blood pressure and turner syndrome

Clinical Endocrinology (2000) 52, 363±370

363q 2000 Blackwell Science Ltd

Blood pressure and Turner syndrome

N. C. Nathwani*, R. Unwin,² C. G. D. Brook* and

P. C. Hindmarsh*

*The London Centre for Paediatric Endocrinology and

²Institute of Urology and Nephrology, University College

London, London, UK

(Received 26 July 1999; returned for revision 31 August 1999;

®nally revised 20 October 1999; accepted 10 January 2000)

Summary

INTRODUCTION Elevated blood pressure (BP) is an

important predictor of morbidity and mortality from

cardiovascular disease. Patients with Turner syn-

drome (TS) have a higher morbidity and mortality in

middle age than the normal population. As BP in

childhood or early adulthood is predictive of BP

later in adult life, we assessed manual and 24 h ambu-

latory BP in patients with TS to determine whether the

BP pattern is altered at an early stage in these patients

who are known to be at risk of cardiovascular disease.

PATIENTS AND METHODS We studied manual and

24 h ambulatory BP pro®les in 75 girls with Turner

syndrome, age range 5´4±22´4 years. A monitor with

an oscillometric device (SpaceLabs model 90207) and

an appropriate sized cuff was used. BP was measured

during the day-time (0800±2000 h) and the night-time

periods (2200±0800 h). The BP measured were com-

pared with population standards. The effect of differ-

ent growth promoting agents on BP was also

evaluated.

RESULTS Mean manual and 24 h ambulatory BP mea-

surements were 118/77 mmHg (range 95/60±140/102)

and 115/70 mmHg (range 93/57±154/99), respectively.

There was minimal difference between the two meth-

ods with a positive bias of 2´4 mmHg for diastolic BP

and a negative bias of 2´1 mmHg for systolic BP. The

mean standard deviation scores (SDS) corresponding

to the mean BP recordings were 24 h systolic � 0´81

(range ÿ 1´26 to � 4´45), 24 h diastolic � 0´43 (range

ÿ 0´85 to � 3´42), day-time systolic � 1´08 (rangeÿ 0´95

to � 4´72), day-time diastolic � 0´70 (range ÿ 0´94 to

� 3´71), night-time systolic � 0´22 (range ÿ2´2 to

� 3´64) and night-time diastolic ÿ 0´18 (range ÿ2´0

to � 2´43). The SDS for both the mean 24 h and

day-time systolic and diastolic BP were shifted to the

right of the normal distribution. 57% of the girls had

less than the normal 10% reduction in nocturnal sys-

tolic blood pressure. 17% had diastolic and 21% had

systolic blood pressure above the 95th percentile for

age and sex. There was no signi®cant difference in the

BP SDS between girls on no treatment and those

receiving treatment.

CONCLUSION Over 50% of girls with Turner syn-

drome have an abnormal BP circadian rhythm,

which is similar to adult patients with secondary

hypertension. Patients with Turner syndrome have

higher blood pressure measurements compared to

published population standards, as evidenced by

the shift to the right of both the systolic and diastolic

BP SDS. These ®ndings suggest that girls with Turner

syndrome should be carefully monitored in childhood

and adulthood for blood pressure and other cardio-

vascular risk factors.

Elevated arterial blood pressure, or hypertension affects 15±

20% of the adult population in industrialized societies. It is an

independent risk factor for cardiovascular disease, cerebrovas-

cular accident and end organ damage (Stamler 1991; Stamler et

al., 1989; MacMahon et al., 1990). A reduction in hyperten-

sion-associated morbidity and mortality correlates with early

treatment and reduction in blood pressure in adults with mild to

severe hypertension (Moser & Gifford, 1985; Grimm et al.,

1987; Maxwell, 1988).

The 1987 report of the Task Force on Blood Pressure Control

in Children (Task Force on Blood Pressure Control in Children,

1987) provides blood pressure distribution curves and guide-

lines for the evaluation of high blood pressure in the paediatric

population. Primary hypertension, which makes up 90% of the

hypertension diagnosed in adults, is rarely found in children,

when using the criteria for the diagnosis of hypertension in

adults. The First Task Force Report introduced the idea of blood

pressure rank and suggested that high blood pressure levels in

children were those above the 95th percentile for age and sex

according to the values presented in nomograms (Task Force on

Blood Pressure Control in Children., 1987).

