British Journal of Cancer (2009) 100, 1191 1197

& 2009 Cancer Research UK All rights reserved 0007 0920/09 $32.00
www.bjcancer.com

Early age at first sexual intercourse and early pregnancy are risk
factors for cervical cancer in developing countries



 KS Louie*,1, S de Sanjose1,2, M Diaz1, X Castellsague1,2, R Herrero3, CJ Meijer4, K Shah5, S Franceschi6,

 N Munoz7 and FX Bosch1 for the International Agency for Research on Cancer Multicenter Cervical Cancer

 Study Group

 1
 Unit of Infections and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology, Hospitalet del Llobregat (Barcelona), Avda. Gran
 Via s/n Km 2,7, Barcelona 080907, Spain; 2CIBER en Epidemiologa y Salud Publica (CIBERESP), Barcelona, Spain; 3Proyecto Epidemiologico

 Guanacaste, Fundacion INCIENSA, Torre La Sabana, 300 Oeste del ICE, Piso 7, Sabana Norte, San Jose, Costa Rica; 4Department of Pathology, VY

 University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands; 5Department of Molecular Microbiology and Immunology, Johns

 Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; 6International Agency for Research on Cancer, 150 cours Albert Thomas, 69372 Lyon

 cedex 08, France; 7Instituto Nacional de Cancerologia, Bogota, Colombia






 Early age at first sexual intercourse (AFSI) has long been associated with an increased risk of invasive cervical carcinoma (ICC). Age at

 first pregnancy (AFP) and ICC have been investigated less, although AFSI and AFP are strongly interrelated in most developing

 countries. A pooled analysis of case control studies on ICC from eight developing countries with 1864 cases and 1719 controls

 investigated the roles of AFSI, AFP, and ICC risk. Age at first sexual intercourse, AFP and age at first marriage (AFM) were highly

 interrelated and had similar ICC risk estimates. Compared with women with AFSI X21 years, the odds ratio (OR) of ICC was 1.80

 (95% CI: 1.50 2.39) among women with AFSI 17 20 years and 2.31 (95% CI: 1.85 2.87) for AFSI p16 years (P-trend o0.001).

 No statistical interaction was detected between AFSI and any established risk factors for ICC. The ICC risk was 2.4-fold among those

 who reported AFSI and AFP at p16 years compared with those with AFSI and AFP at X21 years. These data confirm AFSI and AFB

 as risk factors for ICC in eight developing countries, but any independent effects of these two events could not be distinguished.

 British Journal of Cancer (2009) 100, 1191 1197. doi:10.1038/sj.bjc.6604974 www.bjcancer.com

 Published online 10 March 2009


 & 2009 Cancer Research UK


Keywords: cervical cancer; first sexual intercourse; pregnancy; sexual behaviour; child sexual abuse

Early age at first sexual intercourse (AFSI) has been associated proxy measure for AFSI, and those who engage in early sexual
with an increased risk of high-risk human papillomavirus (HPV) intercourse may also consequently become pregnant at an early age.
infection, a sexually transmitted infection (STIS), that in Besides early AFSI, early childbearing has also been linked as a risk
susceptible women is responsible for virtually all cases of invasive factor for cervical carcinogenesis and attributed to the cervical
cervical cancer (ICC) (Bosch et al, 2002). As sexual behaviour trauma experienced during early age at first pregnancy (AFP), or
determines exposure to HPV, AFSI is of particular interest as it has subsequently, by high-parity births (IARC, 2007). The interpretation
been associated with riskier sexual behaviour, such as having of the mechanisms by which these sexual and reproductive events
unprotected sex, having multiple sexual partners, as well as a occurring early in life might affect ICC risk three or more decades
womans partner having multiple partners. It has also been later is not straightforward. The objective of this study is to further
speculated that the increased risk of HPV is because of a biological characterise and provide robust estimates of the risk of cervical
predisposition of the immature cervix during adolescence that may cancer and its association with AFSI, interrelated characteristics
be more susceptible to persistent HPV infections and therefore such as AFP and AFM in a series of studies that fully considered the
have a greater risk of cancer development (Kjaer et al, 1998). association of HPV with cervical cancer.
A number of studies have identified an increased risk of high-grade
lesions and/or cervical cancer with early AFSI, whereas others have
not (IARC, 2007). However, many of these studies were conducted MATERIALS AND METHODS
before HPV assessment was feasible, and therefore, the association
Epidemiology

