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Advance Access publication November 26, 2008
Cancer Risk After Exposure to Treatments for Ovulation Induction
R. Calderon-Margalit, Y. Friedlander, R. Yanetz, K. Kleinhaus, M. C. Perrin, O. Manor, S. Harlap, andO. Paltiel
Initially submitted January 23, 2008; accepted for publication September 11, 2008.
Uncertainty continues as to whether treatments for ovulation induction are associated with increased risk of
cancer. The authors conducted a long-term population-based historical cohort study of parous women. A total of15,030 women in the Jerusalem Perinatal Study who gave birth in 1974–1976 participated in a postpartum survey.
Cancer incidence through 2004 was analyzed using Cox’s proportional hazards models, controlling for age andother covariates. Women who used drugs to induce ovulation (n ¼ 567) had increased risks of cancer at any site(multivariate hazard ratio (HR) ¼ 1.36, 95% conﬁdence interval (CI): 1.06, 1.74). An increased risk of uterine
cancer was found among women treated with ovulation-inducing agents (HR ¼ 3.39, 95% CI: 1.28, 8.97), specif-ically clomiphene (HR ¼ 4.56, 95% CI: 1.56, 13.34). No association was noted between use of ovulation-inducingagents and ovarian cancer (age-adjusted HR ¼ 0.61, 95% CI: 0.08, 4.42). Ovulation induction was associated witha borderline-signiﬁcant increased risk of breast cancer (multivariate HR ¼ 1.42, 95% CI: 0.99, 2.05). Increasedrisks were also observed for malignant melanoma and non-Hodgkin lymphoma. These associations appearedstronger among women who waited more than 1 year to conceive. Additional follow-up studies assessing theseassociations by drug type, dosage, and duration are needed.
breast neoplasms; cohort studies; incidence; lymphoma, non-Hodgkin; melanoma; ovarian neoplasms; ovulationinduction; uterine neoplasms
Abbreviations: CI, conﬁdence interval; HR, hazard ratio; ICDO-3, International Classiﬁcation of Diseases for Oncology, ThirdEdition.
Approximately 10% of couples in developed countries
follicle-stimulating hormone) have been used to promote
seek health care for infertility (1, 2). The use of fertility treat-
ovulation since the early 1960s (5), and human chorionic
ment has grown substantially in recent decades, as can be
gonadotropins have been used since 1932 (6).
inferred from the increasing utilization of assisted reproduc-
Despite this long-term use, the scientific literature pro-
tive technologies (3). It has been estimated that approximately
vides inconsistent information on the association between
1% of US infants born in 2004 were conceived through
ovulation induction treatment and cancer incidence. An in-
assisted reproductive technologies (4).
creased risk of ovarian cancer following treatment has been
Ovulation-inducing drugs are widely used for ovarian
suggested in previous studies (7, 8), while more recent stud-
follicle stimulation, either as independent therapies or dur-
ies suggest no association (9, 10) (Table 1). Some studies
ing in vitro fertilization cycles. Clomiphene citrate, in use
have suggested an increased risk of breast cancer following
since the 1960s, is still considered the best initial treatment
treatment with clomiphene (11, 12); however, in others, in-
for the majority of women with anovulatory infertility (4).
vestigators have reported a reduced risk among treated
Clomiphene has also been widely used among couples with
women (13, 14) or no effect on risk (15, 16). A few studies
unexplained infertility (4). Similarly, human menopausal
have assessed the association between ovulation induction
gonadotropins (nowadays partly replaced by recombinant
and cancer at other sites, such as the uterus, thyroid, and
Correspondence to Dr. Ronit Calderon-Margalit, Braun School of Public Health and Community Medicine, Hadassah-Hebrew University, P.O.
Box 12272, 91120 Jerusalem, Israel (e-mail: firstname.lastname@example.org).
Findings From Published Studies on the Association Between Fertility Treatment and Incidence of Ovarian and Breast Cancer
Clomiphene >1 year: SIR ¼ 11.1 (95% CI:
1.5, 82.3); clomiphene <1 year: no association
Nulligravid women: OR ¼ 27.0 (95% CI: 2.3, 316);
gravid women: OR ¼ 1.4 (95% CI: 0.52, 3.6)
Clomiphene: SIR ¼ 2.7 (95% CI: 0.97, 5.8); not
signiﬁcantly higher than SIR for untreated
infertile women (SIR ¼ 1.6, 95% CI: 0.6, 3.5)
induction vs. generalpopulation and vs.