Clinical studies have generally shown that among children

under the age of 13 years referred for the evaluation of

hypertension, secondary hypertension (usually related to renal

pathology) is more common than primary hypertension, but this

quickly reverses in adolescence (McCrory, 1992). However, it is

Correspondence: Dr N.C. Nathwani, Cobbold Laboratories, The

Middlesex Hospital, Mortimer Street, London W1N 8AA, UK.

Fax:� 44 (0)171 636 9941; E-mail: [email protected]

generally felt that primary hypertension in adults, has its origin

in childhood. Blood pressure tracking studies infer that a child

with elevated blood pressure will continue to have elevated

blood pressure as an adult (Lauer et al., 1984, 1991, 1993;

Shear et al., 1986; Julius et al., 1990; Nelson et al., 1992).

Measurement of casual blood pressure with a mercury

sphygmomanometer has been the gold standard for the

diagnosis and treatment of hypertension. Several problems,

are associated with the use of a sphygmomanometer such as

imprecision, observer errors and bias and `white-coat hyper-

tension'. Clinic pressures may not re¯ect the `true' blood

pressure in an individual and therefore may not be an ideal

method for diagnosing hypertension and for predicting its

clinical outcome.

Ambulatory 24 h blood pressure monitoring (ABPM) is now

used frequently in both the adult and paediatric population.

ABPM has indicated that the normal circadian rhythm of blood

pressure may differ in hypertensive patients, some maintaining

the normal variability (Kastrup et al., 1993) and others having

a decreased or total loss of the normal night-time fall in blood

pressure (`non-dipper') (Pickering et al., 1982). Patients who

are `non-dippers' have a higher incidence of secondary

hypertension and are at a higher risk of end-organ damage

(Devereux et al., 1983; Verdecchia et al., 1990; Coca, 1994;

Middeke & Schrader, 1994).

Turner syndrome (TS) is one of the most common

chromosomal abnormalities with an incidence of 1 in 2500

live female births. The phenotypic manifestations are varied

and encompass a wide variety of organ systems. It is

characterized by short stature and gonadal dysgenesis but is

also associated with a number of congenital abnormalities

including cardiovascular malformations (Miller et al., 1983;

Allen et al., 1986; Lin et al., 1986) and renal abnormalities

(Reveno & Palubinskas, 1966; Matthies et al., 1971; Litvak et

al., 1978).

A survey of morbidity and mortality in patients with TS

identi®ed by a chromosomal defect register found that

cardiovascular diseases, congenital or acquired, were the

single highest cause of death (Price et al., 1986; Gravholt et

al., 1998). Hypertension has been described with increased

frequency in patients with TS (Strader et al., 1971; Virdis et al.,

1986) even in the absence of aortic coarctation and obvious

structural renal abnormalities or history of repeated urinary

infections (Nivelon et al., 1970; Swinford & Ingel®nger, 1999).

To date no study has been performed to evaluate the prevalence

of high blood pressure and hypertension in TS.

This study was undertaken to evaluate the prevalence of

hypertension in patients with TS and to establish the blood

pressure circadian rhythm. The effects on BP of the various

therapeutic modalities commonly used in the treatment of these

patients were also evaluated.

Methods and patients

Patients

75 girls with Turner syndrome (age range 5´4±22´4 years) who

attended endocrine clinics at the London Centre for Paediatric

Endocrinology were studied. The clinical diagnosis of Turner

syndrome was con®rmed by karyotype analysis in all cases.

Referral was made to the unit for assessment of short stature or

pubertal delay. None had been referred with a history of

hypertension. A detailed family history was taken extending

back two generations. Of the 75 patients 33 were found to have

a positive family history of cardiovascular disease or diabetes

mellitus.

Height was measured using a Harpenden stadiometer

(Holtain Ltd, Crymmych, Pembs UK.) and weight using

electronic scales (Weylix, model 824/890). The coef®cient of

variation for height measurements was 0´1% at 100 cm. Body

mass index (BMI) was calculated as weight(kg)/height(m)2.

BMI measures were expressed as standard deviation scores

(SDS) using the 1990 British standards (Freeman et al., 1995).

Birth weight was recorded from maternal recall.

Study design

The study was cross sectional in nature and included patients

who were receiving growth promoting agents for the manage-

ment of short stature and/or oestrogen � progesterone for

pubertal induction due to ovarian failure associated with TS.

