DOI: 10.1111/j.1471-0528.2011.03055.x www.bjog.

org

Systematic review

A meta-analysis of adverse perinatal outcomes in women with asthma

VE Murphy,a JA Namazy,b H Powell,a,c M Schatz,d C Chambers,e J Attia,f PG Gibsona,c
Centre for Asthma and Respiratory Diseases, University of Newcastle and Hunter Medical Research Institute, Newcastle, NSW, Australia Department of Allergy-Immunology, Scripps Clinic, San Diego, CA, USA c Department of Respiratory Medicine, John Hunter Hospital, Newcastle, NSW, Australia d Department of Allergy, Kaiser Permanente Medical Center, San Diego, CA, USA e Pediatrics and Family and Preventative Medicine, University of California, San Diego, CA, USA f School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia Correspondence: Prof. PG Gibson, Level 3 HMRI, John Hunter Hospital, Locked Bag 1 Hunter Region Mail Centre, Newcastle, NSW 2310, Australia. Email Peter.Gibson@hnehealth.nsw.gov.au
b a

Accepted 8 May 2011. Published Online 13 July 2011.

Background Asthma is a common condition during pregnancy

Main results Maternal asthma was associated with an increased

and may be associated with adverse perinatal outcomes.

Objective This meta-analysis sought to establish if maternal

asthma is associated with an increased risk of adverse perinatal outcomes, and to determine the size of these effects.
Search strategy Electronic databases were searched for the

following terms: (asthma or wheeze) and (pregnan* or perinat* or obstet*).

Selection criteria Cohort studies published between 1975 and

risk of low birthweight (RR 1.46, 95% CI 1.221.75), small for gestational age (RR 1.22, 95% CI 1.141.31), preterm delivery (RR 1.41, 95% CI 1.221.61) and pre-eclampsia (RR 1.54, 95% CI 1.321.81). The relative risk of preterm delivery and preterm labour were reduced to non-signicant levels by active asthma management (RR 1.07, 95% CI 0.911.26 for preterm delivery; RR 0.96, 95% CI 0.731.26 for preterm labour).
Authors conclusions Pregnant women with asthma are at increased risk of perinatal complications, including pre-eclampsia and outcomes that affect the babys size and timing of birth. Active asthma management with a view to reducing the exacerbation rate may be clinically useful in reducing the risk of perinatal complications, particularly preterm delivery.
Keywords Asthma, meta-analysis, perinatal outcomes, pregnancy.

March 2009 were considered for inclusion. Studies were included if they reported at least one perinatal outcome in pregnant women with and without asthma.
Data collection and analysis A total of 103 articles were

identied, and of these 40 publications involving 1 637 180 subjects were included. Meta-analysis was conducted with subgroup analyses by study design and active asthma management.

Please cite this paper as: 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.

Introduction
Asthma is the most common chronic medical condition to affect pregnancy, with a prevalence of between 8% and 13% worldwide.13 It has been suggested that asthma may have an effect on pregnancy outcomes, and also that pregnancy may affect the course of asthma.4 Since 1970, there have been reports that maternal asthma is associated with an increased risk of perinatal complications,5 but the published data have been conicting, with studies varying substantially in terms of design and sample size. In general, larger database studies have reported increased risks,612 whereas smaller clinical prospective cohort studies have not found

signicantly increased risks.1319 There are two primary explanations for this discrepancy. The rst is that the smaller studies individually lack sufcient power to detect the increased risks. The second is that these smaller, prospective, clinical studies are associated with better asthma management and disease control, which mitigates the increased risk. Indeed, several studies have reported a relationship between increased asthma severity or decreased asthma control and increased perinatal complications.18,2028 To address these issues, we have undertaken a systematic review of the literature and performed meta-analyses of cohort studies to investigate whether maternal asthma is associated with an increased risk of perinatal complications

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Adverse perinatal outcomes in women with asthma

related to size at birth, timing of birth, and maternal pre-eclampsia in cohort studies.

they contained data on size at birth and timing of birth outcomes, and maternal pre-eclampsia (Table S1).

Sources
Systematic review of the literaturesearch strategy
A review protocol was established by the investigators prior to commencement. English language studies published between 1975 (when inhaled corticosteroids were introduced) and March 2009 were identied for possible inclusion from Medline (n = 1642), Embase (n = 1755), CINAHL (n = 417), and the Cochrane Clinical Trials Register (n = 75), using the search terms (asthma or wheeze) and (pregnan* or perinat* or obstet*). All identied abstracts were independently assessed by two reviewers. The full-text version of each potential article was obtained for assessment by two independent reviewers to establish whether it met the inclusion criteria. Hand searching and reference checking of articles was not conducted, and it was considered unfeasible to search non-English language publications.

Data extraction
Data were extracted using a standardised form by one reviewer and checked by a second reviewer. Any discrepancies were discussed by the investigators in order to reach a consensus. Study authors were contacted to clarify an outcome denition where necessary. Data were extracted for: study design, study characteristics (including year and country of study), subject characteristics (including gestational age at recruitment, subject exclusions, maternal age, body mass index, age, smoking, socio-economic status, prenatal care, race/ethnicity, and co-morbidities), asthma diagnosis, severity, management, and perinatal outcome data for asthma and control groups [mostly reported as n (%), mean (SD), or adjusted odds ratios]. Active asthma management was indicated when the study investigators were involved in the management and treatment of subjects with asthma (Table S1). Perinatal outcome data from each study was entered into a database for electronic extraction prior to analysis. Study quality was assessed independently and scored by two reviewers using the NewcastleOttawa Scale (NOS).29 The NOS is a validated tool for assessing the quality of non-randomized studies, including cohort and casecontrol studies, and has a maximum score of 9. Quality scores of the 40 studies ranged from 4 to 9 (mean 7.7; Table S1), with most studies (76%) scoring 8 or 9. All were considered of adequate quality for inclusion in the analyses.

