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Archives: Medical Journal Reviews

Medical Journal Review

Posted: April 2011

Reviewed and edited by Dr. Juan Carlos Ivancevich and Dr. Phil Lieberman

1. The use of beclomethasone dipropionate plus salbutamol as rescue treatment for exacerbations in children.
The TREXA study examined the use of beclomethasone dipropionate (BDP) in children with mild, persistent asthma. The two goals of the study were to establish (1) whether discontinuation of daily inhaled corticosteroids (ICSs) in children with well-controlled, mild, persistent asthma would increase the risk of exacerbations, and (2) whether the use of BDP plus salbutamol for relief, with or without concomitant use of daily BDP, protects against exacerbations better than a rescue strategy of salbutamol alone. The study enrolled 843 children and adolescents (ages 6-18 years) who had mild persistent asthma during the previous 2 years. Those who were using daily ICSs prior to inclusion had to qualify for interruption or discontinuation due to well-controlled disease. Following a 4-week run-in period, those whose asthma remained well controlled with no exacerbations (n = 288) were randomized to one of four treatment groups: 1) BDP (40 mcg puff) twice daily with BDP plus salbutamol as rescue (combined group); 2) BDP twice daily with placebo plus salbutamol as rescue (daily BDP group); 3) placebo twice daily with BDP plus salbutamol as rescue (rescue BDP group); 4) placebo twice daily with placebo plus salbutamol rescue (placebo group). In the rescue groups, two puffs of BDP (80 mcg) or placebo were given for each two puffs of salbutamol (180 mcg) required for symptom relief. The primary outcome was time to first exacerbation requiring oral corticosteroids. The probability of a first exacerbation by the end of the study was 31% (21%-43%) in the combined group (P = 0.07 vs. placebo), 28% (18%-40%) in the daily group (P = 0.03), and 35% (24%-47%) in the rescue group (P = 0.07), compared to 49% (37%-61%) in the placebo group. The hazard ratios for asthma exacerbations were lower in the daily BDP and combined groups compared to placebo, but the difference was not statistically significant for the rescue BDP group. More treatment failures occurred in the placebo group than in the other three groups. ICSs can impair growth, and children in the combined and daily arms grew 1.1 cm (SD 0.3) less than children in the placebo group (P < 0.0001), but growth did not differ between the rescue and placebo groups (P = 0.26). The authors concluded that daily ICSs are the most effective treatment to prevent exacerbations and reduce treatment failure in children with mild persistent asthma, and that salbutamol rescue therapy alone is not suitable. Rescue BDP decreases the risk of an exacerbation and treatment failure compared to rescue salbutamol alone and may be useful as a step-down strategy for children with well-controlled, mild asthma.
Editor's comment: Rescue BDP is not as effective as daily corticosteroids at preventing exacerbations, but is more effective than salbutamol alone and avoids the growth impairment associated with corticosteroids in children.
Martinez FD, Chinchilli VM, Morgan WJ, et al. Use of beclomethasone dipropionate as rescue treatment for children with mild persistent asthma (TREXA): a randomised, double-blind, placebo-controlled trial. The Lancet 2011; 377: 650-657.

2. No association of obesity and adiposity with eosinophilic airway inflammation in people without asthma.
Obesity and adiposity are closely associated with the development and severity of asthma, but data on their effects on airway inflammation have been inconsistent. To resolve the issue, the authors assessed whether fractional exhaled nitric oxide (FeNO) was associated with obesity/adiposity in 117 healthy, nonsmoking, Korean adults without a previous diagnosis of asthma or current asthma symptoms. Associations between FeNO and measures of obesity/adiposity (body mass index [BMI], body fat mass, and body fat percentage) and serum levels of adipose-derived hormones and adipokines were examined by correlation analyses and uni- and multi-variate linear regression analyses. In the multivariate linear regression model, after adjusting for age, gender, chronic rhinitis, atopy, and lung function, FeNO was not significantly associated with BMI, body fat mass, or body fat percentage, although it was associated with age and male sex. FeNO was also not significantly associated with serum levels of leptin, adiponectin, tumor necrosis factor (TNF)-α, or interleukin (IL)-6. These findings suggest that in healthy subjects without asthma, neither obesity/adiposity nor hormones and systemic inflammation derived from adipose tissue significantly affect eosinophilic airway inflammation.
Editor's comment: In patients without asthma, the association between obesity and airway inflammation seems quite different from that in asthmatics.
Kim SH, Kim TH, Lee JS, et al. Adiposity, Adipokines, and Exhaled Nitric Oxide in Healthy Adults Without Asthma. Journal of Asthma 2011; 48(2): 177-182.

