atopy risk
DESCRIPTION
atopy risk and pretermTRANSCRIPT
Preterm birth reduces the incidence of atopy in adulthood
Mirjami Siltanen, MD, PhD,a,b Karoliina Wehkalampi, MD, PhD,a,c Petteri Hovi, MD,a,c Johan G. Eriksson, MD, PhD,a,d,e,f,g
Sonja Strang-Karlsson, MD,a,c Anna-Liisa J€arvenp€a€a, MD, PhD,c Sture Andersson, MD, PhD,c and
Eero Kajantie, MD, PhDa,c Helsinki, Hyvink€a€a, and Vasa, Finland
Background: Immunologic pathways are primed in early life.Preterm birth can influence this process and thereby affectwhether a person will have atopy later in life. Previous studieson the effects of preterm birth on atopy in adulthood have beeninconclusive and limited to children or subjects bornmoderately preterm.Objective: Our aim was to compare the incidence of atopyamong young adults who were born preterm and at very lowbirth weight (<_1500 g) with that of term-born young adults(control subjects).Methods: The study comprised 166 adultswhowere bornpretermand at very low birth weight and 172 control subjects, all of whomwere from the Helsinki Study of Very Low Birth Weight Adults.We assessed atopic predisposition at ages 18 to 27 years using skinprick tests for 6 common aeroallergens and measurements ofserum concentrations of total IgE and 3 types of allergen-specific(cat, birch, and timothy) IgE.We asked the subjects whether theyhad been given a diagnosis of asthma or allergic rhinitis or hadatopic eczema and analyzed data by using logistic or linearregression, adjusting for potential confounding factors.Results: The risk for having at least 1 positive reaction on a skinprick test was reduced (adjusted odds ratio, 0.43; 95% CI,
From athe Division of Welfare and Health Promotion, Department of Chronic Disease
Prevention, Diabetes Prevention Unit, National Institute for Health and Welfare, Hel-
sinki; bHyvink€a€a Hospital, Hyvink€a€a; cthe Hospital for Children and Adolescents andfthe Unit of General Practice, Helsinki University Central Hospital, Helsinki; dthe De-
partment of General Practice and Primary Health Care, University of Helsinki; eVasa
Central Hospital, Vasa; and gFolkh€alsan Research Centre, Helsinki.
The Helsinki Study of Very LowBirthWeight Adults has received grant support from the
following sources: the Finnish Foundation for Pediatric Research (E.K., K.W., M.S.,
P.H., and S.A.), Finska L€akares€allskapet (J.G.E. and S.A.), the Finnish Special Gov-
ernmental Subsidy for Health Sciences (J.G.E. and S.A.), the Academy of Finland
(K.W., J.G.E., S.A., and E.K.), the Biomedicum Helsinki Foundation (S.S.K.), the
Emil Aaltonen Foundation, the Finnish Concordia Foundation (S.S.K.), the Finnish
Medical Society Duodecim (E.K.), the Finnish National Graduate School of Clinical
Investigation (S.S.K.), the Jalmari and Rauha Ahokas Foundation (E.K.), the Juho
Vainio Foundation (J.G.E. and E.K.), the Novo Nordisk Foundation (J.G.E. and
E.K.), the P€aivikki and Sakari Sohlberg Foundation (J.G.E. and E.K.), the Pediatric
Graduate School (P.H. and S.S.K.), the Clinical Graduate School in Paediatrics and
Obstetrics/Gynaecology (P.H.), the University of Helsinki (J.G.E.), the Perkl�en Foun-
dation (S.S.K.), the Research Foundation for the Orion Corporation (P.H.), the Signe
and Ane Gyllenberg Foundation (J.G.E. and E.K.), the Sigrid Juselius Foundation
(S.A. and E.K.), the Waldemar von Frenckell Foundation (S.S.K.), Vasa Nation
(S.S.K.), Wiipurilainen Osakunta (E.K.) at Helsinki University, the Wilhelm and
Else Stockmann Foundation (S.S.K.), and the Yrj€o Jahnsson Foundation (P.H.,
J.G.E., and E.K.).
Disclosure of potential conflict of interest: M. Siltanen has received research support
from the Finnish Foundation of Pediatric Research. The rest of the authors have de-
clared that they have no conflict of interest.
Received for publication April 18, 2010; revised December 12, 2010; accepted for pub-
lication December 16, 2010.
Available online February 18, 2011.
Reprint requests: Eero Kajantie, MD, PhD, National Institute for Health and Welfare,
Mannerheimintie 164, PO Box 30, FIN-00271 Helsinki, Finland. E-mail: eero.
