Does an expanding fetal abdominal mass produce pulmonary hypoplasia?

Does an Expanding Fetal Abdominal Mass Produce Pulmonary Hypoplasia? By Loie Sauer, Michael R. Harrison, Alan W. Flake, and Thomas R. Krummel San Francisco, Cafifornia and Richmond, Virginia 9 Fatal pulmonary hypoplasia has been related to multiple factors. In an effort to define which fetuses may benefit f r o m prenatal intervention to prevent or reverse pulmonary hypoplasia, w e studied the relative contribution of an enlarging abdominal mass in the fetus. We produced abdominal masses in fetal rabbits at 24 days gestation by t w o methods. In one group, a small cylindrical chip of Takasen, (a synthetic polymer t h a t expands to 50 times its size in 1 w e e k ; Grobeast, Pop A r t Co, Cleveland, OH) was inserted into the peritoneal cavity of the fetal rabbit; in another group, the bladder neck was obstructed w i t h a surgical clip. Amniotic fluid v o l u m e was restored at the surgical procedure. Sham-operated littermates served as controls. A t cesarean delivery on day 30, fetal lung, liver, and body weights w e r e measured, and the abdominal masses w e r e quantitated by volume displacement of the removed mass or bladder. In both groups large abdominal masses of comparable size w e r e produced. Newborns w i t h the synthetic abdominal mass did not have significant pulmonary hypoplasia, but often had a prune belly deform i t y of the abdominal wall, whereas newborns w i t h bladder obstruction had significant pulmonary hypoplasia. Liver w e i g h t was not significantly affected. We conclude t h a t (1) a fetal abdominal mass does not independently produce pulmonary hypoplasia, possibly because the "'mass effect'" is relieved by distension of the abdominal wall rather than elevation of the diaphragm; (2) the pulmonary hypoplasia t h a t occurs in bladder outlet obstruction is probably due to the associated oligohydramnios r a t h e r than the mass effect of the dilated urinary tract; and (3) prenatal decompression of an abdominal mass or dilated urinary tract is not justified to prevent pulmonary hypoplasia in the absence of oligohydramnios. 9 1987 by Grune R, Stratton, Inc. INDEX W O R D S : Pulmonary hypoplasia; fetal surgery.

~ETAL PULMONARY HYPOPLASIA often leads to neonatal death. Multiple factors contribute to fetal lung growth, and abnormalities in any of these factors can potentially impair normal pulmonary development. To understand the relative importance of each of the factors, models isolating each of the

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From the Fetal Treatment Program, Department of Surgery, University of California, San Francisco, and the Department of Surgery, Medical College of Virginia, Richmond. Presented at the 35th Annual Meeting of the Surgical Section of the American Academy of Pediatrics, Washington, DC, November 1-2, 1986. Address reprint requests to Michael R. Harrison, MD, Room 585 HSE, University of California, 550 Parnassus Ave, San Francisco, CA 94143. 9 1987 by Grune & Stratton, Inc. 0022-3468/87/2206-0009503.00/0 508

variables are needed. Ultimately we aim to identify which fetuses are at high risk for pulmonary hypoplasia, and which may potentially benefit from prenatal intervention. The physical factors that impair lung growth include space compression of the lung, decreased amniotic fluid and lung fluid, and absent fetal breathing movements (Fig 1). 1-4 Space occupying masses in the fetal chest (ie, diaphragmatic hernia) result in pulmonary hypoplasia.5 Oligohydramnios and decreased lung fluid result in a smaller uterine cavity and reduced volume of internal stenting of the developing airways.61~ Compression of the fetal chest by a distended abdomen could potentially impede lung growth by upward pressure on the diaphragm. However, no study has been reported in which abdominal distension alone was studied. Fetal urinary tract obstruction produces both oligohydramnios and distension of the abdomen by the dilated urinary tract. The resulting pulmonary hypoplasia is often fatal. It is unknown whether the pulmonary hypoplasia results from abdominal distension or the associated oligohydramnios.812 To investigate this question, we developed a model of an enlarging fetal abdominal mass. We have previously described a model for urinary tract obstruction in the fetal rabbit and fetal lambs. 3'13"14 We tested the effects of an abdominal mass alone, compared with abdominal mass associated with oligohydramnios, to measure the effect on fetal lung and liver growth. MATERIALS AND METHODS

Fet a l Urethral Obstruction Time-dated pregnant New Zealand white rabbits underwent operation on day 24 of pregnancy. The hindquarters of the fetus were delivered through a small hysterotomy. A transverse incision was made over the pubis, and the bladder exposed. A small Week clip (Edward Week Co, Durham, NC) was applied to the bladder just above the pubis, avoiding the nearby umbilical arteries (Fig 2). The fetus was returned to the amniotic sac, 3 mL of warm saline was added to replace the lost amniotic fluid, and the uterus was closed.

