Pediatric Surgery International (2019) 35:293–301

https://doi.org/10.1007/s00383-018-4415-1

ORIGINAL ARTICLE

Direct hyperbilirubinemia in newborns with gastroschisis

Sarah B. Cairo1 · Alex H. Osak2 · Sara K. Berkelhamer2,3 · Cara McLaughlin4 · David H. Rothstein1,5

Accepted: 2 November 2018 / Published online: 10 November 2018

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Abstract
Background  Patients with gastroschisis and prolonged total (or partial) parenteral nutrition (PN) commonly develop direct
hyperbilirubinemia (DH).
Objective  To quantify the prevalence and severity of DH in newborns with gastroschisis and characterize the diagnostic
work-up for DH in this patient population.
Design/Methods  Retrospective chart review of patients born with gastroschisis between 2005 and 2015 for the first 6 months
of life.
Results  29 patients were identified with gastroschisis. Mean gestational age and birthweight were 36.4 (± 1.8) weeks and
2.5 (± 0.6) kg. 41% were treated with primary reduction versus staged closure. Peak total and direct bilirubin (DB) levels
were 10.17 ± 6.21 mg/dL and 5.58 ± 3.94 mg/dL, respectively. 23 patients (79.3%) were diagnosed with DH and 78.2%
underwent additional work-up for hyperbilirubinemia consisting of imaging and laboratory studies, none of which revealed
a cause for DH other than the presumed PN-associated cholestasis. In all patients, DB began to decline within 1–10 days of
initiation of enteral feeds.
Conclusion(s)  DH is common in patients with gastroschisis and is unlikely to be associated with pathology aside from PN.
Additional work-up may lead to unnecessary resource utilization.
Levels of evidence  Case series with no comparison group, Level IV.

Keywords  Direct hyperbilirubinemia · Gastroschisis · Resource utilization · Cholestasis · Outcomes

Abbreviations PNALD Parenteral nutrition associated liver

PN Parenteral nutrition disease
CH Conjugated hyperbilirubinemia NASPGHAN North American Society for pediatric gas-
DB Direct bilirubin troenterology, hepatology, and nutrition
DOL Day of life
SD Standard deviation
Abstract was presented in its original form at the Eastern Society
for Pediatric Research Annual Meeting, Philadelphia, PA, March
24, 2017 and as a poster at the Pediatric Academic Society Annual
Meeting, San Francisco, CA, May 6, 2017. Introduction
* David H. Rothstein Cholestatic jaundice affects approximately 1 in 2500 infants
[email protected]
and is commonly documented in neonatal intensive care
1
Department of Pediatric Surgery, John R. Oishei Children’s (NICU) patients [11, 36]. Elevation of direct bilirubin lev-
Hospital, 1001 Main Street, Buffalo, NY 14203, USA els (DB) may result from hepatobiliary dysfunction and be
2
Department of Pediatrics, John R. Oishei Children’s Hospital, indicative of serious illness or pathology [11, 34]. Diagnos-
Buffalo, USA tic criteria for direct hyperbilirubinemia (DH) vary, with
3
Department of Pediatrics, University at Buffalo Jacobs DB that is > 2 mg/dL or accounts for greater than 20% of
School of Medicine and Biomedical Sciences, Buffalo, USA the total bilirubin after 2 weeks of life commonly cited [27,
4
Department of Nutrition, John R. Oishei Children’s Hospital, 31]. The most recent recommendations from North Ameri-
Buffalo, USA can Society for Pediatric Gastroenterology, Hepatology, and
5
Department of Surgery, University at Buffalo Jacobs School Nutrition (NASPGHAN), however, define abnormal as a
of Medicine and Biomedical Sciences, Buffalo, NY, USA