0091-6749/$36.00
� 2011 American Academy of Allergy, Asthma & Immunology
doi:10.1016/j.jaci.2010.12.1107
0.23-0.79, P 5 .007), and the concentration of cat-specific IgEwas less (25% less; 95% CI, 43% to 2.3% less; P 5 .033) in serafrom very-low-birth-weight subjects compared with that seen insera from control subjects. Within the very-low-birth-weightgroup, those born at an earlier gestational age were less likely tohave positive skin prick test reactions (adjusted odds ratio for1 week, 0.82; 95% CI, 0.68-0.98, P5 .029) and less likely to havehigh levels of allergen-specific IgE. Cumulative incidences ofatopic disease were similar between adults of very low birthweight and control subjects.Conclusions: Young adults born prematurely and at very lowbirth weight have a lower incidence of atopy than adults whowere born full term. This finding supports the hypothesis thatthe risk for atopy is determined during early stages ofdevelopment. (J Allergy Clin Immunol 2011;127:935-42.)
Key words: Atopy, allergy, skin prick test, total IgE, allergen-specific IgE, prematurity, very low birth weight, gestational age
Early-life circumstances have a significant effect on health anddisease in adult life.1,2 Early-life conditions affect the structureand function of adult organs: this is referred to as programmingor the developmental origins of health and disease.2 The conceptof programming of adult health and disease applies to atopy;priming of the fetal immune system changes the balance of theTH cell response from type 2 to type 1 in infancy or even in theprenatal period.3-7
Prenatal and immediate postnatal lives of subjects born pretermdiffer markedly from those of subjects born at term. Preterm birthcan affect the development of tolerance versus sensitization toantigens. This effect has been analyzed in population-basedstudies of children and adults born at a wide range of gestationalage. Some studies linked immaturity or low birth weight to anincreased risk of atopy,8-12 whereas others found the opposite re-sult13-18 or made no association.19-27 These discrepancies can beattributed, in part, to different study designs, but there is much ev-idence that risk for atopy is determined during early stages of de-velopment. However, few studies have been performed withsubjects born very preterm or at very low birth weight, in whomthe largest differences are likely to be observed. Siltanen et al16
reported a reduced incidence of atopy in 72 ten-year-old childrenborn at very low birth weight (<_1500 g) compared with that in 65control subjects, whereasMai et al22 found no difference among asimilar number of 12-year-old children. We are not aware of stud-ies of this type that have been performed with adults.We evaluated the association between preterm birth at very low
birth weight and atopy in young adulthood.
METHODS
Study participantsThe original study cohort consisted of 474 consecutive subjects who were
born at very lowbirthweight between1978 and 1985 at one of severalmaternity
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936 SILTANEN ET AL
Abbreviation used
OR: O
dds ratiohospitals that serve the province of Uusimaa, Finland. Of these, 335 (70.7%)
were discharged alive from the neonatal intensive care unit of Children’s Hos-
pital at theHelsinkiUniversity Central Hospital, the only tertiary neonatal care
center of this area. We selected a comparison group of term-born (gestational
age >_37 weeks) subjects who were not born small for their gestational age
(birth weight no more than 2 SDs below the mean)28 and matched for sex,
age, and birth hospital (clustered matching; control subjects). We invited
255 subjects of very low birth weight and 314 control subjects whowere living
in the greater Helsinki area to participate in the Helsinki Study of Very Low
BirthWeight Adults. One hundred sixty-six (65.1%) subjects of very low birth
weight and 172 (54.8%) control subjects attended. Baseline characteristics of
the nonparticipating very-low-birth-weight subjects were similar to those of
the subjects who participated in the study, except that cerebral palsy at age
15 months was more common among nonparticipants. The nonparticipating
and participating control subjects did not differ in any characteristics.29
Race or ethnicity are not recorded in Finnish hospital records, but at the
time the study subjects were born, almost all inhabitants of Finland were of
Finnish ancestry.
Data collectionTheHelsinki Study of Very LowBirthWeight Adults was designed to study
in detail the adult health of subjects born preterm at very low birth weight,
including analysis of allergies. The participants completed a structured
questionnaire that covered their own and their parents’ medical, psychosocial,
educational, and environmental histories. The subjects also attended a clinical
examination, which included height and weight measurements.
History of atopic diseases. Data on atopic diseases, such as
asthma, allergic rhinitis, and atopic eczema, were obtained from the ques-
tionnaire. Although the questionnaire has not, to our knowledge, been
validated against medical records, it has been used in previous population
studies.30 Asthma and allergic rhinitis were recorded if the participant re-
ported that these were diagnosed by a doctor. Atopic eczema was recorded
if the participant had a history of infant eczema (milk crust) or atopic derma-
titis. Perinatal and neonatal data were obtained from hospital records.
Skin prick testing. During the clinical examination, skin prick tests
were performed by 1 trained research nurse on the volar surface of the forearm,
according to a standard technique. We used 6 common aeroallergen Soluprick
solutions from ALK-Abell�o (Copenhagen, Denmark): birch, timothy, mug-
wort, cat, dog, and Dermatophagoides pteronyssinus; histamine hydrochlo-
ride (10 mg/mL) was used as the positive control, and 50% glycerol
(Soluprick) was used as the negative control. Test results were considered to
be positive if the mean diameter of the wheal (calculated by using the largest
diameter of the wheal and the diameter perpendicular to that) was 3 mm or
greater and the negative control solution caused no reaction.31
IgE measurements. Blood samples were collected during the clinic
visit. From frozen serum samples, we determined total concentrations of IgE
and concentrations of 3 types of allergen-specific IgE (timothy, birch, and cat).
