IEA

International Journal of Epidemiology, 2021, 965–974

doi: 10.1093/ije/dyab018
Advance Access Publication Date: 27 February 2021
International Epidemiological Association Original article

Smoking

Early life exposure to tobacco smoke and

ovarian cancer risk in adulthood
Tianyi Wang,1* Mary K Townsend,1 Christine Vinci,2,3

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Danielle E Jake-Schoffman4 and Shelley S Tworoger1,3,5
1
Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL,
USA, 2Department of Health Outcomes and Behavior, H. Lee Moffitt Cancer Center and Research
Institute, Tampa, FL, USA, 3Department of Oncologic Sciences, University of South Florida, Tampa, FL,
USA, 4Department of Health Education and Behavior, University of Florida, Gainesville, FL, USA and
5
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
*Corresponding author. Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, 12902
Magnolia Drive, Tampa, FL, USA. E-mail: Tianyi.Wang@moffitt.org
Received 14 October 2020; editorial decision 21 January 2021; Accepted 29 January 2021

Abstract
Background: Ovarian cancer risk in adulthood may be affected by early life exposure to
tobacco smoke. We investigated this relationship in two large prospective cohorts, the
Nurses’ Health Study (NHS) and NHSII.
Methods: In total, analyses included 110 305 NHS participants (1976–2016) and 112 859
NHSII participants (1989–2017). Self-reported early life smoking exposures were queried
at baseline or follow-up questionnaires. Cox proportional hazards models were used to
estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of ovarian cancer
overall and by tumour histotype.
Results: Overall, ovarian cancer risk was not different among participants whose moth-
ers did versus did not smoke during pregnancy (HR ¼ 1.05, 95% CI: 0.87–1.27); however,
an increased risk was observed among women who themselves were never smokers
(HR ¼ 1.38, 95% CI: 1.05–1.81) but not among ever smokers (HR ¼ 0.86, 95% CI: 0.66–1.14;
Pheterogeneity ¼ 0.02). Compared with women who never smoked, ovarian cancer risk was similar
for women who started to smoke at age <18 (HR ¼ 0.98, 95% CI: 0.86–1.11) or 18 (HR ¼ 1.02,
95% CI: 0.93–1.12). These associations did not differ by histotype (Pheterogeneity 0.35). Parental
smoking in the home during childhood/adolescence was related to a 15% increased risk
of ovarian cancer in adulthood (HR ¼ 1.15, 95% CI: 1.04–1.27) and this association was
suggestively stronger among women with non-serous/low-grade serous tumours
(HR ¼ 1.28, 95% CI: 1.02–1.61) versus high-grade serous/poorly differentiated tumours
(HR ¼ 1.09, 95% CI: 0.93–1.28; Pheterogeneity ¼ 0.25).
Conclusions: Exposure to parental tobacco smoke in the home, but not early initiation of
smoking, was associated with a modest elevated risk of ovarian cancer. Further investi-
gations are required to confirm these findings and elucidate underlying mechanisms.

C The Author(s) 2021; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association
V 965
966 International Journal of Epidemiology, 2021, Vol. 50, No. 3

Key words: Ovarian neoplasm, smoking, early life, cohort studies

Key Messages

• Early life exposure to cigarette smoke-derived carcinogens may contribute to the developmental origin of future

diseases, including cancers.

• Using data from two large prospective cohorts, this study provides new evidence that early life exposure to parental

smoking is associated with a modest elevated risk of adult ovarian cancer, especially for non-serous or low-grade
serous tumours.
• Further studies with detailed information on early life and adult smoking exposure are required to confirm our

findings and elucidate underlying mechanisms.

