Asthma During Pregnancy and Clinical Outcomes inOffspring: A National Cohort Study

WHAT’S KNOWN ON THIS SUBJECT: Asthma is a common medicalcomplication during pregnancy that is associated with anincreased risk of adverse obstetric outcomes.

WHAT THIS STUDY ADDS: This study adds knowledge on potentiallong-term consequences of maternal asthma during pregnancyfor offspring health, demonstrating that maternal asthma duringpregnancy is linked to a wide spectrum of offspring diseasesduring childhood.

abstractBACKGROUND AND OBJECTIVE: Maternal asthma is a common preg-nancy complication, with adverse short-term effects for the offspring.The objective was to determine whether asthma during pregnancy isa risk factor of offspring diseases.

METHODS: We studied pregnant women from the Danish National BirthCohort (births: 1996–2002; prospective data) giving birth to live sin-gletons (n = 66 712 mother-child pairs), with 4145 (6.2%) womensuffering from asthma during pregnancy. We estimated the associationsbetween asthma during pregnancy and offspring diseases (InternationalClassification of Diseases, 10th Revision diagnoses from nationalregistries), controlling for potential confounders and validatingfindings by secondary analyses.

RESULTS: Offspring median age at end of follow-up was 6.2 (3.6–8.9)years. Asthma was associated with an increased offspring risk ofinfectious and parasitic diseases (hazard ratio [HR] 1.34; 95%confidence interval [CI] 1.23–1.46), diseases of the nervous system(HR 1.43; CI 1.18–1.73), ear (HR 1.33; CI 1.19–1.48), respiratory system(HR 1.43; CI 1.34–1.52), and skin (HR 1.39; CI 1.20–1.60), and potentially(not confirmed in secondary analyses) of endocrine and metabolicdisorders (HR 1.26; CI 1.02–1.55), diseases of the digestive system (HR1.17; CI 1.04–1.32), and malformations (odds ratio 1.13; CI 1.01–1.26),but not of neoplasms, mental disorders, or diseases of the blood andimmune system, circulatory system, musculoskeletal system, andgenitourinary system.

CONCLUSIONS: To the best of our knowledge, this is the first compre-hensive study of the associations between asthma during pregnancyand a wide spectrum of offspring diseases. In line with previous dataon selected outcomes, asthma during pregnancy may be a risk factorfor numerous offspring diseases, suggesting that careful monitoring ofwomen with asthma during pregnancy and their offspring is impor-tant. Pediatrics 2013;132:483–491

AUTHORS: Marion Tegethoff, PhD,a Jørn Olsen, MD, PhD,b,c

Emmanuel Schaffner, MSc,d,e and Gunther Meinlschmidt,PhDf,g,h

Divisions of aClinical Psychology and Psychiatry, dAppliedStatistics in Life Sciences, and fClinical Psychology andEpidemiology, Department of Psychology, University of Basel,Basel, Switzerland; bDepartment of Epidemiology, School ofPublic Health, University of California at Los Angeles, Los Angeles,California; cThe Danish Epidemiology Science Centre, Departmentof Epidemiology, Institute of Public Health, University of Aarhus,Aarhus, Denmark; eBiostatistics and Computational Sciences,Department of Epidemiology and Public Health, Swiss Tropicaland Public Health Institute, Basel, Switzerland; gResearchDepartment of Psychobiology, Psychosomatics, andPsychotherapy, Clinic of Psychosomatic Medicine andPsychotherapy, LWL University Hospital and School of Medicine,Ruhr-University Bochum, Bochum, Germany; andhNational Centre of Competence in Research “Swiss EtiologicalStudy of Adjustment and Mental Health,” Basel, Switzerland

KEY WORDSantenatal, child, prenatal exposure delayed effects, prenatal,programming

ABBREVIATIONSCI—confidence intervalDNBC—Danish National Birth CohortHPA—hypothalamic-pituitary-adrenalHR—hazard ratioICD-10—International Classification of Diseases, 10th Revision

Dr Tegethoff conceptualized and designed the study, carried outthe statistical analyses, interpreted data, drafted the initialmanuscript, critically reviewed the manuscript, and obtainedfunding; Dr Olsen acquired data, interpreted data, criticallyreviewed the manuscript, and obtained funding; Mr Schaffnercarried out the statistical analyses, interpreted data, andcritically reviewed the manuscript; Dr Meinlschmidtconceptualized and designed the study, carried out thestatistical analyses, interpreted data, critically reviewed themanuscript, and obtained funding; and all authors approved thefinal manuscript as submitted.

