Vol. 113, February
THE JOURNAL OF UROLOGY
Printed in U.S.A.
Copyright© 1975 by The Williams & Wilkins Co.
FETAL VESICOURETERAL REFLUX EDWARD J. BOOTH, THOMAS E. BELL, CLARENCE MCLAIN
AND
ARTHUR T. EVANS
From the Division of Urology and the Department of Obstetrics and Gynecology, University of Cincinnati Medical Center and The Christ Hospital, Cincinnati, Ohio
There has been considerable controversy over whether vesicoureteral reflux can occur in normal children. Hutch believed that maturation and lengthening of the short intravesical ureter of newborns, infants and young children accounted for a decreasing incidence of vesicoureteral reflux as these children approach adolescence. 1 Indeed, it would seem to us that the demonstration of reflux is more rare in adults than in children. However, Peters and associates obtained voiding cine-cystourethrography on 66 normal premature infants without evidence of urologic disease or urinary infection and did not find a single case of vesicoureteral reflux. 2 Lich and associates obtained voiding cystourethrograms on 26 urologically normal newborn infants less than 48 hours old and also found no cases of vesicoureteral reflux.• It must be added that this was an unbiased investigation and urological disease was not known before, thus keeping the cases studied a more random population. If the length of the intravesical ureter and the maturation of the vesicoureteral junction were the predominant factors as to whether vesicoureteral reflux was present, then the premature infant and newborn should supposedly have vesicoureteral reflux more often than one would expect in the general pediatric population. 2 This does not appear to be the case or at least the data supplied by Peters and Lich and their associates refute the concept proposed by Hutch. We herein report the first case of fetal vesicoureteral reflux demonstrated during needle placement for intrauterine blood transfusion in an infant affected with erythroblastosis fetalis. A survey of other intrauterine fetal cystograms will be presented. It seems that vesicoureteral reflux in these young fetuses (24 to 34 weeks of gestation) is unusual and rare but may be present more frequently than expected. This study provides an unusual opportunity to follow these children after birth concerning the natural history of the congenital vesicoureteral reflux. Accepted for publication July 19, 1974. Read at annual meeting of American Urological Association, St. Louis, Missouri, May 19-23, 1974. 1 Hutch, J. A.: Theory of maturation of the intravesical ureter. J. Urol., 86: 534, 1961. 'Peters, P. C., Johnson, D. E. and Jackson, J. H., Jr.: The incidence of vesicoureteral reflux in the premature child. J. Urol., 97: 259, 1967. 3 Lich, R., Jr., Howerton, L. W:·, Jr:, Goode, L. S. and Davis, L. A.: The ureterovesical Junction of the newborn. J. Urol., 92: 436, 1964. 258
CASE MATERIAL
Intrauterine fetal peritoneal blood transfusions for erythroblastosis fetalis was first described in 1963 by Liley• and was reviewed in 1969 by Queenan. 6 Briefly, the procedure involves percutaneous intrauterine placement of a large bore needle into the peritoneal cavity of a fetus affected by erythroblastosis fetalis and then insertion of a polyethylene catheter for red blood cell transfusion. Radiopaque contrast material is used to determine proper needle positioning. Infrequently the bladder may be entered because of its relatively intra-abdominal position and provides a fetal cystogram upon instillation of contrast material. Our patient, M. B., C. H. 1581354, is a 39-yearold gravida VII, Para 5, abortion 0, stillbirths 1, white woman who was admitted to our hospital after 23 25 and 27 weeks of gestation for intrauterine tradsfusions of a fetus with evidence on amniocentesis of erythroblastosis fetalis. The proced1:1re performed at 25 weeks of gestation resulted in a fetal cystogram, demonstrating bilateral vesicoureteral reflux (part A of figure). An 18 gauge needle was used and 2 to 3 cc 50 per cent hypaque was instilled into the bladder. The baby was born at 29 weeks of gestation, following premature rupture of the membranes and weighed 1,200 gm. When the child was 1 year old she was doing well and had no evidence of urinary tract abnormality and no documented urinary infections, although there have been episodes of fever of undetermined origin. A followup cine-cystourethrogram confirmed the persistence of bilateral high pressure vesicoureteral reflux (part B of figure). An excretory urogram or cystoscopy has not been performed. DISCUSSION
A personal survey of 17 physicians performing intrauterine fetal transfusion was undertaken to determine how many additional times vesicoureteral reflux has been seen on fetal cystograms. Including our own, 28 cases of fetal cystograms were collected with none of the others showing vesicoureteral reflux. Two additional contributing physicians stated that on several occasions the fetal bladder was outlined but no reflux was ever seen; the exact number of cases was not given. 'Liley, A. W.: Intrauterine transfusion of foetus in haemolytic disease. Brit. Med. J., 2: 1107, 1963. • Queenan, J. T.: Intrauterine transfusion. A cooperative study. Amer. J. Obst. Gynec., 104: 397, 1969.