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Introduction
Ovarian cancer is the deadliest gynaecological cancer,
with about 75% of patients diagnosed at an advanced
stage for which 5-year overall survival is less than 30%.2
Currently there are relatively few modifiable risk factors
that have been established; thus, consideration of novel
exposures that influence ovarian cancer risk may provide
new opportunities for prevention. Previously our group
found that adiposity changes during the peripubertal pe-
riod were positively associated with ovarian cancer risk,
and that this association was stronger than for adulthood
adiposity changes.3 This, and other pubertal risk factors
such as age at menarche, suggest that the peripubertal pe-
riod, when ovaries undergo development and maturation,
represents a critical window of ovarian carcinogenic sus-
ceptibility to various exposures.4–7
Tobacco smoke is a highly pro-inflammatory and toxic
substance, and tobacco use is the leading preventable cause
of morbidity and mortality in the USA and accounts for
30% of all cancer deaths.8,9 Parental smoking is related to
several adverse health conditions in children, including mid-
dle ear disease, respiratory symptoms, impaired lung func-
tion, sudden infant death syndrome and childhood
cancers.10,11 Specifically of relevance to ovarian cancer, pre-
natal smoke exposure and environmental smoke during
childhood has been associated with earlier age at pubic hair
development and younger onset of menarche.12–14 However,
which facets of early exposure to cigarette smoke have the
most impact on later life carcinogenesis is unclear.15–18
There have been no published studies, to our knowledge, of
childhood active and environmental tobacco smoke expo-
sure and risk of ovarian malignancy in prospective studies.
Considering the importance of early life periods for
both aetiological and prevention opportunities, and that
approximately half of students in the USA in grades 6
through 12 reported exposure to second-hand smoke in
1 2013,19 we conducted an analysis in two large prospective
studies, the Nurses’ Health Study (NHS) and NHSII, to ex-
amine the associations of early exposure to cigarette smoke
with ovarian cancer risk overall, by tumour histotype and
adult smoking status, using a prospective and retrospective
longitudinal cohort study design.
Methods
The study protocol was approved by the institutional re-
view boards of the Brigham and Women’s Hospital,
Harvard T.H. Chan School of Public Health and H. Lee
Moffitt Cancer Center & Research Institute, and those of
participating registries as required. Completion of the
questionnaire was considered to imply informed consent.
Study participants
The NHS was initiated in 1976 among 121 700 female reg-
istered nurses aged 30–55 years in the USA.20 The NHSII
began in 1989 among 116 429 female registered nurses
aged 25–42 years in the USA.21 In both cohorts, detailed
information on demographics, individual lifestyle and
medical history was obtained from questionnaires at base-
line and biennially thereafter. Eligible women provided in-
formation on whether they had early life smoking
exposure. Women were excluded if they had a bilateral oo-
phorectomy, pelvic irradiation or a previous diagnosis of
cancer (other than non-melanoma skin cancer) before
ovarian cancer diagnosis.
Identification of ovarian cancer
Ovarian cancer cases were identified by self-report on the
biennial questionnaires or by connection to the National
International Journal of Epidemiology, 2021, Vol. 50, No. 3
Death Index. Diagnoses were confirmed by a gynaecologi-
cal pathologist’s review of the participant’s pathology
report or, if medical records could not be obtained, by link-
age with the relevant cancer registry. The gynaecological
pathologist abstracted data on tumour stage, histology,
grade and morphology.
Early life smoking exposures and other covariates
At baseline, participants with a smoking history were
asked about the age when they first started to smoke regu-
larly. Participants were also asked whether their mothers
smoked during pregnancy with them (2004 in NHS and
1999 in NHSII), if either parent smoked while the partici-
pant lived at home (1982 in NHS) or if either parent
smoked regularly inside the home when the participant
was a child (1999 in NHSII). We created a variable to com-
bine the information for women who had data on both
mother’s smoking status during pregnancy and parents’
smoking while the participant lived at home/inside the
home when the participant was a child. Father’s smoking
status during mother’s pregnancy was available only in
NHS (2004).
Adult height and age at menarche were reported at
study enrolment. Weight at age 18 was recalled in 1980
(NHS) or 1989 (NHSII) and somatotype at age 10 was