Measurements of total IgE levels were performed with a clinical chemistry
analyzer (Architect c8000l Abbott Laboratories, Abbott Park, Ill) with an
immunoturbidimetric method (Biokit, Barcelona, Spain) at the Disease Risk
Unit of the National Institute for Health andWelfare in Helsinki, Finland. The
detection limit of this assay is 13 IU/mL; values of less than this were entered
in our database as 12 IU/mL. Allergen-specific IgE levels were measured by
using an immunofluoroenzymemethod on an ImmunoCAP Specific IgE FEIA
analyzer (ImmunoCAP 1000; Phadia AB, Uppsala, Sweden) at the Helsinki
University Central Hospital Allergy Laboratory. The allergen-specific IgE
concentrations were reported as values ranging from 0 to 100 kU/L or greater
than 100 kU/L; values of greater than this were entered as 101 kU/L.
Outcome measuresSkin prick test results and IgE concentrations. The
primary outcomewas atopy, whichwas defined as presence of at least 1 positive
skin prick test reaction. Additional indicators of atopy included serum concen-
trations of total IgE or allergen-specific IgE (timothy, birch and cat), whichwere
used as continuous variables; each allergen-specific IgE concentration was
also dichotomized, with a high value defined as greater than 0.8 kU/L.16
History of atopic diseases. The secondary outcomes included a
self-reported history of any of the following atopic diseases: asthma (doctor
diagnosed), allergic rhinitis (doctor diagnosed), and atopic eczema.
Main exposure groupsVery low birth weight versus term. Frequencies of skin
prick test reactions and history of atopic diseases, as well as serum levels of
total and allergen-specific IgE, were compared between subjects of very low
birth weight and control subjects.
Small-for-gestational-age versus appropriate-for-
gestational-age subjects of very low birth weight. We
also performed analyses within the group of subjects of very low birth weight;
some had birth weights equal to or less than 1500 g (the inclusion criterion)
because of extremely preterm birth, whereas others, with a lesser degree of
prematurity, had birth weights of 1500 g or less because of poor intrauterine
growth. To examine whether poor prenatal growth or preterm birth were
specifically associated with predisposition to atopy, we examined the primary
and secondary outcomes between very-low-birth-weight subjects born at
weights that were defined small for gestational age (weighed <2 SDs below the
mean, according to Finnish birth weight charts) and very-low-birth-weight
subjects born at weights that were defined as appropriate for gestational age
(weighed within 2 SDs of the mean).28
Other comparisons among the very-low-birth-
weight group. To investigate other differences in perinatal character-
istics of the very-low-birth-weight group, we examined the effects of length of
gestation and early-life events, such as the effect of infections on skin prick test
results.
Statistical analysesTo compare background characteristics between groups, we used the x2 test
for dichotomous variables and the Student t test for continuous variables.
To compare dichotomous outcome measures (positive skin prick test
reactions, high concentrations of allergen-specific IgE, and history of atopy)
between groups, we used logistic regression for a crude assessment and
multivariate logistic regression to include covariates in the model. The
potential covariates used in this adjustment included maternal and paternal
atopy, defined as a history of >_1 of the atopic diseases (asthma, allergic rhinitis,
or atopic eczema [yes/no]). Parental education was categorized into 4 levels:
elementary school, high school, intermediate, and university (dummy coded).
Analyses also include the number of older siblings (dummy coded),
maternal smoking during pregnancy (yes/no), birth by means of cesarean
section (yes/no), sex, current age, bodymass index, current weekly smoking of
the participant (yes/no), and cats or dogs at home during the first year of life
(yes/no) or currently (yes/no); these factors can affect predisposition to atopy
or very low birth weight.32,33
Serum concentrations of total and allergen-specific IgE were log trans-
formed to attain normality and entered as dependent variables in linear
regression adjusted for the same covariates as in logistic regression (see above).
The results were reported in odds ratios (ORs) or percentage differences
with 95% CIs and P values. P values of less than .050 were considered statis-
tically significant. Significance tests were 2-sided.
EthicsThe study protocol was approved by the Ethics Committee of Children and
Adolescents’ Diseases and Psychiatry at Helsinki and Uusimaa Hospital Dis-
trict. Each participant signed an informed consent form.