Synthetic Abdominal Mass Fetal rabbits at 24 days gestation were exposed as described above. A transverse incision was made in the fetal abdominal wall in the left lower quadrant. An eliptical piece of Takasen, a synthetic expandable polymer (Grobeast, Pop Art Co, Cleveland, OH) 0.5 x 0.5 x 0.7 era, was inserted into the peritoneal cavity of the fetal rabbit (Fig 3). The wound was closed with interrupted silk sutures. Warm saline (3 mL) was added to the uterus and the uterine pursestring was closed. Journal of Pediatric Surgery, Vol 22, No 6 (June), 1987: pp 508-512

ABDOMINAL MASS AND PULMONARY HYPOPLASIA

~. SPACE ~, AMNIOTIC FLUID LUNG FLUID ~, BREATHING

Fig 1. The physical factors that impair fetal lung growth. Pulmonary hypoplasia.

Sham-Operated Littermate Controls Littermates of both experimental groups were exposed as described. Left lower quadrant abdominal incisions were made and the peritoneal cavity entered. The woundswere closed, fluid replaced in the uterus, and uterus closed. The pregnanciesthen continued until day 30 of gestation, when all fetuses underwent cesarean delivery. The fetuses were killed with ether inhalation. The synthetic abdominal mass was removedand its volume quantatitated by water volume displacement in a graduated cylinder. In the bladder obstruction group, the intact obstructed bladder was dissected from the fetus and its volumequantitated by water volume displacement in a graduated cylinder. Fetal body weight (BW), lung weight (LW), and liver weight (LiW) were then determined. In an effort to standardize lung and liver weight for differences in body weight, ratios were calculated LW/BW and LiW/BW (Table 1).

Statistical Analysis The unpaired Student's t-test was used to analyze the data. RESULTS

We produced abdominal distension by two methods. The fetuses with bladder neck obstruction all had megacystis, and some degree of hydroureter and hydronephrosis. The enlarged bladder occupied most of the abdominal cavity. In the second group, an abdominal mass was produced by insertion of the Takasen piece into the fetal peritoneal cavity. Synthetic material was inserted in 33 fetuses at 24 days gestation; 23 were viable at term delivery; the remaining ten had been resorbed. At insertion, the elipticalshaped piece of Takasen measured 5 x 5 • 7 mm, and at removal, the average mass measured 8 x 11 x 18 mm. The size of the mass produced by the two methods was comparable (Table 1). The synthetic masses were actually larger than the dilated bladder. The animals with obstruction of the bladder neck had significant pulmonary hypoplasia. The animals with a large synthetic abdominal mass did not have significant pulmonary hypoplasia relative to shamoperated littermate controls (Fig 4, Table 1). The majority of the fetal rabbits with the bladder obstruction had increased respiratory effort, with use of accessory muscles of respiration. Pulmonary hypo-

509

plasia was significant in this group. Lung weight and lung/body weight ratios were significantly decreased relative to controls. These findings are in accord with our previous experiments using this same m o d e l Y 4 The term fetuses with intraabdominal masses had no apparent respiratory difficulty. Lung weight and lung/ body weight ratios of the abdominal mass group were lower than controls, but the decrease was not statistically significant. The abdominal wall was distended, and several of the animals with synthetic masses had a prune belly appearance. Two had ascites. Liver weight and liver/body weight ratios were not altered by bladder obstruction or the synthetic abdominal mass. DISCUSSION

Fetal lung development is influenced by multiple variables during gestation. Since pulmonary hypoplasia is often irreversible in the postnatal period, the critical time period to identify or correct any inciting factors may be before birth. But which fetuses are at risk for compromise of lung growth? Physical and neuroendocrine factors influence lung growth. ~ The physical factors include space, fluid, and fetal breathing movements. If the fetal thorax is filled with abdominal organs, in the case of diaphragmatic hernia, or with fluid, for example, the lungs are hypoplastic. 5 The relationship between oligohydramnios and pulmonary hypoplasia is well documented, yet still incompletely understood. Some authors have attributed this to a "compressive" effect on the fetal thorax by a small uterine cavity and absence of amniotic fluid. Pulmonary hypoplasia is considered the pulmonary analogy of the compressive deformities noted in the face and extremities in Potter's syndrome. ~0 It is unlikely, however, that oligohydramnios actually results in compression of the fetal chest, since hydraulic pressure with or without the amniotic fluid should be the same on the fetal thoracic cage. Instead, two other explanations are advanced for oligohydramnios-induced pulmonary hypoplasia. The absence of amniotic fluid alters the fluid gradient between the amniotic cavity and the fetal lungs, resulting in an outward flow of lung fluid and loss of the internal stenting of the fetal airways. 94~ Another possible etiology is that oligohydramnios inhibits fetal breathing movements that contribute to lung growth. 1'3 Thus, the fetal lung is susceptible to encroachment of its space by external masses and by loss of internal stenting. One factor that remains unknown is whether the fetal abdominal cavity, when distended, causes upward pressure on the diaphragms and compromises fetal lung growth. Fetal abdominal distension is corn-