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294 Pediatric Surgery International (2019) 35:293–301

serum DB > 1.0 mg/dL (or > 17umol/L) [11]. NASPGHAN Data source

provides recommendations for evaluation of cholestatic
jaundice in infants but does not specifically address the We performed a retrospective review of neonates at a single
management of patients who are ill or who have coexisting, institution in Western New York. Medical records including
possibly confounding, conditions. Cerner Powerchart, the primary electronic medical record
While work up is not performed on all infants with DH, employed by the NICU to capture vital signs, laboratory and
the differential diagnosis is broad including both obstruc- imaging results, and consultant documentation and Neodata,
tive and intrinsic processes [13, 39, 41]. Obstructive causes, a complementary multi-user data system purpose-designed
including biliary atresia, account for 20–30% of cases in for NICU care to assist in daily patient management from
full-term neonates. Intrinsic processes include infection, admission through discharge, were utilized.
metabolic disease, endocrine abnormalities and autoim-
mune processes. Clinical practice guidelines published by
Case selection
NASPGHAN and updated in 2017 based on literature review
and expert opinion include differentiation between direct
Neonatal patients at the Women and Children’s Hospital of
bilirubinemia and total bilirubinemia with other laboratory
Buffalo with a diagnosis of gastroschisis based on ICD-9 and
studies frequently employed to help define the etiology and
10 codes between January 1, 2005 and December 31, 2015
severity of DH [22, 39]. Parenteral nutrition associated liver
were identified for inclusion. Patients with and without diag-
disease (PNALD) is a common cause of neonatal cholesta-
nosis of DH were included in the study for comparison pur-
sis, present in up to 20% of neonates receiving parenteral
poses where DH was defined using the NASPGHAN guide-
nutrition (PN) for greater than 2 weeks [20]. PNALD is fre-
lines of a serum direct bilirubin > 1 mg/dL. Those patients
quently observed after the first 2 weeks of PN or later [14].
with an initial direct bilirubin > 1.0 who normalized before
In studies evaluating congenital or surgical anomalies, an
2 weeks were placed in the non-cholestatic group.
incidence of PNALD up to 25–85% is reported in neonates
A variety of patient demographic and clinical variables
with intestinal failure requiring prolonged PN [8, 9]. The
were included in the analysis. Outcomes of interest included
estimated incidence of PNALD is higher in children than
the duration of PN administration, day of feeding initiation
adults and frequently occurs along with a primary gastro-
and time to full enteral nutrition, trends in total and conju-
intestinal disorder causing intestinal failure and prolonged
gated bilirubin, length of stay (LOS) and studies or evalu-
need for PN (congenital intestinal abnormalities, necrotizing
ations performed as part of a diagnostic work-up for DH.
enterocolitis, etc.).
Workup and findings were collected from the first 6 months
Major risk factors for PNALD include prematurity, low
of life.
birthweight, early and prolonged exposure to parenteral
nutrition, infection, and insufficient use of the gastrointes-
tinal tract, many of which are present in the setting of gas- Statistical analysis
troschisis, a common congenital abdominal wall defect [25,
38]. The average patient with gastroschisis undergoes surgi- A retrospective descriptive analysis of the data was per-
cal intervention within the first few hours of life and receives formed. Categorical variables were compared using the
an average of 2–3 weeks of PN, with gradual advancement Pearson’s Chi-squared and Fisher’s exact test, with Student’s
of enteral feeds [2]. In contrast to other neonates with DH, t test for continuous variables. All statistical analyses were
there is limited literature on a specific relationship between performed using Excel and IBM SPSS Statistics Software
gastroschisis and DH including the utility of additional diag- 24. Where possible based on limitations in data availabil-
nostic work up for these patients. ity and skewing, data are represented as mean and standard
The primary objectives of this study were to describe the deviation or median and interquartile range.
incidence and degree of DH in neonates with gastroschisis,
according to the 2017 NASPGHAN definition, and deter-
mine the frequency and yield of diagnostic workup. Results

Patient demographics
Methods
A total of 30 patients were identified with diagnosis of gas-
The study protocol and use of electronic medical records troschisis confirmed on chart review. Of these, 24 patients
were reviewed by the Institutional Review Board of the State were found to have a serum direct bilirubin greater than
University of New York, University at Buffalo and need for 1 mg/dL within first 6 months of life (but after the first 2
informed consent was waived (UB IRB: 00001120).

