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2012

databasesthey contain a wealth of critical biological information.

To realize the promise of translational research, the need for interactive, interdisciplinary research teams cannot be overemphasized.
Initial formulation of basic research questions based on sound clinical
observations, and further refined by an iterative and supple approach,
will allow us to more rapidly impact the care of our patients.
Author disclosures are available with the text of this article at www.atsjournals.org.

Victor J. Thannickal, M.D.

Division of Pulmonary, Allergy
and Critical Care Medicine
University of Alabama at Birmingham
Birmingham, Alabama
James S. Hagood, M.D.
Division of Respiratory Medicine
University of California, San Diego
and
Rady Childrens Hospital of San Diego
La Jolla, California

References
Figure 1. Schematic of a potential mechanism by which statins may
promote pulmonary fibrosis. In a COPDGene cohort of current/former
smokers, statin use was found to be associated with a higher risk of
interstitial lung abnormalities on high-resolution computed tomography, an effect seen in subjects of age greater than 65 years, but not in
the 45- to 55-year age group; the significance of this finding was
greater with hydrophilic (versus hydrophobic) statins. In an animal
model of bleomycin-induced lung injury and fibrosis, pre-treatment
of mice with statins increased fibrosis by a mechanism that may involve
the activation of mitchondrial reactive oxygen species (mtROS) and
NLRP3 inflammasome activation in macrophages (1).

fibrosis, aging, and responses to environmental stimuli. It remains

to be determined whether the proposed mechanism of NLRP3
inflammasome activation in monocytes/macrophages is sufficient
to explain the apparent priming effect of statins on cigarette
smokeassociated ILA observed in human subjects. It also reinforces the importance of starting at the bedside, and of framing
research questions based on clinically relevant, even unexpected,
observations. Although clinical observations such as the one
made by this study may not immediately impact clinical care
(as acknowledged by the authors), they are hypothesis-generating and set the stage for more in-depth bench studies that may
then be re-tested in human subjects. For example, this study
provides a strong rationale for characterizing macrophage
activation/phenotypes in patients with distinct clinical syndromes
associated with cigarette smoke exposure. In response to a noninfectious injury to the lung, whether activation of specific macrophage phenotypes skews the tissue repair response from
emphysema to fibrosis would be of significant interest.
There are now ample opportunities for bedside-to-bench research
with the growing number of clinical registries and clinical trial

1. Xu J-F, Washko G, Nakahira K, Hatabu H, Patel A, Fernandez I,

Nishino M, Okajima Y, Yamashiro T, Ross J, et al. Statins and pulmonary fibrosis: the potential role of NLRP3 inflammasome activation. Am J Respir Crit Care Med 2012;185:547556.
2. Washko GR, Hunninghake GM, Fernandez IE, Nishino M, Okajima Y,
Yamashiro T, Ross JC, Estepar RS, Lynch DA, Brehm JM, et al. Lung
volumes and emphysema in smokers with interstitial lung abnormalities. N Engl J Med 2011;364:897906.
3. Cassel SL, Eisenbarth SC, Iyer SS, Sadler JJ, Colegio OR, Tephly LA,
Carter AB, Rothman PB, Flavell RA, Sutterwala FS. The NALP3
inflammasome is essential for the development of silicosis. Proc Natl
Acad Sci USA 2008;105:90359040.
4. Dostert C, Petrilli V, Van Bruggen R, Steele C, Mossman BT, Tschopp J.
Innate immune activation through NALP3 inflammasome sensing of
asbestos and silica. Science 2008;320:674677.
5. Biswas R, Bunderson-Schelvan M, Holian A. Potential role of the
inflammasome-derived inflammatory cytokines in pulmonary fibrosis.
Pulm Med 2011;2011:105707.
6. Riteau N, Gasse P, Fauconnier L, Gombault A, Couegnat M, Fick L,
Kanellopoulos J, Quesniaux VF, Marchand-Adam S, Crestani B, et al.
Extracellular atp is a danger signal activating P2X7 receptor in lung
inflammation and fibrosis. Am J Respir Crit Care Med 2010;182:774783.
7. Artlett CM, Sassi-Gaha S, Rieger JL, Boesteanu AC, Feghali-Bostwick
CA, Katsikis PD. The inflammasome activating caspase 1 mediates
fibrosis and myofibroblast differentiation in systemic sclerosis. Arthritis Rheum 2011;63:35633574.
8. Zhou Q, Liao JK. Pleiotropic effects of statins: basic research and clinical
perspectives. Circ J 2010;74:818826.
9. Farsaei S, Khalili H, Farboud ES. Potential role of statins on wound
healing: review of the literature. Int Wound J (In press)
10. Mawhinney LJ, de Rivero Vaccari JP, Dale GA, Keane RW, Bramlett
HM. Heightened inflammasome activation is linked to age-related
cognitive impairment in fischer 344 rats. BMC Neurosci 2011;12:123.
Copyright 2012 by the American Thoracic Society
DOI: 10.1164/rccm.201201-0047ED

