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
rvenpa
a
, MD, PhD,c Sture Andersson, MD, PhD,c and
Sonja Strang-Karlsson, MD,a,c Anna-Liisa Ja
Eero Kajantie, MD, PhDa,c Helsinki, Hyvinkaa, and Vasa, Finland
Background: Immunologic pathways are primed in early life.
Preterm birth can influence this process and thereby affect
whether a person will have atopy later in life. Previous studies
on the effects of preterm birth on atopy in adulthood have been
inconclusive and limited to children or subjects born
moderately preterm.
Objective: Our aim was to compare the incidence of atopy
among young adults who were born preterm and at very low
_1500 g) with that of term-born young adults
birth weight (<
(control subjects).
Methods: The study comprised 166 adults who were born preterm
and at very low birth weight and 172 control subjects, all of whom
were from the Helsinki Study of Very Low Birth Weight Adults.
We assessed atopic predisposition at ages 18 to 27 years using skin
prick tests for 6 common aeroallergens and measurements of
serum concentrations of total IgE and 3 types of allergen-specific
(cat, birch, and timothy) IgE. We asked the subjects whether they
had been given a diagnosis of asthma or allergic rhinitis or had
atopic eczema and analyzed data by using logistic or linear
regression, adjusting for potential confounding factors.
Results: The risk for having at least 1 positive reaction on a skin
prick 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, Helsinki; bHyvinkaa Hospital, Hyvinkaa; cthe Hospital for Children and Adolescents and
f
the Unit of General Practice, Helsinki University Central Hospital, Helsinki; dthe Department of General Practice and Primary Health Care, University of Helsinki; eVasa
Central Hospital, Vasa; and gFolkhalsan Research Centre, Helsinki.
The Helsinki Study of Very Low Birth Weight 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 Lakaresallskapet (J.G.E. and S.A.), the Finnish Special Governmental 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 Paivikki 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 Perklen Foundation (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 Yrjo 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 declared that they have no conflict of interest.
Received for publication April 18, 2010; revised December 12, 2010; accepted for publication 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.
kajantie@helsinki.fi.
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 IgE

was less (25% less; 95% CI, 43% to 2.3% less; P 5 .033) in sera
from very-low-birth-weight subjects compared with that seen in
sera from control subjects. Within the very-low-birth-weight
group, those born at an earlier gestational age were less likely to
have positive skin prick test reactions (adjusted odds ratio for
1 week, 0.82; 95% CI, 0.68-0.98, P 5 .029) and less likely to have
high levels of allergen-specific IgE. Cumulative incidences of
atopic disease were similar between adults of very low birth
weight and control subjects.
Conclusions: Young adults born prematurely and at very low
birth weight have a lower incidence of atopy than adults who
were born full term. This finding supports the hypothesis that
the risk for atopy is determined during early stages of
development. (J Allergy Clin Immunol 2011;127:935-42.)
Key words: Atopy, allergy, skin prick test, total IgE, allergenspecific IgE, prematurity, very low birth weight, gestational age

Early-life circumstances have a significant effect on health and

disease in adult life.1,2 Early-life conditions affect the structure
and function of adult organs: this is referred to as programming
or the developmental origins of health and disease.2 The concept
of programming of adult health and disease applies to atopy;
priming of the fetal immune system changes the balance of the
TH cell response from type 2 to type 1 in infancy or even in the
prenatal period.3-7
Prenatal and immediate postnatal lives of subjects born preterm
differ markedly from those of subjects born at term. Preterm birth
can affect the development of tolerance versus sensitization to
antigens. This effect has been analyzed in population-based
studies of children and adults born at a wide range of gestational
age. Some studies linked immaturity or low birth weight to an
increased risk of atopy,8-12 whereas others found the opposite result13-18 or made no association.19-27 These discrepancies can be
attributed, in part, to different study designs, but there is much evidence that risk for atopy is determined during early stages of development. However, few studies have been performed with
subjects born very preterm or at very low birth weight, in whom
the largest differences are likely to be observed. Siltanen et al16
reported a reduced incidence of atopy in 72 ten-year-old children
_1500 g) compared with that in 65
born at very low birth weight (<
control subjects, whereas Mai et al22 found no difference among a
similar number of 12-year-old children. We are not aware of studies 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 participants
The original study cohort consisted of 474 consecutive subjects who were
born at very low birth weight between 1978 and 1985 at one of several maternity
935

