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Low risk of adverse obstetrical and perinatal outcome in pregnancies complicated by asthma: A case control study
Accepted Manuscript Low risk of adverse obstetrical and perinatal outcome in pregnancies complicated by asthma: A case control study Zarqa Ali, Lisbeth Nilas, Charlotte Suppli Ulrik PII:
S0954-6111(16)30257-8
DOI:
10.1016/j.rmed.2016.10.004
Reference:
YRMED 5025
To appear in:
Respiratory Medicine
Received Date: 12 May 2016 Revised Date:
20 September 2016
Accepted Date: 10 October 2016
Please cite this article as: Ali Z, Nilas L, Ulrik CS, Low risk of adverse obstetrical and perinatal outcome in pregnancies complicated by asthma: A case control study, Respiratory Medicine (2016), doi: 10.1016/ j.rmed.2016.10.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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ACCEPTED MANUSCRIPT
Low risk of adverse obstetrical and perinatal outcome in pregnancies complicated by asthma: A case control study
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Zarqa Ali MD1, Lisbeth Nilas MD DMSc2,3 & Charlotte Suppli Ulrik MD DMSc1,3 Department of Pulmonary Medicine, Hvidovre Hospital
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Department of Gynaecology and Obstetrics, Hvidovre Hospital
3
Institute of Clinical Medicine, University of Copenhagen
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Copenhagen, Denmark
The authors (ZA, LN & CSU) declare that they have no conflict of interests in relation to this manuscript.
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Correspondence:
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Key words: asthma, pregnancy, outcome, management program, case-control
Zarqa Ali MD
Dept. of Pulmonary Medicine 253 Hvidovre Hospital
DK-2650 Hvidovre E-mail [email protected]
ACCEPTED MANUSCRIPT Abstract Background: Asthma in pregnancy have been associated with an increased risk of pregnancy complications. Our aim was to estimate incidence and describe risk factors for adverse obstetrical and perinatal outcomes in pregnant women with asthma. Methods: Women enrolled in the Management of Asthma during Pregnancy (MAP) program were
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each matched with three controls (i.e. consecutive women giving birth at our obstetrical service). Asthma severity was classified according to treatment step. Data on obstetrical and perinatal outcomes were obtained from medical records. Logistic regression analysis was applied, and findings expressed as odds ratios (OR) unadjusted and adjusted (adj) for BMI, age, parity, smoking,
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ethnicity and marital status.
Results: Nine-hundred-thirty-nine pregnancies in women with asthma (i.e. cases) were compared to
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2.782 controls. Overall, the incidence of complications was low, although women with asthma had a statistically significant higher risk of pre-eclampsia (5% vs.3%, ORadj 1.60, 95% CI 1.07-2.38; p=0.02) and small for gestational age neonates (SGA) (ORadj 1.30, 95% CI 1.10-1.54; p<0.01) compared to controls. Compared to mild asthma, more severe asthma was associated with a higher risk of SGA (60% vs 53%, ORadj. 1.30, 95% CI 1.10-1.54; p<0.01). Women with asthma exacerbation during pregnancy tended to have a higher risk of severe pre-eclampsia (ORadj 3.33
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95% CI 0.96-11.65, p=0.06) compared to pregnancies without any exacerbations. Conclusion: The overall risk of adverse obstetrical and perinatal outcomes in pregnancies complicated by asthma is low compared to non-asthmatic women. Our observations suggest that
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outcome.
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enrollment into an asthma management program has a positive impact on overall pregnancy
ACCEPTED MANUSCRIPT Introduction Asthma is a common respiratory disorder among women of child-bearing age (1), which has been associated with an increased risk of pregnancy complications and adverse perinatal outcomes, but the observations published so far are conflicting (2). While several studies have reported an association between maternal asthma and adverse pregnancy outcome such as pre-eclampsia (3, 4),
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gestational diabetes (5, 6), placenta praevia (4), premature rupture of the membranes (PROM) (5), postpartum hemorrhage (5, 7), anemia (7), caesarean delivery (7-11), malformations (12), small for gestational age (SGA) (10, 13, 14), low birth weight (LBW) (11, 15, 16), and preterm delivery (4, 15), others have not found an association (11, 16-19). In general, larger database studies have
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reported increased risks (4, 5, 13, 14), whereas smaller clinical prospective studies have not found significantly increased risks (6, 7, 18, 20, 21). This discrepancy may be caused by variation in study
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size, regular follow-up visits in prospective studies, and lack of information on asthma characteristics, including severity, treatment and incidence of exacerbations (15). Due to these conflicting results, prospective studies of large cohorts are needed to clarify the association between asthma, asthma severity and pregnancy outcome.
The aim of the present study was, therefore, to investigate the effect of maternal asthma, including asthma severity and occurrence of exacerbations, on obstetrical and perinatal outcomes in a case-
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control study of a large sample of pregnant women.
ACCEPTED MANUSCRIPT Materials and Methods Material The prospective cohort study, the Management of Asthma during Pregnancy (MAP) program, was initiated in 2007, and since then pregnant women have consecutively been recruited through the
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Department of Gynecology and Obstetrics, Hvidovre Hospital. All pregnant women referred to Hvidovre Hospital (approximately 7.000 per year, corresponding to 10% of infants born in Denmark) are informed about the study as part of the welcome letter from the Department of Gynecology and Obstetrics. The letter includes an invitation to participate in the MAP-program
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together with an e-mail address for response ([email protected]). All women who accepted the invitation were, irrespective of time point during pregnancy, given a scheduled
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appointment (by letter) at the out-patient clinic, Department of Pulmonary Medicine. In the present analysis, only women who fulfilled all of the following inclusion criteria were included: 1) Current diagnosis of asthma (defined according to the GINA-guidelines) (22), 2) Current prescribed treatment with at least rescue bronchodilator, 3) First visit to the outpatient clinic at the Department of Pulmonary Medicine within the first 18 weeks of pregnancy, and 4) age 17 to 50 years old.
The participants were prospectively followed from recruitment and seen
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approximately every 4 weeks during pregnancy and 3 months postpartum; if necessary, patients were also seen at unscheduled visits. Case history, incl. age at diagnosis, tobacco exposure and acute exacerbations (previously and/or during first trimester of pregnancy) were obtained, attention was also paid to adherence and device technique. Medication use and exacerbation incidence were
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confirmed by pharmacy records. Level of asthma control was, according to GINA guidelines (22), assessed on the basis of history of day- and night-time symptoms, use of rescue medication together
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with objective assessment, incl. spirometry and level of fractional exhaled nitric oxide (FENO). The adjustment of medication was done in accordance with what was later described by Powell et al. (23) to maintain the women under tight asthma control. Each case was matched to three controls. The controls were the three consecutive women giving birth at Hvidovre Hospital. Data on obstetrical and perinatal outcomes were extracted from the patient’s medical records.
ACCEPTED MANUSCRIPT Ethics statement This study was performed in accordance with the Helsinki II declaration, and according to Danish legislation. The study was approved by the Research Ethics Committee of the Capital Region of Denmark (H-D-2007-0051) and permission has also been obtained from the Danish Data Protection
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Agency (2007-41-0770).
