Maternal smoking during pregnancy and intellectual performance in young adult Swedish male offspring

Article (PDF Available)inPaediatric and Perinatal Epidemiology 24(1):79-87 · January 2010with36 Reads
DOI: 10.1111/j.1365-3016.2009.01073.x · Source: PubMed
Abstract
Smoking during pregnancy has been linked to an increased risk of several adverse birth outcomes. Associations with deficits in cognitive development have also been suggested. It is unclear whether these associations are due to genetic and/or environmental confounding. In a population-based Swedish cohort study on 205,777 singleton males born to Nordic mothers between 1983 and 1988, we examined the association between maternal smoking during pregnancy and the risk of poor intellectual performance in young adult male offspring. In the cohort analyses, the risk of poor intellectual performance was increased in sons of smoking mothers compared with sons of non-smokers. Stratifying for maternal smoking habits across two pregnancies, there was an increased risk of poor intellectual performance for both sons if the mother was only smoking in the first pregnancy, but in neither son if the mother was only smoking in the second pregnancy. The effect of smoking during pregnancy on intellectual performance was not present when the association was evaluated within sibling pairs. Thus, the association between prenatal smoking exposure and offspring risk of low intellectual performance appears to be completely confounded by familial (genetic and early environmental) factors.

Figures

Maternal smoking during pregnancy and intellectual performance
in young adult Swedish male offspring
ppe_1073 79..87
Frida Lundberg
a
, Sven Cnattingius
a
, Brian D’Onofrio
b
, Daniel Altman
a
, Mats Lambe
a
, Christina Hultman
a
and
Anastasia Iliadou
a
a
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden, and
b
Department of Psychological and Brain
Sciences, Indiana University, Bloomington, IN, USA
Summary
Correspondence:
Frida Lundberg MSc.,
Department of Medical
Epidemiology and
Biostatistics, Karolinska
Institute, PO Box 281, SE-171
77 Stockholm, Sweden.
E-mail: frida.lundberg@ki.se
Lundberg F, Cnattingius S, D’Onofrio B, Altman D, Lambe M, Hultman C, Iliadou A.
Maternal smoking during pregnancy and intellectual performance in young adult
Swedish male offspring. Paediatric and Perinatal Epidemiology 2010; 24: 79–87.
Smoking during pregnancy has been linked to an increased risk of several adverse
birth outcomes. Associations with deficits in cognitive development have also been
suggested. It is unclear whether these associations are due to genetic and/or environ-
mental confounding. In a population-based Swedish cohort study on 205 777 singleton
males born to Nordic mothers between 1983 and 1988, we examined the association
between maternal smoking during pregnancy and the risk of poor intellectual perfor-
mance in young adult male offspring.
In the cohort analyses, the risk of poor intellectual performance was increased in sons
of smoking mothers compared with sons of non-smokers. Stratifying for maternal
smoking habits across two pregnancies, there was an increased risk of poor intellectual
performance for both sons if the mother was only smoking in the first pregnancy, but
in neither son if the mother was only smoking in the second pregnancy. The effect of
smoking during pregnancy on intellectual performance was not present when the
association was evaluated within sibling pairs. Thus, the association between prenatal
smoking exposure and offspring risk of low intellectual performance appears to be
completely confounded by familial (genetic and early environmental) factors.
Keywords: maternal prenatal smoking, adult IQ, siblings, confounding.
Introduction
Maternal smoking during pregnancy has been causally
linked to fetal growth restriction, and probably also
with placental abruption, preterm birth, stillbirth and
sudden infant death syndrome.
1–3
Several studies have
found evidence of associations between prenatal expo-
sure to smoking and subsequent deficits in childhood,
including cognitive development, school achievement
and behavioural adjustment.
4–10
An association
between smoking during pregnancy and offspring
adult intelligence has also been suggested.
11
Smoking during pregnancy is correlated with low
parental education and socio-economic status (SES),
poor parenting, early age at childbearing and use of
other drugs during pregnancy, all potential risk factors
for poor outcomes in children.
6,8,12–15
Two US studies,
using retrospectively collected information concerning
smoking during pregnancy, found that the association
between prenatal smoking exposure and offspring
intellectual abilities was substantially or entirely con-
founded by maternal factors, in particular maternal IQ
and education.
14,15
Sibling studies provide an alternative approach to
reducing confounding when investigating effects of
prenatal smoking exposure on offspring. Since siblings
share childhood environments and half of their segre-
gating genes, sibling analyses adjust for unmeasured
familial (common genetic and shared environmental)
factors. Importantly, studies of successive pregnancies
also allow us to investigate how changes of smoking
habits between pregnancies influence intellectual per-
formance in the offspring.
