ISSN 1015-4361 (PHILIPPINES) JAN/FEB 2012 Vol. 38 No. 1 JOURNAL OF PAEDIATRICS, OBSTETRICS & GYNAECOLOGY Your partner in paediatric and O&G practice JUL/AUG 2013 Vol. 39 No. 4 Your partner in paediatric and O&G practice www.jpog.com CME ARTICLE Hormonal Contraception and Cancers JOURNAL WATCH PAEDIATRICS Management of Hearing Loss in Children Constipation in Infants and Children GYNAECOLOGY Ovarian Cancer: Current Management and Future Directions OBSTETRICS Management of Early Pregnancy Complications
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ISSN 1015-4361(PHILIPPINES)
PhilippinesJAN/FEB 2012 Vol. 38 No. 1
JOURNAL OF PAEDIATRICS, OBSTETRICS & GYNAECOLOGY
Your partner in paediatric and O&G practice
JUL/AUG 2013 Vol. 39 No. 4 Your partner in paediatric and O&G practice
www.jpog.com
CME ARTICLE
Hormonal Contraception and Cancers
JOURNAL WATCH
PAEDIATRICS
Management of Hearing Loss in Children
Constipation in Infants and Children
GYNAECOLOGY
Ovarian Cancer: Current Management and Future Directions
OBSTETRICS
Management of Early Pregnancy
Complications
JPOG_JulAug13_CVR_FINAL.indd 1 8/5/13 2:00 PM
JUL/AUG 2013
Vol. 39 No. 4
JOURNAL OF PAEDIATRICS, OBSTETRICS & GYNAECOLOGY
Journal Watch
133 • Calcium intake and mortality in Swedish women
• Outcome of extreme preterm birth in England, 1995–2006
134 • New anti-interleukin therapies for systemic JIA
• CPAP vs surfactant and higher vs lower oxygen saturation for extremely preterm infants: Outcomes at 18–22 months
135 • Paromomycin for cutaneous leishmaniasis
• HMPV infection in young children in the US
136 • Risk factors for stillbirth • Fetal macrosomia in developing countries
Board Director, Paediatrics
Professor Pik-To CheungAssociate ProfessorDepartment of Paediatrics and Adolescent MedicineThe University of Hong Kong
Board Director, Obstetrics and Gynaecology
Professor Pak-Chung HoHead, Department of Obstetrics and GynaecologyThe University of Hong Kong
Editorial Board Professor Biran AffandiUniversity of Indonesia
Dr Karen Kar-Loen ChanThe University of Hong Kong
Professor Oh Moh ChayKK Women’s and Children’s Hospital, Singapore
Associate Professor Anette JacobsenKK Women’s and Children’s Hospital, Singapore
Professor Rahman JamalUniversiti Kebangsaan Malaysia
Dato’ Dr Ravindran JegasothyHospital Kuala Lumpur, Malaysia
Associate Professor Kenneth KwekKK Women’s and Children’s Hospital, Singapore
Dr Siu-Keung LamPrestige Medical Centre, Hong Kong
Professor Terence LaoChinese University of Hong Kong
Dr Kwok-Yin LeungThe University of Hong Kong
Dr Tak-Yeung LeungChinese University of Hong Kong
Professor Tzou-Yien LinChang Gung University, Taiwan
Professor Somsak LolekhaRamathibodi Hospital, Thailand
Professor Lucy Chai-See LumUniversity of Malaya, Malaysia
Professor SC NgNational University of Singapore
Professor Hextan Yuen-Sheung NganThe University of Hong Kong
Professor Carmencita D PadillaUniversity of the Philippines Manila
Professor Seng-Hock QuakNational University of Singapore
Dr Tatang Kustiman SamsiUniversity of Tarumanagara, Indonesia
Professor Alex SiaKK Women’s and Children’s Hospital, Singapore
Dr Raman SubramaniamFetal Medicine and Gynaecology Centre, Malaysia
Professor Walfrido W Sumpaico MCU-FDT Medical Foundation, Philippines
Professor Cheng Lim TanKK Women’s and Children’s Hospital, Singapore
Professor Kok Hian TanKK Women’s and Children’s Hospital, Singapore
Professor Surasak TaneepanichskulChulalongkorn University, Thailand
Professor Eng-Hseon TayThomson Women Cancer Centre, Singapore
Professor PC WongNational University of Singapore
Adjunct Professor George SH YeoKK Women’s and Children’s Hospital, Singapore
Professor Hui-Kim YapNational University of Singapore
Professor Tsu-Fuh YehChina Medical University, Taiwan
133
136
JPOG JUL/AUG 2013 • i
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JUL/AUG 2013
Vol. 39 No. 4
JOURNAL OF PAEDIATRICS, OBSTETRICS & GYNAECOLOGY
Enquiries and Correspondence
137
JPOG JUL/AUG 2013 • ii
Publisher Ben YeoPublication Manager Marisa LamManaging EditorGreg TownAssociate Editor Grace LingDesignersAgnes Chieng, Sam ShumProduction Edwin Yu, Ho Wai Hung, Steven Cheung Circulation Christine ChokAccounting Manager Minty KwanAdvertising CoordinatorRachael Tan
Published by: MIMS Asia Pacific27th Floor, OTB Building160 Gloucester Road, Wan Chai, Hong KongTel: (852) 2559 5888 Email: [email protected]
Universal neonatal hearing screening aims to detect the 1 in 1,000 babies born in the UK with a permanent hearing loss detectable at birth. However, children may present later to the paediatrician with hearing difficulties. This article aims to discuss the clinical assessment of hearing and provides an overview of the management options available in the treatment of hearing loss.
Marianne D Elloy, Andrew H Marshall
Review ArticleObstetrics
146 Management of Early Pregnancy Complications
Complications of early pregnancy are common, including pregnancy loss, threatened miscarriage, ectopic pregnancy, molar pregnancy and hyperemesis. This review discusses the different presentations, diagnoses and management of the common problems complicating early pregnancy.
Harriet Pugsley, Judith Moore
146
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JOURNAL OF PAEDIATRICS, OBSTETRICS & GYNAECOLOGY
JPOG JUL/AUG 2013 • iii
Review ArticlesComprehensive reviews providing the latest clinical information on all aspects of the management of medical conditions affecting children and women.
Case StudiesInteresting cases seen in general practice and their management.
Pictorial MedicineVignettes of illustrated cases with clinical photographs.
For more information, please refer to the Instructions for Authors on our website www.jpog.com, or contact:The EditorMIMS Pte Ltd, 6 Shenton Way, #15-08 Tower 2, Singapore 068809Tel: (65) 6290 7400 Fax: (65) 6290 7401 E-mail: [email protected]
155 Ovarian Cancer: Current Management and Future Directions
Ovarian cancer has the highest mortality of all the gynaecological malignancies. Treatment of advanced epithelial ovarian cancer usually involves debulking surgery and chemotherapy. Treatment may prolong life and palliate symptoms but it is rarely curative. New treatments are constantly being developed and offer the hope of improved outcomes.
Siân E Taylor, John M Kirwan
Review ArticlePaediatrics
164 Constipation in Infants and Children
Constipation is a common problem in children and is usually functional, related to stool-withholding. Successful management requires parent education, behavioural strategies, laxative agents (often long term) and ongoing review.
Taya Dowling, Scott Nightingale
Continuing Medical Education
169 Hormonal Contraception and Cancers
This article reviews the evidence regarding the relationship between hormonal contraceptive use and the development of cancer, with the discussion focusing mainly on carcinoma of the breast and female genital tract.
Wong Yuen Kwan Alice
155
169
Philippines
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Continuing Medical Education
JPOG JUL/AUG 2013 • 169
Hormonal Contraception and Cancers Wong Yuen Kwan Alice, MBBS, FRCOG, FHKAM(O&G), FHKCOG, Cert HKCOG(Reprod Med)
Oral contraceptive use puts women at risk for certain carcinomas.
INTRODUCTION
The use of hormones has provided great
convenience to a woman’s life, be it for
therapeutic use or as a lifestyle drug, ie,
contraceptives. However, the duration of
hormone use is frequently long, in terms
of years. Concerns have been raised about
the possibility of a relationship between
cancer development and long-term hormo-
nal influence. This article reviews the evi-
dence regarding the relationship between
hormonal contraceptive use and the devel-
opment of cancer, with the discussion fo-
cusing mainly on carcinoma of the breast
and female genital tract.
