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Amnioexchange for fetuses with gastroschisis:

is it effective?
Article in Journal of Pediatric Surgery June 2007
DOI: 10.1016/j.jpedsurg.2006.12.029 Source: PubMed

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Journal of Pediatric Surgery (2007) 42, 777 782

www.elsevier.com/locate/jpedsurg

Amnioexchange for fetuses with gastroschisis:

is it effective?
Paola Midrioa,*, Giorgio Stefanuttia, Michele Mussapb, Donato DAntonac,
Elisa Zolpia, Piergiorgio Gambaa
a

Paediatric Surgery Unit, University of Padova, 35121 Padova, Italy

Department of Laboratory Medicine, University of Padova, 35121 Padova, Italy
c
Department of Gynecological and Human Reproduction Science, University of Padova, 35121 Padova, Italy
b

Index words:
Gastroschisis;
Amnioexchange;
Amnioinfusion;
Inflammatory mediators

Abstract
Background/Purpose: Amniotic fluid of fetuses with gastroschisis (GS) contains inflammatory
mediators, gastrointestinal, and urinary waste products. Dilution and removal of such harmful
substances have been advocated to prevent damage to the herniated intestine. We evaluated the
effectiveness of serial amnioexchange procedures in 8 consecutive fetuses with GS.
Methods: Amnioexchange was performed bimonthly during the third trimester. Amniotic fluid collected
before each procedure was tested for pH, osmolarity, urea, creatinine, cystatin-C, proteins, albumin,
bilirubin, biliary salts, pancreatic amylase, serum amyloid A, C-reactive protein, alanine transaminase
(ALT), alcaline phosphatase (ALP), gamma-glutamyl transpetidase (cGT), tumor necrosis factor a,
interleukin 2, interleukin 6, epidermal growth factor, transforming growth factor b, and myeloperoxidase.
Results: A total of 25 samples (median, 3 per fetus) were examined. Biochemical or inflammatory
markers did not correlate with gestational age, nor was any trend observed in values from individual
patients during the course of amnioexchange treatment. There was no correlation between biochemical or
inflammatory markers and clinical outcome, including time to full enteral feeding.
Conclusions: Serial amnioexchanges did not modify the biochemical or inflammatory status of amniotic
fluid nor appeared to prevent injury to the herniated gut. Because repeated amnioexchanges may carry
some risks, their use in fetuses with GS is not recommended outside the setting of a prospective
randomized trial.
D 2007 Elsevier Inc. All rights reserved.

The herniated intestine of babies born with gastroschisis

(GS) may present with different degrees of damage at birth,
varying from normal-looking gut to matted edematous bowel
loops covered by a thick peel. This variability has been
* Corresponding author. Clinica Chirurgica Pediatrica, Universita` di
Padova, 35121 Padova, Italy. Tel.: +39 049 8218042; fax: +39 049
8211781.
E-mail address: [email protected] (P. Midrio).
0022-3468/$ see front matter D 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.jpedsurg.2006.12.029

attributed to a series of possible causes, including gestational

age [1], size of the abdominal defect [2], amount of
inflammatory mediators in the amniotic fluid (AF) [3-5], or
a combination of these factors. In the last decade, amnioexchange (AE) has been proposed as a therapeutic strategy to
prevent or to limit intestinal damage [6,7]. Amnioexchange
consists in the replacement of the AF, containing a number of
inflammatory mediators and other possibly harmful substances, with an equal amount of sterile warm normal saline or

778
Table 1

P. Midrio et al.
Maternal characteristics and number of procedures

Patient

Age (y)

Associated conditions

GA at diagnosis (wk)

Oligohydramnios

Procedures (AE and AI)

1
2
3
4
5
6
7
8

21
32
24
30
19
19
22
26

Marfan
Coeliac disease

Heavy smoker

17
17
21
20
21
17
14
21

Yes
Yes
No
Yes
No
No
No
No

3
2
3
6
4
4
3
2

AI
AI, 2 AE
AE
AI
AE
AE
AE
AE

GA indicates gestational age.

pregnancies complicated by GS and to investigate the possible correlation of these metabolites with patient outcome.