79doi: 10.1111/j.1365-3016.2009.01073.x
Paediatric and Perinatal Epidemiology, 24, 79–87. © 2009 Blackwell Publishing Ltd.
We investigated the association between exposure to
maternal smoking during pregnancy and subsequent
risk of poor intellectual performance in young adult
Swedish males, taking both parental and birth charac-
teristics into account. Further, to investigate whether
the association was confounded by unmeasured famil-
ial factors (shared environment and common genes),
we studied maternal smoking habits across two
pregnancies.
Methods
Five Swedish population-based registers were used to
obtain data for the study: the Medical Birth Register,
the Multigeneration Register, the Population and
Housing Census of 1990, the Education Register of
2000 and the Swedish Conscript Register. The records
were linked using the unique national registration
number assigned to each Swedish citizen at birth and
included in each register.
The Swedish Medical Birth Register was used to
obtain data on maternal characteristics (age at delivery,
parity, smoking, pre-pregnancy weight and height)
and birth characteristics (gestational age, birthweight
and head circumference). This register contains data on
>99% of all births in Sweden since 1973.
16
During preg-
nancy and delivery, information is prospectively
recorded in standardised records. More than 95% of
pregnant women in Sweden attend for prenatal care
before gestational week 15.
17
A previous study on the
Birth Register has found that the quality of the vari-
ables included in this study is high.
16
At the first prenatal care visit, women reported
whether they were daily smokers [categorised as mod-
erate (1–9 cigarettes per day) or heavy smokers (10
cigarettes per day)] or not. Maternal body mass index
(BMI) before pregnancy was calculated as the ratio
between weight in kilograms and the square of the
height in meters (kg/m
2
), and was categorised accord-
ing to World Health Organisation recommendations.
18
Family situation was categorised into parents living or
not living together in early pregnancy. Birthweight and
head circumference for gestational age were expressed
in standard deviation scores for gestational age accord-
ing to Swedish standard curves.
19
The Multigeneration Register was used to identify
the biological father of each son. Data on the parents’
SES were collected from the Population and Housing
Census of 1990 and classified according to the recom-
mendations of Statistics Sweden.
20
The Education Reg-
ister of 2000 was used to establish the educational level
of the parents. A validation study has shown that the
highest level of formal education is correctly reported
for 83% of the population.
21
The Swedish Conscript Register includes informa-
tion about Swedish males conscripted for military
service. Intellectual performance and age at conscrip-
tion were obtained at conscription. The only informa-
tion obtained from the Conscript Register regarding
intellectual performance is that it is tested in four
dimensions: logical/inductive, verbal, spatial and
theoretical/technical. The time-limited test consists of
40 questions for each dimension. Results are presented
as a combined standard nine (stanine) score with mean
5 and standard deviation 2. Poor intellectual perfor-
mance in the current study was defined as a score of
2. These individuals can be expected to have difficul-
ties coping with basic educational programmes. While
there was no formal evaluation of the data quality avail-
able, data from the Conscript Register has been suc-
cessfully used in previous studies on intellectual
performance.
22,23
Sample and subsets
Data on 232 378 Swedish liveborn males born between
1983 and 1988 and conscripted between 2000 and 2006
were obtained from the Swedish Birth Register linked
with the Swedish Conscript Registry. In order to obtain
a more homogeneous study population, we excluded
13 240 males born to non-Scandinavian mothers, 4260
males resulting from multiple pregnancies and 9101
males with congenital malformations. Fewer non-
Scandinavian mothers smoked during pregnancy, but
the frequency of poor intellectual performance was
higher in this group, indicating that these offspring
may be exposed to other risk factors. For males result-
ing from multiple pregnancies and with congenital
malformations, the frequency of maternal smoking
and of low intellectual performance did not differ sig-
nificantly from those in the cohort. Of the remaining
205 777 males, we obtained data on intellectual perfor-
mance for 172 182 individuals. Information on mater-
nal smoking habits during pregnancy was available for
94% of this population.
The sibling subset included 14 722 full sibling pairs.
The first two sons with data on intellectual perfor-
mance were selected from each family with more than
one child in the cohort. The small sample size of half-
siblings (n = 386 pairs) limited our statistical power to
80 F. Lundberg et al.
Paediatric and Perinatal Epidemiology, 24, 79–87. © 2009 Blackwell Publishing Ltd.
investigate the association within these pairs. Com-
plete information on maternal smoking during preg-
nancy was available for 88% of the sibling pairs. In
order to get an estimate from the unrelated individuals,
one son per mother was randomly selected from the
total sample to represent the unrelated group
(n = 156 663), where 94% had information on maternal
smoking during pregnancy.