HISTORICAL EVIDENCE
The first report dated back to 1972 when
combined oral contraceptive pills (COC)
containing mestranol and norethynodrel
appeared to cause a case of metastatic
breast cancer in a female rhesus monkey.1
Soon after, there were further similar re-
ports of development of breast cancer in
beagles and rodents after exposure to hor-
mones contained in today’s COC.2–4
In June 2005, the International Agen-
cy for Research on Cancer (IARC) Working
Group of the World Health Organization
(WHO) met in Lyon, France, and classified
combined oral contraceptives and com-
bined oestrogen-progestogen hormone
therapy as ‘carcinogenic’ to humans.
THEORY OF ‘CARCINOGENESIS’
Carcinogenesis involves two steps, name-
ly, initiation and promotion. Most of the
studies on the relationship between hor-
mones and cancer development involved
the latter step. In 1989, Anderson et al
reported that nulliparous women who
took COC had a significantly higher rate of
breast cell division.5 It was also found that
COC caused a rise in epithelial cell pro-
liferation of the glandular breast,6 leading
to an increase in accumulation of random
genetic errors.7
However, whether these proliferat-
ing effects on normal epithelia, as a result
of replication error, may cause malignant
transformation has not yet been proven,
although DNA repair is hampered by ac-
tivated proliferation.8 With the end point
being ‘chromosomal mutation’, numer-
ous chromosomal aberrations have been
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observed with natural and synthetic oes-
trogens and progestogens. There was no
proof of sufficient strength to show that
these proliferative effects could induce
tumours. Hormonal tumour promotion also
cannot be discriminated from a causal re-
lation with breast tumour induction.
Moreover, toxicity studies used
animal models. Species-specific effects
might not allow for extrapolation of the ef-
fects to humans. Supraphysiological doses
had been used in animal studies and this
might not reflect actual clinical use. Pos-
sibility of genetic predisposition and other
environmental factors were not taken into
account.
CARCINOMA OF THE BREAST
In 1981, Pike et al reported that women
who took COC for 4 years or more prior to
their first full-term pregnancy experienced
a 125% increased risk of developing carci-
noma of the breast and a 250% increase
in risk with 8 years or more of COC use.9
Similarly, in 1989, Chilvers et al reported
that women under the age of 36 who used
COC for at least 4 years before their first
full-term pregnancy had at least 44% in-
creased risk of breast cancer.10
However, the Cancer and Steroid Hor-
mone Study (CASH), which was one of the
largest case-control studies in the 1980s,
Combined oral contraceptives play a role in the promotion of carcinogenesis.
found no association between breast can-
cer and COC use for women up to the age
of 54. Risk was found only among a sub-
group of women who underwent menarche
before age 13 and used COC for more than
10 years before their first birth.11
In the 1990s, the Collaborative Group
on Hormonal Factors in Breast Cancer in
Oxford, UK, analysed individual data of
53,297 women with breast cancer and
100,239 women without breast cancer
from 54 studies conducted in 25 countries.
The results provided two strong conclu-
sions. First, while women are taking COC
and in a period of 10 years after stopping,
there is a small increase in the relative
risk (RR) of having breast cancer: RR of
1.24 (95% CI, 1.15–1.33) for current users;
RR of 1.16 (95% CI, 1.08–1.23) 1–4 years
after stopping; and RR of 1.07 (95% CI,
1.02–1.13) 5–9 years after stopping. Sec-
ond, there is no significant excess risk of
having breast cancer diagnosed 10 or more
years after stopping use (RR, 1.01 [95%
CI, 0.96–1.05]). The cancers diagnosed in
women who had used COC were less ad-
vanced clinically than those diagnosed in
never-users; the RR for tumours that had
spread beyond the breast compared with
localized tumours was 0.88 (95% CI, 0.81–
0.95). There was no pronounced variation
in the results for recency of use between
women with different background risks of
breast cancer, including women from dif-
ferent countries and ethnic groups, women
with different reproductive histories, and
those with or without a family history of
breast cancer. Other features of hormonal
use, such as duration of use, age at first
use, and the dose and type of hormone
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within the contraceptives, had little ad-
ditional effect on breast cancer risk, once
recency of use had been taken into ac-
count.12
Other important studies worth men-
tioning include the Nurses’ Health Study
(1997),13 Women’s Lifestyle and Health
Cohort Study (2002),14 Oxford-Family Plan-
ning Association study (1981),15 Mayo
Clinic Meta-analysis (2006),16 and Royal
College of General Practitioners study
(2007).17 There were some inconsistencies
among their findings, and the increase in
RR shown by some of these studies was
modest. Possible confounders that may
be related to the use of high-dose COC
include the clinical practice during the
time of these studies and the possibil-
ity of the nature of recall bias. The study
by the Collaborative Group on Hormonal
Factors in Breast Cancer12 also shared a
similar problem. Another weakness of this
study was that it analysed pooled data
from studies which examined women with
breast cancer from as far back as the early
1970s. Taking data from studies which in-
terviewed women before the 1980s might
underestimate the risk of breast cancer
development because the latent period
for cancer development was too short and
few women had used COC for significant
periods of time prior to their first full-term
pregnancy in the late 1960s and early
1970s as compared with women of the
late 1970s and 1980s.
In 2005, the IARC classified COC and
combined oestrogen-progestogen hor-
mone therapy as carcinogenic to humans.
The Working Group mentioned a ‘slightly
increased risk of breast cancer in current
and recent users of hormonal contracep-
tives’. This risk disappears 10 years after
cessation of COC use and will be similar to
that in never-users.18 The Working Group
also acknowledged that their statement
does not meet the overall net public health
outcome, be this of a beneficial or ad-
verse effect other than cancer, and there
is no reason to change the current clini-
cal practice, particularly when the risks of
unwanted pregnancy are taken into con-
sideration.18
For BRCA mutation carriers, who al-
ready have a 50–80% increase in risk of
breast cancer, the use of COC will be of
concern. Among BRCA1 mutation carriers,
those who first used COC before 1975,
who used them before age 30, or who
used for 5 years or more might have an
increased risk of breast cancer. COC do not
appear to be associated with risk of breast
cancer in BRCA2 carriers; however, data to
support this are limited.19
On the use of depot medroxyproges-
terone acetate (MPA), pooled analysis of
two major case-control studies (one in
New Zealand20 and the other under the
auspices of the WHO21) found no increase
in risk for breast cancer. A currently unex-
plained pattern of increased risk in recent
users mimics that seen with COC.22
In a study involving completed ques-
Hormonal contraceptive use increases the relative risk of having breast cancer.
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tionnaires from 17,360 levonorgestrel-
releasing intrauterine system (LNG-IUS)
users, there was no apparent associa-
tion between the length of time elapsed
from the LNG-IUS insertion up to 10 years
and yearly incidence of breast cancer in
the Finnish female population (data from
the Finnish Cancer Registry). A causal
relationship between LNG-IUS use and
occurrence of breast cancer was not sup-
ported.23
CARCINOMA OF THE UTERINE CORPUS
A meta-analysis of 10 case-control stud-
ies (published up to 1996; 1,728 cases and
6,243 controls) and another cohort study
(440,000 woman-years of observation)
both showed statistically reduced RR for
carcinoma of endometrium in COC users.
This RR was negatively associated with
the duration of COC use; the risk reduction
was 56% with 4 years’ use, 67% with 8
years’ use, and 72% with 12 years’ use.24
The Oxford-Family Planning Asso-
ciation (Oxford-FPA) contraceptive study,
which took place in 1968–2004, involved
540,000 woman-years of observation.
There were 50 women with carcinoma of
the uterine corpus in the control group and
27 women in the COC user group. The RR
for ever-users versus never-users was 0.3
(95% CI, 0.2–0.6). The risk was further
found to be negatively related to the du-
ration of COC use, ie, a RR of 0.6 (95%
CI, 0.3–1.1) for up to 48 months’ use, 0.4
(95% CI, 0.2–0.5) for 49–96 months’ use,
and 0.1 (95% CI, 0.0–0.4) for > 97 months’
use.25 The Royal College of General Prac-
titioners oral contraceptive study also
showed similar findings.17
Another meta-analysis of 11 epide-
miological studies found that the more
recent the use of COC, the lower the risk
for carcinoma of the uterine corpus. Such
protective effect from the previous use of
COC would attenuate with time after dis-
continuation. The RR was 0.33, 0.41 and
0.51 for 5, 10, and 20 years of ceasing, re-
spectively. Even after more than 20 years
of cessation of use, the protective effect
is still significant, ie, at 50% less than
non-users.24
Prolonged and unremitting mitotic
activity of the endometrium due to unop-
posed oestrogenic stimulation has been
proposed to be the cause of development
of the majority of cases of endometrial ad-
enocarcinoma. COC suppress endometrial
mitotic activity, leading to apoptosis, thus
reducing the risk of endometrial cancer.
