Trends in utilization and off-label use of polyethylene glycol 4000 laxatives and the prevalence of constipation in children in France.

Abstract

To determine trends in utilization and off-label use of polyethylene glycol (PEG) 4000 in children and to determine the prevalence of constipation.
Retrospective cross-sectional analyses were conducted from 1997 to 2007 in a French health care database comprising general practitioners and pediatricians. Patients prescribed PEG 4000 (Forlax(®); Ipsen Pharma, Paris, France) were used to assess PEG 4000 use; constipation was defined by a diagnosis of constipation or use of any laxative. Analyses used linear regression models to fit trends over time.
The study sample consisted of a nationally representative sample of 1200 general practitioners with 1.6 million patient medical records and 100 pediatricians with 70,000 patient medical records. Data were available from 1997 to 2007 for general practitioners and from 2003 to 2007 for pediatricians and were extrapolated to the national level. Among both groups of physicians there were statistically significant increases in the number of patients prescribed 4 g. For the 10 g dose, there was a decline among pediatricians. The largest increases were in children aged 0-8 years and in females. The prevalence of constipation in children aged 0-18 years was 4%.
There has been an increase in the use of PEG 4000 laxative in children, particularly in the younger ages and in females. Use of the 4 g dose has increased. There was considerable off-label use of PEG 4000 in children aged 0-8 years before the introduction of the 4 g pediatric dose, which reflected clinical need.

Full text

Page 1

© 2011 Qizilbash and Mendez, publisher and licensee Dove Medical Press Ltd. This is an Open Access
article which permits unrestricted noncommercial use, provided the original work is properly cited.
Clinical and Experimental Gastroenterology 2011:4 181–188
Clinical and Experimental GastroenterologyDovepress
submit your manuscript | www.dovepress.com
Dovepress
181
O r i G i n A L r E s E A r C h
open access to scientific and medical research
Open Access Full Text Article
Trends in utilization and off-label use
of polyethylene glycol 4000 laxatives and the
prevalence of constipation in children in France
http://dx.doi.org/10.2147/CEG.S23055
nawab Qizilbash1,2
ignacio Mendez1
1OXOn Epidemiology, Madrid,
spain, and London, UK; 2Department
of Primary Care and social Medicine,
imperial College, London
University, UK
Correspondence: nawab Qizilbash
OXOn Epidemiology, 200 northcote
road, London E177Dh, UK
Tel +44 629 846 059
Fax +44 208 509 0334
Email n.qizilbash@oxonepi.com
Purpose: To determine trends in utilization and off-label use of polyethylene glycol (PEG)
4000 in children and to determine the prevalence of constipation.
Methods: Retrospective cross-sectional analyses were conducted from 1997 to 2007 in a French
health care database comprising general practitioners and pediatricians. Patients prescribed PEG
4000 (Forlax®; Ipsen Pharma, Paris, France) were used to assess PEG 4000 use; constipation was
defined by a diagnosis of constipation or use of any laxative. Analyses used linear r egression
models to fit trends over time.
Results: The study sample consisted of a nationally representative sample of 1200 general
practitioners with 1.6 million patient medical records and 100 pediatricians with 70,000 patient
medical records. Data were available from 1997 to 2007 for general practitioners and from
2003 to 2007 for pediatricians and were extrapolated to the national level. Among both groups
of physicians there were statistically significant increases in the number of patients pre-
scribed 4 g. For the 10 g dose, there was a decline among pediatricians. The largest increases
were in children aged 0–8 years and in females. The prevalence of constipation in children aged
0–18 years was 4%.
Conclusion: There has been an increase in the use of PEG 4000 laxative in children, particularly
in the younger ages and in females. Use of the 4 g dose has increased. There was considerable
off-label use of PEG 4000 in children aged 0–8 years before the introduction of the 4 g pediatric
dose, which reflected clinical need.
Keywords: polyethylene glycol, macrogol 4000, children, drug utilization, database, laxative,
off-label use, prevalence, constipation, time trends
Introduction
Constipation in children is a common condition.1 The prevalence of constipation varies
from 1% to 30% depending on the diagnostic methodology employed, the sampling
frames, and the populations sampled.2 The prevalence of constipation over time is
uncertain3 and few population-based studies exist in the literature.
The lack of studies on constipation in children, despite its high prevalence, may
be due to a view that constipation is something that children “grow out of.” However,
a long-term follow-up study of chronically constipated children found that in a
third of their subjects, complaints of constipation persisted into young adulthood.4
Approximately 50% of the children also experienced at least one relapse within the first
5 years after initial successful treatment.4 After intensive medical and/or psychosocial
treatment, a subgroup of children with persistent constipation will have an unsuccessful
outcome, necessitating surgical intervention (eg, cecostomy).5 Constipation also causes
Number of times this article has been viewed
This article was published in the following Dove Press journal:
Clinical and Experimental Gastroenterology
27 July 2011