Definitions and Methods Definitions:
The severity of asthma was categorized as mild or moderate/severe based on the prescribed level
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of treatment according to the GINA guidelines (22), with mild asthma defined as treatment step 1 or 2 and moderate/severe asthma as disease that required step 3, 4 or 5 treatment (22). Exacerbations
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were defined according to the official American Thoracic Society/European Respiratory Society guidelines on asthma control and exacerbations (24), and categorized as mild (defined as exacerbations managed by an increase in therapy, but not requiring oral corticosteroids) or severe (defined as exacerbations requiring hospital admission, emergency department treatment and/or a rescue course of systemic corticosteroid).
Body Mass Index (BMI) was calculated based on self-reported pre-pregnancy bodyweight in
non-western countries.
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kilograms divided by height in meters2 at the first visit. Immigrants were defined as patients born in
Low birth weight (LBW) was defined as birth weight 1000-2500g, very low birth weight (VLBW)
gestational age.
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as less than or equal to 1000 g, and macrosomia as birth weight more than 4500 g irrespective of
The gestational age (GA) of the infant was calculated from the nucheal translucency scan at week
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12-14, or if this was not performed, from the first day of the last menstrual period. Preterm birth was defined as delivery between GA 32 and 37 weeks, very preterm birth between GA 28 and 32 weeks and extremely preterm birth as delivery before 28 weeks of gestation. Post-term pregnancy was defined as a pregnancy exceeding 42 weeks of pregnancy. Each infant's z score, the deviation of the measured fetal weight from the expected fetal weight for each gestational age and sex using published ultrasonically estimated fetal weights, was calculated and expressed as standard deviations (25). Small for gestational age (SGA) was defined as birth weight z-score ≤ -2 and large for gestational age (LGA) as z-score ≥ +2.
ACCEPTED MANUSCRIPT Apgar score was evaluated after 5 minutes, and the cut-off point was set to 7 (26). Fetal malformations and chromosomal abnormality included spina bifida, cleft lip, tongue-tie, hydro nephrosis, Down’s syndrome, and talipes equinovarus. Instrumental delivery was defined as vaginal delivery using vacuum extraction or forceps.
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Pregnancy complications were recorded according to The International Classification of Diseases 10 (ICD-10), including pre-eclampsia/eclampsia (O14-15), gestational diabetes (O24), gestational hypertension (O13), premature rupture of membranes (PROM) (O42), and anemia (D64.9). Psychiatric co-morbidity included mental and behavioral disorders, incl. mental development
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disorders (F00-F99).
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Statistical analysis
Data analyses were performed using SAS Enterprise Guide 7.1. Continuous data were analyzed using the two-tailed Student t-test. Binary outcomes were analyzed using the chi-square test. Logistic regression analysis was used to estimate odds ratio (OR) as the measure of association, with 95% confidence intervals (CI). The crude OR and OR adjusted for potential confounding
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variables were estimated, with the following included as potential confounding variables: pregnancy maternal age and BMI (continuous variables), primiparity, smoking at onset of pregnancy, immigrant status and cohabitating with the child’s father (categorical variables). A p-value < 0.05
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was considered significant.
ACCEPTED MANUSCRIPT Results Baseline characteristics Over a 7-year period, 1,018 pregnancies (i.e. cases) in 986 women with asthma were enrolled prospectively. However, 80 cases were excluded due to delivery at another hospital, leaving 938 for analysis. Of the 2,820 women in the control group, 42 were excluded due to missing data in the
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medical records, leaving 2,778 for analysis. Compared to the controls, women with asthma were more often non-smokers and primiparous, were less often immigrants, and had more often attended prenatal screening (Table 1).
Based on the current level of therapy, the majority of cases had mild asthma (71%, n=666),
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whereas 29% (n=272) were classified as having moderate to severe asthma (Table 2). At the first visit, 58% (n=541) of the cases were prescribed inhaled corticosteroids (ICS), increasing to 67%
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later in pregnancy. The proportion of women classified as having uncontrolled asthma at each of the visits to the respiratory outpatient clinic is given in Fig. 1. At least one exacerbation during pregnancy was seen in 37% (n=343) of the women; and 41% of the exacerbations could be classified as severe. The frequency of exacerbations in each trimester is given in Fig.2.
Pregnancy complication in women with asthma vs women without asthma
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The mean fetal weight was lower in women with asthma than in controls: 3379g (SD 571) versus 3438g (SD 561) (p=0.006). Of the women with asthma, 5% had pre-eclampsia compared to 3% in controls (ORadj 1.54, 95% CI 1.05-2.25; p=0.027). Furthermore, women with asthma had increased risk of having a SGA child (ORadj 1.31, 95% CI 1.12-1.55; p=0.001). Maternal asthma was
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associated with a statistically significant increase in risk of gestational diabetes (ORadj 1.78, 95% CI
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1.01-3.13; p=0.047) (Table 3).
Pregnancy complications in women with asthma Women with moderate/severe asthma had significantly increased risk of pregnancies complicated by SGA (60% versus 53%, ORadj. 1.43, 95% CI 1.05-1.94; p=0.022), whereas the risk of preterm birth were significantly higher in women with mild asthma (6%) compared to women with moderate/severe asthma (3%) (ORadj 0.42, 95% CI 0.19-0.92; p=0.030) (Fig 3). The risk of SGA was not different in women with and without an exacerbation of asthma during pregnancy (Fig 4). In line with this, no difference in risk of SGA was found between women having severe vs. mild exacerbation during pregnancy and severe vs. mild or no exacerbation.
ACCEPTED MANUSCRIPT The analysis was repeated after exclusion of twin pregnancies and women giving birth to more than one child during study period, beyond those already mentioned induction of labor and planned and
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emergency caesarian section were significant.
ACCEPTED MANUSCRIPT Discussion This large case-control study of pregnant women with asthma managed regularly in a specialist care setting during pregnancy experience pregnancy complications and adverse outcomes close to what was seen among non-asthmatic controls; although we observed a statistically significant
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increase in risk for preeclampsia and SGA, with an increase in the latter risk with increasing asthma severity.
The increased risk of SGA in women with asthma is in keeping with a number of other studies (4, 8, 13, 27, 28). Chronic hypoxia at high altitudes (more than 2,500 m), is associated with reduced
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blood volume, interferes with the maternal circulatory adjustments to pregnancy, and leads to a reduced uteroplacental blood flow and reduced birth weight (29, 30). Asthma in pregnancy can also
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induce hypoxia, which combined with respiratory alkalosis, may reduce placental blood flow (19, 31) and adversely affect fetal growth (32-34). It is therefore likely, that the increased risk of SGA found both in the women with asthma compared to the controls, and in women with moderate/severe asthma compared to those with mild asthma, may be caused by reduced fetal oxygen supply to the developing fetus.