Clomiphene only: SIR ¼ 1.40 (95% CI: 1.05, 1.83);
hMG only: SIR ¼ 0.66 (95% CI: 0.21, 1.54);
clomiphene, then hMG: 1.06 (95% CI: 0.59, 1.75)
Infertility: SIR ¼ 1.29 (95% CI: 1.1, 1.4);
clomiphene: SIR ¼ 1.29 (95% CI: 1.1, 1.5);
gonadotropins: SIR ¼ 1.40 (95% CI: 0.9, 2.0).
and 20 years of follow-up:RR ¼ 1.6 (95% CI: 1.0, 2.5);
high dose of gonadotropins:RR ¼ 1.79 (95% CI: 1.0, 3.3)
Ovulation induction (yes/no): SIR ¼ 0.93 (95%
CI: 0.79, 1.09); <12 months of exposure:
Clomiphene: OR ¼ 2.1 (95% CI: 0.99, 4.3); hMG:
OR ¼ 0.6 (95% CI: 0.1, 2.2); clomiphene, thenhMG: OR ¼ 0.8 (95% CI: 0.3, 2.2)
or gonadotropin-releasing hormone. Progestins:
RR ¼ 3.36 (95% CI: 1.3, 8.6); hMG, 5–9 years
from exposure: hazard ratio ¼ 1.96(95% CI: 1.06, 3.64)
Clomiphene: RR ¼ 0.5 (95% CI: 0.2, 1.2); hCG:
Abbreviations: CI, conﬁdence interval; hCG, human chorionic gonadoptropins; hMG, human menopausal gonadotropins; NA, not available; OR, odds ratio; RR, rate ratio; SIR, standardized incidence ratio.
Downloaded from http://aje.oxfordjournals.org
colon, and malignant melanoma; results have been incon-
well as site-specific cancer at sites for which the total num-
sistent (17). Overall, most investigators studying the asso-
ber of events exceeded 30. These included non-Hodgkin
ciation between fertility treatment and cancer have reported
lymphoma (morphologic codes 95903–96502, 96674–
on outcomes occurring before the age at which women are
97143, and 97273; n ¼ 50), malignant melanoma (morpho-
at substantial risk of cancer and/or have used the general
logic codes 87202–87743; n ¼ 78), and solid tumors of the
population as the comparison group, precluding control for
breast (ICDO-3 codes 50.0–50.9; n ¼ 530), colon and rec-
major confounders and risk factors (17). Some of these
tum (ICDO-3 codes 18.0–20.9; n ¼ 102), ovary (ICDO-3
studies compared exposures within cohorts of infertile
codes 56.0–56.9; n ¼ 43), uterus (ICDO-3 codes 54.0–55.9;
women (Table 1); however, it is likely that infertile women
n ¼ 44), thyroid (ICDO-3 codes 73.0–73.9; n ¼ 68), uter-
who were not assigned to fertility treatment had different
ine cervix (ICDO-3 codes 53.0–53.9; n ¼ 43), and brain
causes of infertility than those who underwent ovulation
(ICDO-3 codes 70.0, 71.0–72.9, 75.1, and 75.2; ICDO-3
induction. Those causes may be associated with a different
code 30.0 with morphologic code 95223; and ICDO-3 code
risk of cancer (16, 18), calling into question the compara-
75.3 with morphologic code 93611; n ¼ 58).
Ovulation induction treatments were coded in the ques-
We aimed to study the association between ovulation-
tionnaires as clomiphene citrate (n ¼ 312), human meno-
inducing treatments and the incidence of cancer in a unique
pausal gonadotropins (n ¼ 61), other (n ¼ 54), unknown
population-based cohort of parous women.
(n ¼ 87), and combinations of some or all of the above.