remains inconclusive. Age at first marriage (AFM) is often used as a The programme of HPV and cervical cancer studies has been
coordinated by the International Agency for Research on Cancer
(IARC) in Lyon, France and the Institut Catala dOncologia (ICO)
*Correspondence: KS Louie, Unit of Infections and Cancer, Cancer in Barcelona, Spain. They included a series of case-control studies
Epidemiology Research Program, Institut Catala dOncologia, Avda. Gran on ICC from eight developing countries with a broad range of rates
Via s/n Km 2,7, Hospitalet de Llobregat, Barcelona 80907, Spain; of incidence of cervical cancer that were pooled for analysis.
E-mail: klouie@iconcologia.net Regions covered include Morocco (Chaouki et al, 1998) and
Received 22 January 2009; revised 13 February 2009; accepted 16 Algeria (Hammouda et al, 2005) in Africa; the Philippines
February 2009; published online 10 March 2009 (Ngelangel et al, 1998), Thailand (Chichareon et al, 1998) and
 Cervical cancer in developing countries
KS Louie et al
1192
Madras in Asia; and Brazil (Eluf-Neto et al, 1994), Colombia was not adjusted for HPV DNA status, (2) a second model included
(Munoz et al, 1993), Paraguay (Rolon et al, 2000) and Peru all patients and controls, and included a variable to adjust for HPV
(Eluf-Neto et al, 1994) in South America. Although Spain (Munoz DNA status, and (3) a third model was restricted to HPV DNA-
et al, 1993) was part of the series of case control studies, the positive cases and controls. To control for potential confounding,
sexual and reproductive behaviour of this population was final models were adjusted for age (o40, X40), country, lifetime
heterogeneous to the other countries (late AFSI and low parity) number of sexual partners (1,41), parity (0, 1 4,X5), and
and the study site was therefore excluded from this analysis. educational level (never, primary, secondary or higher). Each
The methods of each study have been described elsewhere. variable included in the adjustment models was assessed for
Briefly, women with histologically confirmed incident invasive interaction with AFSI. Test for trend was carried out when
squamous cell carcinoma (SCC), adenocarcinoma or adeno- appropriate, using the log-likelihood-ratio test. Only subjects who
squamous-cell carcinoma were recruited from reference hospitals reported ever having been married and/or ever having had
before treatment. Written informed consent was obtained from children were included in the analyses of AFM and AFP.
those who agreed to participate. Hospital-based controls were We evaluated other potential confounding factors such as
frequency-matched to case patients by 5-year age groups. smoking (never, ever), oral contraceptive use (never, 1 4 years,
A standardised questionnaire was administered to the partici- X5 years), history of pap smears excluding those in the 12 months
pants by a trained interviewer, which included questions about before enrolment (never, ever), having had first sexual intercourse
sociodemographic factors, sexual and reproductive behaviour, before menarche and the timing of first sexual intercourse relative
smoking habits, pap screening history, hygienic practices, and to age at menarche (data not shown), but they were not adjusted
history of sexually transmitted diseases. for in the final analysis as they did not contribute any change to
Two samples of cervical exfoliated cells were collected with the OR estimates for AFSI in the adjusted models.
wooden spatulae and endocervical brushes. After preparation of
one Papanicolaou smear, the remaining cells were eluded in saline,
centrifuged and frozen at
701C until shipment to the central
laboratory for HPV DNA testing. A tumor-biopsy sample was RESULTS
obtained from cases and frozen. Cytology and histology diagnoses Table 1 describes some characteristics of the 1864 ICC cases and
were reviewed and confirmed by a panel of expert pathologists that 1719 corresponding controls that entered the final analysis.
agreed on a diagnosis by consensus or majority. Ninety-five percent of case patients and 17% of controls tested
Detailed descriptions of the polymerase-chain-reaction (PCR) positive for HPV DNA. The majority of cases (92%) had SCC. Case
assays used in these studies have been described elsewhere. HPV patients were older than controls with a median age of 49 vs 48,
DNA detection was detected by PCR amplification of a small respectively. Median AFSI was earlier in case patients (17 years)
fragment of the L1 gene using MY09 and MY11 consensus primers compared with controls (19 years), and this was found to be
for the study in Colombia (Hildesheim et al, 1994) and the consistent in each country.
GP5 /6 general primer system for the other studies Table 2 shows the risk of ICC by AFSI according to the three
(Walboomers et al, 1992; Jacobs et al, 1995; Roda Husman et al, different adjustment models. An increased risk of ICC was
1995). b-Globin primers were used to amplify the b-globin gene to consistently observed with decreasing AFSI (P-trend o0.001).
assess the quality of the DNA in the specimen. HPV DNA in PCR Compared with AFSI X21 years, the OR of ICC was 1.80 (95% CI:
products was analysed using a cocktail of HPV-specific probes and 1.50 2.16) for AFSI 17 20 years, and 2.31 (95% CI: 1.85 2.87) for
genotyped by hybridisation with type-specific probes for 33 HPV AFSI p16 years, after adjusting for age, centre, lifetime number
types. Samples that tested positive for HPV DNA but did not of partners, parity, and education level in the HPV-unadjusted
hybridise with any of the type-specific probes were labelled as model. According to the different model adjustments, women
HPV X. reporting AFSI p16 years of age had a 2.3 2.5-fold risk of ICC and
1.8 2.1-fold risk for AFSI 17 20 years of age (Table 2). Given
Statistical analysis the consistent association of AFSI and the risk of ICC across
the different models, HPV-unadjusted models were used for the
Unconditional logistic regression was used to estimate odds ratios remainder of the results.
(ORs) and 95% confidence intervals (95% CI). To assess the We calculated the risk of ICC for each country study, and, in
association of AFSI with the risk of ICC, three different statistical general, each study showed an increasing risk of ICC with
models to adjust for HPV DNA detection were computed and decreasing AFSI (data not shown). There was no evidence of
compared: (1) one model included all patients and controls, and it heterogeneity with respect to study country (P 0.58).