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RESULTS
Characteristics of study participantsTable I shows the characteristics of the study participants. The
mean birth weight of the very-low-birth-weight group was 1120 g(range, 600-1500 g), and that of the control subjects was 3593 g(range, 2560-4930 g); the mean gestational ages were 29.2 weeks(range, 24.0-35.6) and 40.1 weeks (range, 37.0-42.9), respec-tively. The control subjects smoked more often than subjectsfrom the very-low-birth-weight group, whereas the very-low-birth-weight participants were more likely to have a pet athome. Parental atopy did not differ between the groups, but theeducational level of parents was higher among control subjects.The mean gestational age of the very-low-birth-weight subgroup
who were born small for gestational age was, by definition, greaterthan of the subgroup who were of the appropriate size forgestational age (31.2weeks [range, 27.0-35.6weeks] vs 28.2weeks[range, 24.0-31.7 weeks],P <.001). Therewere also other expecteddifferences in obstetric backgrounds of the mothers; preeclampsiacomplicated the pregnancy (41.8% vs 10.8%, P < .001), and deliv-ery was performed by means of cesarean section (85.5% vs 50.5%,P < .001) more often among infants born small for gestationalage than those who were appropriate size for gestational age.
Skin prick test reactions and IgE concentrationsSubjects of very low birth weight were less likely to have
positive skin prick test reactions than control subjects: 45.5% hadat least 1 positive reaction to one of the 6 common aeroallergenscompared with 57.9% of the control subjects (crude OR, 0.61;95% CI, 0.39-0.93; P5 .023; Table II). Adjustment for covariatesreduced the OR for allergic reactions among the very-low-birth-weight group (adjusted OR, 0.48; 95% CI, 0.27-0.86; P 5 .013).We also compared positive skin prick test reactions between thesubgroup of subjects of extremely low birth weight (birth weight<_1000 g) and control subjects, which further reduced the OR forreactivity (adjusted OR, 0.24; 95% CI, 0.10-0.58; P 5 .002).Of the covariates, male sex (OR, 2.03; 95% CI, 1.26-3.29; P5
.004) and maternal atopy (OR, 1.98; 95% CI, 1.16-3.35; P5 .012)were independently associated with an increased risk of having atleast 1 positive skin prick test reaction. Older age of the participantwas associated with positive reactions to dog (OR, 1.16; 95% CI,1.02-1.31; P 5 .020) and timothy (OR, 1.14; 95% CI, 1.01-1.28;P 5 .040) allergens. Maternal smoking during pregnancy wasassociated with positive reactions to mugwort (OR, 2.80; 95%CI, 1.11-7.08;P5.030), and delivery bymeans of cesarean sectionwas associated with positive reactions to birch (OR, 2.59; 95% CI,1.34-5.02; P5 .005).
Very-low-birth-weight subjects were less likely than controlsubjects to have high serum concentrations of any of the types ofallergen-specific IgE measured (adjusted OR, 0.48; 95% CI,0.25–0.91), especially cat-specific IgE (Table II). When theconcentrations were analyzed as continuous variables, the meanconcentration of IgE for cat allergen was significantly less inthe very-low-birth-weight group than in the control group (25%less than control subjects; 95% CI, 43% to 2.3% less; P 5 .033;Table III). The mean concentration of total IgE did not differ sig-nificantly between the very-low-birth-weight group and the con-trol subjects when adjusted for all covariates.Subgroup comparison of small versus appropriate
size for gestational age. The numbers of subjects having atleast 1 positive reaction on a skin prick test were similar between
the small and appropriately sized for gestational age subgroups ofvery low birth weight (Table IV). A positive reaction toDermato-phagoides pteronyssinuswas more common in the subgroup bornsmall for gestational age compared with those born of appropriatesize for gestational age after adjustment for covariates.Subjects in the subgroup born small for gestational age were
more likely to have high concentrations of any of types ofallergen-specific IgE measured compared with subjects born atappropriate size for their gestational age (adjusted OR, 2.57; 95%CI, 1.10-5.99; Table IV) and to have high concentrations of birch-and timothy-specific IgE (Table IV). They also had higher meanserum concentrations of IgE for timothy (50.1% higher; 95%CI, 18.2% to 121.2%; P 5 .040; Table III). The mean concentra-tion of total IgE was significantly higher in very-low-birth-weightsubjects born small for gestational age compared with those bornof appropriate size for gestational age (76.3%; 95% CI, 11.4% to178.7%; P 5 .016).Subgroup analyses of length of gestation and ma-
ternal and neonatal infections. Within the very-low-birth-weight group, a 1-week lower gestational agewas associated withan adjusted OR of 0.82 (95% CI, 0.68-0.98) for at least 1 positiveskin prick test reaction and an OR of 0.82 (95% CI, 0.68-0.99) forat least 1 high serum concentration of an allergen-specific IgE.The association between gestation period and atopy becamemoreevident when participants whowere born small for gestational agewere excluded from the analysis (adjusted OR of 0.63 [95% CI,0.44-0.90] for a positive reaction and 0.67 [95%CI, 0.45-1.01] fora high concentration of an allergen-specific IgE). Figs 1 and 2show percentages of atopy among subgroups of very-low-birth-weight subjects born at different gestational ages comparedwith those of control subjects.We analyzed whether perinatal and neonatal complications
were associated with atopy within the very-low-birth-weightgroup. Neonatal sepsis was associated with an adjusted OR of3.32 (95%CI, 0.85-12.95) for a positive skin prick test reaction and4.43 (95% CI, 1.02-19.30) for a high concentration of an allergen-specific IgE; ORs for maternal preeclampsia were 2.54 (95% CI,1.02-6.36) and 2.40 (95% CI, 0.92-6.27), respectively. Whenadjusted for gestational age at birth, ORs for a positive skin pricktest reaction and a high concentration of an allergen-specific IgEamong infants who experienced neonatal sepsis remained similar(3.18 and 4.42, respectively), whereas the ORs for preeclampsiawere reduced (1.89 and 1.85, respectively). Maternal chorioam-nionitis, prolonged rupture of membranes, placental ablation,bronchopulmonary dysplasia, and multiple births were unrelatedto skin prick test results or concentrations of allergen-specific IgE.