Ringers lactate solution. A similar procedure is the

amnioinfusion (AI), which is performed in case of severe
oligohydramnios and consists in the infusion of the appropriate amount of warm normal saline solution required to
achieve a normal AF volume.
Amnioexchange and AI proved to be effective on
different surgical animal models of GS, in which either
urinary and gastrointestinal waste products were measured
[8,9] or morphometric measurements were obtained [10-12].
However, the experience with AE and AI in the management of human GS is extremely limited, and the only case
series reported are limited to few patients from different
centers [3,4,6,13-15]. The largest series published to date
confirmed the presence of an inflammatory process in the
AF, but only a weak correlation was found between one of
the metabolites measured (eg, AF lipase) and the short-term
clinical outcome [3]. Randomized studies in humans have
been advocated [7,16] to confirm the encouraging clinical
impression, but no results are yet available. Finally, the
advantage of AE has been recently questioned on the rabbit
model of GS, where no morphometric differences were
found between treated and nontreated fetuses [17].
The aim of this study was to evaluate the effects of the AE
procedure on AF metabolites and inflammatory markers in

Table 2

1. Materials and methods

From July 2003 to July 2006, all patients with a fetus
affected by GS, who decided to carry the pregnancy until
term, underwent AE or AI as appropriate. Written informed
consent was obtained from each patient before beginning
the treatment. All patients referred for counseling to the
pediatric surgery department of the University of Padova
because of a prenatal diagnosis of GS undergo a planned
c-section at 37 weeks of gestation.

1.1. Amnioexchange and AI procedures

Amnioexchange and AI were performed under continuous
ultrasound surveillance. After the insertion of a 20-gauge
needle, aspiration of as much AF as possible was performed.
Fifty milliliters of 378C sterile saline was then injected, AF
aspiration was repeated, and the required volume of 378C
sterile saline was eventually administered. In case of severe
oligohydramnios (maximal pouch b2 cm) [18], AI was

Type of delivery, neonatal characteristics and initial treatment

Patient

Delivery

Days after
last AE

Gestational
age (wk)

Weight

11 d

32 + 2

1160

2
3
4

Spontaneous
vaginal
Planned c/s
Emergent c/s
Planned c/s

12 d
18 d
13 d

37
36 + 6
35 + 2

5
6
7
8

Planned c/s
Emergent c/s
Planned
Emergent c/s

12
36
13
96

37
35 + 6
37
32 + 2

d
h
d
h

Apgar

Herniated loops

Initial treatment

Full feeds (d)

5-5

Stomach, sb (peel 1+)

Silo

48

2000
2095
2400

8-9
7-8
7-8

Sb (peel 3+)
Sb (peel 1+)
Intestinal necrosis

2845
2100
2100
1800

9-10
7-8
8-9
8-10

Sb, colon (peel 0)

Stomach, sb (peel 1+)
Stomach, sb (peel 2+)
Sb (peel 2+)

Silo
Primary closure
Primary closure
with stomas
Primary closure
Primary closure
Silo
Silo

40
15
Discharged on
PPN and PEN
10
15
42
60 (ileal
membrane)

Apgar score at first and fifth minute; peel graduated from 0 (no peel), 1+ (thin peel), 2+ (moderate peel), and 3+ (thick peel). PPN, partial parenteral
nutrition; PEN, partial enteral nutrition. c/s, cesarean section; sb, small bowel.

Amnioexchange for fetuses with gastroschisis

779

performed by adding 100 mL of saline to the calculated

volume at the end of the infusion. The following formula was
applied to calculate the required volume of fluid to infuse:
required volume (mL) = weeks of gestation  10 [18]. The
procedure took an average of 30 minutes (range, 2045 minutes). Amniotic fluid was placed on ice immediately
after collection and then stored at 808C until analysis.