The use of depot MPA is associated
with an 80% risk reduction of endometrial
adenocarcinoma, a level of protection even
greater than that observed with COC. The
effect was also found to be long-term.22
CARCINOMA OF THE OVARY
The Collaborative Group on Epidemiologi-
cal Studies of Ovarian Cancer published a
collaborative reanalysis of data from 45
epidemiological cohort and case-control
The protective effect of combined oral contraceptives against ovarian carcinoma is long-lasting.
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JPOG JUL/AUG 2013 • 173
studies, which included 23,257 women
with ovarian cancer and 87,303 controls
from 21 countries. It was found that 7,308
(31%) of the women with ovarian cancer
and 32,717 (37%) of the controls had used
COC, and the average duration of use was
4.4 and 5.0 years, respectively. The over-
all RR for ever-users versus never-users
was 0.73 (95% CI, 0.70–0.76). The longer
the duration of use, the lower the risk for
ovarian cancer development. The overall
RR decreased by 20% for each 5 years of
use. For women who had used COC for 15
years, the risk was almost halved. The pro-
tective effect started after at least 1 year
of COC use. The RR for < 1 year, 1–4 years,
5–9 years, 10–14 years, and ≥ 15 years of
use were 1.0, 0.78, 0.64, 0.56, and 0.42,
respectively.26
This reanalysis also found that the
more recent the use of COC, the lower the
RR of ovarian cancer. The proportional de-
cline in RR per 5 years of COC use was
29% for < 10 years of cessation of use,
19% for 10–19 years, and 15% for 20–29
years. The longer the duration of use, the
higher the protective effect irrespective
of the time elapsed from ceasing. The
start age of COC use and age of last use
seemed to have no effect on the protec-
tion. Low-dose pill use was found to have
an identical RR compared with high-dose
pill use.26
The Oxford-FPA contraceptive study,
which included 17,032 women aged 25–39
recruited at 17 family planning clinics in
England and Scotland between 1968–1974
with a long follow-up till 2004, analyzed
a total of 540,000 woman-years of ob-
servation and 58 ovarian cancer cases in
the control group and 48 cases in the COC
group.25 The overall ovarian cancer RR for
ever-users versus never-users was 0.5
(95% CI, 0.3–0.7). The risk of ovarian can-
cer was significantly lower in women on
oral contraceptives for more than 4 years.
The Royal College of General Prac-
titioners oral contraceptive study, which
started in 1968, collected data from
23,377 COC users and 23,796 never-users
over a period of 14 months, with 339,000
woman-years of observation for never-
users and 744,000 woman-years for ever-
users.17 It was found that the RR was 0.51
for ever-users as compared with never-
users. Similarly, a statistically significant
gradual decrease in risk with increasing
duration of COC use was observed. The
protective effect was found to last for at
least 15 years after stopping COC.
In the early 1970s, it was proposed
that defective cellular repair after ovula-
tion represents the major risk factor for
ovarian cancer development.27 More re-
cent theories assume that ovarian can-
cer development is attributed to either
activated proto-oncogenes or inactivated
tumour-suppressor genes,27,28 which seem
to point to abnormalities of genomic DNA
quantity and quality, with the resulting de-
fects in post-ovulatory ovarian cellular re-
pair being the causative factor for ovarian
cancer. Thus, the protective effect of COC
against ovarian cancer may be attributed
to the resulting anovulation during their
use, which prevents genetic predisposing
cellular repair defects to be expressed.
Although depot MPA also suppresses
ovulation and would theoretically lower
the risk of ovarian cancer, a hospital-based
WHO case-control study failed to uncover
such a protective effect.22
CARCINOMA OF THE CERVIX
There is evidence suggesting that long-
term use of COC for 5 years or more may
be associated with an increased risk of
cervical cancer.29 A meta-analysis of 28
studies, involving 12,531 women with
cervical cancer, suggested that the risk of
cervical cancer may decrease after stop-
ping the use of COC.30 Another IARC analy-
sis which included eight studies found a
fourfold increase in risk among women
with over 5 years of COC use. The risk was
also increased in women who started us-
ing COC before the age of 20 and in those
who had used COC within the previous 5
years.31
The mechanism for increased risk of
cervical cancer in COC users is uncertain.
Human papillomavirus (HPV) has been
recognized to be the major cause of carci-
noma of the cervix. Steroid contraception
has been postulated to be able to bind to
specific DNA sequences within transcrip-
tional regulatory regions on the HPV DNA,
either to increase or suppress the tran-
The protective effect of
COC against ovarian cancer
may be attributed to the
resulting anovulation
during their use
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JPOG JUL/AUG 2013 • 174
scription of various genes. It was suggest-
ed that the regulatory region of HPV type
16 viral genome indicates transcriptional
control of the HPV genome and might con-
tain enhancer elements that are activated
by steroid hormones.32
In COC users, the cervical mucus be-
comes scanty, thick, and highly viscous. It
has been hypothesized that such mucus
may modulate and prolong the effect of
carcinogenic agents and pathogens (in-
cluding HPV), which might have been car-
ried by coitus, on the cervical squamoco-
lumnar junction, causing them to become
difficult to be removed.33
However, the majority of studies did
not analyse the HPV status of COC users
and controls. Moreover, early use of COC
might be related to early onset of sexual
activity, which is itself a significant risk
factor for HPV infection and development
of cervical cancer. The lower use of the
barrier method of contraception in COC
users might be another accountable fac-
tor for the increase in risk of HPV infec-
tion. However, with the development of
HPV vaccines, the observed association
of increased risk of cervical cancer in COC
users might be changed, and fear of cervi-
cal cancer should not be a reason to avoid
COC use.
A large, population-based, case-con-
trol study in Costa Rica, a hospital-based
WHO case-control study in Thailand, Mex-
ico and Kenya, and a study in New Zealand
found that the risk of cervical cancer did
not appear to be affected by depot MPA
use.22
CONCLUSION
The majority of studies on the relationship
between hormonal contraceptive use and
development of cancer have focused on
COC and breast cancer, albeit with con-
flicting results. From the cumulative expe-
rience and meta-analyses of large epide-
miological studies with a long follow-up
duration, the present evidence suggests
an increase in risk of breast cancer devel-
opment mainly in current COC users, with
Figure 1. Risks of cancer development with duration of oral contraceptive pill (OCP) use
10
1.0
0.1
Rela
tive
risk
for c
ance
r dev
elop
men
t
Duration of OCP use (mo)0–48 49–96 > 97
Increased risk (?) of cervical cancer(Decreased risk on stopping OCP)
Increased risk of breast cancer(Decreased risk on stopping OCP)
Decreased risk of ovary cancer
Decreased risk of endometrial cancer
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JPOG JUL/AUG 2013 • 175
REFERENCES
the risk decreased on stopping therapy.
By 10 years of cessation of use, the risk
is similar to that in never-users. Similar-
ly, the risk of carcinoma of the cervix is
found to be increased in current COC us-
ers. However, COC use confers a strong
and prolonged protective effect against
carcinoma of the endometrium and ovary,
which will last even after over 20 years of
cessation of therapy (Figure 1).
Depot MPA was observed to cause
a plausible increased risk of breast can-
cer in current or recent users, similar to
that observed in COC users. It does not
seem to affect the overall breast cancer
risk. However, there is strong evidence of
prolonged decreased risk for carcinoma of
the uterine corpus. No strong association
has been noted for carcinoma of the cervix
and ovary.
When counselling women regarding
hormonal contraception, the issue of po-
tential carcinogenic effect from its use is
to be included. However, its prescription
should be based on an individual risk-
benefit assessment, provided contraindi-
cations are taken into account and regular
visits to doctors or health-care profession-
als are made.
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abortion as risk factors for breast cancer in young women. Br J Cancer 1981;43:72–76.
