Elsevier

The Lancet

Volume 378, Issue 9795, 10–16 September 2011, Pages 983-990
The Lancet

Articles
Management of asthma in pregnancy guided by measurement of fraction of exhaled nitric oxide: a double-blind, randomised controlled trial

https://doi.org/10.1016/S0140-6736(11)60971-9Get rights and content

Summary

Background

Asthma exacerbations during pregnancy are common and can be associated with substantial maternal and fetal morbidity. Treatment decisions based on sputum eosinophil counts reduce exacerbations in non-pregnant women with asthma, but results with the fraction of exhaled nitric oxide (FENO) to guide management are equivocal. We tested the hypothesis that a management algorithm for asthma in pregnancy based on FENO and symptoms would reduce asthma exacerbations.

Methods

We undertook a double-blind, parallel-group, controlled trial in two antenatal clinics in Australia. 220 pregnant, non-smoking women with asthma were randomly assigned, by a computer-generated random number list, before 22 weeks’ gestation to treatment adjustment at monthly visits by an algorithm using clinical symptoms (control group) or FENO concentrations (active intervention group) used to uptitrate (FENO >29 ppb) or downtitrate (FENO <16 ppb) inhaled corticosteroid dose. Participants, caregivers, and outcome assessors were masked to group assignment. Longacting β2 agonist and minimum dose inhaled corticosteroid were used to treat symptoms when FENO was not increased. The primary outcome was total asthma exacerbations (moderate and severe). Analysis was by intention to treat. This study is registered with the Australian and New Zealand Clinical Trials Registry, number 12607000561482.

Findings

111 women were randomly assigned to the FENO group (100 completed) and 109 to the control group (103 completed). The exacerbation rate was lower in the FENO group than in the control group (0·288 vs 0·615 exacerbations per pregnancy; incidence rate ratio 0·496, 95% CI 0·325–0·755; p=0·001). The number needed to treat was 6. In the FENO group, quality of life was improved (score on short form 12 mental summary was 56·9 [95% CI 50·2–59·3] in FENO group vs 54·2 [46·1–57·6] in control group; p=0·037) and neonatal hospitalisations were reduced (eight [8%] vs 18 [17%]; p=0·046).

Interpretation

Asthma exacerbations during pregnancy can be significantly reduced with a validated FENO-based treatment algorithm.

Funding

National Health and Medical Research Council of Australia.

Introduction

Asthma is the most common chronic medical disorder to complicate pregnancy, and both mothers and health professionals expect asthma to be controlled with minimum drug exposure to the developing fetus.1 Asthma exacerbations are frequent in pregnant women, even when the asthma is considered to be mild,2 and can lead to low birthweight babies,2 maternal distress, and increased health-care use.3

Maintenance treatment with inhaled corticosteroids can effectively reduce the frequency and severity of asthma exacerbations.4, 5 Inhaled corticosteroid therapy is started and dose adjustments are made on the basis of measures of asthma control (the assessment of symptoms and lung function). Although inhaled corticosteroids treat airway inflammation, the relation between these measures of asthma control and airway inflammation is poor.6 However, when therapy is adjusted according to direct measures of airway inflammation, results improve.7, 8, 9, 10, 11

Studies using the fraction of exhaled nitric oxide (FENO) to guide therapy have shown variable benefit,10, 11, 12, 13 possibly because of the complex design issues related to studies of asthma treatment algorithms.14 In the Managing Asthma in Pregnancy (MAP) study, we developed an improved FENO-based treatment algorithm and tested its applicability for the adjustment of therapy for asthma during pregnancy. We tested the hypothesis that control of asthma in pregnancy would be improved when based on measures of FENO compared with a clinical algorithm for the primary study outcome of asthma exacerbations.

Section snippets

Study design and participants

We undertook a double-blind, parallel, randomised controlled trial of FENO-guided therapy in two antenatal clinics (John Hunter Hospital and Maitland Hospital; NSW, Australia) from June, 2007, to December, 2010. Non-smoking pregnant women (aged >18 years) with asthma attending the antenatal clinics were recruited between weeks 12 and 20 of gestation. Women had a doctor's diagnosis of asthma and were using inhaled therapy for asthma within the past year. The diagnosis was confirmed by a

Results

Figure 1 shows the trial profile. We recruited 242 women and randomly assigned 220, of whom 203 completed the study. Women had a mean age of 28 years (SD 5·4), 80 (39%) were past smokers with a mean smoking history of 4·5 pack-years (SD 5·2), 156 of 206 (76%) were atopic, and the mean gestational age was 16·1 weeks (SD 2·6). At enrolment, mean FEV1 was 95·1% (13·9) predicted, the ratio of FEV1 to forced vital capacity (FVC) was 79·6% (7·4), and median ACQ score was 0·85 (IQR 0·29–1·14). In the

Discussion

In this randomised controlled trial of inflammatory marker-based management of asthma in pregnancy, we have shown that a treatment algorithm based on FENO and ACQ score led to a significant reduction in asthma exacerbations and less use of β2 agonist compared with a clinical algorithm. These benefits occurred because the FENO treatment algorithm was associated with a different profile of maintenance asthma treatment, with inhaled corticosteroids being used by more women, but at a lower average

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