259
FETAL VESICOURETERAL REFLUX
stream demonstrated reflux in only 1 of 100 normal children between 14 days and 14 years old.9 The single patient with reflux later proved to have an abnormal urinary tract with residual urine, bladder neck contracture and trabeculation. Iannaccone and Panzironi contributed cystograms in 50 normal infants between 10 days and 6 months and demonstrated reflux on 1 occasion. 10 Politano found no reflux in 50 urologically normal children. 11 Therefore, the incidence of vesicoureteral reflux in the aforementioned studies of urologically ma! premature infants and newborns was 0 cent of 92 total cases studied. A total of 242 urologically normal infants and children were stud ied for reflux and only 3 cases were found (see table). This would indicate an incidence of occa sional vesicoureteral reflux of only 3 of 242 children (1.2 per cent), excluding the 3 cases reported Kretschmer and the 1 case reported Jones and Headstream. Our survey indicates fetal vesicoureteral reflux in at least 3.6 per cent and may be more than 10 per cent. Vesico ·
Reference
Lecky has indicated that he has seen vesicoureteral reflux on fetal intrauterine cystograms fairly frequently but at present he has incomplete data to confirm the exact number. 6 Also none of these cases has been reported or followed when the fetus survived. The incidence of fetal vesicoureteral reflux in the 28 documented cases in the survey is 3.6 per cent, which approaches the 4.6 per cent incidence of vesicoureteral reflux reported by Gibson 7 seen on cystograms performed on 43 normal children up to 14 years old. The children described by Gibson had no urologic symptoms or disease, and the reflux was on the right side only in 2 of the 43 patients. If the cases of Lecky are included, which may number as high as 6, then the percentage of apparently normal or at least uninfected fetal bladders with reflux may approach 10 to 15 per cent. Since this figure is unknown it remains only speculation but if it could be ascertained to be factual then perhaps there is a factor of maturation. Currently it is believed that vesicoureteral reflux may occur in the normal bladder but it is rare. The first demonstration of vesicoureteral reflux in normal children was reported in 1916 by Kretschmer.• He reported reflux in 3 of 10 normal infants but he used irritable contrast material. Jones and Head'Lecky, J. W.: University of Pittsburgh, personal communication. 7 Gibson, H. M.: Ureteral reflux in the normal child. J. Urol., 62: 40, 1949. 'Kretschmer, H. L.: Cystography. Surg., Gynec. & Obst., 23: 709, 1916.
Pt. Group
ureter al Reflux
Peters and associates 2
Premature infants
0/66
Lich and associates' Total
Newborns
0/26 0/92
Kretschmer' Iannaccone and Panzironi 10 Jones and Headstream'
Children Infants Children and infants Children Children and infants
3/10* 1/50
Politano" Gibson' Total
0/991 0/50 2/4:J. 3/242
* Cases eliminated because irritating contrast material w2s used. t One case of reflux in an abnormal genitourinary tract eliminated. CONCLUSIONS
The first reported case of fetal intrauterine vesicoureteral reflux is presented and additional fetal cystograms are reviewed. Definite conclusions as to the significance of fetal vesicoureteral reflux are difficult because of the few cases obtained and the presence of an unknown number of additionai cases. It appears that the incidence of reflux higher than that of normal premature newborns, infants and children. In our series fetal vesicoureteral reflux was present and documented in 1 of 28 fetal cystograms. Several other cases have apparently been documented but at present are 'Jones, B. W. and Headstream, J. Vv.: Vesicoureteral reflux in children. J. Urol., 80: 114, 1958. 10 Iannaccone, G. and Panzironi, P. E.: Ureteral reflux in normal infants. Acta Radio!., 44: 451, 1955. 11 Politano, V. A.: Vesicoureteral reflux in children J.A.M.A., 172: 1252, 1960.