Table 1 Characteristics of cases of invasive cervix carcinoma and controls

HPV tested HPV positive Agea Age at sexual debuta

Cases Controls Cases % Controls % Cases Controls Cases Controls

Country 1864 1719 1769 94.9 285 16.6 49 48 17 19

Algeria 142 145 132 93.0 18 12.4 53.5 52 16 18
Epidemiology

Morocco 188 176 182 96.8 38 21.6 49 40 16 18

Madras (India) 187 184 180 96.3 51 27.7 48 46.5 17 18
Philippines 364 380 349 95.9 35 9.2 47.5 47 19 21
Thailand 378 259 363 96.0 41 15.8 49.5 50 18 20
Brazil 187 190 181 96.8 32 16.8 51 52 18 19
Colombia 110 124 87 79.1 21 16.9 46 45.5 17 18
Paraguay 112 86 109 97.3 18 20.9 48.5 45.5 16 19
Peru 196 175 186 94.9 31 17.7 48 48 16 18

Abbreviation: HPV human papillomavirus. aMedian.

British Journal of Cancer (2009) 100(7), 1191 1197 & 2009 Cancer Research UK
 Cervical cancer in developing countries
KS Louie et al
1193
Table 2 Effect of different strategies of multivariate model adjustments on the association between age at first sexual intercourse and risk of ICC (from
IARC case control studies)

Age and centre adjusted HPV unadjusteda HPV adjusteda HPV-positive onlya
Sexual debut Cases n (%) Controls n (%) Odds ratio (95% CI) Odds ratio (95% CI) Odds ratio (95% CI) Odds ratio (95% CI)

X21 years 341 (16.9) 656 (35.4) 1.00 1.00 1.00 1.00
17 20 years 813 (40.2) 667 (36.0) 2.44 (1.07 2.87) 1.80 (1.50 2.16) 1.78 (1.32 2.39) 2.10 (1.49 2.97)
p16 years 710 (35.1) 396 (21.4) 4.09 (3.38 4.94) 2.31 (1.85 2.87) 2.09 (1.48 2.96) 2.48 (1.65 3.73)
P-trend o0.001 o0.001 o0.001

Abbreviations: HPV human papillomavirus; ICC invasive cervical carcinoma; IARC International Agency for Research on Cancer; CI confidence interval. aAdjusted for age,
study country, lifetime number of partners (1, X2), parity (0, 1 4, X5), and education (never, primary, secondary).