Analyses
We used generalised estimating equation models
24
to
estimate risks of poor intellectual performance in early
adulthood in relation to maternal smoking during
pregnancy, other parental characteristics and birth
characteristics. A correlation matrix was specified in
order to control for the dependence between siblings.
Analyses were performed using Proc Genmod in SAS
(SAS Institute, Inc, Cary, NC, USA) and risks were
presented as odds ratios (OR) with 95% confidence
intervals [CI]. Associations between smoking during
pregnancy and intellectual performance were esti-
mated using both univariable and multivariable analy-
ses. Risks of poor intellectual performance associated
with smoking during pregnancy were investigated in
three multivariable models. In the first model, we
adjusted for parental characteristics (mother’s age,
parity, height and BMI, family situation in early preg-
nancy, parents’ educational level and socio-economic
status) and age at conscription of the son. In the second
model, we adjusted for birth characteristics (gesta-
tional age, birthweight and head circumference for
gestational age), and in the third model, we adjusted
for both parental and birth characteristics simulta-
neously. The final models only included variables that
significantly influenced the risk of poor intellectual
performance.
To examine whether the effect was influenced by
unmeasured familial factors, we proceeded in two
ways. First, we estimated the risks of poor intellectual
performance in first- and second-born sons, stratified
by maternal smoking habits across pregnancies. Risks
of poor intellectual performance by changes in mater-
nal smoking habits (non-smoker, continuous smoker,
starting or quitting smoking between pregnancies)
were estimated in first- and second-born siblings sepa-
rately using logistic regression models.
Second, to further examine the importance of famil-
ial confounding, we estimated the effects of smoking
during pregnancy on intellectual performance in unre-
lated individuals and within sibling pairs. The effects
of smoking during pregnancy on offspring intellectual
performance within and between families were esti-
mated using Proc Mixed in SAS. In these analyses, the
exposure was decomposed into between- and within-
family components.
25
The between-family component
was measured by the maternal mean of smoking across
pregnancies, and the within-family component was
centred on the family-mean for each son. The within-
family component estimates the difference in intellec-
tual performance between two siblings.
25
For
comparison, the effect of smoking on the continuous
measure of intellectual performance was also esti-
mated in an unrelated subset of the cohort. If familial
confounding is present one should expect the estimate
of the within component to decrease compared with
the effect seen between unrelated males. Because of the
complexity of these analyses we treated smoking
during pregnancy as a dichotomous variable (smokers
vs. non-smokers). The stanine scale of intellectual per-
formance was used as the outcome in these models.
Results
Parental and birth characteristics in relation to the off-
spring’s risk of poor intellectual performance are
presented in Table 1. Risks of poor intellectual perfor-
mance increased with declining maternal age and
height. Sons of overweight (BMI 25–29) and obese
(BMI 30) mothers also showed increased risks of low
test scores. The risks were also highly influenced by
socially related factors, including lower education and
socio-economic status of mothers and fathers, and
single motherhood.
Males with a low birthweight or a small head cir-
cumference for gestational age were at higher risk of
poor intellectual performance than males born with a
normal birthweight or head circumference, respec-
tively. Compared with males born at term (37–41
weeks), the risk of a low score on the general intellec-
tual performance test was slightly higher for those born
moderately preterm (32–36 weeks) and substantially
higher for very preterm (<32 weeks) births.
Maternal smoking habits during pregnancy were
closely associated with parental socio-economic and
educational status. More than half of the teenage
mothers were smokers in comparison with <25% of
those mothers who were aged 30 years or more.
Mothers of low education level (49%) and low socio-
economic status (39%) were more likely to smoke than
Maternal smoking and intellectual performance in males 81
Paediatric and Perinatal Epidemiology, 24, 79–87. © 2009 Blackwell Publishing Ltd.