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Pediatric Surgery International (2019) 35:293–301 295

weeks of life), for an overall incidence of DH of 79.3% Specific patient characteristics related to surgical proce-
using the NASPGHAN definition The gestational age, dure and intensive unit care were evaluated as a proxy for
birth weight and gender distribution in the DH and non- illness severity. On average, there was no difference in the
DH cohorts were comparable (Table 1). While there was likelihood of ventilator use or duration of time on the venti-
no significant difference in average birth weight percentile, lator at 10.7 ± 11.2 days for patients with DH and 7.3 ± 8.2
patients with DH were noted to have a statistically signifi- days for patients without (p = 0.53). With regard to compli-
cantly lower discharge weight percentile (9.6th percentile for cations associated with gastroschisis, there was no signifi-
DH, 37.0th percentile for patients without DH, p < 0.001). cant difference in the incidence of intestinal atresia, necrosis
The percentile change was also statistically significantly dif- or perforation, need for bowel resection, and need for stoma
ferent between the two groups with an average decline of creation between the two groups. Type of procedure was also
23.2 ± 20.6 for patients with DH and an average increase comparable with the majority of patients undergoing silo
in weight percentile of 2.0 ± 33.9 for patients without DH placement for an average of 9.2 ± 7.3 days. There was no sig-
(p = 0.03). nificant difference in the type of repair performed overtime.

Table 1  Characteristics of Patients with DH Patients without DH Total p ­valueb

patients with gastroschisis
Total, n (%) 23 (79.3) 6 (20.7) 29
Gender (%)
 Male 10 (71.4) 4 (28.6) 14 (48.3) 0.31
 Female 13 (86.7) 2 (13.3) 15 (51.7)
Birth weight
 Average, kg (SD) 2.45 (0.6) 2.72 (0.5) 2.50 (0.6) 0.33
 Birth weight percentile (SD) 29.8 (22.5) 35.0 (18.0) 30.7 (21.6) 0.61
 Discharge weight percentile (SD) 9.6 (6.5) 37.0 (27.2) 11.8 (17.8) < 0.001
 Change weight percentile (SD) − 23.2 (20.6) + 2.0 (33.9) − 18.9 (24.7) 0.03
Gestational age
 Average, weeks (SD) 36.22 (1.8) 36.91 (1.8) 36.36 (1.8) 0.41
Ventilator use (%)
 At time of delivery 7 (30.4) 2 (33.3) 9 (31.0) 1.00
 Following Procedure 22 (95.7) 4 (66.7) 26 (89.7) 0.10
 Time on ventilator, days (SD) 10.68 (11.2) 7.33 (8.2) 9.96 (11.2) 0.53
Type of procedure (%)
 Primary reduction 10 (43.5) 2 (33.3) 12 (41.4) 0.39
 Silo placement, no reduction 13 (56.5) 4 (66.7) 17 (58.6)
 Duration silo usage, days (SD) 9.85 (8.1) 7.25 (4.0) 9.24 (7.3) 0.55
Associated intestinal complications (%)
 Bowel matting 3 (13.0) 0 (0.0) 3 (10.3) 0.49
 Atresia 2 (8.7) 0 (0.0) 2 (6.9) 0.62
 Necrosis, perforation 7 (30.4) 1 (16.7) 8 (27.6) 0.08
 Bowel resection 8 (34.8) 1 (16.7) 9 (31.0) 0.38
 Stoma creation 3 (13.0) 1 (16.7) 4 (13.8) 0.63
 Any bowel related complication 10 (43.5) 1 (16.7) 11 (37.9) 0.23
NICU related complications (%)
 Urinary tract infection 5 (22.0) 0 (0.0) 5 (17.0) 0.55
 Central line-associated sepsis 8 (34.0) 1 (16.7) 9 (31.0) 0.39
 Any infectious complication 13 (56.5) 1 (16.7) 14 (48.3) 0.08
Length of stay
 Average length of stay, days (SD) 82.5 (40.9) 64.2 (37.0) 79.34 (40.3) 0.36
a
 Direct hyperbilirubinemia defined per NASPGHAN guidelines as direct bilirubin after 2 weeks of age of
> 1.0 mg/dL or > 17 mmol/L
b
 Fisher’s exact test for binary results, ANOVA for continuous variable

