Early Life Exposures
Parental smoking during pregnancy and the risk
of gestational diabetes in the daughter
Wei Bao,1,2 Karin B Michels,3,4,5 Deirdre K Tobias,6,7 Shanshan Li,1
Jorge E Chavarro,3,4,7 Audrey J Gaskins,7 Allan A Vaag,8
Frank B Hu3,4,7 and Cuilin Zhang1*
1Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child
Health and Human Development, Rockville, MD, USA, 2Department of Epidemiology, University of Iowa
College of Public Health, Iowa City, IA, USA, 3Department of Epidemiology, Harvard T.H. Chan School of
Public Health, Boston, MA, USA, 4Channing Division of Network Medicine, 5Department of Obstetrics,
Gynecology and Reproductive Biology, 6Division of Preventive Medicine, Brigham and Women’s
Hospital and Harvard Medical School, Boston, MA, USA, 7Department of Nutrition, Harvard T.H. Chan
School of Public Health, Boston, MA, USA and 8Department of Endocrinology, Rigshospitalet,
Copenhagen, Denmark
*Corresponding author. Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy
Shriver National Institute of Child Health and Human Development, National Institutes of Health, 6100 Executive Blvd,
Rockville, MD 20852, USA. E-mail: zhangcu@mail.nih.gov
The abstract of this study was included in poster presentation at the American Heart Association’s EPI/Lifestyle2015
Scientific Sessions (March 3–6, 2015, Baltimore, MD).
Accepted 19 November 2015
Abstract
Background: Fetal exposure to parental smoking may have long-term impact on the de-
velopment of disease in adulthood. We examined the association of parental smoking
during pregnancy with risk of gestational diabetes mellitus (GDM) in the daughter.
Methods: We included 15 665 singleton pregnancies from 10 152 women in the Nurses’
Health Study II cohort whose mothers participated in the Nurses’ Mothers’ Cohort Study.
Data on maternal and paternal smoking during pregnancy and associated covariates
were recalled by the mothers. GDM diagnosis was self-reported by the daughters
and was validated by medical record review in a previous study. We used log-binomial
models with generalized estimating equations to estimate relative risks (RRs) and 95%
confidence intervals (CIs).
Results: We observed a positive association between maternal heavy smoking during
pregnancy and risk of GDM in the daughter. The multivariable-adjusted RRs (95% CIs) of
GDM among women whose mothers did not smoke during pregnancy, continued smoking
1–14, 15–24, and�25 cigarettes/day were 1.00 (reference), 1.05 (0.81–1.35), 1.27 (0.95–1.70)and 1.98 (1.18–3.30), respectively (P for trend¼0.01). Further adjustment for the women’sperinatal variables, adult-life characteristics and body mass index during various periods
of life modestly attenuated the association. No association was observed between pater-
nal smoking during the pregnancy period and risk of GDM in the daughter.
Published by Oxford University Press on behalf of International Epidemiological Association 2016.
This work is written by US Government employees and is in the public domain in the US. 160
International Journal of Epidemiology, 2016, 160–169
doi: 10.1093/ije/dyv334
Advance Access Publication Date: 9 January 2016
Original article
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Conclusions: Maternal heavy smoking (�25 cigarettes/day) during pregnancy was associ-ated with higher risk of gestational diabetes in the daughter. Further studies are warranted
to confirm our findings and to elucidate the underlying mechanisms.
Key words: Gestational diabetes mellitus, maternal smoking during pregnancy
Introduction
The developmental origins of health and disease hypothesis,
or ‘Barker hypothesis’,1 continues to fuel research interest in
examining the health consequences of in utero exposures.
Maternal smoking during pregnancy represents a common
deleterious fetal exposure in many populations.2–4 The
short-term effects of maternal smoking during pregnancy on
multiple adverse pregnancy and perinatal outcomes, includ-
ing fetal growth restriction and low birthweight, have long
been recognized and established.5 Maternal smoking during
pregnancy has also been associated with an increased risk of
obesity during childhood and adulthood in some, although
not all, studies.6–10 There is limited evidence regarding the
long-term impact of fetal exposure to maternal smoking on
the risk of chronic disease in adulthood, which emerges as a
new focus of research interests.11
Gestational diabetes mellitus (GDM) is a common preg-
nancy complication characterized by glucose intolerance,
with onset or first recognition during pregnancy.12 GDM is
not only associated with short-term adverse perinatal out-
comes,13 but also related to long-term metabolic risk in both
mothers and their children.12,14,15 Thus, it is crucial to iden-
tify modifiable risk factors that may contribute to the preven-
tion of GDM in current and subsequent generations.
Animal studies have suggested that fetal exposure to maternal
smoking may lead to impaired glucose metabolism by alter-
ing pancreatic islet development and inducing beta cell apop-
tosis.16,17 In addition, epidemiological studies, although still
limited, suggest that maternal smoking during pregnancy
may increase the risk of diabetes in adulthood.18,19 However
the association, in particular the dose-response relation, be-
tween fetal exposure to maternal smoking and risk of GDM
is not well established. Moreover, no previous study has
examined the association between fetal exposure to paternal
smoking, a major source of maternal passive smoking, and
subsequent risk of GDM. In this study, we aimed to examine
the dose-response relation of maternal and/or paternal smok-
ing during pregnancy with risk of GDM in the daughter.