The patients were divided into three groups:

X Group 1 ÿ No treatment (n� 29);

X Group 2ÿRecombinant human growth hormone (rhGH)

alone (30 IU/m2/wk) with or without oxandrolone

(0´0625 mg/day) (n� 24);

X Group 3ÿDaily oestrogen therapy (starting at 2 micrograms

increasing to 5, 10 & 20 mg every 6 months) with or without

rhGH (30 IU/m2/wk) and oxandrolone (0´0625 mg/day)

(n� 22). Progesterone treatment was started once oestrogen

treatment reached a dose of 15 micrograms/day.

Blood pressure measures

All clinical evaluation was conducted in hospital. Free exercise

was allowed within the constrains of the hospital admission. As

part of the initial evaluation all the patients also had

echocardiography and renal imaging (renal ultrasonography).

Manual single BP measurement. A standard mercury sphyg-

momanometer that had been calibrated by the hospital

biomedical instrumentation department was used to measure

blood pressure in all the patients at the beginning and the end of

the test period. The patients were asked to sit comfortably and

364 N. Nathwani et al.

q 2000 Blackwell Science Ltd, Clinical Endocrinology, 52, 363±370

relax; blood pressure was then measured using the right arm.

An appropriate sized cuff (one which extended completely

around the arm with a bladder width that covered at least two-

thirds of the upper arm) was used. Phase 1 of the Korotkoff

sounds corresponded to the systolic BP and the diastolic BP was

assessed as phase IV in patients under 12 years of age and phase

V in children over 12 years of age. An average of two

recordings was used as a measure of the manual BP for data

analysis.

24 h Ambulatory BP monitoring. A SpaceLabs model 90207

monitor (SpaceLabs, Inc., Redmond, Washington, USA)

weighing 340 g (including batteries) was used. This device

employs an oscillometric method for determining BP, with a

de¯ation rate of 8 mmHg/s. An appropriate size cuff (see above)

was placed on the right arm of the patient. The accuracy of the

monitor was tested in each subject under resting conditions at

the beginning and at the end of the test period. For this a T tube

was used to connect the ambulatory monitor to the mercury

sphygmomanometer tubing and the blood pressure was

measured. We calculated the difference between the manual

BP and the average of the ®rst measurements taken by the

monitor. The mean of the average of the casual BP minus

monitor BP was 9´3 6 1´28 mmHg for systolic BP and 8´85 6

1´22 mmHg for diastolic BP.

ABPM was performed over a 24-h period. The subjects were

ask to continue normal activity but advised against excessively

vigorous physical exercise. The recording frequency was

programmed for every 20 mins from 0800 to 2200 h and

every 30 mins from 2200 to 0800 h. If there was an interference

or error in the reading the process was automatically repeated

after 2 mins while retaining the pre-established sequence.

During the day-time period (0700±2200 h) an acoustic signal

before the measurement was automatically programmed to

remind the subject to relax the arm.

Blood pressure results are presented as raw data and as

Standard Deviation Scores (SDS) using the Task Force

Standards. The use of SDS allows for a comparison to be

made of the subjects at different ages.

The studies were approved by the ethical committee of the

University College London Hospital NHS Trust and informed

consent was obtained from the parents and patients on each

occasion.

Analysis of blood pressure data

24 h-ABPM measurements were rejected automatically or after

visual inspection if the systolic BP (SBP) was > 220 or

< 70 mmHg and diastolic BP (DPB) was > 140 or < 40 mmHg,

the DBP was greater than SBP, or the reading was higher than

double the previous or subsequent readings. These readings

were considered to be erroneous. Recordings in which > 30% of

the measurements were erroneous were excluded from the

analysis.

The 24 h mean values for blood pressure were calculated

and in addition day-time and night-time means were also

obtained. To rule out bias by individually different rest habits

we chose to analyse our data for standardized day-time (8am

to 8 pm) and night-time (midnight to 6 am) periods. For each

subject we calculated total number of readings, mean SBP,

DBP during the 24 h, day-time and night-time periods. To

evaluate the circadian variability, the night-time mean (mid-

night to 6am) was compared with the day-time mean (8am to

8 pm) and the difference expressed as percentage of the day-

time mean.