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Coexisting infections were evaluated with no significant with DH. Average caloric intake and use of low-lipid for-
difference in the rate of urinary tract infections (22.0% in mulation, defined as 1 gm/kg per week, was not different
patients with DH, 0 in patients without, p = 0.55) or central between the groups. Similarly, percentage of hospital stay on
line-associated sepsis (34.0% in patients with DH, 16.0% in any PN, average calories from PN, and average weight gain
patients without, p = 0.39). The average length of stay (LOS) did not differ significantly between the two groups. Weight
was longer for patients with DH at 82.5 ± 40.9 days com- gain in grams per day was lower but not significantly so
pared to 64.2 ± 37 days for patients without DH, although for patients with DH compared to those without DH (aver-
the difference was not statistically significant (p = 0.36). age 18.8 ± 4.5 g versus average 20.0 ± 8.9 g, respectively;
p = 0.66). Similarly, changes in zscore for weight, and length
Nutritional characteristics (but not head circumference) were more negative for patients
with DH but again without statistical significance (p = 0.21
There were no significant differences in nutritional practices and p = 0.31, respectively).
between the two groups despite variability within the cohort
as a whole. Patients with DH remained on PN for an average Assessment and Management of Cholestasis
of 59.7 days (median 54, IQR 35–74), started enteral feeds
on day of life 31.6 (median 25, IQR 17.8–35.3) and were on Cholestasis was first observed, on average, on DOL 17.9
full feeds by day of life 64.2 (median 54, IQR 24.3–78.8) (range, DOL 2–38). The first DB recorded above the thresh-
(Table 2). Patients without DH remained on PN for an aver- old of 1 mg/dL is denoted as “First abnormal DB.” The DB
age of 42.0 days (median 31, IQR 18–56), started enteral peaked, on average, on day 50.3 (range, DOL 20–101) at
feeds on day 17.8 (median 19, IQR 13–27), and were on 6.48 ± 3.9 mg/dL. Three patients from the original cohort
full feeds by day 43.2 (median 31, IQR 23–56), none of of 29 patients had a rise in DB within the first week of life
which are statistically significantly different from patients which normalized within this week and did not reach the two

Table 2  Nutritional information for neonates with gastroschisis

Patients with DH (20)a Patients without DH (6) Total (26) p ­valueb

Total days on ­PNc, median (IQR) 54 (35, 74) 31 (18, 56) 53 (31.3, 74.0) 0.97
Day of life enteral feeds initiated, median (IQR) 25 (17.8, 35.3) 19 (13, 27) 24 (17, 30) 0.07
Day of life PN started, average (SD) 1.3 (0.7) 1.2 (0.4) 1.3 (0.7) 0.74
Days until full feeds, median (IQR) 54 (24.3, 78.8) 31 (23, 56) 54 (31.0, 77.5) 0.21
Low lipid formulation used, n (%)d
 Yes 12 (60.0) 2 (33.3) 14 (53.8) 0.49
 No 8 (40.0) 4 (66.7) 12 (46.2)
Day low lipid formulation started, average (SD) 28.0 (13.4) 14.0 (n/a) 26.3 (13.4) 0.37
Initial enteral formula, n (%)
 Breast milk 7 (30.4) 1 (16.7) 8 (27.6) 0.23
 Breast milk, fortified 1 (4.3) 1 (16.7) 2 (6.9)
 Formula (with breast milk) 8 (34.8) 2 (33.3) 10 (34.5)
 Formula (without breast milk) 3 (13.0) 1 (16.7) 4 (13.8)
 Malabsorptive formula 4 (17.4) 1 (16.7) 5 (17.2)
Average caloric intake, kcal/kg/day (SD) 95.6 (8.6) 97.2 (7.3) 96.0 (8.2) 0.68
Average % days on any PN (SD) 82.7 (18.1) 75.1 (23.0) 81.0 (19.1) 0.40
Average % calories from PN (SD) 73.0 (19.6) 58.2 (18.4) 69.6 (20.0) 0.11
Average weight gain, g/day (SD) 18.8 (4.5) 20.0 (8.9) 19.1 (5.6) 0.66
Average weight gain, g/kg/day (SD) 6.2 (2.0) 7.5 (2.3) 6.5 (2.1) 0.19
Change zscore (weight), median (IQR) − 1.3 (− 1.8, − 0.7) − 0.8 (− 1.0, − 0.6) − 1.2 (− 1.8, − 0.7) 0.21
Change zscore (head circumference), median (IQR) 0.2 (− 1.0, 0.5) 0 (− 0.1, 0.1) 0.1 (− 0.7, 0.5) 0.77
Change zscore (length), median (IQR) − 1.5 (− 2.3, 0.0) − 0.6 (− 1.2, 0.4) − 1.2 (− 2.1, 0.1) 0.31
a
 Complete nutrition, weight data available for 100% patients without DH (6 of 6), 87% of patients with DH (20 of 23)
b
 Fisher’s exact test and Pearson Chi-squared for categorical variables, ANOVA for continuous variables
c
 PN: total or partial parenteral nutrition
d
 Total number of patients on low lipid formulation not equal to total on PN due to missing or unavailable data at the time of review