Methods
Study population
The Nurses’ Health Study II (NHSII) is an ongoing prospect-
ive cohort study of 116 430 female nurses aged 24–44 years
at study inception in 1989. The participants receive a biennial
questionnaire regarding lifestyle behaviours, anthropometric
variables and disease outcomes. In 2001, mothers of the
NHSII participants were invited to complete a questionnaire
regarding their nurse daughter. Details about the Nurses’
Mothers’ Cohort Study have been described elsewhere.20 We
included NHSII participants in the current analyses if they re-
ported at least one singleton pregnancy lasting greater than 6
months between 1989 and 2001 and their mothers partici-
pated in the Nurses’ Mothers’ Cohort Study and reported
data on pregnancy and perinatal variables associated with
the nurse daughter. The NHSII participants were excluded if
they had been adopted, were missing information on mater-
nal smoking or had type 2 diabetes reported in 1989 or be-
fore GDM. Figure 1 depicts the flowchart of study
participants. This study has been approved by the Partners
Human Research Committee (Boston, MA), with partici-
pants’ consent implied by the return of the completed
questionnaires.
Assessment of parental smoking
We used information on parental smoking during pregnancy
from the 2001 Nurses’ Mothers’ Cohort Study question-
naire.21 The mothers reported whether they ever smoked
cigarettes during pregnancy with the nurse daughter, the
number of cigarettes (i.e. 1–14, 15–24, 25–34 or� 35) they
Key Messages
• This study examined the association of parental smoking during pregnancy with risk of gestational diabetes in the
daughter among 15 665 singleton pregnancies from 10 152 women in the Nurses’ Health Study II cohort whose moth-
ers participated in the Nurses’ Mothers’ Cohort Study.
• We demonstrated that maternal heavy smoking (�25 cigarettes/day) during pregnancy was associated with higherrisk of gestational diabetes in the daughter. We did not observe an association between paternal smoking during
pregnancy and risk of gestational diabetes in the daughter.
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smoked daily during pregnancy, whether they quit smoking
during pregnancy, and if so, in which trimester. In a separ-
ate validation study, the validity of recalled maternal smok-
ing during pregnancy was found to be high in the National
Collaborative Perinatal Project (sensitivity¼0.86, specifi-city¼0.94).22 We categorized maternal smoking as: neversmoked; quit smoking in first trimester of pregnancy; con-
tinued smoking 1–14 cigarettes/day during pregnancy; con-
tinued smoking 15–24 cigarettes/day during pregnancy; and
continued smoking 25 or more cigarettes/day during preg-
nancy. We also asked the mothers whether the nurse’s father
ever smoked during pregnancy and the number of cigarettes
he smoked. We categorized paternal smoking as: never
smoked; smoked 1–14 cigarettes/day during pregnancy;
smoked 15–24 cigarettes/day during pregnancy; and
smoked 25 or more cigarettes/day during pregnancy.
Previous studies based on the same cohort as the current
analysis have found maternal smoking during pregnancy be
associated with an increased risk of overweight and obesity
in the daughter across adolescence and adult life.7
Ascertainment of gestational diabetes
The NHSII participants (i.e. the daughters) reported preva-
lent GDM in 1989 and incident GDM on each biennial
questionnaire through 2001. GDM was not ascertained
after the 2001 questionnaire in the NHSII cohort, because
the majority of NHSII participants had passed reproduct-
ive age by then. In a previous validation study among a
subgroup of the NHSII cohort, 94% of GDM self-reports
were confirmed by medical records.23 In a random sample
of parous women without GDM, 83% reported a glucose
screening test during pregnancy and 100% reported fre-
quent prenatal urine screenings, suggesting a high level of
GDM surveillance in this cohort.23
Covariates assessment
Covariates for maternal, paternal and perinatal characteris-
tics were obtained from the Nurses’ Mothers’ Cohort Study.
The 2001 Nurses’ Mothers’ Cohort Study questionnaire re-
quested data on the daughter’s gestational age at birth, birth-
weight and breastfeeding status, maternal and paternal age
at birth of the daughter, educational level, occupation and
home ownership at the time of the daughter’s birth, maternal
height, maternal pre-pregnancy weight, weight gain during
pregnancy (< 10, 10–14, 15–19, 20–29, 30–40, > 40
pounds; to convert pounds into kilograms, multiply pounds
by the conversion factor 0.453592.), paternal weight, pater-
nal height, maternal consumption of alcoholic beverages dur-
ing pregnancy, and the occurrence of maternal pregnancy
Nurses’ Health Study II cohort (n = 116 430)
Inclusion criteria: pregnancy ≥ 6 months 1989-2001 (NHSII)
(n = 10 862)
Exclusion criteria:• Nurses were adopted (NMS): n = 34• Missing data on parental smoking (NMS): n = 643• T2DM at baseline or before GDM (NHSII): n = 6• Missing main questionnaire (NHSII): n = 33• Missing data on the daughters’ smoking status
(NHSII): n = 76
Analytical population(n = 10 152)
Mothers participated in the Nurses’ Mothers’ Cohort Study
(n = 35 794)
Figure 1. The flowchart of study participants. Exclusion criteria are not mutually exclusive and individual reasons may not total the number of
excluded participants. GDM denotes gestational diabetes mellitus; NHSII, Nurses’ Health Study II; NMS, Nurses’ Mothers’ Cohort Study; T2DM, type
2 diabetes mellitus.