Page 2

Clinical and Experimental Gastroenterology 2011:4
submit your manuscript | www.dovepress.com
Dovepress
Dovepress
182
Qizilbash and Mendez
physical and emotional distress and is associated with a
significantly decreased quality of life, another factor arguing
against the problem’s supposedly benign nature.6
More studies have been conducted on the population
prevalence of constipation in adults, with report rates that
range from 2% to 28%.7–14 A recent study of a questionnaire-
based assessment of constipation in nationally representative
samples of subjects found France to have the highest
prevalence of constipation (14.0%) among the other
European countries in the study (the prevalence rates for
Germany, Italy, and the UK were 5.4%, 8.0%, and 7.7%,
respectively).15 For French subjects under age 30 years (no
lower age limit was reported in the study), the prevalence
was 12%.15
The use of laxatives is not well documented, although
a few studies in the USA indicate that it is considerable
in children, with a heavy medical cost burden that is
increasing over time.3,16 In the USA, the use of laxatives
is greater in children and is increasing.3 The increase in
laxative use from 1997 to 2006 was predominantly among
hyperosmolar laxatives.16 A multicountry cross-sectional
survey documented laxative use but could not differentiate
the types of laxatives used.14 Additionally, there is a suspicion
that off-label use of PEGs was common due to the clinical
need for laxatives in younger children until the approval of
agents specifically for them.17
Few data are available in Europe on laxative use.
However, in France, where constipation has a higher reported
prevalence than in many other EU countries,15 a large
health care database was available to obtain these data (see
Methods). Therefore, the current study was conducted in
children in France to:
•? quantify the degree of use of hyperosmolar laxatives, such
as polyethylene glycol (PEG) 4000 and to test whether
PEG laxative use has increased over time
•? describe and quantify time trends in use
•? describe and quantify the degree of off-label use
•? examine the influence of the introduction of a pediatric
dose on prescription trends
•? determine the prevalence of constipation in children in
France.
Forlax® (Ipsen Pharma, Paris, France), a 4000 molecular
weight macrogol PEG without electrolytes, is considered
to be a frequently used PEG for constipation in France and
was used to reflect patterns of hyperosmolar PEG laxative
use in that country. It is packaged in two doses, 4 g and 10 g.
In France, the 10 g dose was approved in 1995 for adults
and children aged . 8 years. The 4 g dose was approved for
children from age 6 months to 8 years and launched in July
2005,3,16 thus allowing the quantification of the off-label use
of Forlax to be feasible. Therefore, to track changes over time,
the analysis used this particular trade-named product as a
measure of PEG 4000 use for constipation in children.
Methods
This study was a retrospective cross-sectional observational
study in the Longitudinal Patient Database (LPD), a database
used by general practitioners and pediatricians in France over
the period 1997 to 2007, held by the market research company
Cegedim Strategic Data, France. The general practitioners
and office-based pediatricians forming the panel of physicians
for the study used clinical management software in their daily
practice. The office-based active general practitioners and
pediatricians uploaded anonymous and coded excerpts from
the medical files of patients who had consulted them. The
representativeness of the panel of physicians reflected France
based on age, gender, and geography. Data items included:
age, gender, medical history (event dates, diagnoses, risk
factors, referrals to specialists), therapeutic history (date/
length of prescription, molecule/product, dose), additional
information (test results, immunizations, height, weight,
blood pressure), and date of data input.
For assessing hyperosmolar PEG laxative use, this
study used patients prescribed the PEG 4000 product trade-
named Forlax as a measure of hyperosmolar PEG laxative
use in France from 1997 to 2007. Inclusion criteria for
the study included a prescription of Forlax at doses of 4 g
and 10 g in subjects aged 0–18 years, at least once in each
relevant year, from January 1, 1997 to December 31, 2007.
Inclusion criteria for identifying constipation was one or
more prescriptions of any laxative or enema (Code A06A
of the Anatomical Therapeutic Classification [ATC]) or an
assignment of a diagnosis of constipation in subjects aged
0–18 years between January 1, 1997 and December 31,
2007. As the data have already been collected and are totally
anonymous, no ethical approval was required in France to
conduct the analysis.
Statistical analysis used descriptive measures of binary
data with total numbers and frequencies. The base population
for the calculation of drug utilization in each year comprised
patients aged 0–18 years prescribed Forlax 4 g and 10 g by
general practitioners and pediatricians. The base population
for the calculation of prevalence in 2007 comprised patients
aged 0–18 years who had consulted general practitioners
and/or pediatricians. Analyses used gender and the age groups
0–18, 9–18, and 0–8 years. Hypothesis testing was conducted