We stratified the analysis according to the established risk cence has also been proposed as an additional susceptibility factor
factors for ICC and the positive association of ICC with decreasing (Moscicki et al, 1989; Elson et al, 2000; Singer and Monaghan,
AFSI remained at each level of exposure for each of these 2000). During adolescence and pregnancy, the cervix is exposed to
characteristics (Table 3). Similar associations were observed for augmented levels of hormonal changes (Singer and Monaghan,
AFP. No interaction was observed between any of the examined 2000), in which oestrogen stimulation facilitates acidification of
risk factors and AFSI. Although not statistically significant, the risk the vaginal cavity, a determinant of squamous metaplasia when the
linked to AFSI seemed to be stronger among parous women endocervical epithelial everts (Elson et al, 2000). When this
compared with nulliparous women. oestrogen-stimulated metaplastic transformation occurs in the
Age at first pregnancy and AFM were both directly correlated presence of HPV, the probability of cell transformation increases,
with AFSI in these populations (Po0.001). Approximately, 92% of resulting in neoplastic changes (Elson et al, 2000; Shai et al, 2007,
women reported AFSI to be the same as AFM. One-quarter of 2008; Hwang et al, 2009). This phenomenon is dependent
women reported AFP to be the same as AFSI. Cumulatively, 62.4% primarily on parity, and is more likely to occur during the first
of women reported giving birth within the first year of AFSI. pregnancy rather than subsequent pregnancies (Singer and
Among women with AFSI p16 years, 52.4% were pregnant within Monaghan, 2000). Although it has been postulated that these
the first year of sexual intercourse. Figure 1 shows the high metaplastic changes are also influenced by the trauma and repair
correlation between AFSI and AFP, and the similar decreasing risk experienced during delivery, no increased risk for cervical
of ICC with increasing age of AFSI/AFP. Given the high correlation carcinoma was observed in this same dataset when traumatic
between the two variables, we did not adjust for AFSI in the AFP partition was evaluated (Munoz et al, 2002).
final model and vice versa. Increased risks of cervical carcinoma have been identified in
We further evaluated the combined effect of AFP and AFSI on women with long-term use of hormonal steroids (Moreno et al,
the risk of cervical cancer (Table 4). An increased risk emerged in 2002) and those who are highly parous (Munoz et al, 2002).
subsequent strata of decreasing AFP with decreasing AFSI. Given In addition, HPV-16 transgenic mouse models have shown that
this combined effect, we assessed the latency period (AFP
AFSI) those treated with longer durations of oestrogen were more likely
between these two events to clarify whether it affected the cervical to develop larger tumours and have a significantly higher number
cancer risk. Although there was no statistical difference across of tumours than those treated with a shorter duration (Elson et al,
strata, the data suggested that within each AFSI strata, women with 2000; Brake and Lambert, 2005), supporting the human observa-
a latency period for a subsequent pregnancy of o2 years may be at tions of a susceptible cervix to carcinogenic progression by conti-
a slight increased risk compared with women with a larger time nuous exogenous oestrogen exposure or increased endogenous
gap (data not shown). oestrogen levels. If indeed oestrogen is needed for cervical
carcinogenesis, close follow-up of young women and of their
early pregnancies may be relevant to further understanding the
DISCUSSION role of steroids in the acquisition and persistence of HPV
infections.
The IARC/ICO series of case control studies remain the largest The influence of oestrogens on immune response may offer
set of aetiological investigations on ICC that fully addresses the another explanatory effect (Mitrani-Rosenbaum et al, 1989; Arbeit
role of HPV DNA and of the independent established cofactors. et al, 1996), particularly during the follicular phase of the ovarian
This is probably also the largest dataset reporting on ICC in the cycle and pregnancy, when levels of oestrogens are increased up to
developing world in which early AFSI, AFP and high parity are 3 8-fold the normal levels (Duncan et al, 1994; Marzi et al, 1996;
prevalent phenomenons. The results show that early AFSI and Jabbour et al, 2008). The higher density of oestrogen receptors
early AFP are risk factors for cervical cancer, irrespective of other and their expression in the transformation zone may synergise
known risk factors for the disease. The data presented show a with the effects of HPV oncoproteins, decreasing levels of cytotoxic
possible additional increase in risk when the early event of first cytokines that may down-regulate the cervical cell-mediated
sexual intercourse is shortly followed by a pregnancy. immune response, which favour persistent HPV infections instead
The mechanism by which the early experience of first sexual of clearance (Marzi et al, 1996; Giannini et al, 1998; 2002;
Epidemiology