assessed in 1988 (NHS) or 1989 (NHSII) using the
nine-figure Stunkard somatotype pictogram.22 Then we
imputed body mass index (BMI) at age 10 using data from
the Growing Up Today Study (offspring of NHSII partici-
pants) which collected both Stunkard pictograms and BMI
of girls at age 10.23 Adult BMI, menopausal status, dura-
tion of oral contraceptive use, hormone therapy use, tubal
ligation, hysterectomy, family history of breast or ovarian
cancer, and parity were queried at baseline and on biennial
questionnaires.
Statistical analysis
To estimate risk of ovarian cancer in association with early
life smoking exposures across the full follow-up period,
Cox proportional hazards models stratified on age, calen-
dar year and cohort were constructed to estimate hazard
ratios (HRs) and 95% confidence intervals (CIs).24 We
computed person-time from the return of the baseline
questionnaire to the date of self-reported ovarian cancer
diagnosis, death from any cause or the end of follow-up
(31 May 2016 in NHS, 31 May 2017 in NHSII), whichever
came first. Model 1 evaluated the risk of ovarian cancer by
early life smoking exposures: age of smoking initiation
(never smoker, <18 years, 18 years), mother smoked
while pregnant (no, yes), parents smoked in the home (nei-
ther, mother and/or father), and parents smoked during
967
the pregnancy/in the home (no, yes). Models 2 and 3 addi-
tionally adjusted for established or putative ovarian cancer
risk factors that could be confounders or mediators.
Specifically, Model 2 additionally adjusted for potential
confounding variables during early life: age at menarche
(<12 years, 12 years), height (meters, continuous),
change in BMI from age 10 to age 18 (kg/m2, <2, 2–3.9,
4–5.9, 6–7.9, 8, missing), and BMI at age 10 (kg/m2,
<14, 14–15.9, 16–17.9, 18–19.9, 20, missing). Model 3
further adjusted for biennially updated adult covariates
and potential mediators, including menopausal status (pre-
menopausal/unknown, postmenopausal), duration of oral
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contraceptive use (never, <1 year, 1–4.9 years, 5–9.9 years,
10 years), hormone therapy use (never, ever), tubal liga-
tion (never, ever), hysterectomy (never, ever), family his-
tory of breast or ovarian cancer (no, yes), parity (0, 1, 2, 3,
4 children) and BMI (kg/m2, <20, 20–24.9, 25–29.9,
30, missing). An early socioeconomic status index (con-
structed by summing three indicators of adverse family so-
cioeconomic exposures, including manual occupation of at
least one parent, unemployment by father and parents not
owning a home at the time of the participant’s birth or in-
fancy) 25 and birthweight did not substantially alter risk
estimates and thus were not included in the final models.
As it is plausible that the effect of early life environmental
tobacco smoke could be weaker among adult smokers ver-
sus non-smokers,26 we carried out analyses stratified by
the participants’ own smoking status (never, ever) and
tested potential heterogeneity in effect estimates using a
likelihood ratio test comparing models with versus without
interaction terms. The association of father’s smoking sta-
tus during mother’s pregnancy with ovarian cancer risk
was evaluated in NHS.
We performed a sensitivity analysis among 1 750 epi-
thelial ovarian cancer, primary peritoneal or fallopian tube
cancer cases (these types are typically grouped together be-
cause of common histological subtypes and origins 27) con-
firmed by their medical record. Among these cases, we also
assessed whether associations differed by tumour histotype
(high-grade serous/poorly differentiated histology versus
non-serous/low-grade serous histology) using competing
risks Cox models.28 As active smoking is an established
risk factor for mucinous ovarian cancer,29 we also evalu-
ated the association of the early life smoking exposures
with mucinous cancer risk. Additionally, we conducted a
stratified analysis by the age of ovarian cancer diagnosis,
and a secondary fully prospective analysis examining
smoking exposures at the return of the questionnaire with
the relevant exposure assessment.
The proportional hazards assumption was evaluated by
comparing models with versus without interaction terms
between early life smoking exposures and calendar year,
968
using likelihood ratio test. No deviation was detected. To
test for heterogeneity by cohort, HRs were calculated sepa-
rately in each cohort and pooled using random-effects
meta-analysis. All statistical tests were two-sided and con-
ducted with SAS statistical software version 9.4 (SAS
Institute Inc., Cary, NC, USA).
Results
Characteristics of the study population
In total, analyses included 110 305 NHS and 112 859
NHSII participants. Median age at baseline was 42 years in