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Asthma is a frequently occurringmedical condition in pregnancy,1 af-fecting up to 8% of all pregnant womenand women of childbearing age.2,3

A recent meta-analysis, including 40publications from cohort studies,showed that maternal asthma was as-sociated with an increased risk of lowbirth weight, small for gestational age,preterm delivery, and preeclampsia.4

Moreover, in a cohort including.40 000pregnancies, maternal asthma duringpregnancy was related to an increasedrisk of any congenital malformation inthe offspring, and, specifically, to anincreased risk of malformations of thenervous system, respiratory system,and digestive system.5 Maternalasthma during pregnancy was alsoshown to play a role in cardiac mal-formations in the offspring.6 However,the focus of these previous studies wason short-term adverse outcomes in theoffspring, whereas long-term effects ofmaternal asthma on child health re-main largely unknown. First studies ona narrow range of selected diseasessuggest that maternal asthma duringpregnancy is associated with an in-creased risk of asthma,7,8 bronchiolitis,9

atopic dermatitis,10 and autism spec-trum disorder11 in the offspring duringchildhood, which is in line with animalmodels documenting intrauterine sus-ceptibility to hypoxia-induced damage.12

These findings, together with the highprevalence of maternal asthma duringpregnancy, make it important to furtherput a focus on follow-up time extendedbeyond the perinatal period and tocover a larger spectrum of offspringdiseases.

Thepurposeof this studywas toassessthe associations between asthmaduring pregnancy and the offspring’srisk of a wide range of diseases, cat-egorized according to major chaptersof the International Classification ofDiseases, 10th Revision (ICD-10), dur-ing early childhood.

METHODS

Study Cohort

Briefly, this study is based on pro-spectively collected data from theDanish National Birth Cohort (DNBC),including births between 1996 and2002.13 The Danish National Committeefor Biomedical Research Ethics, Copen-hagen, approved the study on behalf ofall committees in the country. All par-ticipants gave written informed consent.Womenwere invited when they had theirfirst pregnancy visit between 6 and 12weeks’ gestation. Approximately 50% ofall general practitioners in the countrytook part in the recruitment, and 60% ofthe invited women participated, so thatfinally 101 042 women could be enrolledin the DNBC. Computer-assisted inter-views with mothers were performedrepeatedly during and after pregnancy.Through linkage to medical registries,information on offspring diseases wascontinuously recorded. We consideredas eligible all pregnancies in the DNBCwith live singleton births. We excludedmultiple births, as the intrauterinephysiology underlying maternal-fetaltransmission differs between multi-ples and singletons and multiple preg-nancies have a significant risk ofcomplications.14 Moreover, multiplesthemselves are a heterogeneous group,for example, regarding number of pla-centas and cygocity, reflecting hetero-geneous maternal-fetal physiology,with poorer outcome in higher-orderpregnancies.14,15 The well-establishedassociations between intrauterine con-ditions and long-term health also may bedifferent in multiples and singletons.16

Asthma

Information on maternal asthma (“yes,”“no”) is based on computer-assistedinterviews taken at ∼12 and 30 weeks’gestation and at 6 months postpartum.A mother was considered to have asthmaduring pregnancy if self-reportedasthma of any type had occurred at

any time during the current pregnancy,without further specification accord-ing to previously suggested asthmadefinitions.17,18 Women were asked ifthey had a lifetime history of asthma, ifa doctor had diagnosed the asthma,and if they were suffering/had sufferedfrom asthma during pregnancy. Theagreement of case ascertainment bypatient self-report and physician di-agnosis has been shown to be high(k: 0.83),19 and additional analysis ofthe study cohort revealed that 95.85%of women reporting lifetime asthmahad received this diagnosis by a doctor.