intercourse and first pregnancy could influence the risk of cervical Jacobs et al, 2003). Additional research is needed to further
carcinogenesis may be explained by the steroid hormonal understand the interaction between oestrogens and the regulation
influence on HPV infection and on the hosts immune response of immunomodulators, which may contribute to anti-tumour
to HPV during pre-adolescence and adolescence. The transforma- immunity.
tion zone of the cervical epithelium has been recognised as the site The varying results between studies regarding the roles of AFSI
in which HPV infection tends to cause cancer, and the suscepti- and AFP may reflect the true differences between the study
bility of this area is believed to be related to its denudation of the populations. In our study, the similar increased risks shown for
stratified epithelium, thus facilitating exposure of the basal layer to AFSI and AFP may, in general, reflect the fact that in most
HPV with minimal trauma. Biological immaturity during adoles- developing countries women initiate these events at an early age,

& 2009 Cancer Research UK British Journal of Cancer (2009) 100(7), 1191 1197
 Cervical cancer in developing countries
KS Louie et al
1194
Table 3 Age at first sexual intercourse and risk of cervical cancer according to various characteristics

Number of cases/controls Odds ratio (95% CI)a Odds ratio (95% CI)b P-trend

Parity
Nulliparous
X21 years 14/40 1.00 1.00
17 20 years 7/14 1.88 (0.53 6.66) 1.61 (0.40 6.57)
p16 years 7/6 3.60 (0.83 15.52) 1.50 (0.17 13.55) 0.56
Ever parous
X21 years 327/614 1.00 1.00
17 20 years 804/645 2.47 (2.07 2.94) 1.97 (1.63 2.36)
p16 years 703/387 4.10 (3.36 4.99) 2.59 (2.08 3.21) o0.001

P-heterogeneity between AFSI and ever parous 0.64

Parity (1 4 births)
X21 years 171/399 1.00 1.00
17 20 years 273/287 2.58 (1.98 3.35) 1.99 (1.51 2.62)
p16 years 169/115 4.72 (3.41 6.54) 2.71 (1.89 3.87) o0.001
Parity (X5 births)
X21 years 156/215 1.00 1.00
17 20 years 531/358 2.01 (1.57 2.59) 1.71 (1.32 2.23)
p16 years 534/272 2.88 (2.19 3.78) 2.08 (1.55 2.78) o0.001
P-heterogeneity between AFSI and parous groups (nulliparous, 1 4 births, and X5 births) 0.90

Oral contraceptive use

Never
X21 years 218/400 1.00 1.00
17 20 years 453/364 2.33 (1.87 2.90) 1.77 (1.40 2.25)
p16 years 376/184 4.28 (3.29 5.55) 2.45 (1.82 3.29) o0.001
1 4 years
X21 years 64/162 1.00 1.00
17 20 years 117/114 2.64 (1.76 3.94) 1.67 (1.07 2.61)
p16 years 111/89 3.94 (2.53 6.13) 1.95 (1.15 3.30) 0.01
X5 years
X21 years 36/52 1.00 1.00
17 20 years 124/72 3.26 (1.85 5.72) 2.46 (1.36 4.46)
p16 years 96/49 4.48 (2.39 8.40) 2.80 (1.38 5.65) 0.006

Smoking
Never
X21 years 272/569 1.00 1.00
17 20 years 587/552 2.34 (1.93 2.83) 1.68 (1.36 2.06)
p16 years 550/348 3.76 (3.03 4.67) 2.06 (1.61 2.64) o0.001
Ever
X21 years 67/85 1.00 1.00
17 20 years 221/113 2.73 (1.81 4.13) 2.32 (1.50 3.60)
p16 years 152/43 5.63 (3.42 9.27) 3.62 (2.10 6.26) o0.001

