maternal risk factors and perinatal characteristics for hirschsprung

ARTICLEPEDIATRICS Volume 138 , number 1 , July 2016 :e 20154608

Maternal Risk Factors and Perinatal Characteristics for Hirschsprung DiseaseAnna Löf Granström, MD, a, b Anna Svenningsson, MD, PhD, a, b Eva Hagel, c Jenny Oddsberg, MD, PhD, a, b Agneta Nordenskjöld, MD, PhD, a, b, d Tomas Wester, MD, PhDa, b

abstractBACKGROUND AND OBJECTIVES: Hirschsprung disease (HSCR) is a congenital defect of the enteric

nervous system characterized by a lack of ganglion cells in the distal hindgut. The aim of

this study was to assess the birth prevalence, perinatal characteristics, and maternal risk

factors in HSCR patients in Sweden.

METHODS: This was a nationwide, population-based, case-control study of all children born

in Sweden between 1982 and 2012 and registered in the Swedish Medical Birth Register.

Cases were identified in the Swedish National Patient Register and data on potential

maternal risk factors and patient characteristics were collected from the Swedish National

Patient Register and the Swedish Medical Birth Register. Five age- and sex-matched controls

were randomly selected for each case. The association between studied risk factors and

HSCR was analyzed using conditional logistic regression to calculate the odds ratio (OR)

and 95% confidence interval (CI).

RESULTS: The study population comprised 600 HSCR cases and 3000 controls with a male-

to-female ratio of 3.7:1. The birth prevalence of HSCR was 1.91/10 000. Maternal obesity

was associated with an increased risk for the child to have HSCR (OR 1.74; CI 1.25–2.44).

Children with HSCR were born at an earlier gestational age (OR 1.60; CI 1.18–2.17) than

control children. Associated malformations were identified in 34.5% of the cases.

CONCLUSIONS: This study showed that the Swedish birth prevalence of HSCR was 1.91/10 000.

Children with HSCR disease were born at a lower gestational age than controls. Maternal

obesity may increase the risk for the child to have HSCR.

Departments of aWomen’s and Children’s Health and cLearning, Informatics, Management and Ethics (LIME),

Unit for Medical Statistics, Karolinska Institute, Stockholm, Sweden; and bDivision of Pediatric Surgery, Astrid

Lindgren Children’s Hospital and dCenter of Molecular Medicine, Karolinska University Hospital, Stockholm,

Sweden

Dr Löf Granström conceptualized and designed the study, analyzed the data, drafted the article,

and revised the manuscript; Dr Svenningsson and Ms Hagel carried out the initial analyses and

critically reviewed and revised the manuscript; Drs Oddsberg and Nordenskjöld conceptualized

and designed the study, acquired the data, and critically reviewed and revised the manuscript;

Dr Wester conceptualized and designed the study, analyzed the data, and critically reviewed and

revised the manuscript; and all authors approved the fi nal manuscript as submitted.

DOI: 10.1542/peds.2015-4608

Accepted for publication Apr 20, 2016

Address correspondence to Anna Löf Granström, MD, Division of Pediatric Surgery, Astrid

Lindgren Children’s Hospital, Q3:03, Karolinska University Hospital, Solna, SE-17176 Stockholm.

E-mail: [email protected]

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

To cite: Löf Granström A, Svenningsson A, Hagel E, et al.

Maternal Risk Factors and Perinatal Characteristics for

Hirschsprung Disease. Pediatrics. 2016;138(1):e20154608

WHAT’S KNOWN ON THIS SUBJECT: Hirschsprung

disease (HSCR) is a multifactorial disease. The

incidence varies from 1 per 2000 to 1 per 12 000.

Being fi rstborn may decrease the risk of having the

disease.

WHAT THIS STUDY ADDS: The incidence of HSCR is

1.91 per 10 000 live newborns in Sweden. Maternal

obesity increases the risk for having a child with

HSCR, and there is increased risk for children with

HSCR to be born prematurely.

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LÖF GRANSTRÖM et al

Hirschsprung disease (HSCR) is

a congenital defect of the enteric

nervous system characterized by a

lack of ganglion cells in the distal

hindgut. Motility disturbances in the

distal colon usually lead to neonatal

intestinal obstruction. The majority

of the patients undergo surgical

treatment during the first year of

life.

