International Journal of Epidemiology

International Epidemiological Association 1991

Vol. 20, No. 4
Printed in Great Britain
Invasive Cervical Cancer and
Intrauterine Device Use
DEBORAH L LASSISE***. DAVID A SAVITZ'f. RICHARD F HAMMAN*. ANNA E BARON*,
LOUISE A BRINTONt AND ROBERT S LEVINES
Lassise D L (Department of Preventive Medicine and Biometrics, University of Colorado Health Sciences Center,
Denver, CO, USA), Savitz D A, Hamman R F, Baron A E, Brinton L A and Levine R S, Invasive cervical cancer and in-
trauterine device use. International Journal of Epidemiology 1991: 20: 865-870.
Although the hypothesis that intrauterine device (IUD) use might promote cervical cancer has been considered since
the introduction of lUDs in the early 1900s, previous studies are inconclusive. Data collected in interviews with 481
invasive cervical cancer cases and 801 general population controls from Birmingham, Chicago, Denver, Miami and
Philadelphia were used to address this issue. These data were analysed to determine the relationship between IUD use
and the risk of cervical cancer, with consideration of the type of IUD (copper and inert) and duration of use. A non-
significant reduced risk of cervical cancer was associated with copper IUD use, indicated by an adjusted odds ratio (OR)
of 0.6 (95% Cl: 0.3-1.2), but virtually no effect was found for inert IUD use (OR = 1.1, 95% Cl: 0.9-1.7). Decreased risk
with increased duration of copper IUD use supports a possible protective effect of copper IUD use on the development
of invasive cervical cancer.
Invasive cervical cancer risk has been linked with sev-
eral contraceptive methods. Barrier methods have
been associated with a decreased risk of cervical
cancer,
1
while oral contraceptives are associated with
an increased risk.
2
An increased risk for invasive cervi-
cal cancer has also been suggested from intrauterine
devices (IUDs).
3
There are at least two possible mech-
anisms through which IUD use might increase the risk
of cervical cancer: 1) the IUD as a foreign body might
cause chronic irritation which could stimulate tumour
production; 2) the copper in some devices might react
with amino acids and proteins, forming chelates that
may increase normal cellular metabolism.
3
Clinical and epidemiological studies conducted in
several countries have examined a possible association
between cervical cancer and IUD use .
4
~
16
These studies
have usually been based on examination of patient cyt-
ological smears for dysplasia subsequent to inserting
an IUD. Pincus and Garcia
4
reported a positive associ-
* Department of Preventive Medicine and Biometrics, University of
Colorado Health Sciences Center, Denver, CO, USA.
"* Present Address: 4 Hampshire Court, Mason City, IA 50401, USA.
t Present Address: Department of Epidemiology, School of Public
Health, University of North Carolina, Chapel Hill, NC, USA.
t Environmental Epidemiology Branch, National Cancer Institute,
Bethesda, MD, USA.
Community and Preventive Medicine Unit, Department of Internal
Medicine, Our Lady of Mercy Medical Center, Bronx, NY, USA.
ation between the rate of dysplasia and IUD use, and
Engineer et al
nn
similarly found an elevated risk of
dysplasia for copper IUD users. A significant increase
in the prevalence of carcinoma in-situ (CIS) and invas-
ive cervical cancer in IUD users compared to non-users
was found by Jones et aP' in a retrospective study of 300
women. The remaining studies found no association
between dysplasia or invasive cervical cancer and IUD
use.
5
"
1014
"
16
Most studies have focused on dysplasia rather than
invasive cervical cancer. Dysplasia clearly has signifi-
cance as a precursor to invasive disease, but not all
determinants of dysplasia are necessarily determinants
of invasive cervical cancer. In addition to short fol-
low-up, lack of controls and small study groups, the
past studies did not consider potential sexual, social
and demographic confounders. The question of
whether IUDs affect the risk for cervical cancer thus
remains unanswered. To explore the hypothesis that
IUD use increases the risk of jnvasive cervical cancer,
we used data collected from a case-control study con-
ducted in five metropolitan areas in the US which pro-
vided detailed information on contraceptive history
and numerous risk factors for cervical cancer.
METHODS
Incident cases of cervical carcinoma in situ and invas-
ive carcinoma were identified through hospitals in each
865

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866 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
geographical area, chosen by the National Cancer
Institute on the basis of diagnosing or treating a suf-
ficiently large number of cases. The 24 participating
hospitals collected cases from April 1982 to January
1984. As cervical cancer patients were identified, the
responsible physician was asked for permission to con-
tact the patient; the approval of the patient was then
secured for an interview.