Child Diseases

We obtained information on children’sdiseases from the Danish National Hos-pital Register containing information onall inpatients and outpatients in Danishhospitals. The validity of the diagnoses inthe registry has been studied for severaldiseases (eg, epilepsy, asthma, and fe-brile seizures, with positive predictivevalues of 81%, 85%, and 93%, re-spectively).20–24 Diagnoses, based on theDanish version of the ICD-10,25 wereclassified into dichotomous diagnosticcategories according to chapters 1 to 17of the ICD-10. In addition, we used asoutcome a dichotomous overall cate-gory (“any disease”), indicating whetherany disease of any diagnostic categorywas present (see also refs 26 and 27).

Statistical Analyses

To estimate the associations betweenasthma during pregnancy and the off-spring’s risk of disease, we conductedseparate Cox proportional hazards re-gression models28 for each of the di-agnostic categories 1 to 14 and “anydisease.” In each regression model, weused the first diagnosis in the categoryas outcome measure. Data on timing ofcompeting events, such as deaths andemigration, were not available in thisdata source, but these events were fewin Denmark.29 Data on all children

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without a diagnosis were censored atthe end of follow-up (December 31,2006), meaning these cases were con-sidered as having no diagnosis untilthen. Age in days was used as the timevariable. We evaluated the proportionalhazards assumption by visually check-ing Schoenfeld residuals and using thetest of Grambsch and Therneau.30

We used separate logistic regressionmodels to assess the associations be-tween asthma during pregnancy andthe risk of conditions originating in theperinatal period (diagnostic category16) and congenital malformations (di-agnostic category 17) in the offspring,as these conditions are present aroundbirth, and reasons for latency until di-agnosis are likely unrelated to asthmaduring pregnancy.

To obtain less confounded estimates,we adjusted the analyses for severalpotential predictors of child health thatmight confound or suppress effects,selected a priori, including socioeco-nomic status31 based on the mother’soccupation (see ref 32), parity,33 ma-ternal age,34 general maternal health,to account for potential comorbidconditions that are frequently ob-served in asthma patients,35,36 smok-ing,37 and infant gender,38,39 with thecategories indicated in Table 1. Weobtained information on offspringgender and maternal age at deliveryfrom the Danish Medical Birth Regis-try,40 and on socioeconomic status,parity, smoking during pregnancy, andgeneral maternal health from theinterviews taken at 12 and 30 weeks’gestation and at 6 months postpartum.

Because 3453 singletons were born tomothers who contributed .1 preg-nancy to the study, we calculated allSEs using the clustered sandwich es-timator to correct for possible de-pendence between health outcomes ininfants born to the same mother.41

All tests were 2-tailed and we set the levelof significance at .05. In addition, we

reevaluated the results after adjustingP values corresponding to the 17 maintests for multiple comparisons using theBonferroni method. We interpreted withcaution all results that were statisticallysignificant in the main (adjusted) ana-lyses but not stable after either Bonferroni-correction or secondary analyses (fordetails, see online supplemental in-formation). We dealt with loss to follow-up and missing data by restrictinganalyses to mother-child pairs withcomplete and unambiguous data onasthma status during pregnancy, and byincluding an extra category in the ana-lyses for those with missing informationin the covariates. For statistical analy-ses, we used Stata/SE software, version11.2 (Stata Corp, College Station, TX).