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week threshold suggested in the NASPGHAN guidelines findings suggesting contracted gallbladder, biliary sludge,
(1). These patients were not included in the analysis of DH and non-visualization of the gallbladder in the remaining
and per chart review, were felt to represent the population patients. Hepatobiliary Scintigraphy (HIDA scan) was ini-
of newborns with physiologic jaundice peaking and resolv- tially ordered for 5 (21.7%) patients with DH but canceled
ing within the first 96 h of life and not requiring additional for three patients due to improving DB. Of the HIDA scans
diagnostic evaluation (Bhutani et al., 2013). performed, one was normal and one was significant for
60% of the 23 patients with DH were treated with on adequate radiotracer uptake in liver but non-visualization
choleretic medications or specialized lipid formulations of radiotracer activity in intestines. The latter study was
including Ursodiol alone (34.5%), Phenobarbital alone reportedly suboptimal due to excessive blood pool activ-
(17.4%), Ursodiol and Phenobarbital (4.3%), or Sincalide, ity resulting in a high background activity; the patient
(a cholecystokinin-octapeptide) and Omegaven™ (a fish oil- subsequently underwent repeat ultrasound consistent
based lipid emulsion containing omega-3 fatty acids) (4.3%) with gallbladder ghost. In the setting of normalizing labs,
(Table 3). Follow-up until normalization of DB was only however, no further work up or gastroenterology follow-up
available for 65.2% of patients; when available, DB normal- was performed. Metabolic, endocrine, and infectious work
ized, on average, by DOL 110.8 (range, DOL 38–365). Of ups were also performed to evaluate for associated anoma-
patients without documentation of normalization of DB, 11 lies that may contribute to DH including thyroid studies,
were discharged from the hospital with an elevated DB but amino acid analysis, alpha-1 antitrypsin deficiency, and
on a downward trajectory. work up for parvo virus, EBV, CMV, hepatitis, and toxo-
Of the patients with DH, 18 (78.2%) underwent addi- plasmosis, all of which were normal (Table 4). There was
tional diagnostic work up (Table 4). Evaluation was lim- no significant difference in rate of urinary tract infections
ited to septic work up with blood and urine cultures in 7 (17% overall) or central line-associated sepsis (31% over-
of these patients. A right upper quadrant ultrasound was all) between the patients with DH and patients without DH
performed on 11 (61%) of patients, at a mean DOL of (Table 1). No liver biopsies were performed in this cohort.
48, demonstrating a normal gallbladder in 3 (27%), and