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complications (gestational diabetes and preeclampsia) during
the pregnancy of the daughter.
Covariates related to the daughters’ characteristics were
obtained from the NHSII questionnaires. The 1989 NHSII
questionnaire assessed the daughters’ age, height, race/ethni-
city and family history of diabetes at baseline. The daugh-
ters’ weight at 18 years old and current weight, parity, and
smoking status (including the number of cigarettes per day)
were self-reported from the 1989 NHSII questionnaire and
were updated with data from each biennial questionnaire
cycle. Self-reported weight was highly correlated with meas-
ured weight (r¼0.97) in a previous validation study.24
Body mass index (BMI) was computed as weight in kilo-
grams divided by height in metres squared. Dietary intake
was collected every 4 years since 1991 using a previously
validated semi-quantitative food frequency question-
naire.25–27 To assess the overall diet quality of the partici-
pants, we derived a diet score, the Alternate Healthy Eating
Index 2010 (AHEI-2010) for each participant, as previously
described.28 The overall AHEI-2010 ranged from 0 to 110
points, with a higher score indicating a better diet quality.
Physical activity was ascertained in 1989, 1991, 1997 and
2001 by frequency of engaging in common recreational
activities, from which metabolic equivalent (MET)-hours
per week were derived. The questionnaire-based estimates
of total physical activity correlated well with detailed activ-
ity diaries in a previous validation study (r¼0.56).29
Cumulative average of physical activity, total energy intake
and AHEI-2010 score were calculated for each individual at
each time period throughout the follow up, to reduce
within-subject variation and represent long-term habitual
diet and physical activity.30
Statistical analysis
We used log-binomial models with generalized estimating
equations to estimate the relative risks (RRs) and 95% confi-
dence intervals (CIs) of GDM for maternal and paternal
smoking, separately and jointly. Generalized estimating equa-
tions allowed us to account for correlations among repeated
observations (pregnancies) contributed by a single participant
(i.e. the nurse daughter). In the multivariable regression mod-
els, we adjusted for: age and race/ethnicity of the daughters
(Model 1); and additionally for maternal and paternal vari-
ables including maternal and paternal age at time of daugh-
ter’s birth, maternal pre-pregnancy BMI, paternal BMI,
maternal weight gain during pregnancy, maternal pregnancy
complications (gestational diabetes, preeclampsia) and mater-
nal alcohol consumption during pregnancy (Model 2); for the
daughters’ perinatal variables including gestational age at
birth, birthweight, and breastfeeding status (Model 3); for
the daughters’ adult life variables including parity, family
history of diabetes, cigarette smoking, total energy intake,
overall diet quality (i.e. Alternate Healthy Eating Index) and
physical activity (Model 4); for the daughters’ BMI at 18
years old (Model 5); and for the daughters’ pre-pregnancy
BMI (Model 6). We mutually adjusted for maternal and pa-
ternal smoking during pregnancy in all these models. Wald
tests were used to assess the differences between maternal
and paternal associations. The daughters’ BMI and other
adult life covariates were updated during the follow-up.
When categorizing each categorical covariate, we created a
category for missing data. We considered Model 3–Model 6
as sensitivity analyses, because the daughter’s perinatal vari-
ables, adult-life variables and adulthood BMI in these models
are potential intermediates or explanatory variables for the
associations of maternal and paternal smoking during preg-
nancy with the risk of GDM. Tests for linear trend were per-
formed across the categories of the number of cigarettes
smoked for mothers who continued to smoke throughout
pregnancy, with non-smoking during pregnancy as the refer-
ence group (for maternal smoking, the test for trend excluded
the category of mothers who quit smoking during preg-
nancy). Statistical analyses were performed using the SAS
statistical software version 9.2 (SAS Institute Inc., Cary, NC)
and the Stata statistical software version 14.0 (StataCorp LP,
College Station, TX).
Results
We included 15 665 singleton pregnancies from 10 152
women in the Nurses’ Health Study II cohort whose mothers
participated in the Nurses’ Mothers’ Cohort Study. Of them,
736 GDM pregnancies were documented. Characteristics of
mothers, fathers and daughters are shown in Table 1 accord-
ing to maternal smoking status during pregnancy. Mothers
who smoked more frequently during pregnancy were more
likely to consume alcoholic beverages during the pregnancy.