Lifetime number of sexual partners

Monogamous
X21 years 270/569 1.00 1.00
17 20 years 529/499 2.33 (1.92 2.83) 1.80 (1.46 2.22)
p16 years 349/214 3.89 (3.05 4.96) 2.38 (1.83 3.11) o0.001
Partners 41
X21 years 69/74 1.00 1.00
17 20 years 280/151 2.03 (1.37 3.01) 1.74 (1.15 2.63)
p16 years 352/156 2.75 (1.84 4.11) 2.14 (1.39 3.28) 0.001
P-heterogeneity 0.36

Education
Never go to school
X21 years 54/57 1.00 1.00
17 20 years 255/155 1.68 (1.09 2.60) 1.46 (0.93 2.30)
p16 years 402/173 2.41 (1.55 3.75) 2.09 (1.31 3.35) 0.001
Primary school
Epidemiology

X21 years 164/238 1.00 1.00

17 20 years 404/311 1.99 (1.54 2.56) 1.62 (1.24 2.12)
p16 years 236/167 2.51 (1.87 3.39) 1.71 (1.24 2.36) 0.001
Secondary school
X21 years 118/359 1.00 1.00
17 20 years 150/198 2.68 (1.95 3.68) 2.29 (1.65 3.20)
p16 years 72/55 4.79 (3.07 7.47) 3.36 (2.07 5.47) o0.001
P-heterogeneity 0.08

British Journal of Cancer (2009) 100(7), 1191 1197 & 2009 Cancer Research UK
 Cervical cancer in developing countries
KS Louie et al
1195
Table 3 (Continued )

Number of cases/controls Odds ratio (95% CI)a Odds ratio (95% CI)b P-trend

Ever have a pap smear 12 months before study enrolment

Never
X21 years 183/320 1.00 1.00
17 20 years 434/371 2.20 (1.74 2.79) 2.29 (1.65 3.20)
p16 years 416/205 3.65 (2.79 4.78) 3.36 (2.07 5.47) o0.001
Ever
X21 years 158/336 1.00 1.00
17 20 years 379/296 2.65 (2.02 3.46) 1.92 (1.44 2.57)
p16 years 294/191 4.49 (3.32 6.06) 2.30 (1.63 3.24) o0.001
a b
Abbreviations: CI confidence interval; AFSI age at first sexual intercourse. Adjusted for age and study centre. Adjusted for age, study country, lifetime number of partners
(1, X2), parity (0, 1 4, X5), and education (never, primary, secondary).

10 tend to indicate a significant increase in risk of neoplastic disease

9 when early AFSI occurs (surrogate of early HPV exposure and a
8
period of increased cervical susceptibility) and is followed closely
Risk of cervical cancer

by an early pregnancy (surrogate of early exposure to high

7
oestrogen levels).
6 Irrespective of their lifetime number of sexual partners, women
5 have a similar increased risk of ICC with early AFSI as shown by
4 the 2.4-fold risk among monogamous women with AFSI p16 years
3 as compared with the 2.2-fold risk among women with 41 lifetime
number of sexual partners. It has long been suggested that a
2
cervical cancer risk will also depend on the sexual history of the
1 womans male partner in addition to her own behaviour (Skegg
0 et al, 1982). This is particularly relevant in societies where most
-13 14 15 16 17 18 19 20 .21 women are virgins at marriage and monogamous thereafter, where
Age the incidence of cervical cancer for a population may vary
depending on the behaviour of the male partner. Of our study
Age at first sexual intercourse (AFSI) 95% Confidence interval (CI) women, 70% were monogamous. In several studies among
Age at first pregnancy (AFP) 95% Confidence interval (CI) monogamous women, the risk of cervical cancer was reported to
Figure 1 Age at first sexual intercourse and age at first pregnancy be two to eight times for women with husbands who had multiple
are highly correlated with the risk of invasive cervical cancer (P- partners (Pridan and Lilienfeld, 1971; Buckley et al, 1981; Brinton
trendo0.001). Models were adjusted for age, centre, lifetime number of et al, 1989). The sexual history of the male partner was not
sexual partners (1, 41), parity (0, 1 4, X5), and education (never, evaluated in this analysis; however, promiscuity, history of other
primary, secondary). STIS, and lack of male circumcision are factors that have been
associated with the male role in cervical carcinogenesis (Castellsa-
gue et al, 2003).
Table 4 Interaction between age at first pregnancy and age at first sexual In interpreting our results, we must emphasise the difficulty in
intercourse in the risk of cervical cancer fully disentangling a womans sexual and reproductive profile in
relation to her cancer risk (Schroder et al, 2003). We cannot
Age at first pregnancy exclude misclassification bias if AFSI and the number of sexual
partners were inaccurately reported, leading to some residual
Age at sexual debut X21 17 20 p16 confounding, However, the presence of established risk factors for
ICC, use of oral contraceptives, smoking, and pap smear history
X21 years 1.00
17 20 years 1.58 (1.22 2.03) 1.93 (1.58 2.36) did not seem to significantly affect the strength of the association
p16 years 2.17 (1.35 3.47) 2.28 (1.74 2.99) 2.36 (1.82 3.07) between AFSI, AFP, and risk of ICC.
We examined the different stratified methodologies (unadjusted,
HPV-adjusted, and HPV-positive restricted) used to evaluate the
association between AFSI and risk of ICC traditionally employed in
and experience high parity, making their effects difficult to the literature. This was done to exclude any spurious association
distinguish from one another. In contrast, results of studies in related to statistical adjustment and to clarify inconsistent findings
more developed countries where there is a longer latency period of the association found in earlier studies. Although in strict terms
between sexual initiation and AFP, as in Spain, the US (Brinton restriction of analyses to HPV-positive cases and controls seemed
et al, 1987) or Italy (Parazzini et al, 1989) tend to show an preferable, the consistency of the results across the three different
Epidemiology