Page 3

Clinical and Experimental Gastroenterology 2011:4
submit your manuscript | www.dovepress.com
Dovepress
Dovepress
183
Constipation and use of PEG laxatives in children in France
to examine for statistically significant increases with time in
utilization and to quantify the trends. Time trends in patients
prescribed PEG 4000 were analyzed by linear regression
techniques following the ordinary least squares technique after
the transformation of data, if required. Where a linear model
was clearly inappropriate from inspection of the graphical plot
of the data, an exponential model with transformation of the
data using a logarithmic function was employed. Regression
values are displayed using the beta coefficient, the standard
error, the proportion of the variability of the data fitted by
the model (R2) and statistical significance with P values. The
Stata statistical package (Stata IC v 11; Stata Corp, College
Station, TX) was used to conduct the analysis.
Results
The study sample consisted of 1200 general practitioners from
a total of approximately 56,000 with 12.8 million children
nationally who consulted them at least once in the relevant year,
and 100 pediatricians from a total of approximately 2670. Data
were available from 1997 to 2007 for general practitioners and
from 2003 to 2007 for pediatricians. The general practitioners
were representative of French general practitioners according
to the criteria of age, gender, and geographical region (Table 1).
The results from the sample in the study were extrapolated
to the national level for France based on the number of
subjects in the study population and are presented nationally.
Among general practitioners, there was an absolute
increase in patients aged 0–18 years prescribed both doses
of PEG 4000 during the period 1997 to 2007, with 15,002
patients in 1997 and 133,952 patients in 2007 (test of trend
Table 1 Comparison of general practitioners in the study sample
and nationally in France
Variable Study sampleFrance nationally
Age of physician
  ,41
41–45
46–50
51+
Gender
Male
Female
region of France
West
Paris region
south West
Central East
south West
north
East
Central West
9.8%
14.2%
22.7%
53.4%
9.6%
14.3%
22.3%
53.9%
78.3%
21.8%
74.7%
25.3%
18.1%
19.6%
15.0%
13.3%
9.5%
9.3%
8.3%
6.9%
18.0%
16.2%
15.4%
13.9%
10.9%
9.7%
8.8%
7.2%
P , 0.001; see Table 2 and Figure 1). The increase was gradual
in older children aged 9–18 years: from 14,015 patients in
1997 to 2005 to an abrupt increase to 60,194 patients in
2007 (test of trend P , 0.001) (Figure 1). The increase was
initially less steep in younger children aged 0–8 years, with
987 patients in 1997 and 10,557 patients in 2004, followed
by an abrupt increase to 32,799 patients in 2005 and rising to
73,759 patients in 2007 (test of trend P , 0.001, Figure 1).
The relative proportion of patients prescribed PEG 4000 in the
9–18 years age group declined from 93.4% in 1997 to 44.9%
in 2007, while the proportion of patients in the 0–8 year age
group increased from 6.6% in 1997 to 55.1% in 2007.
A statistically significant trend (P , 0.001) described the
pattern of increase in patients prescribed the 10 g dose, which
rose from 15,002 in 1997 to 47,053 in 2007 (Figure 2). The
4 g dose recorded 0 patients from 1997 to 2004, with a subse-
quent increase reaching 88,454 in 2007 (Figure 2). However,
the trend was not statistically significant with either a simple
linear or exponential model (Figure 2). The proportion of
female patients prescribed the 10 g dose was greater than the
proportion of males (increment per year of 1839 female patients
prescribed compared with 1129 males, both statistically sig-
nificant) and for the 4 g dose the linear increment per year was
18,409 females compared with 14,839 males, both statistically
significant. The proportion of female patients prescribed the
10 g dose declined from 70.4% in 1997 to 62.9% in 2007.
The proportion of female patients prescribed the 4 g dose was
fairly static at approximately 57% between 2005 and 2007.
Among pediatricians, there was an absolute increase in
the number of patients prescribed both doses of PEG 4000
from 2003 to 2007 in all children (aged 0–18 years), with
20,734 patients in 2003 and 58,691 in 2007 (test of trend
P = 0.01) (Table 3, Figure 3). There was a small increase
among children aged 9–18 years over the 4 years available for
the study, with 2818 patients in 2003 and 5242 in 2007 (test of
trend P = 0.05, Figure 3). The number of patients prescribed
PEG 4000 was greater in the younger (0–8 years) age group,
with 17,916 patients in 2003, which increased after 2005 to
53,449 patients in 2007 (test of trend P = 0.001) (Figure 3).
The relative proportion of patients prescribed PEG 4000 in
the 9–18 years age group declined from 13.6% in 2003 to
8.9% in 2007, while the proportion in the 0–8 years age group
increased from 86.4% in 2003 to 91.1% in 2007.
There was a decrease in the number of patients prescribed
the 10 g dose, from 20,734 in 2003 to 8030 in 2007 (test of
trend P = 0.03) (Figure 4). The number of patients prescribed
the 4 g dose was recorded as 0 from 2003 to 2004 (as this
dose was unavailable until 2005), rising to 51,540 patients