History of atopic diseasesThere were no differences between the very-low-birth-weight
group and control subjects in the frequencies of asthma, allergicrhinitis, or atopic eczema (Table II), nor were there differences inhistories of atopy between very-low-birth-weight subjects bornsmall or of appropriate size for gestational age (Table IV).
DISCUSSIONYoung adults who were born at very low birth weight had a
significantly lower incidence of atopy, which was defined as apositive skin prick test reaction, compared with those born atterm. The lowest risk of atopy was observed among subjects born
TABLE I. Characteristics of the study participants
Characteristics VLBW (n 5 166) Term (n 5 172) P value*
Missing value,
VLBW/term
Male sex, no. (%) 71 (42.8) 69 (40.1) .620 0/0
Prenatal/neonatal
Birth weight (g [SD]) 1120 (221) 3593 (471) <.001 0/0
Gestational age (wk [SD]) 29.2 (2.2) 40.1 (1.1) <.001 0/0
Cesarean section, no. (%) 103 (62.0) 20 (11.6) <.001 0/0
Multiple birth, no. (%) 27 (16.3) 0 0/0
Preeclampsia, no. (%) 35 (21.1) 13 (7.6) <.001 0/0
Premature rupture of membranes, no. (%)� 28 (16.9) 3
Chorioamnionitis, no. (%)� 14 (8.4) 3
Placental ablation, no. (%)� 19 (11.4) 3
Neonatal sepsis, no. (%)� 12 (7.2) 3
Bronchopulmonary dysplasia, no. (%)� 30 (21.7) 0 6
Cerebral palsy, no. (%) 14 (8.4) 0 5/1
Maternal age (y [SD]) 29.8 (4.7) 29.7 (4.7) .911 0/0
Maternal smoking during pregnancy, no. (%) 31 (18.7) 28 (16.3) .562 0/0
Cats or dogs at home during the first year, no. (%) 36 (22.1) 32 (18.6) .428 3/0
Current
Age (y [SD]) 22.4 (2.1) 22.5 (2.2) .895 0/0
Height (cm [SD])
Women 162.0 (7.7) 167.3 (6.8) <.001 0/0
Men 174.6 (7.7) 180.6 (6.4) <.001 0/0
Body mass index, mean (SD)
Women 22.3 (4.0) 22.8 (3.7) .382 0/0
Men 22.0 (3.6) 23.3 (3.2) .021 0/0
Smoking weekly, no. (%) 45 (27.8) 70 (40.7) .013 4/0
Cats or dogs at home currently, no. (%) 62 (37.3) 46 (26.7) .037 0/0
Parental
Asthma, no. (%)
Maternal 17 (10.5) 14 (8.1) .459 4/0
Paternal 9 (5.7) 9 (5.3) .873 8/2
Atopic eczema, no. (%)
Maternal 13 (8.6) 12 (7.6) .757 14/14
Paternal 7 (4.7) 7 (4.5) .950 17/18
Allergic rhinitis, no. (%)
Maternal 29 (18.4) 36 (21.8) .438 8/7
Paternal 18 (11.8) 23 (14.5) .494 14/13
Highest education of either parent, no. (%) .024 3/1
Elementary 17 (10.4) 11 (6.4)
High school 42 (25.8) 31 (18.1)Intermediate 59 (36.2) 56 (32.7)
University 45 (27.6) 73 (42.7)
Siblings, no. (range)
All 1.5 (0-6) 1.8 (0-13) .116 3/0
Elder 0.7 (0-4) 0.8 (0-6) .341 3/0
VLBW, Very low birth weight (<_1500 g).
*The t test was used for continuous variables, and the x2 test was used for categorical variables.
�Data available or relevant for the VLBW group only.