The incidence of HSCR

has been assessed in both

demographic and epidemiologic

studies and varies from 1 in 2000

to 1 in 12 000 live births.1 Best

et al recently reported a slightly

increasing prevalence of HSCR in

Europe.2

HSCR is known to be a multifactorial

disease caused by both genetic

and environmental factors.

Mutations in >10 genes have been

associated with HSCR, particularly

the RET gene, in which 15% to 20%

of patients with isolated HSCR have

mutations.3 Familial occurrence,

male predominance, and the

pattern of associated malformations,

encountered in 4% to 35% of the

cases, also imply a genetic etiology.4

Furthermore, patients with

Down syndrome (trisomy 21)

have a 100-fold risk for HSCR

compared with the normal

population.5 The importance

of environmental factors is not

well known. In a small study of

patients with Down syndrome and

HSCR, extensive coffee drinking

and maternal fever during the

first trimester increased the

risk for HSCR.6 There have been

speculations about the role

of hypothyroidism, vitamin A

deficiency, and maternal intake

of Ibumetin or mycophenolate

during pregnancy, but none of

these associations have been

confirmed.7–11

The purpose of this study was

to investigate the maternal risk

factors and perinatal characteristics

of HSCR in Sweden.

METHODS

Design

This was a nationwide, population-

based case-control study. The study

base includes all neonates born in

Sweden during the observational

period January 1, 1982, to December

31, 2012, and registered in the

Swedish Medical Birth Register

(MBR). The study outcome involved

HSCR and the study exposures being

assessed through linkage with the

Swedish National Patient Register

(NPR) for both cases and their

mothers. All residents in Sweden are

assigned a unique 10-digit personal

identification number after birth or

immigration, which enables linkage

among different national registers.

Registers

The NPR contains prospectively

collected information on all hospital

admissions in Sweden. The register is

maintained by the Swedish National

Board of Health and Welfare. It

was initiated in 1964 and covers all

hospitals in Sweden since 1987. The

data include sex, age, geographic

data, surgical procedures, primary

and secondary diagnoses, and dates

of admission and discharge. The

International Classification of Diseases

(ICD) has been modified over the

years: ICD-8 in 1969–1986, ICD-9

in 1987–1996, and ICD-10 since

1997. Since 2001, data on outpatient

specialist care have also been

included in the register. The latest

validation of the register showed that

the diagnoses are valid in 85% to

95% of the cases.12

The MBR contains data on all

pregnancies and deliveries in

Sweden since 1973. The Swedish

National Board of Health and Welfare

administers the register. Correlation

between register data, corresponding

original medical records, and the

validity of the study exposures has

been shown to be excellent.13 The

data are collected prospectively

from antenatal care clinics, obstetric

clinics, and maternity wards and

include maternal age and parity,

maternal weight and height, maternal

smoking and diseases, duration of

pregnancy, single or multiple birth,

parity, and birth weight.

Cases and Controls

All cases with an ICD code for HSCR

in the Swedish NPR (ICD-8 751.39;

ICD-9 751D; ICD-10 Q431) during

the study period were identified

(n = 816) to confirm that the subjects

had HSCR and were not misclassified

by mistake. For instance, we wanted

to avoid including neonates with

suspected HSCR admitted for rectal

suction biopsies in cases in which the

biopsies turned out to be negative or

patients admitted only to a hospital

without pediatric surgery. Each

case had to satisfy 1 of the following

inclusion criteria:

1. HSCR as the main diagnosis and

a surgical intervention number

specific for HSCR;

2. admission to a pediatric surgical

center at least twice, with a

hospital stay of at least 4 days at

least once, and HSCR as the main

diagnosis for both hospital stays;

and/or

3. One long admission to a pediatric

surgical center once and >1

outpatient visit to a pediatric

surgical center with HSCR as the

main diagnosis.

Using these criteria, 216 patients

were excluded, ending up with 600

HSCR cases; because there were

10 siblings among the cases, 590

mothers were identified. For each

case, 5 controls matched for birth

year and sex and without a history

of HSCR (n = 3000) were randomly

sampled from the study base by

incidence density sampling by using

the RANUNI function in SAS 9.4 (SAS

Institute, Cary, NC). A flowchart is

shown in Fig 1.