1.2. Quantification of biochemical parameters

Biochemical constituents (urea, creatinine, ALT, ALP,
cGT, amylase, etc) were measured on an Hitachi 912
instrument (Roche Diagnostics, Milan, Italy). Serum amyloid A (SAA) and C-reactive protein (CRP) were measured
by a particle-enhanced nephelometric immunoassay on a
fully automated BN II nephelometer system (Dade Behring,
Milan, Italy). The method is based on a immune reaction
involving human antibodies covalently coated with 260-nmdiameter core shell-type particles. The analytical imprecision for SAA assay, expressed as coefficient of variation
(CV [%]), was found to range from 3.3% to 5.0% (withinrun) and 3.1% to 6.9% (between-run).

1.4. Quantification of myeloperoxidase

Myeloperoxidase (MPO) activity was measured in AF as
previously described [19]. Briefly, after 3 thaw-freeze cycles
in liquid nitrogen to ensure complete cellular lysis was
achieved, AF was centrifuged at 40,790g for 30 minutes. A
total of 100 lL of supernatant was added to 2.9 mL buffer
containing 0.53 mmol/L O-dianisidine hydrochloride and
0.0005% hydrogen peroxide, and MPO activity followed
spectrophotometrically at 258C at a wavelength of 460 nm.
Myeloperoxidase activity was expressed as units per liter.

1.5. Statistical analysis

Data regarding AF metabolites are expressed as median F
range. Concentrations of metabolites from the first and last
AE in individual patients were compared by Wilcoxon
signed rank test. Spearman r was used to analyze the
relationship between levels of metabolites in the AF and
gestational age. Results showing P values of less than .05
were considered significant.

2. Results
1.3. Quantification of tumor necrosis factor a ,
interleukin 2, interleukin 6, epidermal growth
factor, and transforming growth factor b
Quantitative measurement of tumor necrosis factor a
(TNF-a) and interleukin (IL) 6 in AF were performed by
a solid-phase, enzyme-labeled, chemiluminescent sequential immunometric assay on an Immulite 1000 analyzer
(Medical System, Genova, Italy). Analytical imprecision,
expressed as CV within- and between-run (CV [%]) was
found ranging from 5.1% to 7.5%. IL-2, epidermal
growth factor receptor, and transforming growth factor
b were measured by enzyme-linked immunosorbent assay
(Instant ELISA, Bender MedSystems GmbH, Vienna,
Austria).
Table 3

Eight women were enrolled in the study. Maternal

characteristics and number of procedures are reported in
Table 1. All women were primiparous.
In case of normal amount of AF (5 patients) the first AE
was performed at 30 weeks of gestation and repeated every
2 weeks until 36 weeks of gestation. If severe oligohydramnios was present (3 patients), AI was carried out as
early as needed, the earliest being at 26 weeks. A total of
29 procedures (median, 3.5 procedures per patient; range,
2-6) were performed and 25 samples of AF were collected.
During the procedures, 3 patients complained of pain at
the site of needle insertion and general discomfort (nausea
and anxiety). All symptoms resolved at the end of the
procedure. No infective complications ever occurred. Cesar-

Concentrations of proteins and digestive enzymes in the AF

pH
Osmolarity (mosm/L)
Albumin (mg/L)
Tot protein (g/L)
Creatinine (lmol/L)
Urea (mmol/L)
Cystatine C (mg/L)
ALT (U/L)
ALP (U/L)
cGT (U/L)
Total bilirubin (lmol/L)
P-amylase (U/L)
Biliary salts

1st AE

2nd AE

3rd AE

4th AE

8.09
265.5
67
7.67
60.5
4.65
1.375
1.5
63.0
367
2.8
5.0
1.4

8.16
261.0
2095
6.78
72.0
3.75
1.190
1.0
36.5
140
2.6
4.5
1.5

8.00
261.0
3230
6.40
73.5
3.85
1.050
1.0
59.5
31
1.1
5.0
0.9

7.87
260.0
176
4.18
76.0
4.0
0.620
4.0
1384.0
305
4.6
6.0
8.2

(7.95-8.40)
(248.0-268.0)
(10-4090)
(2.76-15.90)
(46.0-97.0)
(2.8-5.0)
(0.220-2.130)
(0.0-7.0)
(19.0-3285.0)
(31-1260)
(1.2-11.5)
(3.0-10.0)
(0.2-21.9)