Table 1. Birth and parental characteristics and the risk of poor intellectual performance (IP) in the offspring
N
Low IP
Unadjusted OR [95% CI]n (%)
Parental characteristics
Mother’s age (years)
<20 4808 764 (15.9) 2.01 [1.85, 2.18]
20–24 39 954 4493 (11.2) 1.36 [1.31, 1.42]
25–29 64 647 5472 (8.5) 1.00 Reference
30–34 43 773 3079 (7.0) 0.82 [0.78, 0.86]
35 19 000 1337 (7.0) 0.82 [0.77, 0.87]
Maternal parity
Primipara 72 109 5853 (8.1) 1.00 Reference
Multipara 100 073 9292 (9.3) 1.16 [1.13, 1.20]
Mother’s height (cm)
<155 2765 311 (11.2) 1.42 [1.25, 1.60]
155–164 50 384 4789 (9.5) 1.18 [1.13, 1.23]
165–174 75 706 6184 (8.2) 1.00 Reference
175 10 865 777 (7.2) 0.87 [0.80, 0.94]
Missing 32 462 3084 (9.5)
Mother’s BMI (kg/m
2
)
<18.5 9389 841 (9.0) 1.12 [1.04, 1.21]
18.5–24 100 553 8093 (8.0) 1.00 Reference
25–29 15 333 1646 (10.7) 1.38 [1.30, 1.45]
30 2525 349 (13.8) 1.83 [1.63, 2.05]
Missing 44 382 4216 (9.5)
Mother’s education
9-year compulsory 21 494 3461 (16.1) 1.55 [1.48, 1.62]
Secondary school 1–2 years 68 483 7536 (11.0) 1.00 Reference
Secondary school 3 years 20 773 1569 (7.6) 0.66 [0.62, 0.70]
Higher education < 3 years 31 033 1532 (4.9) 0.42 [0.40, 0.45]
Higher education 3 years 30 040 1005 (3.3) 0.28 [0.26, 0.30]
Missing 359 42 (11.7)
Maternal socio-economic category
Unskilled blue collar worker 46 721 5980 (12.8) 3.23 [3.04, 3.43]
Skilled blue collar worker 19 743 1853 (9.4) 2.27 [2.12, 2.44]
Low-level white collar worker 26 202 1877 (7.2) 1.70 [1.58, 1.82]
Intermediate-level white collar worker 32 943 1436 (4.4) 1.00 Reference
High-level white collar worker 11 726 310 (2.6) 0.60 [0.53, 0.68]
Self-employed 4854 363 (7.5) 1.77 [1.56, 1.99]
Employed, uncategorised 9870 1022 (10.4) 2.53 [2.33, 2.76]
Missing 20 123 2304 (11.4)
Father’s education
9-year compulsory 35 474 4902 (13.8) 1.29 [1.24, 1.34]
Secondary school 1–2 years 61 091 6767 (11.1) 1.00 Reference
Secondary school 3 years 21 767 1336 (6.1) 0.53 [0.50, 0.56]
Higher education < 3 years 23 336 1057 (4.5) 0.38 [0.36, 0.41]
Higher education 3 years 28 359 858 (3.0) 0.25 [0.23, 0.27]
Missing 2155 225 (10.4)
Paternal socio-economic category
Unskilled blue collar worker 32 745 4194 (12.8) 2.73 [2.57, 2.90]
Skilled blue collar worker 36 569 4095 (11.2) 2.34 [2.20, 2.49]
Low-level white collar worker 14 915 1115 (7.5) 1.50 [1.39, 1.63]
Intermediate-level white collar worker 29 222 1490 (5.1) 1.00 Reference
High-level white collar worker 25 676 852 (3.3) 0.64 [0.59, 0.70]
Self-employed 13 162 1232 (9.4) 1.92 [1.78, 2.08]
Employed, uncategorised 8882 919 (10.3) 2.15 [1.97, 2.34]
Missing 11 011 1248 (11.3)
82 F. Lundberg et al.
Paediatric and Perinatal Epidemiology, 24, 79–87. © 2009 Blackwell Publishing Ltd.
mothers with the highest level of education and high-
level white collar workers (14% in both groups). Mater-
nal smoking habits during pregnancy were similarly
associated with lower paternal educational level and
socio-economic status. More than half of those mothers
who were not living with the father of the child were
smokers. Males with a low birthweight-for-gestational
age and males born preterm were far more likely to
have smoking mothers (51 % and 44%, respectively)
than males born with a normal birthweight or born at
term (29% in both groups).
Table 2 displays the association of smoking during
pregnancy and intellectual performance as unadjusted
ORs and ORs adjusted for parental and birth charac-
teristics. In the unadjusted analysis, sons of moderate
and heavy smokers were at increased risks of having a
low score on the intellectual performance test
(OR = 1.70 [95% CI 1.63, 1.78] and 1.91 [95% CI 1.81,
2.00], respectively). After adjusting for parental charac-
teristics, corresponding ORs were decreased, but
remained significant (OR = 1.27 [95% CI 1.19, 1.34] and
1.22 [95% CI 1.14, 1.31], respectively). While all paren-
tal characteristics were significantly associated with
the outcome, the reduction in the smoking-related risk
was primarily attributed to adjustment for mother’s
and father’s educational level. Next, to examine
whether the effects on intellectual performance were
mediated by fetal growth restriction, adjustments were
made for birth characteristics. The decrease in risk was
negligible, although birthweight and head circumfer-
ence were found to be significantly and independently
associated with poor intellectual performance. When
in the final model we adjusted for both birth and
parental characteristics, smoking during pregnancy
was still significantly associated with increased risk of
poor intellectual performance (OR = 1.25 [95% CI 1.18,
1.33] for sons of moderate smokers and 1.21 [95% CI
1.12, 1.30] for sons of heavy smokers).