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The incidence of preeclampsia was higher in women with asthma compared to controls in our study, and this finding is in line with a meta-analyses by Murphy et al. (15). We did not find increased risk of preeclampsia among women with moderate/severe asthma; however a larger proportion of women experiencing an exacerbation of asthma during pregnancy had severe
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preeclampsia compared to women not experiencing any exacerbation. Preeclampsia is a condition particularly seen in primiparous women. The majority of first-time mothers in the case group could
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overestimate the risk of preeclampsia although we have adjusted for primiparity.
We found no significant association between maternal asthma and neither LBW nor preterm delivery, which also is in accordance with most other prospective studies (6, 35). Contrary, retrospective studies of asthmatics often find a larger number of adverse outcomes. This discrepancy may partly be explained by varying definition of asthma (in retrospective studies a history of asthma rather than current asthma during pregnancy is used) and lack of adjustment for potential confounding variables. In addition, asthma management and disease control is often more intense in prospective studies which potentially may improve the pregnancy outcome.
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The risk of emergency caesarean was almost significantly elevated (p=0.059) in pregnancies complicated by exacerbations. The increased rate of acute caesarean section is in agreement with most previous studies (7, 8, 13, 28, 36). Higher rate of caesarean section is also seen in other chronic conditions such as inflammatory bowel disease (17, 37) and epilepsy (18). It has been
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suggested that the higher rates of surgical interventions during delivery are related to fetal stress associated with the underlying disease, but may also be explained by both the doctors and the patient’s attitude.
Following enrollment in the management of asthma during pregnancy program, a reduction in
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prevalence of uncontrolled asthma of 80% was observed, likely to be due to the close management strategy applied in specialist care. Furthermore, the majority of exacerbations in our study occurred
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in first trimester of pregnancy. Our results differ from others who found that exacerbations primarily occur in the late second trimester (38). Uncontrolled asthma is a well-known risk factor for an exacerbation (22) and a reduction in cases of uncontrolled asthma could have prevented some exacerbation in second trimester. The standard care program for pregnant women in Denmark includes three visits to their general practitioner, and asthma is not likely to be on the agenda due to other mandatory health issues. The intervention in the present MAP program differs from standard
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care in Denmark with regard to number of visits, objective assessment of asthma control, and by providing specialist care also to patients with mild to moderate asthma. Our study showed, in keeping with previous studies, although the number of studies are limited, that enrollment of pregnant women in an asthma management program improves asthma control (23, 39, 40) and
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probably by that reduces the risk of exacerbations , though we would like to emphasize that no direct comparisons were made between standard care regime and enrollment in an asthma
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management program.
The present study is a large prospective case-control study with several strengths. The study was performed at the hospital with the largest number of deliveries in Denmark covering 10% of all births every year, with a power to detect small, but clinically important differences. Secondly, cases were seen in specialist care by one doctor (CSU) at all visits. Thirdly, the asthma severity classification was based on medication information gathered prospectively and was not registerbased. Fourthly, information on outcomes was prospectively collected, which precludes recall bias. Finally, we adjusted our results for confounding variables (age, BMI, smoking status, marital status,
ACCEPTED MANUSCRIPT primiparity and immigrant status). The confounders are related to the outcome and by adjusting for a number of confounding variables it lead to a better model that is more representative of “real life”. The severity of asthma in our study was categorized based on prescribed step of therapy. Asthma severity assessed by medication intensity may lead to underestimation of severity since many
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pregnant women stop of reduce especially their controller medication during pregnancy. A patient could be classified with mild asthma due to omitting the ICS, even though the asthma is
uncontrolled. This problem appears less relevant in our study, since the proportion of pregnant with uncontrolled asthma subsequently to enrollment into the management program was very low.
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Compared to the women in the control group, the women enrolled in the MAP program were more often non-smokers, had more stable relationships, more often attended for prenatal screening, and were less often immigrants. The participants in the MAP program, therefore, seem more overall
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resourceful than the control group. Gesche et al. (41) have earlier shown that pregnant women declining participation in a randomized lifestyle intervention study have higher parity, are more often single, and more likely to be smokers. However, in the present study, no adjustment was done for socio-economic status.
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Conclusion
In conclusion, the overall risk of adverse obstetrical and perinatal outcomes in women with asthma followed in out-patient clinic during pregnancy is low compared to non-asthmatic women. Maternal asthma during pregnancy is associated with an increased risk of SGA which increases with
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increasing asthma severity. Maternal asthma is also a risk factor for pre-eclampsia.
Acknowledgements
The MAP program was initiated and developed by CSU, and CSU takes responsibility for the integrity of all data on cases as well as responsibility for the content of the manuscript. ZA had full access to all of the data in the study, and takes responsibility for the accuracy of the data analysis. ZA drafted and revised the manuscript. LN and CSU contributed substantially to the study design, data analysis and interpretation, and the writing of the manuscript.
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ACCEPTED MANUSCRIPT Table 1 Background characteristics of the 3,716 pregnancies enrolled in the study, divided according to asthma status into controls (n=2,778) and cases (n=938). p-value
899 (95.8) 40 (4.3) 71 (7.6) 39 (4.2)
2688 (96.8) 90 (3.2) 325 (11.7) 200 (7.2)
NS NS p<0.01 p<0.01
2682 (96.5) 100 (3.6) 2521 (90.7)
NS NS p<0.01
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897 (95.6) 42 (4.5) 877 (93.5)
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Controls 2778 31.3 (18 - 46) 23.4 (15.6 - 45.9) 1511 (54.3)
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Age, yrs BMI, kg/cm2 Primiparity Marital status Living with the child’s father Single parent Immigrants* Current smokers Deliveries Singleton Twin Prenatal screening
Cases 938 31.1 (17 - 44) 24.1 (15.6 - 48.5) 630 (67.1)
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Data are given as mean with range in brackets or numbers with percentages in brackets. * Women from non-western countries.
NS p<0.01 p<0.01
ACCEPTED MANUSCRIPT Table 2: Data on medication use in 1,018 pregnancies with asthma (666 with mild asthma and 272 with moderate/severe asthma) enrolled in the MAP program.
5 (1) 115 (17) 199 (30) 0 12 (2) 0 0 0 0 0
0 21 (8) 98 (36) 1 (1) 139 (51) 2 (1) 5 (2) 1 (0) 17 (6) 8 (3)
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Moderate/severe asthma N=272 272 (100)
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Inhaled corticosteroids Dailydose (Beclometasone equivalent doses) 100 µg 200 µg 400 µg 600 µg 800 µg 1200 µg 1600 µg Oral corticosteroids Long-acting beta-2 agonist Leukotriene receptor antagonist
Mild asthma N=666 357 (54)
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Data are given as numbers with percentages in brackets.
ACCEPTED MANUSCRIPT Table 2 Incidence of pregnancy, delivery and perinatal complications in 3,721 pregnancies, 938 cases with asthma and 2,778 controls, reported as crude and adjusted* odds ratio (OR) with 95% confidence interval (95% CI).