increased risk with early AFSI but not with AFP as first methods provides convincing evidence of the risk associated with
pregnancies tend to occur much later. It is interesting that, in AFSI. Furthermore, these results indicate that for the evaluation of
countries like the UK, where the rates of teenage pregnancies are other risk factors, adjusting for HPV status is not necessary as
high, women with AFSI of p17 years had a 2 3-fold increased risk the adjustments do not contribute to remove any confounding
for cervical cancer compared with those with AFSI X20 years effect.
(Green et al, 2003). Consistently, women with an early AFP of Sexual practices in the world indicate that very early intercourse
15 19 years had a two-fold increased risk for cervical cancer might be occurring in adolescents with 44, 45 and 52% of girls
compared with those with AFP X25 years (Green et al, 2003). between the ages of 13 19 years reporting being sexually
These observations merit further exploration but, in aggregate, experienced in Argentina, Botswana and Nigeria, respectively

& 2009 Cancer Research UK British Journal of Cancer (2009) 100(7), 1191 1197
 Cervical cancer in developing countries
KS Louie et al
1196
(Brown et al, 2001). In several case studies among young females, incidence of cervical cancer; additional efforts are required in
first sexual intercourse has been reported as forced in 5 15% of family planning and sexual education adapted to the extremely
cases, and in some extreme cases worldwide, the estimates range variable sociocultural contexts in the world.
from 21% among out-of-school adolescents in Botswana, 20%
among secondary schools in Peru, and 41% among young urban
females attending night schools in Peru. Among 15 30% of ACKNOWLEDGEMENTS
sexually active girls aged 15 19 years report forced first sexual
intercourse (Brown et al, 2001). It is likely that the partners of We thank Margaret Stanley for her comments on this manuscript.
these adolescents who report sexual coercion are adult males who This work was partially supported by Spanish public grants from
are sexually experienced (Wellings et al, 2006) and at high risk of the Instituto de Salud Carlos III (Grants FIS PI030240, FIS
HPV exposure. Globally, these exposures might affect a high PI061246, RCESP C03/09, RTICESP C03/10, RTIC RD06/0020/0095
proportion of very young girls in areas of human strife, thus and CIBERESP), from the Agencia de Gestio dAjuts Universitaris i
adding child sexual abuse to the burden of a lifetime increased risk de Recerca (AGAUR 2005SGR 00695), and from the Marato de TV3
of genital cancer. Foundation (051530).
Our study shows that women who initiate first sexual
intercourse and experience their first pregnancy at a young age
are at an increased risk of cervical cancer. The importance of Conflict of interest
HPV-vaccination programmes targeting young adolescents before
first sexual intercourse can have a great effect in decreasing the No conflict of interest is declared in relation to this manuscript.

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