Inclusion criteria
Articles were included if they contained data from a group of pregnant women with asthma and a control group of pregnant women without asthma, reported at least one perinatal outcome of interest, and were cohort studies (either prospective or retrospective in design). Asthma was dened as physician-diagnosed asthma (whether conrmed or subject self-report), an asthma diagnosis as coded in a database, or asthma fullling American Thoracic Society criteria. In this paper, we report our evaluation of perinatal outcomes related to size at birth [low birthweight, mean birthweight, small for gestational age (SGA), and high birthweight], timing of birth (preterm delivery and preterm labour), and pre-eclampsia.

Included studies
Schatz et al. 14,30 published overlapping data in 1988 and 1995. Only the most recent data, which covered the longest time period (19781989) and included the most denitively matched subjects, were included.14 Stenius-Aarniala et al. 20,31 published two papers with the same total number of subjects in 1995 and 1996, and outcome data was included from the original publication only.31 Data from Mihrshahi et al.16 was not included in the analysis of low birthweight, as recruitment after 36 weeks of gestation could bias results by underestimating the size of the effect.

Study selection
Description of studies
A total of 103 papers were identied for possible inclusion in the review. Of these, 63 publications were excluded for the following reasons: no control group (n = 27), no clear asthma group (n = 5), asthma subjects selected by exacerbation only (n = 3), study published after 1975 but conducted prior to 1975 (n = 2), cross-sectional survey (n = 3), abstract only (n = 3), asthma subgroups only compared with control group (n = 8), no perinatal outcomes reported (n = 3), review article (n = 1), and casecontrol study design (n = 8). Of the 40 remaining publications that met the inclusion criteria, 33 papers describing 11 prospective and 15 retrospective cohort studies were included in the analyses reported in this paper, as

Meta-analysis
Although there are potential challenges inherent in conducting a meta-analysis of observational studies related to biases and diversity in the original studies, performing such analyses is an accepted technique with well-described guidelines,32 which we have followed in this report. The relative risk of the perinatal outcome was examined in women with asthma compared with women without asthma using RevMan version 4.2.7 (Wintertree Software Inc., available from http://ims.cochrane.org/revman). For

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dichotomous outcomes the relative risk with 95% condence interval was calculated using a random-effects model. The difference between relative risks for the active management and no active management subgroups was determined using Altman and Blands method,33 and expressed as a relative risk ratio (RRR) with 95% condence intervals. Where original data had been adjusted for potential confounding factors (Table S1), adjusted odds ratios were pooled using the generic inverse variance method. For continuous outcomes, the weighted mean difference was calculated along with the 95% condence interval. Heterogeneity was examined using the chi-square test (with P < 0.1 considered to indicate signicant heterogeneity), the I2 parameter, and meta-regression. When outcomes were reported in at least ten studies, funnel plots and the Egger test were used to investigate study size effects, which are indicative of possible publication bias (stata 7). Power calculations were conducted using the power and sample size program ps 2.1.30.34 In reporting results of the metaanalysis we followed recommendations from the recent Preferred Reporting Items for Systematic Reviews and MetaAnalyses (PRISMA) consensus statement.35

Results
Low birthweight
Data on low birthweight (dened as a birthweight < 2500 g6,11,13,14,16,21,22,30,3639 or 2500 g40) was reported in 13 publications involving 1 109 907 subjects. The presence of asthma was associated with a signicantly increased risk for low birthweight when compared with women without asthma (RR 1.46, 95% CI 1.221.75; Figure 1). The mean birthweight of infants of mothers with asthma was 93 g lower (95% CI )160, )25 g)17,22,36,38,4144 than that of infants of control mothers. The funnel plot indicated no signicant publication bias (P = 0.336); however, there was signicant heterogeneity between studies (I2 = 87.7%, P < 0.1), which was not improved by removing the three smaller studies (also the studies of lowest quality),21,38,39 nor was it explained by variables included in univariate and multivariate meta-regression analyses (Table S2). However, subgroup analyses of prospective and retrospective studies were suggestive of study design as a possible source of the heterogeneity: there was no effect of asthma on low birthweight in the prospective subgroup (n = 3, RR 1.07, 95% CI 0.76, 1.49, I2 = 4%, P > 0.1), but the retrospective subgroup did indicate a signicant difference (n = 8, RR 1.54, 95% CI 1.261.87, I2 = 90.9%, P < 0.1), even though signicant heterogeneity remained in this subgroup. Subgroup analysis of three studies in which subjects had active management of their asthma by the study investigators or local hospital14,22,38 and eight studies where no active management of asthma was given6,11,13,21,36,37,39,40 demonstrated similar effect sizes (active management, RR 1.55, 95% CI 0.693.46; no active management, RR 1.50, 95% CI 1.231.82; RRR 1.03, 95% CI 0.452.37,

Meta-regression
For meta-analyses with more than ten studies, meta-regression was performed using stata 7 (Stata Corporation, www.stata.com). Where possible, simple and multiple metaregression were conducted for possible explanatory differences among the studies. Potential explanatory variables were control event rate, study design (retrospective/prospective), continent of study, decade conducted, and participant characteristics (proportion experiencing an exacerbation, proportion using ICS, difference between asthma and control groups for current smokers and maternal age).

Doucette13 Jana22 Sheiner11 Kallen37 Demissie6 Acs36 Breton40 Schatz14 Perlow21 L Lao38 Karimi39

Asthma n/N 1/32 36/184 186/1963 919/24750 213/2289 / 68/757 20/486 21/81 9/87 18/76

Control n/N 163/3826 76/370 11800/137205 26510/849254 559/9156 / 2100/37394 12/486 6/130 1/87 1/152 Total (95%CI)

RR (95%CI)

1211/13100 1599/28042

Heterogeneity:P < 0.00001, I = 87.7% Effect: P < 0.0001

1.46 (1.22, 1.75)

0.1

Decreased risk

Increased risk

10

100

Figure 1. Meta-analysis of cohort studies for low birthweight. Increased Risk indicates that the outcome was more likely in subjects with asthma; RR, relative risk; CI, condence interval.

