Maternal asthma is associated with increased risk of perinatal mortality
Maternal asthma is associated with increased risk of perinatal mortality
Mari Kemppainen 0 3 5
Anna-Maria Lahesmaa-Korpinen 3 5
Paula Kauppi 3 5
Martti Virtanen 3 5
Suvi M. Virtanen 1 2 3 5
Riitta Karikoski 3 4 5
Mika Gissler 3 5
Turkka Kirjavainen 0 3 5
0 Department of Paediatrics, Children's Hospital Helsinki University Hospital , Helsinki , Finland , 2 National Institute for Health and Welfare, Information Services Department, Unit of Statistics and Registers , Helsinki , Finland , 3 Helsinki University, Respiratory Medicine and Allergology , Helsinki , Finland , 4 Helsinki University Central Hospital, Skin and Allergy Hospital , Helsinki , Finland , 5 Nordic Casemix Center , Helsinki , Finland
1 Unit of Nutrition, National Institute for Health and Welfare , Helsinki , Finland , 7 Health Sciences Center, University of Tampere, Center for Child Health Research, University of Tampere , Tampere , Finland
2 Tampere University Hospital, and the Science Center of Pirkanmaa Hospital District , Tampere , Finland
3 Editor: Fabio Luigi Massimo Ricciardolo, University of Torino , ITALY
4 Regional State Administrative Agencies , Tampere , Finland , 10 Karolinska Institute, Department of Neurobiology, Care Sciences and Society, Division of Family Medicine , Stockholm , Sweden
5 Data Availability Statement: Because of the national legal restrictions, authors cannot make deidentified dataset available. Data contains confidential patient information for which access is strongly prohibited. An authorisation from the National Institute of Health and Welfare (THL) and Social Insurance Institution (KELA) is necessary for any use of similar confidential data for research purposes. The contact information for a data access committee in THL is
Asthma is the most common chronic disease during pregnancy and it may have influence Our goal was to assess the association between maternal asthma and the perinatal risks as well as possible effects of asthma medication. The study was based on a nationwide Finnish register-based cohort between the years 1996 and 2012 in the Drug and Pregnancy Database. The register data comprised 962 405 singleton live and stillbirths, 898 333 (93.3%) pregnancies in mothers with neither confirmed asthma nor use of asthma medication (controls), and 26 674 (2.8%) pregnancies with confirmed maternal asthma. 71% of mothers with asthma used asthma medication. The diagnosis of asthma was based on the mothers' right for subsidised medication which is carefully evaluated by strict criteria including pulmonary function testing. Odds ratio was used in comparison. Premature birth (PB), low birth weight, small for gestational age (SGA), neonatal death were the main outcome measures.
Maternal asthma was associated with adjusted odds ratios (aORs) for perinatal mortality
1.24 (95% CI 1.05 to 1.46), preterm birth 1.18 (1.11 to 1.25), low birth weight 1.29 (1.21 to
1.37), fetal growth restriction (SGA) 1.32, (1.24 to 1.40), and asphyxia 1.09 (1.02 to 1.17).
Asthma treatment reduced the increased risk of preterm birth aOR 0.85 (95% CI 0.76 to
on pregnancy outcome.
Funding: Drugs and Pregnancy database is a
collaboration by THL National Institute for Health
and Welfare, Kela Social Insurance Institution and
Fimea Finnish Medicines Agency (main funder).
The funders had no role in study design, data
collection and analysis, decision to publish, or
preparation of the manuscript. The author(s)
received no specific funding for this work.
Competing interests: The authors have declared
that no competing interests exist.