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PEDIATRICS Volume 138 , number 1 , July 2016

Defi nition and Categorization of Study Variables

Birth Prevalence

The birth prevalence of HSCR was

assessed by dividing the number of

HSCR cases that met the inclusion

criteria by the number of live

births in Sweden in 1987–2012,

according to the Swedish National

Board of Health and Welfare. The

birth prevalence was also assessed

separately for males and females. We

chose the study period from 1987

instead of 1982 because the NPR

became national in 1987.

Maternal Risk Factors

Exposure data on maternal age,

maternal smoking, parity, and

maternal BMI were obtained from the

MBR. Maternal age was categorized

into 5 groups: <20 years, 20 to 24

years, 25 to 29 years, 30 to 35 years,

and >35 years. Data on maternal

smoking were defined as smoking

at the time of registration at the

antenatal care clinic at gestational

weeks 10 to 12 and were categorized

into nonsmoker, <10 cigarettes

daily, and ≥10 cigarettes daily. Birth

order was categorized into 3 groups;

first, second, and third or greater.

Maternal BMI was measured in

kg/m2 and calculated from the periods

1982 to 1989 and 1992 onward

because of changes in the register.

Maternal BMI was registered at the

first antenatal care clinic visit. BMI

was categorized into 4 groups: <18.5

(underweight), 18.5 to 24.9 (normal

weight), 25.0 to 29.9 (overweight),

and ≥30.0 (obese) according to

the World Health Organization

classification.14

The exposure data on maternal

diseases were based on occurrences

of the following ICD codes: ICD-8:

242, 244, 245, 250, 340.99, 563,

00-563, 10; ICD-9: 242, 244, 245, 250,

340A-341×, 555A-X, 556; ICD-10:

E03, E05, E06, E10, E11, E12, E13,

E89, G35.9, K50-51.

Perinatal Characteristics

Exposure data on delivery mode,

gestational age, birth weight, and

neonatal mortality were obtained

from the MBR. Delivery mode was

categorized concerning caesarean

and vaginal delivery. Gestational

age was categorized into 2 groups:

<37 gestational weeks (preterm)

and ≥37 gestational weeks (term).

Birth weight for gestational age was

categorized into 2 groups according

to Marsál et al: small for gestational

age (SGA) or not, based on growth

curves.15 For the analysis of weight

for gestational age (SGA), twins were

excluded. Data on preeclampsia were

collected from both the MBR and

the NPR, based on the following ICD

codes: ICD 8: 637.00-637.04, 637.09-

637.10, 637.99; ICD 9: 642 E-G;

ICD-10: O14.0-O14.1, O14.9, O11.9.

Neonatal mortality was collected

from the MBR.

Congenital Malformations

Congenital malformations and

chromosomal abnormalities

comprised the following diagnoses

in either the NPR or the MBR: ICD-8:

750.00-759.99; ICD-9: 740-759×;

ICD-10: Q00-Q99. The following

diagnoses were excluded: Meckel

diverticulum (751, 751A, Q430),

undescended testis (752.1, 752F,

Q531-532, Q539), and urachus

remnant (753H, Q644) due to a

diagnostic bias. The malformations

were categorized into the following

categories: gastrointestinal,

cardiovascular, musculoskeletal,

urogenital, ophthalmic, central

nervous system, and other

malformations. The gastrointestinal

malformations were further

analyzed, and cases with only 1

diagnosis from an outpatient visit

or 1 admission to a hospital without

pediatric surgery were excluded.

Data on newborns with Down

syndrome during 1999–2012 were

collected from the Swedish National

Board of Health and Welfare to

assess the cumulative incidence of

HSCR among patients with Down

syndrome.

Statistical Analysis

The associations between HSCR

and perinatal characteristics were

examined by using univariable

logistic regression models with

preterm delivery, SGA, and mode

of delivery as the outcomes and

HSCR as an explanatory variable,

presented with odds ratio (OR)

estimates and 95% confidence

intervals (CIs). Possible risk factors

for HSCR (maternal age, maternal

BMI, maternal smoking, and parity)

were analyzed by using a conditional

logistic regression procedure (clogit

in R) stratifying over the matched

pairs. The results were presented

3

FIGURE 1Flowchart of the study.



with OR and 95% CI. All odds of

HSCR were evaluated by using a

univariable approach. A multivariable

analysis was considered if the

univariable analysis showed that it

was appropriate. All statistics are

performed in R software version

2.38 (http:// CRAN. R- project. org/

package= survival).16

Ethics

The Regional Ethics Review Board

at Karolinska Institutet, Stockholm,

approved the study.