RESULTS

Study Cohort Descriptives

Complete information on maternalasthma status and offspring diagnoses

was available for 66 712 mother-childpairs (71.98% of all eligible mother-child pairs in the DNBC, Fig 1). Of these,4145 (6.2%) reported having asthmaduring pregnancy, whereas 62 567(93.8%) reported having no asthma dur-ing pregnancy. Table 1 presents thecharacteristics of the total study sampleandaccording tomaternal asthmaduringpregnancy.Most of thewomenwere olderthan 27 years, had a medium to high so-cioeconomic status, and average to verygood general health; slightly more thanhalf of the women were multiparous, andapproximately one-fourth of the womenreported smoking. Maximum time offollow-up was 8.9 years, with median ageof offspring at end of follow-up being 6.2years (range: 3.6–8.9 years).

Cox Proportional Hazards Modelsand Logistic Regression Analyses

The results of the adjusted Cox and lo-gistic regression analyses are presented

TABLE 1 Sample Characteristics According to Maternal Asthma During Pregnancy

All Mother-Child Pairs No Asthma Asthma

n (% of total group) 66 712 (100.0) 62 567 (93.8) 4145 (6.2)Discrete variables, n (%a)Maternal age, y,27 13 744 (20.6) 12 604 (20.1) 1140 (27.5)27–29 18 005 (27.0) 16 938 (27.1) 1067 (25.7)30–32 16 634 (24.9) 15 666 (25.0) 968 (23.3).32 18 329 (27.5) 17 359 (27.7) 970 (23.4)

ParityPrimiparous 29 848 (44.7) 27 885 (44.6) 1963 (47.4)Multiparous 34 434 (51.6) 32 381 (51.8) 2053 (49.5)Unknown 2430 (3.6) 2301 (3.7) 129 (3.1)

General maternal healthVery good 33 698 (50.5) 32 310 (51.6) 1388 (33.5)Average 28 309 (42.4) 26 073 (41.7) 2236 (53.9)Bad 2293 (3.4) 1899 (3.0) 394 (9.5)Unknown 2412 (3.6) 2285 (3.7) 127 (3.1)

Socioeconomic statusHigh 32 840 (49.2) 30 985 (49.5) 1855 (44.8)Medium 23 481 (35.2) 22 002 (35.2) 1479 (35.7)Low 5281 (7.9) 4806 (7.7) 475 (11.5)Unknown 5110 (7.7) 4774 (7.6) 336 (8.1)

Smoking during pregnancyYes 17 170 (25.7) 15 949 (25.5) 1221 (29.5)No 47 256 (70.8) 44 448 (71.0) 2808 (67.7)Unknown 2286 (3.4) 2170 (3.5) 116 (2.8)

Infant genderBoys 34 056 (51.1) 31 850 (50.9) 2206 (53.2)Girls 32 656 (49.0) 30 717 (49.1) 1939 (46.8)

a May not total 100 due to rounding.

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in Tables 2 and 3. Asthma duringpregnancy was associated with a sig-nificantly increased offspring risk forthe first disease diagnosis in 8 of 16diagnostic categories, including infec-tious and parasitic diseases; endocrineand metabolic disorders; diseases ofthe nervous system, ear, respiratorysystem, digestive system, and skin; aswell as malformations, and a signifi-cantly increased offspring risk ofhaving any disease. When P valueswere Bonferroni-adjusted, asthmaduring pregnancy was no longer as-sociated with the offspring’s risk forendocrine and metabolic diseasesand diseases of the digestive system.Results of the secondary analyses arereported in the online supplementalinformation.

DISCUSSION

We report findings based on 66 712mother-child pairs who were followedup from early pregnancy into child-hood in a population-based cohortstudy. Maternal asthma, as comparedwith no maternal asthma, duringpregnancy was related to an increasedrisk of a wide range of diseases in theoffspring during childhood, includinginfectious and parasitic diseases; dis-eases of the nervous system, ear,respiratory system, and skin; and po-tentially to endocrine and metabolicdisorders, diseases of the digestivesystem, and malformations. To the bestof our knowledge, this is the first studycovering a wide spectrum of diseasesduring childhood to suggest that

maternal asthma during pregnancymay be a risk factor of a wide range ofpediatric diseases. This corroboratesthe clinical relevance of asthma duringpregnancy with regard to long-termconsequences emerging beyond theperinatal period, thereby further em-phasizing that careful medical andobstetric monitoring of the asthmaticpregnant woman and her developingfetus and child are highly warranted.Yet, it should be noted that effect sizeswere rather small to moderate (alladjusted hazard ratios [HRs] #1.43),indicating that each additional step ofobstetric care should be well consid-ered and dosed, thereby balancing itsbenefits with potential risks that mightbe induced by unjustified overrating ofthe role of asthma during pregnancy.