0.96) but mothers with treated asthma had higher risks of fetal growth restriction (SGA) aOR
1.26 (1.10 to 1.45), and asphyxia aOR 1.37 (1.17 to 1.61) than mothers with untreated
Asthma is associated with increased risks of perinatal mortality, preterm birth, low birth
weight, fetal growth restriction (SGA), and asphyxia. Asthma treatment reduces the risk of
preterm delivery, but it does not seem to reduce other complications such as perinatal
Asthma is the most common chronic disease during pregnancy[
]. In Finland, the prevalence
of physician diagnosed asthma has increased from six to ten percent from 1996 to 2006,
asthma mortality and hospitalisation rates are low, and asthma treatment results are excellent
in general [
The importance of public health questions on maternal asthma and asthma medication use
during pregnancy has inspired several studies. However, previous cohort study findings based
on single small cohorts on the relationships between maternal asthma and risk of perinatal
complications have been conflicting [4?9]. By combining cohorts by meta-analysis, asthma
has been shown to increase the risks of preeclampsia, preterm birth, low birth weight, fetal
growth restriction (SGA), neonatal death, and congenital anomalies [
]. There are large
cohort studies of mothers with asthma: three Swedish cohorts of 24 750, 26 586, and a recent
cohort of 108 225, one US of 17,044, and one Canadian cohort of 13 100 mothers with asthma
[4,12?16]. All these cohorts confirmed the association between maternal asthma and the
risks of preterm birth and SGA. In addition, the Canadian cohort also showed an association
between maternal asthma and increased perinatal mortality. Maternal asthma has been
associated also with several mild neonatal complications such as hyperbilirubinemia and transient
respiratory problems [
]. Based on small clinical studies, improved asthma
management is suggested to decrease the asthma related increased perinatal risks[19?21].
We studied pregnancy complications in mothers with asthma in Finland based on
complete, high quality registry data[
]. The data were acquired from the Drugs and Pregnancy
database, which combines information from Finnish health registers. Our aim was to
investigate the pregnancy complication risks associated with asthma and asthma medication.
This is a national, population register based, cohort investigation including information on all
the singleton live and stillbirths in Finland between 1996 and 2012. The data were acquired
from the Finnish Drugs and Pregnancy database [
]. This database is a collaboration by THL
National Institute for Health and Welfare, KELA Social Insurance Institution, and FIMEA
Finnish Medicines Agency. The database contains medical and sociodemographic information
on parents, pregnancy and perinatal outcomes, and reimbursed medication purchases. The
linkage of registers has been approved by the data keepers (THL and KELA). An ethical
committee has approved the formation of this database, and its utilisation in research studies of
general interest. Since the registered women were not contacted, the ethical committee did not
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require informed consent from the study population. Each citizen and permanent resident of
Finland has a personal identity code enabling data linkage between registers. All data were
fully anonymized before analysis. Reporting to the official healthcare registers by public and
private hospitals, and primary health care is mandatory by law.
The Medical Birth Register (MBR) was used to identify all the pregnancies and information
on the outcomes. The registry data is recorded at the time of birth, and include all the live
births and stillbirths ( 22 weeks of pregnancy or birth weight 500 grams).
The National Drug Reimbursement Register (DRR) contains individual-level data on
reimbursed prescription medication purchases and data on the reimbursement for discounted
medication for a restricted number of diseases. In Finland, all of the included asthma
medications require a prescription for purchase. For asthma, the right for subsidised medication is
granted according to strict criteria which include asthma symptoms, six months of regular
medication use, and a reversible airway obstruction diagnostic for asthma in pulmonary
function testing (Table 1). Once a person fulfils the criteria they are offered a right for subsidised
medication, which is permanent for applicants over 16 years of age. In this study, the right for
subsidised asthma medication indicates confirmed asthma. Asthma medication use was
defined as asthma medication purchases during the period between three months prior the
pregnancy and the end of the pregnancy. The three month period before the pregnancy was
selected, because in Finland, the pharmacies are entitled to sell medications for up to three
months at one time.
For comparisons, we identified three groups of mothers: 1) controls as mothers with neither
confirmed asthma nor current use of asthma medication, 2) untreated asthma as mothers with
confirmed asthma but no use of asthma medication, and 3) treated asthma as mothers with
confirmed asthma and use of asthma medication (Fig 1). Also, a fourth group was recognised
as mothers without confirmed asthma but use of asthma medication. This group was excluded
from analysis (Fig 1).