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*
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Adjusted for age, BMI, smoking status, marital status, primiparity and immigrant status. § Premature rupture of membranes BW = birth weight VLBW = Very low birth weight LBW = Low birth weight SGA = Small for gestational age LGA = Large for gestational age
Adjusted OR (95% CI) 2.52 (0.66-9.68) 0.30 (0.04-2.40) 1.05 (0.61-1.81) 1.17 (0.83-1.65) 1.78 (1.01-3.13) 1.28 (0.75-2.19)
47 (5.0) 12 (1.3) 81 (8.6) 101 (10.7) 106 (11.3)
1.69 (1.17-2.43) 1.98 (0.95-4.14) 1.23 (0.94-1.60) 1.24 (0.97-1.58) 1.21 (0.96-1.54)
1.54 (1.05-2.25) 1.77 (0.81-3.88) 1.06 (0.79-1.41) 1.26 (0.97-1.63) 0.98 (0.76-1.27)
0.027 NS NS NS NS
89 (9.5) 119 (12.7)
0.95 (0.74-1.22) 1.31 (1.04-1.64)
1.09 (0.85-1.43) 1.13 (0.88-1.45)
NS NS
3 (0.3) 49 (5.2) 15 (1.6) 518 (55.2) 260 (27.7)
0.81 (0.22-2.90) 1.20 (0.85-1.68) 0.66 (0.37-1.16) 1.30 (1.12-1.50) 0.84 (0.71-0.99)
1.17 (0.29-4.66) 1.11 (0.77-1.59) 0.73 (0.41-1.30) 1.31 (1.12-1.55) 0.85 (0.71-1.02)
NS NS NS 0.001 NS
1 (0.1) 3 (0.3) 53 (5.6) 25 (2.7) 7 (0.7)
0.42 (0.05-3.43) 0.49 (0.14-1.67) 0.95 (0.69-1.31) 1.16 (0.73-1.86) 0.86 (0.37-2.01)
0.49 (0.06-4.36) 0.28 (0.06-1.26) 0.96 (0.69-1.34) 1.09 (0.67-1.80) 0.80 (0.32-2.02)
NS NS NS NS NS
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Unadjusted OR (95% CI) 2.37 (0.64-8.85) 0.23 (0.03-1.74) 1.06 (0.63-1.77) 1.33 (0.96-1.83) 1.94 (1.16-3.27) 1.56 (0.92-2.63)
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Fetal malformations Intrauterine fetal death Anemia Psychiatric co-morbidity Gestational diabetes Gestational hypertension Pre-eclampsia Mild to moderate 84 (3.0) Severe 18 (0.6) § PROM 199 (7.1) Induction of labor 246 (8.8) Vaginal instrumental delivery 264 (9.5) Caesarian section Planned 277 (10.0) Emergency 278 (10.0) Birth weight VLBW (BW≤1000g) 11 (0.4) LBW (10004500g) 67 (2.4) SGA, z-score < -2 1354 (48.7) LGA, z-score > +2 873 (31.4) Birth 7 (0.2) Extremely preterm, GA≤28 18 (0.6) Very preterm, 2842 64 (2.3) Apgar 5 min < 7 24 (0.9)
Cases N (%) 4 (0.4) 1 (0.1) 20 (2.1) 57 (6.1) 24 (2.6) 22 (2.3)
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Controls N (%) 5 (0.2) 13 (0.5) 56 (2.0) 129 (4.6) 37 (1.3) 42 (1.5)
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Complications
p-value adjusted NS NS NS NS 0.047 NS
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Figure 1:
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Uncontrolled asthma (%)
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The proportion of women (%) classified as having uncontrolled asthma at each of the visits to the respiratory out-patient clinic during pregnancy (visit 1 to 7).
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88 150
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Exacerbations (n)
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Occurrence of mild vs. moderate to severe exacerbations according to trimester in 1,283 pregnancies enrolled in the management of asthma during pregnancy (MAP) program.
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Fig.3: Impact of asthma severity (defined as treatment step according to GINA-guidelines) on pregnancy, delivery and perinatal complications in 938 women (666 with mild asthma and 272 with moderate/severe asthma) expressed as adjusted odds ratio with 95% confidence intervals.
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PROM=Premature repture of membranes OR are adjusted for age, BMI, smoking status, marital status, primiparity and immigrant status.
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Fig.4: Impact of exacerbations on pregnancy, delivery and perinatal complications expressed as adjusted odds ratio with 95% confidence intervals.
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PROM=Premature repture of membranes OR are adjusted for age, BMI, smoking status, marital status, primiparity and immigrant status.
ACCEPTED MANUSCRIPT Highlights
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Enrollment in an asthma management program reduces the cases of uncontrolled asthma The risk of adverse pregnancy outcomes are low in women followed in out-patient clinic Maternal asthma is associated with increased risk of pre-eclampsia The risk of small for gestational age babies increases with asthma severity
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-
S0954-6111(16)30257-8
DOI:
10.1016/j.rmed.2016.10.004
Reference:
YRMED 5025
To appear in:
Respiratory Medicine
Received Date: 12 May 2016 Revised Date:
20 September 2016
Accepted Date: 10 October 2016
Please cite this article as: Ali Z, Nilas L, Ulrik CS, Low risk of adverse obstetrical and perinatal outcome in pregnancies complicated by asthma: A case control study, Respiratory Medicine (2016), doi: 10.1016/ j.rmed.2016.10.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Low risk of adverse obstetrical and perinatal outcome in pregnancies complicated by asthma: A case control study
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Zarqa Ali MD1, Lisbeth Nilas MD DMSc2,3 & Charlotte Suppli Ulrik MD DMSc1,3 Department of Pulmonary Medicine, Hvidovre Hospital
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Department of Gynaecology and Obstetrics, Hvidovre Hospital
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Institute of Clinical Medicine, University of Copenhagen
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Copenhagen, Denmark
The authors (ZA, LN & CSU) declare that they have no conflict of interests in relation to this manuscript.
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Correspondence:
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Key words: asthma, pregnancy, outcome, management program, case-control
Zarqa Ali MD
Dept. of Pulmonary Medicine 253 Hvidovre Hospital
DK-2650 Hvidovre E-mail [email protected]
ACCEPTED MANUSCRIPT Abstract Background: Asthma in pregnancy have been associated with an increased risk of pregnancy complications. Our aim was to estimate incidence and describe risk factors for adverse obstetrical and perinatal outcomes in pregnant women with asthma. Methods: Women enrolled in the Management of Asthma during Pregnancy (MAP) program were
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each matched with three controls (i.e. consecutive women giving birth at our obstetrical service). Asthma severity was classified according to treatment step. Data on obstetrical and perinatal outcomes were obtained from medical records. Logistic regression analysis was applied, and findings expressed as odds ratios (OR) unadjusted and adjusted (adj) for BMI, age, parity, smoking,
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ethnicity and marital status.