The biological fathers of the daughters whose mothers
smoked during pregnancy were also more likely to smoke
during the pregnancy. Women who were exposed to frequent
maternal smoking during pregnancy had a lower birthweight,
were less likely to be breastfed and were heavier and more
likely to smoke in adulthood.
We observed a dose-response relation between in utero
exposure to maternal smoking and risk of GDM (Table 2).
After adjustment for the daughter’s age, race/ethnicity and
maternal and paternal variables, the RRs (95% CIs) of GDM
among women whose mothers did not smoke during preg-
nancy or continued smoking 1–14, 15–24 or � 25 cigarettes/day were 1.00 (reference), 1.05 (0.81–1.35), 1.27
(0.95–1.70) and 1.98 (1.18–3.30), respectively (P for
trend¼0.02). Further adjustment for the daughter’s perinatalvariables and adult life variables, including pre-pregnancy
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BMI, only slightly changed the association. No association
was observed between paternal smoking during pregnancy
and the risk of GDM (Table 3). Wald tests showed suggestive
statistical evidence that the maternal smoking associations
may differ from the paternal smoking associations with
GDM risk (P¼0.10). We further examined the joint effect ofboth maternal and paternal smoking during pregnancy on
the risk of GDM. Women whose mother or both parents
smoked during pregnancy � 15 cigarettes/day had a higherrisk of GDM (RR 1.43, 95% CI 1.11–1.85), compared with
women whose parents did not smoke during pregnancy or
smoked < 15 cigarettes/day (Supplementary Figure 1, avail-
able as Supplementary data at IJE online).
In an analysis on the joint effect of maternal smoking
during pregnancy and the participants’ smoking during
adulthood, we found that the women who smoked < 15
cigarettes/day and whose mothers smoked � 15 cigarettes/day during pregnancy had an RR (95% CI) of 1.28 (1.00–
1.64) for GDM, compared with neither the mothers nor
the participants smoking � 15 cigarettes/day (Figure 2).We also performed a stratified analysis according to the
daughters’ own smoking status. Among the daughters who
never smoked, the adjusted RRs (95% CIs) of GDM were
1.30 (0.79–2.13), 0.94 (0.67–1.32), 1.13 (0.77–1.65) and
2.15 (1.19–3.88) for the daughters whose mothers smoked
but quit smoking in the first trimester, continued smoking
Table 1. Age-standardized maternal, paternal, and the daughter’s characteristics by maternal smoking status during pregnancya
Maternal cigarette smoking during pregnancy
Non-smoker Quit smoking in
the first trimester
Continued smoking
1–14 cigarettes/day
Continued
smoking 15–24
cigarettes/day
Continued smoking
�25 cigarettes/day
Number of participants 7478 373 1369 793 139
Maternal characteristics
Age at daughter’s birth (years) 26.68 (4.83) 25.33 (4.34) 26.39 (4.75) 26.23 (4.66) 26.90 (4.65)
Prepregnancy BMI (kg/m2) 21.41 (2.60) 21.00 (2.26) 20.88 (2.46) 21.09 (2.70) 21.24 (2.61)
Attended college (%) 40.21 47.11 43.04 40.89 46.57
Ever consumed alcoholic beverages
during pregnancy (%)
25.03 44.82 60.43 63.59 63.68
Pregnancy complicationsb (%) 4.03 4.26 3.90 3.84 3.44
Paternal characteristics
Age at daughter’s birth (years) 28.70 (4.78) 27.85 (4.68) 28.59 (4.67) 28.57 (4.64) 29.63 (4.52)
BMI at daughter’s birth (kg/m2) 23.80 (2.81) 23.86 (3.08) 23.78 (2.80) 23.72 (2.83) 23.40 (2.75)
Attended college (%) 45.90 54.68 51.51 48.45 57.90
Ever smoked during pregnancy (%) 44.61 71.72 73.86 78.26 74.26
Characteristics of the daughter in early life
Gestational age at birth (weeks) 39.42 (2.26) 39.55 (2.32) 39.32 (2.40) 39.12 (2.54) 39.25 (2.54)
Birthweight (g) 3358.28 (493.41) 3291.89 (491.44) 3176.63 (498.50) 3070.21 (514.39) 3056.42 (523.58)
Caucasian (%) 95.05 95.42 96.03 95.84 95.86
Breastfed during infancy (%) 43.46 47.81 32.07 34.65 23.07
Characteristics of the daughter
during adulthoodc
Age in 1989 (years) 30.62 (3.42) 30.57 (3.27) 30.85 (3.42) 30.33 (3.31) 30.40 (3.29)
BMI (kg/m2) 22.81 (3.93) 23.01 (4.01) 22.87 (3.64) 23.32 (4.13) 23.64 (4.66)
Nulliparous (%) 7.68 7.50 6.02 8.21 5.81
Family history of diabetes (%) 10.08 8.51 8.60 7.55 7.88
Current smoking (%) 6.54 11.06 10.86 11.36 10.95
Alcohol intake (g/day) 2.55 (4.67) 3.15 (4.79) 3.42 (5.74) 3.30 (5.66) 3.33 (6.12)
Physical activity (MET-h/week) 25.88 (36.49) 26.26 (38.56) 27.59 (37.17) 28.19 (44.22) 28.31 (34.78)
Total energy intake (kcal/day) 1882.42 (545.50) 1837.95 (522.48) 1871.40 (549.03) 1850.16 (540.46) 1873.85 (559.33)
AHEI-2010d 47.42 (10.67) 48.72 (10.70) 48.38 (11.09) 48.08 (10.56) 47.85 (10.75)
AHEI-2010 indicates Alternate Healthy Eating Index 2010; BMI, body mass index; MET, metabolic equivalent.aValues are means (standard deviations) for continuous variables and percentages for categorical variables and are standardized to age distribution of the
NHSII participants (i.e. the daughters).bMaternal pregnancy complications included gestational diabetes and preeclampsia.cAdulthood characteristics are provided for 1989, except diet information (i.e. total energy intake, alcohol intake and the derived alternate healthy eating
index) which was first collected in the Nurses’ Health Study II cohort in 1991.dAHEI-2010 was derived for each participant, as previously describe,28 to assess the overall diet quality of the participants.