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Fig 1. Demographics of the 962 405 singleton live and stillbirths between 1996 and 2012. The separation into
For study purposes, the Anatomical Therapeutic Chemical (ATC) grouping was used, and
the following categories were identified: inhaled short- and long-acting ?2 agonists (R03AC),
inhaled glucocorticoids (R03BA), inhaled combination of ?2 agonists and glucocorticoids
(R03AK), inhaled short- and long-acting anticholinergics (R03BB), xanthines (R03DA),
leukotriene receptor antagonists (R03DC), and oral glucocorticoids (H02AB).
The primary outcomes of this study were preterm birth (<37 weeks), low birth weight
(<2500 grams), perinatal mortality (stillbirths and early neonatal deaths), and small for
gestational age (defined by population based sex-specific references).[
] In perinatology, the
length of the pregnancy and perinatal mortality are the most commonly used core outcomes of
The secondary outcomes were umbilical cord arterial pH <7.10, Apgar score <7, and
urgent section. Apgar score is a well-established classification system of newborn health. The 5
minute Apgar scores were available in the Medical Birth Register since 2004. The asphyxia
diagnose is made postnatally from the arterial or venous cord pH and Apgar score, or
prenatally from cardiotocogram. The information regarding urgent sections was selected as an
outcome measure to represent an observed consequence of the fetal distress and asphyxia. Urgent
section takes place within 30 minutes on section decision.
The used confounding factors were maternal age, smoking while pregnant, socioeconomic
status based on maternal occupation during pregnancy, and parity. As the reported prevalence
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of epilepsy did not differ between the maternal asthma groups, and as the amount of mothers
with type 1 and 2 diabetes was small, these factors were not used for adjusting.
Differences between different exposure groups were evaluated by chi-squared test for
dichotomous and categorical variables. Adjusted odds ratios (aOR) and 95% confidence
intervals (CI) were estimated to measure all associations, using unconditional logistic regression
analysis. Possible confounding factors were selected based on the literature (see above).
Individuals with missing outcome variables were excluded from the analysis.
The demographic data and criteria for confirmed asthma diagnosis are presented in Fig 1 and
Table 1. Supplemental S1 Table shows characteristics of mothers in detail. The study cohort
included of 962 405 live and stillbirths, 898 333 (93.3%) control mothers and 26 674 (2.8%)
mothers with confirmed asthma, and 5 292 perinatal deaths. For subgroup analysis, asthmatic
mothers were subdivided into 19 059 (2.0%) mothers with treated confirmed asthma, and 7
624 (0.8%) mothers with untreated confirmed asthma. Of the mothers with treated confirmed
asthma, 64.6% used at least two asthma medications belonging to separate ATC-groups.
The main study results are presented in Table 2, and S2 and S3 Tables. S3 Table represents
all adjusted and unadjusted odds ratios. Compared to control pregnancies, the infants born to
mothers with asthma showed increased risk of perinatal mortality, preterm birth, low birth
weight, fetal growth restriction (SGA), umbilical arterial pH below 7.1, Apgar score below 7 at
1 minutes and 5 minutes of age, delivery by urgent section, and birth asphyxia. In a subgroup
analysis comparing pregnancies between mothers with asthma, asthma treatment reduces the
increased risk of preterm birth. However, mothers with treated asthma had higher risks of fetal
growth restriction (SGA) and asphyxia than mothers with untreated asthma.
Table 3 and S4 Table present risk factors associated with each medication type and their
combinations in pregnancies. The use of short-acting ?2 agonists was associated with increased
perinatal mortality, but on the other hand, 71% of mothers with treated asthma used these
short-acting ?2 agonists, and the increased risk of perinatal mortality could be a result of the
underlying disease. The number of used asthma medications increased the risk of low birth
weight and fetal growth restriction in logistic regression analysis on 0, 1, 2, and 3 or more
medications. Each purchased medication group increased the risk of low birth weight by 6% aOR
1.06 (95% CI 1.00 to 1.13, P = 0 .0356), and fetal growth restriction (SGA) by 13% aOR 1.13
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(95% CI 1.07 to 1.19, P < 0.0001). However, the risk of perinatal mortality or preterm birth
did not increase in logistic manner.