The study definition of invasive cervical cancer
included tumours of the endocervix, exocervix, cervix
uteri and other parts of the cervix. Invasive cervical
disease included both micro and frankly invasive
stages. Cases with the cervix as the primary cancer site
must have met the diagnostic definition of the tumour
and have been between 20 and 74 years of age at time
of diagnosis. No review of pathology slides by a central
reading centre was conducted.
The control group was selected by random digit
dialling
17
'
18
in the same three-digit telephone exchange
as the cases and matched by age (+/ 5 years) and race
to the case. Control selection consisted of a four-step
process: 1) generation of random numbers within the
telephone exchanges of the eligible cases; 2) telephone
enumeration of each selected occupied household for
female race and age (20-69 years); 3) a random selec-
tion of two matched controls from the enumerated
eligibles for each eligible case in the study; 4) adminis-
tration of a brief telephone interview to select matched
controls to ascertain histories of prior hospitalization
for hysterectomy.
This telephone interview indicated that 25% of iden-
tified controls had hysterectomies and were not eligible
for the study. These women were replaced with
another control. A total of 23 404 telephone numbers
were sampled; 13 561 (57.9%) were eligible residential
numbers. A profile of female household members was
obtained for 84.1% of telephones assumed to be work-
ing and residential.
2
Data on all cases and controls were collected
through interviews in the home. The majority of cases
were interviewed within six months of diagnosis and
35% were interviewed within three months of diag-
nosis. Information was obtained on demographic
characteristics, pregnancies, menstrual factors, sexual
behaviour, contraceptive history, medical history,
smoking, diet, family history of cancer and marital
history. This included information on all pregnancies
and number of sexual partners from first sexual experi-
ence up to the time of the interview. Contraceptive
information was obtained up to the last menstrual
period. A lifetime calendar was used to record such
events as menarche, first intercourse, pregnancies and
menopause. Illustrations of all commonly used IUDs
TABLE 1 Relation of invasive cervical cancer to demographic and
sexual factors in 479 cases and 789 controls in five US cities, 1982-1984
Study Site
Birmingham
Chicago
Denver
Miami
Philadelphia
Age
<3 5
35-44
45-54
55+
Race
White/non-hispanic
White/hispanic
Black
Other
Education
< 9 years
9-11
12
12+
Income
< $5,000
5,000-10,000
10,001-20,000
20,000+
Missing
Pack-years of smoking
0
< 3
4-.9
10-19
20-39
>3 9
Missing
Interval since last Pap
0-2
3-9
> 10/never
Missing
Age of first coitus
<1 6
16-17
18-19
20-21
>2 1
No. sexual partners
1
2
3-4
5-9
> 9
Missing
Parity
0
1
2
3
4-6
> 6
Cases
No.
96
132
91
79
81
87
135
116
141
269
44
155
11
105
129
131
114
126
95
95
140
23
191
26
44
75
86
57
225
108
136
10
105
146
125
54
49
111
75
107
109
73
4
40
53
65
82
167
72
%
20
28
19
16
17
18
28
24
30
56
9
33
2
22
27
27
24
26
20
20
29
5
40
5
9
16
18
12
-
47
23
28
2
22
31
26
11
10
23
16
22
23
15
1
8
11
14
17
35
15
Controls
No.
151
220
154
117
147
192
233
176
188
492
57
238
2
90
121
262
316
90
107
214
350
28
407
57
72
102
101
48
2
585
124
69
11
114
176
203
142
154
296
132
144
129
84
4
81
114
168
153
200
73
%
19
28
19
15
19
24
29
23
24
62
7
30
1
12
15
33
40
11
14
27
44
4
52
7
9
13
13
6
<1
74
16
9
1
14
22
26
18
20
38
17
18
16
11
<1
10
15
21
19
26
9
Odds
Ratio

*
3.2
3.0
1.4
1.0

3.5
2.2
1.1
1.0
-
1.0
0.9
1.3
1.6
1.8
2.5
-
1.0
2.3
5.0
-
*
2.9
2.6
1.9
1.2
1.0
**
1.0
1.5
2.0
2.3
2.3
-

1.0
0.9
0.8
1.1
1.7
2.0
* OR and test for trend not applicable due to matching.
"* Chi-square test for trend < 0.01.
INVASIVE CERVICAL CANCER AND INTRA UTERINE DEVICE USE 867
along with photographs of oral contraceptive packages
were shown to aid respondents' recall. No independent
validation of this information was obtained.