Treatments were further categorized into any treatment ver-sus none and treatments that included clomiphene versus no
Maternal demographic and social variables included age
at earliest birth in the subcohort as a continuous variable;
The Jerusalem Perinatal Study is a population-based
mother’s geographic origin, defined according to her father’s
cohort study of all births to residents of West Jerusalem,
country of birth (categorized as Israeli, North African, West
Israel, and its surroundings in 1964–1976 (19). The database
Asian, European (including North America, Europe, Australia/
includes demographic, obstetric, and neonatal information
New Zealand, and South Africa), and non-Jewish); mater-
on 92,408 births to 41,206 mothers collected from birth
nal education (12 and >12 years); and social class (socioeco-
notifications and maternity ward log books. Between
nomic status), defined according to occupation of the child’s
November 1974 and December 1976, 15,426 mothers were
interviewed in the hospital on the first or second day after
Body mass index was calculated as the ratio between self-
giving birth. This postpartum subcohort included 98% of
reported prepregnancy weight (kg) and squared height (m2)
births occurring in the 3 major obstetric units in West
and was subdivided into the categories <25 and 25.
Jerusalem and covered 91% of all births in the area at the
First birth in the Jerusalem Perinatal Study cohort was
time. The questionnaire collected information on obstetric
considered a proxy for the first birth in a woman’s life, and
and gynecologic history, time to conception, and whether
family size in the cohort was considered a surrogate for
the couple had sought advice for infertility, including me-
parity, divided into 1, 2–3, and 4 offspring. Ovulatory
chanical treatments such as tubal insufflation. Women were
disorders were defined as either irregular menstrual periods
asked whether they had received medical treatment for in-
or regular menstrual periods with cycle lengths of less than
duction of ovulation prior to the index pregnancy.
21 days or more than 35 days. Other reproductive variables
Linkage of the cohort with the Israel Population Registry
included use of oral contraceptives (ever vs. never), mechan-
using mothers’ identity numbers permitted tracing and as-
ical assessments and treatments for infertility (combination of
certainment of vital status for 97.5% (n ¼ 15,047) of moth-
the codes for tubal insufflation, dilation and curettage, and
ers. Information on cancer incidence as of December 31,
other vs. none), and time to conception.
2004, was obtained by linking the ascertained cohort withthe Israel Cancer Registry, which receives notification of all
malignancies diagnosed throughout the country. Since 1981,reporting of cases to the Registry has been mandatory by
For every woman, follow-up time was counted from the
law, but reporting was considered relatively complete even
earliest birth in the subcohort (i.e., births that took place
before this. We excluded from this study 17 mothers who
after November 1974) until the diagnosis of cancer, death,
were diagnosed with cancer prior to their first birth in the
or December 31, 2004. Bivariate and multivariate Cox pro-
portional hazards models were used to calculate hazard ra-
The study was approved by the institutional review
tios for the development of cancer among women who
boards of Hadassah-Hebrew University (Jerusalem, Israel)
received any ovulation induction or clomiphene in particular
and Columbia University (New York, New York).
in comparison with women who received no ovulationinduction.
Data were virtually complete for all variables except body
mass index, where missing values were present for 8% of
Cancer diagnoses were coded according to the Interna-
the study population. Missing values were replaced by the
tional Classification of Diseases for Oncology, Third Edi-
reference category (body mass index < 25) after examina-
tion (ICDO-3). We analyzed the incidence of all cancer as
tion of the data and sensitivity analysis.
Age 50 years was used as the cutoff point for estimation
of pre- or postmenopausal status. A time-dependent survivalanalysis was performed for the association between fertility
No association was found between fertility treatment
treatment and cancer incidence, testing for interaction be-
and cancers of the colon (age-adjusted HR ¼ 1.05, 95%
tween menopausal status and fertility treatment.
CI: 0.39, 2.86), thyroid (HR ¼ 1.60, 95% CI: 0.58, 4.40),
In order to estimate possible misclassification of expo-
or cervix (HR ¼ 1.68, 95% CI: 0.40, 7.04) (Table 3).
sure, we conducted sensitivity analyses in which we re-
No brain cancer events were diagnosed among treated
stricted the exposure either to women who were treated
women, but the small numbers precluded any further
with clomiphene and human menopausal gonadotropins or
women who were treated with clomiphene and/or an un-
tumors, 1 had been treated with clomiphene and was diag-
In the tables we present hazard ratios, 95% confidence
nosed with a germ-cell tumor (morphologic code 90603).