FIGURE 1Flowchart of study participants.

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Our results are in line with previoushuman studies on short-term re-productive failures afterasthmaduringpregnancy, which have shown associ-ationsof asthmaduringpregnancywithadverse obstetric outcomes and con-genital malformation,4–6 and extendknowledge to an overview of potentiallong-term consequences. Indeed, pre-vious studies on long-term conse-quences of asthma during pregnancywith regard to selected child diseasesalso demonstrated an increased risk ofasthma, bronchiolitis, atopic dermatitis,and autism spectrum disorder, in off-spring of mothers with asthma.7–11

If the observed associations betweenmaternal asthma during pregnancy

and offspring diseases are causal,there may be several potential un-derlying mechanisms explaining theselinks.42 First, low maternal oxygensupply is related to restricted fetaloxygenation,43 which has been associ-ated with delays in the development ofthe nervous system,44 adverse neuro-developmental outcomes,45 and im-pairment of vascular function46 inanimals. Moreover, maternal asthmaduring pregnancy has been shown toresult in dysfunction of bronchial re-laxation in offspring rats via inhibitionof epinephrine synthesis.47 Further-more, maternal hypoxia has beenshown to affect fetal growth, placentalfunction, and length of gestation,48–50

and these birth outcomes have beenlinked with adverse health outcomes innumerous studies.51,52 Therefore, ma-ternal hypoxia may, via restricted fetaloxygenation, result in multiple organpathology that manifests in a widerange of offspring diseases. Second,cytokines play an important role in theinflammatory processes of the airwaysin asthma,53 and cytokine receptorsare widely expressed in the human fe-tus from early gestation.54 Indeed,maternal exposure to cytokines duringpregnancy was associated with ad-verse offspring outcome in rats,55 andthe association between maternal in-fection during pregnancy and offspringdeficits appears to be mediated bycytokines,56 even though the perme-ability of the placenta to cytokines re-mains unclear.57,58 Third, the hypothalamic-pituitary-adrenal (HPA) axis is anothercandidatemechanism linkingmaternalasthma during pregnancy with off-spring diseases, as dysregulation ofthe HPA axis is a frequently observedfeature of asthma59 and changes inintrauterine glucocorticoid exposurehave been shown to take effect in thefetus.60 Fourth, one may speculate thatasthma medication adversely affectsthe fetus. However, children of motherswith asthma taking asthma medicationwere at similar risk for diseases aschildren of mothers with asthma butwithout asthma medication, indicatingthat asthma medication does not playan important role in the offspring’s riskof diseases. Notably, the risk of neo-plasms was even decreased in the off-spring of mothers with asthma undermedication. Moreover, there is consid-erable evidence mostly indicating thatcommonly used asthma medications,such as inhaled corticosteroids andinhaled short-acting b-agonists, do notincrease the risk of adverse perinataloutcomes, even though high doses ofinhaled corticosteroids have been as-sociated with an increased prevalenceof congenital malformations,61 but that

TABLE 2 Cox Regression Models of Offspring Diseases Predicted by Asthma During Pregnancy

ICD-10 Category No. ChildrenWith a Diagnosis

Crudea

HR [95% CI]Adjustedb

HR [95% CI]