260
BOOTH AND ASSOCIATES
not reported. A followup cine-cystourethrogram in our patient when she was 1 year old demonstrated that reflux was still present but occurred only on the voiding phase of the cystourethrogram. This possibly may be evidence of a trend toward the more normal situation or maturation. Further urologic evaluation of this patient has not been completed. It can only be speculative as to whether reflux in this child represents a normal variant that will resolve with maturation or an early manifestation of urinary tract pathology. One might also speculate that the reflux seen in 1 fetal patient is a result of erythroblastosis fetalis. This would certainly be untrue as to explaining the reflux on the basis of edema of the bladder at the ureterovesical junction, similar to what one sees in acute cystitis. However, this is not the situation. While the bladder and all organs may become edematous in hydrops fetalis as part of the generalized anasarca owing to Rh incompatability, this child did not progress to involvement of that extreme degree. Likewise, that argument would not be tenable now, 1 year later, when reflux is still demonstrable in this patient. What we believe to have represented here serves as evidence that vesicoureteral reflux without distal obstruction or contributing cause is indeed an abnormality which is congenital or developmental from onset. Perhaps maturation or some other process does develop later in life in these patients to cause the apparent fall in the incidence of reflux as one approaches adolescence. 1 Perhaps those
patients without this so-called maturation are the ones who undergo microscopic changes in the ureter proposed by Tanagho and associates, 12 and do become the ones with the classic abnormal ureteral orifice noted by Lyon and associates, 1 • and ultimately may come to ureteroneocystostomy. SUMMARY
Intrauterine fetal vesicoureteral reflux has been demonstrated in a 25-week fetus. A voiding cystourethrogram when the patient was 1 year old showed persistence of the bilateral reflux. No urinary tract infections have been documented. A survey of other physicians performing fetal transfusions indicates that fetal cystograms are infrequently obtained and that vesicoureteral reflux has been observed by ourselves and one other contributing physician. The incidence of reflux in fetal cystograms reviewed appears to be higher than would be expected when compared to normal premature babies, newborns, infants and children. This procedure provides an unusual opportunity to document intrauterine fetal vesicoureteral reflux and later obtain followup cystourethrograms in these children to determine the resolution or progression of this urinary tract abormality. 12 Tanagho, E. A., Guthrie, T. H. and Lyon, R. P.: The intravesical ureter in primary reflux. J. Urol., 101: 824, 1969. "Lyon, R. P., Marshall, S. and Tanagho, E. A.: The ureteral orifice: its configuration and competency. J. Urol., 102: 504, 1969.
THE JOURNAL OF UROLOGY
Printed in U.S.A.
Copyright© 1975 by The Williams & Wilkins Co.
FETAL VESICOURETERAL REFLUX EDWARD J. BOOTH, THOMAS E. BELL, CLARENCE MCLAIN
AND
ARTHUR T. EVANS
From the Division of Urology and the Department of Obstetrics and Gynecology, University of Cincinnati Medical Center and The Christ Hospital, Cincinnati, Ohio
There has been considerable controversy over whether vesicoureteral reflux can occur in normal children. Hutch believed that maturation and lengthening of the short intravesical ureter of newborns, infants and young children accounted for a decreasing incidence of vesicoureteral reflux as these children approach adolescence. 1 Indeed, it would seem to us that the demonstration of reflux is more rare in adults than in children. However, Peters and associates obtained voiding cine-cystourethrography on 66 normal premature infants without evidence of urologic disease or urinary infection and did not find a single case of vesicoureteral reflux. 2 Lich and associates obtained voiding cystourethrograms on 26 urologically normal newborn infants less than 48 hours old and also found no cases of vesicoureteral reflux.• It must be added that this was an unbiased investigation and urological disease was not known before, thus keeping the cases studied a more random population. If the length of the intravesical ureter and the maturation of the vesicoureteral junction were the predominant factors as to whether vesicoureteral reflux was present, then the premature infant and newborn should supposedly have vesicoureteral reflux more often than one would expect in the general pediatric population. 2 This does not appear to be the case or at least the data supplied by Peters and Lich and their associates refute the concept proposed by Hutch. We herein report the first case of fetal vesicoureteral reflux demonstrated during needle placement for intrauterine blood transfusion in an infant affected with erythroblastosis fetalis. A survey of other intrauterine fetal cystograms will be presented. It seems that vesicoureteral reflux in these young fetuses (24 to 34 weeks of gestation) is unusual and rare but may be present more frequently than expected. This study provides an unusual opportunity to follow these children after birth concerning the natural history of the congenital vesicoureteral reflux. Accepted for publication July 19, 1974. Read at annual meeting of American Urological Association, St. Louis, Missouri, May 19-23, 1974. 1 Hutch, J. A.: Theory of maturation of the intravesical ureter. J. Urol., 86: 534, 1961. 'Peters, P. C., Johnson, D. E. and Jackson, J. H., Jr.: The incidence of vesicoureteral reflux in the premature child. J. Urol., 97: 259, 1967. 3 Lich, R., Jr., Howerton, L. W:·, Jr:, Goode, L. S. and Davis, L. A.: The ureterovesical Junction of the newborn. J. Urol., 92: 436, 1964. 258
