Medium and long-term growth in children receiving intranasal beclomethasone dipropionate: A clinical experience.

ABSTRACT

Background. A 12-month controlled pediatric study of intranasal beclomethasone dipropionate (BDP) reported a 0.9 cm decrease in annual height growth velocity. Since children with allergic rhinitis may be treated for years, this report evaluates long-term height growth effects.

Methods. We reviewed the clinical charts of children with allergic rhinitis who were treated for the first time with intranasal BDP and were less than 10 years of age at initiation. Height was determined by stadiometry before intranasal corticosteroid therapy and compared with height at a final visit.

Results. Sixty children aged 24 to 117 months (mean age, 70 months) were treated for an average of 36 months. The pretherapy height percentile was 44.6, which increased to the 52.2 percentile at the final visit.

Conclusions. Long-term clinical use of intranasal BDP in children was not associated with decreased height growth. This outcome may reflect decreased long-term compliance compared with a short-term study. However, the treatment remained effective. Some children may he at special risk. Careful height measurements are recommended every 6 months.

INITIALLY, available evidence indicated that use of beclomethasone dipropionate (BDP), 336 mg/day or less, to treat children with asthma avoided the side effects of systemic cortico-steroids, including inhibition of growth. (1-1) Five studies done within the past decade have challenged this assumption. Four double-blind, placebo-controlled studies of inhaled BDP and one study of intranasal BDP at 332 mg daily reported decreased annual height growth velocity in BDP-treated children compared with the children who did not receive BDP. (5-9) Each of these studies encompassed a year of observation, with 6 to 12 months of treatment. The loss in annual height velocity was between 0.8 and 1.8 cm per year.

In a 12-month placebo-controlled, double-blind study in which treated children received 168 mg of beclomethasone delivered twice daily, Skonner et al (10) observed rapid onset of a decrease in height velocity in the beclomethasone-treated group compared with the placebo group. This difference was maintained throughout the entire 12-month period of observation, so that by the end of the year the children treated with beclomethasone had grown by 5 cm and the control group by. an average of 5.9 cm. One has to view this suggestion with caution, since almost 30% of the placebo group had dropped out compared with a little more than 10% of the treatment group, which may have caused some bias in results.

In all studies cited, observation was stopped at 12 months, with a significant amount of conjecture about long-term outcomes. Published studies of longer use of BDP for asthma at a dose of 332 mg/day or less have stated there was no growth inhibition. [1-4] We found no similar observations on the medium to long-term growth effects of intranasal beclomethasone or other intranasal corticosteroid.

The Food and Drug Administration has changed the product labeling of all inhaled and intranasal corticosteroids to "possibly causing growth inhibition." (11) With current lack of long-term follow-up data on children in the previous double-blind investigations and because of the raised concerns, we chose to review our clinical experience in children with allergic rhinitis treated with intranasal BDP for longer than 12 months.

MATERIALS AND METHODS

The records of children aged 2 to 10 years with the diagnosis of allergic rhinitis were reviewed. Those who had concomitant asthma or allergic dermatitis and those who had previously used systemic or topical corticosteroids were excluded from the study. The study group had perennial symptoms with seasonal exacerbations, as is typical in this region of the United States. Because outdoor allergens are present almost year around, perennial symptoms may occur either from indoor or outdoor exposures. Patients were tested by prick-puncture skin testing and had positive responses to the relevant airborne allergens.

Because of the severity of the symptoms (Table 1), therapy had been initiated with intranasal BDP aqueous, 168 [micro] twice daily. Also, the duration of BDP therapy had to be 12 months or more, with at least two height measurements annually after initiation of the BDP therapy.

We did not have pretherapy height determinations before the initial visits and chose to use the percentiles for height growth from a normal population as the control. (12) The height percentile at initiation of therapy was compared with the height percentile at the final recorded visit, or when BDP therapy was discontinued.