10. Chilvers C, McPherson K, Peto J, et al; UK Na-tional Case-Control Study Group. Oral contracep-tive use and breast cancer risk in young women. Lancet 1989;333:974–982.
11. Cancer and Steroid Hormone Study of the Centers for Disease Control and the National In-stitute of Child Health and Human Development. Oral contraceptive use and the risk of breast can-cer. N Engl J Med 1986;315:405–411.
12. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal con-traceptives: collaborative reanalysis of individual data on 53297 women with breast cancer and 100239 women without breast cancer from 54 epidemiological studies. Lancet 1996;347:1713–1727.
13. Colditz GA, Manson JE, Hankinson SE. The Nurses’ Health Study: 20-year contribution to the understanding of health among women. J Wom-ens Health 1997;6:49–62.
14. Kumle M, Weiderpass E, Braaten T, Persson I, Adami HO, Lund E. Use of oral contraceptives and breast cancer risk: The Norwegian-Swedish Women’s Lifestyle and Health Cohort Study. Cancer Epidemiol Biomarkers Prev 2002;11:1375–1381.
15. Vessey MP, McPherson K, Doll R. Breast can-cer and oral contraceptives: findings in Oxford-Family Planning Association contraceptive study. Br Med J (Clin Res Ed) 1981;282:2093–2094.
16. Kahlenborn C, Modugno F, Potter DM, Severs WB. Oral contraceptive use as a risk factor for premenopausal breast cancer: a meta-analysis.
Mayo Clin Proc 2006;81:1290–1302.
17. Hannaford PC, Selvaraj S, Elliott AM. Cancer risk among users of oral contraceptives: cohort data from the Royal College of General Practition-er’s oral contraception study. BMJ 2007;335:651.
18. Schneider HPG, Mueck AO, Kuhl H. IARC monographs program on carcinogenicity of com-bined hormonal contraceptives and menopausal therapy. Climacteric 2005;8:311–316.
19. Narod SA, Dubé MP, Klijn J, et al. Oral contra-ceptives and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 2002;94:1773–1779.
20. Paul C, Skegg DCG, Spears GFS. Depot me-droxyprogesterone (Depo-Provera) and risk of breast cancer. BMJ 1989;299:759–762.
21. Breast cancer and depot-medroxyprogester-one acetate: a multinational study. WHO Collabo-rative Study of Neoplasia and Steroid Contracep-tives. Lancet 1991;338:833–838.
22. Kaunitz AM. Depot medroxyprogesterone acetate contraception and the risk of breast and gynecologic cancer. J Reprod Med 1996;41(5 Suppl):419–427.
23. Backman T, Rauramo I, Jaakkola K, et al. Use of the levonorgestrel-releasing intrauter-ine system and breast cancer. Obstet Gynecol 2005;106:813–817.
24. Schlesselman JJ. Risk of endometrial cancer in relation to use of combined oral contraceptives: a practitioner’s guide to meta-analysis. Hum Re-prod 1997;12:1851–1863.
25. Vessey M, Painter R. Oral contraceptive use and cancer: findings in a large cohort study,
1968–2004. Br J Cancer 2006;95:385–389.
26. Collaborative Group on Epidemiological Stud-ies of Ovarian Cancer. Ovarian cancer and oral contraceptives: collaborative reanalysis of data from 45 epidemiological studies including 23,257 women with ovarian cancer and 87,303 controls. Lancet 2008;371:303–314.
28. Casagrande JT, Louie EW, Pike MC, Roy S, Ross RK, Henderson BE. “Incessant ovulation” and ovarian cancer. Lancet 1979;314:170–173.
29. Franceschi S. The IARC commitment to can-cer prevention: the example of papillomavirus and cervical cancer. Recent Results Cancer Res 2005;166:277–297.
30. Smith JS, Green J, Berrington de Gonzalez A, et al. Cervical cancer and use of hormonal contraceptives: a systematic review. Lancet 2003;361:1159–1167.
31. Moreno V, Bosch FX, Munoz N, et al . Effect of oral contraceptives on risk of cervical cancer in women with human papillomavirus infection: the IARC multicentric case-control study. Lancet 2002;359:1085–1092.
32. Moodley M, Moodley J, Chetty R, Herrington CS. The role of steroid contraceptive hormones in the pathogenesis of invasive cervical cancer: a review. Int J Gynecol Cancer 2003;13:103–110.
33. Guven S, Kart C, Guvendag Guven ES, Gu-nalp GS. The underlying cause of cervical can-cer in oral contraceptive users may be related to cervical mucus changes. Med Hypotheses 2007;69:550–552.
About the Author
Dr Wong is Consultant in the Department of Obstetrics and Gynaecology, Kwong Wah Hospital, Hong Kong.
JPOG_JulAug_2013_CME_PH_Final_Hormonal Contraception and Cancers.indd 175 8/5/13 2:13 PM
This continuing medical education service is brought to you by MIMS. Read the article ‘Hormonal Contraception and Cancers’ and answer the following questions. Answers are shown at the bottom of this page. We hope you enjoy learning with JPOG.
CME Answers for JPOG Jan/Feb 2012
HKCOG CME Article: Management of Pregnancies With Previous Caesarean Section
Answers
1 2 3 4 5 6 7 8 9 10
T F F T T T T T T F
CME Article
Hormonal Contraception and Cancers
Answer True or False to the questions below.
1. Combined oral contraceptives (COC) are classified by IARC as ‘carcinogenic’ to humans.
2. There is strong evidence for COC to cause a rise in epithelial cell proliferation of the glandular breast, leading to increase in genetic error and resulting in malignant transformation and breast cancer development.
3. The results of COC toxicity studies using animal models can accurately reflect the effects in humans.
4. The Collaborative Group on Hormonal Factors in Breast Cancer concluded that there was a small increase in the relative risk of having breast cancer in current and recent COC users.
5. Depot medroxyprogesterone acetate (MPA) users have decreased risk of carcinoma of the breast.
6. The protective effect of COC against carcinoma of the uterine corpus disappears after 10 years of stopping.
7. Low-dose COC has been shown to have a similar protective effect against carcinoma of the ovary compared with high-dose COC.
8. There is good evidence for the protective effect of depot MPA against carcinoma of the ovary.
9. There is evidence suggesting that long-term use of COC increases the risk of cervical cancer.
10. The carcinogenic potential of hormonal therapy should not be discussed during contraceptive counselling.
True False
JPOG JUL/AUG 2013 • 176
CME Questions CME QuestionsAnswers
1 2 3 4 5 6 7 8 9 10
T F F T F F T F T F
JPOG_JulAug_2013_CME_PH_Final_Hormonal Contraception and Cancers.indd 176 8/5/13 2:13 PM
Journal Watch
JPOG JUL/AUG 2013 • 133
Peer reviewed
GYNAECOLOGY
Calcium intake and mortality in Swedish women
Meta-analyses of randomized studies have shown
that taking calcium supplements is associated with
increased risk of coronary disease and stroke. A
Swedish cohort study has confirmed the increased
risk for cardiovascular disease in general but not
for stroke.
The Swedish mammography cohort was set
up in 1987 and included 61,433 women born be-
tween 1914 and 1948. National registries provided
data about all-cause and cardiovascular mortality
over a mean follow-up of 19 years. Food frequency
questionnaires in 1987 and 1997 provided data
about dietary intake and use of calcium supple-
ments for 38,984 women. The relationship between
calcium intake and all-cause mortality took the
form of a ‘J-shaped curve’, with higher mortality
at both extremes of intake. An intake of 1,400 mg
a day of calcium was associated with significant
increases of 40% in all-cause mortality, 49% in
cardiovascular mortality, and 114% in coronary
disease mortality, and no significant change in
stroke mortality, compared with a calcium intake of
600–1,000 mg a day. After further statistical analy-
sis, low intakes of calcium (< 600 mg/day) were
no longer significantly associated with increased
mortality. Among people taking calcium tablets and
with a dietary calcium intake of > 1,400 mg/day,
all-cause mortality was increased 2.6-fold.
High-calcium intake is associated with in-
creased all-cause and cardiovascular mortality.
Michaëlson K et al. Long-term calcium intake and rate of all cause and cardiovascular mortality: community-based prospective longitudinal cohort study. BMJ 2013; 346: 14 (f228).
Outcome of extreme preterm birth in England, 1995–2006
Two successive papers in the BMJ have examined
short-term and long-term outcomes for extremely
preterm births in England in 1995 and 2006.