Analysing intellectual performance as a continuous
variable showed the same increase in risk of low
Table 1. Continued
Parental characteristics N
Low IP
Unadjusted OR [95% CI]n (%)
Family situation
Parents living together 157 657 13 566 (8.6) 1.00 Reference
Parents not living together 8187 1014 (12.4) 1.48 [1.39, 1.59]
Missing 6338 565 (8.9)
Age at conscription (years)
<17.5 1516 150 (9.9) 1.21 [1.02, 1.43]
17.5–18.5 144 098 11 959 (8.3) 1.00 Reference
>18.5 26 568 3036 (11.4) 1.42 [1.36, 1.48]
Birth characteristics
Birthweight-for-gestational age (SDS)
<-2 3770 449 (11.9) 1.40 [1.27, 1.55]
-2 to 2 162 704 14 198 (8.7) 1.00 Reference
>2 4213 354 (8.4) 0.96 [0.86, 1.08]
Missing 1495 144 (9.6)
Head circumference for gestational age (SDS)
<-2 6717 749 (11.2) 1.32 [1.22, 1.42]
-2 to 2 157 871 13 751 (8.7) 1.00 Reference
>2 4186 300 (7.2) 0.81 [0.72, 0.91]
Missing 3408 345 (10.1)
Gestational age (weeks)
28–31 495 71 (14.3) 1.74 [1.36, 2.24]
32–36 6262 591 (9.4) 1.08 [0.99, 1.18]
37–41 142 571 12 477 (8.8) 1.00 Reference
>41 22218 1922 (8.7) 0.99 [0.94, 1.04]
Missing 636 84 (13.2)
Men born 1983–88 and conscripted for military service 2000–06. Low IP was defined as an IP test score at conscription of 2. All analyses
accounted for the clustered data structure.
Maternal smoking and intellectual performance in males 83
Paediatric and Perinatal Epidemiology, 24, 79–87. © 2009 Blackwell Publishing Ltd.
intellectual performance with increasing level of
smoking (data not shown). Similar effects on intellec-
tual performance could also be seen in the original
dataset (including males born to non-Scandinavian
mothers, in multiple births and with congenital mal-
formations) and in complete case analyses (data not
shown).
We also investigated possible interactions of
smoking with maternal age, education and socio-
economic index. None of the tested interactions were
significant in the adjusted analysis (data not shown).
The comparison of the risk of poor intellectual per-
formance between full brothers in relation to the
mothers’ smoking across pregnancies is shown in
Table 3. In the crude analysis, the risk of a low score on
the intellectual performance test was nearly doubled
among sons of mothers who smoked in both pregnan-
cies, compared with sons of mothers who did not
smoke in any pregnancy (OR = 1.85 [95% CI 1.57, 2.18]
for the first son and 1.89 [95% CI 1.65, 2.17] for the
second son). If the mother smoked in the first but not in
the second pregnancy, the risk of poor intellectual per-
formance was similarly increased in both sons. If the
mother had started smoking after the first pregnancy,
both sons also seemed to have an increased risk of a
low score. In the adjusted analyses, all smoking-related
risks were decreased. However, not only smoking in
both pregnancies but also smoking in first but not in
second pregnancy was still associated with increased
risks of poor intellectual performance in both sons
(OR = 1.40 [95% CI 1.03, 1.91] for the first son and 1.39
[95% CI 1.08, 1.79] for the second son). Compared with
mothers not smoking in either pregnancy, maternal
smoking only in the second pregnancy was not associ-
ated with an increased risk of poor intellectual perfor-
mance in either son.
Table 2. Maternal smoking and the risk of
poor intellectual performance (IP) in the
offspring
Maternal smoking (cigarettes/day)
None 1–9 10+ Missing
N 115 159 28 568 17 321 11 134
Low IP % 7.4 12.0 13.2 8.8
UOR [95% CI] 1.00 Reference 1.70 [1.63, 1.78] 1.91 [1.81, 2.00]
AOR
a
[95% CI] 1.00 Reference 1.27 [1.19, 1.34] 1.22 [1.14, 1.31]
AOR
b
[95% CI] 1.00 Reference 1.69 [1.62, 1.76] 1.88 [1.79, 1.98]
AOR
c
[95% CI] 1.00 Reference 1.25 [1.18, 1.33] 1.21 [1.12, 1.30]
Men born 1983–88 and conscripted for military service 2000–06. Low IP was defined as an
IP test score at conscription of 2. All analyses accounted for the clustered data structure.
a
Adjusted for maternal age, height and BMI, maternal and paternal education and socio-
economic category, family situation, birth order and age at conscription.
b
Adjusted for birthweight and head circumference for gestational age.
c
Adjusted for the birth and parental characteristics listed above.