NHS and 35 years in NHSII. Overall, 2 853 ovarian cancer
cases were identified (2 184 from NHS, 669 from NHSII)
with a median age at diagnosis as 62 years. Among them,
1 750 epithelial ovarian cancer, primary peritoneal or
fallopian tube cancer cases (including 1 511 invasive, 169
borderline, 70 unknown morphology; 1 020 high-grade se-
rous/poorly differentiated histology, 56 low-grade serous,
115 mucinous, 196 endometrioid, 97 clear cell and 266 tu-
mour with other/unknown histotypes) and 105 other type
of ovarian cancer cases (e.g. sex cord stromal, germ cell,
fibro-thecoma) were confirmed by their medical record.
Among women who were alive at the time of the exposure
assessment, 100%, 55% and 76% women provided data
on their age of smoking initiation, mother’s smoking status
while pregnant and parents’ smoking status in the home,
respectively. In NHS, women with parents who smoked in
the home tended to be more likely to smoke at baseline. In
NHSII, women with parents who smoked in the home
tended to be more likely to have menarche before age 12
and smoke at baseline, as well as have higher BMI at ages
10 and 18 (Table 1). Compared with never smokers,
women who started smoking before age 18 were more
likely to have higher BMI at age 10 and age 18 and
5 years’ oral contraceptive use (Supplementary Table S1,
available as Supplementary data at IJE online). Women
whose mothers smoked during pregnancy were more likely
to have 5 years’ oral contraceptive use and be ever smok-
ers at baseline (Supplementary Table S2, available as
Supplementary data at IJE online).
Early life smoking exposures and risk of ovarian
cancer, overall and by tumour histotype
As no heterogeneity was found across cohorts (Pheterogeneity
0.08; Supplementary Table S3, available as
Supplementary data at IJE online), pooling data from two
cohorts was used with adjustment of early life covariates
(Table 2, Model 2). No association with ovarian cancer
risk was observed for women who started to smoke before
International Journal of Epidemiology, 2021, Vol. 50, No. 3
age 18 (compared with never smokers, HR ¼ 0.98, 95%
CI: 0.86–1.11) or 18 years (HR ¼ 1.02, 95% CI: 0.93–
1.12). No association was observed comparing women
whose mothers smoked during pregnancy with them versus
not (HR ¼ 1.05, 95% CI: 0.87–1.27). These associations
did not differ by tumour histotype (Pheterogeneity 0.35;
Table 3). However, parental smoking in the home was as-
sociated with a 15% increased risk (HR ¼ 1.15, 95% CI:
1.04–1.27), which was suggestively stronger among
women with non-serous/low-grade serous tumours
(HR ¼ 1.28, 95% CI: 1.02–1.61) than high-grade serous/
poorly differentiated tumours (HR ¼ 1.09, 95% CI:
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0.93–1.28, Pheterogeneity ¼ 0.25). A suggestively higher risk
was also noted for those who were exposed to smoke either
in utero or while living with parents (HR ¼ 1.16, 95% CI:
0.98–1.37), which was seen for non-serous/low-grade se-
rous tumour histotype (HR ¼ 1.72, 95% CI: 1.14–2.59)
but not high-grade serous/poorly differentiated tumour his-
totype (HR ¼ 1.01, 95% CI: 0.77–1.32; Pheterogeneity ¼
0.03). Risk estimates were similar for models without
covariates (Model 1) or with further adjustment of adult
factors (Model 3).
Early life smoking exposures and risk of ovarian
cancer by adult smoking status and other
analyses
Among never smokers whose mothers smoked while preg-
nant, there was an increased risk observed (HR ¼ 1.38,
95% CI: 1.05–1.81) though this did not hold for ever
smokers whose mothers smoked while pregnant
(HR ¼ 0.86, 95% CI: 0.66–1.14; Pheterogeneity ¼ 0.02;
Table 4). Results were not different by adult smoking sta-
tus for women with parental smoking in the home
(Pheterogeneity ¼ 0.78). A suggestively increased risk of mu-
cinous tumours was found for all early life smoking expo-
sures (HRs ranged from 1.19 to 1.61; Table 5). Findings
were similar among 1 750 histologically confirmed epithe-
lial ovarian cancer, primary peritoneal or fallopian tube
cancer cases, as well as in fully prospective analyses that
only considered incident cases after exposure assessment
[including 2 201 (100%), 479 (55%) and 1 574 (89%)
cases with data on their age of smoking initiation, mother’s
smoking status while pregnant and parents’ smoking status
in the home, respectively]. We did stratified analysis and
observed similar results by the median age of ovarian can-
cer diagnosis (data not shown). However, the associations
were suggestively stronger among women diagnosed before
versus after age 62 (e.g. for parents smoked while preg-
nant/in the home, HR ¼ 1.51 and 1.04, respectively). No
clear association was found with paternal smoking during
International Journal of Epidemiology, 2021, Vol. 50, No. 3 969