936 SILTANEN ET AL

Abbreviation used
OR: Odds ratio

hospitals that serve the province of Uusimaa, Finland. Of these, 335 (70.7%)
were discharged alive from the neonatal intensive care unit of Childrens Hospital at the Helsinki University Central Hospital, the only tertiary neonatal care
center of this area. We selected a comparison group of term-born (gestational
_37 weeks) subjects who were not born small for their gestational age
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 who were living
in the greater Helsinki area to participate in the Helsinki Study of Very Low
Birth Weight 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 collection
The Helsinki Study of Very Low Birth Weight 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 questionnaire. 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 reported that these were diagnosed by a doctor. Atopic eczema was recorded
if the participant had a history of infant eczema (milk crust) or atopic dermatitis. 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, mugwort, cat, dog, and Dermatophagoides pteronyssinus; histamine hydrochloride (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 and Welfare 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 immunofluoroenzyme method 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.

J ALLERGY CLIN IMMUNOL

APRIL 2011

Outcome measures
Skin prick test results and IgE concentrations. The
primary outcome was atopy, which was defined as presence of at least 1 positive
skin prick test reaction. Additional indicators of atopy included serum concentrations of total IgE or allergen-specific IgE (timothy, birch and cat), which were
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 groups

Very 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-forgestational-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-birthweight group. To investigate other differences in perinatal characteristics 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 analyses
To 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
_1 of the atopic diseases (asthma, allergic rhinitis,
atopy, defined as a history of >
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, body mass 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 transformed 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 statistically significant. Significance tests were 2-sided.

Ethics
The study protocol was approved by the Ethics Committee of Children and
Adolescents Diseases and Psychiatry at Helsinki and Uusimaa Hospital District. Each participant signed an informed consent form.

J ALLERGY CLIN IMMUNOL

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RESULTS
Characteristics of study participants
Table 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), respectively. The control subjects smoked more often than subjects
from the very-low-birth-weight group, whereas the very-lowbirth-weight participants were more likely to have a pet at
home. Parental atopy did not differ between the groups, but the
educational 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, greater
than of the subgroup who were of the appropriate size for
gestational age (31.2 weeks [range, 27.0-35.6 weeks] vs 28.2 weeks
[range, 24.0-31.7 weeks], P <.001). There were also other expected
differences in obstetric backgrounds of the mothers; preeclampsia
complicated the pregnancy (41.8% vs 10.8%, P < .001), and delivery was performed by means of cesarean section (85.5% vs 50.5%,
P < .001) more often among infants born small for gestational
age than those who were appropriate size for gestational age.
Skin prick test reactions and IgE concentrations
Subjects of very low birth weight were less likely to have
positive skin prick test reactions than control subjects: 45.5% had
at least 1 positive reaction to one of the 6 common aeroallergens
compared with 57.9% of the control subjects (crude OR, 0.61;
95% CI, 0.39-0.93; P 5.023; Table II). Adjustment for covariates
reduced the OR for allergic reactions among the very-low-birthweight group (adjusted OR, 0.48; 95% CI, 0.27-0.86; P 5 .013).
We also compared positive skin prick test reactions between the
subgroup of subjects of extremely low birth weight (birth weight
<
_1000 g) and control subjects, which further reduced the OR for
reactivity (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; P 5
.004) and maternal atopy (OR, 1.98; 95% CI, 1.16-3.35; P 5 .012)
were independently associated with an increased risk of having at
least 1 positive skin prick test reaction. Older age of the participant
was 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 was
associated with positive reactions to mugwort (OR, 2.80; 95%
CI, 1.11-7.08; P 5.030), and delivery by means of cesarean section
was associated with positive reactions to birch (OR, 2.59; 95% CI,
1.34-5.02; P 5 .005).
Very-low-birth-weight subjects were less likely than control
subjects to have high serum concentrations of any of the types of
allergen-specific IgE measured (adjusted OR, 0.48; 95% CI,
0.250.91), especially cat-specific IgE (Table II). When the
concentrations were analyzed as continuous variables, the mean
concentration of IgE for cat allergen was significantly less in
the 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 significantly between the very-low-birth-weight group and the control subjects when adjusted for all covariates.
Subgroup comparison of small versus appropriate
size for gestational age. The numbers of subjects having at
least 1 positive reaction on a skin prick test were similar between