The Task Force de®nition of normal or high blood pressure

was used to categorize the patients (Task Force on Blood

Pressure Control in Children, 1987); normal BP ÿ systolic and

diastolic BP below the 90th percentile, borderline BP ÿ systolic

and diastolic BP between the 90th to 95th percentile and

hypertension ÿ systolic and diastolic BP greater than the 95th

percentile for age and sex.

Statistics

One-way analysis of variance (ANOVA) with the Student

Newman-Keuls post hoc test was used to compare the means

of three treatment groups.

We analysed the degree of agreement of the two methods of

blood pressure recording used in our patients, i.e. manual and

24 h ambulatory recordings, using the method of Bland &

Altman (1986).

The mean difference gives an estimate of the average bias of

one method vs. another, in this case manual BP vs. 24 h-ABPM

measurements. The 95% limits of agreement (2 X SD of the

difference) give an idea of the range of values covering the

agreement.

Results

Anthropometric measures

Comparison of the clinical data, manual and 24 h-ABPM for the

patients are presented in Tables 1 and 2, No signi®cant

differences in birth weight were found between the groups,

although the mean values were less than that of the UK popu-

lation (�2´7 mean and 0´62 SD; Freeman et al., 1995). Patients

on rhGH and oestrogen 6 rhGH were signi®cantly older and

therefore taller and heavier as re¯ected by the signi®cantly

different BMI (ANOVA, F� 7´29, P� 0´045) compared to

patients on no treatment (Group 1), but there was no signi®cant

difference in the BMISDS between the three groups.

Blood pressure and Turner syndrome 365


Difference between manual and ambulatory blood

pressure recordings

When the difference between manual and 24 h ambulatory

blood pressure (manual ÿ mean 24 h-ABPM) was plotted

against the average of the two measurements, the data were

distributed around zero. The bias of one method relative to the

other for diastolic BP was� 2´4 mmHg and for systolic BP

ÿ2´4 mmHg. The 95% limits of agreement were 6 18´7 mmHg

and 6 21´1 mmHg, respectively.

Blood pressure and anthropometric measures

There was no relationship between the mean day-time systolic

and diastolic BPSDS and birth weight (r� 0´066, for systolic,

P > 0´05 and r� 0´013, P> 0´05, for diastolic). In comparison

BMI in¯uences both systolic and diastolic BP, the in¯uence

was more on mean systolic blood pressure (r� 0´424,

P� 0´047, BMI) than mean diastolic blood pressure(r� 0´211,

P > 0´05, BMI). In both the in¯uence is reduced when the

differing age of the three groups is taken into account, using

BMISDS (r� 0´320, P� 0´004, systolic & r� 0´147, P > 0´05,

diastolic)

Relationship of blood pressure in Turner syndrome and

age percentiles

Figure 1(a±d) represent the mean day-time systolic and

diastolic blood pressure recorded by 24 h-ABPM plotted on

age-speci®c means and percentiles of systolic and diastolic

blood pressure measurements (adapted from The report of the

second task force report on blood pressure control in children).

Twenty-®ve percent of the patients had mean manual day-time

diastolic and 16 percent had mean manual day-time systolic BP

above the 95th percentile, for age and sex. Seventeen percent

had mean day-time 24 h-ABPM diastolic BP and 21 percent had

mean day-time 24 h-ABPM systolic BP above the 95th

percentile, for age and sex, i.e. hypertensive (Table 3).

Figure 1(a) to 1(d) depict the distribution of mean blood

pressure recorded by 24 h-ABPM compared to Task Force age-

speci®c percentiles (1a to 1d), and expressed as SDS (Fig. 2a,b)