Table 1 Age-standardized characteristics of study population by parental smoking during childhood or adolescence, NHS and
NHSII

Characteristic Parents smoked in the home NHS Parents smoked in the home NHSII

No Yes No Yes

n 27256 57313 31609 57628

Age at baseline,a median (IQR) 44 (37-50) 42 (36-48) 34 (31-38) 35 (32-39)
Height at baseline, meters, median (IQR) 1.6 (1.6-1.7) 1.6 (1.6-1.7) 1.7 (1.6-1.7) 1.7 (1.6-1.7)
Age at menarche at 12 years old or later (%) 78.2 77.4 77.5 74.9
Imputed BMI at age 10,b kg/m2 (%)
<14 16.0 15.7 14.4 13.8
14–15.9 35.3 34.6 33.9 32.6
16–17.9 27.1 27.0 28.4 27.8

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18–19.9 11.0 11.1 12.4 13.2
20 10.6 11.6 10.9 12.7
BMI at age 18,, kg/m2 (%)
<20 34.6 34.1 42.2 37.9
20–24.9 56.2 55.9 49.3 51.0
25 9.2 10.0 8.5 11.0
Change in BMI from age 10 to age 18,b kg/m2 (%)
<2 16.9 17.0 20.8 20.1
2–3.9 22.5 22.7 25.1 23.8
4–5.9 27.5 27.1 26.8 26.2
6–7.9 19.2 19.3 16.0 16.4
8 13.9 13.9 11.3 13.4
BMI at baseline,b kg/m2 (%)
<20 12.9 12.8 18.1 14.5
20–24.9 59.4 59.6 56.3 54.6
25–29.9 20.1 19.6 16.9 18.9
30 7.5 8.0 8.8 12.1
Postmenopausal at baseline (%) 13.4 13.6 0.2 0.3
Oral contraceptive use at baseline (%)
Never 51.4 50.5 31.3 26.5
Less than 1 year 12.7 13.4 10.7 10.4
1–<5 years 20.4 20.5 35.3 36.4
5–<10 years 11.7 11.9 18.1 21.1
10 years 3.8 3.7 4.6 5.7
Parity at baseline (%)
0 children 5.8 5.7 29.3 28.1
1 child 7.8 7.5 18.6 18.8
2 children 29.5 28.0 32.7 34.3
3 children 28.5 28.6 14.7 14.6
4 children 28.3 30.3 4.8 4.2
Family history of breast or ovarian cancer at baseline (%) 8.9 8.1 7.0 7.6
Tubal ligation at baseline (%) 10.8 10.4 14.6 16.4
Hysterectomy at baseline (%) 12.2 12.7 3.0 3.7
Ever hormone therapy use at baseline (%) 8.4 8.6 0.2 0.2
Smoking status at baseline (%)
Never smoker 54.4 40.6 74.1 62.0
Former smoker 22.0 25.0 17.9 23.4
Current smoker 23.5 34.4 8.0 14.6

Percentages may not add up to 100% due to rounding.

BMI, body mass index; NHS, Nurses’ Health Study; IQR, interquartile range.
a
Value is not age-adjusted.
b
Percentages exclude missing values. The percentages of participants missing BMI data in NHS and NHSII were respectively as follows: 19% and 1% for im-
puted BMI at age 10, 7% and 1% for BMI at age 18, 23% and 2% for change in BMI from age 10 to age 18, and 1% and 0.5% for BMI at baseline.
970 International Journal of Epidemiology, 2021, Vol. 50, No. 3

Table 2 Associations between early life smoking exposures and risk of ovarian cancer, NHS and NHSII

Cases/person-years HR (95% CI)