SILTANEN ET AL 937

the small and appropriately sized for gestational age subgroups of

very low birth weight (Table IV). A positive reaction to Dermatophagoides pteronyssinus was more common in the subgroup born
small for gestational age compared with those born of appropriate
size 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 of
allergen-specific IgE measured compared with subjects born at
appropriate size for their gestational age (adjusted OR, 2.57; 95%
CI, 1.10-5.99; Table IV) and to have high concentrations of birchand timothy-specific IgE (Table IV). They also had higher mean
serum concentrations of IgE for timothy (50.1% higher; 95%
CI, 18.2% to 121.2%; P 5 .040; Table III). The mean concentration of total IgE was significantly higher in very-low-birth-weight
subjects born small for gestational age compared with those born
of appropriate size for gestational age (76.3%; 95% CI, 11.4% to
178.7%; P 5 .016).
Subgroup analyses of length of gestation and maternal and neonatal infections. Within the very-low-birthweight group, a 1-week lower gestational age was associated with
an adjusted OR of 0.82 (95% CI, 0.68-0.98) for at least 1 positive
skin prick test reaction and an OR of 0.82 (95% CI, 0.68-0.99) for
at least 1 high serum concentration of an allergen-specific IgE.
The association between gestation period and atopy became more
evident when participants who were born small for gestational age
were 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] for
a high concentration of an allergen-specific IgE). Figs 1 and 2
show percentages of atopy among subgroups of very-low-birthweight subjects born at different gestational ages compared
with those of control subjects.
We analyzed whether perinatal and neonatal complications
were associated with atopy within the very-low-birth-weight
group. Neonatal sepsis was associated with an adjusted OR of
3.32 (95% CI, 0.85-12.95) for a positive skin prick test reaction and
4.43 (95% CI, 1.02-19.30) for a high concentration of an allergenspecific IgE; ORs for maternal preeclampsia were 2.54 (95% CI,
1.02-6.36) and 2.40 (95% CI, 0.92-6.27), respectively. When
adjusted for gestational age at birth, ORs for a positive skin prick
test reaction and a high concentration of an allergen-specific IgE
among infants who experienced neonatal sepsis remained similar
(3.18 and 4.42, respectively), whereas the ORs for preeclampsia
were reduced (1.89 and 1.85, respectively). Maternal chorioamnionitis, prolonged rupture of membranes, placental ablation,
bronchopulmonary dysplasia, and multiple births were unrelated
to skin prick test results or concentrations of allergen-specific IgE.

History of atopic diseases

There were no differences between the very-low-birth-weight
group and control subjects in the frequencies of asthma, allergic
rhinitis, or atopic eczema (Table II), nor were there differences in
histories of atopy between very-low-birth-weight subjects born
small or of appropriate size for gestational age (Table IV).
DISCUSSION
Young adults who were born at very low birth weight had a
significantly lower incidence of atopy, which was defined as a
positive skin prick test reaction, compared with those born at
term. The lowest risk of atopy was observed among subjects born

938 SILTANEN ET AL

J ALLERGY CLIN IMMUNOL

APRIL 2011

TABLE I. Characteristics of the study participants

Characteristics

Male sex, no. (%)