CASE MATERIAL
Intrauterine fetal peritoneal blood transfusions for erythroblastosis fetalis was first described in 1963 by Liley• and was reviewed in 1969 by Queenan. 6 Briefly, the procedure involves percutaneous intrauterine placement of a large bore needle into the peritoneal cavity of a fetus affected by erythroblastosis fetalis and then insertion of a polyethylene catheter for red blood cell transfusion. Radiopaque contrast material is used to determine proper needle positioning. Infrequently the bladder may be entered because of its relatively intra-abdominal position and provides a fetal cystogram upon instillation of contrast material. Our patient, M. B., C. H. 1581354, is a 39-yearold gravida VII, Para 5, abortion 0, stillbirths 1, white woman who was admitted to our hospital after 23 25 and 27 weeks of gestation for intrauterine tradsfusions of a fetus with evidence on amniocentesis of erythroblastosis fetalis. The proced1:1re performed at 25 weeks of gestation resulted in a fetal cystogram, demonstrating bilateral vesicoureteral reflux (part A of figure). An 18 gauge needle was used and 2 to 3 cc 50 per cent hypaque was instilled into the bladder. The baby was born at 29 weeks of gestation, following premature rupture of the membranes and weighed 1,200 gm. When the child was 1 year old she was doing well and had no evidence of urinary tract abnormality and no documented urinary infections, although there have been episodes of fever of undetermined origin. A followup cine-cystourethrogram confirmed the persistence of bilateral high pressure vesicoureteral reflux (part B of figure). An excretory urogram or cystoscopy has not been performed. DISCUSSION
A personal survey of 17 physicians performing intrauterine fetal transfusion was undertaken to determine how many additional times vesicoureteral reflux has been seen on fetal cystograms. Including our own, 28 cases of fetal cystograms were collected with none of the others showing vesicoureteral reflux. Two additional contributing physicians stated that on several occasions the fetal bladder was outlined but no reflux was ever seen; the exact number of cases was not given. 'Liley, A. W.: Intrauterine transfusion of foetus in haemolytic disease. Brit. Med. J., 2: 1107, 1963. • Queenan, J. T.: Intrauterine transfusion. A cooperative study. Amer. J. Obst. Gynec., 104: 397, 1969.
259
FETAL VESICOURETERAL REFLUX
stream demonstrated reflux in only 1 of 100 normal children between 14 days and 14 years old.9 The single patient with reflux later proved to have an abnormal urinary tract with residual urine, bladder neck contracture and trabeculation. Iannaccone and Panzironi contributed cystograms in 50 normal infants between 10 days and 6 months and demonstrated reflux on 1 occasion. 10 Politano found no reflux in 50 urologically normal children. 11 Therefore, the incidence of vesicoureteral reflux in the aforementioned studies of urologically ma! premature infants and newborns was 0 cent of 92 total cases studied. A total of 242 urologically normal infants and children were stud ied for reflux and only 3 cases were found (see table). This would indicate an incidence of occa sional vesicoureteral reflux of only 3 of 242 children (1.2 per cent), excluding the 3 cases reported Kretschmer and the 1 case reported Jones and Headstream. Our survey indicates fetal vesicoureteral reflux in at least 3.6 per cent and may be more than 10 per cent. Vesico ·
Reference
Lecky has indicated that he has seen vesicoureteral reflux on fetal intrauterine cystograms fairly frequently but at present he has incomplete data to confirm the exact number. 6 Also none of these cases has been reported or followed when the fetus survived. The incidence of fetal vesicoureteral reflux in the 28 documented cases in the survey is 3.6 per cent, which approaches the 4.6 per cent incidence of vesicoureteral reflux reported by Gibson 7 seen on cystograms performed on 43 normal children up to 14 years old. The children described by Gibson had no urologic symptoms or disease, and the reflux was on the right side only in 2 of the 43 patients. If the cases of Lecky are included, which may number as high as 6, then the percentage of apparently normal or at least uninfected fetal bladders with reflux may approach 10 to 15 per cent. Since this figure is unknown it remains only speculation but if it could be ascertained to be factual then perhaps there is a factor of maturation. Currently it is believed that vesicoureteral reflux may occur in the normal bladder but it is rare. The first demonstration of vesicoureteral reflux in normal children was reported in 1916 by Kretschmer.• He reported reflux in 3 of 10 normal infants but he used irritable contrast material. Jones and Head'Lecky, J. W.: University of Pittsburgh, personal communication. 7 Gibson, H. M.: Ureteral reflux in the normal child. J. Urol., 62: 40, 1949. 'Kretschmer, H. L.: Cystography. Surg., Gynec. & Obst., 23: 709, 1916.