This comprehensive register based study shows that confirmed maternal asthma is associated
with the risk of perinatal mortality with the adjusted odds ratio of 1.24 (95% CI 1.05 to 1.46).
In addition, like previously shown, maternal asthma is associated with increased risks of
preterm birth, low birth weight, fetal growth restriction (SGA), and asphyxia. When comparing
treated and untreated group of mothers with asthma, there was no significant difference in
perinatal mortality between the groups, but asthma treatment decreased the increased risk of
preterm birth. However, the risks of SGA and asphyxia remained higher in mothers with
Strengths and limitations
The major strengths of this study are national coverage of the two obligatory registers, the
large size of the study cohort, the strict criteria applied for the diagnosis of persistent asthma,
the exclusion of the use of any asthma medication in the group of control mothers, and
possibility to control several confounding factors such as parity, maternal age, socioeconomic
status, self-reported smoking, and epilepsy.[
] In this study, we have been able to cover some of
the possible weaknesses of previous three published large cohort studies on this subject. The
Swedish study by Ka?lle?n and associates was based on self-reported use of asthma medication
on maternity care visit between 10 and 12 weeks of pregnancy [
]. The US cohort was
based on asthma diagnosis (ICD-9) in patient records, in well-selected hospitals across US and
contained no information on use of asthma medications [
]. The Canadian cohort was
based on purchases of asthma medication of substantial but not whole population of one
province in Canada [
Our cohort included 26 674 (2.8%) children born to mothers with confirmed asthma, and
71% of these mothers used asthma medication. We estimated the use of medication through
the medicine reimbursement registry with full coverage of medications purchased in Finland.
Although not confirmed, we assume that asthma medication purchase reliably correlates to
the real use of medication, and thus serves well for the study purposes.
The limitations of this study are that from this registry data, we were unable to separate
different asthma phenotypes such as allergic and non-allergic asthma or dosing of medication.
Like none of the cohort studies so far, we were not able to control the severity of maternal
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asthma through pulmonary function testing or internationally validated test of asthma control
The data on asthma diagnosis was based on reimbursement records of the national Drug
Reimbursement Register. The criteria for the right for subsidised medication are a key element
when interpreting our results (Table 1). The use of strict criteria through medical
reimbursement guidelines imply that a significant number of mothers with some degree of asthma were
not included in the group of treated confirmed asthma. The results that 37 398 (3.9%) of
mothers had purchased asthma medications without the right for subsidised asthma medication
support this assumption. These mothers were likely to have asthma symptoms but had either
no objective verification of airway reversibility or the need for previous regular asthma
medication for more than six months. The exclusion of mothers with intermittent asthma
medication use made it possible to compare the fetal effects of asthma itself irrespective of asthma
medication. The criteria for asthma used in Finland are according to international asthma
guidelines, making the study generalizable [29?31].
Since asthma symptoms may vary over time, we assumed that most mothers with untreated
asthma were currently asymptomatic, and therefore, without purchases of asthma medication
despite previously diagnosed asthma. However, we cannot exclude poor adherence to asthma
treatment. Nevertheless, we suggest that the observed association with the risk of perinatal
mortality in this group is caused by the asthma process itself.