Table 3  Detailed assessment Mean Standard deviation Range

and management of direct
hyperbilirubinemia (n = 23) Day of first reported ­DBa 6.9 4.1 2–18 days
 First DB 0.97 0.83 0.3–3.6 mg/dL
DOLb when DB is first a­ bnormalc 17.9 9.5 2–38 days
 First abnormal DB (mg/dL) 1.71 0.74 1.1–3.9 mg/dL
DOL at peak DB 50.3 20.7 20–101 days
 Peak DB (mg/dL) 6.48 3.92 1.7–15.4 mg/dL
 Peak TB (mg/dL)d 9.59 6.63 3.0–25.0 mg/dL
DOL DB normalized 110.8 78.3 38–365 days
DOL enteral feeds started 31.6 19.3 7–88
DOL parenteral nutrition discontinued 62.8 31.8 22–133 days
DOL medication ­startede 50.9 22.2 11–103 days
Medication given, n (%) 14 (60.0)
 Ursodiol 8 (34.5)
 Phenobarbital 4 (17.4)
 Ursodiol and phenobarbital 1 (4.3)
 Omegaven and Sincalide 1 (4.3)

Direct hyperbilirubinemia = serum direct bilirubin > 1 mg/dL after first 2 weeks of life

a
 DB: direct bilirubin (mg/dL)
b
 DOL: day of life from birth
c
 Elevated DB defined as direct bilirubin > 1.0  mg/dL when the total bilirubin is < 5 or DB > 20% of the
total when TB is > 5
d
 TB: total bilirubin (mg/dL)
e
 Day of life medication started for conjugated hyperbilirubinemia. 34.5% Ursodiol (Actigall) alone. 17.4%
Phenobarbital alone. 21.7% Ursodiol and Phenobarbital. 4.3% Phenobarbital and Actigall. 4.3% ADEK
vitamin supplement and Actigall. 4.3% Sincalide and Omegaven. 17.4% with conjugated hyperbilirubine-
mia not started on medication

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Table 4  Diagnostic work up in patients with direct hyperbilirubinemia (total n = 23)

Test performed Number (% of patients Average DOL test Results, comments (n)
with DH) performed

Right upper quadrant ultrasound 11 (47.8) 47.8 Normal gallbladder, common bile duct (3)
Contracted gallbladder (3)
Sludge in gallbladder (4)
Gallbladder not visualized (1)
Hepatobiliary Scintigraphy (HIDA scan) 5 (21.7) 48 Canceled due to improved direct hyper-
bilirubinemia (3)
Normal anatomy and excretion patterns
(1)
Inconclusive results (1)
Metabolic work ­upa 2 (8.6) 68 Normal results (2)
Endocrine work ­upb 2 (8.6) 49.5 Normal results (2)
Infectious work u­ pc 4 (17.3) 65 Normal results (2)
a
 Metabolic work up: amino acid analysis, alpha-1 antitrypsin deficiency
b
 Endocrine work up: thyroid function studies
c
 Infectious work up: hepatitis screening, toxoplasmosis, parvovirus, EBV, CMV