(7.90-8.50)
(256.0-267.0)
(19-8080)
(2.49-11.40)
(47.0-109.0)
(2.8-5.0)
(0.480-1.740)
(0.0-6.0)
(23.0-3045.0)
(25-1709)
(1.2-19.8)
(2.0-9.0)
(0.4-5.9)

(7.1-8.35)
(255.0-270.0)
(11-3650)
(3.23-13.50)
(54.0-149.0)
(1.9-6.1)
(0.850-1.650)
(1.0-4.0)
(27.0-1152.0)
(25-598)
(0.3-7.3)
(2.0-9.0)
(0.3-7.9)

P
(7.70-8.04)
(257.0-264.0)
(11-1500)
(1.75-12.40)
(63.0-126.0)
(2.4-7.1)
(0.430-1.660)
(1.0-7.0)
(34.0-4001.0)
(53-315)
(0.4-34.6)
(4.0-10.0)
(0.3-50.0)

NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS

Data are shown as median (range). Results from the first and last AE in individual patients were compared by Wilcoxon signed rank test. P b .05 was
considered significant.

780
Table 4

P. Midrio et al.
Concentrations of inflammatory markers, cytokines, and growth factors in the AF

CRP (mg/L)
SAA (mg/L)
Epidermal growth factor (pmol/L)
Transforming growth factor b (lg/L)
IL-2 (ng/L)
IL-6 (ng/L)
TNF-a (ng/L)
Myeloperoxidase (U/L)

1st AE

2nd AE

3rd AE

4th AE

0.215
b2.8
17.5
4.20
b2
2821
26.30
2.80

0.110
b2.8
14.5
3.65
b2
3302
24.45
4.19

0.130
b2.8
41.0
2.90
b2
3900
31.10
6.72

2.80
b2.8
b10.0
4.00
b2
603
37.70
37.98

NS
NS
NS
NS
NS
NS
NS
NS

(0.070-0.470)
(b2.8-b2.8)
(b10.0-75.0)
(1.00-7.30)
(b2-b2)
(157-11,570)
(14.80-31.90)
(0.27-30.82)

(0.040-0.300)
(b2.8-b2.8)
(b10.0-30.0)
(1.30-8.60)
(b2-85)
(312-9984)
(20.60-35.70)
(0.28-23.79)

(0.050-3.610)
(b2.8-b2.8)
(b10.0-63.0)
(1.00-7.50)
(b2-33)
(351-4492)
(20.00-40.90)
(0.07-39.69)

(0.090-6.930)
(b2.8-b2.8)
(b10.0-34.0)
(1.00-19.00)
(b2-b2)
(341-2314)
(20.00-95.90)
(1.31-135.00)

Data are shown as median (range). Results from the first and last AE in individual patients were compared by Wilcoxon signed rank test. P b .05 was
considered significant.

ean section was performed emergently in 3 cases for preterm

premature rupture of membranes (PPROM) at 36 + 6, 35 + 6,
and 32 + 2, respectively. Of 3 PPROMs, 2 occurred 36 and 96
hours, respectively, after the last AE procedure. Newborns
characteristics are reported in Table 2.
One patient, whose AF was persistently below the
threshold in spite of repeated AI, presented with extensive
bowel necrosis at birth, required an ileostomy and colostomy, and eventually developed short bowel syndrome. In 3 of
4 cases in which primary closure was possible at birth, the
minimal enteral feeding (2 mL of formula every 3 hours)
was begun after 72 hours, and full enteral feeding was
reached after 10 to 15 days. In the 4 cases in which a silo
was required, full feeding was reached between 40 and 60
days. One of these patients had an ileal membrane that
required resection, tapering of the dilated proximal bowel,
and ileo-ileal anastomosis at 23 days of age.
Concentrations of proteins and digestive enzymes at each
AE/AI procedure are shown in Table 3. No significant
differences were seen in the concentration of any of these
metabolites between the first and last AE/AI procedure in
each patient. Furthermore, there was no correlation between
gestational age and concentrations of any of these metabolites ( P = nonsignificant [NS], Spearman r).
Levels of inflammatory markers, growth factors, cytokines and MPO (marker of neutrophil infiltration) are shown
in Table 4. Again, there were no differences in any of these
markers between the first and last AE/AI of each individual
patient, and values did not appear to correlate with
gestational age ( P = NS, Spearman r).