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Tab
le2.M
ate
rna
lcig
are
tte
sm
okin
gd
uri
ng
pre
gn
an
cy
an
dth
eri
sk
of
ge
sta
tio
na
ld
iab
ete
sin
the
da
ug
hte
r
Mate
rnalcig
are
tte
smokin
gduri
ng
pre
gnancy
Pfo
rtr
end
d
Non-s
mokerQ
uit
smokin
gin
the
firs
ttr
imest
erC
onti
nued
smokin
g
1–14
cig
are
ttes/
day
Conti
nued
smokin
g
15–24
cig
are
ttes/
day
Conti
nued
smokin
g
‡25
cig
are
ttes/
day
GD
Mca
ses/
pre
gnanci
es522/1
1525
33/5
59
95/2
122
68/1
238
18/2
21
Model
1:A
dju
sted
for
the
daughte
r’s
age
and
race
/eth
nic
ity
1.0
01.2
6(0
.84–1.8
7)1.0
0(0
.79–1.2
8)
1.2
2(0
.92–1.6
2)
1.8
6(1
.12–3.0
9)
0.0
2
Model
2:M
odel
1þ
addit
ionally
adju
sted
for
mate
rnaland
pate
rnalvari
able
sa1.0
01.2
7(0
.85–1.8
9)1.0
5(0
.81–1.3
5)
1.2
7(0
.95–1.7
0)
1.9
8(1
.18–3.3
0)
0.0
1
Model
3:M
odel
2þ
addit
ionally
adju
sted
for
the
daughte
r’s
per
inata
lvari
able
sb1.0
01.2
5(0
.84–1.8
6)1.0
1(0
.78–1.3
0)
1.2
1(0
.90–1.6
3)
1.8
9(1
.13–3.1
5)
0.0
4
Model
4:M
odel
3þ
addit
ionally
adju
sted
for
the
daughte
r’s
adult
-lif
ech
ara
cter
isti
csc
1.0
01.2
8(0
.87–1.9
0)1.0
1(0
.78–1.3
0)
1.2
3(0
.91–1.6
5)
1.9
7(1
.20–3.2
4)
0.0
2
Model
5:M
odel
4þ
addit
ionally
adju
sted
for
the
daughte
r’s
BM
Iat
age
18
yea
rs1.0
01.2
7(0
.86–1.8
7)1.0
0(0
.77–1.2
8)
1.2
2(0
.91–1.6
4)
1.8
8(1
.15–3.0
7)
0.0
3
Model
6:M
odel
5þ
addit
ionally
adju
sted
for
the
daughte
r’s
most
rece
nt
pre
-pre
gnancy
BM
I1.0
01.2
4(0
.85–1.8
1)1.0
0(0
.78–1.2
9)
1.1
7(0
.88–1.5
6)
1.8
5(1
.12–3.0
4)
0.0
5
Pate
rnalsm
okin
gduri
ng
pre
gnancy
was
adju
sted
inall
the
model
s.aT
he
mate
rnaland
pate
rnalvari
able
sin
cluded
mate
rnaland
pate
rnalage
at
tim
eof
the
daughte
r’s
bir
th,m
ate
rnalpre
-pre
gnancy
body
mass
index
,pate
rnalbody
mass
index
,m
ate
rnalw
eight
gain
duri
ng
pre
gnancy
,m
ate
r-
nalpre
gnancy
com
plica
tions
(ges
tati
onaldia
bet
es,pre
ecla
mpsi
a),
and
mate
rnalco
nsu
mpti
on
of
alc
oholic
bev
erages
duri
ng
pre
gnancy
.T
he
info
rmati
on
was
report
edin
the
Nurs
es’M
oth
ers
Stu
dy
ques
tionnair
e.