1. Infections, parasitic diseases 6754 1.42 [1.31–1.55] 1.34 [1.23–1.46]2. Neoplasms 721 0.94 [0.69–1.28] 0.90 [0.66–1.23]3. Diseases of blood, immune system 519 0.93 [0.64–1.35] 0.85 [0.58–1.23]4. Endocrine, metabolic disorders 1194 1.33 [1.07–1.63] 1.26 [1.02–1.55]5. Mental disorders 552 1.35 [1.00–1.83] 1.18 [0.87–1.60]6. Diseases of nervous system 1296 1.51 [1.25–1.83] 1.43 [1.18–1.73]7. Diseases of eye 1474 1.26 [1.04–1.53] 1.20 [0.99–1.46]8. Diseases of ear 4398 1.41 [1.27–1.57] 1.33 [1.19–1.48]9. Diseases of circulatory system 367 1.20 [0.81–1.78] 1.12 [0.76–1.68]10. Diseases of respiratory system 12 592 1.51 [1.42–1.61] 1.43 [1.34–1.52]11. Diseases of digestive system 4103 1.25 [1.11–1.40] 1.17 [1.04–1.32]12. Diseases of skin 2519 1.43 [1.24–1.65] 1.39 [1.20–1.60]13. Diseases of musculoskeletal system 3134 1.05 [0.91–1.21] 1.02 [0.89–1.18]14. Diseases of genitourinary system 2271 1.16 [0.99–1.36] 1.10 [0.93–1.29]Any 35 052 1.22 [1.18–1.27] 1.17 [1.13–1.22]

Hazard ratios (HR) for the offspring having an initial diagnosis within the respective diagnostic category (outcomes)according to maternal asthma during pregnancy (predictor) (n = 66 712). Information on the children’s diagnoses wereobtained from the database-linked Danish National Hospital Register, which contains information on all diagnoses ofinpatients and outpatients in Danish hospitals. In each diagnostic category, we used the initial diagnosis.a Crude model presented in support of transparency.b All models adjusted for general maternal health, infant gender, maternal age, parity, smoking during pregnancy, andsocioeconomic status.

TABLE 3 Logistic Regression Models of Offspring Diseases Predicted by Asthma During Pregnancy

ICD-10 Category No. ChildrenWith a Diagnosis

Crudea OR [95% CI] Adjustedb OR [95% CI]

16. Conditions originating inperinatal period

12 897 1.11 [1.03–1.20] 1.05 [0.97–1.14]

17. Malformations 5613 1.18 [1.06–1.31] 1.13 [1.01–1.26]

Odds ratios (OR) for the offspring’s risk of having conditions originating in the perinatal period and malformations (out-comes) according to maternal asthma during pregnancy (predictor) (n = 66 712). Information on the children’s diagnoseswere obtained from the database-linked Danish National Hospital Register, which contains information on all diagnoses ofinpatients and outpatients in Danish hospitals. In each diagnostic category, we used the initial diagnosis.a Crude model presented in support of transparency.b All models adjusted for general maternal health, infant gender, maternal age, parity, smoking during pregnancy, andsocioeconomic status.

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treatment with inhaled corticosteroidsmay actually be protective againstoutcomes such as low birth weight.42

Moreover, we recently reported reas-suring data demonstrating that gluco-corticoid inhalation during asthmaticpregnancy was not related to an in-creased risk of a wide range of off-spring diseases during childhood,except for endocrine and metabolicdisorders.27,62 This is in line with ourhere presented finding that the risk ofendocrine and metabolic disorderswas no longer significant when com-paring offspring of mothers withasthma without medication and off-spring of mothers without asthma,suggesting that endocrine and meta-bolic disorders are not a consequenceof asthma per se.