No association was found between clomiphene exposureand cancer of the ovaries (age-adjusted HR ¼ 0.98, 95%CI: 0.14, 7.11) (Table 3).
Breast cancer. Women who underwent ovulation induc-
tion treatment had a significantly increased risk of develop-
Table 2 shows the characteristics of the study population
ing breast cancer (age-adjusted HR ¼ 1.65, 95% CI: 1.15,
by type of treatment. Compared with untreated women,
2.36). Controlling for geographic origin, socioeconomic sta-
those who received treatment to induce ovulation were more
tus, body mass index, and parity weakened this association
affluent, more educated, and more likely to have fathers
(HR ¼ 1.42, 95% CI: 0.99, 2.05) (Table 4). The results were
born in Israel or Europe. Treated women were older at the
minimally altered with further adjustment for history of oral
time of their first birth, had lower parity than untreated
contraceptive use (HR ¼ 1.47, 95% CI: 1.02, 2.11) or age at
women, and were more likely to have waited more than
first birth (HR ¼ 1.42, 95% CI: 0.99, 2.05), and there was
no interaction of the association with either age at first birth(30 years vs. >30 years) or menopausal status. No asso-ciation was found between ovulation induction and breast
cancer among primiparous women (Table 3).
During 424,193 person-years of follow-up (median, 29),
Women who were exposed to ovulation induction in gen-
1,215 women developed cancer (median age at diagnosis,
eral or clomiphene in particular had twice the risk of breast
49.4 years). Women who received ovulation induction treat-
cancer as untreated women, but only among women who
ment had an age-adjusted 50% increased risk of developing
waited more than 12 months to conceive (Table 5). Analysis
cancer at any site (Table 3). Adjustment for socioeconomic
by time from birth showed significantly increased risks of
status, mother’s geographic origin, and body mass index did
breast cancer in the first 20 years (Table 6).
not materially change the association. Additional adjust-
Women who were treated only with clomiphene (n ¼
ment for parity yielded a hazard ratio of 1.36 (95%
312) had an age-adjusted hazard ratio of 1.74 (95% CI:
confidence interval (CI): 1.06, 1.74) (Table 4). Further ad-
1.09, 2.79; P ¼ 0.02), irrespective of time to conception,
justments either for ovulation disorders or for mechanical
and a multivariate hazard ratio of 1.51 (95% CI: 0.94,
treatments or assessments for infertility did not alter the
2.42; P ¼ 0.092). Women who were treated only with clo-
results (not shown). There was no interaction of menopausal
miphene and waited more than 12 months to conceive had
status with the association between fertility treatment and
an age-adjusted hazard ratio of 2.82 (95% CI: 1.40, 5.65;
Analyses restricted to primiparous women or to women
Uterine cancer. Women who received ovulation induc-
who received clomiphene yielded virtually unchanged re-
tion treatment had a 3-fold increased risk of uterine cancer
(age-adjusted HR ¼ 3.32, 95% CI: 1.31, 8.42) compared
When results were stratified by time to conception (Table 5),
with unexposed women. Controlling for age, socioeconomic
treated women who waited more than 12 months to conceive
status, geographic origin, body mass index, family size, and
had double the risk of cancer compared with untreated women
ovulatory disorders did not materially change this associa-
(age-adjusted hazard ratio (HR) ¼ 2.03, 95% CI: 1.36, 3.01),
tion (HR ¼ 3.39, 95% CI: 1.28, 8.97) (Table 4).
whereas exposed women who had a shorter time to conception
Clomiphene treatment was associated with an age-
did not experience an increased risk of cancer (HR ¼ 1.23,
adjusted hazard ratio of 4.33 (95% CI: 1.55, 12.13) for the
95% CI: 0.80, 1.89; P for interaction ¼ 0.153).
development of uterine cancer. In the multivariate model,
When results were stratified by time since birth, signifi-
the adjusted hazard ratio for cancer of the uterus among
cantly increased risks were observed during the first 20
women who were treated with clomiphene was 4.56 (95%
CI: 1.56, 13.34; P ¼ 0.006). Mothers treated with clomi-
The sensitivity analysis of exposure yielded similar re-
phene who waited more than 12 months to conceive had
sults (Table 7). Similarly, exclusion of women with un-
an 8-fold increased risk of uterine cancer (age-adjusted
known treatment had a minimal effect on the association
HR ¼ 8.26, 95% CI: 1.24, 55.0; P ¼ 0.029) (Table 5).