Results: Nine-hundred-thirty-nine pregnancies in women with asthma (i.e. cases) were compared to
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2.782 controls. Overall, the incidence of complications was low, although women with asthma had a statistically significant higher risk of pre-eclampsia (5% vs.3%, ORadj 1.60, 95% CI 1.07-2.38; p=0.02) and small for gestational age neonates (SGA) (ORadj 1.30, 95% CI 1.10-1.54; p<0.01) compared to controls. Compared to mild asthma, more severe asthma was associated with a higher risk of SGA (60% vs 53%, ORadj. 1.30, 95% CI 1.10-1.54; p<0.01). Women with asthma exacerbation during pregnancy tended to have a higher risk of severe pre-eclampsia (ORadj 3.33
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95% CI 0.96-11.65, p=0.06) compared to pregnancies without any exacerbations. Conclusion: The overall risk of adverse obstetrical and perinatal outcomes in pregnancies complicated by asthma is low compared to non-asthmatic women. Our observations suggest that
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outcome.
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enrollment into an asthma management program has a positive impact on overall pregnancy
ACCEPTED MANUSCRIPT Introduction Asthma is a common respiratory disorder among women of child-bearing age (1), which has been associated with an increased risk of pregnancy complications and adverse perinatal outcomes, but the observations published so far are conflicting (2). While several studies have reported an association between maternal asthma and adverse pregnancy outcome such as pre-eclampsia (3, 4),
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gestational diabetes (5, 6), placenta praevia (4), premature rupture of the membranes (PROM) (5), postpartum hemorrhage (5, 7), anemia (7), caesarean delivery (7-11), malformations (12), small for gestational age (SGA) (10, 13, 14), low birth weight (LBW) (11, 15, 16), and preterm delivery (4, 15), others have not found an association (11, 16-19). In general, larger database studies have
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reported increased risks (4, 5, 13, 14), whereas smaller clinical prospective studies have not found significantly increased risks (6, 7, 18, 20, 21). This discrepancy may be caused by variation in study
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size, regular follow-up visits in prospective studies, and lack of information on asthma characteristics, including severity, treatment and incidence of exacerbations (15). Due to these conflicting results, prospective studies of large cohorts are needed to clarify the association between asthma, asthma severity and pregnancy outcome.
The aim of the present study was, therefore, to investigate the effect of maternal asthma, including asthma severity and occurrence of exacerbations, on obstetrical and perinatal outcomes in a case-
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control study of a large sample of pregnant women.
ACCEPTED MANUSCRIPT Materials and Methods Material The prospective cohort study, the Management of Asthma during Pregnancy (MAP) program, was initiated in 2007, and since then pregnant women have consecutively been recruited through the
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Department of Gynecology and Obstetrics, Hvidovre Hospital. All pregnant women referred to Hvidovre Hospital (approximately 7.000 per year, corresponding to 10% of infants born in Denmark) are informed about the study as part of the welcome letter from the Department of Gynecology and Obstetrics. The letter includes an invitation to participate in the MAP-program
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together with an e-mail address for response ([email protected]). All women who accepted the invitation were, irrespective of time point during pregnancy, given a scheduled
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appointment (by letter) at the out-patient clinic, Department of Pulmonary Medicine. In the present analysis, only women who fulfilled all of the following inclusion criteria were included: 1) Current diagnosis of asthma (defined according to the GINA-guidelines) (22), 2) Current prescribed treatment with at least rescue bronchodilator, 3) First visit to the outpatient clinic at the Department of Pulmonary Medicine within the first 18 weeks of pregnancy, and 4) age 17 to 50 years old.
The participants were prospectively followed from recruitment and seen
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approximately every 4 weeks during pregnancy and 3 months postpartum; if necessary, patients were also seen at unscheduled visits. Case history, incl. age at diagnosis, tobacco exposure and acute exacerbations (previously and/or during first trimester of pregnancy) were obtained, attention was also paid to adherence and device technique. Medication use and exacerbation incidence were
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confirmed by pharmacy records. Level of asthma control was, according to GINA guidelines (22), assessed on the basis of history of day- and night-time symptoms, use of rescue medication together
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with objective assessment, incl. spirometry and level of fractional exhaled nitric oxide (FENO). The adjustment of medication was done in accordance with what was later described by Powell et al. (23) to maintain the women under tight asthma control. Each case was matched to three controls. The controls were the three consecutive women giving birth at Hvidovre Hospital. Data on obstetrical and perinatal outcomes were extracted from the patient’s medical records.
ACCEPTED MANUSCRIPT Ethics statement This study was performed in accordance with the Helsinki II declaration, and according to Danish legislation. The study was approved by the Research Ethics Committee of the Capital Region of Denmark (H-D-2007-0051) and permission has also been obtained from the Danish Data Protection
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Agency (2007-41-0770).
Definitions and Methods Definitions:
The severity of asthma was categorized as mild or moderate/severe based on the prescribed level
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of treatment according to the GINA guidelines (22), with mild asthma defined as treatment step 1 or 2 and moderate/severe asthma as disease that required step 3, 4 or 5 treatment (22). Exacerbations
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were defined according to the official American Thoracic Society/European Respiratory Society guidelines on asthma control and exacerbations (24), and categorized as mild (defined as exacerbations managed by an increase in therapy, but not requiring oral corticosteroids) or severe (defined as exacerbations requiring hospital admission, emergency department treatment and/or a rescue course of systemic corticosteroid).
Body Mass Index (BMI) was calculated based on self-reported pre-pregnancy bodyweight in
non-western countries.
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kilograms divided by height in meters2 at the first visit. Immigrants were defined as patients born in
Low birth weight (LBW) was defined as birth weight 1000-2500g, very low birth weight (VLBW)
gestational age.
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as less than or equal to 1000 g, and macrosomia as birth weight more than 4500 g irrespective of
The gestational age (GA) of the infant was calculated from the nucheal translucency scan at week
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12-14, or if this was not performed, from the first day of the last menstrual period. Preterm birth was defined as delivery between GA 32 and 37 weeks, very preterm birth between GA 28 and 32 weeks and extremely preterm birth as delivery before 28 weeks of gestation. Post-term pregnancy was defined as a pregnancy exceeding 42 weeks of pregnancy. Each infant's z score, the deviation of the measured fetal weight from the expected fetal weight for each gestational age and sex using published ultrasonically estimated fetal weights, was calculated and expressed as standard deviations (25). Small for gestational age (SGA) was defined as birth weight z-score ≤ -2 and large for gestational age (LGA) as z-score ≥ +2.
ACCEPTED MANUSCRIPT Apgar score was evaluated after 5 minutes, and the cut-off point was set to 7 (26). Fetal malformations and chromosomal abnormality included spina bifida, cleft lip, tongue-tie, hydro nephrosis, Down’s syndrome, and talipes equinovarus. Instrumental delivery was defined as vaginal delivery using vacuum extraction or forceps.
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Pregnancy complications were recorded according to The International Classification of Diseases 10 (ICD-10), including pre-eclampsia/eclampsia (O14-15), gestational diabetes (O24), gestational hypertension (O13), premature rupture of membranes (PROM) (O42), and anemia (D64.9). Psychiatric co-morbidity included mental and behavioral disorders, incl. mental development
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disorders (F00-F99).