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P = 0.938),33 although only the no-active-management subgroup remained signicant.

Preterm delivery
Preterm delivery (birth prior to 37 completed weeks of gestation) was reported in 18 publications, including 988 252 subjects.6,10,13,14,18,2022,25,30,31,3640,45,46 Maternal asthma was associated with a signicant increased risk of preterm delivery (RR 1.41, 95% CI 1.231.62; Figure 3). There was signicant heterogeneity between studies (I2 = 85.4%, P < 0.1), driven mainly by differences between the retrospective studies. The seven prospective cohort studies showed a signicant effect (RR 1.15, 95% CI 1.011.32) without heterogeneity (I2 = 0%). Multiple meta-regression (Table S2) indicated that the location of the study (Scandinavia),37 also explained some of the variance (P = 0.013). The funnel plot was not signicant (P = 0.224). Further adjustment for covariates in four studies similarly conrmed the effect of asthma on preterm delivery (OR 1.38, 95% CI 1.241.53, heterogeneity P = 0.97, I2 = 0%).6,10,13,25 There were ve studies where asthma was actively managed,14,18,22,31,38 and ten studies where no active asthma management was described.6,10,13,21,25,36,37,39,40,45 There was a signicant effect of maternal asthma on preterm delivery in the no-active-management subcategory (RR 1.50, 95% CI 1.281.75, heterogeneity P < 0.1, I2 = 89.6%; Figure 4), but not in the active management subcategory (RR 1.07, 95% CI 0.911.26, heterogeneity not signicant). The active management studies had 100% power to detect a relative risk of 1.50, as observed in the no-active-management studies. The difference between the relative risks of the no-active-management and active-management subgroups was also signicant (RRR 0.71, 95% CI 0.570.89, P = 0.003).33 Maternal asthma was also associated with a signicantly increased risk of preterm labour (premature uterine

Small for gestational age (SGA)

Infants born SGA were dened as <10th percentile for gestational age, based on normal data from the population,2,14,18,21,25,30,37,40,45 or by a fetal growth ratio < 0.85 (birthweight divided by the mean birthweight of the study population).6,10,44 There was a signicantly increased risk of SGA with maternal asthma (<10th centile, RR 1.23, 95% CI 1.111.37; fetal growth ratio < 0.85, RR 1.20, 95% CI 1.121.27; Figure 2). If all studies were combined regardless of the SGA denition, the overall result was an increased risk of SGA with maternal asthma (RR 1.22, 95% CI 1.141.31). Publication bias was not present (P = 0.604). Although heterogeneity was moderate, this was probably a result of the very large sample size used in some of the studies (signicant heterogeneity was not found among the smaller studies with <2000 asthma subjects, but remained among the larger studies with more than 2000 asthma subjects; data not shown). Results obtained from retrospective and prospective study subgroups were similar (<10th centile: RR 1.24, 95% CI 1.071.42 for retrospective studies; RR 1.21, 95% CI 1.001.46 for prospective studies), and when adjusted for confounding factors, analysis of two studies showed a similar effect size of asthma on SGA (fetal growth ratio < 0.85, OR 1.21, 95% CI 1.10 1.34).6,10 Analysis of data from three studies on high birthweight (>4 kg) was supportive of the effect of maternal asthma on fetal growth (RR 0.84, 95% CI 0.74 0.96, no heterogeneity).6,16,46
Asthma Control n/N n/N th Birth Weight Centile < 10 Centile 201/718 203/717 38/654 15/303 119/1739 51/881 74/871 94/1330 650/24750 17612/849254 29/486 22/486 1888/13100 2954/28042 6/81 2/130 Sub total (95%CI) Fetal Growth Ratio < 0.85 Liu10 268/2193 965/8772 1058/9156 12710/131145 Enriquez44 346/2289 1080/9156 Demissie6 Sub total (95%CI) Total (95%CI) Heterogeneity: P = 0.002, I 2 = 63.7% Effect: P < 0.00001 Clark2 Bakhireva45 Dombrowski18 Bracken25 Kallen37 Schatz14 Breton40 Perlow21

RR (95%CI)

1.23 (1.11, 1.37)

1.20 (1.12, 1.27) 1.22 (1.14, 1.31)

0.1

Decreased risk

Increased risk

10

Figure 2. Meta-analysis of small for gestational age, by outcome denition (birthweight < 10th centile or fetal growth ratio < 0.85). Increased Risk indicates that the outcome is more likely in women with asthma; RR, relative risk; CI, condence interval.

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Dombrowski18 Kallen37 Jana22 Bakhireva 45 Stenius-Aarniala31 Bracken25 D i i 6 Demissie Liu10 Breton40 Acs36 Schatz14 Doucette13 Lao38 Perlow21 Karimi39

Asthma n/N 278/1739 1372/24750 24/184 57/654 32/504 74/872 412/2289 219/2193 1359/13100 107/757 23/486 3/32 3/87 24/81 5/76

Control n/N 139/881 41724/849254 42/370 23/303 13/237 77/1334 1108/9156 570/8772 1887/28042 3390/37394 14/486 204/3850 1/87 5/130 1/152

RR (95%CI)

Total (95%CI) Heterogeneity: P < 0.00001, I 2 = 85.4% Effect: P < 0.00001

1.41 (1.23, 1.62)

0.1

Decreased risk

Increased risk

10

100

Figure 3. Meta-analysis of cohort studies for preterm delivery. Increased Risk indicates that the outcome is more likely in women with asthma; RR, relative risk; CI, condence interval.