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=rfery

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mon, and occurs in several settings. About half of the causes of abdominal masses in newborns arise in the genitourinary tract and include hydronephrosis, renal cysts, megacystis, and ovarian cysts] 5 Other causes include intestinal cysts and fetal ascites. Should all of these "masses" be decompressed prenatally in an effort to prevent pulmonary hypoplasia? The answer relies on documentation that the mass effect of abdominal distension alone causes pulmonary hypoplasia, rather than the effect of associated abnormalities in the amount of amniotic fluid. In fetal urinary tract obstruction, the pulmonary hypoplasia is conceivably due to the effects of the oligohydramnios, or to the mass effect of the dilated urinary tract, or to the additive effect of the two. We wanted to study the effect of abdominal distension alone, without alteration of the amniotic fluid volume, to see if abdominal enlargement independently produced pulmonary hypoplasia. To perform this comparison, we needed models of urinary tract obstruction and a model of a fetal abdominal mass. We have

Weck clip "occluding bladder neck

Fig 2. Urethral obstruction. A small Weck clip is applied to the distal bladder neck. Place pursestring suture, open uterus with electrocautery. Deliver hindquarters of fetal rabbit.

already developed a model of urinary tract obstruction in the fetus. But to design a model of an abdominal mass alone proved to be challenging. Criteria for a good model required a mechanism that would not be lethal to the fetus, would not alter amniotic fluid volume, and would progressively enlarge to occupy most of the fetal abdominal cavity as an analogy to the massive fetal bladder found in urethral obstruction. We considered synthetic tissue expanders, hydrophilic chips, infusion catheters, and even laminaria, but found that none of these had the expansion characteristics necessary for our study. Somewhat by chance we came upon the Grobeast model. The Grobeast material, Takasen, has been extensively studied by its manufacturer) 6 For our purposes, it proved ideal: the material expands at a relatively constant rate for the first four days and plateaus at maximum expansion by the end of a week. We performed preliminary studies and found that we could sterilize the Grobeasts by gas sterilization techniques; we could cut the toys into the pieces and the

Place pursestring suture, open uterus with electrocautery Deliver hindquarters of fetal rabbit Left lower incision Insertion of expandable mass

Fig 3. Synthetic abdominal mass, A premeasured piece of self-expanding material is inserted into the fetal peritoneal cavity,

ABDOMINAL MASS AND PULMONARY HYPOPLASIA

511

Table 1. Effect of Synthetic Abdominal Mass or Bladder Ligation on Fetal Lung and Liver Growth No.

8W (g)

Li (g)

Li/BW (%)

Controls

23

40.25 _+ 6.42

0.85 • 0.18

LW (g)

2.10 + 0.30

LW/BW (%)

2.57 • 0.44

6.42 • 0.97

Synthetic mass

23

38.56 _+ 5.81

0.78 _+ 0.14

2.01 + 0,28

2.49 • 0.55

6.43 _+ 0.85

Bladder ligation

7

36.48 _+ 2.88

0.59 _+ 0 . 1 0 "

1,62 _+ 0 . 2 6 *

2.30 _+ 0.32

6.32 -+ 0.79

Abbreviations: BW, body weighti LW, lung weight; Li, liver weight. P < .05 compared with controls.

pieces grew at the same rate as the whole piece; and in pilot studies, we found that the material was not toxic to the fetus when implanted intraperitoneally. When inserted into the fetal rabbit abdominal cavity at 24 days gestation, the piece of Grobeast Takasen material-expanded to a size greater than the size of the obstructed fetal bladder. We found that the group of fetuses with the synthetic abdominal masses did not have pulmonary hypoplasia. Lung weight and lung/body weight ratios were diminished somewhat, but not to a significant degree. In contrast, as expected, the fetuses who underwent bladder outlet obstruction had significant pulmonary hypoplasia and respiratory depression at birth. The synthetic mass group had no apparent respiratory distress. One noticeable feature was the appearance of prune belly deformity of the abdominal wall in the fetuses with distension from the large synthetic abdominal mass. This is in accord with the hypothesis that the prune belly deformity reflects thinning and