Discussion often undergo a wide range of tests before reaching a diag-

nosis. Tests performed often include abdominal ultrasound,
Gastroschisis, a congenital anomaly involving failure of HIDA scan, percutaneous cholangiogram and a variety of
the abdominal wall to fully mature has a low prevalence laboratory studies to evaluate for metabolic, endocrine, and
of associated congenital anomalies or genetic abnormalities infectious etiologies [18]. Screening algorithms have been
[28]. Additionally, neonates with gastroschisis are frequently proposed to exclude biliary atresia but, as noted, no predic-
full-term and with normal birthweight, such that the primary tive models specific to patients with gastroschisis have been
risk factor for prolonged intravenous nutrition is the ileus described. This study demonstrated a wide variety of diag-
secondary to amniotic fluid contacting the intestines and to nostic tests being performed without any pathologic diag-
a lesser degree, the risk of necrotizing enterocolitis, elevated noses or identification of conditions other than parenteral
intraabdominal pressure, and need for bowel resection [1, 12, nutrition associated liver disease (PNALD), consistent with
25; Miranda da Silva 25]. Early cholestasis can be identified the low incidence of reported anatomical or alternative diag-
in almost 1 of every 50 NICU patients but typically resolves noses in the literature. As noted, patients with gastroschisis
spontaneously and is not always associated with structural or often require prolonged PN due to intestinal dysmotility pro-
functional etiologies [7, 10, 27]. Though limited to a single hibiting the provision of adequate enteral nutrition [16]. In
institution and modest sample size, our data supports that this study, although the incidence of central line-associated
prolonged use of total (or partial) parenteral nutrition (PN) sepsis was higher in the group diagnosed with DH, this was
in patients with gastroschisis is associated with high rates of not statistically significant (p = 0.39).
cholestasis or conjugated hyperbilirubinemia. In comparison The discussion of DH in patients with gastroschisis is
to previous series published by Fallon et al., the rate of DH additionally complicated by the lack of a unifying or consist-
observed in this study is slightly higher, which is likely asso- ent diagnosis of PNALD, which in many cases is a diagnosis
ciated with variable definitions of DH and later initiation of exclusion. The patients in this study all demonstrated res-
of enteral feeds [10]. Interestingly, total PN days in the DH olution of DH without findings to suggest a surgically-cor-
cohort did not vary from the non-DH cohort, suggesting that rectable, mechanism cause for DH (such as biliary atresia).
there may be as-yet unidentified confounders that mitigate There was no significant difference in average gestational
the pejorative cholestatic effects of PN. age or birth weight percentile, but patients with DH were
In a 2015 systematic review, the most common etiologies noted to have a statistically significantly lower discharge
of DH identified in newborn patients included idiopathic weight percentile and average decline in weight percentile
neonatal hepatitis (26.0%), extrahepatic biliary atresia from birth to discharge compared to an increase in weight
(25.9%), infection (11.5%) and PN associated cholestasis percentile in patients without DH (p = 0.03). In a cohort
(6.4%) [13]. Due to the non-specific lab finding of DH and of patients with gastroschisis evaluated by Fallon et al.,
high morbidity of delayed diagnosis of biliary atresia or ana- younger gestational age and cholestasis were found to be
tomical cause of laboratory derangement, patients with DH independently associated with compromised growth [10].