Asthma n/N Active Management Lao38 Schatz14 St i A i l 31 Stenius-Aarniala Jana22 Dombrowski18 No Active Management Karimi39 Doucette13 Perlow21 Bakhireva45 Bracken25 Acs36 Liu10 Demissie6 Breton40 Kallen37

Control n/N

RR (95%CI)

3/87 1/87 23/486 14/486 32/504 13/237 24/184 42/370 278/1739 139/881 Subtotal (95%CI) 5/76 1/152 3/32 204/3850 24/81 5/130 57/654 23/303 74/872 77/1334 107/757 3390/37394 219/2193 570/8772 412/2289 1108/9156 1359/13100 1887/28042 1372/24750 41724/849254 Subtotal (95%CI) Total (95%CI)

1.07 (0.91, 1.26)

1.50 (1.28, 1.75) 1.41 (1.23, 1.62)

Heterogeneity: P < 0.00001, I = 85.4% Effect: P < 0.00001

0 .1

Decreased risk

Increased risk

10

100

Figure 4. Meta-analysis of cohort studies for preterm delivery by active asthma management. Increased Risk indicates that the outcome is more likely in women with asthma; RR, relative risk; CI, condence interval.

contractions prior to 37 completed weeks of gestation; RR 1.71, 95% CI 1.142.57, P = 0.009).6,9,10,13,14,2022,36,44 This pooled estimate showed signicant heterogeneity (I2 = 98.2%, P < 0.1) that was partly explained by study design and age differences among subjects (meta-regression, data not shown). In particular, the retrospective subgroup of studies showed a signicant effect on preterm labour (RR 2.18, 95% CI 1.303.66, with heterogeneity), whereas analysis of the prospective subgroup was not signicant (RR 1.08, 95% CI 0.771.51, no heterogeneity). There was no signicant publication bias in the studies reporting preterm labour (P = 0.967). Subgroup analysis by active asthma management demonstrated a signicant effect of asthma on preterm labour

(RR 2.19, 95% CI 1.353.57, heterogeneity 98.7%, P < 0.1), but not in the active management subcategory (RR 0.96, 95% CI 0.731.26, heterogeneity not signicant). This subcategory was adequately powered to detect a relative risk of 2.19 (100% power), as observed in the no-active-management subcategory. The difference between the relative risks of the no-active-management and active-management subgroups was signicant (RRR 0.44, 95% CI 0.250.77, P = 0.004).33

Pre-eclampsia
Data on pre-eclampsia (dened as elevated blood pressure of either >140 mmHg systolic or >90 mmHg diastolic, accompanied by proteinuria) were analysed from 15 cohort

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studies.6,9,10,14,18,19,21,26,31,36,4143,47,48 Two studies excluded cases of pre-existing hypertension,26,47 and one study specically stated that subjects with chronic hypertension were included.14 The remaining studies used International Classication of Diseases, 9th Revision (ICD9) codes or textual descriptions to dene pre-eclampsia. There was a signicantly increased risk of pre-eclampsia among mothers with asthma (RR 1.54, 95% CI 1.321.81) compared with mothers without asthma (Figure 5), although there was heterogeneity (I2 = 80.3%). Meta-regression analysis did not reveal the source of the heterogeneity (P > 0.05; Table S2), and additional subgroup analysis by study design did not explain the heterogeneity (data not shown). Publication bias was not signicant (P = 0.328). Adjustment for various covariates in six studies conrmed the effect of asthma on pre-eclampsia, as the adjusted odds of pre-eclampsia remained signicantly increased in women with asthma compared with women without asthma (OR 1.57, 95% CI 1.241.98, P = 0.0002).6,9,10,19,26,36 Subgroup analysis by active asthma management demonstrated that both subcategories showed signicant effects of maternal asthma on pre-eclampsia (six studies with active management, RR 1.70, 95% CI 1.112.59; nine studies with no active management, RR 1.54, 95% CI 1.281.85). The difference between the relative risks of the no-active-management and active-management subgroups was not signicant (RRR 1.10, 95% CI 0.701.75, P = 0.675).33

Discussion
Asthma is a common chronic disease among pregnant women, and the extent of the risks for both mother and baby during the perinatal period make this a signicant health issue. This meta-analysis indicates that pregnant women with asthma are at a signicantly increased risk of
Asthma n/N 7/153 213/1739 140/27318 25/656 1208/24369 48/486 33/757 494/8672 64/504 4/81 103/2289 3/48 28/198 7/88 Control n/N 5/116 98/881 804/180325 34/1052 31257/835848 36/486 1128/37394 1041/34688 15/237 3/130 192/9156 0/18 9/198 0/106

a range of adverse perinatal outcomes, including low birthweight, SGA, preterm labour and delivery, and pre-eclampsia. These observations are derived from a substantial body of literature spanning several decades and including very large numbers of pregnant women, (over 1 000 000 for low birthweight and over 250 000 for preterm labour), suggesting these results are robust across many settings. As the majority of women with asthma have asthma of mild severity, the size of these risks may be greater in subgroups of asthmatic women, such as those with severe or uncontrolled asthma, or those experiencing exacerbations during pregnancy.49 Maternal asthma reduces fetal growth, with data from our meta-analyses consistently indicating an increased risk of low birthweight and SGA, and a signicant reduction in mean birthweight, among women with asthma. Signicant heterogeneity in the retrospective studies may have been caused by differences in ethnicity between study populations, as the studies from Asia and the Middle East reported the highest risks of low birthweight among women with asthma.38,39 The effect of asthma itself on low birthweight is not as large as that previously described in a smaller meta-analysis for the risk of low birthweight among asthmatic women with severe exacerbations (RR 2.54, 95% CI 1.524.25),49 suggesting that a subgroup of women with exacerbations of asthma may contribute to this overall risk. Other work has suggested that the use of inhaled corticosteroids during pregnancy may protect against low birthweight.24 Further analyses and meta-analyses of subgroups of asthmatic women, perhaps at an individual patient data level, stratied by treatment and disease control, are needed to directly verify these ndings. Maternal asthma signicantly increases the risk of both preterm labour and delivery prior to 37 weeks of gestation. The pooled analysis was conrmed by a smaller analysis of
RR (95%CI)

Dombrowski43 Dombrowski18 Tata19 Triche26 Kallen48 Schatz14 Acs36 Wen9 Stenius-Aarniala31 Perlow21 Demissie6 Tamasi41 Stenius-Aarniala47 Sobande42

Total (95%CI) Heterogeneity: P < 0.00001, I 2 = 80.3% Effect: P < 0.00001

1.54 (1.32, 1.81)

0.1

Decreased risk

Increased risk

10

100

Figure 5. Meta-analysis of cohort studies for pre-eclampsia. Increased Risk indicates that the outcome was more likely in women with asthma; RR, relative risk; CI, condence interval.