RESULTS

Birth Prevalence

The birth prevalence of HSCR in

Sweden was 1.91 in 10 000 births

between 1987 and 2012. The birth

prevalence by sex and the total birth

prevalence over the years are shown

in Fig 2.

Maternal Risk Factors

The maternal risk factors are

summarized in Table 1, and the most

prominent finding was the increased

risk for obese females to have

children with HSCR. There appears

to be a linear increase over BMI

categories; the ORs are not significant

for underweight and overweight, but

this is evident from the effect sizes.

The same gradient effect is shown

in male cases. An analysis using a

multivariate model did not change

the results. A subanalysis of infant

sex is shown in Table 2.

Perinatal Characteristics

Of the 600 HSCR cases, 466 were

boys, resulting in a male-to-female

ratio of 3.7:1. There were 19

discordant twins among the cases

and 77 among the controls (OR 1.24,

95% CI 0.75–2.07). One of the cases

did not survive the first month of life,

and 6 controls died (OR 0.83, 95%

0.10–6.92). Data on gestational age,

birth weight, and delivery mode are

summarized in Table 3. The data

presented are not causative factors

but could instead be associated with

HSCR. The gestational age of cases

and controls is shown in Fig 3. The

odds of HSCR were significantly

greater in preterm compared with

term deliveries in girls (OR 2.69,

95% CI: 1.38–5.26) and in boys (OR:

1.41, 95% CI: 1.00–1.99). The odds

of HSCR for SGA were as follows:

girls, OR 1.59 (95% CI: 0.51–4.97);

boys, OR 1.22 (95% CI: 0.62–2.37).

Preeclampsia occurred as frequently

in mothers of cases as in those of

controls (24 and 95, respectively).

Congenital Malformations

Among the HSCR cases, 207 (34.5%)

individuals had at least 1 other

congenital malformation, including

chromosomal anomalies. Excluding

the cases with only chromosomal

anomalies, 191 of the cases had

associated malformations (Fig 4).

Altogether, 59 (9.8%) of the cases

had Down syndrome and 18 (3%)

had other chromosomal anomalies.

Between 1999 and 2012, 2203

children with Down syndrome were

born in Sweden. Of these, 25 also had

HSCR, which gives a birth prevalence

of 1.1%.

DISCUSSION

This is the first population-based

case-control study including 600

cases of HSCR. The study shows that

the birth prevalence of HSCR was 1

in 5000 in Sweden between 1987

and 2012. We found an association

between HSCR in the child and

maternal obesity during the first

trimester. Also mothers pregnant

with their third child or greater

showed an increased risk of having

a child with HSCR, and patients with

HSCR tended to be born at a lower

gestational age than healthy control

children.

Sweden has well-recognized

population-based medical registers

that make it possible to perform

powerful studies like this one. All

data are prospectively collected,

thus avoiding the risk for recall

bias. The controls were randomly

selected from the study base, thereby

decreasing the risk of selection bias.

Our study assesses a large number

of HSCR cases with cross-linked

data on exposures with the same

definition in cases as in controls.

This methodology decreases the risk

of differential misclassification of

exposure. However, the study also

4

FIGURE 2Total birth incidence and male/female birth incidence. The middle lines are a sliding estimate of average incidence.



has limitations because there was

no histopathology register available

for linkage to confirm the HSCR

diagnosis. This means that it was

necessary to base the diagnosis on

the ICD code, which was the reason

for using additional inclusion criteria

to increase the specificity of the

study. Among the excluded cases, we

found that the majority had only been

admitted once during the neonatal

period without having surgery,

or admitted to a hospital without

pediatric surgery services. Another

possible limitation is the risk for type

II errors due to the limited sample

size. Data on HSCR that occurred

in stillbirth or termination for

fetal anomaly were not possible to

retrieve from the registers and may

be a limitation of the study.

Our study showed that 1.91 of 10 000

or 1 in 5000 live births involved

HSCR in Sweden from 1987 to 2012.