Prenatal/neonatal
Birth weight (g [SD])
Gestational age (wk [SD])
Cesarean section, no. (%)
Multiple birth, no. (%)
Preeclampsia, no. (%)
Premature rupture of membranes, no. (%)
Chorioamnionitis, no. (%)
Placental ablation, no. (%)
Neonatal sepsis, no. (%)
Bronchopulmonary dysplasia, no. (%)
Cerebral palsy, no. (%)
Maternal age (y [SD])
Maternal smoking during pregnancy, no. (%)
Cats or dogs at home during the first year, no. (%)
Current
Age (y [SD])
Height (cm [SD])
Women
Men
Body mass index, mean (SD)
Women
Men
Smoking weekly, no. (%)
Cats or dogs at home currently, no. (%)
Parental
Asthma, no. (%)
Maternal
Paternal
Atopic eczema, no. (%)
Maternal
Paternal
Allergic rhinitis, no. (%)
Maternal
Paternal
Highest education of either parent, no. (%)
Elementary
High school
Intermediate
University
Siblings, no. (range)
All
Elder

VLBW (n 5 166)

71 (42.8)
1120
29.2
103
27
35
28
14
19
12
30
14
29.8
31
36

P value*

Missing value,
VLBW/term

69 (40.1)

.620

0/0

3593 (471)
40.1 (1.1)
20 (11.6)
0
13 (7.6)

<.001
<.001
<.001

0
0
29.7 (4.7)
28 (16.3)
32 (18.6)

.911
.562
.428

0/0
0/0
0/0
0/0
0/0
3
3
3
3
6
5/1
0/0
0/0
3/0

22.4 (2.1)

22.5 (2.2)

.895

0/0

162.0 (7.7)
174.6 (7.7)

167.3 (6.8)
180.6 (6.4)

<.001
<.001

0/0
0/0

.382
.021
.013
.037

0/0
0/0
4/0
0/0

22.3
22.0
45
62

(221)
(2.2)
(62.0)
(16.3)
(21.1)
(16.9)
(8.4)
(11.4)
(7.2)
(21.7)
(8.4)
(4.7)
(18.7)
(22.1)

Term (n 5 172)

(4.0)
(3.6)
(27.8)
(37.3)

22.8
23.3
70
46

(3.7)
(3.2)
(40.7)
(26.7)

<.001

17 (10.5)
9 (5.7)

14 (8.1)
9 (5.3)

.459
.873

4/0
8/2

13 (8.6)
7 (4.7)

12 (7.6)
7 (4.5)

.757
.950

14/14
17/18

29 (18.4)
18 (11.8)

36 (21.8)
23 (14.5)

.438
.494
.024

8/7
14/13
3/1

17
42
59
45

11
31
56
73

.116
.341

3/0
3/0

(10.4)
(25.8)
(36.2)
(27.6)

1.5 (0-6)
0.7 (0-4)

(6.4)
(18.1)
(32.7)
(42.7)

1.8 (0-13)
0.8 (0-6)

_1500 g).
VLBW, Very low birth weight (<
*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.

most immature; risk of atopy in adulthood increased with

gestational age at birth. Subjects of very low birth weight were
also less likely to have serum IgE for specific allergens, and the
risk was again lowest among those born the most immature.
Previous studies have evaluated associations between predisposition to atopy and body size or gestational age at birth. However,
most of these were designed differently than our study and included
populations from a range of birth weights and gestational ages;
many did not distinguish between the effects of preterm birth and
fetal growth. Some studies associated atopy with higher birth
weight14,17,34,35 (or larger head circumference, indirectly reflecting
larger birth size or disproportionate growth),36-38 whereas others
associated it with low birth weight9-12 or made no association at

all.19-21,23-27 Results are also inconsistent among studies of preterm

birth. Some found a decreased risk of atopy among subjects born
preterm,13-15,17,35 usually defined as less than 37 weeks of gestation, but others found the opposite8-12; some made a U-shaped association.39,40 We are aware of only 2 studies that focused on
subjects of very low birth weight; a study of Swedish children
did not associate positive skin prick test reactions at age 12 years
with preterm birth or very low body weight,22 whereas a different
study reported that 10-year-old Finnish children of very low birth
weight were less likely than control subjects to have positive skin
prick test reactions,16 which is consistent with our findings from
young adults. Both studies were small and had limited power to assess the effects of other perinatal characteristics.