Table 3. Maternal smoking in first and second pregnancy and the risk of poor intellectual performance (IP) in the sons
Maternal smoking
N
First son Second son
First Second Low IP
OR [95% CI]
Low IP
OR [95% CI]
Pregnancy Pregnancy (%) Unadjusted Adjusted
a
% Unadjusted Adjusted
a
No no 9346 (5.2) 1.00 Reference 1.00 Reference (7.6) 1.00 Reference 1.00 Reference
No yes 356 (6.2) 1.21 [0.78, 1.87] 0.93 [0.56, 1.55] (9.3) 1.24 [0.86, 1.78] 0.91 [0.60, 1.39]
Yes no 813 (8.1) 1.62 [1.24, 2.11] 1.40 [1.03, 1.91] (11.9) 1.64 [1.31, 2.06] 1.39 [1.08, 1.79]
Yes yes 2482 (9.2) 1.85 [1.57, 2.18] 1.25 [1.02, 1.53] (13.5) 1.89 [1.65, 2.17] 1.24 [1.05, 1.46]
Missing missing 1725 (5.9) (8.4)
Brothers born 1983–88. Low IP was defined as an IP test score of 2.
a
Adjusted for parental education level and socio-economic status, birth order (first son only) and age at conscription.
84 F. Lundberg et al.
Paediatric and Perinatal Epidemiology, 24, 79–87. © 2009 Blackwell Publishing Ltd.
Finally, to investigate the importance of familial
factors, we studied the effect of smoking during
pregnancy on intellectual performance between unre-
lated sons and within siblings (Fig. 1). Similar to the
preceding results, sons of mothers who had smoked
during pregnancy scored approximately 0.65 points
less than sons of non-smoking mothers in the unre-
lated subset [95% CI -0.67, -0.63]. Adjusting for paren-
tal characteristics resulted in a decrease of this
difference to 0.24 points [95% CI -0.27, -0.22]. In the
sibling subset, there was a small but significant
increase in intellectual performance for the sons
exposed to smoking during pregnancy (regression
coefficient b = 0.22 [95% CI 0.10, 0.34] ). However, after
adjustment for birth order and maternal age, this effect
was no longer statistically significant (b = 0.06 [95% CI
-0.06, 0.18] ).
Analysing the complete dataset without exclusions
showed similar results (data not shown).
Discussion
We found that the association between maternal
smoking during pregnancy and poor intellectual per-
formance in young adult male offspring can be
explained partly by parental education but also by
unmeasured familial factors, such as common genes
and shared environment.
In the cohort analyses, more than half of the
smoking-related increased risk was accounted for by
parental educational level, indicating that the associa-
tion largely depends on familial factors. Two recent
studies reported that the association between maternal
smoking and offspring intellectual performance was
diminished after adjusting for maternal education and
IQ.
14,15
Our results in relation to these studies indicate
that other familial effects besides education are of
importance for the association. In the current study,
smoking-related birth outcomes did not mediate the
association between smoking during pregnancy and
poor intellectual performance in the offspring. This
indicates that any effect of prenatal smoking exposure
on intellectual performance in the offspring is indepen-
dent of fetal growth or gestational age.
In the sibling subset of the studied cohort, we found
an increased risk of poor intellectual performance for
both sons if the mother was smoking in the first preg-
nancy, regardless of her smoking habits during the
second pregnancy. In contrast, if the mother was only
smoking in the second pregnancy there was no
increase in risk for either son. The finding that change
of exposure to maternal smoking across pregnancies
seems to be unrelated to offspring risk of poor intellec-
tual performance does not support the hypothesis that
prenatal smoking exposure influences the intellectual
performance in the offspring.
The effect of maternal smoking on the intellectual
performance of the offspring could not be seen within
full sibling pairs, suggesting that the association seen
in the cohort was confounded by unmeasured familial
(genetic or environmental) factors. Similarly, a recent
study on siblings from the Collaborative Perinatal
Project found no effect of maternal smoking during
pregnancy on 12 different outcomes of cognitive and
physical development within 2064 sibling sets where
the mothers had changed smoking habits between
pregnancies.