From 1994 on, the height of the children was measured by a stadiometer (Accustat). Previously, a standard physician's scale height rod had been used. With the stadiometer, height was measured to the nearest 1/8 inch for clinical use. Measurements were done at various times of the day (at appointment time) and were not controlled for diurnal effects on height. Of the paired measurements, 42 pairs were done at the same time of day plus or minus 2 hours. In 13 pairs, the first measurement was at 9:30 AM [+ or -] 1 hour, the second in the afternoon at 2:30 PM [+ or -] 90 minutes. Five of the pairs had an initial measurement at 12:30 PM or 1:30 PM, and the second at 9:30 AM [+ or -] 90 minutes.

The children were not restricted from other therapies for allergic rhinitis to include avoidance, oral antihistamines or decongestants, and immunotherapy.

Statistical comparisons were done by t test for parametric data or the Wilcoxon's signed rank test for data not distributed normally. A least squares regression line was constructed using the beginning and final height percentiles for the groups.

Mean height velocities for the groups were calculated by converting the percentile to absolute measurements in centimeters, subtracting the beginning height (BH) from the final height (FH), dividing by the months of treatment (M), and then annualizing the data by multiplying by 12:

Annual Height Velocity = FR - BR/M x 12

The predicted height velocities for the groups were calculated by taking the mean age and mean percentile at the initial visit and at the final visit and converting to centimeters (ie, FMH = calculated final height based on mean percentile at initial visit and mean age at final visit):

Predicted Height Velocity = FMH - BH/M X 12

RESULTS

Sixty children (40 boys and 20 girls) met the inclusion criteria. Their mean age was 70 months (range, 24 to 117 months). Duration of treatment averaged 36 months (range, 12 to 91 months). The median dosing of intranasal BDP was 168 [micro]g twice daily, with occasional dosing of 168 [micro] once daily.

Review of the clinical charts suggested the children had achieved significant relief of nasal signs and symptoms. Children who had not benefited were switched to alternate therapies and are not included in this report. They used the BDP for shorter periods (2 weeks to 3 months).

Height Growth

The mean height percentile on entry was 44.6 and increased to 52.2 at the final visit (P = .0006) (Fig 1). The 20 female patients began treatment with intranasal BDP at a mean age of 75.4 months, with a mean age of 105 months at the final visit. Beginning mean height percentile was 47, which increased to 57.9 (P = .007) (Fig 2). For the 40 male patients (mean age at entry, 67.2 months; mean final age, 105 months), the initial mean height percentile was 44.4, and the final mean height percentile was 49.5 (P = .02) (Fig 3).

Each Figure displays the scatter of the individuals within the groups described, and the least squares regression line for the height percentiles at the first and the final visit.

Effect of Age at Initiation of Therapy

Twenty-two children (14 boys, 8 girls) started intranasal BDP therapy before 60 months of age (mean age, 39.8 months). Pretherapy mean height percentile was 47. Final mean height percentile was 49.6 after an average treatment time of 34 months (not statistically significant).

In the 38 children (25 boys, 13 girls) who began therapy after age 5 years (mean age, 87.3 months), the pretherapy mean height percentile was 43.2. The final mean height percentile was 53.9 after a mean of 37 months of therapy with intranasal BDP.

Effect of Age at Final Visit

The 29 children older than 10 years at the final visit (10 girls, 19 boys) had a pretreatment mean height percentile of 44.2, and 56.9 at the final visit (P = .0001). Their initial age was 90 months (range, 44 to 117 months) and their average treatment time was 44.6 months (range, 13 to 91 months).

The 31 children (10 boys, 21 girls) who were less than 10 years old at the final visit had a baseline mean height percentile of 45, which increased to 48 (P = .069). The age at initiation was 51 months (range, 24 to 87 months), with an average treatment time of 27 months (range, 12 to 59 months).

Duration of Therapy

Figure 4 shows the predicted mean height in centimeters, the actual mean height, and the beginning mean height for the children at various times during therapy. At no time was the actual mean height less than the predicted mean height. The greatest variation was in the group treated for the longest period (37 to 60 months), with the actual height exceeding the predicted height for each group. The baseline mean height is included because the patients comprising the group at any time point were not always the same children.