The birth prevalence did not change

significantly over the study period.

Earlier studies have reported an

incidence of HSCR of 1 in 5000,

although this varies from 1 in 2000 to

1 in 12 000 live births.1 To calculate

the incidence, the population at risk

is needed. Because the population

at risk for HSCR, which includes the

number of conceptions that reach

the gestational age when the defect

occurs, is unknown, it is impossible

5

TABLE 1 Maternal Characteristics With Univariable, Unadjusted ORs With 95% CIs

Cases (n = 600) Controls (n = 3000) Unadjusted OR (95% CI)

Maternal age, y

<20 9 68 0.65 (0.32–1.33)

20–24 102 520 0.97 (0.75–1.26)

25–29 203 1005 1

30–34 170 898 0.94 (0.75–1.17)

≥35 116 509 1.13 (0.88–1.46)

Maternal smoking (cigarettes daily)

None 469 2369 1

1–9 62 277 1.12 (0.83–1.51)

≥10 18 151 0.62 (0.38–1.03)

Missing data 51 203

Parity

1 233 1249 1

2 215 1100 1.05 (0.86–1.28)

≥3 152 651 1.25 (1.00–1.56)

Maternal BMI

Underweight <18.5 9 80 0.62 (0.31–1.26)

Normal weight 18.5–24.9 279 1533 1

Overweight 25.0–29.9 113 514 1.24 (0.96–1.58)

Obese ≥30.0 57 193 1.74 (1.25–2.44)a

Missing data 142 680

Maternal diseases

Diabetes 11 58 0.95 (0.49–1.82)

Infl ammatory bowel disease 0 3 —

Multiple sclerosis 1 3 0.6 (0.06–5.77)

Thyroid diseases 26 101 1.3 (0.84–2.03)

a Statistical signifi cance.

TABLE 2 Subanalysis for Child Sex, Unadjusted ORs With 95% CIs

Girls Boys

Cases (n = 134) Cases (n = 466)

Controls (n = 670) Controls (n = 2330)

Maternal age, y

<20 — 0.96 (0.46–2.00)

20–24 — 1.00 (0.742–1.34)

25–29 1 1

30–34 — 0.97 (0.75–1.26)

≥35 — 1.20 (0.90–1.60)

Maternal smoking (cigarettes daily)

None 1 1

1–9 1.40 (0.75–2.63) 1.05 (0.75–1.48)

≥10 0.78 (0.27–2.28) 0.59 (0.33–1.04)

Missing data 66 188

Parity

1 1 1

2 1.26 (0.83–1.91) 0.99 (0.78–1.25)

≥3 1.05 (0.64–1.72) 1.30 (1.01–1.68)a

Maternal BMI

Underweight <18.5 0.70 (0.20–2.47) 0.57 (0.24–1.35)

Normal wt 18.5–24.9 1 1

Overweight 25.0–29.9 0.80 (0.46–1.38) 1.40 (1.05–1.85)a

Obese ≥30.0 1.03 (0.50–2.15) 2.03 (1.39–2.96)a

Missing data 186 636




to calculate the incidence. Therefore,

Mason et al recommended calculation

of birth prevalence instead. The

previously published incidence

data are comparable to our birth

prevalence data.17

Our results indicate that obesity

may be a maternal risk factor or at

least a risk indicator for the child

to have HSCR. It is well known that

prepregnancy obesity is associated

with several birth defects, but this

has not been shown specifically

for HSCR.18–21 Two known risk

factors for birth defects that may

confound this association are blood

folate levels and prepregnancy

diabetes. The blood folate level

among the cases’ mothers is not

available from the registers and

is therefore unknown. The rate

of diabetes among the mothers

was analyzed, and no differences

could be demonstrated between

cases and controls. However,

there is 1 uncommon syndrome,

small left colon syndrome, that

occurs particularly in infants of

diabetic mothers and with an

unknown etiology.22 The syndrome

can simulate HSCR in neonates

within the first 24 to 48 hours of

life, but in our data, there was no

overrepresentation of maternal

diabetes, which makes this an

unlikely explanation.