The strengths of our study include theprospective data collection for a total of66 712 mother-child pairs, linkage ofa comprehensive medical registry withcomplete and medically verified diag-noses, accounting for bias by asthmamedication and control for severalpotential confounders, even thoughresidual or uncontrolled confoundingcannot be excluded, including con-founding by genetic factors63 or fur-ther specific comorbidities that havebeen observed in patients with asthma,including rhinitis, sinusitis, gastro-esophageal reflux disease, obstructivesleep apnea, endocrine disorders, andmental disorders.35 Indeed, if condi-tions such as psychopathologies arepresent during pregnancy, the off-spring is at increased risk of adversehealth outcomes.64 However, comor-bidities may well be mediators of theobserved associations, meaning that,in this case, comorbidities are onlytriggered by asthma, and adjusting formediators bears the risk of under-estimation. The same is true for psy-chosocial factors during pregnancythat have been shown to be associatedwith a wide range of offspring dis-

eases,26 and that may either trigger orbe triggered by asthma.65

Our findings have clinical and publichealth relevance, as asthma is a com-mon serious medical problem to com-plicate pregnancy, with approximatelyup to 8% of pregnant women affected.3

Ongoing follow-up of children in theDNBC enables further research at laterstages.

The rather low participation rate en-countered in the DNBC13 was partlycaused by a lack of participation byfamily doctors and partly by pregnantwomen who declined the invitation.66

Comparing data from DNBC partic-ipants with data from the source pop-ulation based on all births in 2well-definedgeographical areas in Denmark, in-dependent of the DNBC, revealed somesociodemographic and health-relateddifferences between both groups, in-cluding among others in DNBC partic-ipants a modest overrepresentation of25- to 35-year- old women, nonsmokers,and in vitro fertilization pregnancies,and a lower rate of small-for-gestational-age birth outcome.66 However, the ef-fect of nonparticipation on selectedexposure-risk associations, for exam-ple the association between in vitrofertilization and preterm birth, wasnegligible, indicating that initial selec-tion bias caused by the relatively highrate of nonparticipation in the DNBCdoes not place a major threat to theexternal validity of DNBC studies.66

Moreover, on the basis of (1) the ac-ceptable retention and follow-up ratein the current study, together with thefact that the validity of regressionmodels is only marginally affected byselective drop-out,67 (2) the high per-centage of complete data, and (3)completeness of diagnoses throughlinkage to the Danish National HospitalRegister, we think it is unlikely that lossof mother-child pairs has introducedmeasurable selection bias.

The study also has some limitations andour findings need replication in an in-dependent dataset. One limitation isthat we did not have information onasthma severity, including duration ofasthma episodes, even though it couldbe hypothesized that the magnitude ofdisease risk may be lower in offspringof mothers with less severe asthmaduring pregnancy.4,68 Moreover, wewere not able to operationalize asthmaaccording to a specific definition (eg,taking into account key characteristics,such as inflammation, hyperrespon-siveness, reversible airway obstruc-tion, and respiratory symptoms17,18),as the required information, includingdiagnostic test results or informationon asthma subtypes, was not availablefrom the interviews, and it is hardlyfeasible in a large cohort to assesssuch details. However, validation ofself-reported asthma against physi-cian diagnoses,19 together with thehigh percentage of women withasthma during pregnancy and a doc-tor-diagnosis of lifetime asthma inthis study, allows to at least approachthe definition of asthma according tothe ICD-10. Another limitation is thatinterview questions had to be designedto fit the telephone condition and wereonly partially validated. Moreover, inthe current study, in some diagnosticcategories, the number of cases wasnotably smaller than in other catego-ries, resulting in less precise estima-tion of HRs. However, post hoc poweranalyses, assuming small effect sizesdefined as HR = 1.3, as suggested pre-viously,69 revealed a statistical powerof 94%, 85%, 87%, and 71% for thecategories including,1000 cases witha diagnosis, namely neoplasms, dis-eases of the blood and immune system,mental disorders, and diseases of thecirculatory system, respectively. Sta-tistical power was .99% in all othercategories. It should be noted that posthoc power analyses have been stronglycriticized,70 and, therefore, conclusions