3. No negative effect of long-term treatment with intranasal budesonide on bone mineral density in children.
Intranasal corticosteroids (INS) are an effective treatment for allergic rhinitis (AR) and, unlike glucocorticoids, have not been associated with loss of bone density. However, this risk to bone metabolism has not been sufficiently studied in children. This retrospective case-control study evaluated the effects of long-term treatment with intranasal budesonide spray on bone mineral status in pediatric patients with AR. The 230 children with perennial AR (145 boys, ages 7 to 11) had used nasal budesonide intermittently for at least 3 years at a mean daily dose of 100 mcg (range, 89-132 mcg). The mean (± SEM) steroid dosage used was 73.5 ± 7.0 mcg daily, with 65.2 ± 5.2 g total steroid use during treatment. Bone mineral density of the lumbar spine was measured by dual-energy X-ray absorptiometry. Levels of serum calcium, phosphorus, alkaline phosphatase (ALP), parathyroid hormone, and osteocalcin were also assessed. The results were compared to sex- and age-matched controls that were newly diagnosed with AR and had not previously received any corticosteroid treatment. The 140 control patients (90 boys) were aged from 6 to 11 years. No significant differences were observed in bone mineral density, mean serum ALP, cortisol, phosphorus and osteocalcin levels between the study and the control groups. The findings suggest that long-term intermittent treatment with intranasal budesonide spray has no negative effects on BMD and associated bone health parameters.
Editor's comment: The use of intranasal budesonide appears to be safe in children.
Ozkaya E, Mete F, Dibek E, et al. Lack of bone metabolism side effects after 3 years of nasal topical steroids in children with allergic rhinitis. Journal of Bone and Mineral Metabolism 2011 [Published online before print. doi: 10.1007/s00774-010-0255-3].

4. Association between acetaminophen (paracetamol) use and an increased risk for asthma symptoms.
Acetaminophen use has increased worldwide over the last 30 years and may increase the risk of developing asthma. To further investigate the association of acetaminophen use with asthma, the researchers studied data on 322,959 adolescents, ages 13-14 years, from 113 centers in 50 countries who participated in the International Study of Asthma and Allergies in Childhood (ISAAC). All of the children completed written and video questionnaires in which they provided information on their use of acetaminophen in the previous 12 months. They also provided information on whether they had recently experienced symptoms of asthma, rhinoconjunctivitis, and eczema. Overall, 73% of adolescents had used acetaminophen at least once in the previous 12-month period (medium use), ranging from 41% in China to 92% in Panama, and 30% had used the drug at least once a month (high use). Acetaminophen use in the past 12 months was associated with a significant increase in the risk for current asthma symptoms that increased with level of exposure. Indeed, after accounting for factors such as sex, maternal smoking and diet, medium and high use of acetaminophen in the previous 12 months were associated with 1.38- and 2.36-fold increased risk, respectively, for current asthma symptoms versus no use. They also found that, compared with no use, medium and high use of acetaminophen in the past 12 months were associated with 1.33- and 2.18-fold increased risk, respectively, for current rhinoconjunctivitis symptoms and 1.32- and 1.87-fold increased risk for current symptoms of eczema. The authors conclude that acetaminophen use in childhood may be an important risk factor for the development and/or maintenance of asthma. However, the study design does not distinguish whether the relationship is causal.
Editor's comment: Randomized controlled trials are now urgently required to investigate the relationship between acetaminophen use in childhood and asthma.
Beasley RW, Clayton TO, Crane J, et al. Acetaminophen Use and Risk of Asthma, Rhinoconjunctivitis, and Eczema in Adolescents. International Study of Asthma and Allergies in Childhood Phase Three. American Journal of Respiratory Critical Care Medicine 2011; 183: 171-178.