Table 1 Anthropometric data of the study population

Group 1 Group 2 Group 3 ANOVA

(n� 29) (n� 23) (n� 22) P-value

Age (years) 10´6 (5´45±22´33) *13´06 (8´76±16´63) *16´53 (12´94±21´84) < 0´001

Birth weight (kg) 2´66 (1´32±3´7) 2´65 (1´0±3´7) 2´89 (2´15±4´1) 0´348

Weight (kg) 31´32 (13´0±53´0) *43´62 (21´0±73´0) *52´13 (37´0±64´0) < 0´001

Height (m) 1´24 (0´97±1´49) *1´40 (1´17±1´53) *1´48 (1´42±1´58) < 0´001

BMI (kg/m2) 19´4 (14´0±33´0) *21´8 (14´0±33´0) *23´8 (7´0±31´0) 0´001

BMISDS 0´51 (ÿ 1´08±3´34) 0´86 (ÿ 1´33±2´95) 0´90 (ÿ 1´08±2´61) 0´451

Results shown as medians,(range) * P< 0´05 Student Newman±Keuls test

Table 2 Blood pressure expressed as standard deviation scores

ANOVA

Group 1 Group 2 Group 3 P-value

Manual systolic BP SDS 1´17 (1´21) 0´96 (0´89) 1´23 (0´9) 0´71

Manual diastolic BP SDS 1´22 (1´29) 1´0 (0´9) 1´06 (0´73) 0´76

Mean 24 h systolic BP SDS 0´90 (1´18) 0´65 (0´62) 0´87 (0´69) 0´56

Mean 24 h diastolic BP SDS 0´55 (1´0) 0´23 (0´64) 0´49 (0´53) 0´3

Mean day-time systolic BP SDS 1´14 (1´21) 0´94 (0´68) 1´15 (0´71) 0´67

Mean day-time diastolic BP SDS 0´80 (1´02) 0´52 (0´7) 0´76 (0´51) 0´41

Mean night-time systolic BP SDS 0´38 (1´17) 1´3 (0´56) 0´23 (0´73) 0´34

Mean night time diastolic BP SDS 1´70 (1´0) ± 0´46 (0´68) ± 0´13 (0´72) 0´12

Nocturnal drop in systolic BP (% fall) 8 10 12 0´063

Nocturnal drop in diastolic BP (% fall) 13 16 16 0´15

Results shown as SDS of mean (sd) blood pressure recorded

to allow for the varying age ranges of the study population.

Standard deviation scores for both systolic and diastolic BP

were signi®cantly shifted positively to the right (Skewness

�1´096 diastolic BP; �1´018 systolic BP).

Blood pressure circadian rhythm

In the general population night-time systolic and diastolic blood

pressure falls by at least 10% compared to the day-time values.

We found in this study that patients with Turner syndrome had

an abnormal blood pressure circadian rhythm. The night-time

fall in both systolic and diastolic blood pressure was blunted in

57% of the patients.

Blood pressure measurements and growth and pubertal

therapy

The results of the manual and 24 h-ABPM results are presented

in Table 2. No signi®cant difference was observed between the

three groups. A normal blood pressure circadian rhythm would

be a re¯ected by at least a 10% fall in the night-time blood

pressure readings compared to the day-time readings. We found



95th90th

75th

50th

150

140

130

120

110

100

90

1 2 3 4 5 6 7 8 9 10 11 12 13

Sys

tolic

BP

(m

mH

g)

(a)

95th90th

75th

50th

155

145

135

125

115

10513 14 15 16 17 18

(b)

95th90th

75th

50th

100

90

80

70

60

50

1 2 3 4 5 6 7 8 9 10 11 12 13

Dia

sto

lic B

P (

mm

Hg

)

(c)

95th

90th

75th

50th

90

80

70

6013 14 15 16 17 18

(d)

Age (Years)

Fig. 1 Distribution of mean day-time blood pressure recorded by 24 h ambulatory BP monitoring compared to Report of the Second Task Force

on blood pressure control in children, age-speci®c percentiles. a, systolic BP 1±13 years; b, systolic BP 13ÿ18 years; c, diastolic BP 1±13 years;

d, diastolic BP 13±8 years. W group 1, no treatment; X group 2, Growth hormone; B group 3, oestrogen 6 growth hormone.

that patients on oestrogen therapy had a better fall in the night-

time blood pressure (12%) compared to patients on no

treatment and growth hormone treatment (8% and 9%), this

was not statistically signi®cant (P� 0´06).

Blood pressure and family history

Forty-four percent (33/75) of the patients had a positive family

history for cardiovascular disease or diabetes mellitus. We

compared the blood pressure recordings and SDS values for

day-time systolic and diastolic blood pressure, in patients with

and without a positive family history of cardiovascular disease

and diabetes mellitus. No signi®cant difference in the blood

pressure recordings was found (P> 0´05).