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938 SILTANEN ET AL
most immature; risk of atopy in adulthood increased withgestational age at birth. Subjects of very low birth weight werealso less likely to have serum IgE for specific allergens, and therisk was again lowest among those born the most immature.Previous studies have evaluated associations between predispo-
sition to atopy and body size or gestational age at birth. However,most of thesewere designed differently than our study and includedpopulations from a range of birth weights and gestational ages;many did not distinguish between the effects of preterm birth andfetal growth. Some studies associated atopy with higher birthweight14,17,34,35 (or larger head circumference, indirectly reflectinglarger birth size or disproportionate growth),36-38 whereas othersassociated it with low birth weight9-12 or made no association at
all.19-21,23-27 Results are also inconsistent among studies of pretermbirth. Some found a decreased risk of atopy among subjects bornpreterm,13-15,17,35 usually defined as less than 37 weeks of gesta-tion, but others found the opposite8-12; some made a U-shaped as-sociation.39,40 We are aware of only 2 studies that focused onsubjects of very low birth weight; a study of Swedish childrendid not associate positive skin prick test reactions at age 12 yearswith preterm birth or very low body weight,22 whereas a differentstudy reported that 10-year-old Finnish children of very low birthweight were less likely than control subjects to have positive skinprick test reactions,16 which is consistent with our findings fromyoung adults. Both studies were small and had limited power to as-sess the effects of other perinatal characteristics.
TABLE II. Numbers and differences (crude and adjusted ORs and 95% CIs) in the numbers of subjects having positive skin prick test
reactions, high serum allergen-specific IgE concentrations, or atopic diseases between those born preterm at VLBW and control
subjects born at term
Atopic manifestation
VLBW
(n 5 166)
Term
(n 5 172)
Crude
OR (95% CI)
Adjusted
OR (95% CI)yMissing value,
VLBW/term
Skin prick test positivity, no. (%)
At least 1 positive 75 (45.5%) 99 (57.9%) 0.61 (0.39-0.93)* 0.48 (0.27-0.86)* 1/1
Birch 45 (27.3%) 53 (31.0%) 0.84 (0.52-1.34) 0.58 (0.30-1.11) 1/1
Timothy 43 (26.1%) 58 (33.8%) 0.69 (0.43-1.09) 0.71 (0.38-1.33) 1/1
Mugwort 22 (13.3%) 44 (25.7%) 0.44 (0.25-0.78)* 0.41 (0.20-0.86)* 1/1
Cat 33 (20.0%) 52 (30.6%) 0.57 (0.34-0.94)* 0.48 (0.24-0.95)* 1/2
Dog 38 (23.0%) 53 (31.0%) 0.67 (0.41-1.08) 0.55 (0.28-1.07) 1/1
Dermatophagoides pteronyssinus 14 (8.5%) 15 (8.8%) 0.96 (0.45-2.05) 1.43 (0.53-3.90) 1/2
High allergen-specific IgE level (>0.8 kU/L), no. (%)
At least 1 high level 51 (30.4%) 65 (37.8%) 0.73 (0.46-1.15) 0.48 (0.25-0.91)* 0/0
Birch 30 (18.1%) 44 (25.6%) 0.75 (0.45-1.25) 0.60 (0.29-1.24) 0/0
Timothy 34 (20.2%) 44 (25.6%) 0.64 (0.38-1.08) 0.67 (0.33-1.37) 0/0
Cat 25 (14.9%) 39 (22.7%) 0.60 (0.35-1.05) 0.41 (0.19-0.91)* 0/0
Atopic disease, no. (%)
Asthma 29 (17.9%) 21 (12.2%) 1.57 (0.85-2.88) 1.71 (0.80-3.68) 4/0
Allergic rhinitis 49 (30.1%) 42 (24.4%) 1.33 (0.82-2.16) 1.34 (0.71-2.50) 3/0
Atopic eczema 31 (19.7%) 40 (23.7%) 0.79 (0.47-1.35) 0.61 (0.30-1.24) 9/3
VLBW, Very low birth weight (<_1500 g).
*Boldfaced text denotes P < .05.
�Covariates used in the adjustment: maternal and paternal atopy, parental education, number of elder siblings, maternal smoking during pregnancy, cesarean section, sex, current
age and body mass index, smoking, cats or dogs at home during the first year, or currently.
TABLE III. Mean differences in percentages and 95% CIs in levels of serum total IgE and 3 types of allergen-specific IgE between VLBW
and term-born control subjects and between subjects at VLBW born SGA and AGA obtained by means of linear regression adjusted for
covariates*
Atopic manifestation
VLBW (n 5 166) vs
term (n 5 172) P value
VLBW SGA (n 5 55) vs
VLBW AGA (n 5 111) P value
Serum total IgE 211.0% (–36.7% to 25.1%) .499 76.3% (11.4% to 178.7%) .016
Allergen-specific IgE
Birch 226.2% (247.4% to 3.5%) .078 27.3% (217.1% to 95.4%) .267
Timothy 213.6% (236.9% to 18.3%) .361 50.1% (18.2% to 121.2%) .040
Cat 225.0% (242.5% to 22.3%) .033 32.6% (24.9% to 85.0%) .096
Values are shown as mean differences (percentages) and 95% CIs. Boldfaced text denotes P < .05.