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Statistical analysis
Data analyses were performed using SAS Enterprise Guide 7.1. Continuous data were analyzed using the two-tailed Student t-test. Binary outcomes were analyzed using the chi-square test. Logistic regression analysis was used to estimate odds ratio (OR) as the measure of association, with 95% confidence intervals (CI). The crude OR and OR adjusted for potential confounding
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variables were estimated, with the following included as potential confounding variables: pregnancy maternal age and BMI (continuous variables), primiparity, smoking at onset of pregnancy, immigrant status and cohabitating with the child’s father (categorical variables). A p-value < 0.05
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was considered significant.
ACCEPTED MANUSCRIPT Results Baseline characteristics Over a 7-year period, 1,018 pregnancies (i.e. cases) in 986 women with asthma were enrolled prospectively. However, 80 cases were excluded due to delivery at another hospital, leaving 938 for analysis. Of the 2,820 women in the control group, 42 were excluded due to missing data in the
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medical records, leaving 2,778 for analysis. Compared to the controls, women with asthma were more often non-smokers and primiparous, were less often immigrants, and had more often attended prenatal screening (Table 1).
Based on the current level of therapy, the majority of cases had mild asthma (71%, n=666),
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whereas 29% (n=272) were classified as having moderate to severe asthma (Table 2). At the first visit, 58% (n=541) of the cases were prescribed inhaled corticosteroids (ICS), increasing to 67%
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later in pregnancy. The proportion of women classified as having uncontrolled asthma at each of the visits to the respiratory outpatient clinic is given in Fig. 1. At least one exacerbation during pregnancy was seen in 37% (n=343) of the women; and 41% of the exacerbations could be classified as severe. The frequency of exacerbations in each trimester is given in Fig.2.
Pregnancy complication in women with asthma vs women without asthma
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The mean fetal weight was lower in women with asthma than in controls: 3379g (SD 571) versus 3438g (SD 561) (p=0.006). Of the women with asthma, 5% had pre-eclampsia compared to 3% in controls (ORadj 1.54, 95% CI 1.05-2.25; p=0.027). Furthermore, women with asthma had increased risk of having a SGA child (ORadj 1.31, 95% CI 1.12-1.55; p=0.001). Maternal asthma was
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associated with a statistically significant increase in risk of gestational diabetes (ORadj 1.78, 95% CI
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1.01-3.13; p=0.047) (Table 3).
Pregnancy complications in women with asthma Women with moderate/severe asthma had significantly increased risk of pregnancies complicated by SGA (60% versus 53%, ORadj. 1.43, 95% CI 1.05-1.94; p=0.022), whereas the risk of preterm birth were significantly higher in women with mild asthma (6%) compared to women with moderate/severe asthma (3%) (ORadj 0.42, 95% CI 0.19-0.92; p=0.030) (Fig 3). The risk of SGA was not different in women with and without an exacerbation of asthma during pregnancy (Fig 4). In line with this, no difference in risk of SGA was found between women having severe vs. mild exacerbation during pregnancy and severe vs. mild or no exacerbation.
ACCEPTED MANUSCRIPT The analysis was repeated after exclusion of twin pregnancies and women giving birth to more than one child during study period, beyond those already mentioned induction of labor and planned and
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emergency caesarian section were significant.
ACCEPTED MANUSCRIPT Discussion This large case-control study of pregnant women with asthma managed regularly in a specialist care setting during pregnancy experience pregnancy complications and adverse outcomes close to what was seen among non-asthmatic controls; although we observed a statistically significant
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increase in risk for preeclampsia and SGA, with an increase in the latter risk with increasing asthma severity.
The increased risk of SGA in women with asthma is in keeping with a number of other studies (4, 8, 13, 27, 28). Chronic hypoxia at high altitudes (more than 2,500 m), is associated with reduced
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blood volume, interferes with the maternal circulatory adjustments to pregnancy, and leads to a reduced uteroplacental blood flow and reduced birth weight (29, 30). Asthma in pregnancy can also
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induce hypoxia, which combined with respiratory alkalosis, may reduce placental blood flow (19, 31) and adversely affect fetal growth (32-34). It is therefore likely, that the increased risk of SGA found both in the women with asthma compared to the controls, and in women with moderate/severe asthma compared to those with mild asthma, may be caused by reduced fetal oxygen supply to the developing fetus.
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The incidence of preeclampsia was higher in women with asthma compared to controls in our study, and this finding is in line with a meta-analyses by Murphy et al. (15). We did not find increased risk of preeclampsia among women with moderate/severe asthma; however a larger proportion of women experiencing an exacerbation of asthma during pregnancy had severe
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preeclampsia compared to women not experiencing any exacerbation. Preeclampsia is a condition particularly seen in primiparous women. The majority of first-time mothers in the case group could
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overestimate the risk of preeclampsia although we have adjusted for primiparity.
We found no significant association between maternal asthma and neither LBW nor preterm delivery, which also is in accordance with most other prospective studies (6, 35). Contrary, retrospective studies of asthmatics often find a larger number of adverse outcomes. This discrepancy may partly be explained by varying definition of asthma (in retrospective studies a history of asthma rather than current asthma during pregnancy is used) and lack of adjustment for potential confounding variables. In addition, asthma management and disease control is often more intense in prospective studies which potentially may improve the pregnancy outcome.
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The risk of emergency caesarean was almost significantly elevated (p=0.059) in pregnancies complicated by exacerbations. The increased rate of acute caesarean section is in agreement with most previous studies (7, 8, 13, 28, 36). Higher rate of caesarean section is also seen in other chronic conditions such as inflammatory bowel disease (17, 37) and epilepsy (18). It has been
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suggested that the higher rates of surgical interventions during delivery are related to fetal stress associated with the underlying disease, but may also be explained by both the doctors and the patient’s attitude.
Following enrollment in the management of asthma during pregnancy program, a reduction in
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prevalence of uncontrolled asthma of 80% was observed, likely to be due to the close management strategy applied in specialist care. Furthermore, the majority of exacerbations in our study occurred
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in first trimester of pregnancy. Our results differ from others who found that exacerbations primarily occur in the late second trimester (38). Uncontrolled asthma is a well-known risk factor for an exacerbation (22) and a reduction in cases of uncontrolled asthma could have prevented some exacerbation in second trimester. The standard care program for pregnant women in Denmark includes three visits to their general practitioner, and asthma is not likely to be on the agenda due to other mandatory health issues. The intervention in the present MAP program differs from standard
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care in Denmark with regard to number of visits, objective assessment of asthma control, and by providing specialist care also to patients with mild to moderate asthma. Our study showed, in keeping with previous studies, although the number of studies are limited, that enrollment of pregnant women in an asthma management program improves asthma control (23, 39, 40) and
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probably by that reduces the risk of exacerbations , though we would like to emphasize that no direct comparisons were made between standard care regime and enrollment in an asthma
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management program.