26
In the current study, the apparent posi-
tive effect of prenatal smoking exposure on intellectual
performance within siblings was lost after adjusting
for birth order. Though debatable, intellectual perfor-
mance has been negatively associated with increasing
birth order within families in previous studies.
27,28
The data on maternal smoking during pregnancy
were collected at the first prenatal care visit. The propor-
tion of women who stop smoking during pregnancy
has been reported to be around 30% in previous
Swedish studies. In these studies, women with a higher
level of education and a higher age at the initiation of
smoking were more likely to stop smoking when preg-
nant, while women not living with the father of the
child, heavy smokers and women exposed to daily
Between unrelated sons Within sibling pairs
0,4
0,2
0
-0,2
-0,4
-0,6
-0,8
Unadjusted
Adjusted
Effect size
Figure 1. Relationship between prenatal smoking and intellec-
tual performance of sons.
Maternal smoking and intellectual performance in males 85
Paediatric and Perinatal Epidemiology, 24, 79–87. © 2009 Blackwell Publishing Ltd.
passive smoking at home were more likely to continue
smoking throughout the pregnancy.
29,30
Thus, misclassi-
fication of smoking exposure during pregnancy may
have influenced the risk estimates obtained. Finally,
most pregnant smokers continue to smoke after preg-
nancy, and we cannot distinguish between the effects of
prenatal and postnatal smoking exposure in this study.
Some strengths of this study are its size, the prospec-
tive design and the range of covariates gathered from
population-based registers.
16
An advantage of measur-
ing intellectual performance in early adulthood is that
it is less affected by the postnatal environment than
other measures of cognitive ability at early ages. Intel-
ligence measured in children and, even more so, scho-
lastic achievements are likely to be influenced by
motivation and ability to concentrate, and may conse-
quently reflect attention deficits or behavioural prob-
lems rather than life-long cognitive ability. A limitation
of this study was residual confounding that we could
not control for by the parental education and SES, such
as parental intellectual abilities and behavioural prob-
lems, parenting and environmental stimulation,
passive smoking and maternal alcohol consumption
during pregnancy. We were also unable to control for
the duration of breast feeding. However, while breast
feeding has been positively linked to intellectual devel-
opment,
31
other studies have found no significant
advantage of breast feeding on offspring intelligence
when adjusting for maternal characteristics and home
environment.
32,33
In conclusion, our results support the importance of
familial factors in the association between mothers
smoking during pregnancy and poor intellectual per-
formance in young adult males. Further research in
this field is warranted to clarify the nature of the famil-
ial risk factors and their potential role in the association
between smoking during pregnancy and intellectual
performance.
Acknowledgements
This project was supported by grants from the Swedish
Research Council (Project number K2007-70P-20518-
01-4).
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    • "In contrast, quasi-experimental studies, which use design features to rule out confounding factors rather than statistical controls, suggest unmeasured confounds better explain the statistical associations between maternal substance use during pregnancy and offspring psychosocial problems (Knopik 2009; D'Onofrio et al. 2013 ). For example, siblingcomparison studies, which compare siblings differentially exposed to maternal substance use during pregnancy (for a review of the sibling-comaprison approach, see Lahey and D'Onofrio 2010) suggest that the statistical association between maternal SDP and cognitive functioning (Gilman et al. 2008a, b; Lundberg et al. 2010; D'Onofrio et al. 2010a, b), externalizing outcomes (Lindblad and Hjern 2010), delinquency (D'Onofrio et al. 2010a, b; D'Onofrio et al. 2012), stress-coping (Kuja-Halkola et al. 2010), and other indices of adjustment are due to confounding factors, not the specific influences of SDP. Further, in vitro fertilization studies, in which mothers are not genetically related to the offspring but provide the prenatal and postnatal environments , also suggest that the association between maternal SDP and offspring conduct problems (Rice et al. 2009) and ADHD (Thapar et al. 2009) are due to confounding factors, notably genetic factors passed down from mothers to their offspring. "
    [Show abstract] [Hide abstract] ABSTRACT: Prenatal exposure to substances of abuse is associated with numerous psychological problems in offspring, but quasi-experimental studies controlling for co-occurring risk factors suggest that familial factors (e.g., genetic and environmental effects shared among siblings) confound many associations with maternal smoking during pregnancy (SDP). Few of the quasi-experimental studies in this area have explored normative psychological traits in early childhood or developmental changes across the lifespan, however. The current study used multilevel growth curve models with a large, nationally-representative sample in the United States to investigate for potential effects of SDP on the developmental trajectories of cognitive functioning, temperament/personality, and disruptive behavior across childhood, while accounting for shared familial confounds by comparing differentially exposed siblings and statistically controlling for offspring-specific covariates. Maternal SDP predicted the intercept (but not change over time) for all cognitive and externalizing outcomes. Accounting for familial confounds, however, attenuated the association between SDP exposure and all outcomes, except the intercept (age 5) for reading recognition. These findings, which are commensurate with previous quasi-experimental research on more severe indices of adolescent and adult problems, suggest that the associations between SDP and developmental traits in childhood are due primarily to confounding factors and not a causal association.
