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Exercise-induced bronchoconstriction in school-aged children who had chronic lung disease in infancy

Exercise-Induced Bronchoconstriction in School-Aged Children Who Had Chronic Lung Disease in Infancy Suchita Joshi, PhD, MRCPaed1, Thomas Powell, PhD2, William J. Watkins, PhD1, Mark Drayton, MD, FRCPCH3, E. Mark Williams, PhD2, and Sailesh Kotecha, PhD, FRCPCH1 Objectives To assess for exercise-induced bronchoconstriction in 8- to 12-year-old children who had chroniclung disease (CLD) in infancy, and to evaluate the response of bronchoconstriction to bronchodilation with albuterolin comparison with preterm and term controls.
Study design Ninety-two children, including 29 with CLD, 33 born preterm at #32 weeks' gestation, and 30 bornat term, underwent lung spirometry before and after cycle ergometry testing and after postexercise bronchodilationwith albuterol.
Results Doctor-diagnosed asthma and exercise-induced wheeze were reported more frequently in the CLD groupthan in the preterm and term groups, but only 10% were receiving a bronchodilator. There were no differencesamong the groups in peak minute ventilation, oxygen uptake, or carbon dioxide output at maximum exercise. Aftermaximal exercise, predicted forced expiratory volume in 1 second (FEV1) decreased from a mean baseline value of81.9% (95% CI, 76.6-87.0%) to 70.8% (95% CI, 65.5-76.1%) after exercise in the CLD group, from 92.0% (95% CI,87.2-96.8%) to 84.3% (95% CI, 79.1-89.4%) in the preterm group, and from 97.5% (95% CI, 92.5-102.6%) to90.3% (95% CI, 85.1-95.5%) in the term group. After albuterol administration, FEV1 increased to 86.8% (95%CI, 81.7-92.0%) in the CLD group, 92.1% (95% CI, 87.3-96.9%) in the preterm group, and 97.1% (95% CI, 92.0-102.3%) in the term group. The decrease in predicted FEV1 after exercise and increase in predicted FEV1 after bron-chodilator use were greatest in the CLD group (11.0% [95% CI, 18.4 to 3.6%] and 16.0% [95% CI, 8.6-23.4%],respectively; P < .005 for both), with differences of <8% in the 2 control groups.
Conclusion School-age children who had CLD in infancy had significant exercise-induced bronchoconstrictionthat responded significantly to bronchodilation. Reversible exercise-induced bronchoconstriction is common in chil-dren who experienced CLD in infancy and should be actively assessed for and treated. (J Pediatr 2013;162:813-8).
Survivorsofchroniclungdisease(CLD)ofprematurity,oftenalsocalledbronchopulmonarydysplasia(BPD),havein- creased respiratory morbidity,increased hospitalizatioand poor lung function during infancy and early child-hoChildren who had CLD in infancy exhibit evidence of airway obstruction,bronchial hyperreactivity, and air-trappingcompared with term-born controls at school age and in early adulthood.Lung function abnormalitiesin childhood and early adulthood have been reported in preterm-born children without CLD as The increased airwayobstruction is thought to be due to increased airway muscle mass,but data on whether the airway obstruction is reversible inchildhood survivors of CLD are very limited. The EpiCure group studying preterm infants at the edge of viability (ie, #25weeks' gestation at birth) recently reported that 56% of 11-year old survivors had abnormal airway obstruction and 27%had a positive bronchodilator response at rest, but many of these children were not receiving appropriate treatmTheseinfants also were found to have lower lung diffusion capacity of CO (DLCO) and lower peak oxygen consumption ( _VO2) duringexerBalinotti et alreported significantly lower DLCO and DLCO/alveolar volume ratio in infancy in preterm infants withCLD compared with term controls, suggesting impaired alveolar development. Other studies of DLCO, including those con-ducted in preterm-born children and young adults, have reported varying results.Current data on cardiopulmonary ex-ercise testing (CPET) in school-aged childreand young adults who had been born preterm are inconThesedifferences may be related to variation among study groups and CPET methods. Furthermore, it is unclear whether exercise isassociated with bronchoconstriction in children who had CLD in infancy, and whether this bronchoconstriction responds tobronchodilator therapy.
