Maternal obesity during pregnancy as a risk for early-life asthma

Abstract

To the Editor: The prevalence of both asthma1Anandan C. Nurmatov U. van Schayck O.C. Sheikh A. Is the prevalence of asthma declining? Systematic review of epidemiological studies.Allergy. 2010; 65: 152-167Crossref PubMed Scopus (415) Google Scholar and obesity2Rokholm B. Baker J.L. Sorensen T.I. The levelling off of the obesity epidemic since the year 1999—a review of evidence and perspectives.Obes Rev. 2010; 11: 835-846Crossref PubMed Scopus (454) Google Scholar has increased over the past 4 to 5 decades in westernized countries. Correspondingly, the proportion of mothers who are overweight or obese when commencing pregnancy has increased. It has been hypothesized that maternal obesity might be associated with an increased risk that the child will have asthma through a number of mechanisms, including increasing the child’s own risk of obesity, exposing the fetus to high concentrations of proinflammatory cytokines, or influencing the sympathetic nervous system and metabolism of brown fat3Weiss S.T. Obesity: insight into the origins of asthma.Nat Immunol. 2005; 6: 537-539Crossref PubMed Scopus (156) Google Scholar or through increased risk of metabolic syndrome.4Catalano P.M. Obesity, insulin resistance, and pregnancy outcome.Reproduction. 2010; 140: 365-371Crossref PubMed Scopus (272) Google Scholar Maternal obesity is associated with increased risk of pregnancy-related complications,5Poston L. Harthoorn L.F. Van Der Beek E.M. Obesity in pregnancy: implications for the mother and lifelong health of the child. A consensus statement.Pediatr Res. 2011; 69: 175-180Crossref PubMed Scopus (177) Google Scholar some of which have also been associated with increased risk of allergic disease in the child.6Jaakkola J.J. Ahmed P. Ieromnimon A. Goepfert P. Laiou E. Quansah R. et al.Preterm delivery and asthma: a systematic review and meta-analysis.J Allergy Clin Immunol. 2006; 118: 823-830Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar To explore the association between maternal body mass index (BMI) in early pregnancy and asthma risk in the child, we used data from Swedish national registers held by the National Board of Health and Welfare and linked by using the Swedish unique identification number. The study was approved by the Regional Ethical Review Board in Umeå. We identified all children (189,783 children born to 129,239 mothers) born in Stockholm County, Sweden, between 1998 and 2009. Maternal BMI was calculated from the measured height and weight at each pregnancy during the initial antenatal care visit, which was typically at 8 to 10 weeks after conception, and recorded in the Swedish Medical Birth Registry. Data on the mother’s health (including history of asthma and hypertension and diabetes), the pregnancy (including complications), and the mode of delivery were also collected. Two outcomes were assessed in this study. The first, asthma medication use was defined as the purchase of at least 1 prescription of inhaled steroids or montelukast. These data were obtained from the Swedish Prescribed Drug Register, which contains all drugs prescribed and dispensed to the whole population of Sweden from July 2005 until the end of February 2011. The second outcome, hospital admission for asthma (International Classification of Diseases–Tenth Revision [ICD-10] code J45 or J46) was collected from the Swedish Inpatient Registry for the period from January 1998 until December 31, 2009. Logistic regression models were used to adjust for standard potential confounders (model 1). Because the nature of wheeze changes with age, the exposure to asthma medications was classified into discrete age groups, and the main outcomes were asthma medication use from age 6 to 8 years and age 8 to 10 years. Medicine use at younger ages is reported in the supplemental tables for the sake of completeness. The generalized estimating equation approach was used to