Asthma in Pregnancy: Are Inhaled Corticosteroids Safe?

Inhaled glucocorticosteroids (ICS) are the most effective preventive
antiinflammatory medications for long-term management of asthma.
International guidelines recommend that the pharmacological
treatment of asthma during pregnancy should be the same as for
nonpregnant women (14). The safety of ICS in the treatment of

asthma during pregnancy has been established in systematic

reviews (5, 6). They are the preferred preventive medications
for managing asthma during pregnancy. Budesonide, with the
most gestational data, remains the preferred ICS for use in pregnancy. Hodyl and coworkers have recently shown that fetal

Editorials

adrenal activity and growth are unaffected by continued ICS

treatment during pregnancy (7).
In this issue of the Journal, Tegethoff and colleagues (pp.
557563) have reported a population-based cohort study that
included data from 65,085 motherchild pairs followed from
early pregnancy into childhood (8). There were 4,083 mothers
who self-reported asthma during pregnancy. The authors claim
that the agreement between participant self-report of conditions
and physician diagnosis was high. In addition, 95.85% of women
reporting lifetime asthma had a diagnosis made by a doctor,
although the actual number of women self-reporting lifetime
asthma was unknown. Budesonide was the most commonly used
ICS according to self-reports by women (n = 983 [79.9%]). The
study has shown an increased risk of endocrine and metabolic
disorders during childhood in offspring of mothers with asthma
using ICS during pregnancy (hazard ratio, 1.84; 95% confidence
interval, 1.132.99), although details of these diagnoses are lacking. Exploratory case-control analyses revealed only that cases
of metabolic disorders and volume depletion were more
likely to be exposed to ICS during pregnancy than controls.
This is the first longitudinal cohort study addressing the potential
effects of ICS during pregnancy on child health. This is new evidence,
whereas prior studies have focused on outcomes during pregnancy or
at birth. The other strengths of the study are the large cohort, national registry data of inpatient and outpatient reported diagnoses,
and the length of follow-up after birth, although many disorders
would not be fully expressed at a median 6.1 years. The authors claim
that their findings are consistent with some animal studies in which
intrauterine exposure to glucocorticoids has been shown to have
long-term effects on endocrine and metabolic function, although
these studies did not use inhaled route of administration.
The findings of Tegethoff and colleagues (8) should be interpreted with caution in light of limitations, some of which were
acknowledged. A recent meta-analysis has shown that pregnant
women with asthma are at a significantly increased risk of adverse perinatal outcomes, including low birth weight, small size
for gestational age, preterm labor and delivery, and preeclampsia (9). The meta-analysis found that active asthma
management strategies were effective in minimizing complications (in particular, preterm labor and delivery), confirming
their importance. Tegethoff and coworkers (8) did not control
for asthma severity or management in their analysis, except for
reported use of non-ICS inhalation. There was no objective
information on asthma severity or symptoms during pregnancy.
It is unclear whether those women using ICS also used oral
corticosteroids during pregnancy. Information on dose of ICS,
or steroid exposure for other indications during pregnancy, was
not available either. Pregnant women with asthma have concerns
about the safety of many medications, especially ICS. Despite
worsening of asthma symptoms, many pregnant women do not
take regular preventive asthma medicines (10). Adherence to
medications was not measured by Tegethoff and coworkers.
Hence, it is difficult to conclude whether the effects observed
were the result of more severe disease (thus requiring more
treatment, including ICS), poor asthma control (e.g., due to
ICS nonadherence), or ICS use per se.
The authors propose that ICS may be biologically implicated
in the development of long-term metabolic sequelae through
long-term effects on the fetal hypothalamic-pituitary-adrenal
(HPA) axis, but other possibilities warrant consideration. Although birth weight was not reported in this cohort, it is another
potential mechanism by which poor asthma control and/or ICS
exposure, and long-term metabolic sequelae, may be linked.
Poor asthma control is associated with impaired fetal growth,
and human studies addressing corticosteroid exposure are dominated by associations between repeated antenatal corticosteroid