The study population, consisting of 481 invasive cer-
vical cancer cases and 801 controls, represent response
proportions of 73% for cases and 72% for controls.
Eleven women reported never having sexual inter-
course and three women provided incomplete calendar
data. Because these results pertain to sexually active
women and this group was too small to examine, these
11 women were removed from the study. The final
study group consisted of 479 invasive cervical cancer
cases and 789 controls.
The odds ratio (OR) and test-based 95% confidence
intervals (95% CI)
19
were used to characterize the
association between IUD use and risk of invasive cervi-
cal cancer. The exposure definition considered years of
IUD use and type of device used (copper or non-
copper). Potential confounding variables were identi-
fied from the current literature and selected on the
basis of an association with cervical cancer in this popu-
lation. Variables considered as potential confounders
include age, race, number of sexual partners, age at
first coitus, parity, cigarette smoking (pack-years),
number of marriages, self-reported history of genital
or venereal infections, income, interval since last
Papanicolaou (Pap) smear, and oral and barrier con-
traceptive use.
Variables considered as potential effect modifiers
TABLE 2 Report of genital infections and method of contraception
by case-control status in five US cities, 1982-1984
Cases Controls
No. % No. % OR(95%CI)
Yeast
No 362 75
Yes 117 25
Pelvic inflammatory
disease
No 467 97 773 98
Yes 12 3 16 2 1.2(0.6-2.6)
Genital infection/
sore
No 424 89 734 93
Yes 55 11 55 7 1.7(1.2-2.6)
Oral contraceptive use
0 269 56
sj 5 years 115 24
> 5 years 95 20
Barrier contraceptive
use*
0 293 61 419 53 1.0
$ 5 years 126 26 232 29 0.8(0.6-1.0)
> 5 years 60 13 138 18 0.6(0.4-0.9)
* Condom or diaphragm use.
4 69 60
3 2 0 4 0 0.5 (0.4-0.6)
383 4 9 1.0
2 66 3 4 0.6 (0.5-0.8)
140 17 1.0(0.7-1.3)
included number of sexual partners, age at first coitus,
parity, cigarette pack-years, and history of genital and
venereal infections. These variables were chosen
because they may increase the irritability or suscepti-
bility of the cervix in conjunction with IUD use.
Inclusion of variables in a logistic regression model
was determined by univariate calculations of F-statis-
tics on each variable.
20
Data analyses were done using
the SPSS
X
statistical package.
21
IUD use was held con-
stant in the model and variables with a p-value for the
F-statistic of less than 0.05 were added in a stepwise
manner using BMDP-LR, an approach to logistic
regression based on maximum likelihood estimation.
22
RESULTS
The relationship between demographic character-
istics, sexual behaviour and risk of invasive cervical
cancer are shown in Table 1. Matching precludes
examination of age and race as risk factors. With the
exception of parity in the range of 0-2, all variables
listed in Table 1 were associated with disease as
TABLE 3 Number and percentage of IUD users by case-control status
and selected demographic variables in five US cities, 1982-84
Cases*
No.
Controls*
No. %
Study site
Birmingham
Chicago
Denver
Miami
Philadelphia
Age (years)
<35
35-44
45-54
55 +
Race
White
White/hispanic
Black
Other
Education
< 9 years
9-11
12
12+
Income
< $5,000
5,001-10,000
10,001-20,000
20,001 +
Missing
7
10
19
18
6
15
36
7
2
36
7
17
0
7
21
13
19
15
11
12
22
_
7
8
21
23
7
17
27
6
1
13
16
11
0
7
16
10
17
12
12
13
16
24
36
41
26
29
67
65
21
3
93
14
49
0
7
16
48
85
11
15
48
79
3
16
16
27
22
20
35
28
12
2
19
25
21
0
8
13
18
27
12
14
22
23
11
TOTAL 60 156
* Denominator for percentage is the total number of cases or controls
within the category (Table 1).
868 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
TABLE 4 Crude and adjusted odds ratios (OK) for IUD use and
invasive cervical cancer in five US cities, 1982-1984
IUD use
Yes
No
Years of use
0
> 5
TOTAL
Cases
' 60
419
419
42
18
479
Controls
156
633
633
105
51
789
Crude OR
(95% CI)
0.6
(0.4-0.8)
1.0
0.6
(0.4-0.9)
0.5
(0.3-0.9)
Adjusted OR
(95% CI)*
0.8
(0.5-1.2)
1.0
0.8
(0.5-1.2)
0.9
(0.5-1.6)
* Adjusted for history of yeast infection, total household income,
interval since last Pap, oral contraceptive use, number of sexual
partners, race, history of genital infections or sores, and age at first
coitus.
reflected by an increased OR corresponding with an
increase in exposure.