Model 1 Model 2 Model 3

Age of smoking initiation

Never smoker 1058/3112097 1.00 (ref) 1.00 (ref) 1.00 (ref)
<18 years 304/993647 1.00 (0.88-1.14) 0.98 (0.86-1.11) 0.99 (0.87-1.13)
18 years 839/1767424 1.04 (0.94-1.14) 1.02 (0.93-1.12) 1.03 (0.93-1.13)
Mother smoked while pregnant
No 739/2120979 1.00 (ref) 1.00 (ref) 1.00 (ref)
Yes 136/434525 1.05 (0.87-1.28) 1.05 (0.87-1.27) 1.06 (0.87-1.28)
Parents smoked in the home
Neither 543/1543107 1.00 (ref) 1.00 (ref) 1.00 (ref)

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Mother and/or father 1228/3007653 1.15 (1.04-1.28) 1.15 (1.04-1.27) 1.15 (1.04-1.28)
Parents smoked while pregnant/in the home
No 202/562750 1.00 (ref) 1.00 (ref) 1.00 (ref)
Yes 598/1750052 1.16 (0.98-1.37) 1.16 (0.98-1.37) 1.18 (0.99-1.39)

Model 1: Cox proportional hazards model stratified on age, calendar year and cohort. Model 2: Model 1þ adjusted for age at menarche, height, change in
body mass index (BMI) from age 10 to age 18 and imputed BMI at age 10. Model 3: Model 2 þ adjusted for menopausal status, duration of oral contraceptive
use, hormone therapy use, tubal ligation, hysterectomy, family history of breast or ovarian cancer, parity and adult BMI.
CI, confidence interval; HR, hazard ratio; NHS, Nurses’ Health Study.

Table 3 Associations between early life smoking exposures and risk of ovarian cancer by tumour histotype, NHS and NHSII

High-grade serous or poorly differentiated histology Non-serous or low-grade serous histology Pheterogeneity

n, cases HR (95% CI) n, cases HR (95% CI)

Age of smoking initiation

Never smoker 385 1.00 (ref) 234 1.00 (ref) 0.52
<18 years 117 1.09 (0.88-1.34) 54 0.74 (0.55-1.00)
18 years 360 1.09 (0.94-1.26) 171 1.03 (0.84-1.27)
Mother smoked while pregnant
No 267 1.00 (ref) 157 1.00 (ref) 0.35
Yes 41 0.97 (0.69-1.37) 38 1.24 (0.85-1.80)
Parents smoked in the home
Neither 225 1.00 (ref) 106 1.00 (ref) 0.25
Mother and/or father 482 1.09 (0.93-1.28) 269 1.28 (1.02-1.61)
Parents smoked while pregnant/in the home
No 84 1.00 (ref) 30 1.00 (ref) 0.03
Yes 197 1.01 (0.77-1.32) 148 1.72 (1.14-2.59)

CI, confidence interval; HR, hazard ratio; NHS, Nurses’ Health Study.
HRs were calculated using Cox proportional hazards models stratified by age, calendar year and cohort, and adjusted for age at menarche, height, change in
body mass index (BMI) from age 10 to age 18 and imputed BMI at age 10.

mother’s pregnancy with the participant (Model 2
HR ¼ 1.15, 95% CI: 0.97–1.37).
Discussion
This is the largest analysis to date of the association of
early life smoking exposure with adult ovarian cancer risk.
We observed that exposure to parental smoke, but not
early initiation of smoking, was associated with elevated
risk of adult ovarian cancer, especially for non-serous/low-
grade serous histology.
Among limited prospective studies, early life environ-
mental smoke exposure has generally been associated with
an increased risk of pancreatic, lung, colon and breast can-
cers in adulthood.15–18 For example, a life course smoking
study of breast cancer observed a 17% higher breast cancer
risk with exposure to smoke during childhood and adoles-
cence, and a suggestive 7% higher risk with in utero expo-
sure to maternal smoking, very similar to our results.15
Specifically for ovarian cancer, a case-control study in
Hawaii and Los Angeles [558 cases; including 37% Asian-
American cancer patients and 23% borderline tumours
International Journal of Epidemiology, 2021, Vol. 50, No. 3 971