enable the results for children from the same mother to be included. Potential nonlinear effects of maternal BMI were assessed by using the “fracpoly” command within Stata software (release 10.1; StataCorp, College Station, Tex). Effect modification for asthma medication use from age 6 to 10 years by the factors listed in Table I was assessed by using Wald tests. A further adjusted model was created (model 2), which included factors (potential mediators) that might explain why mothers who were obese had children at increased risk for asthma.Table IDemographic and pregnancy-related details for the study population (n = 189,783)CharacteristicsSummaryProportion MissingMaternal detailsn = 129,239 Median (IQR) maternal age at delivery (y)31 (28-35) Maternal smoking in early pregnancy5.9%13.1% Maternal smoking in late pregnancy3.4%23.4% Maternal asthma5.8% Maternal diabetes0.4% Maternal hypertension0.4% Swedish-born mother72% Maternal parity149.2%234.9%≥315.9%Maternal BMI Underweight (<18.5 kg/m2)3.0%19.82% Normal (18.5-24.9 kg/m2)69.5% Overweight (25.0-29.9 kg/m2)20.1% Obese (30.0-34.9 kg/m2)5.3% Very obese (≥35 kg/m2)1.8%Pregnancy complications (ICD-10 code) Preeclampsia (O11, O14, or O15)2.7% Gestational hypertension (O13)1.0% Gestational diabetes (O244)0.5%Birth and child details Proportion female subjects48.7% Median (IQR) gestational age at delivery (wk)40 (39-41)0.1% Median (IQR) birth weight (kg)3.5 (3.2-3.9)0.3% Proportion delivered by means of cesarean section19.2%Child asthma outcomes Proportion receiving asthma medicine∗Either inhaled steroids (Anatomical Therapeutic Chemical code starting with R03BA, RO3AK06, or RO3AK07) or montelukast (R03DC03).0-1 y†The number of children with data available at various ages differed because of the differing dates that data were available from the prescription and hospital registries.4.3% (3,453/80,933)1-5 y†The number of children with data available at various ages differed because of the differing dates that data were available from the prescription and hospital registries.15.1% (4,230/27,964)6-8 y†The number of children with data available at various ages differed because of the differing dates that data were available from the prescription and hospital registries.7.7% (3,974/51,420)8-10 y†The number of children with data available at various ages differed because of the differing dates that data were available from the prescription and hospital registries.7.3% (2,951/37,730) Proportion hospitalized for asthma (ICD-10 codes J45 or J46)0-2 y†The number of children with data available at various ages differed because of the differing dates that data were available from the prescription and hospital registries.1.5% (2,267/152,688)2-5 y†The number of children with data available at various ages differed because of the differing dates that data were available from the prescription and hospital registries.0.7% (969/131,840)IQR, Interquartile range.∗ Either inhaled steroids (Anatomical Therapeutic Chemical code starting with R03BA, RO3AK06, or RO3AK07) or montelukast (R03DC03).† The number of children with data available at various ages differed because of the differing dates that data were available from the prescription and hospital registries. Open table in a new tab IQR, Interquartile range. In this population approximately 7.2% of mothers were obese (≥30 kg/m2), and 20.1% were overweight (Table I). Higher maternal BMI was consistently associated with an increased risk of asthma in the child, both in terms of medicine use (Table II and see Table E1 in this article’s Online Repository at www.jacionline.org) and hospitalization (see Table E2 in this article’s Online Repository at www.jacionline.org). This association was linear at all ages. At age 6 to 8 years, the effect of maternal BMI was somewhat stronger in girls (odds ratio [OR], 1.04 [95% CI, 1.02-1.05] per unit increase in BMI) than in boys (OR, 1.01 [95% CI, 1.00-1.03]; P for interaction = .01) and was also weaker