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four studies that adjusted their results for important confounding factors such as maternal age, education, race, and co-morbid conditions such as diabetes and hypertension. Several large cohort studies have also shown a signicant effect of maternal asthma on preterm delivery, which may be related to the use of oral steroids.18,25 Dombrowski et al. 18 found that only the subgroup of women with severe asthma (dened as a forced expiratory volume in 1 s, FEV1 < 60% of that predicted, and/or used oral steroids in the 4 weeks prior to study enrolment) had a signicantly increased risk of preterm delivery compared with non-asthmatic women (adjusted OR 2.2, 95% CI 1.24.2). Schatz et al. 50 found a signicant relationship between lower lung function and premature birth, consistent with the concept that more severe asthma is a risk factor. Importantly, our results demonstrated that the risk of preterm labour and delivery is greatly reduced, to a non-signicant level, when active asthma management was provided, suggesting a benecial effect of active asthma management. This is plausible, given that one of the assumed benets of active management would be a reduction in the number of exacerbations, or courses of oral steroids used, both of which have been implicated as contributing to the risk of preterm delivery.25,51 Maternal asthma signicantly increases the risk of preeclampsia, by at least 50%, and this nding was supported by an analysis of six studies where data were adjusted for possible confounding factors. Data from casecontrol studies also support a relationship between pre-eclampsia and asthma, where women were symptomatic during pregnancy,27 or had admissions or emergency department visits for asthma prior to pregnancy.52,53 A recent cohort study found a signicant association between hypertension during pregnancy and lower FEV1 after adjustment for covariates,50 suggesting that the underlying severity of asthma may be important. It is possible that asthma itself is not causing the increased risk of these perinatal outcomes, and rather that the risks described are associations resulting from confounding factors such as socio-economic status. All studies had a control group of women drawn from the same population, which makes this possibility unlikely, and where possible we investigated studies that presented odds ratios adjusted for important confounding factors, and these were supportive of the unadjusted analyses. If the association between maternal asthma and poor perinatal outcome is indeed real, there are three main explanations that could account for the increased risk. Firstly, uncontrolled asthma during pregnancy may lead to adverse outcomes, as a result of chronic maternal hypoxia. Maternal hypoxia could inuence fetal oxygenation,54 with consequences for fetal growth via alterations in placental function.5561 A specic mechanism has been proposed for the effect of maternal asthma on reduced fetal growth, with a reduction in placental 11 b-hydroxysteroid dehydrogenase enzyme activity (resulting

in higher cortisol transfer to the fetus) in women who did not use inhaled steroids associated with reduced birthweight.56,57 The ndings of Schatz et al.50 indicate that reduced lung function may be a marker of poor control of asthma, which could inuence outcomes such as preterm delivery and pre-eclampsia via hypoxic mechanisms. Alternatively, the release of inammatory mediators from the mother in response to asthma may also be involved.4 Other inammatory diseases, when they are active, are also associated with adverse perinatal outcomes, such as low birthweight and preterm delivery.6264 Secondly, there may be a common pathogenesis of both severe asthma and perinatal complications.50 A common pathway leading to hyperactivity of the smooth muscle in both the bronchioles and the myometrium has been proposed to explain the increased incidence of preterm labour in women with asthma;13,65,66 a common pathway of mast cell inltration has been proposed to explain the connection between asthma and preeclampsia.67 Finally, asthma medications may have a direct adverse effect on the mother or fetus during pregnancy. However, the preponderance of the evidence to date suggests that commonly used asthma medications, such as inhaled corticosteroids and inhaled short-acting b-agonists, do not increase perinatal risk, and that treatment with inhaled corticosteroids may actually be protective against outcomes such as low birthweight.4 Further meta-analyses of perinatal outcomes in subgroups of women with asthma using particular medications (theophylline, short acting b2-agonists, inhaled corticosteroids, and oral steroids, in particular) will be useful to further examine this possibility. Whereas the meta-analyses of observational studies in epidemiology (MOOSE) is well described and accepted,32 consideration should be given to the observational nature of the cohort studies used in this review, and the inuence of potential confounding factors, the extent of heterogeneity between studies, and the possibility of publication bias for some outcomes. However, for several outcomes, including SGA, preterm labour and delivery, and pre-eclampsia, we investigated adjusted data where possible and found similar results. In addition, we investigated confounding factors as contributors to the heterogeneity between studies using meta-regression, and in almost all cases there was no change in effect size, making it less likely that confounding explains the observations in the current meta-analysis. It is likely that the heterogeneity is overstated in our meta-analysis compared with traditional meta-analyses because of the very large sample sizes of some of the retrospective cohort studies. We have also investigated the consistency between retrospective and prospective studies, and where there is similarity between these, the analyses are less likely to be inuenced by bias or confounding. The risk of publication bias appears small as none of the formal tests for publication bias reached signicance, making it unlikely that the