SILTANEN ET AL 939

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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
VLBW
(n 5 166)

Atopic manifestation

Skin prick test positivity, no. (%)

At least 1 positive
Birch
Timothy
Mugwort
Cat
Dog
Dermatophagoides pteronyssinus
High allergen-specific IgE level (>0.8 kU/L), no. (%)
At least 1 high level
Birch
Timothy
Cat
Atopic disease, no. (%)
Asthma
Allergic rhinitis
Atopic eczema

Term
(n 5 172)

Crude
OR (95% CI)

Adjusted
OR (95% CI)y

Missing value,
VLBW/term

75
45
43
22
33
38
14

(45.5%)
(27.3%)
(26.1%)
(13.3%)
(20.0%)
(23.0%)
(8.5%)

99
53
58
44
52
53
15

(57.9%)
(31.0%)
(33.8%)
(25.7%)
(30.6%)
(31.0%)
(8.8%)

0.61
0.84
0.69
0.44
0.57
0.67
0.96

(0.39-0.93)*
(0.52-1.34)
(0.43-1.09)
(0.25-0.78)*
(0.34-0.94)*
(0.41-1.08)
(0.45-2.05)

0.48
0.58
0.71
0.41
0.48
0.55
1.43

(0.27-0.86)*
(0.30-1.11)
(0.38-1.33)
(0.20-0.86)*
(0.24-0.95)*
(0.28-1.07)
(0.53-3.90)

1/1
1/1
1/1
1/1
1/2
1/1
1/2

51
30
34
25

(30.4%)
(18.1%)
(20.2%)
(14.9%)

65
44
44
39

(37.8%)
(25.6%)
(25.6%)
(22.7%)

0.73
0.75
0.64
0.60

(0.46-1.15)
(0.45-1.25)
(0.38-1.08)
(0.35-1.05)

0.48
0.60
0.67
0.41

(0.25-0.91)*
(0.29-1.24)
(0.33-1.37)
(0.19-0.91)*

0/0
0/0
0/0
0/0

29 (17.9%)
49 (30.1%)
31 (19.7%)

21 (12.2%)
42 (24.4%)
40 (23.7%)

1.57 (0.85-2.88)
1.33 (0.82-2.16)
0.79 (0.47-1.35)

1.71 (0.80-3.68)
1.34 (0.71-2.50)
0.61 (0.30-1.24)

4/0
3/0
9/3

_1500 g).
VLBW, Very low birth weight (<
*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

Serum total IgE

Allergen-specific IgE
Birch
Timothy
Cat

VLBW (n 5 166) vs
term (n 5 172)

P value

VLBW SGA (n 5 55) vs

VLBW AGA (n 5 111)

P value

211.0% (36.7% to 25.1%)

.499

76.3% (11.4% to 178.7%)

.016

226.2% (247.4% to 3.5%)

213.6% (236.9% to 18.3%)
225.0% (242.5% to 22.3%)

.078
.361
.033

27.3% (217.1% to 95.4%)

50.1% (18.2% to 121.2%)
32.6% (24.9% to 85.0%)

.267
.040
.096

Values are shown as mean differences (percentages) and 95% CIs. Boldfaced text denotes P < .05.
_1500 g).
AGA, Appropriate for gestational age; SGA, small for gestational age; VLBW, very low birth weight (<
*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.