The present study is a large prospective case-control study with several strengths. The study was performed at the hospital with the largest number of deliveries in Denmark covering 10% of all births every year, with a power to detect small, but clinically important differences. Secondly, cases were seen in specialist care by one doctor (CSU) at all visits. Thirdly, the asthma severity classification was based on medication information gathered prospectively and was not registerbased. Fourthly, information on outcomes was prospectively collected, which precludes recall bias. Finally, we adjusted our results for confounding variables (age, BMI, smoking status, marital status,
ACCEPTED MANUSCRIPT primiparity and immigrant status). The confounders are related to the outcome and by adjusting for a number of confounding variables it lead to a better model that is more representative of “real life”. The severity of asthma in our study was categorized based on prescribed step of therapy. Asthma severity assessed by medication intensity may lead to underestimation of severity since many
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pregnant women stop of reduce especially their controller medication during pregnancy. A patient could be classified with mild asthma due to omitting the ICS, even though the asthma is
uncontrolled. This problem appears less relevant in our study, since the proportion of pregnant with uncontrolled asthma subsequently to enrollment into the management program was very low.
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Compared to the women in the control group, the women enrolled in the MAP program were more often non-smokers, had more stable relationships, more often attended for prenatal screening, and were less often immigrants. The participants in the MAP program, therefore, seem more overall
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resourceful than the control group. Gesche et al. (41) have earlier shown that pregnant women declining participation in a randomized lifestyle intervention study have higher parity, are more often single, and more likely to be smokers. However, in the present study, no adjustment was done for socio-economic status.
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Conclusion
In conclusion, the overall risk of adverse obstetrical and perinatal outcomes in women with asthma followed in out-patient clinic during pregnancy is low compared to non-asthmatic women. Maternal asthma during pregnancy is associated with an increased risk of SGA which increases with
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increasing asthma severity. Maternal asthma is also a risk factor for pre-eclampsia.
Acknowledgements
The MAP program was initiated and developed by CSU, and CSU takes responsibility for the integrity of all data on cases as well as responsibility for the content of the manuscript. ZA had full access to all of the data in the study, and takes responsibility for the accuracy of the data analysis. ZA drafted and revised the manuscript. LN and CSU contributed substantially to the study design, data analysis and interpretation, and the writing of the manuscript.
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18. Schatz M, Zeiger RS, Hoffman CP, Harden K, Forsythe A, Chilingar L, et al. Perinatal outcomes in the pregnancies of asthmatic women: a prospective controlled analysis. American journal of respiratory and critical care medicine. 1995;151(4):1170-4. 19. Stenius-Aarniala BS, Hedman J, Teramo KA. Acute asthma during pregnancy. Thorax. 1996;51(4):411-4. 20. Doucette JT, Bracken MB. Possible role of asthma in the risk of preterm labor and delivery. Epidemiology. 1993;4(2):143-50. 21. Littner Y, Mandel D, Sheffer-Mimouni G, Mimouni FB, Deutsch V, Dollberg S. Nucleated red blood cells in infants of mothers with asthma. American journal of obstetrics and gynecology. 2003;188(2):409-12. 22. Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention www.ginasthma.com [updated 2015]. 23. Powell H, Murphy VE, Taylor DR, Hensley MJ, McCaffery K, Giles W, et al. Management of asthma in pregnancy guided by measurement of fraction of exhaled nitric oxide: a double-blind, randomised controlled trial. Lancet. 2011;378(9795):983-90. 24. Reddel HK, Taylor DR, Bateman ED, Boulet LP, Boushey HA, Busse WW, et al. An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice. American journal of respiratory and critical care medicine. 2009;180(1):59-99. 25. Marsal K, Persson PH, Larsen T, Lilja H, Selbing A, Sultan B. Intrauterine growth curves based on ultrasonically estimated foetal weights. Acta Paediatr. 1996;85(7):843-8. 26. Ehrenstein V, Pedersen L, Grijota M, Nielsen GL, Rothman KJ, Sorensen HT. Association of Apgar score at five minutes with long-term neurologic disability and cognitive function in a prevalence study of Danish conscripts. BMC Pregnancy Childbirth. 2009;9:14. 27. Firoozi F, Lemiere C, Beauchesne MF, Perreault S, Forget A, Blais L. Impact of maternal asthma on perinatal outcomes: a two-stage sampling cohort study. European journal of epidemiology. 2012;27(3):205-14. 28. Rejno G, Lundholm C, Gong T, Larsson K, Saltvedt S, Almqvist C. Asthma during pregnancy in a population-based study--pregnancy complications and adverse perinatal outcomes. PloS one. 2014;9(8):e104755. 29. Mortola JP, Frappell PB, Aguero L, Armstrong K. Birth weight and altitude: a study in Peruvian communities. J Pediatr. 2000;136(3):324-9. 30. Wilson MJ, Lopez M, Vargas M, Julian C, Tellez W, Rodriguez A, et al. Greater uterine artery blood flow during pregnancy in multigenerational (Andean) than shorter-term (European) high-altitude residents. Am J Physiol Regul Integr Comp Physiol. 2007;293(3):R131324. 31. Guy ES, Kirumaki A, Hanania NA. Acute asthma in pregnancy. Critical care clinics. 2004;20(4):731-45, x. 32. Liccardi G, D'Amato M, D'Amato G. Asthma in pregnant patients: pathophysiology and management. Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace / Fondazione clinica del lavoro, IRCCS [and] Istituto di clinica tisiologica e malattie apparato respiratorio, Universita di Napoli, Secondo ateneo. 1998;53(2):151-9. 33. Cousins L. Fetal oxygenation, assessment of fetal well-being, and obstetric management of the pregnant patient with asthma. The Journal of allergy and clinical immunology. 1999;103(2 Pt 2):S343-9. 34. Braems G. Fetal hypoxemia on a molecular level: adaptive changes in the hypothalamic-pituitary-adrenal (HPA) axis and the lungs. European journal of obstetrics, gynecology, and reproductive biology. 2003;110 Suppl 1:S63-9.
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35. Mihrshahi S, Belousova E, Marks GB, Peat JK. Pregnancy and birth outcomes in families with asthma. The Journal of asthma : official journal of the Association for the Care of Asthma. 2003;40(2):181-7. 36. Kim S, Kim J, Park SY, Um HY, Kim K, Kim Y, et al. Effect of pregnancy in asthma on health care use and perinatal outcomes. The Journal of allergy and clinical immunology. 2015;136(5):1215-23 e6. 37. Stephansson O, Larsson H, Pedersen L, Kieler H, Granath F, Ludvigsson JF, et al. Crohn's disease is a risk factor for preterm birth. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2010;8(6):50915. 38. Murphy VE, Clifton VL, Gibson PG. Asthma exacerbations during pregnancy: incidence and association with adverse pregnancy outcomes. Thorax. 2006;61(2):169-76. 39. Lim AS, Stewart K, Abramson MJ, Walker SP, Smith CL, George J. Multidisciplinary Approach to Management of Maternal Asthma (MAMMA): a randomized controlled trial. Chest. 2014;145(5):1046-54. 40. Grzeskowiak LE, Smith B, Roy A, Dekker GA, Clifton VL. An observational study of the impact of an antenatal asthma management service on asthma control during pregnancy. European journal of obstetrics, gynecology, and reproductive biology. 2015;197:48-53. 41. Gesche J, Renault K, Norgaard K, Nilas L. Representativeness of participants in a lifestyle intervention study in obese pregnant women - the difference between study participants and non-participants. Obes Facts. 2014;7(6):351-60.