Annual Height Growth Velocity

The height growth velocity per year was calculated as described in the Materials and Methods section. These results are shown in Table 2. No further statistical analysis was applied.

Time of Day When Measured

The height percentiles for the paired measurements are shown as greater, equal, or lesser from the initial to the second measurement, according to whether the pairs were done at the same time of day, with the initial measurement in the morning and the second in the afternoon, or with the initial measurement in the afternoon followed by a morning measurement (Table 3).

DISCUSSION

Our clinical experience with the effects of intranasal BDP on children's medium to long-term height growth is what we believe is the usual situation in a clinical practice. Although our review is not a replacement for a doubleblind, placebo-controlled growth study with the criteria set forth by Allen et al (13) (Table 4), our results probably reflect the experience of most practicing allergy specialists. These results may explain why there are no previous clinical observations of growth retardation in children receiving the routine doses of intranasal BDP.

The study by Skonner et al (10) involved 12 months of nasal BDP therapy at the same dose that most of our patients had been prescribed. Monitoring of use and attention to detail are typically greater during a clinical research study than in usual clinical practice. Therefore, it is not our intent to make direct comparisons with the response to intranasal BDP in a clinical study condition. Our findings do not validate the findings of Skonner et al (10) or the results of our experience.

Skonner et al (10) reported that the difference in standing height was still increasing at the end of the study, raising the possibility that they might have seen the effect of growth inhibition persist for a longer time. There is some confusion in the literature about whether the inhibitory effects occur only in the earliest months of administration. However, even this effort is confounded by the fact that the treatment group and the placebo group were different at the study's inception. Prestudy height measurements appear to have been done with a physician's scale height rod. These measurements were used to calculate prestudy height velocities, which were actually higher than expected. The authors reported an equal daily prestudy growth rate of 0.17 to 0.18 mm in both groups. This is unexpected, since the older group of children would generally grow slower than the younger group. There were significantly more dropouts in the placebo group (14/49 or 28%) than in the BDP group (5/50 or 10%), which could have a profound influence on the results. About half of the children in each group had used corticosteroids in some form during the 12 months before the study. This previous use was associated with a slightly lower growth rate during the study, in both the placebo and the BDP group. The results would seem to suggest that even minimal steroid use has adverse effects on height growth, which are cumulative and carry over after steroid use is ended.

Our intent is not to be overly critical of the study by Skonner et al (10) but to emphasize that a double-blind, placebo-controlled study does not always obviate a large number of confounding factors, which could influence the results.

In our report, there was variation regarding the time of day when measurements were made in 18 of 60 pairs, which could affect the results. However, if anything, the biases caused by these 18 pairs was against our ultimate conclusion that no adverse growth effects occurred. Five of these 18 pairs show decreased growth percentiles (28%), versus 2 of 42 (4.5%) measured at the same time of day. Of the 5 showing a decreased percentile, 4 had their first measurement in the morning and the second in the afternoon, consistent with the recognized diurnal variation in standing height.

The patients in our clinical report were prescribed intranasal BDP at the dose of 168 [micro]g twice daily for a longer average period (30 months) than in the controlled studies. Our patients used the BDP frequently enough to obtain significant clinical improvement. In our experience, when there is significant improvement of symptoms, parents or patients will be less diligent about following a dose regimen. Compliance rates with twice daily inhaled corticosteroids have been reported to be between 60% and 70%. (14) We could not establish the degree of compliance from the records. However, we did find evidence of significant clinical improvement by history and physical examination.

In addition to the use of intranasal BDP, the children also took as needed antihistamines or decongestants, practiced avoidance measures, and in some cases received immunotherapy. This reflects the clinical goal of relief as complete as prudently possible, not simply a statistically significant change in symptom scores. Our patient outcomes and results would likely differ from those found in children using intranasal BDP as monotherapy.