Untreated hypothyroidism, which

may lead to obesity in the mothers,

could also be considered as a possible

confounder. A case report describing

congenital hypothyroidism associated

with HSCR speculates about the

importance of thyroxin levels and

the development of HSCR.7 Another

speculation may be that obese

mothers have vitamin deficiencies due

to nutritional habits. In mice, vitamin

A deficiency increased the penetrance

and severity of aganglionosis in

an experimental model of HSCR.8

Another possible confounder could be

that obese mothers may use medical

treatments that may increase the

risk for HSCR in the embryo. It has

been suggested in animal models

that maternal intake of ibuprofen or

mycophenolate may cause enteric

nervous system malformations with

an HSCR-like pathology, which calls

for studies on maternal intake of drugs

6

TABLE 3 Perinatal Characteristics With Univariable, Unadjusted ORs With 95% CIs

Cases

(n = 600)

Controls

(n = 3000)

Unadjusted OR (95% CI)

Gestational age, wk

<37 60 196 1.60 (1.18–2.17)a

≥37 537 2793 1

Missing data 3 11

SGA status

SGA 15 56 1.32 (0.74–2.36)

Not SGA 557 2752 1

Missing data 9 97

Delivery mode

Caesarean delivery 88 430 1.03 (0.80–1.32)

Vaginal delivery 493 2475 1

Missing data 19 95


FIGURE 3Distribution of gestational age for cases and controls. *Signifi cant difference; OR 1.6, 95% CI 1.18–2.17.

FIGURE 4Congenital malformations among the cases. CNS, central nervous system.



during pregnancy and the associated

risk for HSCR.9, 11

In our study, we found that a parity

of ≥3 children increases the risk

of having a child with HSCR. On

subanalysis for child sex, boys show

the same pattern, but not girls,

perhaps because of the small sample

size and lack of power. This result is

similar to what Ryan et al described,

namely, that being firstborn

decreased the risk for having HSCR.23

Goldberg showed an association

between maternal age and the risk

for HSCR in the offspring, which

could not be confirmed by Best et al

or Russel et al.2, 24, 25

No correlation could be found

between the risk of having a child

with HSCR and maternal diseases.

Our group previously reported a

family with autosomal dominantly

inherited HSCR associated with

multiple sclerosis. This family

had a novel EDNRB gene mutation

that could potentially play a

role in the development of the

diseases.26 However, in this study,

maternal multiple sclerosis was

not associated with HSCR in the

offspring.

We also showed that HSCR patients

were born at a lower gestational

week than controls, thus confirming

earlier studies.23 The prevalence

of HSCR in premature infants in a

systemic review extending from

2000 to 2013 was 4% to 19.4%

(overall prevalence, 14%).27

Preterm birth may have many

causes, for example, preeclampsia

or congenital malformations.

Maternal preeclampsia was not

overrepresented among the cases’

mothers in this study. Another

possible marker for a problematic

pregnancy, caesarean delivery, was

not statistically different between the

groups. Downey et al studied preterm

patients with HSCR and concluded

that they had more associated

anomalies than term patients with

HSCR.28 The rate of associated

malformations reported in this study

(34.5%) is fairly high compared

with other studies. This could be

explained by our broad definition of

malformation: at least 1 diagnosis

in any of the registers, which

could cause an overrepresentation

of the patients with associated

malformations. Because a high

frequency of gastrointestinal

malformations was found, these

malformations were further

investigated. The birth prevalence

of congenital malformation in the

Swedish general birth population in

2012 was 1.5%; however, that might

be underestimated due to lack of

insufficient validity of that specific

register.29

CONCLUSIONS

This study shows a stable birth

prevalence of HSCR of 1.91 of 10 000

in Sweden. Maternal obesity and

parity may be a risk factor for the

child to develop HSCR and affected

children were born at a lower

gestational age than control subjects.

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ABBREVIATIONS

CI: confidence interval

HSCR: Hirschsprung disease

ICD: International Classification of Diseases

MBR: Swedish Medical Birth

Register

NPR: National Patient Register

OR: odds ratio

SGA: small for gestational age

Copyright © 2016 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they have no fi nancial relationships relevant to this article to disclose.

FUNDING: This study was supported by the Foundation Frimurare Barnhuset, Her Royal Highness Crown Princess Lovisa Foundation, and the Sällskapet

Barnavård Foundation.

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential confl icts of interest to disclose.



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