The prospective national cohort studies pro-
vided short-term data about 666 babies born at 22–
25 weeks’ gestation in England in March to Decem-
ber 1995 and all 3,133 babies born at 22–26 weeks’
gestation in 2006. In 2006, 56% of infants born at
22 weeks and 98% of those born at 26 weeks were
born alive. Active care at birth was withheld from
73% of infants born at 22 weeks, 16% at 23 weeks,
and < 2% at 24 weeks or later. Survival rates for
live-born infants were 2% at 22 weeks, 19% at 23
weeks, 40% at 24 weeks, 66% at 25 weeks, and
77% at 26 weeks. More than two-thirds (68%) of
survivors had bronchopulmonary dysplasia, 16%
were treated (laser treatment) for retinopathy of
prematurity, and 13% had a serious abnormality on
cerebral ultrasound. In 2006, compared with 1995,
44% more infants born alive at 22–25 weeks were
admitted to neonatal intensive care, and survival
of infants born at 23, 24, and 25 weeks increased
by 9.5%, 12%, and 16%, respectively. Overall, the
proportion treated for retinopathy increased from
12% in 1995 to 22% in 2006.
Neurodevelopmental outcomes at ages 2–3
years were assessed for 1,031 survivors in the 2006
cohort. The prevalence of moderate or severe im-
pairment was 45% among survivors born at 22–23
weeks, 30% at 24 weeks, 25% at 25 weeks, and
20% at 26 weeks. Overall, one in seven (14%) had
cerebral palsy, usually mild or moderate. Mean
predicted adjusted mental development index quo-
tients (Bayley scales) were 80 (22–23 weeks), 87
(24 weeks), 88 (25 weeks), and 91 (26 weeks). In
the 2006 cohort, a greater absolute number of chil-
dren than in 1995 will need lifelong special care. It
is calculated that of every 100 infants born at 24
weeks, 60 will die despite intensive care and 12
of the 40 survivors will have serious impairments.
editorial point out that in the Netherlands, infants
born before 24 completed weeks are not routinely
offered neonatal intensive care.
Costeloe KL et al. Short term outcomes after extreme preterm birth in England: comparison of two birth cohorts in 1995 and 2006 (the EPICure studies). BMJ 2012; 345: 14 (e7976); Moore T. Neurological and developmental outcome in extremely preterm children born in England in 2006 and 1995: the EPICure studies. Ibid: 15 (e7961), Groenendaal F, Uiterwaal C. Long-term follow-up of extremely preterm neonates. Ibid:10 (e8252) (editorial).
frequently leads to joint damage and disability and
is accompanied by systemic features such as fever,
rash, hepatosplenomegaly, and serositis. High-
dose steroid treatment may lead to severe toxicity,
and treatments such as methotrexate and tumour
necrosis factor inhibitors may be ineffective. The
effectiveness of antibodies to the interleukin-6
receptor and to interleukin-1β has been shown in
successive papers in the New England Journal of
Medicine.
The humanized, antihuman interleukin-6-re-
ceptor monoclonal antibody, tocilizumab, was as-
sessed in a placebo-controlled trial at 43 centres
in Europe North America, and South America. The
trial included 112 children aged 2–17 years with
active, treatment-resistant systemic JIA. Random-
ization (2:1) was to intravenous tocilizumab or
placebo every 2 weeks for 12 weeks. At 12 weeks,
an improvement of at least 30% on the American
College of Rheumatology JIA score (JIA ACR 30)
was achieved by 85% (tocilizumab) vs 24% (pla-
cebo), a highly significant difference. At week 52
a JIA ACR 70 response (at least 70% improvement)
was achieved by 80% in the tocilizumab group and
a JIA ACR 90 response by 59%. Steroid therapy had
been stopped by 52% in this group, and 48% had no
active arthritis. Common adverse events with tocili-
zumab included infections, neutropenia, and raised
aminotransferase levels.
The fully human, anti-interleukin-1β mono-
clonal antibody, canakinumab, was assessed in two
international trials reported together, including 84
and 100 patients. In the first trial, randomization
was to subcutaneous canakinumab or placebo, and
an adapted JIA ACR 30 response was achieved by
84% (canakinumab) vs 10% (placebo). In the sec-
ond trial, 100 patients who had responded to 32
weeks of canakinumab were randomized to con-
tinued canakinumab or to placebo. A disease flare
occurred in 74% (canakinumab) vs 25% (placebo).
The median time to disease flare was incalculable
in the canakinumab group and 236 days in the pla-
cebo group. The disease became inactive in 62%
vs 34%. One in three patients on canakinumab was
able to discontinue steroid therapy. Infections were
frequent with canakinumab and five patients (ver-
sus two in the placebo group) developed the mac-
rophage activation syndrome.
Both tocilizumab and canakinumab were ef-
fective treatment for systemic JIA but more data
are needed about toxicity.
De Benedetti F et al. Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. NEJM 2012; 367: 2385–95; Ruperto N et al. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. Ibid: 2396–406; Sandborg C, Mellins ED. A new era in the treatment of systemic juvenile idiopathic arthritis. Ibid: 2439–40 (editorial).
CPAP vs surfactant and higher vs lower oxygen saturation for extremely preterm infants: Outcomes at 18–22 months
The Surfactant, Positive Pressure, and Pulse Oxim-
etry randomized trial was a multicentre, random-
ized, controlled trial with a 2 × 2 multifactorial
design in which 1,316 extremely preterm infants
(born at 24 weeks 0 days to 27 weeks 6 days) were
randomized at 20 US centres to early continuous
positive airway pressure (CPAP), or early surfactant
via an endotracheal tube and to a target oxygen
saturation of 85–89% or of 91–95%. Early assess-
ment (at 36 weeks’ postmenstrual age) showed
similar rates of death or bronchopulmonary dyspla-
sia with either CPAP or surfactant, and the lower
target range for oxygen saturation was associ-
ated with less retinopathy of prematurity but more
increased risk of caesarean section and of adverse
maternal outcomes. The risk of adverse perinatal
outcome was increased in Asia.
The increase in obesity and diabetes in
women of reproductive age might have led to an
increase in fetal macrosomia worldwide. Research
into ways of controlling these factors is needed.
Koyanagi A et al. Macrosomia in 23 developing countries: an analysis of a multicountry, facility-based, cross-sectional survey. Lancet 2013; 381: 476–83; Dennedy M, Dunne F. Macrosomia: defining the problem worldwide. Ibid: 435–6 (comment).
Indian, or Pakistani), maternal obesity (BMI 30 or
greater), smoking, pre-existing diabetes, history of
mental health problems, and pregnancy complica-
tions (antepartum haemorrhage, fetal growth re-
striction). The greatest risk factor was fetal growth
restriction which increased the risk of stillbirth by a
factor of 7.8 in non-smoking mothers, 5.7 in smok-
ing mothers, and 10.0 in mothers only exposed to
passive smoking. The population attributable risk
from fetal growth restriction was 6.2% if detected
antenatally and 32.0% when not detected antena-
tally. Antenatal detection of fetal growth restric-
tion was associated with delivery 10 days earlier
on average. The stillbirth rate (per 1,000 births)
was 4.2 overall, 2.4 in pregnancies with no fetal
growth restriction, 9.7 when fetal growth restric-
tion was detected antenatally, and 19.8 when fetal
growth restriction was not detected antenatally.
This study identifies fetal growth restriction
as the main risk factor for stillbirth. Antenatal de-
tection of fetal growth restriction and appropriate
early delivery might prevent 600 stillbirths each
year in the UK.
Gardosi J et al. Maternal and fetal risk factors for stillbirth: population based study. BMJ 2013; 346: 15 (f108); McCowan LME, Groom KM. Identifying risk factors for stillbirth. Ibid: 7 (f416) (editorial).
benefit of hearing aids. The main contraindications
to cochlear implantation include lack of a cochlear
nerve and complete ossification of the cochlea.
Patients who are candidates for cochlear im-
plantation will be assessed by a specialist multi-
disciplinary cochlear implant team including au-
diological investigations, imaging, trial of hearing
aids, review by the speech and language therapists,
and teachers of the deaf to assess for suitability.
Confirmation that children are vaccinated against
pneumococcus will be sought preoperatively from
the general practitioner.