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pooled estimates are inated. This review has provided the most comprehensive analysis to date of the risks of poor perinatal outcomes in women with asthma, and shows a consistently moderate effect of asthma on these outcomes. These results have implications for the antenatal care of these women. Some of the reported complications may be minimised by effective asthma-management strategies: in particular, preterm labour and delivery. Exacerbations are key events that may contribute to poor perinatal outcomes,49 and are common in pregnancy, being related to asthma severity, viral infection, poor adherence, and other risk factors such as obesity.28,68 Active asthma management has the potential to reduce the number and severity of exacerbations in pregnancy, but further improvements in this area are needed. As changes in asthma during pregnancy can be unpredictable, and are not always consistent between pregnancies in the same woman,69 it is recommended that women have their asthma monitored at least monthly during pregnancy.70 Further studies should dene optimal management strategies to improve asthma control during pregnancy and prevent exacerbations, with the aim of reducing perinatal complications. In the meantime, despite some heterogeneity, the increased risks demonstrated in these analyses of pregnancies of asthmatic women, suggest that careful medical and obstetric monitoring of the asthmatic mother and her developing baby are warranted.

Acknowledgement
Dr Patrick McElduff is thanked for statistical advice.

Supporting information
The following supplementary materials are available for this article: Table S1. Details of the included studies. Table S2. Results of meta-regression analyses. Data S1. Powerpoint slides summarising the study. Additional Supporting Information may be found in the online version of this article. Please note: Wiley-Blackwell are not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing material) should be directed to the corresponding author. j

References
1 Kwon HL, Belanger K, Bracken MB. Asthma prevalence among pregnant and childbearing-aged women in the United States: estimates from national health surveys. Ann Epidemiol 2003;13:31724. 2 Clark JM, Hulme E, Devendrakumar V, Turner MA, Baker PN, Sibley CP, et al. Effect of maternal asthma on birthweight and neonatal outcome in a British inner-city population. Paediatr Perinat Epidemiol 2007;21:15462. 3 Kurinczuk JJ, Parsons DE, Dawes V, Burton PR. The relationship between asthma and smoking during pregnancy. Women Health 1999;29:3147. 4 Murphy VE, Gibson PG, Smith R, Clifton VL. Asthma during pregnancy: mechanisms and treatment implications. Eur Respir J 2005;25:73150. 5 Gordon M, Niswander KR, Berendes H, Kantor AG. Fetal morbidity following potentially anoxigenic obstetric conditions VII. Bronchial asthma. Am J Obstet Gynecol 1970;106:4219. 6 Demissie K, Breckenridge MB, Rhoads GG. Infant and maternal outcomes in the pregnancies of asthmatic women. Am J Respir Crit Care Med 1998;158:10915. 7 Demissie K, Marcella SW, Breckenridge MB, Rhoads GG. Maternal asthma and transient tachypnea of the newborn. Pediatrics 1998;102(1 Pt 1):8490. 8 Kallen B, Rydhstroem H, Aberg A. Asthma during pregnancy a population based study. Eur J Epidemiol 2000;16:16771. 9 Wen SW, Demissie K, Liu S. Adverse outcomes in pregnancies of asthmatic women: results from a Canadian population. Ann Epidemiol 2001;11:712. 10 Liu S, Wen SW, Demissie K, Marcoux S, Kramer MS. Maternal asthma and pregnancy outcomes: a retrospective cohort study. Am J Obstet Gynecol 2001;184:906. 11 Sheiner E, Mazor M, Levy A, Wiznitzer A, Bashiri A. Pregnancy outcome of asthmatic patients: a population-based study. J Matern Fetal Med 2005;18:23740. 12 Tamasi L, Somoskovi A, Muller V, Bartfai Z, Acs N, Puho E, et al. A population-based case-control study on the effect of bronchial asthma during pregnancy for congenital abnormalities of the offspring. J Asthma 2006;43:816. 13 Doucette JT, Bracken MB. Possible role of asthma in the risk of preterm labor and delivery. Epidemiology 1993;4:14350. 14 Schatz M, Zeiger RS, Hoffman CP, Harden K, Forsythe A, Chilingar L, et al. Perinatal outcomes in the pregnancies of asthmatic women: a

Disclosure of interests
M.S. has been awarded investigator-initiated research grants from Aerocrine, Genentech, GlaxoSmithKline, and Merck, and acts as a research consultant for Amgen and Merck.

Contribution to authorship
VM: conception, study search and identication, inclusion/ exclusion, data extraction, quality assessment, interpretation and writing. JN: study search and identication, inclusion/exclusion, data extraction, quality assessment, and interpretation. HP: study search and identication, inclusion/exclusion, data extraction, quality assessment, and analysis. MS: conception, interpretation, writing and editing. CC: interpretation and editing. JA: statistical advice and editing. PG: study design and conception, interpretation, writing and editing.

Details of ethics approval

Not applicable.

Funding
Funding was granted by the Kaiser Permanente Southern California Regional Research Committee. Vanessa Murphy was the recipient of an Australian Research Training Fellowship (Part-time) from the National Health and Medical Research Council.

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Murphy et al.