Page 4

Clinical and Experimental Gastroenterology 2011:4
submit your manuscript | www.dovepress.com
Dovepress
Dovepress
184
Qizilbash and Mendez
in 2007 (Table 2). This trend was statistically significant
(P = 0.03) (Figure 4) and applied to females and males.
Among general practitioners in the database, out of
274,000 children who consulted in 2007, 10,309 had a
diagnosis of constipation. Therefore, the prevalence of
constipation in children aged 0–18 years treated at least once
with any laxative or enema (A06A ATC codes), or identi-
fied by a diagnosis of constipation in 2007 was 3.8% among
general practitioners. Among pediatricians in the database,
out of 102,345 children who consulted in 2007, 4323 children
135,000
120,000
105,000
90,000
75,000
60,000
45,000
30,000
15,000
0
1997 1998199920002001 200220032004200520062007
9–18 years
0–8 years
0–18 years
−15,000
Year
Patients prescibed PEG 4000 (n)
Figure 1 number of patients prescribed PEG 4000 (Forlax®; ipsen Pharma, Paris, France) in children aged 0–8, 9–18, and 0–18 years, by calendar year among general practitioners.
Notes: smooth lines are the modeled data. Model (exponential) for patients aged 0–18 years: y = 9,895.2 e0.22x; (r2 = 0.93); P , 0.001. Model (exponential) for patients
aged 0–8 years: y = 647.0 e0.41x; (r2 = 0.92); P , 0.001. Model (linear) for patients from 9 to 18 years old: y = 4,698.3x + 2,845.5; (r2 = 0.88); P , 0.001.
Abbreviations: n, number; PEG, polyethylene glycol.
Table 2 number of patients prescribed PEG 4000 (Forlax®; ipsen Pharma, Paris, France) among general practitioners by dose, gender,
and year
YearAll Forlax Forlax 10 gForlax 4 g*
All FemaleMale Total
patients
Forlax
10 g
Female Male Total
patients
Forlax
4 g
FemaleMale
Total
number
of patients
n%n%n%n%n%n%
1997 15,002
(100%)
19,482
(100%)
16,744
(100%)
24,381
(100%)
27,973
(100%)
29,481
(100%)
37,495
(100%)
45,074
(100%)
74,043
(100%)
128,348
(100%)
133,952
(100%)
10,561 70.4 4441 29.615,00210,56170.44441 29.6–––––
199813,618 69.9586530.1 19,482 13,61869.9586530.1–––––
1999 11,46668.5527831.5 16,74411,46668.5527831.5–––––
2000 17,879 73.3650226.7 24,381 17,87973.36502 26.7–––––
2001 19,64770.2832629.827,973 19,64770.2832629.8–––––
2002 19,67466.7980733.3 29,481 19,67466.7980733.3–––––
2003 25,71468.6 11,78131.4 37,495 25,71468.6 11,78131.4–––––
200428,33162.9 16,74337.1 45,07428,33162.9 16,74337.1–––––
2005 45,17261.0 28,871 39.0 42,913 27,25163.515,66336.531,81718,413 57.913,404 42.1
200675,077 58.553,270 41.5 44,651 28,91964.8 15,731 35.284,780 46,770 55.238,010 44.8
2007 79,081 59.054,872 41.0 47,05329,67363.117,380 36.988,45450,256 56.838,19843.2
Notes: *Forlax 4 g launched in July 2005 in France; base for each year, patients aged 0–18 years treated at least once with Forlax 4 g and 10 g by general practitioners.
Abbreviations: n, number; PEG, polyethylene glycol.