5. Link between early acetaminophen (paracetamol) use and childhood asthma and atopy.
To investigate the effect of early acetaminophen use on asthma symptoms at age 6, the researchers studied children at two sites (Christchurch and Wellington) who were born between 1997 and 2001 and participated in the New Zealand Asthma and Allergy Cohort Study. Data on the children's exposure to acetaminophen was collected from maternal questionnaires given at the ages of 3 and 15 months for children in the Christchurch cohort and at 6 years (for doses given in the previous year) for children at both sites. At the age of 6 years, 914 children were assessed for atopy and common allergies using serum and skin prick tests, including 464 children in the Christchurch subsample. The prevalence of wheeze and diagnosed asthma was assessed in the maternal interviews using standard questions from the International Study of Asthma and Allergies in Childhood (ISAAC). Overall, 89.9% of the Christchurch children had received at least one dose of acetaminophen by the age of 15 months. At the age of 6 years, the prevalence of diagnosed asthma with and without atopy was 13.0% and 9.2%, respectively, while the prevalence of wheeze with and without atopy was 14.1% and 12.0%, respectively. The prevalence of atopy without current asthma or wheeze was 16.1% and 15.1%, respectively. After accounting for potential confounding factors, such as number of chest infections in early life, family history of allergies, birth weight, maternal age and maternal smoking during pregnancy, the team found that any use of acetaminophen in the first 15 months of life was associated with a 3.61-fold increased risk for atopy at the age of 6 years. The researchers also found a dose-dependent association between acetaminophen use at the age of 5-6 years and the risk for wheeze and diagnosed asthma. Indeed, compared with acetaminophen use on 0-2 occasions, use on 3-10 and more than 10 occasions was associated with adjusted odds ratios of 1.83 and 2.30, respectively, for wheeze, and 1.63 and 2.16 for diagnosed asthma. The authors conclude that paracetamol may have a role in the development of atopy and the maintenance of asthma symptoms.
Editor's comment: These findings provide more evidence that randomized, controlled trials are needed to determine whether the association between acetaminophen use and asthma is causal.
Wickens K, Beasley R, Town I, et al. The effects of early and late paracetamol exposure on asthma and atopy: a birth cohort. Clinical & Experimental Allergy 2011; 41: 399-406.

6. The potential role of heparin in allergic and inflammatory reactions.
Heparin is a highly sulfated glycosaminoglycan that is synthesized exclusively by mast cells. Activated mast cells trigger edema in allergic and inflammatory disease, but the role of heparin in this process is not clear. The authors used a variety of approaches, including studies of human plasma and endothelial cells in vitro, in vivo rat and mouse models, and patients with hereditary angioedema (HAE), to investigate the role of heparin in inducing vascular permeability through the contact system and bradykinin. Heparin isolated from mast cells induced bradykinin formation in plasma only in the presence of the contact system protease factor XII (FXII). In rats infused with heparin, leukocytes adhered to and transmigrated through blood vessel endothelium; treatment with the bradykinin B2 receptor antagonist icatibant abolished this behavior. Mast cell-driven drops in blood pressure were prevented in rats treated with icatibant and in mice lacking FXII or the B2 receptor. Heparin provoked leakage of fluid from mouse skin microvessels in wild-type mice, but not in mice lacking FXII, B2 receptor, mast cells, or Serpin, the gene encoding C1 esterase inhibitor. C1 esterase inhibitor is a major inhibitor of FXII, and its disruption is the cause of most cases of HAE. Heparin and activated mast cells induced excessive edema in mice deficient in C1 esterase inhibitor. Thirty eight patients with hereditary angioedema were asked to report potential triggers of edema. Eleven of these associated episodes of edema with allergic reactions to food and 3 with "insect toxins". Together, these results indicate that heparin-induced bradykinin formation plays a fundamental role in allergic or inflammatory diseases mediated by mast cells. Drugs that block bradykinin or factor XII activity could therefore offer a new strategy to treat the vascular permeability associated with allergic and other immune-mediated diseases.
Editor's comment: Heparin plays a key role in allergic and inflammatory reactions driven by mast cells.
Oschatz C, Maas C, Lecher B, et al. Mast Cells Increase Vascular Permeability by Heparin-Initiated Bradykinin Formation In Vivo. Immunity 2011; 34(2): 258-268.