The risks of surgery include altered taste, in-
fection, meningitis, device failure, and facial nerve
injury. It is also important to note that children with
cochlear implants cannot undergo MRI.
Outcome measures have been used to assess
the efficacy of cochlear implantation, and there is
a wealth of literature supporting the success of
hearing rehabilitation and these include ‘sound lo-
calization’ and ‘speech recognition in noise’ meas-
ures and quality of life. Reports have revealed that
many children who received cochlear implants at an
early age are achieving age-appropriate academic
performance.
FURTHER READING
Browning G. Clinical otology & audiology. London: Arnold, 2001.Gerber S. The handbook of pediatric audiology. Washington: Gallau-
det, 1996.Graham J, Scadding G, Bull P. Pediatric ENT. Heidelberg: Springer,
2007.Johnston J, Durieux-Smith A, O’Connor A, Fitzpatrick E. Bilateral
cochlear implants: a critical review. Int J Audiol 2009;48:601–617.Kral A, O’Donoghue G. Profound deafness in childhood. N Engl J Med
2010;363:1438–1450.Kunst D, Kremer H, Cremers C. Genetics for ENT specialists. London:
Remedica, 2005.McDermott A-L, Sheehan P. Bone anchored hearing aids in children.
Curr Opin Otolaryngol Head Neck Surg 2009;17:488–493.NHS. Newborn Hearing Screening Programme. Available online at
http://hearing.screening.nhs.uk/; 2011 (accessed 5 Mar 2011).NICE. Cochlear implants for children and adults with severe to
profound deafness: NICE technology appraisal guidance 166. Avail-able online at http://guidance.nice.org.uk/TA166; 2009 (accessed 5 Mar 2011).
NICE. Surgical management of otitis media with effusion in children: NICE clinical guideline 60. Available online at http://guidance.nice.org.uk/CG60; 2008 (accessed 5 Mar 2011).
Papsin B, Gordon K. Bilateral cochlear implants should be the stan-dard for children with bilateral sensorineural deafness. Curr Opin Otolaryngol Head Neck Surg 2008;16:69–74.
Phillips J, Yung M, Burton M, Swan I. Use of aminoglycoside contain-ing ear drops in the presence of a perforation evidence review and ENT UK consensus statement. Available online at http://www.entuk.org/news/news/attachments/eardrops; 2007 (accessed 5 Mar 2011).
US Preventative Services Task Force. Universal screening for hearing loss in newborns: US Preventative Services Task Force recommen-dation statement. Pediatrics 2008;122:143–148.
About the AuthorsMarianne D Elloy is Specialist Registrar in Otolaryngology at the Royal Derby Hospital, Derby, UK. Andrew H Marshall is Consul-tant in Otolaryngology at the Queens Medical Centre, Notting-ham, UK.
Practice points
• Universal neonatal hearing screening identifies 1 in 1,000 babies with a permanent hearing impairment at birth.
• Management of hearing loss is a multidisciplinary approach.• Hearing loss can be associated with a syndrome, and associated
features should be identified and investigated.• Early identification and intervention of hearing loss improves
speech and language outcomes.• Conventional digital hearing aids or soft band bone conductor
hearing aids can be used for children.• If hearing aids provide inadequate response to sound, patients
can be referred for assessment for either bone-anchored hearing aid or cochlear implants, depending on their hearing thresholds and pathology.
Professor Nimish Vakil talks about management of patients with refractory GERD.“Successful treatment of refractory GERD requires thorough investigation of the patient situation.”
Professor David Liebermanshares his perspective on the present and future of colorectal cancer screening.“There is a lot of potential to prevent many cancers if we can improve the rate of CRC screening.”
Dr Markus Cornbergdiscusses the management of chronic hepatitis B.“The aim of therapy should be the cure or control of HBV infection without the need for life-long treatment.”
In this Series, find out what these medical experts have to say about latest updates in the management of refractory GERD, the management of chronic hepatitis B and the present & future of colorectal cancer screening.
Current Opinion in Gastroenterology
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Royal College of Obstetricians and Gynaecologists. The manage-ment of early pregnancy loss. Green-top Guideline No. 25. London: RCOG, 2006.
Trinder J, Brocklehurst P, Porter R, Read M, Vyas S, Smith L. Management of miscarriage: expectant, medical or surgical? Results of randomized controlled trial (miscarriage treatment (MIST) trial). BMJ 2006;332:1235.
Smith LFP, Ewings PD, Quinain C. Incidence of pregnancy after expectant, medical or surgical management of spontaneous first trimester miscarriage. Long term follow-up of miscar-riage treatment (MIST) randomized controlled trial. BMJ 2009;339:b3827.
Nanda K, Peloggia A, Grimes DA, Lopez LM, Nanda G. Expect-ant care versus surgical treatment for miscarriage. Cochrane Database Syst Rev 2006. Issue 2. Art. No.: CD003518. pub. 2.
Neilson JP, Gyte GML, Hickey M, Vaquez JL, Don L. Medical treatments for incomplete miscarriage (less than 24 weeks). Cochrane Database Syst Rev 2010. Issue 1. Art. No.: CD007223. pub. 2.
Neilson JP, Hiskey M, Vaquez JL. Medical treatment for early fetal death (less than 24 weeks). Cochrane Database Syst Rev 2006. Issue 3. Art. No.: CD002253. pub. 3.
Rai RS, Clifford K, Cohen H, Regan L. High prospective fetal loss rate in untreated pregnancies of women with recurrent miscarriage and antiphospholipid antibodies. Hum Reprod 1995;10:3301–3304.
Royal College of Obstetricians and Gynaecologists. The manage-ment of recurrrent miscarriage. Green-top Guideline No. 17. London: RCOG, 2011.
Royal College of Obstetricians and Gynaecologists. The manage-ment of gestational trophoblastic neoplasia. Green-top Guide-line No. 38. London: RCOG, 2010.
Royal College of Obstetricians and Gynaecologists. The manage-ment of tubal pregnancy. Green-top Guideline No. 21. London: RCOG, 2004.
About the AuthorsHarriet Pugsley is Specialist Registrar in Obstetrics and Gynae-cology. Judith Moore is Consultant Obstetrician and Gynaecolo-gist at Nottingham United Hospitals NHS Trust, Nottingham City Hospital, Nottingham, UK.
to be informed of the risks and benefits of all the
available treatment options.
The role of the EPAU, with open access and
support in future pregnancies in terms of regular
scanning and as a point of contact for the individual,
has been shown to improve the successful outcome
of future pregnancies following miscarriage. Open
access and choice in care options have also been
advocated as helping women to feel more in con-
trol of their treatment and reducing post-treatment
rates of anxiety and depression.
Besides the feeling of loss, it is normal for
women to feel guilt, blame, and anxiety. Women
will have concern for their own health, particularly
if they have required emergency treatment. Part-
ners may also harbour feelings of guilt, responsi-
bility, and helplessness for the situation, and may
have conflicting emotions with concerns regarding
the risk to their loved ones’ health in a future preg-
nancy, balanced with their desire to increase their
family.
It is important for patients who have had an
ectopic pregnancy to understand that they require
an early ultrasound in subsequent pregnancies to
exclude a recurrence and to seek a medical assess-
ment early in pregnancy.
Previously, in future conceptions, early open
access and regular specialist follow-up have been
available, enabling reassurance, investigations,
early detection of further complications, along with
support throughout subsequent pregnancies. Unfor-
tunately as healthcare services are put under ever
increasing pressure to reduce costs, open access
may no longer be deemed a financially viable ser-
vice.
It is important that appropriate investigations
are arranged and results collated and explained. It
is also necessary that patients are given appropri-
ate counselling, information, and links to support
not reduce ovarian cancer mortality. Indeed, a sig-
nificant number of women had major complications
from surgery performed because of a false-positive
screening test.
There are also two large UK-based multicentre
trials investigating ovarian cancer screening. The
first is in postmenopausal women without a signifi-
cant family history of ovarian cancer and also uses a
combination of transvaginal ultrasound and CA 125
(UK Collaborative Trial of Ovarian Cancer Screen-
ing [UKCTOCS]). The second is in women with a
significant family history and is testing a panel of
biomarkers in addition to CA 125 and transvaginal
ultrasound (UK Familial Ovarian Cancer Screening
Study). Both have now finished recruitment and are
due to report in the next few years.