Page 5

Clinical and Experimental Gastroenterology 2011:4
submit your manuscript | www.dovepress.com
Dovepress
Dovepress
185
Constipation and use of PEG laxatives in children in France
160,000
All Forlax
Forlax 10 g
Forlax 4 g
140,000
120,000
100,000
80,000
60,000
40,000
20,000
0
1997
19981999200020012002
Year
200320042005
20062007
Patients prescibed PEG 4000 (n)
Figure 2 number of patients prescribed the 4 g, 10 g, and all doses of PEG 4000 (Forlax®; ipsen Pharma, Paris, France), by calendar year among general practitioners.
Notes: smooth lines are the modeled data. Model (exponential) for patients with prescriptions for all Forlax doses: y = 9,857.3 e0.22x; (r2 = 0.93); P , 0.001. Model (linear) for
patients with prescription of Forlax 10 g: y = 3,485.6x + 10,550; (r2 = 0.96); P , 0.001. Model (linear) adjusted for patients with Forlax 4 g: y = 28,319x + 11,713; r2 = 0.80.
Abbreviations: n, number; PEG, polyethylene glycol.
Table 3 number of patients prescribed PEG 4000 (Forlax®; ipsen Pharma, Paris, France) among pediatricians by dose, gender, and year
YearAll Forlax Forlax 10 gForlax 4 g*
All FemaleMale Total
patients
Forlax
10 g
FemaleMaleTotal
patients
Forlax
4 g
FemaleMale
Number
of subjects
n%n%n%n%n%n%
200320,734
(100%)
21,981
(100%)
32,166
(100%)
54,298
(100%)
58,691
(100%)
11,74356.6899143.4 20,73411,74356.6899143.4–––––
2004 11,46552.2 10,51647.821,98111,46552.210,51647.8–––––
200517,882 55.6 14,28444.417,066 946155.4760644.6 16,695916454.9 753145.1
2006 28,28552.1 26,01347.99927487449.1505350.9 45,299 23,95052.9 21,34947.1
200732,179 54.8 26,51345.28030406050.6396949.451,540 28,54355.4 22,99844.6
Notes: *Forlax 4 g launched in July 2005 in France; base: for each year, patients aged 0–18 years treated at least once with Forlax 4 g and 10 g among paediatricians.
Abbreviations: n, number; PEG, polyethylene glycol.
had a diagnosis of constipation. Therefore, the prevalence of
constipation in children aged 0–18 years treated at least once
with any laxative or enema (A06A ATC codes) or identified
by a diagnosis of constipation in 2007 was 4.2% among
pediatricians. The proportion of females conforming to this
definition of constipation among general practitioners was
57.1% and 53.2% among pediatricians.
Discussion
The is the first study to describe the temporal pattern of utiliza-
tion of hyperosmolar PEG laxatives, using patients prescribed
Forlax as a representative agent for PEG use, in children aged
0–18 years in France. The study demonstrates the large overall
increase in the use of PEG laxatives from 1997 to 2007. There
have been consistent increases in patients prescribed PEG
laxatives by general practitioners, with less dramatic and
less consistent patterns observed among pediatricians. The
changes have reflected much greater use in younger children
aged 0–8 years by both general practitioners and pediatricians,
and in females. However, for older children aged 9–18 years,
general practitioners have prescribed an increasing number of
patients PEG 4000, while the number of patients prescribed
PEG 4000 by pediatricians has been almost static.
The statistical models have quantified the degree and pattern
of changes in the use of hyperosmolar laxatives such as poly-
ethylene glycol (PEG) 4000 and demonstrate that the increases
over time have been statistically significant. Regression models
using either simple linear or exponential regression models