AGA, Appropriate for gestational age; SGA, small for gestational age; VLBW, very low birth weight (<_1500 g).
*Covariates used in the adjustment: maternal and paternal atopy, parental education, number of older siblings, maternal smoking during pregnancy, cesarean section, sex, current
age and body mass index, smoking, cats or dogs at home during the first year, or currently.
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SILTANEN ET AL 939
Inconsistency among results might result from differences inresearch methods, such as sampling, as well as in outcomemeasures and methodologies applied. An important limitation ofthe studies of population-based birth cohorts is that they includedonly a small number of subjects in extreme categories, such asthose born severely preterm. Our study makes a significantaddition to the literature because we compared data from youngadults born severely preterm with data from young adults born atterm; we found that the more preterm one is born, the lower therisk for atopy in adult life.The measure of outcome is important in studies of atopy risk.
Several studies have examined atopic diseases, such asasthma.15,41 Asthma, however, includes several underlying pa-thologies and phenotypes that are not always related to atopy.42,43
Atopy, which was defined as a positive skin prick test reaction oran increased level of allergen-specific IgE, has been investigatedin some studies.16,22,35 In a community sample of preschool-agedchildren, length of gestation was associated with skin prick testreactions and increased levels of allergen-specific IgE, although
not with asthma, atopic dermatitis, or hay fever.35 In line withthis finding, we did not observe a difference in the frequency ofhistory of atopy between preterm subjects and control subjects,although skin prick test reactions and concentrations ofallergen-specific IgE were reduced among subjects born preterm.In addition, discrepancies in atopic diseases, skin prick test reac-tions, and concentrations of allergen-specific IgE might resultfrom variations in sample sizes or questionnaire-based assess-ments of atopic diseases, which are prone to misclassification.Furthermore, the presence of atopic disease was not diagnosedby a doctor in many studies; this was required in our study.We examined early-life determinants of atopy within the very-
low-birth-weight group. This was essential because the criteria (ie,preterm birth at a weight of <_1500 g) allowed inclusion of aheterogeneous group of subjects who were born preterm. Somewere born extremely preterm, whereas others of a lesser degree ofprematurity had birth weights of 1500 g or less because of poorintrauterine growth. Two previous studies reported no difference inpredisposition for atopy between subjects born small or of
TABLE IV. Numbers and differences (crude and adjusted ORs and 95% CIs) in the numbers of subjects with positive skin prick test
reactions, high serum allergen-specific IgE concentrations, or atopic diseases between VLBW subjects born SGA compared with VLBW
subjects born AGA
Atopic manifestation
VLBW SGA
(n 5 55)
VLBW AGA
(n 5 111) Crude OR (95% CI)
Adjusted OR
(95% CI)yMissing value,
SGA/AGA
Skin prick test positivity, no. (%)
At least 1 positive 30 (55.6%) 45 (40.5%) 1.83 (0.95-3.54) 1.68 (0.75-3.72) 1/0
Birch 19 (35.2%) 26 (23.4%) 1.78 (0.87-3.61) 1.26 (0.54-2.97) 1/0
Timothy 17 (31.5%) 26 (23.4%) 1.50 (0.73-3.09) 1.19 (0.42-2.88) 1/0
Mugwort 8 (14.8%) 14 (12.6%) 1.20 (0.47-3.07) 0.95 (0.30-3.04) 1/0
Cat 13 (24.1%) 20 (18.0%) 1.44 (0.66-3.18) 1.47 (0.55-3.93) 1/0
Dog 18 (33.3%) 20 (18.0%) 2.28 (1.08-4.79)* 1.89 (0.75-4.74) 1/0
Dermatophagoides pteronyssinus 8 (14.8%) 6 (5.4%) 3.04 (1.00-9.27)* 4.37 (1.02-18.69)* 1/0
High allergen-specific IgE level
(>0.8 kU/L), no. (%)
At least 1 high level 24 (43.7%) 27 (24.3%) 2.41 (1.21-4.79)* 2.57 (1.10-5.99)* 0/0
Birch 18 (32.7%) 16 (14.4%) 2.89 (1.33-6.26)* 2.81 (1.09-7.22)* 0/0
Timothy 14 (25.5%) 16 (14.4%) 2.03 (0.91-4.54) 2.87 (1.04-7.94)* 0/0
Cat 11 (20.0%) 14 (12.7%) 1.73 (0.73-4.12) 2.01 (0.69-5.89) 0/0
Atopic diseases, no. (%)
Asthma 9 (17.3%) 20 (18.2%) 0.94 (0.40-2.24) 0.71 (0.25-1.98) 3/1
Allergic rhinitis 17 (32.1%) 32 (29.1%) 1.15 (0.57-2.34) 0.70 (0.28-1.73) 2/1
Atopic eczema 11 (22.4%) 29 (18.5%) 1.27 (0.56-2.92) 1.04 (0.37-2.86) 6/3
AGA, Appropriate for gestational age; SGA, small for gestational age; VLBW, very low birth weight (<_1500 g).