bT
he
per
inata
lvari
able
sin
cluded
the
daughte
r’s
ges
tati
onalage
at
bir
th,bir
thw
eight
and
bre
ast
feed
ing
statu
s.T
he
info
rmati
on
was
report
edin
the
Nurs
es’M
oth
ers
Stu
dy
ques
tionnair
e.
cT
he
daughte
rs’adult
-lif
evari
able
sin
cluded
pari
ty,fa
mily
his
tory
of
dia
bet
es,ci
gare
tte
smokin
g,physi
calact
ivit
y,to
talen
ergy
inta
ke,
and
over
all
die
tquality
(i.e
.A
lter
nate
Hea
lthy
Eati
ng
Index
).T
he
info
rmati
on
was
re-
port
edin
the
Nurs
es’H
ealt
hStu
dy
IIques
tionnair
e.dP
for
tren
dacr
oss
non-s
moker
s,sm
okin
g1–14
cigare
ttes
/day,sm
okin
g15–24
cigare
ttes
/day
and
smokin
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cigare
ttes
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ate
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lcig
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sm
okin
gd
uri
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gn
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cy
an
dth
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ge
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ld
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ete
sin
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da
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r
Pate
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smokin
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gnancy
Pfo
rtr
end
Non-s
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1–14
cigare
ttes
/day
15–24
cigare
ttes
/day
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cigare
ttes
/day
GD
Mca
ses/
tota
lpart
icip
ants
350/7
527
128/3
071
166/3
433
92/1
634
Model
1:A
dju
sted
for
the
daughte
r’s
age
and
race
/eth
nic
ity
1.0
00.9
1(0
.73–1.1
3)
1.0
2(0
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6)
1.1
9(0
.92–1.5
4)
0.2
6
Model
2:M
odel
1þ
addit
ionally
adju
sted
for
mate
rnaland
pate
rnalvari
able
sa1.0
00.9
2(0
.74–1.1
5)
1.0
2(0
.82–1.2
5)
1.1
6(0
.90–1.5
1)
0.3
2
Model
3:M
odel
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addit
ionally
adju
sted
for
the
daughte
r’s
per
inata
lvari
able
sb1.0
00.9
1(0
.73–1.1
3)
1.0
1(0
.82–1.2
4)
1.1
4(0
.88–1.4
8)
0.3
8
Model
4:M
odel
3þ
addit
ionally
adju
sted
for
the
daughte
r’s
adult
-lif
ech
ara
cter
isti
csc
1.0
00.9
1(0
.73–1.1
4)
1.0
0(0
.81–1.2
2)
1.0
9(0
.84–1.4
1)
0.5
9
Model
5:M
odel
4þ
Addit
ionally
adju
sted
for
the
daughte
r’s
BM
Iat
age
18
yea
rs1.0
00.9
1(0
.73–1.1
3)
0.9
8(0
.80–1.2
1)
1.0
7(0
.82–1.3
9)
0.6
9
Model
6:M
odel
5þ
addit
ionally
adju
sted
for
the
daughte
r’s
most
rece
nt
pre
-pre
gnancy
BM
I1.0
00.9
2(0
.74–1.1
5)
0.9
9(0
.80–1.2
1)
1.0
3(0
.80–1.3
3)
0.8
6
BM
Iden
ote
sbody
mass
index
.
Mate
rnalsm
okin
gduri
ng
pre
gnancy
was
adju
sted
inall
the
model
s.aT
he
mate
rnal
and
pate
rnal
per
inata
lvari
able
sin
cluded
mate
rnal
and
pate
rnal
age
at
tim
eof
the
daughte
r’s
bir
th,
mate
rnal
pre
-pre
gnancy
body
mass
index
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rnal
body
mass
index
,m
ate
rnal
wei
ght
gain
duri
ng
pre
g-
nancy
,m
ate
rnalpre
gnancy
com
plica
tions
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es,pre
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a),
and
mate
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nsu
mpti
on
of
alc
oholic
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erages
duri
ng
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gnancy
.T
he
info
rmati
on
was
report
edin
the
Nurs
es’M
oth
ers
Stu
dy
ques
tionnair
e.bT
he
per
inata
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able
sin
cluded
the
daughte
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ges
tati
onalage
at
bir
th,bir
thw
eight
and
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ast
feed
ing
statu
s.T
he
info
rmati
on
was
report
edin
the
Nurs
es’M
oth
ers
Stu
dy
ques
tionnair
e.cT
he
daughte
rs’adult
-lif
evari
able
sin
cluded
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ty,fa
mily
his
tory
of
dia
bet
es,ci
gare
tte
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g,physi
calact
ivit
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ergy
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and
over
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tquality
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lter
nate
Hea
lthy
Eati
ng
Index
).T
he
info
rmati
on
was
re-
port
edin
the
Nurs
es’H
ealt
hStu
dy
IIques
tionnair
e.