From the 1Department of Child Health, School of Cardiopulmonary exercise testing Medicine, Cardiff University, Cardiff, United Kingdom;2 Chronic lung disease Faculty of Health, Sport and Science, University of Glamorgan, Pontypridd, United Kingdom; and Lung diffusion capacity of carbon monoxide Department of Neonatology, University Hospital of Forced expiratory volume in 1 second Wales, Cardiff, United Kingdom Maximum voluntary ventilation Partially supported by Cardiff and Vale National HealthService Trust Research and Development Small Grants.
Minute ventilation The authors declare no conflicts of interest.
Carbon dioxide output 0022-3476/$ - see front matter. Copyright ª 2013 Mosby Inc.
Oxygen consumption All rights reserved. THE JOURNAL OF PEDIATRICS In this study, we compared exercise capacity in similarly Pulmonary diffusion capacity was measured using a single- aged preterm-born children with and without CLD and breath carbon monoxide techn(MS-PFT; Jaeger, term-born children. We also measured airway function after Hoechberg, Germany) and corrected for the child's hemoglo- exercise and after postexercise bronchodilator administration bin level. Each participant rested for 10-15 minutes before to assess whether these preterm-born children had exercise- performing baseline spirometry testing. All subjects were induced bronchoconstriction, and whether this was reversible trained to perform the breath-holding maneuver before test- by a b2 bronchodilator administered after exercise.
ing. All subjects performed at least 3 consecutive tests, witha 4-minute interval between maneuvers. All diffusion capac- ity tests were performed by a single investigator (E.W.). He-moglobin assessment was performed in 64 children (70%); Three groups of children aged 8-12 years were studied, includ- average values were 13.8 mg/dL (95% CI, 13.5-14.1) in the ing 2 preterm groups (born at #32 weeks' gestation) who de- CLD group, 13.6 mg/dL (95% CI, 13.2-14.0) in the preterm veloped CLD (ie, oxygen-dependent or breathing air by 36 group, and 13.1 mg/dL (95% CI, 12.8-13.5) in the term weeks' gestation) and a control term group born at $37 weeks' group. The average hemoglobin value for each group was gestation. CLD was diagnosed pragmatically and would have used to complete the missing data on 30% of the subjects been classified as moderate to severe using the National Insti- who did not consent for blood testing. DLCO was adjusted tutes of Health's definition of BPNeonatal clinical records for hemoglobin value using the equation recommended by for each preterm-born child were reviewed. Children with the American Thoracic a congenital anomaly, cardiopulmonary defect, neuromuscular To measure static lung volumes, the method of measuring disease, severe neurodevelopmental impairment, or inability to mouth pressure during a brief airway occlusion was practiced comply with the research protocol were excluded. Children by each child, until the maneuver was repeated at least three with a respiratory tract infection within the previous 3 weeks times to obtain at least 2 satisfactory tests within 10% of the were asked to return at a later date. Children with asthma or mean. Baseline spirometry was performed before commenc- atopy were not excluded. Children receiving inhaled medica- ing exercise. All spirometric (Flowscreen; Viasys Healthcare) tion were asked to stop the treatment for at least 12 hours before and plethysmographic (Masterscreen; Viasys Healthcare) attending. Ethical approval was obtained from the local tests were carried out by a single investigator (S.J.).
Research Ethics Committee. Written informed consent was ob-tained for each participant.
Height and weight were measured using a calibrated stadi- Maximal exercise capacity was measured using an incremen- ometer and beam-balance scale (Model 424; Weylux, Lon- tal symptom limited, electrically braked cycle ergometer (Jae- don, United Kingdom), and baseline pulse rate and oxygen ger). Pedaling was started on an unloaded cycle, and then, saturation were measured with a Dinamap Procare monitor every 3 minutes thereafter, the load was increased in 30-W in- (GE Healthcare, Hatfield, United Kingdom). Parents com- crements until volitional exhaustion or until the heart rate pleted a modified International Study of Asthma and Aller- reached 80-90% of the predicted maximum (220 - age in gies in Childhood questionnaire eliciting data on the child's years). Pedaling cadence was held at approximately 60 rpm.