Page 6

Clinical and Experimental Gastroenterology 2011:4
submit your manuscript | www.dovepress.com
Dovepress
Dovepress
186
Qizilbash and Mendez
were able to fit the data extremely well in all analyses except
one, and provide robust and statistically significant estimates
for the increments each year between 1997 to 2007 in patients
prescribed PEG 4000 in 4 g and 10 g doses, by gender, and
by age. Information for Forlax 4 g was the exception as there
were data for only three time points from 2005 to 2007, which
limited the power of the statistical models.
The study is the first to show and quantify off-label use
of PEG laxatives in France and describe its influence on
prescription patterns. Children aged 0–8 years have been
prescribed the PEG 4000 trade-named product since 1997
by general practitioners and since 2003 by pediatricians (the
earliest data available from the database). These prescriptions
consisted of the 10 g dose as the 4 g dose was not launched
in France until 2005. This represents off-label use, as the
Summary of Product Characteristics for the 10 g dose states
that it is for use in children older than 8 years.18 However,
the study was unable to determine whether parents were
requested to adjust the administration of the 10 g dose during
the preparation of the medication. Nevertheless, the dramatic
and rapid increase in the number of patients aged 0–8 years
prescribed PEG 4000 laxatives, and in the 4 g dose among
both general practitioners and pediatricians from the time
the 4 g dose of Forlax was introduced (approved in 2005 for
children from age 6 months to 8 years),19 revealed the large
medical need for an approved laxative in this age group. The
authors were not able to identify any studies that describe
drug utilization of hyperosmolar laxatives in children in
France with which to compare our results. However, prior
to approval of the 4 g dose, there was a published clinical
trial that used PEG 4000 as a comparator arm in young
children,20 which may have influenced physicians to prescribe
the 10 g dose of PEG 4000 as an off-label indication.
General practitioners have also been responsible for a
large increase in the prescription of the 10 g dose, while
pediatricians prescribed fewer patients the 10 g dose. This
may reflect changing clinical practice, with pediatricians
treating the more severe and younger cases, and general
practitioners taking more responsibility for the less severe
and older cases. The finding of a higher proportion of females
prescribed PEG 4000 compared with males supports another
study with nationally representative data from France in
subjects ,30 years old.16 The present study found that
increases in prescriptions of laxatives to females were greater
than in males between 1997 and 2007.
The overall patterns of results in our study are supported
by prescribing patterns over time observed in the USA using a
different methodology. Data from a nationally representative
0
200320042005
Year
2006 2007
10000
20000
30000
40000
50000
60000
70000
All doses
Forlax 10 g
Forlax 4 g
Patients prescibed PEG 4000 (n)
Figure 4 number of patients prescribed the 4 g, 10 g, and all doses of PEG 4000
(Forlax®; ipsen Pharma, Paris, France), by calendar year by pediatricians.
Notes: smooth lines are the modeled data. Model (linear) adjusted for patients with
a prescription of All Forlax doses: y = 10,823x + 5,104.5; r2 = 0.91; P = 0.011. Model
(linear) adjusted for patients with a prescription of Forlax 10 g: y = 3,746.3x + 26,786;
r2 = 0.88; P = 0.017.
Abbreviations: n, number; PEG, polyethylene glycol.
70,000
60,000
50,000
40,000
30,000
20,000
10,000
0
20032004200520062007
9–18 years
0–8 years
0–18 years
Year
Patients prescibed PEG 4000 (n)
Figure 3 number of patients prescribed PEG 4000 (Forlax®; ipsen Pharma, Paris, France) in children aged 0–8, 9–18, and 0–18 years, by calendar year among pediatricians.
Notes: smooth lines are the modeled data. Model (linear) adjusted for the increase in the number of patients aged 0–18 years with a prescription of Forlax: y = 10,823x + 15,928;
r2 = 0.91; P = 0.011. Model (linear) adjusted for the increase in the number of patients aged 0–8 years with a prescription of Forlax: y = 10,017x + 13,344; r2 = 0.92; P = 0.010.
Model (linear) adjusted for the increase in the number of patients aged 9–18 years with a prescription of Forlax: y = 805.3x + 2,584.1; r2 = 0.77; P = 0.049.
Abbreviations: n, number; PEG, polyethylene glycol.