In the meta-analysis by Murphy and associates, maternal asthma increased the risk of
neonatal death [
]. In the single large Canadian cohort, maternal asthma increased the risk of
perinatal mortality in general, but this correlation vanished after adjustment for preterm birth
and SGA [
]. These US and Canadian cohorts were not able to differentiate effects of asthma
treatment on the risk analysis. Ka?lle?n and associates showed in the Swedish cohort of 24 369
births to mothers with asthma, that the use of three or more asthma medications indicating
severe asthma increased the risk of perinatal mortality [
]. The Swedish cohort was not able to
differentiate untreated asthma or oral glucocorticoid treatment, and they did not have
coverage of medication prescriptions for the whole pregnancy. In our cohort, unlike in the study of
Ka?lle?n, the use of increasing number of asthma medications did not significantly increase the
risk of perinatal mortality [
Our data showed that asthma medication diminishing the risk of preterm birth but not the
increased risks of SGA or perinatal death. This observation is supported by Rejno? and
associates in newer Swedish cohorts [
According to the current asthma guidelines, asthma medications are recommended to be
used in a stepwise manner [29?31]. The number of used asthma medications or the use of did
not correlate with the increased risk of perinatal mortality or preterm birth but it did correlate
with low birth weight and SGA. We suggest that these correlations with low birth weight and
SGA reflect the severity of asthma more than the drug effect. Schatz and associates showed,
that the severity of asthma during pregnancy determined by spirometry adjusted for the use of
oral glucocorticoids increased the risk of preterm birth [
]. In the large Canadian cohort
reported by Cossette and associates, the use of a combination of low to moderate doses of
inhaled corticosteroids and long-acting ?2 agonists adjusted for asthma severity did not
associate with perinatal risks [
In the future, we will analyse the effect of intermittent asthma-medication use, dosage, the
use of asthma medication in different trimesters of pregnancy, and consider of combining
registry based data with other available information such as medical records.
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Asthma is frequently encountered in pregnant women. Asthma is associated with increased
risk of perinatal mortality, preterm birth, low birth weight, fetal growth restriction (SGA), and
asphyxia. Asthma treatment reduces the increased risk for preterm delivery but it does not
seem to reduce the risk of perinatal mortality and other complications. The mechanisms
remain elusive. The entire causal pathway from maternal asthma to adverse perinatal
outcomes especially growth retardation may not be targeted by current medications for asthma.
S1 Table. Characteristics of the mothers. The study consisted of 962 405 singleton live and
stillbirths in Finland between the years 1996 and 2012.
S2 Table. Frequency of perinatal outcomes. The study consisted of 962 405 live- and stillborn
singletons in Finland between the years 1996 and 2012, Chi-square test between groups.
S3 Table. Perinatal outcomes in mothers with confirmed, treated or untreated asthma for
singleton live and stillbirths. Unadjusted and adjusted odds ratios.
S4 Table. Perinatal outcomes of treated, confirmed asthma by ATC-groups compared to
controls for singleton live and stillbirths.
Conceptualization: Mari Kemppainen, Paula Kauppi, Martti Virtanen, Suvi M. Virtanen,
Riitta Karikoski, Mika Gissler.
Data curation: Anna-Maria Lahesmaa-Korpinen, Mika Gissler.
Formal analysis: Mari Kemppainen, Anna-Maria Lahesmaa-Korpinen, Paula Kauppi.
Investigation: Mari Kemppainen, Anna-Maria Lahesmaa-Korpinen, Paula Kauppi, Suvi M.
Virtanen, Turkka Kirjavainen.
Methodology: Paula Kauppi, Martti Virtanen, Suvi M. Virtanen.
Resources: Mika Gissler.
Software: Anna-Maria Lahesmaa-Korpinen, Mika Gissler.
Supervision: Paula Kauppi, Mika Gissler, Turkka Kirjavainen.
Validation: Paula Kauppi, Mika Gissler.
Visualization: Turkka Kirjavainen.
Writing ? original draft: Mari Kemppainen, Anna-Maria Lahesmaa-Korpinen, Paula Kauppi,
Martti Virtanen, Suvi M. Virtanen, Riitta Karikoski, Mika Gissler, Turkka Kirjavainen.
Writing ? review & editing: Mari Kemppainen, Anna-Maria Lahesmaa-Korpinen, Paula
Kauppi, Martti Virtanen, Suvi M. Virtanen, Riitta Karikoski, Mika Gissler, Turkka
8 / 10
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