respiratory health Each child was given the same vigorous verbal encourage-ment to cycle as long as possible. Heart rate was monitored throughout the exercise test using a telemetric monitor (Po- After equipment calibration, the forced expiratory methods lar t31; Polar Electro, Warwick, United Kingdom). The face- were demonstrated to the children who then practiced the mask was connected to a calibrated flow sensor and O2/CO2 maneuver using an animated, computer-programmed spi- breath-by-breath analysis system (MS-CPX; Jaeger). The test rometer (Flowscreen; Viasys Healthcare, Basingstoke, United was continued until at least 2 of the following 4 criteria were Kingdom). Once deemed competent, the children were as- met: (1) maximum heart rate was $80% of predicted maxi- sessed using a screen pneumotachograph (Masterscreen; mum; (2) respiratory exchange ratio was >1; (3) peak _VO2 Viasys Healthcare). Nose clips and mouthpiece bacterial fil- was achieved; or (4) volitional exhaustion was present, as as- ters were worn throughout all procedures. Each child per- sessed by the Borg scale of perceived exhaustion.At maxi- formed at least 3 acceptable and reproducible spirometric mum exercise, _VO2, CO2 output ( _VCO2), and minute maneuvers in accordance with American Thoracic Society ventilation ( _VE) were calculated as mean values of the final and European Respiratory Society guidelines.Reproduc- 15 seconds of exercise. Maximum voluntary ventilation ibility was assessed visually by observing the flow volume (MVV) was calculated as baseline FEV1  Ventilatory curves and by ensuring that the differences in forced vital ca- reserve was calculated as (1  peak _VE/MVV)  100%.
pacity and forced expiratory volume in 1 second (FEV1) be-tween the maneuvers were within 5%. Absolute values for Postexercise Spirometry and Reversibility Test forced vital capacity, FEV1, forced expiratory flow at 25- Spirometry was performed at 5, 10, 15, 30, and 40 minutes 75% of vital capacity, and peak expiratory flow, along with after the exercise, and the lowest FEV1 value was recorded percent predicted values corrected for age, sex, and height, for each child. At each stage, at least 3 spirometry maneuvers with at least 2 reproducible recordings were recorded.
ORIGINAL ARTICLES Albuterol was administered 45-60 minutes after exercise via FEV1, forced expiratory flow at 25-75% of vital capacity, and a pediatric Aerochamber (GSK, Brentford, United Kingdom) peak expiratory flow were significantly lower, and functional with an appropriate-sized facemask. Four 100-mg doses (total residual capacity, residual volume, and residual volume/total dose, 400 mg) were administered, with the child instructed to lung capacity ratio were significantly higher in the CLD take 10 normal breaths after each dose. Spirometry was re- group compared with the preterm and term groups. Values for peated after 15 minutes. Only data from the 75 children the preterm group were intermediate, but not significantly who had data recorded at baseline, after exercise, and after al- different from those for the term group.
buterol administration (26 in the CLD group, 23 in the pre- Hemoglobin-adjusted DLCO values differed signifi- term group, and 26 in the term group) were included in these cantly among the groups (P < .05 between the CLD and preterm groups [4.9 (95% CI, 4.5-5.2) mmol/min/kPa vs 5.5 (95% CI, 5.1-5.6) mmol/min/kPa]; P < .05 be- Statistical Analyses tween the CLD and term groups [4.9 (95% CI, 4.5-5.2) Because the data were normally distributed, they are pre- mmol/min/kPa vs 5.5 (95% CI, 5.1-6.0) mmol/min/ sented as mean  SD or 95% CI. Differences in CPET kPa]). However, predicted hemoglobin-adjusted DLCO among groups were tested for using ANOVA with post was significantly lower in the CLD group compared hoc Bonferroni corrections. Differences in FEV1 at baseline, with the preterm group, but not compared with the minimum FEV1 after exercise, and postbronchodilation FEV1 among groups were assessed by 2-way ANOVA. AP value <.05 was considered to indicate statistical signifi- cance. SPSS 18.0 (IBM, Armonk, New York) was used for Four children (2 CLD, 1 preterm, 1 term) of insufficient all analyses.