Table 2 reports the effect of venereal and genital
infections, and method of contraception on the risk of
disease. History of non-specific genital infections or
sores showed a positive association with cervical
cancer risk while yeast infections displayed an inverse
association. Barrier contraceptive use was related to
some reduction in risk, while the effect of oral contra-
ceptive use is unclear, with a reduced risk only among
short-term users. Brinton etal's
23
analysis of these data
revealed that while the crude OR suggested a pro-
tective effect, after adjustment, the OR for oral contra-
ceptive use rose to a significant excess of 1.2.
Of the respondents, 17%, a total of 216 women,
reported a history of IUD use (13% of the cases, 20%
of the controls). Table 3 indicates that the proportion
of IUD users in the control population varied from
16% to 27% across the five sites with case-control
differences absent only in Miami. History of IUD use
increased with increasing education and income
among the controls. IUD use was markedly more
prevalent among women less than 45 years of age.
Table 4 shows the crude and adjusted ORs for the
association of IUD use and invasive cervical cancer.
The crude OR was 0.6 (95% CI: 0.4-0.8). Adjusting
for potential confounders individually yielded ORs
between 0.5 and 0.8. Simultaneously adjusting for all
potential confounders resulted in an OR of 0.8. When
duration of IUD use was considered, no dose-response
gradient was observed in the adjusted ORs (Table 4).
Potential effect modification was examined for number
of sexual partners, age at first coitus, cigarette pack-
years, genital infections, and history of genital and
venereal infections, but no strong modifiers were
identified.
The two possible mechanisms for an effect of IUD
use on cervical cancer were explored by distinguishing
between copper and non-copper IUD use. Seventeen
per cent of the exposed cases, and 16% of the exposed
controls used more than one device. The most com-
monly used device was the Lippes Loop (TM), with
copper device use reported second most often, consis-
tent with the identification of the Copper '7' (Cu7) and
Lippes Loop as the two most extensively used IUDs in
the US.
24
Due to the small frequencies for specific brands of
IUDs, the devices were divided into two groups for
analysis, based on the presence or absence of copper.
Thirty-eight women who had reported a history of
IUD use but could not identify the type of device were
excluded from this analysis. The copper subgroup con-
tained the Copper'T' (CuT) and Cu7. The non-copper
subgroup included all other identified types. Of the 178
women who identifed their device use, 14 reported
both copper and non-copper devices. Because these
women reported exposure to both types of device, the
analysis of IUD subgroups included adjustment for the
other type of IUD.
The crude OR reflects a reduced risk which is greater
among copper than non-copper IUD users (Table 5).
As in the analysis of all IUDs, the crude ORs for both
copper and non-copper IUDs moved towards 1.0 after
adjustment. In these subgroup analyses, the precision
of the effect estimates are reduced, but a protective
TABLE 5 Association of IUD use and invasive cervical cancer by type
of IUD in five US cities, 1982-1984
Device
Copper use
None
Any
s=5
> 5
Inert use
None
Any
^ 5
> 5
Cases
458
13
11
2
428
43
32
11
Controls
711
48
32
16
671
88
65
23
Crude OR
(95% CI)
1.0
0.4
(0.2-0.8)
0.5
(0.3-1.0)
0.2
(0.1-0.9)
1.0
0.8
(0.5-1.1)
0.8
(0.5-1.2)
0.8
(0.4-1.6)
Adjusted OR
(95% CI)*
1.0
0.6
(0.3-1.2)
0.6
(0.3-1.4)
0.4
(0.1-2.0)
1.0
1.1
(0.9-1.7)
1.1
(0.7-1.9)
1.1
(0.5-2.4)
* Adjusted for history of yeast infection, total household income,
interval since last Pap, oral contraceptive use, number of sexual
partners, race, history of genital infections or sores, and age at first
coitus (also inert and copper use, respectively).
INVASIVE CERVICAL CANCER AND INTRA UTERINE DEVICE USE 869
effect for copper-containing IUDs is suggested
(adjusted OR = 0.6, 95% CI: 0.3-1.2) whereas none is
observed for use of inert IUDs (adjusted OR = 1.1,
95% CI: 0.9-1.7).
When copper and non-copper device use were ana-
lysed by years of use it was found that the reduced risk
associated with copper device use increased with
increasing duration of use (Table 5). The OR associ-
ated with inert use remained relatively constant and
close to the null regardless of the duration of use.