Table 4 Associations between early life smoking exposures and risk of ovarian cancer by adult smoking status, NHS and NHSII

Never smokers Ever smokers Pheterogeneity

n, cases HR (95% CI) n, cases HR (95% CI)

Mother smoked while pregnant

No 346 1.00 (ref) 392 1.00 (ref) 0.02
Yes 71 1.38 (1.05-1.81) 65 0.86 (0.66-1.14)
Parents smoked in the home
Neither 319 1.00 (ref) 224 1.00 (ref) 0.78
Mother and/or father 551 1.13 (0.99-1.31) 676 1.20 (1.03-1.40)
Parents smoked while pregnant/in the home
No 113 1.00 (ref) 89 1.00 (ref) 0.80
Yes 281 1.17 (0.92-1.48) 316 1.20 (0.94-1.54)

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HRs were calculated using Cox proportional hazards models stratified by age, calendar year and cohort, and adjusted for age at menarche, height, change in
body mass index (BMI) from age 10 to age 18 and imputed BMI at age 10.
CI, confidence interval; HR, hazard ratio; NHS, Nurses’ Health Study.

Table 5 Associations between early life smoking exposures and risk of mucinous tumours, NHS and NHSII

Mucinous tumour

Cases/person-years HR (95% CI)

Age of smoking initiation

Never smoker 41/3112392 1.00 (ref)
<18 years 19/993745 1.61 (0.93-2.79)
18 years 45/1767610 1.57 (1.01-2.46)
Mother smoked while pregnant
No 41/2121176 1.00 (ref)
Yes 12/434564 1.55 (0.78-3.08)
Parents smoked in the home
Neither 27/1543252 1.00 (ref)
Mother and/or father 62/3007962 1.23 (0.78-1.94)
Parents smoked while pregnant/in the home
No 10/562803 1.00 (ref)
Yes 36/1750216 1.19 (0.56-2.53)

HRs were calculated using Cox proportional hazards models stratified by age, calendar year and cohort, and adjusted for age at menarche, height, change in
body mass index (BMI) from age 10 to age 18 and imputed BMI at age 10..
CI, confidence interval; HR, hazard ratio; NHS, Nurses’ Health Study.