7. Association of low vitamin D levels and allergy in children.
This study of more than 3,000 children associates low vitamin D levels with increased likelihood that children will develop allergies. The samples were derived from the National Health and Nutrition Examination Survey (NHANES), a program of studies designed to assess the health and nutritional status of adults and children in the United States. The survey is unique in that it combines interviews, physical examinations and laboratory studies. Researchers looked at the serum vitamin D levels in blood collected in 2005 and 2006 from a nationally representative sample of 3136 children and adolescents and 3,454 adults. Sensitivity to 17 different allergens was assessed by measuring levels of allergen specific serum immunoglobulin E (sIgE). When the data were analyzed, no association between vitamin D levels and allergies was observed in adults, but for children and adolescents, low vitamin D levels correlated with sensitivity to 11 of the 17 allergens tested, including both environmental allergens (e.g., ragweed, oak, dog, cockroach) and food allergens (e.g., peanuts). For example, children who had vitamin D deficiency (defined as less than 15 nanograms of vitamin D per milliliter of blood) were 2.4 times as likely to have a peanut allergy than were children with sufficient levels of vitamin D (more than 30 nanograms of vitamin D per milliliter of blood). The latest dietary recommendations call for children to take in 600 IU of vitamin D daily; this dose should prevent vitamin-D deficiency and may reduce the risk of allergy.
Editor's comment: The research shows only an association and does not prove that vitamin D deficiency causes allergies in children.
Sharief S, Jariwala S, Kumar J, et al. Vitamin D levels and food and environmental allergies in the United States: Results from the National Health and Nutrition Examination Survey 2005-2006. Journal of Allergy & Clinical Immunology 2011 [Published online before print. doi: 10.1016/j.jaci.2011.01.017]

8. Additive effect of mometasone and desloratadine on allergic rhinitis and chronic rhinosinusitis.
Inflammation of the upper airway mucosa results from increased levels of pro-inflammatory cytokines and eosinophils. Recommended treatments include corticosteroids and antihistamines, but studies of combination therapies with these two classes of drugs have produced inconsistent results. The aim of this study was to investigate whether mometasone and desloratadine have additive effects on the secretion of cytokines and soluble intercellular adhesion molecule 1 (sICAM-1) by epithelial cells or on the survival of eosinophils. Epithelial cells were obtained from the nasal mucosa or polyps of patients (n = 9 in each group). Stimulation of these cells with 10% fetal bovine serum increased the secretion of interleukin (IL)-6, IL-8, granulocyte macrophage colony-stimulating factor (GM-CSF), and sICAM-1. Mometasone furoate (10-11 M to 10-5 M) decreased the levels of these FBS-stimulated secreted factors, more so in mucosal cell cultures than in polyp cell cultures. For all factors except sICAM-1 this reduction was dose-dependent. Desloratadine (10-5 M) combined with 10-9 M mometasone significantly reduced IL-6 secretion (to 48% ± 11% of the FBS-only control) relative to mometasone alone (68% ± 10% relative to control; P < 0.05). Epithelial cell-conditioned medium promoted eosinophil survival over 4 days, and mometasone inhibited the survival. The combination of 1-11 M mometasone and 10-5 M desloratadine inhibited eosinophil survival (to 27% ± 5% of control) more than mometasone alone (44% ± 7% survival) or desloratadine alone (46% ± 7% survival) alone (P < 0.01). Thus, the combination of desloratadine and mometasone furoate demonstrated a greater anti-inflammatory effect in an in vitro model of eosinophil inflammation than either drug alone.
Editor's comment: Antihistamines and topical corticosteroids have greater anti-inflammatory effects when used in combination, but their additive effect on allergic rhinitis has not yet been demonstrated clinically.
Mullol J, de Borja Callejas F, Martínez-Antón MA, et al. Mometasone and desloratadine additive effect on eosinophil survival and cytokine secretion from epithelial cells. Respiratory Research 2011; 12: 23. doi:10.1186/1465-9921-12-23
Full text, open access