height and 8 children (3 CLD, 3 preterm, and 2 term)who did not meet the criteria for CPET were excluded from the cycle ergometry testing. Another 2 children (1preterm, 1 term) were unable to perform the CPET be- We studied 92 children, including 29 with CLD, 33 born pre- cause of equipment failure and 2 children from the pre- term, and 30 term-born controls, with 1 subject in the CLD term control group missed the CPET for other reasons reclassified into the preterm group after a detailed review (1 was temporarily on crutches and 1 was unable to com- of each subject's neonatal records. Characteristics of the plete due to parental time constraint). Thus, a total of 76 study population and reported symptoms are presented in children completed cycle ergometry testing. Baseline heart and ; available at As rate, respiratory rate, oxygen saturation, and peak _VO2, expected, the CLD group was significantly more immature _VCO2, and _VE were similar in the 3 groups (; and had a lower mean birth weight compared with the available at ). MVV and ventilatory preterm and term groups. They also received mechanical reserve were both markedly lower in the CLD group ventilation and oxygen therapy for longer periods. All compared with the preterm and term groups (25.8% infants in the CLD group had received exogenous [95% CI, 19.7-31.9%], 37.5% [95% CI, 32.2-42.8%], and surfactant, compared with 45% of those in the preterm 43.7% [95% CI, 38.6-48.7%], respectively) in the term group and none in the term group. Weight at the time of lung function assessment was significantly lower in theCLD group compared with the preterm and term groups, Postexercise Spirometry and Reversibility Test but height and body mass index were not statistically In the CLD group, predicted FEV1 decreased from a mean significantly different among the groups. More parents baseline of 81.9% (95% CI, 76.6-87.0%) to 70.8% (95% smoked in the CLD and preterm groups compared with the CI, 65.5-76.1%) after maximal exercise and increased to term group. The rates of doctor-diagnosed asthma, dry 86.8% (95% CI, 81.7-92.0%) after albuterol administration cough at night, and exercise-induced wheeze were higher in (Corresponding data were 92.0% (95% CI, 87.2- the CLD group compared with the preterm and term 96.8%), 84.3% (95% CI, 79.1-89.4%), and 92.1% (95% groups and but only 10% of those in the CI, 87.3-96.9%) in the preterm group and 97.5% (95% CLD group were receiving current asthma treatment. The CI, 92.5-102.6%), 90.3% (95% CI, 85.1-95.5%), and rate of current asthma treatment was higher in the CLD 97.1% (95% CI, 92.0-102.3%) in the term group. The group compared with the other groups, but the differences lowest postexercise FEV1 was noted at 20.2 minutes for did not reach statistical significance. Self-reported physical the CLD group, 17.9 minutes for the preterm group, and activity was significantly lower in the CLD group compared 19.9 minutes for the term group. Two-way ANOVA with the other 2 groups.
between baseline and postexercise (11.0%; 95% CI, 18.4 to 3.6%: P < .004) and between postexercise and All 92 children underwent spirometry; 90 had satisfactory re- postbronchodilation (16.0%; 95% CI, 8.6-23.4%; P < sults on whole-body plethysmography, and 84 had satisfactory .0001) in the children who had CLD in infancy.
results on the single-breath maneuver Baseline Corresponding differences were 7.8% (95% CI, 14.8 Exercise-Induced Bronchoconstriction in School-Aged Children Who Had Chronic Lung Disease in Infancy THE JOURNAL OF PEDIATRICS Table I. Baseline characteristics of the subjects Gestation, weeks, mean  SD Birth weight, kg, mean  SD Age, years, mean  SD Height, cm, mean  SD Weight, kg, mean  SD Body mass index, kg m2, mean  SD Antenatal and postnatal respiratory status Antenatal steroid use, n (%) Postnatal steroid use, n (%) Surfactant use, n (%) Supplemental oxygen, days, median (range) Assisted ventilation, days, median (range) Reported respiratory symptomszz Asthma ever (doctor-diagnosed), n (%) Current asthma on treatment, n (%) Exercised induced wheeze in previous 12 months, n (%) Parental smoking, n (%) Self-reported physical activity per week, hours, median (range) *P < .001 (CLD vs preterm).
†P < .001 (CLD vs term).
zP < .01 (CLD vs preterm).
xP < .05 (CLD vs term).
{P < .05 (CLD vs term).
**P < .01 (CLD vs term; preterm vs term).
††P < .05 (CLD vs preterm; CLD vs term).
zzFurther details are given in to 0.7%; P = .03) and 7.8% (95% CI, 0.8-14.8%; P = .03) (R = 0.37; P = .001) and with reported physical activity for the preterm group and 7.2% (95% CI, 14.5 to (R = 0.43; P < .001).