International Journal of Epidemiology, 2016, Vol. 45, No. 1 165
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1–14, 15–24 or � 25 cigarettes/day, respectively, com-pared with those whose mothers did not smoke during
pregnancy.
Discussion
We observed a positive association between maternal
smoking during pregnancy and risk of GDM in the daugh-
ter. Specifically, maternal smoking of � 25 cigarettes/dayduring pregnancy was associated with 98% higher risk of
GDM in the daughter. The association was independent of
other major risk factors during and after pregnancy and it
was only slightly changed after adjustment for the daugh-
ter’s birthweight and adult life variables including pre-
pregnancy BMI. We did not find an association between
paternal smoking and GDM in the daughter.
With detailed information on smoking exposure as well as
covariates during and after the pregnancy, our study expands
previous findings on maternal smoking during pregnancy and
GDM risk. The MoBa Cohort in Norway recently reported
that in utero exposure to maternal tobacco smoke was associ-
ated with increased risk of GDM.8 However, the dose-re-
sponse relation between maternal smoking during pregnancy
and GDM risk in the daughter was not assessed in that study
(i.e. maternal smoking was assessed by yes versus no, without
information on the dose). Furthermore, other maternal vari-
ables were not available in that study, which may have lim-
ited its ability to evaluate the impact of potential confounders
on the observed association. A subsequent study using data
from the Swedish Medical Birth Register yielded similar find-
ings in a younger population (age range 13–28 years, with
70% � 24 years).9 However, the generalizability of resultsamong this younger population may be limited, given that
the incidence of GDM is higher in women aged 30 years or
older.31 In addition, the registry had relatively limited infor-
mation on maternal covariates. In the present study, detailed
information on maternal and paternal characteristics was col-
lected in the Nurses’ Mothers’ Cohort Study. Thus, the com-
bination of parental data with the daughter’s data collected
in the NHSII provides a unique opportunity to examine the
long-term intergenerational impact of parental smoking on
adulthood diseases in the daughter. Our results were also in
line with previous studies regarding the association between
maternal smoking during pregnancy and risk of type 2 dia-
betes in adulthood.18,19
The observed association between maternal heavy
smoking during pregnancy and higher GDM risk is bio-
logically plausible. Maternal smoking, as a deleterious in
utero environmental insult, may lead to structural, physio-
logical and metabolic changes to the fetus and result in
0.5
11
.52
Rel
ativ
e ri
sk o
f ges
tatio
nal d
iabe
tes
-/- +/- -/+ or +/+Maternal/the daughter’s smoking status
Figure 2. Joint effect of maternal smoking during pregnancy and the daughter’s smoking during adulthood on the risk of GDM in the daughter. The
symbol ‘þ’ indicates smoking � 15 cigarettes/day, ‘-’ indicates no smoking or smoking < 15 cigarettes/day. The symbol before and after the ‘/’ de-notes smoking status of the mothers and the daughters, respectively. Covariates included the daughters’ age, maternal and paternal age at time of
the daughter’s birth, maternal pre-pregnancy body mass index, paternal body mass index, maternal weight gain during pregnancy, maternal preg-
nancy complications (gestational diabetes, preeclampsia), maternal consumption of alcoholic beverages during pregnancy, paternal smoking during
pregnancy, daughter’s race/ethnicity, gestational age at birth, breastfeeding status, birth eight, parity, family history of diabetes, physical activity,
total energy intake, overall diet quality (i.e. Alternate Healthy Eating Index), BMI at 18 years old and updated adulthood BMI.
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impaired glucose metabolism and metabolic diseases in
adulthood.18,32 Animal studies suggest that fetal exposure
to smoking might lead to altered pancreatic islet and adi-
pose tissue development, beta cell apoptosis at birth and
postnatal endocrine and metabolic changes.16,17 The
observed divergent associations of maternal and paternal
smoking during pregnancy with GDM risk in the daughter
may indicate a specific intrauterine effect of maternal
smoking, rather than shared familial confounding fac-
tors,33 on GDM risk. This is in line with findings from a re-
cent meta-analysis showing greater effect estimates of
maternal smoking in pregnancy than paternal smoking in
association with childhood obesity in the offspring.34
There has been little evidence regarding in which tri-
mester of pregnancy fetal exposure to smoking most influ-
ences pancreatic islet and other metabolic effects that may
increase the risk of GDM or type 2 diabetes. In the current
study, we observed a dose-response relation between con-
tinued maternal smoking during pregnancy and GDM risk
in the daughter. We also observed suggestive evidence that
the daughters of women who smoked only in the first tri-
mester had a higher risk of GDM. Coincidentally, a previ-
ous study found that fetal exposure to maternal smoking
during the first trimester only was associated with type 2
diabetes in adulthood.19 These results indicated that the
first trimester of pregnancy might be a sensitive window
for the development of diabetes induced by maternal
smoking, which warrants confirmation in future studies.
Our study had several strengths, including the large
sample size, the availability of detailed information on
both maternal and paternal smoking during pregnancy
that allows analyses on dose-response relation, and the
comprehensive information on potential confounders col-
lected in the Nurses’ Mothers’ Cohort Study. Moreover,
the study relied primarily on maternal reports of parental
smoking during pregnancy, which is likely to be less mis-
classified than reports by the daughters.