Pt. Group
ureter al Reflux
Peters and associates 2
Premature infants
0/66
Lich and associates' Total
Newborns
0/26 0/92
Kretschmer' Iannaccone and Panzironi 10 Jones and Headstream'
Children Infants Children and infants Children Children and infants
3/10* 1/50
Politano" Gibson' Total
0/991 0/50 2/4:J. 3/242
* Cases eliminated because irritating contrast material w2s used. t One case of reflux in an abnormal genitourinary tract eliminated. CONCLUSIONS
The first reported case of fetal intrauterine vesicoureteral reflux is presented and additional fetal cystograms are reviewed. Definite conclusions as to the significance of fetal vesicoureteral reflux are difficult because of the few cases obtained and the presence of an unknown number of additionai cases. It appears that the incidence of reflux higher than that of normal premature newborns, infants and children. In our series fetal vesicoureteral reflux was present and documented in 1 of 28 fetal cystograms. Several other cases have apparently been documented but at present are 'Jones, B. W. and Headstream, J. Vv.: Vesicoureteral reflux in children. J. Urol., 80: 114, 1958. 10 Iannaccone, G. and Panzironi, P. E.: Ureteral reflux in normal infants. Acta Radio!., 44: 451, 1955. 11 Politano, V. A.: Vesicoureteral reflux in children J.A.M.A., 172: 1252, 1960.
260
BOOTH AND ASSOCIATES
not reported. A followup cine-cystourethrogram in our patient when she was 1 year old demonstrated that reflux was still present but occurred only on the voiding phase of the cystourethrogram. This possibly may be evidence of a trend toward the more normal situation or maturation. Further urologic evaluation of this patient has not been completed. It can only be speculative as to whether reflux in this child represents a normal variant that will resolve with maturation or an early manifestation of urinary tract pathology. One might also speculate that the reflux seen in 1 fetal patient is a result of erythroblastosis fetalis. This would certainly be untrue as to explaining the reflux on the basis of edema of the bladder at the ureterovesical junction, similar to what one sees in acute cystitis. However, this is not the situation. While the bladder and all organs may become edematous in hydrops fetalis as part of the generalized anasarca owing to Rh incompatability, this child did not progress to involvement of that extreme degree. Likewise, that argument would not be tenable now, 1 year later, when reflux is still demonstrable in this patient. What we believe to have represented here serves as evidence that vesicoureteral reflux without distal obstruction or contributing cause is indeed an abnormality which is congenital or developmental from onset. Perhaps maturation or some other process does develop later in life in these patients to cause the apparent fall in the incidence of reflux as one approaches adolescence. 1 Perhaps those
patients without this so-called maturation are the ones who undergo microscopic changes in the ureter proposed by Tanagho and associates, 12 and do become the ones with the classic abnormal ureteral orifice noted by Lyon and associates, 1 • and ultimately may come to ureteroneocystostomy. SUMMARY
Intrauterine fetal vesicoureteral reflux has been demonstrated in a 25-week fetus. A voiding cystourethrogram when the patient was 1 year old showed persistence of the bilateral reflux. No urinary tract infections have been documented. A survey of other physicians performing fetal transfusions indicates that fetal cystograms are infrequently obtained and that vesicoureteral reflux has been observed by ourselves and one other contributing physician. The incidence of reflux in fetal cystograms reviewed appears to be higher than would be expected when compared to normal premature babies, newborns, infants and children. This procedure provides an unusual opportunity to document intrauterine fetal vesicoureteral reflux and later obtain followup cystourethrograms in these children to determine the resolution or progression of this urinary tract abormality. 12 Tanagho, E. A., Guthrie, T. H. and Lyon, R. P.: The intravesical ureter in primary reflux. J. Urol., 101: 824, 1969. "Lyon, R. P., Marshall, S. and Tanagho, E. A.: The ureteral orifice: its configuration and competency. J. Urol., 102: 504, 1969.