0.06%; P = .052) and 6.8% (95% CI, 0.5 to 14.2%; P =.069) for the term group. Similar magnitudes of changes repeated-measures ANOVA (data not shown). We also In this study we studied each child in detail, focusing espe- noted a moderate correlation between duration of cially on his or her ability to exercise, and on whether the exercise testing and the lowest FEV1 value after exercise CLD group exhibited exercise-induced bronchoconstriction Table III. Pulmonary function indices Baseline spirometry FEV1, % predicted 97.5 (93.2-101.9) Forced vital capacity, % predicted 98.9 (94.7-103.1) 100.8 (96.8-104.9) 102.0 (97.2-106.8) FEF25-75, % predicted Peak expiratory flow, % predicted Single-breath test DLCO corrected for hemoglobin, % predicted 95.9 (91.9-100.0) KCO corrected for hemoglobin, % predicted FRCpleth, % predicted 120.6 (105.9-135.3) 99.4 (93.7-105.1) 93.8 (86.8-100.7) 104.9 (96.8-112.9) 96.7 (91.4-102.0) 99.0 (94.5-103.6) 131.6 (110.0-153.1) 103.2 (91.8-114.7) 96.9 (85.6-108.1) RV:TLC, % predicted Vital capacity, % predicted FEF25-75, forced expiratory flow at 25-75% of vital capacity; FRCpleth, functional residual capacity measured by plethysmography; KCO, DLCO/alveolar volume; RV, residual volume; TLC, total lungcapacity.
Data are mean (95% CI).
*P < .01 (CLD vs preterm).
†P < .001 (CLD vs term).
zP < .001 (CLD vs preterm).
xP < .05 (CLD vs preterm).
{P < .01 (CLD vs term).

ORIGINAL ARTICLES at 32 weeks' gestation, and were oxygen-dependent only untilage 28 days. More recently, underdiagnosed reversible airwaydisease in extremely preterm infants, including those withand without lung disease, has been reporteWhether earlierintervention with bronchodilators improves the long-term re-spiratory outlook for these children remains to be seen, but werecommend that reversible bronchoconstriction be actively as-sessed for and treated, given that such basic treatment is likelyto improve their quality of life. Antenatal maternal smokingand postnatal passive exposurcould possibly play a rolein the observed lung function deficits. Children in the CLDand preterm groups had a greater rate of current parentalsmoking compared with the term-born children, suggestinggreater exposure at least during postnatal life, but we did not Figure. Mean (95% CI) percentage of predicted FEV have sufficient data documented during the perinatal period baseline, after exercise, and after bronchodilator use. Solid to determine whether children in the CLD group had greater line, CLD; dashed line, preterm; dotted line, term controls.
exposure to antenatal maternal smoking.
For the exercise tests, peak _VO2, peak _VCO2, and peak _VE values did not differ significantly among our 3 study groups.
that was responsive to bronchodilation. We confirmed previ- The values are lower than some reported previouslybut ous reports of airway obstruction in the CLD group, but also similar to possibly reflecting differences in found that although peak _VO2 values were similar in the 3 choice of protocol, participants, or equipment used for assess- groups after exercise, the children in the CLD group used ment. We found significant differences in the self-reported more ventilatory reserve. In the CLD group, FEV1 decreased hours of physical activity per week between the CLD and con- significantly after exercise and improved markedly after albu- trol groups, however. In view of the explicit large and small terol administration. Modest decreases (<8%) were seen in airway obstruction and the drop in FEV1 after exercise in the preterm and term groups after exercise and after bron- the CLD group, the previously reported lack of limited exer- cise capacity in this is perhaps surprising. Most Children born preterm are known to have higher incidence interestingly, however, both MVV and ventilatory capacity of respiratory illness during infancy and early childhoo were markedly decreased in the CLD group, with intermedi- In our study cohort, 45% of the CLD group and 33% of ate values noted in the preterm group compared with the term the preterm group had been diagnosed with asthma, com- controls. Thus, the CLD and preterm groups were able to ex- pared with only 13% of the term group. Only 10% of the ercise similarly to the term infants but with the need to use CLD and 12% of the preterm group, but no children in the a greater proportion of their ventilatory reserve. Whether term group, were receiving medication for asthma or, more lesser ventilatory reserve is used after satisfactory treatment correctly, for airway symptoms, such as wheeze. However, of the reversible exercise-induced bronchoconstriction is the prevalence of such respiratory symptoms as exercise- open to speculation and will need further study.