in fourth and subsequent children (P for interaction = .03). Mothers born outside of Sweden were on average heavier than Swedish-born mothers (0.94 kg/m2; 95% CI, 0.88-1.00 kg/m2). Excluding children of mothers born outside of Sweden reduced the strength of the association with very obese mothers (ORs of 1.25 [95% CI, 0.88-1.76] for 6-8 years and 1.39 [95% CI, 0.92-2.09] for 8-10 years for adjusted model 2) but did not materially change the associations seen with the other BMI groups.Table IIUnadjusted and adjusted associations between maternal prepregnancy BMI and asthma medication use from 6 years of ageMaternal BMI (kg/m2)UnadjustedModel 1∗Model 1: Typical confounders—adjusted for infant sex, maternal age and parity, birth year, multiple pregnancy (singleton vs multiple pregnancy), maternal country of birth (Swedish born vs other), maternal smoking during pregnancy, and maternal history of asthma.Model 2†Model 2: Possible mediators—adjusted for factors listed above and gestational age at delivery, birth weight, mode of delivery (cesarean section vs vaginal), maternal history of diabetes and hypertension, and pregnancy-related complications (gestational diabetes, hypertension, and preeclampsia).Proportion receiving asthma medicationsOR (95% CI)OR (95% CI)OR (95% CI)After sixth birthday and before eighth birthday <18.56.8% (87/1,280)0.92 (0.74-1.15)0.94 (0.75-1.17)0.94 (0.75-1.17) 18.5-24.97.4% (2,136/28,788)111 25.0-29.98.4% (698/8,334)1.14 (1.04-1.25)1.16 (1.06-1.27)1.16 (1.06-1.27) 30.0-34.99.7% (204/2,095)1.34 (1.15-1.56)1.36 (1.16-1.59)1.34 (1.15-1.57) ≥3510.3% (66/638)1.45 (1.12-1.88)1.46 (1.12-1.89)1.41 (1.08-1.84) Missing7.6% (783/10,285)1.03 (0.95-1.12)1.00 (0.90-1.10)0.99 (0.89-1.10)After eighth birthday and before tenth birthday <18.57.0% (70/1,002)1.00 (0.78-1.28)1.00 (0.77-1.28)0.97 (0.75-1.25) 18.5-24.96.9% (1,440/20,743)111 25.0-29.97.8% (482/6,151)1.14 (1.02-1.27)1.18 (1.06-1.32)1.18 (1.06-1.31) 30.0-34.99.0% (140/1,559)1.32 (1.10-1.58)1.41 (1.17-1.70)1.40 (1.16-1.68) ≥3510.3% (47/458)1.53 (1.12-2.08)1.61 (1.18-2.20)1.57 (1.15-2.15) Missing7.2% (772/10,768)1.03 (0.94-1.13)1.03 (0.91-1.16)1.01 (0.90-1.14)∗ Model 1: Typical confounders—adjusted for infant sex, maternal age and parity, birth year, multiple pregnancy (singleton vs multiple pregnancy), maternal country of birth (Swedish born vs other), maternal smoking during pregnancy, and maternal history of asthma.† Model 2: Possible mediators—adjusted for factors listed above and gestational age at delivery, birth weight, mode of delivery (cesarean section vs vaginal), maternal history of diabetes and hypertension, and pregnancy-related complications (gestational diabetes, hypertension, and preeclampsia). Open table in a new tab Higher parity confounded the association between maternal BMI and asthma medication use in the first 6 years of life (see Table E1, Table E2, model 1; high parity was associated with both greater maternal BMI and increased risk of early-life asthma/wheeze in the child), which is likely to have been due to increased exposure of the infant to respiratory tract infections in early life. Despite this confounding, there was still evidence of an effect of maternal BMI on asthma medicine use in all age groups. There was no evidence of confounding for medicine use after age 6 years (Table II, model 1). There was also no evidence that these associations were mediated by pregnancy-related complications (Table II and see Table E1, Table E2, model 2). To date, this is the largest study on the association between maternal obesity during pregnancy and the risk of childhood asthma.7Scholtens S. Wijga A.H. Brunekreef B. Kerkhof M. Postma D.S. Oldenwening M. et al.Maternal overweight before pregnancy and asthma in offspring followed for 8 years.Int J Obes (Lond). 