It may be inappropriate to draw conclusions from studies of inhaled BDP in asthmatic children and apply them to intranasal BDP in children with allergic rhinitis. Beclomethasone dipropionate is absorbed through the nasal mucosa, but it is also rapidly cleared by nasocilliary mechanisms. Daily dosing of 336 [micro]g was not associated with significant changes in 24hour urinary cortisol levels or low-dose corticotropin (ACTH) stimulation. (14) Beclomethasone dipropionate is not converted to the active metabolite 17 BMP in the nose but is swallowed. Of the swallowed dose, about 70% to 80% is converted to the inactive metabolite 21 BMP on first pass through the liver. (15)

On the other hand, BDP in the lung is almost totally converted to 17 BMP, a biologically active metabolite. The amount of BDP reaching the lung ranges from 10% to 20% with a metered dose inhaler (MDI) to 30% to 35% with a dry powder inhaler. (16) The swallowed dose from inhaled BDP has the same fate as the BDP via the nasal route. Therefore, inhalation of BDP presents a larger systemic exposure than intranasal BDP with equivalent dosing.

The importance of these absorption, retention, and conversion differences is suggested by the fact that three of the inhaled BDP studies showing adverse growth effects used a dry powder inhaler and no mouth rinsing techniques. (6-8) These factors would lead to greater systemic exposure to 17 BMP in these studies on an equivalent dosing basis, compared with the common US practice of using an MDI with spacers and mouth rinsing.

The first report on adverse height growth effect used BDP by MDI at a daily dose of 336 [micro]g divided into four doses, with no spacers or mouth rinsing. (5) Of greater concern about this initial study is that adverse height growth effect did not occur in girls, but only in boys, and predominantly the prepubertal boys. It is difficult to comprehend a sex preference for a corticosteroid effect on growth especially in prepubescent children. We found no other work that supports this concept of sex preference.

Studies of inhaled lower dose fluticasone and budesonide did not reveal any adverse growth effects in a 1-year period.. (13,17-19) Short-term growth measured with knemometry was not affected by intranasal budesonide or mometasone. (20) A 12-month trial of intranasal mometasone did not show adverse height growth effect in treated children compared with children receiving placebo.(21)

A recent clinical report compared adult height in subjects who had been treated for asthma with BDP and subjects who had not received BDP for control of their asthma. The BDP-treated group presumably had more severe asthma as children. The adults' height in the BDP group was less than that of the non-BDP-treated asthmatics but was about that expected from adult height prediction equations. The non-BDP-treated group was significantly taller than predicted. The authors concluded that BDP may have affected growth, but they could not rule out a difference due to the severity of asthma.(22) In our review, we used growth curves based on a normal population as the comparator for expected height growth. In the clinic, these growth charts remain the standard for monitoring growth in children. If a child maintains or exceeds his percentile over time, the clinical assumption has been that growth is appropriate. The approach of using pooled data or normal growth from a large population as a control may have greater clin ical relevance than shorter studies comparing smaller numbers of different children with inherently different growth rates.

The trend toward greater than expected growth in our report was observed among older children and those with the longest treatment time. An explanation for this result may be an earlier onset of pubertal growth in the patients compared with children in the normal population used to form the growth curves. Seventy-five percent of the children were of Mexican-American background. In our experience, the growth charts are adequate to monitor prepubertal growth in Mexican-American children.

An alternate consideration is based on improved sleep patterns. For most of the patients, nasal congestion was a serious problem. They often complained of symptoms related to sleep disturbances. These include difficulty in morning awakening, feeling tired upon awakening, and daytime drowsiness. These symptoms decreased with treatment.

In children with disturbed sleep, there is less delta sleep. Delta sleep is the sleep stage during which growth hormone is secreted. Relief of upper airway obstruction has been shown to increase delta sleep and growth hormone secretion.(23) Growth hormone is the primary stimulus for growth in the prepubertal child with normal nutrition.