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16 17

18

19

20 21

22

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prospective controlled analysis. Am J Respir Crit Care Med 1995; 151:11704. Minerbi-Codish I, Fraser D, Avnun L, Glezerman M, Heimer D. Inuence of asthma in pregnancy on labor and the newborn. Respiration 1998;65:1305. Mihrshahi S, Belousova E, Marks GB, Peat JK. Pregnancy and birth outcomes in families with asthma. J Asthma 2003;40:1817. Littner Y, Mandel D, Sheffer-Mimouni G, Mimouni FB, Deutsch V, Dollberg S. Nucleated red blood cells in infants of mothers with asthma. Am J Obstet Gynecol 2003;188:40912. Dombrowski MP, Schatz M, Wise R, Momirova V, Landon M, Mabie W, et al. Asthma during pregnancy. Obstet Gynecol 2004; 103:512. Tata LJ, Lewis SA, McKeever TM, Smith CJ, Doyle P, Smeeth L, et al. A comprehensive analysis of adverse obstetric and pediatric complications in women with asthma. Am J Respir Crit Care Med 2007;175:9917. Stenius-Aarniala BS, Hedman J, Teramo KA. Acute asthma during pregnancy. Thorax 1996;51:4114. Perlow JH, Montgomery D, Morgan MA, Towers CV, Porto M. Severity of asthma and perinatal outcome. Am J Obstet Gynecol 1992;167(4 Pt 1):9637. Jana N, Vasishta K, Saha SC, Khunnu B. Effect of bronchial asthma on the course of pregnancy, labour and perinatal outcome. J Obstet Gynaecol 1995;21:22732. Alexander S, Dodds L, Armson BA. Perinatal outcomes in women with asthma during pregnancy. Obstet Gynecol 1998;92:43540. Olesen C, Thrane N, Nielsen GL, Sorensen HT, Olsen J. A population-based prescription study of asthma drugs during pregnancy: changing the intensity of asthma therapy and perinatal outcomes. Respiration 2001;68:25661. Bracken MB, Triche EW, Belanger K, Saftlas A, Beckett WS, Leaderer BP. Asthma symptoms, severity, and drug therapy: a prospective study of effects on 2205 pregnancies. Obstet Gynecol 2003;102:73952. Triche EW, Saftlas AF, Belanger K, Leaderer BP, Bracken MB. Association of asthma diagnosis, severity, symptoms, and treatment with risk of preeclampsia. Obstet Gynecol 2004;104:58593. Rudra CB, Williams MA, Frederick IO, Luthy DA. Maternal asthma and risk of preeclampsia A case-control study. J Reprod Med 2006;51:94100. Murphy VE, Gibson P, Talbot PI, Clifton VL. Severe asthma exacerbations during pregnancy. Obstet Gynecol 2005;106:104654. Wells GA, Shea B, OConnell D, Peterson J, Welch V, Tugwell P. The Newcastle-Ottawa Scale (NOS) for assessing the quality of non-randomized studies in meta-analyses. Paper presented at 3rd symposium on systematic reviews: beyond the basics Oxford. 2000. Schatz M, Zeiger RS, Harden KM, Hoffman CP, Forsythe AB, Chilingar LM, et al. The safety of inhaled beta-agonist bronchodilators during pregnancy. J Allergy Clin Immunol 1988;82:68695. Stenius-Aarniala B, Riikonen S, Teramo K. Slow-release theophylline in pregnant asthmatics. Chest 1995;107:6427. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000;283:200812. Altman DG, Bland JM. Interaction revisited: the difference between two estimates. BMJ 2003;326:219. Dupont WD, Plummer WD. PS power and sample size program available for free on the internet. Control Clin Trials 1997;18:274. Moher D, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol 2009;62:100612.

36 Acs N, Puho E, Banhidy F, Czeizel AE. Association between bronchial asthma in pregnancy and shorter gestational age in a populationbased study. J Matern Fetal Med 2005;18:10712. 37 Kallen B, Otterblad Olausson P. Use of anti-asthmatic drugs during pregnancy. 2. Infant characteristics excluding congenital malformations. Eur J Clin Pharmacol 2007;63:37581. 38 Lao TT, Huengsburg M. Labour and delivery in mothers with asthma. Eur J Obstet Gynecol Reprod Biol 1990;35:18390. 39 Karimi M, Davar R, Mirzaei M, Mirzaei M. Pregnancy outcomes in asthmatic women. Iran J Allergy Asthma Immunol 2008;7:1056. 40 Breton M-C, Beauchesne M-F, Lemiere C, Rey E, Forget A, Blais L. Risk of perinatal mortality associated with asthma during pregnancy. Thorax 2009;64:1016. 41 Tamasi L, Bohacs A, Pallinger E, Falus A, Rigo J, Muller V, et al. Increased interferon-gamma- and interleukin-4-synthesizing subsets of circulating T lymphocytes in pregnant asthmatics. Clin Exp Allergy 2005;35:1197203. 42 Sobande AA, Archibong EI, Akinola SE. Pregnancy outcome in asthmatic patients from high altitudes. Int J Gynaecol Obstet 2002;77:11721. 43 Dombrowski MP, Bottoms SF, Boike GM, Wald J. Incidence of preeclampsia among asthmatic patients lower with theophylline. Am J Obstet Gynecol 1986;155:2657. 44 Enriquez R, Griffen MR, Carroll KN, Wu P, Cooper WO, Gebretsadik T, et al. Effect of maternal asthma and asthma control during pregnancy and perinatal outcomes. J Allergy Clin Immunol 2007;120:62530. 45 Bakhireva LN, Jones KL, Schatz M, Johnson D, Chambers CD. Asthma medication use in pregnancy and fetal growth. J Allergy Clin Immunol 2005;116:5039. 46 Schatz M, Zeiger RS, Hoffman CP, Saunders BS, Harden KM, Forsythe AB. Increased transient tachypnea of the newborn in infants of asthmatic mothers. Am J Dis Child 1991;145:1568. 47 Stenius-Aarniala B, Piirila P, Teramo K. Asthma and pregnancy: a prospective study of 198 pregnancies. Thorax 1988;43:128. 48 Kallen B, Otterblad Olausson P. Use of anti-asthmatic drugs during pregnancy. 1. Maternal characteristics, pregnancy and delivery complications. Eur J Clin Pharmacol 2007;63:36373. 49 Murphy VE, Clifton VL, Gibson PG. Asthma exacerbations during pregnancy: incidence and association with adverse pregnancy outcomes. Thorax 2006;61:16976. 50 Schatz M, Dombrowski M, Wise R, Momirova V, Landon M, Mabie W, et al. Spirometry is related to perinatal outcomes in pregnant women with asthma. Am J Obstet Gynecol 2006;194:1206. 51 Schatz M, Dombrowski MP, Wise R, Momirova V, Landon M, Mabie W, et al. The relationship of asthma medication use to perinatal outcomes. J Allergy Clin Immunol 2004;113:10405. 52 Martel MJ, Rey E, Beauchesne MF, Perreault S, Lefebvre G, Forget A, et al. Use of inhaled corticosteroids during pregnancy and risk of pregnancy induced hypertension: nested case-control study. BMJ 2005;330:230. 53 Martel MJ, Rey E, Beauchesne MF, Perreault S, Forget A, Maghni K, et al. Use of short-actine beta2-agonists during pregnancy and the risk of pregnancy-induced hypertension. J Allergy Clin Immunol 2007;119:57682. 54 McClure JH, James JM. Oxygen administration to the mother and its relation to blood oxygen in the newborn infant. Am J Obstet Gynecol 1960;80:5546. 55 Clifton VL, Giles WB, Smith R, Bisits AT, Hempenstall PA, Kessell CG, et al. Alterations of placental vascular function in asthmatic pregnancies. Am J Respir Crit Care Med 2001;164:54653. 56 Murphy VE, Zakar T, Smith R, Giles WB, Gibson PG, Clifton VL. Reduced 11beta-hydroxysteroid dehydrogenase type 2 activity is