DISCUSSION
The analysis of the association between IUD use and
cervical cancer suggested a reduced risk associated
with IUD use in this study. After adjustment for a
number of potential confounding factors, the OR for
IUD use was 0.8 (95% CI: 0.5-1.2). The overall effect
appears to reflect distinct influences from copper (OR
= 0.6) and non-copper (OR = 1.1) device use.
Although the OR for non-copper IUD use suggests vir-
tually no association with invasive cervical cancer, the
OR for copper IUD use suggests a protective effect.
The dose-response gradient by duration of copper
IUD use, although limited to only two categories of
duration, also supports a protective effect of copper
IUD use on the risk of invasive cervical cancer. How-
ever, the imprecision in the effect estimates for copper
IUDs, especially in the analysis by duration of use,
should be noted in evaluating these findings.
Although increased cervical cancer risks were postu-
lated to be related to IUD use, the possibility that cop-
per interferes with the carcinogenic process must also
be considered. The insertion of a copper device into
the uterine cavity is associated with metabolic changes
in the endometrium, resulting in a decrease in enzyme
production and a possible disruption of carbohydrate
metabolism, glyconeogenesis and metabolism of
mucopolysaccharides.
25
In the presence of copper,
there is also decreased synthesis of mucoproteins and
DNA.
26
Disruption of cell growth in the presence of
copper in vitro using adult and fetal cells in culture has
been demonstrated.
27
With an increased concentration
of copper in the culture, no cells were observed in
metaphase. As the copper concentration decreased,
cells resumed normal growth.
Recent research has uncovered the antitumour
activity of copper compounds, though the mechanism
for suppression is not fully understood.
28
The known
reaction of metals with nucleic acids may block the
interactions of carcinogens with nucleic acids, or cop-
per may inhibit the activities of enzymes related to
DNA synthesis.
29
The disruptions in cell metabolism
originally considered toxic may be the same effect now
thought to be antitumourigenic.
The results of this study are largely dependent upon
the quality of exposure data. Previous studies obtain-
ing contraceptive histories suggest that ever/never use
of contraceptives is remembered with 7479% accu-
racy,
x
and accuracy of IUD use may be increased
given the limited number of devices on the market and
the fact that the majority of women used only one type
of device. In the absence of public perception of an
association between IUD use and cervical cancer, mis-
classification would be expected to be similar for cases
and controls, tending to bias the risk estimate toward
the null.
31
The degree of detail requested and the intimate
nature of the questions in this study may have affected
recall. This becomes relevant when examining poten-
tial confounders, for example, number of sexual part-
ners and sexually transmitted disease history. If these
are reported inaccurately, then the effectiveness of
adjustment is reduced, but would not be a likely
explanation for the observed effects.
32
The current study is the largest case-control study
that has explored the relationship between cervical
cancer and IUD use. Two prospective studies have had
large study populations, but an 80% loss to follow-up
over a five-year period and inability to control for con-
founding variables diminished their ability to make
strong conclusions.
1510
Sandmire et al's
9
case-control
study also lacked information on potential confound-
ing factors. The case-control design allowed for an
examination of invasive cervical carcinoma as an end-
point. Prospective studies have often followed subjects
to carcinoma in situ, whereas information on invasive
cancer was not available because of its rarity. The vari-
ability of the progression of in situ to invasive cancer,
inconsistent growth patterns and reversions leave
unanswered questions about the progression to invas-
ive malignancies.
The results of the present study support other
reports that have found no association between IUDs
and increased risk of invasive cervical cancer. In fact,
the results suggest a possible protective effect of use of
copper IUDs on risk of invasive cancer, though the
precision of risk estimates is less than would be
desired. This contrasts with results from the studies of
Engineer et a/
12
'
13
in which an increased risk for dys-
plasia in copper IUD users was found. Rigorous epi-
demiological studies examining the relationship
between IUD use and endometrial cancer are not
available to contribute to the discussion.
Although the risk of cervical cancer may not be a
pervasive concern for women and physicians weighing
the risks and benefits of IUD use, this study lends valu-
able information to an existing issue, as evidenced by
870 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
several studies examining the question. Short-term
risks of IUD use have been in the forefront recently,
but when evaluating contraceptive choices, it is also
important to consider long-term outcomes.
ACKNOWLEDGEMENTS
Special thanks to Phyllis Carosone-Link and Russell
Rickert of the University of Colorado for their assist-
ance in the analysis and to Jeanne Rosenthal of Westat
for her assistance with the use and interpretation of the
data.
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