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concerning potential effects of mater-nal asthma during pregnancy on theoffspring’s disease risk in categorieswith small case numbers are lesscertain at the current stage. Finally, thevalidity of self-report of disease hasbeen suspected to be a potentialsource of bias; however, it has recentlybeen documented that there was ahigh agreement between self-reportedasthma and physician-diagnosed as-thma, with self-report of asthma hav-ing very high specificity (98.14%) andthe highest sensitivity (94.99%) acrossa wide range of somatic disease.19 Wewere also able to ensure in our studycohort that 95.85% of the womenreporting lifetime asthma had receivedthis diagnosis by a doctor, and todemonstrate in our study sample thatresults mostly did not change when werepeated the analyses, including in theasthma group only women with doctor-diagnosed asthma. Moreover, theprevalence of women suffering fromasthma during pregnancy in this co-hort (6.2%) is virtually identical to theprevalence of asthma during preg-nancy, based on medical records, ina recent large epidemiologic study(6.5%).71 Furthermore, asthma datawere mostly collected before the out-come data, making differential mis-

classification unlikely, which was alsoconfirmed by secondary analyses.

The putative biological conclusions ofthe findings should be drawn withcaution, given the heterogeneity of therationales behind the different ICD-10categories (eg, grouping by organsystem, etiology). However, the ICD-10is the international standard diagnosticclassification system of diseases andrecommended for epidemiologic stud-ies, with high reliability at the categorylevel.72

The presented findings should be cor-roborated in a sufficiently large sampleof higher-order pregnancies beforegeneralizing themtomultiples. Aswedidnot have diagnostic information fromgeneral practitioners regarding childpathologies, we probably missed less-severe offspring diseases and the re-lation with asthma during pregnancymay be lower in these cases. Futurefollow-up of the cohort yields the po-tential todeterminewhetheroffspringofmothers suffering from asthma duringpregnancy are also at increased risk fora wide range of pathologies duringadulthood, and whether even furtherdiseases will develop at a later stage.

Provided that our findings are con-firmed in independent data sources,future studies should focus onpotential

underlying mechanisms of the associ-ation betweenmaternal asthma duringpregnancy and the offspring’s diseaserisk, such as cytokines, the HPA axis,placenta, and fetal development, whichhave repeatedly been associated withearly adversities.73–75 Moreover, futurework should analyze long-term con-sequences of intrauterine exposure tomaternal asthmawith regard to specificpathologies within the disease catego-ries for which an increased risk hasbeen identified. Most importantly, mod-ifiable factors within this relationshipshould be identified to improve bothprevention and intervention.

CONCLUSIONS

This is, to the best of our knowledge, thefirst comprehensive study on the as-sociation of maternal asthma duringpregnancy with offspring health, cov-ering a wide spectrum of pediatricdiseases. Our finding that offspring ofmothers suffering from asthma duringpregnancy are at an increased risk fora variety of diseases during childhoodsuggests that careful medical and ob-stetric monitoring of the asthmaticpregnant woman and her developingfetus and child are highly warranted,regardless of the causes for this as-sociation.

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(Continued from first page)

www.pediatrics.org/cgi/doi/10.1542/peds.2012-3686

doi:10.1542/peds.2012-3686

Accepted for publication Jun 19, 2013

Address correspondence to Gunther Meinlschmidt, PhD, Division of Clinical Psychology and Epidemiology, Department of Psychology, University of Basel,Missionsstrasse 60/62, CH-4055 Basel, Switzerland. E-mail: gunther.meinlschmidt@unibas.ch

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2013 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

FUNDING: The Danish National Research Foundation established the Danish Epidemiology Science Centre, which initiated and created the Danish National BirthCohort. The cohort is furthermore a result of a major grant from this foundation. Additional support for the Danish National Birth Cohort is obtained from thePharmacy Foundation, the Egmont Foundation, the March of Dimes Birth Defects Foundation, the Augustinus Foundation, and the Health Foundation. This projectwas financed by the German National Academic Foundation (to Dr Tegethoff), and the Swiss National Science Foundation, project numbers PZ00P1_137023 (toDr Tegethoff) and 51A240_104890 as well as 100014_135328 (to Dr Meinlschmidt). The funding sources had no involvement in study design; in the collection,analysis, and interpretation of the data; in the writing of the report; and in the decision to submit the article for publication.

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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