Reported relief of sleep disturbances has been described in adults with allergic rhinitis who were treated with intranasal corticosteroids. (24) It is our hypothesis, which will be tested, that relief of the patients' nasal congestion increased the amount of delta sleep and the secretion of growth hormone. The increase in growth hormone secretion could offset any adverse effects of the small amount of systemically absorbed corticosteroid on height growth.

In summary, a medium to long-term clinical experience in prepubertal children treated with intranasal BDP at 336 [micro]g daily showed no adverse effects on height growth. We propose as a hypothesis that relief of nasal congestion, leading to improved sleep patterns, may increase growth hormone secretions and militate against the adverse effects of the systemically absorbed corticosteroid at this dose.

Nevertheless, it remains our opinion that careful measurements using a stadiometer, at least every 6 months, should become the standard of care for children receiving corticosteroids in any form on a recurrent basis. Therapy should always aim to achieve the best result with the lowest possible corticosteroid dose.

[Figure 1 omitted]

[Figure 2 omitted]

[Figure 3 omitted]

[Figure 4 omitted]

TABLE 1

Indications for Use of Nasal Corticosteroids

Nasal congestion

Nasal congestion plus recurrent otitis media

Nasal congestion plus nasosinus headaches

Nasal congestion plus recurrent sore throat

Nasal congestion plus disturbed sleep

Nasal congestion plus daytime drowsiness

Nasal congestion plus mouth breathing plus "adenoid facies"

Paroxysmal sneezing (frequent/disturbing)

Extreme runny nose
TABLE 2

Height Growth Velocity (HGV)

                       Predicted  Actual HGV
Group             No.  HGV (cm)      (cm)

Boys               40     6.3        6.66
Girls              20     4.66       5.25
Boys <5 years      14     6.9        7.2
Girls <5 years      8     6.7        6.8
Boys >5 years      25     5.1        5.7
Girls >5 years     13     5.4        6.1
Boys <10 years     10     7.0        7.2
Girls <10 years    21     6.1        6.3
Boys >10 years     19     4.85       5.54
Girls >l0 years    10     5.46       6.14
TABLE 3

Change in Percentiles of Paired Measurements of Height Depending on Time
of Measurements

Measurement  Time          Greater (%)  Equal (%)  Lesser (%)

First        Both at same    27 (65)     13 (31)     2 (4)
Second       time of day
First        Morning          6 (46)      3 (23)     4 (31)
Second       Afternoon
First        Afternoon        2 (40)      2 (40)     1 (20)
Second       Morning

 Total                       35 (58)     18 (30)     7 (12)
TABLE 4

Criteria for Growth Studies (From Allen et al (13))

Adequate untreated similar control group

Baseline growth velocity data

Bone age at start and end

Staging of pubertal status at beginning and end of assessment by Tanner
classification

Controls for use of systemic corticosteroids during observation

References

(1.) Merkus PJFM, van Essen-Zandvliet EEM, Duiverman EJ, et al: Long-term effect of inhaled corticosteroids on growth rate in adolescents with asthma. Pediatrics 1993; 91:1121-1126

(2.) Balfour-Lynn L: Growth and childhood asthma. Arch Dis Child 1986; 61:1049-1055

(3.) Brown DCP, Savacool AM, Letizia BA: A retrospective review of the effects of one year of triamcinolone acetonide aerosol treatment on the growth patterns of asthmatic children. Ann Allergy 1989; 63:47-51

(4.) Allen OB, Mullen M, Mullen B: A meta-analysis of the effect of oral anti inhaled corticosteroids on growth J Allergy Clin Immunol 1994; 93:967-976

(5.) Tinkelman DG, Reed CE, Nelson HS, et al: Aerosol beclomethasone dipropionate compared with theophylline as primary treatment of chronic, mild to moderately severe asthma in children. Pediatrics 1993; 92:64-77

(6.) Simmons FER: A comparison of beclomethasone, salmeterol, and placebo in children with asthma. N Engl J Med 1997; 337:1659-1665

(7.) Verberne AAPH, Frost C, Roorda RJ, et al: One year treatment with salmeterol compared with beclomethasone in children with asthma. Am J Respir Crit Care Med 1997; 156:688-695