Screening with a combination of CA 125, ul-
trasound, and pelvic examination is commonly per-
formed for anxious patients who desire screening
for ovarian cancer. If the findings of the PLCO trial
are duplicated in the UKCTOCS trial, this practice is
likely to become hard to defend in low-risk women.
INVESTIGATION
The first symptoms of ovarian cancer usually
emerge some time before diagnosis. These com-
monly include early satiety, changes in bowel
habit, bloating, urinary frequency, and pelvic and
abdominal pain. Patients with advanced cancer of-
ten complain of abdominal swelling and discomfort
due to ascites with or without a large abdomin-
opelvic mass. Eating is often difficult, and patients
may notice weight loss, apart from the distended
abdomen. It is not uncommon for patients to pre-
sent with a swollen leg secondary to a deep vein
thrombosis. However, most small ovarian cancers
are asymptomatic when confined to the ovaries and
therefore difficult to detect.
Recent National Institute for Clinical Excel-
lence (NICE) guideline recommend that women,
especially those over 50 years old, who experience
symptoms persistent or frequent symptoms as de-
scribed above, or new-onset symptoms suggestive
of irritable bowel syndrome, should have CA 125
Table 2. FIGO staging of ovarian cancer
Stage Description
I Confined to ovaries
Ia One ovary, no ascites present containing malignant cells, no tumour on external surface, capsule intact
Ib Both ovaries, no ascites present containing malignant cells, no tumour on external surfaces, capsule intact
Ic Tumour limited to one or both ovaries with any of the following: tumour on the surface on one or both ovaries, capsule ruptured, ascites present with malig-nant cells or positive peritoneal washings
II Growth involving one or both ovaries with pelvic exten-sion
IIa Extension and/or metastases to uterus and/or fallopian tubes
IIb Extension to other pelvic tissues
IIc Tumour stage IIa or IIb but with tumour on surface of one or both ovaries, capsule ruptured, ascites pres-ent containing malignant cells or positive peritoneal washings
III Tumour involving one or both ovaries with microscopi-cally confirmed peritoneal implants outside the pelvis and/or regional lymph node metastasis
IIIa Microscopic peritoneal metastasis beyond the pelvis
IIIb Macroscopic peritoneal metastasis beyond the pelvis, 2 cm or less in greatest dimension
IIIc Abdominal implants greater than 2 cm in diameter and/or regional lymph nodes metastasis
IV Distant metastasis beyond the peritoneal cavity. Includes liver parenchymal metastasis and/or pleural effusion with positive cytology
FIGO = International Federation of Gynecology and Obstetrics.
About the AuthorsSiân E Taylor is Subspecialty Trainee in the Department of Gynae-cologial Oncology at Liverpool Women’s Hospital, Liverpool, UK. John M Kirwan is Consultant Gynaecological Oncologist at Liverpool Women’s Hospital, Liverpool, UK.
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tion of the child’s stool, stool frequency, incon-
tinence, withholding behaviour and any symp-
toms associated with defaecation, such as pain,
bleeding and straining.
• Important aspects of the history include age at
onset, growth trends, diet history and the pres-
ence of ‘red flags’ (see the box on this page).
• A thorough physical examination should be per-
formed, particularly focusing on growth param-
eters, palpable abdominal faecal masses, in-
spection of the perianal and lumbosacral regions
and lower limb neurological examination. Poor
growth may occur with Hirsch sprung disease,
hypothyroidism and coeliac disease.
• Digital rectal examination should be avoided in
primary health care as it rarely contributes to the
clinical assessment and can be particularly dis-
tressing for the child.
• Impaction is suggested by faecal incontinence or
a palpable faecal mass (preferably determined
via abdominal palpation).
• If the likely diagnosis is functional constipation
then no further invest igation is needed. Abdomi-
nal X- rays are not needed to diagnose constipa-
tion or to determine response to therapy.5
• If a pathological cause for constipa tion is sus-
pected then appropriate investigations should be
performed in consultation with a paediatrician or
paediatric surgeon.
MANAGEMENT
• A combination of management approaches that
complement each other are almost always re-
quired in the management of childhood consti-
pation. Individual elements in isolation (eg, di-
simpaction without maintenance laxatives) are
unlikely to be unsuccessful.
• Education of parents and caregivers about the
relationship between behavioural aspects (eg,
fear of pain and withholding) and functional
‘Red flag’ feature2,3
History• Constipation from the neonatal period• Failure to pass meconium by the age of 48 hours• ‘Ribbon stools’ suggesting anorectal stricture or stenosis• Abdominal distension and vomiting• Poor weight gain or weight loss• Leg weakness or delayed gross motor development
Examination• Gross abdominal distension• Abnormal appearance, position or patency of anus – fistulae, bruis-
ing, multiple fissures or fissures away from the midline, tight or patulous anus, anteriorly placed anus, absent anal wink
• Lumbosacral abnormalities – evidence of sacral agenesis, discol-oured skin, naevi, sinus, hairy patch, lipoma, central pit, scoliosis
• Gluteal asymmetry or wasting• Absent cremasteric reflex• Abnormal results on lower limb neurological examination – de-
formity such as talipes, abnormal reflexes
Rome III diagnostic criteria for functional constipation in children1
At least two of the following features have been present for at least 2 months in a child aged 4 years or older (developmental age):• two or fewer defaecations in the toilet per week• at least one episode of faecal incontinence per week• history of retentive posturing or excessive volitional stool retention• history of painful or hard bowel movements• presence of a large faecal mass in the rectum• history of large diameter stools that obstruct the toilet
sit on the toilet for 5 minutes, two or three times
a day, within 30 minutes after meals to take ad-
vantage of the gastrocolic reflex. Positive rein-
forcement for sitting (eg, using reward charts)
should be encouraged. Children should never be
punished for being constipated or incontinent.
• A healthy diet should be encouraged rather than
a high- fibre diet, as there is little evidence that
increasing dietary fibre is an effective treat-
ment for childhood constipation.2 There is lim-
ited evidence that avoiding cow milk may result
in improvement in some children with chronic
constipation, particularly those with atopic ten-
dencies.9,10 Any trial of such an elimination diet
should be limited to 2 to 4 weeks, and the child
should be re- challenged to confirm any effect.
Prolonged elimination diets require supervision
by a qualified dietitian to prevent any nutritional
deficiencies and there should be repeated at-
tempts to normalize the diet.
• Aside from situations of clinical dehydration,
there is no evidence that increasing water intake
is beneficial in constipation. However, ensuring
adequate fluid intake is important when using
osmotic laxatives to avoid dehydration.
• Regular review is required to monitor response
to therapy, adjust laxative dose, reinforce educa-
Table. Initial laxative options for infants and children
Infants (< 12 months) Children
Disimpaction • Glycerol suppository 700 mg • Macrogol 3350 1 to 1.5 g/kg/day (max 52 g for children aged 2 to 5 years and 78 g for children aged 6 years and over) until disimpacted4*
Maintenance† • Sorbitol-containing fruit juices, such as prune, pear, apple (50 to 100 mL/day) or
• Lactulose 5 mL daily
• Macrogol 3350 0.4 to 0.8 g/kg daily up to 17 g* or• Paraffin oil 1 to 3 mL/kg daily (start 10 to 20 mL
daily)‡ or• Lactulose 10 to 15 mL daily
* Macrogol 3350 (polyethylene glycol) is available in Australia in a variety of formulations, in scoop packs or sachets. † Doses are a guide only and should be titrated to effect every 2 to 3 days as required, with consideration of the maximum recommended dose.‡ Not recommended in infants, or in children with gastro-oesophageal reflux or risk of aspiration.
About the AuthorsDr Dowling is a Paediatric Registrar, Hunter New England Local Health
District, Newcastle. Dr Nightingale is a Paediatric Gastroenterolo-
gist, John Hunter Children’s Hospital; and Conjoint Lecturer, School
of Medicine and Public Health, University of Newcastle, Newcastle,
NSW, Australia.
Series Editor: Associate Professor Simone Strasser, MD, FRACP, Clini-
cal Associate Professor, Central Clinical School (Medicine), University
of Sydney; and Senior Staff Specialist, AW Morrow Gastroenterol-
ogy and Liver Centre, Royal Prince Alfred Hospital, Sydney, NSW,
Australia.
1. Drossman DA. Rome III: the functional gastro-intestinal disorders. 3rd ed. McLean, VA: Degnon Associates; 2006.
2. National Institute for Health and Care Excellence (NICE). Constipation in children and young people: diagnosis and management of idiopathic childhood constipation in primary and secondary care: quick reference guide. London: NICE; 2010.