Page 7

Clinical and Experimental Gastroenterology 2011:4
submit your manuscript | www.dovepress.com
Dovepress
Dovepress
187
Constipation and use of PEG laxatives in children in France
sample from the National Ambulatory Medical Care Survey,
1997 to 2006, a similar time period to our study, observed
an increase from 15% to 42% in the proportion of visits due
to constipation (derived from ICD-9 codes or prescription
of a laxative) where a (unspecified) hyperosmolar laxative
was prescribed in children ,18 years old.3 Other age groups,
including the 65+ age group, did not record such large
increases in the proportion of visits due to constipation where
a (unspecified) hyperosmolar laxative was prescribed.3 Thus,
hyperosmolar laxatives were more likely to be prescribed
to children than adults, reinforcing the importance of the
findings of our study for public health. The higher use of PEG
laxatives in children aged 0–8 years, after approval in 2005
of the 4 g dose of Forlax for children from age 6 months to
8 years, compared with children aged 9–18 years, is supported
by the higher prevalence of constipation in younger children
in the study by Liem et al.16 Although differences in meth-
odology, sampling frames, and populations sampled make
direct comparisons between studies difficult, the trends over
time observed within each study are more reliable.
Constipation in France among children aged 0–18 years
is common and has a prevalence that is approximately 4%.
This figure is a little higher than the prevalence of 1.1% found
in a nationally representative sample of visits to physicians
by US children aged 0–18 years, where the diagnosis was
based on ICD-9 codes or laxative prescription records.16 The
use of recorded ICD-9 codes may be the explanation for
the lower prevalence figure in the US study compared with
the present study. Reassuringly, the US sample also provided
a figure of 51% for constipation in females,16 which is not
very different to the 57% observed in this study. This study
and the US study16 are at odds with prevalence estimates
obtained from a cross-sectional survey of nationally repre-
sentative samples of subjects which found that the proportion
of subjects under 30 years old reporting constipation (from
a questionnaire) was 12% in France and 13% in the USA.15
The use of a representative sample to detect constipation in
patients who do not consult their physician for constipation
and the looser criteria to define constipation than that used
by physicians are likely explanations for the much higher
prevalence rates of constipation in the study.15
There are several limitations to the present study, which
used data collected routinely for clinical care. By using a single
trade-named product (Forlax) as an indicator of PEG 4000 use,
the utilization of PEG 4000 laxatives in children may have been
underestimated. Clinical opinion indicated that most children
were given this product as the preferred PEG 4000 during the
years of the study. However, this study did not have independent
prescription or sales data to verify this assumption. Also, other
PEGs such as PEG 4000 with electrolytes, and PEG 3350 with
and without electrolytes would underestimate the degree of use
of PEG laxatives for constipation in children, as represented
by a single trade-named prescription product. Other non-PEG
laxatives were also not included and will likewise be a source
of underestimation of laxative use. Nonetheless, the absolute
utilization rates and trends for the particular PEG 4000 in this
study remain valid, though they may not describe the entire
picture of laxative use for constipation in France. Patient
medical records in the database refer to unique patients except
when patients move between physician practices and may be
double counted. Thus, although patients are able to change
general practitioner and pediatrician, which could result in a
loss of patients and some double counting, patient movement
among children is low. Patient movement between physicians
may pose problems for cohort analyses, but as this study used
cross-sectional analyses based on the subjects in each practice
in each year, this source of error would have been minimal
and unlikely to affect trends over time. Since data are collected
directly by the physicians and uploaded anonymously, it is not
possible to refer back to patients’ files and perform site qual-
ity control and validation of the diagnosis of constipation. The
comparable figure of 1.1% constipation (using ICD-codes and
laxative prescriptions) in a nationally representative sample of
visits to physicians in the USA indicates that the diagnosis for
constipation in this study was appropriate. However, the quality
of the information from daily clinical practice is assessed by
administrative quality indicators. This and the fact that all data,
which have already been collected without any influence from
investigators (as may occur in protocol-driven observational
studies of drug utilization), come from routine clinical practice
also lends credibility to the data. The data from pediatricians
and the 4 g dose may be subject to overfitting of the models as
there were only 3 or 4 years of data available. However, given
similar trends over a longer period of time from general prac-
titioners, the data from pediatricians are consistent and, hence,
likely to be reasonably robust. Of course, the regression models
are based on the data used and caution should be exercised in
extrapolation of these models beyond the years studied or to
other data sets. Nonetheless, they provide a comparison for
future studies of laxative utilization.
Information on the indication for the prescription was
not requested and it is assumed that most prescriptions were
for constipation. Bowel cleansing may have accounted for
a small number of prescriptions, more among pediatricians
than among general practitioners, but this is likely to be an
insignificant proportion and would have altered the results
only marginally. Furthermore, it is not likely to have affected
the observed trends over time, by age groups or gender.