477

exposure, both topical and systemic, and impaired fetal growth

(11, 12). When linking adverse long-term effects with a disease
such as asthma or its treatment, it is important to consider that
some of these effects may be mediated by the intermediary of
impaired fetal growth. The Developmental Origins of Health
and Disease (DOHAD) model recognizes the importance of
fetal programming for health and disease. In the face of
an adverse intrauterine environment, the fetus undergoes adaptation, preferentially supplying the brain at the expense of
organs such as heart, kidneys, and pancreas with a resultant
increase in hypertension, cardiovascular, and metabolic disease
manifesting in later life. The association between low birth
weight and an increased risk of metabolic disorders in later life
is well documented (13). Hovi and colleagues (14) studied a cohort of young adults (aged 1827 yr) with very low birth weight
(,1,500 g) and a comparison group born at term matched for
age, sex, and hospital. They showed that very low birth weight
was associated with signs of impaired glucose regulation in
young adult life, suggesting that persons with very low birth
weight might be more vulnerable to disorders such as type 2
diabetes and cardiovascular disease in later life. It is plausible
that some of the effect on metabolic sequelae may have been
mediated by the important intermediary of impaired fetal
growth, and warrants further investigation.
Such complexities highlight the difficulties in teasing out the relationship between chronic disease and its treatment in pregnancy to
long-term outcomes, but this study is an important advance. Longitudinal data from cohort studies, stratified by treatment and asthma
control, are needed to confirm the findings of Tegethoff and coworkers. Until then, management of pregnant women with asthma
should be as rigorous as with those who are not pregnant. Management of asthma during pregnancy requires a careful riskbenefit
analysis and should be individualized to the needs of the patient
with close monitoring. Powell and colleagues (15) used an exhaled
nitric oxide (FENO)-guided approach for the management of asthma
during pregnancy, which was associated with a reduction of exacerbations, mainly unscheduled doctor visits. The rate of oral corticosteroid use for exacerbations was also reduced. Pregnant women
with asthma should be advised that the greater risk to the baby lies
with poorly controlled asthma. It is safer to maintain asthma control
with appropriate medications than to have asthma symptoms and
exacerbations. The ICS regimen should not be changed in pregnant
women whose asthma is well controlled. Written asthma action plans
and close monitoring of symptoms are essential.
A collaborative approach involving the obstetrician, respiratory
physician, general practitioner, and midwife is necessary to manage
brittle or poorly controlled asthma during pregnancy. The patients
pharmacist and asthma educator also have a role to play in ensuring patient understanding of the risks of uncontrolled asthma
and the benefits of medications, the effect of asthma on the baby,
and the importance of good medication adherence.
Author disclosures are available with the text of this article at www.atsjournals.org.

Johnson George, Ph.D.