3. Discussion
Damage to the herniated bowel loops of a fetus with GS
has long been known to begin after the 30th week of
gestation and usually increases as the pregnancy progresses
[1]. The degree of damage may be quite different among
cases, varying from normal-looking intestine to matted
edematous gut covered by a thick peel. This observation on
human embryos was supported by similar findings occurring on chick embryos [1]. Macroscopic changes of the

exposed intestinal loops were attributed to the physiologic

changes in the composition of the AF, namely, the
increasing presence of urinary waste products [1] or, more
recently, gastrointestinal waste products in several different
animal models [12,20,21]. Finally, other harmful constituents, such as IL-6, IL-8, TNF-a, and IL-1b were found in
the AF of fetuses with GS [4,5].
Based on this concept, a series of experimental studies
advocated the need to repeatedly remove the AF containing
these detrimental components and to substitute it with an
equal amount of sterile normal saline or Ringers lactate
solution. When applied to different experimental models of
GS, AE proved to reduce concentrations of proteins, urea,
meconium, bile acids, and bilirubin and ultimately improved
injury to the herniated bowel [8,10,21].
Experience with AE/AI on human fetuses with GS is
still extremely limited (about 50 cases in total from at least
6 different centers), and neither time and mode of delivery
nor details of the procedures are standardized. Burc et al [3]
measured levels of several digestive components in the AF
of 30 fetuses with GS undergoing AE. The authors found a
weak correlation between AF lipase and patients outcome
but were unable to demonstrate the beneficial effect of AE
in terms of reduced intestinal damage and faster recovery.
Luton et al [4] could only demonstrate a significant
reduction of curarization among fetuses undergoing AE
(n = 10) compared to nontreated fetuses, whereas the
degree of intestinal damage at birth, primary abdominal
closure, time to full oral feeding, and length of hospitalization did not differ between treated and nontreated
fetuses. Finally, few other articles published the success
of the AE/AI procedure in single cases of GS [6,13-15].
However, in some of these case reports [14] the neonates
were born prematurely between 31 and 34 weeks, and it is
known that intestinal damage develops after 30 weeks and
increases thereafter [1]; other cases [15] underwent just 1
AE procedure, and it seems unlikely that the limited
intestinal damage present at birth could be attributable to
one single procedure.
Although our study also comprised a limited number
of patients, we believe some interesting conclusions can
be drawn.