Page 8

Clinical and Experimental Gastroenterology
Publish your work in this journal
Clinical and Experimental Gastroenterology is an international, peer-
reviewed, open access journal, publishing all aspects of gastroenterology
in the clinic and laboratory, including: Pathology, pathophysiology
of gastrointestinal disease; Investigation and treatment of gastointes-
tinal disease; Pharmacology of drugs used in the alimentary tract;
Submit your manuscript here: http://www.dovepress.com/clinical-and-experimental-gastroenterology-journal
Immunology/genetics/genomics related to gastrointestinal disease.
This journal is indexed on CAS. The manuscript management system
is completely online and includes a very quick and fair peer-review
system. Visit http://www.dovepress.com/testimonials.php to read real
quotes from published authors.
Clinical and Experimental Gastroenterology 2011:4
submit your manuscript | www.dovepress.com
Dovepress
Dovepress
Dovepress
188
Qizilbash and Mendez
Conclusion
This study has found large absolute levels of utilization of PEG
4000 laxatives and increasing use over time in younger and
older children, among general practitioners and pediatricians
in France. These findings may highlight an important public
health issue to address for policy makers, clinicians, and
parents. The results highlight the need for studies in other
European countries to describe patterns and trends in utilization
of different laxatives. Further research should be encouraged in
this relatively neglected area to evaluate whether the prescribing
is based on evidence-based guidelines,21 given that general
practitioners are prescribing PEG laxatives for constipation
more than previously, and whether outcomes have improved.
Contributors
NQ designed and supervised the study, revised the analyses,
and drafted and revised the manuscript. IM conducted the
statistical analysis and revised the manuscript. The LPD
data were provided by Cegedim Strategic Data, the database
provider in France.
NQ is the guarantor of the study.
Acknowledgment
Thanks are owed to Daniel Prieto at Casen-Fleet SLU Labo-
ratories for commissioning the study and its publication.
Disclosure
The study was financed by Casen-Fleet SLU Laboratories,
Madrid, Spain. NQ heads OXON Epidemiology, which
is a contract research organization that conducts research
for health sector companies. IM is an employee of OXON
Epidemiology. Casen-Fleet SLU Laboratories are developing
a PEG 4000 laxative.
References
1. Peppas G, Alexiou VG, Mourtzoukou E, Falagas ME. Epidemiology
of constipation in Europe and Oceania: a systematic review. BMC
Gastroenterol. 2008;8:5.
2. Van den Berg MM, Benninga MA, Di Lorenzo C. Epidemiology of
childhood constipation: a systematic review. Am J Gastroenterol. 2006;
101(10):2401–2409.
3. Trinkley KE, Porter K, Nahata MC. Prescribing patterns for the out-
patient treatment of constipation in the United States. Dig Dis Sci.
2010;55(12):3514–3520.
4. Van Ginkel R, Reitsma JB, Buller HA, van Wijk MP, Taminiau JA,
Benninga MA. Childhood constipation: longitudinal follow-up beyond
puberty. Gastroenterology. 2003;125(2):357–363.
5. Mousa HM, van den Berg MM, Caniano DA, Hogan M, Di Lorenzo C,
Hayes J. Cecostomy in children with defecation disorders. Dig Dis Sci.
2006;51(1):154–160.
6. Youssef NN, Langseder AL, Verga BJ, Mones RL, Rosh JR. Chronic
childhood constipation is associated with impaired quality of life: a case-
controlled study. J Pediatr Gastroenterol Nutr. 2005;41(1):56–60.
7. Johanson JF, Sonnenberg A, Koch TR. Clinical epidemiology of chronic
constipation. J Clin Gastroenterol. 1989;11(5):525–536.
8. Locke GR III, Pemberton JH, Phillips SF. AGA technical review on
constipation. Gastroenterology. 2000;119(6):1766–1778.
9. Higgins PDR, Johanson JF. Epidemiology of constipation in North
America: a systematic review. Am J Gastroenterol. 2004;99(4):
750–759.
10. Talley NJ. Definitions, epidemiology, and impact of chronic
constipation. Rev Gastroenterol Disord. 2004;4(Suppl 2):S3–S10.
11. Brandt LJ, Prather CM, Quigley EMM, Schiller LR, Schoenfeld P,
Talley NJ. Systematic review on the management of chronic constipation
in North America. Am J Gastroenterol. 2005;100(Suppl 1):S5–S21.
12. Curtin F, Morabia A, Bernstein M, Dederding J-P. A population
survey of bowel habits in urban Swiss men. Eur J Pub Health. 1998;8:
170–175.
13. Drossman DA, Sandler RS, McKee DC, Lovitz AJ. Bowel patterns
among subjects not seeking health care. Use of a questionnaire to
identify a population with bowel dysfunction. Gastroenterology. 1982;
83(3):529–534.
14. Ho KY, Kang JY, Seo A. Prevalence of gastrointestinal symptoms in
a multiracial Asian population, with particular reference to reflux-type
symptoms. Am J Gastroenterol. 1998;93(10):1816–1822.
15. Wald A, Scarpignato C, Mueller-Lissner S, et al. A multinational survey
of prevalence and patterns of laxative use among adults with self-defined
constipation. Aliment Pharmacol Ther. 2008;28(7):917–930.
16. Liem O, Harman J, Benninga M, Kelleher K, Mousa H, Di Lorenzo C.
Health utilization and cost impact of childhood constipation in the
United States. J Pediatr. 2009;154(2):258–262.
17. Ekins-Daukes S, Helms PJ, Simpson CR, Taylor MW, McLay JS. Off-
label prescribing to children in primary care: retrospective observational
study. Eur J Clin Pharmacol. 2004;60:349–353.
18. AFSSAPS. [Summary of Product Characteristics for Forlax© 10 g.]
[French.] Paris: AFSSAPS; 2010 [updated Oct 22 2010]. Available
from http://afssaps prd.afssaps.fr/php/ecodex/frames.php?specid=69
298346&typedoc=R&ref=R0180198htm. Accessed March 21, 2011.
19. AFSSAPS. [Summary of Product Characteristics for Forlax© 4 g.]
[French.] Paris: AFSSAPS; 2010 [updated Oct 22 2010]. Available
from http://afssapsprd.afssaps.fr/php/ecodex/frames.php?specid=691
98794&typedoc=R&ref=R0180199.htm. Accessed March 21, 2011.
20. Dupont C, Leluyer B, Maamri N, et al. Double-blind randomized
evaluation of clinical and biological tolerance of polyethylene glycol
4000 versus lactulose in constipated children. J Pediatr Gastroenterol
Nutr. 2005;41(5):625–633.
21. Constipation Guideline Committee of the North American Society for
Pediatric Gastroenterology. Evaluation and treatment of constipation in
infants and children: recommendations of the North American Society
for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr
Gastroenterol Nutr. 2006;43(3):e1–e13.