T, Olguner M. et al . An experimental study investigating the effects of intraperitoneal human neonatal urine and meconium on rat intestines.  Res Exp Med. 1998;  198 207-213
• 12 Olguner M, Akgür FM, Api A. et al . The effects of intraamniotic human neonatal urine and meconium on intestines of chick embryo with gastroschisis.  J Pediatr Surg. 2000;  35 458-461
• 13 Correia-Pinto J, Tavares ML, Baptista MJ. et al . Meconium dependence of bowel damage in gastroschisis.  J Pediatr Surg. 2002;  37 31-35
• 14 Api A, Olguner M, Hakgüder G. et al . Intestinal damage in gastroschisis correlates with the concentration of intraamniotic meconium.  J Pediatr Surg. 2001;  36 1811-1815
• 15 Aktuğ T, Erdağ G, Kargı A. et al . Amnio-allantoic fluid exchange for the prevention of intestinal damage in gastroschisis: an experimental study on chick embryos.  J Pediatr Surg. 1995;  30 384-387
• 16 Aktuğ T, Uçan B, Olguner M. et al . Amnio-allantoic fluid exchange for prevention of intestinal damage in gastroschisis II: Effects of exchange performed by using two different solutions.  Eur J Pediatr Surg. 1998;  8 308-311
• 17 Aktuğ T, Uçan B, Olguner M. et al . Amnio-allantoic fluid exchange for prevention of intestinal damage in gastroschisis III: Determination of the waste products removed by exchange.  Eur J Pediatr Surg. 1998;  8 326-328
• 18 Aktuğ T, Demir N, Akgür FM. et al . Intrauterine pretreatment of gastroschisis with transabdominal amniotic fluid exchange.  Obstet Gynecol. 1998;  91 821-823
• 19 Dommergues M, Ansker Y, Aubry MC. et al . Serial transabdominal amnioinfusion in the management of gastroschisis with severe oligohydramnios.  J Pediatr Surg. 1996;  31 1297-1299
• 20 Luton D, de Lagausie P, Guibourdenche J. et al . Effect of amnioinfusion on the outcome of prenatally diagnosed gastroschisis.  Fetal Diagn Ther. 1999;  14 152-155
• 21 Luton D, de Lagauise P, Guibourdenche J. et al . Influence of amnioinfusion in a model of in utero created gastroschisis in the pregnant ewe.  Fetal Diagn Ther. 2000;  15 224-228
• 22 Sapin E, Mahieu D, Borgnon J. et al . Transbdominal amnioinfusion to avoid fetal demise and intestinal damage in fetuses with gastroschisis and severe oligohydramnios.  J Pediatr Surg. 2000;  35 598-600
• 23 Hakgüder G, Ateş O, Olguner M. et al . Induction of fetal diuresis with intraamniotic furosemide increases the clearance of intraamniotic substances: An alternative therapy aimed at reducing intraamniotic meconium concentration.  J Pediatr Surg. 2002;  37 1337-1342
• 24 Hakgüder G, Ateş O, Olguner M. et al . Is induction of fetal diuresis with intraamniotic furosemide effective for the removal of intestinal waste products from amniotic fluid?.  Eur J Pediatr Surg. 2002;  12 293-298
• 25 Gilbert WM, Newman PS, Brace RA. Potential route for fetal therapy: Intramembranous absorbtion of intraamnioticly injected furosemide.  Am J Obstet Gynecol. 1995;  172 1471-1476
• 26 Correia-Pinto J, Tavares ML, Baptista MJ. et al . A new fetal rat model of gastroschisis: Development and early characterization.  J Pediatr Surg. 2001;  36 213-216
• 27 Olguner M, Hakgüder G, Ateş O. et al . Urinary trypsin inhibitor present in fetal urine prevents intraamniotic meconium induced intestinal damage in gastroschisis.  J Pediatr Surg. 2006;  41 1407-1412
• 28 el Maradny E, Kanayama N, Halim A. et al . Urinary trypsin inhibitor has a protective effect on amnion.  Gynecol Obstet Invest. 1994;  38 169-172
• 29 Karakus OZ, Ateş O, Murat N. et al . The protective effect of urinary tripsin inhibitor on intestinal motility of chick embryos with gastroschisis.  Presented at the 9th European Congress of Pediatric Surgery, Istanbul, Turkey, June 18–21 2008; 
• 30 Morrison JJ, Klein N, Chitty LS. et al . Intra-amniotic inflammation in human gastroschisis: possible aetiology of postnatal bowel dysfunction.  Br J Obstet Gynaecol. 1998;  105 1200-1204
• 31 de Beaufort AJ, Pelikan DM, Elferink JG. et al . Effect of interleukin 8 in meconium on in-vitro neutrophil chemotaxis.  Lancet. 1998;  352 102-105
• 32 Kanayama N. Intrauterine defensive mechanism of amniotic fluid and fetal membranes.  Acta Obst Gynaec Jpn. 1994;  46 673-685
• 33 Crooney DR. Defects of the abdominal wall. In: O’Neill JA, Rowe MI, Grosfeld JL, Fonkalsrud EW, Coran AG, (eds): Pediatric Surgery. St Louis, MO: Mosby; 1998: 1045-1069
• 34 Deans KJ, Mooney DP, Meyer MM. et al . Prolonged intestinal exposure to amniotic fluid does not result in peel formation in gastroschisis.  J Pediatr Surg. 1999;  34 975-976
• 35 Brace RA. Physiology of amniotic fluid volume regulation.  Clin Obstet Gynecol. 1997;  40 280-289
• 36 Kanayama N, Yamazaki T, Naruse H. et al . Determining zinc coproporphyrin in maternal plasma: a new method for diagnosing amniotic fluid embolism.  Clin Chem. 1992;  38 526-529
• 37 Usta IM, Sibai BM, Mercer BM. et al . Use of maternal plasma level of zinc coproporphyrin in the prediction of intrauterine passage of meconium: a pilot study.  J Matern Fetal Med. 2000;  9 201-203
• 38 Brace RA. Fetal blood volume, urine flow, swallowing and amniotic fluid volume responses to long-term intravascular infusion of saline.  Am J Obstet Gynecol. 1989;  161 1049-1054
• 39 Kelly TF, Moore TR, Brace RA. Hemodynamic and fluid responses to furosemide infusion in the ovine fetus.  Am J Obstet Gynecol. 1993;  168 260-268
• 40 Verbeeck RK, Patwardhan RV, Villeneuve JP. et al . Furosemide disposition in cirrhosis.  Clin Pharmacol Ther. 1982;  31 719-725
• 41 Anandakumar C, Biswas A, Chew SS. et al . Direct fetal treatment for hydrops secondary to congenital atrioventricular heart block.  Obstet Gynecol. 1996;  87 835-837
• 42 Anandakumar C, Biswas A, Chua TM. et al . Direct intrauterine fetal therapy in a case of bronchopulmonary sequestration associated with non-immune hydrops fetalis.  Ultrasound Obstet Gynocol. 1999;  13 263-265

Correspondence