(for all cancer, adjusted HR ¼ 1.38, 95% CI: 1.05, 1.82;
Of 5,814 primiparous mothers, uterine cancer was diag-
nosed among 9 untreated women and 4 treated women,
Distribution of Participants According to Type of Ovulation Induction Treatment and
Selected Characteristics, Jerusalem Perinatal Study, 1974–2004
(tubal insufﬂation, dilationand curettage, other)
a Numbers in parentheses, standard deviation.
b Number of children at the end of data collection.
d Deﬁned as irregular menstrual periods or menstrual cycles with lengths of <21 days or >35 days.
yielding a 6-fold increased risk (after adjustment for age,
primiparous women was associated with a similarly adjusted
body mass index, and ovulatory disorders, HR ¼ 6.69, 95%
hazard ratio of 8.33 (95% CI: 2.25, 30.85; P ¼ 0.002) (not
CI: 2.05, 21.8; P ¼ 0.002). Clomiphene treatment in
Age-Adjusted Hazard Ratio for Incident Cancer According to Type of Ovulation Induction Treatment,
Overall and by Cancer Site, Jerusalem Perinatal Study, 1974–2004
Abbreviations: CI, conﬁdence interval; HR, hazard ratio.
a Age-adjusted HR for comparison of treated mothers with untreated mothers.
Malignant melanoma. Treatment for ovulation induction
of the uterus following treatment with clomiphene citrate.
in general was not associated with the development of
Furthermore, this study’s results suggest increased risks of
malignant melanoma (multivariate HR ¼ 1.68, 95% CI: 0.72,
breast cancer, malignant melanoma, and non-Hodgkin lym-
3.92). However, women treated with clomiphene experienced
phoma following ovulation induction treatment that were
a significantly increased risk of malignant melanoma, with
more pronounced among women who waited more than 1
a multivariate-adjusted hazard ratio of 2.56 (95% CI: 1.10,
year to conceive, perhaps representing a dose-response re-
lation. The results of the current study do not support an
Non-Hodgkin lymphoma. For non-Hodgkin lymphoma,
increased risk of ovarian cancer following ovulation induc-
treatment for ovulation induction was associated with a
multivariate-adjusted hazard ratio of 2.63 (95% CI: 1.02,
Possible limitations of this study include the absence of
6.82) (Table 4). The increased risks were evident especially
detailed information regarding type of infertility, type of
among primiparous women (Table 3) and in the first 5 years
treatment, dosage, and number of cycles and lack of in-
following birth (Table 7). Clomiphene treatment was not
formation regarding treatment in other pregnancies. While
associated with a significantly increased risk of non-Hodgkin
introduction of family size into our multivariate models re-
lymphoma (multivariate HR ¼ 2.46, 95% CI: 0.74, 8.13)
duced the magnitude of all associations studied, suggesting
that family size is a confounder, parity might also be a sur-rogate for treatment in previous pregnancies; therefore, con-trolling for family size might partially mask the effects of
ovulation induction. While treatments were self-reported inthis study, the proportion of women reporting exposure to
In this study, women who were treated for ovulation in-
clomiphene treatment (64% of all treated women) was sim-
duction experienced a significantly higher overall risk of
ilar to that reported in other studies with data from the 1970s
cancer. This increased risk was especially evident for cancer
(7, 15). Moreover, according to the sensitivity analysis,
Hazard Ratio for Incident Cancer (Multivariate Analysis) According to Type of Ovulation
Induction Treatment, Overall and by Cancer Site, Jerusalem Perinatal Study, 1974–2004
Abbreviations: CI, conﬁdence interval; HR, hazard ratio.
a Results were adjusted for age, socioeconomic status, country of birth, and body mass index.
b Results were adjusted for family size in addition to the variables included in model 1.
c Results were additionally adjusted for ovulatory disorders.
misclassification of treatment, if any existed, did not mate-
clomiphene and gonadotropins among women with an intact
hypothalamic-hypophysic-ovarian axis are approximately
The current study included only parous women; thus,
40% (4) and 80%–90% (20), respectively, this study is rel-
its results cannot be generalized to women who were treated
evant for a major subset of women who were treated and
but failed to conceive. However, since the success rates for
conceived. While investigators in most other cohort studies
Age-Adjusted Hazard Ratio for Incident Cancer According to Type of Ovulation Induction Treatment and Time to Conception,
Abbreviations: CI, conﬁdence interval; HR, hazard ratio.