(8.) Doull IJM, Freezer NJ, Holgate ST: Growth of prepuberal children with mild asthma treated with inhaled beclomethasone dipropionate. Am J Respir Crit Care Med 1995; 151:1715-1719

(9.) Rachelefsky GS, Chervinsky P, Meltzer EO, et al: An evaluation of the effects of beclomethasone dipropionate aqueous nasal spray [Vancenase AQ (VNS)] on long-term growth in children. J Allergy Clin Immunol 1998;S236:979

(10.) Skonner DP, Rachelefsky GS, Meltzer EO, et al: Detection of growth suppression in children during treatment with intranasal beclomethasone dipropionate. Pediatrics 2000;105:e23

(11.) Kennis T: Inhaled corticosteroids--the FDA takes another look. Ann Allergy Asthma Immunol 1998;81:406-410

(12.) Lowrey GH: Growth and Development of Children. Chicago, Year Book Medical Publishers Inc, 1978, pp 447-448

(13.) Allen DB, Bronsky EA, LaForce CF, et al: Growth in asthmatic children treated with fluticasone propionate. J Pediatr 1998;132:472-477

(14.) Apter AJ, Reisine ST, Affleck G, et al: Adherence with twice-daily dosing of inhaled steroids. socioeconomic and health-belief differences. Am J Respir Crit Care Med 1998; 157:1810-1817

(15.) Lipworth BJ: Systemic adverse effects of inhaled cortico-steroid therapy. Arch Intern Med 1999;159:941-955

(16.) Lipworth BJ: New perspectives on inhaled drug delivery and systemic bioactivity (Editorial). Thorax 1995;50:105-110

(17.) Agertoft L, Pedersen S: Effect of long-term treatment with inhaled budesonide on adult height in children with asthma. N Engl J Med 2000;343:1064-1069

(18.) Volovitz B, Amir J, Malik H, et al: Growth and pituitary-adrenal function in children with severe asthma treated with inhaled budesonide. N Engl J Med 1993;329:1703-1708

(19.) Price JF, Russell C, Hindmarsch PC, et al: Growth during one year of treatment with fluticasone propionate or sodium cromoglycate in children with asthma. Pediatr Pulmonol 1997;24:178-186

(20.) Agertoft L, Pedersen S: Short-term lower leg growth rate in children with rhinitis treated with intranasal mometasone furoate and budesonide. J Allergy Clin Immunol 1999;104:948-952

(21.) Shenkel EJ, Skoner DP, Bronsky EA, et al: Absence of growth retartlation in children with perennial allergic rhinitis after one year of treatment with mometasone furoate aqueous nasal spray. Pediatrics 2000;105:e23

(22.) Van Bever HP, Dasager KN, Lijssens N, et al: Does treatment of asthmatic children with inhaled corticosteroids affect their adult height? Pediatr Pulmonol 1999;27:369-375

(23.) Chiba 5, Asthikawa T, Moriwaki H, et al: The influence of sleep breathing disorder on growth hormone secretion in children with tonsil hypertrophy. Nippon Jibunkoka Gakkai Kaiho 1998;101:873-878

(24.) Craig TJ, Teets 5, Lehman EB, et al: Nasal congestion secondary to allergic rhinitis as a cause of sleep disturbance and daytime fatigue and the response to topical nasal corticosteroids. J Allergy Clin Immunol 1998;101:633-637

RELATED ARTICLE: KEY POINTS

* No adverse growth effects were associated with the clinical use of intranasal beclomethasone in children at low to moderate doses.

* Clinical experience may differ from clinical research investigations.

* Factors such as compliance and physician/patient interactions may alter outcomes.

* Careful measurements of children receiving topical cortico-steroids in any form remains the most prudent medical approach.

From the El Paso Institute for Medical Research and Development, El Paso, Tex.

Reprint requests to Lyndon E. Mansfield, MD, El Paso Institute for Medical Research and Development, 1901 Arizona St, El Paso, TX 79902.