ACCEPTED MANUSCRIPT Table 1 Background characteristics of the 3,716 pregnancies enrolled in the study, divided according to asthma status into controls (n=2,778) and cases (n=938). p-value
899 (95.8) 40 (4.3) 71 (7.6) 39 (4.2)
2688 (96.8) 90 (3.2) 325 (11.7) 200 (7.2)
NS NS p<0.01 p<0.01
2682 (96.5) 100 (3.6) 2521 (90.7)
NS NS p<0.01
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897 (95.6) 42 (4.5) 877 (93.5)
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Controls 2778 31.3 (18 - 46) 23.4 (15.6 - 45.9) 1511 (54.3)
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Age, yrs BMI, kg/cm2 Primiparity Marital status Living with the child’s father Single parent Immigrants* Current smokers Deliveries Singleton Twin Prenatal screening
Cases 938 31.1 (17 - 44) 24.1 (15.6 - 48.5) 630 (67.1)
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Data are given as mean with range in brackets or numbers with percentages in brackets. * Women from non-western countries.
NS p<0.01 p<0.01
ACCEPTED MANUSCRIPT Table 2: Data on medication use in 1,018 pregnancies with asthma (666 with mild asthma and 272 with moderate/severe asthma) enrolled in the MAP program.
5 (1) 115 (17) 199 (30) 0 12 (2) 0 0 0 0 0
0 21 (8) 98 (36) 1 (1) 139 (51) 2 (1) 5 (2) 1 (0) 17 (6) 8 (3)
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Moderate/severe asthma N=272 272 (100)
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Inhaled corticosteroids Dailydose (Beclometasone equivalent doses) 100 µg 200 µg 400 µg 600 µg 800 µg 1200 µg 1600 µg Oral corticosteroids Long-acting beta-2 agonist Leukotriene receptor antagonist
Mild asthma N=666 357 (54)
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Data are given as numbers with percentages in brackets.
ACCEPTED MANUSCRIPT Table 2 Incidence of pregnancy, delivery and perinatal complications in 3,721 pregnancies, 938 cases with asthma and 2,778 controls, reported as crude and adjusted* odds ratio (OR) with 95% confidence interval (95% CI).
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Adjusted for age, BMI, smoking status, marital status, primiparity and immigrant status. § Premature rupture of membranes BW = birth weight VLBW = Very low birth weight LBW = Low birth weight SGA = Small for gestational age LGA = Large for gestational age
Adjusted OR (95% CI) 2.52 (0.66-9.68) 0.30 (0.04-2.40) 1.05 (0.61-1.81) 1.17 (0.83-1.65) 1.78 (1.01-3.13) 1.28 (0.75-2.19)
47 (5.0) 12 (1.3) 81 (8.6) 101 (10.7) 106 (11.3)
1.69 (1.17-2.43) 1.98 (0.95-4.14) 1.23 (0.94-1.60) 1.24 (0.97-1.58) 1.21 (0.96-1.54)
1.54 (1.05-2.25) 1.77 (0.81-3.88) 1.06 (0.79-1.41) 1.26 (0.97-1.63) 0.98 (0.76-1.27)
0.027 NS NS NS NS
89 (9.5) 119 (12.7)
0.95 (0.74-1.22) 1.31 (1.04-1.64)
1.09 (0.85-1.43) 1.13 (0.88-1.45)
NS NS
3 (0.3) 49 (5.2) 15 (1.6) 518 (55.2) 260 (27.7)
0.81 (0.22-2.90) 1.20 (0.85-1.68) 0.66 (0.37-1.16) 1.30 (1.12-1.50) 0.84 (0.71-0.99)
1.17 (0.29-4.66) 1.11 (0.77-1.59) 0.73 (0.41-1.30) 1.31 (1.12-1.55) 0.85 (0.71-1.02)
NS NS NS 0.001 NS
1 (0.1) 3 (0.3) 53 (5.6) 25 (2.7) 7 (0.7)
0.42 (0.05-3.43) 0.49 (0.14-1.67) 0.95 (0.69-1.31) 1.16 (0.73-1.86) 0.86 (0.37-2.01)
0.49 (0.06-4.36) 0.28 (0.06-1.26) 0.96 (0.69-1.34) 1.09 (0.67-1.80) 0.80 (0.32-2.02)
NS NS NS NS NS
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Unadjusted OR (95% CI) 2.37 (0.64-8.85) 0.23 (0.03-1.74) 1.06 (0.63-1.77) 1.33 (0.96-1.83) 1.94 (1.16-3.27) 1.56 (0.92-2.63)
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Fetal malformations Intrauterine fetal death Anemia Psychiatric co-morbidity Gestational diabetes Gestational hypertension Pre-eclampsia Mild to moderate 84 (3.0) Severe 18 (0.6) § PROM 199 (7.1) Induction of labor 246 (8.8) Vaginal instrumental delivery 264 (9.5) Caesarian section Planned 277 (10.0) Emergency 278 (10.0) Birth weight VLBW (BW≤1000g) 11 (0.4) LBW (1000
Cases N (%) 4 (0.4) 1 (0.1) 20 (2.1) 57 (6.1) 24 (2.6) 22 (2.3)
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Controls N (%) 5 (0.2) 13 (0.5) 56 (2.0) 129 (4.6) 37 (1.3) 42 (1.5)
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Complications
p-value adjusted NS NS NS NS 0.047 NS
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2
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Number of visit
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Figure 1:
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Uncontrolled asthma (%)
25
7
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The proportion of women (%) classified as having uncontrolled asthma at each of the visits to the respiratory out-patient clinic during pregnancy (visit 1 to 7).
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88 150
100
50
117
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Exacerbations (n)
200
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0 1 Trimester
2 Trimester
Mild
Figure 2:
40
3 Trimester
Moderate/severe
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Occurrence of mild vs. moderate to severe exacerbations according to trimester in 1,283 pregnancies enrolled in the management of asthma during pregnancy (MAP) program.
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Fig.3: Impact of asthma severity (defined as treatment step according to GINA-guidelines) on pregnancy, delivery and perinatal complications in 938 women (666 with mild asthma and 272 with moderate/severe asthma) expressed as adjusted odds ratio with 95% confidence intervals.
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PROM=Premature repture of membranes OR are adjusted for age, BMI, smoking status, marital status, primiparity and immigrant status.
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Fig.4: Impact of exacerbations on pregnancy, delivery and perinatal complications expressed as adjusted odds ratio with 95% confidence intervals.
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PROM=Premature repture of membranes OR are adjusted for age, BMI, smoking status, marital status, primiparity and immigrant status.
ACCEPTED MANUSCRIPT Highlights
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Enrollment in an asthma management program reduces the cases of uncontrolled asthma The risk of adverse pregnancy outcomes are low in women followed in out-patient clinic Maternal asthma is associated with increased risk of pre-eclampsia The risk of small for gestational age babies increases with asthma severity
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