Age-Adjusted Hazard Ratio for Incident Cancer According to Any Type of Ovulation
Induction Treatment Among All Women and Primiparous Mothers, by Cancer Site and TimeSince Birth, Jerusalem Perinatal Study, 1974–2004
Abbreviations: CI, conﬁdence interval; HR, hazard ratio.
either did not control for parity or controlled for parity at the
tios of 5.7–11.5 for uterine cancer among women treated
time treatment was initiated, considering women who sub-
with clomiphene; however, these standardized incidence ra-
sequently gave birth as nulliparous, this study had no re-
tios were not significantly different from those obtained for
untreated infertile women. Althuis et al. (24) suggested
We did not observe an association between ovulation in-
a dose-response relation for clomiphene with standardized
duction and ovarian cancer, a finding supported by the re-
incidence ratios of 1.63 (95% CI: 0.8, 3.4) and 2.16 (95%
sults of other studies (9, 10, 18, 21); it is possible that the
CI: 0.9, 5.2) among women treated for fewer than 6 cycles
association found in previous studies (7, 8) between ovula-
and 6 or more cycles, respectively. Two small case-control
tion induction in general and clomiphene in particular and
studies showed no significant associations, representing per-
ovarian cancer was restricted to nulliparous women, since
haps lack of statistical power (25, 26). Among women who
nulliparity is a major risk factor for ovarian cancer (22).
underwent in vitro fertilization (16), women treated with
This suggestion could also be implied from a meta-analysis
fertility drugs had a 5-fold increased risk of uterine cancer
(23) in which a 1.5-fold increased risk of ovarian cancer was
within the first year only, suggesting surveillance bias. How-
evident when treated women were compared with the
ever, in this latter study, very few were treated for more than
general population but no excess in risk was shown when
6 cycles, and the follow-up period was relatively short. Our
treated women were compared with untreated infertile
findings cannot be explained by other risk factors for uterine
cancer, such as nulliparity, since all women in our cohort
The increased risk of uterine cancer observed in this study
gave birth; nor can they be explained by ovulation disorders
was prominent among women treated with clomiphene.
or obesity, for which we controlled in our multivariate anal-
Modan et al. (18) demonstrated standardized incidence ra-
ysis. Like tamoxifen, clomiphene is a selective estrogen
Results From Sensitivity Analysis of Multivariate-Adjusted Hazard Ratios for Incident Cancer Among
Women Exposed to Ovulation Induction Treatment, Overall and by Cancer Site, Jerusalem Perinatal Study, 1974–2004a
Clomiphene and/or Human Menopausal Gonadotropins
Abbreviations: CI, conﬁdence interval; HR, hazard ratio.
a In all models, results were adjusted for age, geographic origin, socioeconomic status, body mass index, and
b Results were also adjusted for ovulation disorders.
receptor modulator. While tamoxifen has been proven to
We could not find any previous publications on fertility
reduce recurrence rates of breast cancer and improve sur-
treatments and their association with non-Hodgkin lym-
vival, it is well established that it increases the risk of en-
phoma. Reproductive factors such as age at menarche and
dometrial cancer 2- to 7-fold (27, 28). The structural
parity have been suggested to be associated with non-Hodgkin
similarities as well as the similarities in ovulation induction
lymphoma in a pattern quite similar to that for breast
properties (29) raise the possibility of clomiphene as a car-
cancer (30). However, unlike the case with breast cancer,
oral contraceptives have been suggested to be protective
Our results might suggest that clomiphene as the only
against non-Hodgkin lymphoma (31). While 1 study sug-
treatment is associated with an increased risk of breast can-
gested that hormone replacement therapy increases the
cer. Similarly to the results of Lerner-Geva et al. (11), we
risk of non-Hodgkin lymphoma (32), other studies failed
observed an increased risk of breast cancer of comparable
to demonstrate such an association (33, 34). If indeed
magnitude for women treated only with clomiphene which
estrogens are related to the incidence of non-Hodgkin
disappeared when all women exposed to clomiphene were
lymphoma, an association between ovulation induction
included in the analysis. Brinton et al. (12) suggested an
and non-Hodgkin lymphoma is plausible.