Amnioexchange for fetuses with gastroschisis

Of 8 pregnancies, 3 progressed with severe oligohydramnios and required a series of AI. Why oligohydramnios
occurs in GS remains unknown, but its incidence is reported
with increasing frequency [3]. As previously reported [3],
oligohydramnios can be a potentially life-threatening
complication for a fetus with GS and requires prompt
treatment in an attempt to prevent fetal demise by
compression and twisting of the umbilical cord [13,14]. In
our experience, as well as in the literature [22], AI is a
feasible, worthwhile, and effective procedure.
Amnioexchange and AI, as in any invasive procedure, do
carry some risks, mainly infections and PPROM. To prevent
such events, the protocol applied in our department of
obstetrics includes the administration of intravenous antibiotics and tocolysis. Although none of the 29 AE/AI
procedures were ever complicated with infections, 2 patients
required an emergent c-section 36 and 96 hours after the last
AE, respectively, owing to PPROM.
The 5 patients who underwent serial AE procedures
without oligohydramnios presented with a variable degree
of damage to the herniated intestine, as described in the
literature [23], from minimum presence of peel covering the
gut to frankly necrotic bowel. Although we lack a control
group of GS patients who did not undergo AE/AI, AE did
not seem to substantially improve clinical outcome of our
patients (eg, degree of intestinal damage, possibility of
primary repair at birth, time to full enteral feeding, and
length of hospitalization).
Biochemical analysis of AF before each AE/AI procedure
in our patients seems to support this hypothesis. We, for the
first time, measured myeloperoxidase activity in the AF as a
marker of neutrophil infiltration, and no significant effect of
AE/AI procedures was seen on neutrophil infiltration. In
addition, concentrations of pro-inflammatory cytokines IL2, IL-6, and TNF-a as well as inflammatory markers such as
CRP and SAA did not change significantly between the first
and the last AE/AI in each patient. Taken together, these data
suggest that even repeated procedures did not significantly
affect the inflammatory response in the AF in the long term.
Although sampling the AF at the end of each AE/AI
procedure would have allowed us to demonstrate the degree
of AF dilution achieved, our main interest was to determine
whether diluting the AF by AE/AI procedures could induce
long-lasting effects on AF composition.
No consensus exists on the amount of fluid to exchange
during AE/AI procedures, and different protocols have been
reported in other studies, including infusion of as much as
300 mL repeated 2 to 3 times during each AE procedure, for
a total of 600 to 900 mL [3]. The lack of efficacy of the AE/
AI procedures in our study might be at least in part owing to
the low amount of fluid infused in our patients. However,
each AE/AI session carries a risk of subsequent PPROM,
which would be further increased in case of prolonged and
stressful invasive procedures necessary to infuse high
amounts of fluid. The protocol used in our study was
decided together with our gynecologists to reach a compro-

781
mise between performing an effective procedure and limiting
the duration and stress associated with the procedure itself.
In a recent study, AF from GS patients has been reported
to contain an increased number of leukocytes, predominantly polymorphonuclear cells, at 36 to 38 weeks of gestation
[5]. However, both the extent and the role of the
inflammatory response in the AF of GS patients are unclear,
and few studies investigating cytokines levels in the AF
have been reported, with conflicting results. Morrison et al
[5] found an increase in IL-8 but not in TNF-a; whereas
Fascing et al [24] reported a decrease in IL-1a and IL-1b
and no differences in IL-6 in GS, as compared to controls.
Moreover, Luton et al reported an increase in IL-6 but not in
IL-1b nor TNF-a in patients undergoing AE procedures, as
compared to nonaffected fetuses [4]. Although the absence
of a group of nontreated GS patients in our study makes it
difficult to differentiate between the effects of AE/AI and
the natural course of the disease, our results clearly show
that repeated AE/AI procedures are not associated with a
significant decrease in neutrophil infiltration or levels of
proinflammatory cytokines, nor with a decrease of markers
of inflammation.
This lack of effect could be explained by the fast
turnover of the AF in the third trimester, which is
completely renovated every 24 to 48 hours owing both to
swallowing and urine production by the fetus and to
membrane reabsorption [25]. Because AE is performed
every 7 to 14 days only [3], it might be effective in
removing or diluting metabolites for the first couple of
days, after which, it is likely that the normal turnover of the
AF would restore the concentration of any component as
before the procedure. Our data of biochemical analysis of
AF seem to support this hypothesis. It seems reasonable to
speculate that to be fully effective in permanently reducing
levels of supposedly harmful substances, AE should be
performed every 2 or 3 days, which, of course, cannot be
recommended because of the invasiveness and side effects
of the procedure.
In summary, our experience does not support the
effectiveness of serial AE procedures in reducing concentrations of inflammatory mediators and digestive substances
in the AF, and their use in fetuses with GS is not
recommended outside the setting of a prospective randomized trial. In case of severe oligohydramnios, however, AI
proved to be a life-saving procedure and the risk-to-benefit
ratio seemed worthwhile.

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