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Adverse perinatal outcomes in women with asthma

57

58

59

60

61

62

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associated with decreased birth weight centile in pregnancies complicated by asthma. J Clin Endocrinol Metab 2002;87: 16608. Murphy VE, Gibson PG, Giles WB, Zakar T, Smith R, Bisits AM, et al. Maternal asthma is associated with reduced female fetal growth. Am J Respir Crit Care Med 2003;168:131723. Clifton VL, Murphy VE. Maternal asthma as a model for examining fetal sex-specic effects on maternal physiology and placental mechanisms that regulate human fetal growth. Placenta 2004;25(Suppl A):S4552. Murphy VE, Johnson RF, Wang YC, Akinsanya K, Gibson PG, Smith R, et al. The effect of maternal asthma on placental and cord blood protein proles. J Soc Gynecol Investig 2005;12:34955. Clifton VL, Vanderlelie J, Perkins AV. Increased anti-oxidant enzyme activity and biological oxidation in placentae of pregnancies complicated by asthma. Placenta 2005;26:7739. Clifton VL, Rennie N, Murphy VE. Effect of inhaled glucocorticoid treatment on placental 11beta-hydroxysteroid dehydrogenase type 2 activity and neonatal birthweight in pregnancies complicated by asthma. Aust N Z J Obstet Gynaecol 2006;46:13640. Skomsvoll JF, Ostensen M, Irgens LM, Baste V. Obstetrical and neonatal outcome in pregnant patients with rheumatic disease. Scand J Rheumatol Suppl 1998;107:10912. Fonager K, Sorensen HT, Olsen J, Dahlerup JF, Rasmussen SN. Pregnancy outcome for women with Crohns disease: a follow-up study based on linkage between national registries. Am J Gastroenterol 1998;93:242630.

64 Bowden AP, Barrett JH, Fallow W, Silman AJ. Women with inammatory polyarthritis have babies of lower birth weight. J Rheumatol 2001;28:3559. 65 Bertrand JM, Riley SP, Popkin J, Coates AL. The long-term pulmonary sequelae of prematurity: the role of familial airway hyperreactivity and the respiratory distress syndrome. N Engl J Med 1985;312:7425. 66 Kramer MS, Coates AL, Michoud MC, Dagenais S, Moshonas D, Davis GM, et al. Maternal asthma and idiopathic preterm labor. Am J Epidemiol 1995;142:107888. 67 Siddiqui S, Goodman N, McKenna S, Goldie M, Waugh J, Brightling CE. Pre-eclampsia is associated with airway hyperresponsiveness. BJOG 2008;115:5202. 68 Hendler I, Schatz M, Momirova V, Wise R, Landon M, Mabie W, et al. Association of obesity with pulmonary and nonpulmonary complications of pregnancy in asthmatic women. Obstet Gynecol 2006;108:7782. 69 Schatz M, Harden K, Forsythe A, Chilingar L, Hoffman C, Sperling W, et al. The course of asthma during pregnancy, post partum, and with successive pregnancies: a prospective analysis. J Allergy Clin Immunol 1988;81:50917. 70 National Heart, Lung and Blood Institute; National Asthma Education and Prevention Program Asthma and Pregnancy Working Group NAEPP expert panel report. Managing asthma during pregnancy: recommendations for pharmacologic treatment-2004 update. J Allergy Clin Immunol 2005;115:3446.

Journal club Discussion points

1. Objective and background: Describe the management of pregnant women with asthma in your area and compare with published recommendations (www.brit-thoracic.org.uk/Portals/0/Clinical%20Information/Asthma/Guidelines/ sign101%20revised%20June%2009.pdf).1 Evaluate the pre-existing literature on asthma and pregnancy outcome. Discuss factors that might inuence the outcome for these women. 2. Methods: Compare the use of subject (e.g. MeSH) and free terms for literature searches. Critically appraise the use of sensitivity analysis for systematic reviews, particularly when the heterogeneity of the studies is high, as is the case in this review. 3. Results & implications: Discuss why there was no effect of asthma on birthweight in the prospective studies. Brainstorm plausible pathophysiological reasons for the effect of asthma on birthweight found in retrospective studies. Why do you think the location of the study might have inuenced the rate of preterm delivery for women with asthma? (Data S1). j

D Siassakos NIHR Academic Clinical Lecturer in Obstetrics and Gynaecology, University of Bristol & Southmead Hospital, Bristol, UK Email jsiasakos@gmail.com

Reference
1 Saving Mothers Lives: reviewing maternal deaths to make motherhood safer: 20062008. BJOG 2011;118:1203.

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