Inconsistency among results might result from differences in

research methods, such as sampling, as well as in outcome
measures and methodologies applied. An important limitation of
the studies of population-based birth cohorts is that they included
only a small number of subjects in extreme categories, such as
those born severely preterm. Our study makes a significant
addition to the literature because we compared data from young
adults born severely preterm with data from young adults born at
term; we found that the more preterm one is born, the lower the
risk for atopy in adult life.
The measure of outcome is important in studies of atopy risk.
Several studies have examined atopic diseases, such as
asthma.15,41 Asthma, however, includes several underlying pathologies and phenotypes that are not always related to atopy.42,43
Atopy, which was defined as a positive skin prick test reaction or
an increased level of allergen-specific IgE, has been investigated
in some studies.16,22,35 In a community sample of preschool-aged
children, length of gestation was associated with skin prick test
reactions and increased levels of allergen-specific IgE, although

not with asthma, atopic dermatitis, or hay fever.35 In line with

this finding, we did not observe a difference in the frequency of
history of atopy between preterm subjects and control subjects,
although skin prick test reactions and concentrations of
allergen-specific IgE were reduced among subjects born preterm.
In addition, discrepancies in atopic diseases, skin prick test reactions, and concentrations of allergen-specific IgE might result
from variations in sample sizes or questionnaire-based assessments of atopic diseases, which are prone to misclassification.
Furthermore, the presence of atopic disease was not diagnosed
by a doctor in many studies; this was required in our study.
We examined early-life determinants of atopy within the verylow-birth-weight group. This was essential because the criteria (ie,
_1500 g) allowed inclusion of a
preterm birth at a weight of <
heterogeneous group of subjects who were born preterm. Some
were born extremely preterm, whereas others of a lesser degree of
prematurity had birth weights of 1500 g or less because of poor
intrauterine growth. Two previous studies reported no difference in
predisposition for atopy between subjects born small or of

940 SILTANEN ET AL

J ALLERGY CLIN IMMUNOL

APRIL 2011

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

Skin prick test positivity, no. (%)

At least 1 positive
Birch
Timothy
Mugwort
Cat
Dog
Dermatophagoides pteronyssinus
High allergen-specific IgE level
(>0.8 kU/L), no. (%)
At least 1 high level
Birch
Timothy
Cat
Atopic diseases, no. (%)
Asthma
Allergic rhinitis
Atopic eczema

VLBW SGA
(n 5 55)

VLBW AGA
(n 5 111)

30
19
17
8
13
18
8

(55.6%)
(35.2%)
(31.5%)
(14.8%)
(24.1%)
(33.3%)
(14.8%)

45
26
26
14
20
20
6

(40.5%)
(23.4%)
(23.4%)
(12.6%)
(18.0%)
(18.0%)
(5.4%)

1.83
1.78
1.50
1.20
1.44
2.28
3.04

(0.95-3.54)
(0.87-3.61)
(0.73-3.09)
(0.47-3.07)
(0.66-3.18)
(1.08-4.79)*
(1.00-9.27)*

1.68
1.26
1.19
0.95
1.47
1.89
4.37

(0.75-3.72)
(0.54-2.97)
(0.42-2.88)
(0.30-3.04)
(0.55-3.93)
(0.75-4.74)
(1.02-18.69)*

1/0
1/0
1/0
1/0
1/0
1/0
1/0

24
18
14
11

(43.7%)
(32.7%)
(25.5%)
(20.0%)

27
16
16
14

(24.3%)
(14.4%)
(14.4%)
(12.7%)

2.41
2.89
2.03
1.73

(1.21-4.79)*
(1.33-6.26)*
(0.91-4.54)
(0.73-4.12)

2.57
2.81
2.87
2.01

(1.10-5.99)*
(1.09-7.22)*
(1.04-7.94)*
(0.69-5.89)

0/0
0/0
0/0
0/0

9 (17.3%)
17 (32.1%)
11 (22.4%)

20 (18.2%)
32 (29.1%)
29 (18.5%)

Crude OR (95% CI)

0.94 (0.40-2.24)
1.15 (0.57-2.34)
1.27 (0.56-2.92)