increased breast cancer risk for clomiphene only after 20 years
We found an increased risk of malignant melanoma only
of follow up, irrespective of dosage or number of treat-
among women treated with clomiphene. Althuis et al. (35)
ment cycles. Potashnik et al. (13) suggested an increased
suggested a doubled risk among clomiphene-treated women
risk of breast cancer only among women who received short-
followed for more than 15 years; however, the increased risk
term treatment or a low dose of clomiphene. Contradic-
associated with clomiphene treatment was demonstrated
tory results include those of Terry et al. (29), who showed
only among nulliparous women (35). Hannibal et al. (36)
a significantly reduced risk of breast cancer among women
suggested an increased risk for gonadotropins (but not clo-
with ovulatory infertility who underwent ovulation induc-
miphene) among parous women only. Other studies of the
tion, with a dose-response pattern, and those of Rossing
possible hormonal factors contributing to malignant mela-
et al. (14), which suggested a nonsignificantly reduced risk
noma include conflicting reports on the association between
following receipt of clomiphene. Jensen et al. (15) demon-
exogenous estrogen use and melanoma risk (37, 38) and
strated no association between treatment with clomiphene,
a suggestion that older age at first birth might be associated
human chorionic gonadoptropins, or other gonadotropins
and breast cancer. Similar to their results for uterine cancer,
The strengths of this study included the design of the
Venn et al. (16) found an increased risk of breast cancer
within-cohort comparison and the completeness of follow-
among in-vitro-fertilization-treated women only within 12
up data on cancer incidence. Our study contained a small
number of women who were treated in the 1970s and thus
exposed to different treatment protocols in the era preceding
2. Juul S, Karmaus W, Olsen J. Regional differences in waiting
widespread use of in vitro fertilization. However, this is also
time to pregnancy: pregnancy-based surveys from Denmark,
one of the study’s main strengths, allowing follow-up to the
France, Germany, Italy and Sweden. The European Infertility
age of increasing cancer incidence in women. Our results
and Subfecundity Study Group. Hum Reprod. 1999;14(5):
suggest that the increased risk was most pronounced in the
3. Henne MB, Bundorf MK. Insurance mandates and trends in
first 20 years following exposure. These results parallel
infertility treatments. Fertil Steril. 2008;89(1):66–73.
observations in other studies of associations between other
4. Practice Committee of the American Society for Reproductive
exogenous hormones and cancer, such as oral contraceptives
Medicine. Use of clomiphene citrate in women. Fertil Steril.
and breast cancer, where the increased risks were evident
during exposure and in the first years following exposure
5. Vandewiele RL, Turksoy RN. Treatment of amenorrhea and of
(39–41). Similarly, studies of tamoxifen demonstrated in-
anovulation with human menopausal and chorionic gonado-
creased risks of uterine cancer in the first decade following
tropins. J Clin Endocrinol Metab. 1965;25:369–384.
6. Lunenfeld B. Historical perspectives in gonadotrophin ther-
In conclusion, the present study demonstrated an associ-
apy. Hum Reprod Update. 2004;10(6):453–467.
ation between treatment for ovulation induction and overall
7. Rossing MA, Daling JR, Weiss NS, et al. Ovarian tumors in a
risk of cancer, particularly cancer of the uterus. There are
cohort of infertile women. N Engl J Med. 1994;331(12):771–776.
still gaps in our knowledge regarding dosages and durations
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ORIGINAL CONTRIBUTIONS Reproducibility of Multichannel Intraluminal ElectricalImpedance Monitoring of Gastroesophageal RefluxAlbert J. Bredenoord, M.D., Bas L.A.M. Weusten, M.D., Ph.D., Robin Timmer, M.D., Ph.D.,and Andre J.P.M. Smout, M.D., Ph.D. Department of Gastroenterology, Sint Antonius Hospital, Nieuwegein; and Gastrointestinal Research Unit,University Medical Center, Utrecht, The Nethe