9. Biomass fuel linked to respiratory disease.
It is estimated that 2.4 billion people worldwide live in households where the source of energy for cooking and heating is solid biomass fuels, such as wood, charcoal, dried animal dung, straw and sticks, which have low combustion efficiency and discharge smoke. Although numerous studies have shown that domestic use of solid biomass fuels is associated with an increased risk for respiratory disease, findings regarding the strength of the association have been variable. To assess the risk for respiratory disease associated with exposure to biomass fuels, the authors searched the literature for relevant studies conducted among rural women and children in non-industrialized or domestic settings. In total, 25 studies (nine case-control and 16 cross-sectional studies) conducted in 14 different countries between 1990 and 2007 met criteria for inclusion in the final review and meta-analysis. Study sizes ranged from 50 exposed and unexposed individuals to large groups of more than 33,000 children and 18,000 women. Analysis of the pooled data revealed that, overall, regular exposure to smoke from biomass fuels was associated with a 3.53-fold increased risk of acute respiratory infection in children compared with no exposure. In women, regular use of biomass fuels was associated with a 2.52-fold increased risk of chronic bronchitis and a 2.40-fold increased risk of chronic obstructive pulmonary disease, compared with those who did not use such fuels. The effects of the use of biomass fuels on respiratory health have been reported in the literature. This meta-analysis adds to the previous knowledge by quantifying the association between biomass fuel use and specific respiratory conditions among women and children in a rural setting. Improvements in stove design and efforts to reduce exposure to smoke may reduce respiratory disease in these populations.
Editor's comment: This study supports a strong association between the regular use of solid biomass fuels and an increased risk for respiratory disease in women and children.
Po JYT, J FitzGerald M, Carlsten C. Respiratory disease associated with solid biomass fuel exposure in rural women and children: systematic review and meta-analysis. Thorax 2011; 66: 232-239.

10. Downregulation of lipid biosynthesis protects the host against viral infection.
Connections between lipid metabolism and the immune system are increasingly being revealed. For example such a relationship has been noted in the inflammatory processes occurring in atherosclerosis and the response to viral infection. In this study, the authors used a range of techniques, including bioinformatics, biochemistry, and gene knockdowns, to elucidate the functional connections between sterol biosynthesis and the innate immune response to viral infection. Infection of primary macrophages with murine cytomegalovirus (mCMV) and other viruses selectively downregulated components of the sterol pathway at the gene and protein level, as did treatment with interferon (IFN) α or -β, but not other cytokines. This downregulation led to reduced metabolic output from the sterol pathway. Treating the cells with stimvistatin produced a dose-dependent antiviral effect; further experiments with siRNA knockdown of specific components of the pathway and metabolite rescue indicated that the mevalonate-prenylation branch of the pathway, rather than cholesterol, was responsible for the antiviral effect. Genetic knockout of the shared type I IFN receptor, IFNAR1, abolished the ability of the cells to reduce the expression of sterol genes in response to mCMV infection or treatment with IFNβ. Finally, SREBP2, a transcription factor key to the regulation of the sterol biosynthesis pathway, was shown to be reduced at the RNA and protein levels upon infection or treatment with IFNβ or -&ganma;, an effect that was dependent on the presence of IFNAR1. Together, these findings suggest a model wherein viral infection triggers a type I IFN response, which results in the downregulation of sterol biosynthesis as a means of host defense.
Editor's comment: Selectively targeting the host sterol biosynthesis pathway may provide new antiviral treatments.
Blanc M, Hsieh WY, Robertson KA, et al. Host Defense against Viral Infection Involves Interferon Mediated Down-Regulation of Sterol Biosynthesis. PLoS Biology 2011; 9(3): e1000598. doi:10.1371/journal.pbio.1000598.
Full text, open access

11. Long-term safety of bronchial thermoplasty.
Bronchial thermoplasty (BT), a bronchoscopic procedure that improves asthma control by reducing excess airway smooth muscle, was recently approved as a treatment option for patients with severe asthma. This paper reports safety results from a 4-year extension of the 12-month Asthma Intervention Research Trial, in which a group receiving BT in addition to standard-of-care treatment (inhaled corticosteroids plus long-acting β2 agonists) was compared with a control group receiving only the standard-of-care. Subjects in the BT group who chose to continue in the extension study (45 of 52) were evaluated annually through Year 5, and those in the Control group (24 of 49) were evaluated annually through Year 3. Evaluations included physical examination; spirometry; static lung volumes; diffusing capacity; chest x-ray; methacholine PC20; and active solicitation of adverse events, emergency room (ER) visits and hospitalizations. The BT and Control groups did not differ significantly on any of the measures through Year 3, except that the BT group improved over baseline on the methacholine PC20 doubling compared to the Control group in Years 2 and 3. The percent of subjects in the BT group reporting an adverse event (53%, 56%, 53%, and 52%) and number of adverse events per subject (1.2, 1.3, 1.2, and 1.1) remained stable in Years 2-5. The rates of ER visits and hospitalizations and FVC and FEV1 values also did not worsen over the followup period. These data indicate that BT is safe over a period of at least 5 years.
Editor's comment: This report provides long-term safety data on BT in patients in whom BT was performed by trained operators.
Thomson NC, Rubin AS, Niven RM, et al. Long-term (5 year) safety of bronchial thermoplasty: Asthma Intervention Research (AIR) trial. BMC Pulmonary Medicine 2011; 11: 8. doi: 10.1186/1471-2466-11-8.
Full text, open access