    Full-text · Article · Oct 2013
    • "Although results from previous studies are inconsistent, our results confirm those of studies that rigorously controlled for confounding factors [16,3839404142. In particular, family-based studies that compared siblings born to the same mothers with discrepant smoking status across pregnancies (to minimize residual confounding by unmeasured family factors) have reported no differences in cognitive ability, externalizing behaviors, or overweight/obesity within siblings383940 . Other studies based on large cohorts of children have reported that maternal and paternal smoking during pregnancy are associated to a similar degree with offspring cognitive outcomes [41] and blood pressure [42]. "
    [Show abstract] [Hide abstract] ABSTRACT: Studies on adverse childhood health and development outcomes associated with parental smoking have shown inconsistent results. Using a cohort of Belarusian children, we examined differences in cognition, behaviors, growth, adiposity, and blood pressure at 6.5 years according to prenatal and postnatal exposure to parental smoking. Using cluster-adjusted multivariable regression, effects of exposure to prenatal smoking were examined by comparing (1) children whose mothers smoked during pregnancy with those of mothers who smoked neither during nor after pregnancy and (2) children whose mothers smoked during and after pregnancy with those whose mothers smoked after pregnancy only; effects of postnatal smoking were examined by comparing (1) children whose mothers smoked after pregnancy only with those of mothers who smoked neither during nor after pregnancy and (2) children whose fathers smoked with those whose fathers did not smoke among children of non-smoking mothers after adjusting for a wide range of socioeconomic and family characteristics. After adjusting for confounders, children exposed vs unexposed to prenatal maternal smoking had no differences in mean IQ, teacher-rated behavioral problems, adiposity, or blood pressure. Children exposed to maternal postnatal smoking had slightly increased behavioral problems [0.9, 95% CI: 0.6, 1.2 for total difficulties], higher body mass index [0.2, 95% CI: 0.1, 0.3], greater total skinfold thickness [0.4, 95% CI: 0.04, 0.71], and higher odds of overweight or obesity [1.4, 95 % CI; 1.1, 1.7]. Similar magnitudes of association were observed with postnatal paternal smoking. No adverse cognitive, behavioral and developmental outcomes were associated with exposure to maternal prenatal smoking. Observed associations with postnatal smoking of both parents may reflect residual confounding by genetic and family environmental factors.
    Full-text · Article · Jul 2013
    • "The overall results of the present study are thus in line with previous studies in which statistical adjustment of potentially confounding factors eliminated an apparent effect of smoking exposure on IQ [21–24, 26, 40–43]. Lundberg et al. [44] addressed the causal effect of prenatal smoking exposure by comparing the intellectual performance (as measured by a military draft board test) of 14,722 pairs of full siblings, only one of which had been exposed to smoking in utero. There were no differences between exposed and unexposed siblings but an increased risk of low test performance for both if the mother had smoked only during her first pregnancy and no difference compared to nonexposed controls for either sibling if she had smoked only during her second. "
    [Show abstract] [Hide abstract] ABSTRACT: The aim of the study was to examine the effects of tobacco smoking in pregnancy on children's IQ at the age of 5. A prospective follow-up study was conducted on 1,782 women, and their offspring were sampled from the Danish National Birth Cohort. At 5 years of age, the children were tested with the Wechsler Preschool and Primary Scale of Intelligence-Revised. Parental education, maternal IQ, maternal alcohol consumption in pregnancy, the sex and age of the child, and tester were considered core confounders, but the full model also controlled for prenatal paternal smoking, maternal age and Bodymass Mass Index, parity, family/home environment, postnatal parental smoking, breast feeding, the child's health status, and indicators for hearing and vision impairments. Unadjusted analyses showed a statistically significant decrement of 4 points on full-scale IQ (FSIQ) associated with smoking 10+ cigarettes per day compared to nonsmoking. After adjustment for potential confounders, no significant effects of prenatal exposure to tobacco smoking were found. Considering the indisputable teratogenic effects of tobacco smoking, these findings should be interpreted with caution. Still, the results may indicate that previous studies that failed to control for important confounders, particularly maternal intelligence, may be subject to substantial residual confounding.
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