(low malignant potential disease)] reported that the age of
smoking initiation and gestational tobacco smoke expo-
sure were not related to the risk of invasive or borderline
ovarian cancer, which is similar to our findings.30
However, this study did not observe an association for
childhood environmental tobacco smoke exposure among
never smokers. In contrast, our sample included a higher
proportion of White women and only 10% borderline
tumours. The discrepancies in study findings may have
resulted from differences in study design (prospective or
retrospective) and disparate ovarian cancer histotype dis-
tributions. For example, serous carcinomas are relatively
more common among White women compared with Asian
women, and clear cell carcinomas are more common
among Asian and Pacific Islanders compared with White
women.31 Additional studies should evaluate this associa-
tion in large epidemiological studies.
The mechanism by which early life smoking exposure
may influence risk of ovarian cancer is not completely
clear. Second-hand smoke contains a number of substan-
ces, some of which may act as endocrine disrupters and
contribute to the developmental origin of future diseases,32
reduced fecundity in adulthood33 and transplacental carci-
nogenesis.34,35 Studies suggest that early smoking exposure
may also affect primordial follicle number at puberty and
ovulatory function, as well as fertility in adulthood.36–38
Further, by altering the endocrine and central nervous sys-
tem, early life exposure to smoking is associated with
972
lower age of menarche, which is widely regarded as the
surrogate of puberty timing and is associated with
ovarian function as well as breast and ovarian cancer
risk.5–7,13,39,40 Additionally, children of parents who
smoke are more likely to start smoking in their teenage
years and have more pack-years of cigarette smoking.41,42
As adult smoking is not a strong risk factor for ovarian
cancer overall and we did not observe differential associa-
tions of parental smoking in the home by adult smoking
status, early life may represent a critical window of ovarian
carcinogenic susceptibility to smoke. However, an in-
creased risk was only observed for never smokers whose
mothers smoked while pregnant, not for ever smokers
whose mothers smoked while pregnant. It is plausible that
the effect of early life environmental tobacco smoke could
be reduced among adult smokers.26 However, this finding
should be interpreted with caution as the number of moth-
ers who smoked while pregnant in our study was relatively
small and residual confounding may also have influenced
the results. Notably, adolescent risk behaviours are the re-
sult of a complex combination of social, genetic and devel-
opmental factors43; thus, other lifestyle risk factors related
to smoking exposure adopted at this developmental period
may be associated with ovarian cancer risk,44,45 although
we adjusted for a number of early life factors.
It is also noteworthy that the associations of early life
exposure to smoke were suggestively stronger among
women with non-serous/low-grade serous tumours than
high-grade serous/poorly differentiated tumours, especially
for mucinous tumours, for which cigarette smoke is an
established risk factor.29 Mucinous tumours are character-
ized by the presence of epithelial cells which contain abun-
dant mucin cells and line the inner portion of the cervix
and intestines.46 Those histological similarities support the
biological credibility of our findings, as early life smoking
has been linked to adult cervical abnormalities and colon
cancer.18,47 Additionally, results from one previous study
suggested that the effect of tobacco smoke may be stronger
in the early phase of ovarian carcinogenesis.48 Therefore
the stronger smoking-related risk for mucinous histotype
may be possibly explained by the fact that, for mucinous
tumours, there is a continuum from benign to borderline
and invasive disease, whereas serous tumours, generally
high grade, originate from the distal fallopian tube and do
not originate from borderline tumours.49
Several limitations of our study should be noted. Data
on early life smoking exposures were obtained in adult-
hood, which may have led to misclassification in the expo-
sure assessment; further, many women reported that they
did not know if their mothers smoked while they were in
utero. However, the daughter’s report of childhood expo-
sure to maternal smoking is a good proxy for mothers’
International Journal of Epidemiology, 2021, Vol. 50, No. 3
report of smoking during pregnancy in the Nurses’
Mothers Cohort (approximately 40 000 mothers of NHS
and NHSII participants), yielding 89% sensitivity and
88% specificity.50 To increase power, our primary analy-
ses included person-time starting from baseline, even for
early life smoking exposures that were assessed after base-
line. Nonetheless, a fully prospective analysis that only in-
cluded person-time following the exposure assessment
provided similar results. Moreover, some details on the
early life smoking exposure (e.g. dose, duration, timing) as
well as second-hand smoke exposure in adulthood were
not available; thus, we could not assess total lifetime envi-
Downloaded from https://academic.oup.com/ije/article/50/3/965/6153945 by guest on 02 February 2023
ronmental smoke exposure. Finally, our study population
comprises registered nurses with few non-White women,
which affects the generalizability of our findings. The
strengths of this study include the substantial numbers of
cases over a very long follow-up period and availability of
data on both early life active and environmental tobacco
smoke exposure, as well as biennially updated data on cig-
arette use and other potential covariates in adulthood.
Moreover, we were able to control for confounding of
other early life factors.
In conclusion, using data from two large prospective
cohorts, this study provides new evidence that early life ex-
posure to smoking is related to a modest increased risk of
ovarian cancer during adulthood. Considering such expo-
sure can be prevented, future studies with detailed infor-
mation on the early life and adult smoking exposure are
required to confirm our findings and elucidate underlying
mechanisms.
The data underlying this article will be shared on rea-
sonable request to the corresponding author.
Supplementary data
Supplementary data are available at IJE online.
Funding
This work was supported in part by the National Cancer Institute at
the National Institutes of Health (grant numbers UM1 CA186107,
U01 CA176726 and P01 CA87969) and the James and Esther King
Biomedical Research Program of the Florida Department of Health
(grant number 9JK02). The content is solely the responsibility of the
authors and does not necessarily represent the official views of the
National Institutes of Health or the Florida Department of Health.
The authors take full responsibility for analyses and interpretation
of data.
Acknowledgements
We would like to thank the participants and staff of the NHS and
NHSII for their valuable contributions as well as the following state
cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL,
GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY,
International Journal of Epidemiology, 2021, Vol. 50, No. 3
NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. We
thank the Channing Division of Network Medicine, Department of
Medicine, Brigham and Women’s Hospital as home of the Nurses’
Health Studies.
Conflict of interest
None declared.
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