12. Risk for asthma and allergies with regular swimming pool use.
In recent years, several epidemiological studies have suggested that the rates of asthma and other diseases are higher in children who use chlorinated swimming pools. However, other studies have found no such association. To investigate further, the authors studied 5738 children enrolled in the Avon Longitudinal Study of Parents and Children in the United Kingdom. Data on swimming pool attendance at the ages of 6, 18, 38, 42, 57, 65 and 81 months were collected and compared with data on the presence of rhinitis, wheezing, asthma, eczema, hay fever and use of asthma medications between the ages of 7 and 10 years. Cumulative swimming pool attendance was assessed on a scale of 1-9, with a score of 0-2 defining low attendance and 5-9 defining high attendance. The children also underwent lung function assessments (spirometry) and skin prick tests for allergies between the ages of 7 and 8 years. About half of the children attended swimming pools at least once a week between the ages of 4 and 7 years, whereas 20% never attended or did so very rarely. Overall, 21.4% of children had a positive skin prick test and 20% had suffered from asthma by the age of 7 years. The researchers found that children with high cumulative swimming pool attendance rates between birth and the age of 7 years were 12% less likely to have previously suffered asthma and 50% less likely to have current asthma at the age of 7 years than those with low cumulative attendance rates. High cumulative swimming pool attendance rates were also associated with improved lung function and reduced asthma symptoms, such as wheezing. There was no significant association between swimming pool attendance rates and atopy. These findings remained true after adjustment for potential confounding factors, such as gender, maternal asthma, birth weight and maternal age. Thus, swimming did not increase the risk of asthma, atopy, or any respiratory and allergic symptom in British children; on the contrary, it was actually associated with increased lung function and with a decreased prevalence of current asthma among children with previous respiratory conditions.
Editor's comment: The finding that swimming is associated with decreased asthma prevalence has important public health implications, and further research should be performed to confirm the findings.
Font-Ribera L, Villanueva CM, Nieuwenhuijsen MJ, et al. Swimming Pool Attendance, Asthma, Allergies, and Lung Function in the Avon Longitudinal Study of Parents and Children Cohort. American Journal of Respiratory Critical Care Medicine 2011; 183: 582-588.

13. Safety of inhaled corticosteroid use for asthma during pregnancy.
Inhaled corticosteroids (ICSs) are currently recommended for the control of asthma during pregnancy because of the high risk to mother and child from maternal asthma attacks. However, there is little evidence regarding their systemic effects on the mother and whether any such effects could harm the placenta or fetus. For the current study, the authors assessed plasma levels of cortisol, estriol, osteocalcin and corticotropin-releasing hormone in 156 women with asthma and 51 without. Blood samples were collected from the women during each trimester, and the use of ICSs was recorded. The subjects also underwent ultrasound scans at 18 and 30 weeks gestation, and birth weight and fetal gender were recorded at delivery. Results showed that levels of all hormones increased among the women during pregnancy, but the presence of asthma per se had no significant effects on these levels. However, the use of ICSs during pregnancy had an inhibitory effect on maternal hormone levels in a dose-dependent manner in women carrying a female child. ICS use was inversely associated with maternal cortisol levels in the first trimester and inversely associated with maternal osteocalcin levels in the second and third trimesters. In women carrying a male child, there was no association between ICS dose and maternal cortisol, estriol or osteocalcin levels. However, corticotropin-releasing hormone levels increased with ICS use in the first trimester in these women. ICS use did not correlate with birth weight or other measures of fetal growth of males or females. The authors conclude that the use of ICSs during pregnancy does not affect fetal adrenal function, as demonstrated by the lack of change in estriol concentration with increasing ICS doses, and does not appear to adversely affect fetal growth and development.
Editor's comment: Important evidence for the safe use of ICSs during pregnancy.
Hodyl NA, Stark MJ, Osei-Kumah A et al. Fetal Glucocorticoid-regulated Pathways Are Not Affected by Inhaled Corticosteroid Use for Asthma during Pregnancy. American Journal of Respiratory Critical Care Medicine. 2011; 183: 716-722.

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