*Boldfaced text denotes P <_ .05.
�Covariates used in the adjustment: maternal and paternal atopy, parental education, number of older siblings, maternal smoking during pregnancy, cesarean section, sex, current
age and body mass index, smoking, cats or dogs at home during the first year, or currently.
FIG 1. Percentages of study participants grouped by gestational age at birth
who had at least 1 positive skin prick test reaction. Within the very-low-
birth-weight (VLBW) group (gestational age at birth <37 weeks), reduction
of gestational age by 1 week was associated with a lower risk of atopy
based on skin prick test results (adjusted OR, 0.82; 95% CI, 0.68-0.98).
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APRIL 2011
940 SILTANEN ET AL
appropriate size for their gestational age,44,45 whereas we foundhigher rates of atopy among those born small for gestational age.Our finding might arise because in the present study subjectsborn small for gestational agewere more often delivered bymeansof cesarean section, which has been proposed to affect immunesystemdevelopment.46-48However, thegreater averagegestationalage of subjects born small for gestational age could also accountfor this finding. The specific association between prematurityand lower risk of atopy was also demonstrated by the fact thatthemost preterm subjects had the lowest rates of positive skin pricktest reactions and also the lowest rates of high concentrations ofallergen-specific IgE.An advantage of our study was that the Helsinki Study of Very
Low Birth Weight Adults was designed to evaluate differentaspects of the adult health of subjects born preterm with very lowbirth weight, and therefore the bias toward disease was lower thanthat of studies that focused on atopy. We were able to adjust formost potential confounding factors; this did not affect theobserved difference in atopy between subjects born preterm andcontrol subjects. Unfortunately, we did not have data on parentalsmoking during the early postnatal period, but we did adjust formothers who smoked during pregnancy.Other limitations to our study include differences in participa-
tion rates between the very-low-birth-weight and control groups,which could introduce bias if the reasons for nonparticipationdiffered between the groups. It is also possible that very-low-birth-weight subjects who did not survive through the intensivecare period and were thus not included in the study would have agreater risk for atopy than those who survived. Moreover, ourresults might not be applicable to the present because thetreatment of prematurely born neonates differs between todayand the 1970s and 1980s, when the subjects included in our studywere born.
There are several elements that can modify the development ofthe immune systems of preterm subjects and account for ourfindings of a lower risk of atopy than in control subjects. Pretermneonates have immature immune systems, greater permeability ofthe gastrointestinal tract, and qualitatively and quantitativelydifferent early exposures to antigens than term-born infants; thesecan affect their development of tolerance versus sensitization toantigens. Also, the early-stage composition of the gastrointestinalflora49 can contribute to the risk of atopy among subjects born pre-term because it affects the development of immunologic bal-ance.50 Early infections that are common among pretermneonates might contribute to later development of sensitization.However, we found that neonatal septicemia increased the riskof atopy. Preterm neonates frequently receive antibiotics, which
FIG 2. Percentages of study participants grouped by gestational age at birth
with high concentrations (>0.8 kU/L) of at least 1 serum allergen-specific
IgE. Within the very-low-birth-weight (VLBW) group (gestational age at
birth <37 weeks), a 1-week reduction in gestational age was associated
with a lower risk of high concentrations of allergen-specific IgE (adjusted
OR, 0.82; 95% CI, 0.68-0.99).
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SILTANEN ET AL 941
have been associated with increased risk of asthma,51 althoughasthma is a poor marker for atopy. The influence of early feedingon atopy risk should be evaluated in subjects born preterm.8,52
Preterm infants are more frequently delivered by means ofcesarean section than full-term infants. Delivery by means ofcesarean section has, however, been associated with a greater riskfor atopy, probably because of differences in gastrointestinalflora.46-48 Our study also found that delivery bymeans of cesareansection increased the incidence of atopy, although this associationmight result from the indication for cesarean section. Preeclamp-sia and placental abruption,53 as well as in utero stress,54,55 arefrequently associated with preterm birth. They might modifythe risk for atopy, although it seems that they would increase,rather than reduce, the risk for atopy.In conclusion, subjects born preterm and at very low birth
weight have a lower incidence of atopy than their term-borncounterparts in young adulthood. Although severe preterm birthhas been associated with many disadvantages in later life,29,56-60
not all outcomes are unfavorable. A lower predisposition to atopycould reduce the lifetime burden of disease among adults born atvery low birth weight.
Key messages
d Previous studies have assessed the risk of atopy in personsborn preterm and produced contradictory results,whereas the risk among persons born most prematurelyhas been less well studied.
d Young adults born preterm and at very low birth weighthave a lower rate of atopy than young adults born atterm. The more prematurely a subject is born, the lowertheir risk for atopy.
d The lower incidence of atopy among subjects born pre-term and at very low birth weight supports the hypothesisthat propensity for atopy is determined during earlystages of development.
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