Centre for Medicine Use and Safety
Monash University
Melbourne, Victoria, Australia
Michael J. Abramson, M.B.B.S., Ph.D.
Department of Epidemiology and Preventive Medicine
Monash University
Melbourne, Victoria, Australia
and
Allergy, Immunology, and Respiratory Medicine
The Alfred Hospital
Melbourne, Victoria, Australia

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AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE

Susan P. Walker, M.D.

Department of Perinatal Medicine
Mercy Hospital for Women
Melbourne, Victoria, Australia
and
University of Melbourne
Melbourne, Victoria, Australia

References
1. Global Initiative for Asthma. Special considerations: pregnancy. In:
Global strategy for asthma management and prevention. Cape Town:
Medical Communication Resources, Inc.; 2010 update. p. 76.
2. National Heart, Lung and Blood Institute. Managing special situations:
pregnancy. In: National Asthma Education and Prevention Program
(NAEPP) Expert Panel Report 3: Guidelines for the diagnosis and
management of asthma. U. S. Department of Health and Human
Services. Bethesda, MD: National Institutes of Health; 2007. pp. 364
365.
3. British Thoracic Society. Drug therapy in pregnancy. In: British guideline
on the management of asthma: a national clinical guideline. Edinburgh: Scottish Intercollegiate Guidelines Network; 2011. pp. 8586.
4. National Asthma Council of Australia. Pregnancy and asthma. In: Asthma
management handbook. Melbourne: National Asthma Council Ltd; 2006.
pp. 101103.
5. Lim A, Stewart K, Konig K, George J. Systematic review of the safety of
regular preventive asthma medications during pregnancy. Ann Pharmacother 2011;45:931945.
6. Bakhireva LN, Schatz M, Chambers CD. Effect of maternal asthma and
gestational asthma therapy on fetal growth. J Asthma 2007;44:7176.

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7. Hodyl NA, Stark M, Osei-Kumah A, Bowman M, Gibson P, Clifton VL.

Fetal glucocorticoid regulated pathways are not affected by inhaled
corticosteroid use for asthma during pregnancy. Am J Respir Crit Care
Med 2011;183:716722.
8. Tegethoff M, Greene N, Olsen J, Schaffner E, Meinlschmidt G. Inhaled
glucocorticoids during pregnancy and offspring pediatric diseases:
a national cohort study. Am J Resp Crit Care Med 2012;185:557563.
9. Murphy V, Namazy J, Powell H, Schatz M, Chambers C, Attia J, Gibson
P. A meta-analysis of adverse perinatal outcomes in women with
asthma. BJOG 2011;118:13141323.
10. Sawicki E, Wong S, Leung L, Stewart K, George J. Management of
asthma by pregnant women attending an Australian maternity hospital. Aust N Z J Obstet Gynaecol (In press)
11. Newnham JP, Jobe AH. Should we be prescribing repeated courses of
antenatal corticosteroids? Semin Fetal Neonatal Med 2009;14:157163.
12. Chi CC, Lee CW, Wojnarowska F, Kirtschig G. Safety of topical corticosteroids in pregnancy. Cochrane Database Syst Rev 2009;3:CD007346.
13. Barker DJ, Eriksson JG, Forsen T, Osmond C. Fetal origins of adult disease: strength of effects and biological basis. Int J Epidemiol 2002;31:
12351239.
14. Hovi P, Andersson S, Eriksson JG, Jarvenpaa AL, Strang-Karlsson S,
Makitie O, Kajantie E. Glucose regulation in young adults with very
low birth weight. N Engl J Med 2007;356:20532063.
15. Powell H, Murphy VE, Taylor DR, Hensley MJ, McCaffery K, Giles W,
Clifton VL, Gibson PG. Management of asthma in pregnancy guided
by measurement of fraction of exhaled nitric oxide: a double-blind,
randomised controlled trial. Lancet 2011;378:983990.

Copyright 2012 by the American Thoracic Society

DOI: 10.1164/rccm.201112-2249ED