Adjusted OR
(95% CI)y

0.71 (0.25-1.98)
0.70 (0.28-1.73)
1.04 (0.37-2.86)

Missing value,
SGA/AGA

3/1
2/1
6/3

_1500 g).
AGA, Appropriate for gestational age; SGA, small for gestational age; VLBW, very low birth weight (<
_ .05.
*Boldfaced text denotes P <
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.

appropriate size for their gestational age,44,45 whereas we found

higher rates of atopy among those born small for gestational age.
Our finding might arise because in the present study subjects
born small for gestational age were more often delivered by means
of cesarean section, which has been proposed to affect immune
system development.46-48 However, the greater average gestational
age of subjects born small for gestational age could also account
for this finding. The specific association between prematurity
and lower risk of atopy was also demonstrated by the fact that
the most preterm subjects had the lowest rates of positive skin prick
test reactions and also the lowest rates of high concentrations of
allergen-specific IgE.
An advantage of our study was that the Helsinki Study of Very
Low Birth Weight Adults was designed to evaluate different
aspects of the adult health of subjects born preterm with very low
birth weight, and therefore the bias toward disease was lower than
that of studies that focused on atopy. We were able to adjust for
most potential confounding factors; this did not affect the
observed difference in atopy between subjects born preterm and
control subjects. Unfortunately, we did not have data on parental
smoking during the early postnatal period, but we did adjust for
mothers who smoked during pregnancy.
Other limitations to our study include differences in participation rates between the very-low-birth-weight and control groups,
which could introduce bias if the reasons for nonparticipation
differed between the groups. It is also possible that very-lowbirth-weight subjects who did not survive through the intensive
care period and were thus not included in the study would have a
greater risk for atopy than those who survived. Moreover, our
results might not be applicable to the present because the
treatment of prematurely born neonates differs between today
and the 1970s and 1980s, when the subjects included in our study
were born.

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-lowbirth-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).

There are several elements that can modify the development of

the immune systems of preterm subjects and account for our
findings of a lower risk of atopy than in control subjects. Preterm
neonates have immature immune systems, greater permeability of
the gastrointestinal tract, and qualitatively and quantitatively
different early exposures to antigens than term-born infants; these
can affect their development of tolerance versus sensitization to
antigens. Also, the early-stage composition of the gastrointestinal
flora49 can contribute to the risk of atopy among subjects born preterm because it affects the development of immunologic balance.50 Early infections that are common among preterm
neonates might contribute to later development of sensitization.
However, we found that neonatal septicemia increased the risk
of atopy. Preterm neonates frequently receive antibiotics, which

J ALLERGY CLIN IMMUNOL

VOLUME 127, NUMBER 4

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).

have been associated with increased risk of asthma,51 although

asthma is a poor marker for atopy. The influence of early feeding
on atopy risk should be evaluated in subjects born preterm.8,52
Preterm infants are more frequently delivered by means of
cesarean section than full-term infants. Delivery by means of
cesarean section has, however, been associated with a greater risk
for atopy, probably because of differences in gastrointestinal
flora.46-48 Our study also found that delivery by means of cesarean
section increased the incidence of atopy, although this association
might result from the indication for cesarean section. Preeclampsia and placental abruption,53 as well as in utero stress,54,55 are
frequently associated with preterm birth. They might modify
the 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-born
counterparts in young adulthood. Although severe preterm birth
has been associated with many disadvantages in later life,29,56-60
not all outcomes are unfavorable. A lower predisposition to atopy
could reduce the lifetime burden of disease among adults born at
very low birth weight.
Key messages
d

Previous studies have assessed the risk of atopy in persons

born preterm and produced contradictory results,
whereas the risk among persons born most prematurely
has been less well studied.

Young adults born preterm and at very low birth weight

have a lower rate of atopy than young adults born at
term. The more prematurely a subject is born, the lower
their risk for atopy.

The lower incidence of atopy among subjects born preterm and at very low birth weight supports the hypothesis
that propensity for atopy is determined during early
stages of development.

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