We acknowledge that there were several limitations. First,
the ascertainment of GDM was based on self-reports in the
NHSII cohort. A previous validation study in a subset of this
cohort found a high validity (94%) of GDM self-reports
compared with medical record reviews,23 reducing the con-
cern of outcome misclassification. Second, data on parental
smoking and associated covariates during pregnancy were
collected retrospectively in the Nurses’ Mothers’ Cohort
Study. Although the validity of recalled maternal smoking
during pregnancy was found to be high (sensitivity¼0.86,specificity¼0.94) in a similar study,22 it is possible thatmothers who smoked during pregnancy were more likely to
be misclassified as not smoking than non-smoking mothers
were to be misclassified as smokers. Such differential mis-
classification would lead to an underestimation of the true
association of maternal smoking on daughter’s GDM risk in
this study. In addition, the mothers, in particular those who
had other children besides the nurse daughter, might misre-
member the circumstances (including parental smoking sta-
tus) surrounding the pregnancy of the nurse daughter a long
time after their pregnancies. It would be even more challeng-
ing for the mothers to recall paternal smoking status during
the specific pregnancy with the nurse daughter. However,
since the data about parental smoking during pregnancy
were collected without reference to the daughter’s GDM sta-
tus in the present study, any misclassification due to misre-
membering the parental smoking status during pregnancy
would be non-differential with respect to GDM outcome in
the daughter, which may also lead to an underestimation of
the true association. Therefore, the true detrimental effects
of maternal smoking on daughter’s GDM risk would be even
stronger if misclassification bias could be minimized. Third,
we did not have information about maternal smoking before
pregnancy. Mothers who quit smoking before pregnancy
were combined with never smokers in the reference group,
which may underestimate the true effect of maternal smok-
ing during pregnancy on the daughter’s risk of GDM.
Fourth, the Nurses’ Mothers’ Cohort was limited to mothers
who were alive and able to complete the questionnaire in
2001. At that time, half of the mother participants were over
70 years old. Since smoking is associated with higher risk of
mortality and various morbidities, mothers who had smok-
ing habits were less likely to survive or be able to participate
in this cohort. As a result, the survival effect may underesti-
mate the true association in this study. Fifth, our study popu-
lation consisted mostly of Caucasian American women.
Future research among other race/ethnic groups is needed.
However, the relative homogeneity of the study population
reduces potential confounding due to unmeasured socio-eco-
nomic variability. Finally, although we have considered
many potential confounders in this analysis, we cannot com-
pletely exclude the possibilities of residual confounding from
unmeasured factors. For instance, genetic factors may also
confound the association in addition to other factors. It has
been demonstrated that a genetic variant related to smoking
behaviour is associated with adiposity, which will in turn be
associated with GDM, even among people who have never
smoked.35
In conclusion, maternal heavy smoking (� 25 cigarettes/day) during pregnancy was associated with higher risk of
GDM in the daughter. This study expanded our knowledge
on the adverse health effects of maternal smoking during
pregnancy, not only leading to short-term adverse pregnancy
and perinatal outcomes but also increasing the long-term
intergenerational risk of GDM in the daughter. It adds evi-
dence to support the recommendation that maternal smoking
during pregnancy should be strongly discouraged. Further
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studies are warranted to confirm our findings and to eluci-
date the underlying mechanisms.
Supplementary Data
Supplementary data are available at IJE online.
Funding
This study was supported by the Intramural Research Program of
the Eunice Kennedy Shriver National Institute of Child Health and
Human Development, National Institutes of Health (contract No.
HHSN275201000020C). The Nurses’ Health Study II was funded
by research grants DK58845, CA50385, P30 DK46200 and UM1
CA176726 from the National Institutes of Health. The Nurses’
Mothers’ Cohort Study was funded by the Intramural Research
Program of the National Cancer Institute, Research Contract N02-
RC-17027 from the National Cancer Institute, and by P.O. 263 MQ
411027 from the National Cancer Institute. D.T. was supported by
a mentored fellowship from the American Diabetes Association
(No. 7-12-MN-34) and a K01 grant from National Institute of
Diabetes and Digestive and Kidney Diseases (DK58845). A.G. was
supported by a training grant from National Institute of Diabetes
and Digestive and Kidney Diseases (T32-DK007703-16).
Contributors
W.B. and C.Z. conceived the idea and designed the study.
W.B. wrote the manuscript. K.B.M., D.K.T., S.L., J.E.C,
A.J.G., A.A.V., F.B.H. and C.Z. interpreted the results and
reviewed and edited the manuscript. S.L. conducted tech-
nique review for this manuscript. W.B. and C.Z. had pri-
mary responsibility for final content. All authors provided
intellectual input into the paper, and all authors read and
approved the final manuscript.
Conflict of interest: All the authors declare no conflicts of
interest.
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