induced wheeze and night cough was still higher in the In the present study, hemoglobin-corrected DLCO was CLD group compared with the term group (31% vs 4%).
lower in the CLD group compared with both the preterm Clearly, these children have persistent respiratory symptoms and term groups, but percent predicted values were lower in that they perceive as limiting their activities, and these symp- the CLD group compared only with the preterm group, but toms should be actively assessed for and treated.
not the term group. Our data are consistent with results We assessed both the effect of maximum exercise on FEV1 reported by Tepper et data for 8-year-old ex-preterm and the response to bronchodilator administered at 45-60 min- subjects in the EPICure cohort,and data for a cohort of utes after exercise. We noted significant decrease in predicted 19-year-olds in a Dutch Thus, there is evidence of FEV1 after exercise in the CLD group, which was significantly limitations in alveolar–capillary gas exchange in the ex- greater than for the preterm and term groups. After exercise, preterm children with CLD. Narang et measured DLCO the response to bronchodilator was much greater in the CLD combined with effective pulmonary blood flow at rest and group compared with the 2 control groups, suggesting mark- during exercise in preterm-born young adults in the presur- edly underdiagnosed reversible exercise-induced bronchocon- factant era. Although DLCO was reduced in the preterm group striction in the CLD group. Gross et reported reversible compared with the control population at rest, it normalized postexercise bronchoconstriction in survivors of BPD from during exercise. The investigators suggested that the rise of the presurfactant era. In a study from Brazil, however, Abreu DLCO during exercise may be a mechanical consequence of in- et alobserved no bronchoconstriction or response to bron- creased effective pulmonary blood flow, not a true increase.
chodilators administered after exercise, but the 13 children in In conclusion, 8- to 12-year-old children who had CLD in the CLD/BPD group had mild lung disease in infancy as sug- infancy achieved a similar exercise load as control children gested by the normal FEV1 of 99% (12%), were more mature with exercise testing, but with the need to use greater Exercise-Induced Bronchoconstriction in School-Aged Children Who Had Chronic Lung Disease in Infancy THE JOURNAL OF PEDIATRICS ventilatory reserve. These children had more respiratory longitudinal lung spirometry in school age children and adolescents.
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36. Clemm H, Røksund O, Thorsen E, Eide GE, Markestad T, Halvorsen T.
14. Kotecha SJ, Watkins WJ, Henderson J, Dunstan FD, Kotecha S. Effect of Aerobic capacity and exercise performance in young people born ex- birth weight and birth weight adjusted for gender and gestation on tremely preterm. Pediatrics 2012;129:e97-105.
ORIGINAL ARTICLES Table II. Prevalence of parent-reported respiratory symptoms CLD group (n = 29) Preterm group (n = 33) Term group (n = 28) Dry cough at night in the previous 12 months, n (%) Eczema ever, n (%) Eczema in the previous 12 months, n (%) Family history of asthma, n (%) Family history of eczema, n (%) Family history of hay fever, n (%) Results were expressed in count (%). Two children born at term did not fill their questionairre.
Table IV. CPET results CLD group (n = 24) Preterm group (n = 26) Term group (n = 26) Baseline oxygen saturation, % Baseline respiratory rate, breaths min1 Maximum respiratory rate, breaths min1 Baseline heart rate, beats min1 Maximum heart rate, beats min1 175.3 (171.5-179.1) 178.7 (175.1-182.3) 171.4 (165.0-177.8) Exercise duration, seconds 553.8 (511.6-596.1) 613.6 (559.8-667.5) 625.2 (576.6-673.9) Peak _VO2, mL kg min1 Peak _VCO2, mL kg min1 Ventilatory reserve, % RER at ventilatory aerobic threshold RER, respiratory exchange ratio (_VCO2/_VO2).
Data are mean (95% CI). All values are reported at maximum exercise unless stated otherwise.
*P < .05 (CLD vs preterm).
†P < .001 (CLD vs term).
zP < .01 (CLD vs preterm).
xP < .05 (CLD vs term).
Exercise-Induced Bronchoconstriction in School-Aged Children Who Had Chronic Lung Disease in Infancy


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Australian Public Assessment Report Dienogest Proprietary Product Name: Visanne Submission No: PM-2009-00539-3-5 Sponsor: Bayer Australia Ltd September 2010 Contents AusPAR VISANNE Dienogest PM-2009-00539-3-5 Page 2 of 82 21 September 2010 I.