2010; 34: 606-613Crossref PubMed Scopus (65) Google Scholar, 8Reichman N.E. Nepomnyaschy L. Maternal pre-pregnancy obesity and diagnosis of asthma in offspring at age 3 years.Matern Child Health J. 2008; 12: 725-733Crossref PubMed Scopus (60) Google Scholar, 9Håberg S.E. Stigum H. London S.J. Nystad W. Nafstad P. Maternal obesity in pregnancy and respiratory health in early childhood.Paediatr Perinat Epidemiol. 2009; 23: 352-362Crossref PubMed Scopus (57) Google Scholar Like the current study, previous studies have generally observed an increase in the risk of wheeze and asthma associated with increasing maternal BMI. Two previous studies on this topic have followed children for 3 years or less,8Reichman N.E. Nepomnyaschy L. Maternal pre-pregnancy obesity and diagnosis of asthma in offspring at age 3 years.Matern Child Health J. 2008; 12: 725-733Crossref PubMed Scopus (60) Google Scholar, 9Håberg S.E. Stigum H. London S.J. Nystad W. Nafstad P. Maternal obesity in pregnancy and respiratory health in early childhood.Paediatr Perinat Epidemiol. 2009; 23: 352-362Crossref PubMed Scopus (57) Google Scholar when it is difficult to diagnosis the nature of wheeze. Also, there has been a lack of assessment of the potentially nonlinear relationship between maternal BMI and the risk of asthma in the child. We suspected that a U-shaped association might be observed, with the children of both very thin and obese mothers being at the greatest risk of asthma, although we did not see this. It has been suggested that the effect of maternal obesity is greatest in children with a parental history of asthma,7Scholtens S. Wijga A.H. Brunekreef B. Kerkhof M. Postma D.S. Oldenwening M. et al.Maternal overweight before pregnancy and asthma in offspring followed for 8 years.Int J Obes (Lond). 2010; 34: 606-613Crossref PubMed Scopus (65) Google Scholar which we did not observe, although we did not have a measure of paternal asthma. Because we do not have details on the child’s own weight after birth, we cannot determine whether the observed associations are due to increased risk of the child’s adiposity. However, maternal obesity precedes childhood BMI, and one study suggests that adjustment for individual BMI does not influence the association between maternal obesity and childhood risk of asthma.7Scholtens S. Wijga A.H. Brunekreef B. Kerkhof M. Postma D.S. Oldenwening M. et al.Maternal overweight before pregnancy and asthma in offspring followed for 8 years.Int J Obes (Lond). 2010; 34: 606-613Crossref PubMed Scopus (65) Google Scholar Also, we do not have a measure for socioeconomic status (SES) within this cohort, which could confound these associations. Using maternal smoking as a crude indicator of SES, which has also been associated with low birth weight and increased risk of both childhood obesity and asthma, did not alter the association between maternal BMI and childhood asthma. Furthermore, adjusting for country of origin of the mother, which is likely to be related to SES, did not substantially alter these associations. In conclusion, we found a clear dose-response relationship between the degree of maternal overweight status during pregnancy and increased risk of asthma in the child. If the association between maternal BMI and asthma risk in the child is causal in nature, it might explain between 11% and 13% of childhood asthma (adjusted population-attributable fraction of 10.8% at 6-8 years and 13.0% at 8-10 years when compared with a reference point of 18.5 for maternal BMI). Maternal BMI might potentially confound a range of other early-life risk factors for childhood asthma, and this should be considered in future research. These results highlight the importance of current population interventions to combat the obesity epidemic for a range of child health outcomes. Table E1Unadjusted and adjusted associations between maternal prepregnancy BMI and asthma medication use up to the sixth birthdayMaternal BMI (kg/m2)UnadjustedModel 1∗Model 1: Typical confounders—adjusted for infant sex, maternal age and parity, birth year, multiple pregnancy (singleton vs multiple pregnancy), maternal country of birth (Swedish born vs other), maternal smoking during pregnancy, and maternal history of asthma.Model 2†Model 2: Possible mediators—adjusted for factors listed above and gestational age at delivery, birth weight, mode of delivery (cesarean section vs vaginal), maternal history of diabetes and hypertension, and pregnancy.Proportion receiving asthma medicationsOR (95% CI)OR (95% CI)OR (95% CI)Within the first 12 mo of life <18.52.9% (60/2,035)0.73 (0.56-0.95)0.75 (0.58-0.98)0.74 (0.57-0.97) 18.5-24.94.0% (1,844/46,627)111 25.0-29.94.8% (652/13,659)1.23 (1.12-1.35)1.11 (1.01-1.21)1.10 (1.00-1.21) 30.0-34.96.0% (218/3,615)1.54 (1.32-1.78)1.27 (1.09-1.48)1.23 (1.05-1.43) ≥356.8% (86/1,268)1.78 (1.42-2.24)1.35 (1.07-1.70)1.31 (1.04-1.66) Missing4.3% (593/13,729)1.08 (0.98-1.19)0.98 (0.84-1.14)0.97 (0.83-1.14)After first birthday and before sixth birthday <18.59.4% (56/598)0.61 (0.46-0.80)0.60 (0.45-0.80)0.59 (0.44-0.78) 18.5-24.914.4% (2,139/14,894)111 25.0-29.916.7% (729/4,357)1.19 (1.09-1.31)1.19 (1.08-1.31)1.18 (1.08-1.30) 30.0-34.918.4% (200/1,089)1.35 (1.15-1.58)1.30 (1.11-1.54)1.27 (1.07-1.49) ≥3522.1% (95/429)1.71 (1.35-2.16)1.62 (1.27-2.05)1.55 (1.22-1.98) Missing15.3% (1,011/6,597)1.08 (0.99-1.17)1.09 (0.97-1.21)1.06 (0.95-1.18)∗ Model 1: Typical confounders—adjusted for infant sex, maternal age and parity, birth year, multiple pregnancy (singleton vs multiple pregnancy), maternal country of birth (Swedish born vs other), maternal smoking during pregnancy, and maternal history of asthma.† Model 2: Possible mediators—adjusted for factors listed above and gestational age at delivery, birth weight, mode of delivery (cesarean section vs vaginal), maternal history of diabetes and hypertension, and pregnancy. Open table in a new tab Table E2Unadjusted and adjusted associations between maternal prepregnancy BMI and hospitalization for asthma (ICD-10 code J45 or J46) before and after age 2 yearsMaternal BMI (kg/m2)UnadjustedModel 1∗Model 1: Typical confounders—adjusted for infant sex, maternal age, parity, birth year, multiple pregnancy (singleton vs multiple pregnancy), maternal country of birth (Swedish born vs other), maternal smoking during pregnancy, and maternal history of asthma.Model 2†Model 2: Possible mediators—adjusted for factors listed above and gestational age at delivery, birth weight, mode of delivery (cesarean section vs vaginal), maternal history of diabetes and hypertension, and pregnancy-related complications (gestational diabetes, hypertension, and preeclampsia).Proportion hospitalizedOR (95% CI)OR (95% CI)OR (95% CI)Within the first 2 y of life <18.51.3% (47/3,539)0.94 (0.70-1.26)0.88 (0.65-1.18)0.85 (0.64-1.15) 18.5-24.91.4% (1,154/81,690)111 25.0-29.91.5% (372/24,026)1.09 (0.97-1.23)1.01 (0.90-1.14)1.02 (0.90-1.15) 30.0-34.92.1% (130/6,134)1.51 (1.26-1.82)1.28 (1.06-1.55)1.28 (1.06-1.54) ≥352.9% (60/2,044)2.09 (1.60-2.73)1.71 (1.31-2.24)1.70 (1.30-2.24) Missing1.4% (504/35,255)1.01 (0.91-1.13)0.93 (0.81-1.07)0.92 (0.79-1.06)After second birthday <18.50.6% (19/3,128)0.88 (0.55-1.39)0.84 (0.53-1.33)0.83 (0.53-1.32) 18.5-24.90.7% (501/72,066)111 25.0-29.90.8% (167/21,159)1.13 (0.95-1.35)1.12 (0.93-1.33)1.10 (0.92-1.32) 30.0-34.90.9% (50/5,328)1.35 (1.01-1.81)1.29 (0.96-1.74)1.26 (0.93-1.70) ≥351.0% (18/1,751)1.48 (0.92-2.38)1.39 (0.86-2.25)1.35 (0.83-2.19) Missing0.7% (214/29,377)1.04 (0.89-1.23)0.97 (0.79-1.20)0.96 (0.78-1.18)∗ Model 1: Typical confounders—adjusted for infant sex, maternal age, parity, birth year, multiple pregnancy (singleton vs multiple pregnancy), maternal country of birth (Swedish born vs other), maternal smoking during pregnancy, and maternal history of asthma.† Model 2: Possible mediators—adjusted for factors listed above and gestational age at delivery, birth weight, mode of delivery (cesarean section vs vaginal), maternal history of diabetes and hypertension, and pregnancy-related complications (gestational diabetes, hypertension, and preeclampsia). Open table in a new tab