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Prolonged exposure to PN and delay in enteral nutrition are stay in neonates with a more significant effect by enteral
thought to contribute to poor weight gain and cholestasis nutrition [14, 15, 32]. The fat component, or lipid emul-
via intestinal villous atrophy, increased mucosal permeabil- sion, in parenteral nutrition has been identified as a potential
ity and bacterial translocation [6, 35]. While Fallon et al. causative factor for PNALD making adjustments in lipid
found increased duration of PN and increased incidence of administration, a common strategy for prevention and treat-
DH with silo placement compared to the primary closure ment of PNALD [19, 24, 26].
of the abdominal wall defect, we did not observe this in our With regards to the quantity and type of lipid emulsion
patients. Silo placement and peri-operative fluid adminis- administered, 27.6% of all patients in this study were placed
tration might artificially increase body weight early in the on a “low-lipid” formulation at 1 gm/kg/d for a week or
post-natal period. This likely altered the rate of weight gain/ more but did not differ significantly between patients with
growth and may have disproportionately impacted sicker DH and without (p = 0.46). This is consistent with dos-
patients requiring more aggressive fluid resuscitation. When ing recommendations for the prevention of PNALD in the
examining weight gain per day, the proportional weight gain absence of other risk factors such as sepsis or intestinal bac-
(gm/kg/day) did not differ between patients with and without terial overgrowth [10]. Omega-6 polyunsaturated fatty acids
DH. Measuring gestationally-adjusted weight percentiles at (PUFAs) in soybean oil-based lipid emulsions are known to
a consistent and later post-natal age may be a more accurate be pro-inflammatory and contribute to the development of
measure of growth. Another potential explanation for the hepatotoxicity. Omegaven (Fresenius Kabi AG, Bad Hom-
overall difference in weight gain in patients with DH which burg, Germany) is a fish-oil based product high in omega-3
is currently being explored with regard to fat-soluble vitamin fatty acids which is frequently administered in Europe for
deficiencies and milk protein intolerance is the increased patients receiving prolonged PN for its hepatoprotective,
intestinal permeability in the setting of hyperbilirubinemia anti-inflammatory effects and improvements in jaundice
[17, 30, 33]. and liver function tests [4, 37]. Only one patient in the pre-
Just as there is documented inconsistency in the diag- sent study received Omegaven; causality of improvement
nostic workup for DH, there is variability in this study, as in DB, however, cannot be determined based on the natural
well as the literature, in the management of PNALD. 60% history of patients with gastroschisis and concurrent intro-
of patients in this study who were diagnosed with DH were duction of enteral feeds. Given the relatively small sample
started on choleretic medications with variable involvement size, however, we are unable to definitively state why low
of gastroenterologists. Interestingly, direct bilirubin peaked, lipid formulation may have been started earlier in patients
on average, within a week of starting medication and initiat- without DH than those with DH. We speculate that, as is
ing diagnostic work up. Based on the improvement in DB the case at many institutions, there is variability secondary
in patients with and without medication, small sample size, to provider preferences as well as a shift towards and away
and timing of peak DB, no correlation or causation can be from the prophylactic administration of low lipid formula-
inferred from these data. For patients started on choleretic tions in patients deemed at high risk for PNALD.
medications and those that were not, the day DB is noted to Interpretation of these results should be done with cau-
normalize is within 1–2 days of discontinuing PN. There tion as delay in diagnosis of biliary atresia or other causes
was no significant difference, however, between days until of DH can be devastating in the neonatal population. Lee
enteral nutrition was initiated and patient was tolerating full et al. describe an unfortunate case of concurrent biliary
feeds between patients who were and were not started on atresia and gastroschisis in a patient who developed jaun-
choleretic medications. In a larger series of patients with dice after the transition to enteral feeds and discharge from
PNALD, Ursodiol therapy was not found to be associated the hospital [21]. Extrahepatic biliary atresia is the leading
with duration of PNALD [38]. Sincalide (an analogue of cause for liver transplantation in the pediatric population
the C-terminal octapeptide) and phenobarbital (an induc- and incredibly rare in the setting of gastroschisis. While Lee
tor of bile excretion and bilirubin conjugation) have both et al. suggest that a vascular insult may result in both defects,
been suggested for diagnostic and therapeutic purposes in the presentation of jaundice after transition to enteral nutri-
the management of functional biliary disorders. While both tion makes the diagnosis of PNALD incredibly unlikely and
agents are associated with improved accuracy and diagnostic ultimately describes a very different and unfortunate patient
yield of cholescintigraphy, data demonstrating improvement population than evaluated in the present study [3].
in PNALD are limited and inconsistent [23, 29, 40].
In contrast to pharmacologic interventions, adjustments Limitations
to administration of parenteral nutrition have been shown to
be associated with improved outcomes and decreased dura- Based on the moderately low incidence of gastroschisis
tion of PNALD. Early nutrition of any form is associated and direct hyperbilirubinemia, this study has several limi-
with improved outcomes and decreased hospital length of tations. This is a retrospective study of a single institution

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300 Pediatric Surgery International (2019) 35:293–301

with a relatively small sample size, as noted and, therefore, Compliance with ethical standards 
results must be interpreted and applied with caution by
encouraging larger institutions and collaborative networks Ethical approval  All procedures performed in studies involving human
to continue this investigation. Despite only being con- participants were in accordance with the ethical standards of the insti-
tutional and/or national research committee and with the 1964 Helsinki
ducted at one institution, this study shed light on consider- declaration and its later amendments or comparable ethical standards.
able amounts of variability between providers. There was
variation in timing of initiation of enteral feeds, rate of Informed consent  The need for informed consent was waived by the
feed advancement, work up, and use of choleretic medica- Institutional Review Board as the study was felt to pose less than mini-
mal risk by its nature as a retrospective review.
tions. With neonatologists, surgeons, dieticians, and other
ancillary staff involved in each patient’s care, highly vari-
able practice patterns were observed. Additionally, physi-
cian practice pattern variability contributes to timing of References
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Funding  This research did not receive any specific grant from funding
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https​://doi.org/10.1097/MPG.00000​00000​00133​4

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