Lung W t . / B o d y Wt. (% -+ S.D.) Mass (cc. + S.D.)

stretching of the abdominal wall due to distension rather than a primary mesenchymal defect. 17 From our study, we conclude that abdominal distension alone does not produce small lungs, possibly because the mass effect is relieved by distension of the abdominal wall rather than elevation of the diaphragm. In contrast, urinary tract obstruction, in which there is oligohydramnios in addition to abdominal distension from a dilated urinary tract, does result in pulmonary hypoplasia. We postulate that the compromise in fetal lung growth is due to the sequelae of the oligohydramnios rather than the mass effect of the dilated urinary tract. What are the clinical implications of our study? Perinatologists frequently ask whether they should decompress abdominal masses that are observed by ultrasonography. There are a growing number of case reports of human fetuses that have had prenatal intervention for unilateral hydronephrosis, renal cysts, or bladder distension without oligohydramnios.~82J The

Controls (N = 23)

Bladder Obstruction (N = 7)

Synthetic Abdominal Mass (N = 23)

2.10 + 0.30

1.62 + 0.26

2.01 + 0.28

1.38 + 0.28

1.42 -+ 0.32

Fig 4. Effect of abdominal mass and bladder obstruction on fetal lung growth. The animals with bladder obstruction had significant pulmonary hypoplasia. The animals with a large synthetic abdominal mass did not have significant pulmonary hypoplasia relative to sham-operated littermate controls.

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common argument justifying these interventions is that the abdominal distension was compromising fetal lung growth. Our findings in this study contradict that assumption. We conclude that abdominal distension alone will probably not compromise lung growth. In the absence of oligohydramnios, prenatal decompression of an abdominal mass is not warranted. We continue to apply the criteria previously outlined for identifying the fetus at high risk for pulmonary hypoplasia: the

mid-to-late gestation fetus with dilated urinary tract, progressive oligohydramnios, and favorable renal function, or the fetus with a congenital diaphragmatic hernia. 12-24 ACKNOWLEDGMENT

We wish to thank Peter Callen, MD, and To-Nao Wang, MD, for their helpful suggestions. We gratefully acknowledge technical assistance from Lora Roberts and Robin Troyer, and we wish to thank Gerald Zucker and the Pop Art Co for technical information and donation of the Grobeasts used in this experiment.

REFERENCES

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tal hydronephrosis in utero I. The model: Fetal urethral obstruction produces hydronephrosis and pulmonary hypoplasia in fetal lambs. J Pediatr Surg 18:247-256, 1983 14. Nakayama DK, Glick PL, Harrison MR, et al: Experimental pulmonary hypoplasia due to oligohydramnios and its reversal by relieving thoracic compression. J Pediatr Surg 18:347-353, 1983 15. Hendren WH: Abdominal masses in newborn infants. Am J Surg 107:502-510, 1964 16. Takaroku Shoji Co, Ltd: Safety report for toys made from takasen special compound. Unpublished document available from Pop Art Co, Cleveland, OH, 1984 17. Nakayarna DK, Harrison MR, Chinn DH, et al: The pathogenesis of prune belly. Am J Dis CHild 138:834-836, 1984 18. Hill LM, Breckle R, Ellefson RD: The contribution of the fetal kidney to the amniotic fluid lung profile. Am J Obstet Gynecol 146:709-710, 1983 19. Schaaps JP, Thoumsin H, Lambotte R: Intrauterine unilateral nephrostomy. Am J Obstet Gynecol 146:105-106, 1983 20. Weinstein L, Anderson CF, Finley PR, et al: The in utero management of urinary outflow tract obstruction. J Clin Ultrasound 10:465-468, 1982 21. Vintzileos AM, Nochimson D J, Walzak MP, et al: Unilateral fetal hydronephrosis: Successful in utero surgical management. Am J Obstet Gynecol 7:885-886, 1983 22. Harrison MR, Nakayama KD, Noall R, et al: Correction of congenital hydronephrosis in utero II. Decompression reverses the effects of obstruction on the fetal lung and urinary tract. J Pediatr Surg 17:965-974, 1982 23. Flake AW, Harrison MR, Sauer L, et al: Ureteropelvic junction obstruction in the fetus. J Pediatr Surg 21:1058-1063, 1986 24. Harrison MR, Filly RA, Parer JT, et al: Management of the fetus with a urinary tract malformation. JAMA 246:635-639, 1981