Discussion

Patients with Turner syndrome are known to be at risk of

hypertension (Nivelon et al., 1970; Hall, 1990). In this study we

found that, 17 percent (13/75) had mean day-time 24 h-ABPM

diastolic BP and 21 percent (16/75)had mean day-time 24 h-

ABPM systolic BP above the 95th percentile, for age and sex.

Using the task force de®nition these patients would be de®ned

as being hypertensive.

The importance of blood pressure control in the adult

population has been appreciated for many years and although

the prevalence of hypertension in children/adolescents is

signi®cantly lower than adults, 1´1% (Fixler & Laird, 1983;

Sinaiko et al., 1989), it is not rare and may well be under

reported, as suggested by the ®ndings of the present study.

This study clearly demonstrates that patients with TS have

early detectable mild hypertension both on manual and

ambulatory blood pressure recordings. The 24 h BP pattern

observed in over 50% of our patients could suggest that the

hypertension may have an underlying cause (Baumgart et al.,

1989; Coca, 1994), and is suggestive of an increased incidence

of end-organ damage (Perloff et al., 1989; Verdecchia et al.,

1990) These patients as part of the syndrome have involvement

of many organ systems including the cardiovascular and renal

systems. This combined with the other know associations such

as lymphoedema, obesity, hyperinsulinaemia, raised plasma

renin activity and growth hormone, may be enough to explain

the raised blood pressure levels found in these patients.

The commonest cause of drug induced hypertension in

normal healthy women is still the combined oral hormonal

contraceptive (McAreavey et al., 1983; Weir & Weinberger,

1992). With this the rise in blood pressure is generally found in

women who have a genetic or environmental predisposition to

essential hypertension but in some alterations in the renin-

angiotensin system may also play a role. Due to the gonadal

dysgenesis, TS patients need life long oestrogen replacement,

although this is more as hormone replacement therapy, the

commonest preparations still used are those used for contra-

ception, i.e. the combined oral contraceptives, in healthy

normal women. In this study TS patients on oestrogen therapy

had no signi®cant difference in mean manual and 24 h blood

pressure recordings compared to the other groups. Therefore

oestrogen therapy alone cannot explain the BP rise observed

in TS patients, but we do suggest that careful monitoring of

BP in these patients during pubertal induction is required.



Table 3 Distribution of manual and 24 h ambulatory blood pressure

measurements

Blood pressure measurements

90±95th percentile > 95th percentile

Mean manual diastolic BP 11% 25%

Mean manual systolic BP 21% 16%

Mean 24 h diastolic ABPM 8% 17%

Mean 24 h systolic ABPM 17% 21%

Nu

mb

er

30

20

10

0–1 0 1 2 3 4

(a)

16

12

8

4

0–1 –0.5 0 0.5 1 1.5 2 2.5 3 3.5

SDS

(b)

Fig. 2 Systolic and diastolic BP expressed as standard deviation

scores. a, systolic BPSDS; b, diastolic BPSDS.

Consideration also needs to be given to the use, particularly in

the long term, of alternative modes of oestrogen therapy.

An association between birth weight and subsequent elevated

blood pressure has been suggested by many studies (Launer et

al., 1993; Law & Barker, 1994). It is hypothesized that the

setting of blood pressure in-utero determines blood pressure in

adult life and that retarded intrauterine growth leads to adult

hypertension. In this study no clear relationship between blood

pressure and birth weight was observed but this may be a

re¯ection of the small sample size and small range of the

sample birth weights.

In general, secondary causes for hypertension become less

frequent in late childhood and early adolescents as more children

are recognized as having early mild primary hypertension. Blood

pressure tracking studies suggest that primary hypertension in

adults has its origins in childhood and that children/adolescents

with high blood pressure will continue to exhibit raised blood

pressure in adulthood (Lauer et al., 1984, 1991, 1993; Shear et al.,

1986; Julius et al., 1990; Nelson et al., 1992).

It may be that the mild hypertension observed in these

patients is primary and therefore heterogeneous with a multi-

factorial aetiology. In view of our ®ndings we would

recommend that these patients, who are at an increased risk

of morbidity and mortality, are monitored closely for

hypertension not only in childhood but also in adulthood. If

hypertension is present the various organ systems that may be

involved as part of the syndrome should be investigated to rule

out an underlying aetiology for the hypertension.

Acknowledgements

This study was supported by North East Thames Regional

Health Authority. We are greatly indebted to the children and

parents who participated so willingly in this study.

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