3. Constipation Guideline Committee of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Evaluation and treatment of constipation in infants and children: recommen-
dations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pedi-atr Gastroenterol Nutr 2006;43:e1-e13.
4. North American Society for Pediatric Gastroen-terology, Hepatology and Nutrition. Evaluation and treatment of constipation in children: summary of updated recommendations of the North American Society for Pediatric Gastroenterology, Hepatol-ogy and Nutrition. J Pediatr Gastroenterol Nutr 2006;43:405-407.
5. Berger MY, Tabbers MM, Kurver MJ, Boluyt N, Benninga MA. Value of abdominal radiography, co-
lonic transit time, and rectal ultrasound scanning in the diagnosis of idiopathic constipation in children: a systematic review. J Pediatr 2012;161:44-50, e41-42.
6. Bekkali NL, van den Berg MM , Dijkgraaf MG, et al. Rectal fecal impaction treatment in childhood constipation: enemas versus high doses oral PEG. Pediatrics 2009;124:e1108-E1115.
7. Gordon M, Naidoo K, Akobeng AK, Thomas AG. Osmotic and stimulant laxatives for the manage-ment of childhood constipation. Cochrane Database Syst Rev 2012;7:CD009118.
8. Brazzelli M, Griffiths PV, Cody JD, Tappin D. Be-havioural and cognitive interventions with or with-out other treatments for the management of faecal incontinence in children. Cochrane Database Syst Rev 2011;12:CD002240.
9. Iacono G, Cavataio F, Montalto G, et al. Intoler-ance of cow’s milk and chronic constipation in chil-dren. N Engl J Med 1998;339:1100-1104.
10. Irastorza I, Ibanez B, Delgado-Sanzonetti L, Maruri N, Vitoria JC. Cow’s milk–free diet as a therapeutic option in childhood chronic constipa-tion. J Pediatr Gastroenterol Nutr 2010;51:171-176.
Hormonal Contraception and Cancers Wong Yuen Kwan Alice, MBBS, FRCOG, FHKAM(O&G), FHKCOG, Cert HKCOG(Reprod Med)
Oral contraceptive use puts women at risk for certain carcinomas.
INTRODUCTION
The use of hormones has provided great
convenience to a woman’s life, be it for
therapeutic use or as a lifestyle drug, ie,
contraceptives. However, the duration of
hormone use is frequently long, in terms
of years. Concerns have been raised about
the possibility of a relationship between
cancer development and long-term hormo-
nal influence. This article reviews the evi-
dence regarding the relationship between
hormonal contraceptive use and the devel-
opment of cancer, with the discussion fo-
cusing mainly on carcinoma of the breast
and female genital tract.
HISTORICAL EVIDENCE
The first report dated back to 1972 when
combined oral contraceptive pills (COC)
containing mestranol and norethynodrel
appeared to cause a case of metastatic
breast cancer in a female rhesus monkey.1
Soon after, there were further similar re-
ports of development of breast cancer in
beagles and rodents after exposure to hor-
mones contained in today’s COC.2–4
In June 2005, the International Agen-
cy for Research on Cancer (IARC) Working
Group of the World Health Organization
(WHO) met in Lyon, France, and classified
combined oral contraceptives and com-
bined oestrogen-progestogen hormone
therapy as ‘carcinogenic’ to humans.
THEORY OF ‘CARCINOGENESIS’
Carcinogenesis involves two steps, name-
ly, initiation and promotion. Most of the
studies on the relationship between hor-
mones and cancer development involved
the latter step. In 1989, Anderson et al
reported that nulliparous women who
took COC had a significantly higher rate of
breast cell division.5 It was also found that
COC caused a rise in epithelial cell pro-
liferation of the glandular breast,6 leading
to an increase in accumulation of random
genetic errors.7
However, whether these proliferat-
ing effects on normal epithelia, as a result
of replication error, may cause malignant
transformation has not yet been proven,
although DNA repair is hampered by ac-
tivated proliferation.8 With the end point
being ‘chromosomal mutation’, numer-
ous chromosomal aberrations have been
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JPOG JUL/AUG 2013 • 170
observed with natural and synthetic oes-
trogens and progestogens. There was no
proof of sufficient strength to show that
these proliferative effects could induce
tumours. Hormonal tumour promotion also
cannot be discriminated from a causal re-
lation with breast tumour induction.
Moreover, toxicity studies used
animal models. Species-specific effects
might not allow for extrapolation of the ef-
fects to humans. Supraphysiological doses
had been used in animal studies and this
might not reflect actual clinical use. Pos-
sibility of genetic predisposition and other
environmental factors were not taken into
account.
CARCINOMA OF THE BREAST
In 1981, Pike et al reported that women
who took COC for 4 years or more prior to
their first full-term pregnancy experienced
a 125% increased risk of developing carci-
noma of the breast and a 250% increase
in risk with 8 years or more of COC use.9
Similarly, in 1989, Chilvers et al reported
that women under the age of 36 who used
COC for at least 4 years before their first
full-term pregnancy had at least 44% in-
creased risk of breast cancer.10
However, the Cancer and Steroid Hor-
mone Study (CASH), which was one of the
largest case-control studies in the 1980s,
Combined oral contraceptives play a role in the promotion of carcinogenesis.
found no association between breast can-
cer and COC use for women up to the age
of 54. Risk was found only among a sub-
group of women who underwent menarche
before age 13 and used COC for more than
10 years before their first birth.11
In the 1990s, the Collaborative Group
on Hormonal Factors in Breast Cancer in
Oxford, UK, analysed individual data of
53,297 women with breast cancer and
100,239 women without breast cancer
from 54 studies conducted in 25 countries.
The results provided two strong conclu-
sions. First, while women are taking COC
and in a period of 10 years after stopping,
there is a small increase in the relative
risk (RR) of having breast cancer: RR of
1.24 (95% CI, 1.15–1.33) for current users;
RR of 1.16 (95% CI, 1.08–1.23) 1–4 years
after stopping; and RR of 1.07 (95% CI,
1.02–1.13) 5–9 years after stopping. Sec-
ond, there is no significant excess risk of
having breast cancer diagnosed 10 or more
years after stopping use (RR, 1.01 [95%
CI, 0.96–1.05]). The cancers diagnosed in
women who had used COC were less ad-
vanced clinically than those diagnosed in
never-users; the RR for tumours that had
spread beyond the breast compared with
localized tumours was 0.88 (95% CI, 0.81–
0.95). There was no pronounced variation
in the results for recency of use between
women with different background risks of
breast cancer, including women from dif-
ferent countries and ethnic groups, women
with different reproductive histories, and
those with or without a family history of
breast cancer. Other features of hormonal
use, such as duration of use, age at first
use, and the dose and type of hormone
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JPOG JUL/AUG 2013 • 171
within the contraceptives, had little ad-
ditional effect on breast cancer risk, once
recency of use had been taken into ac-
count.12
Other important studies worth men-
tioning include the Nurses’ Health Study
(1997),13 Women’s Lifestyle and Health
Cohort Study (2002),14 Oxford-Family Plan-
ning Association study (1981),15 Mayo
Clinic Meta-analysis (2006),16 and Royal
College of General Practitioners study
(2007).17 There were some inconsistencies
among their findings, and the increase in
RR shown by some of these studies was
modest. Possible confounders that may
be related to the use of high-dose COC
include the clinical practice during the
time of these studies and the possibil-
ity of the nature of recall bias. The study
by the Collaborative Group on Hormonal
Factors in Breast Cancer12 also shared a
similar problem. Another weakness of this
study was that it analysed pooled data
from studies which examined women with
breast cancer from as far back as the early
1970s. Taking data from studies which in-
terviewed women before the 1980s might
underestimate the risk of breast cancer
development because the latent period
for cancer development was too short and
few women had used COC for significant
periods of time prior to their first full-term
pregnancy in the late 1960s and early
1970s as compared with women of the
late 1970s and 1980s.
In 2005, the IARC classified COC and
combined oestrogen-progestogen hor-
mone therapy as carcinogenic to humans.
The Working Group mentioned a ‘slightly
increased risk of breast cancer in current
and recent users of hormonal contracep-
tives’. This risk disappears 10 years after
cessation of COC use and will be similar to
that in never-users.18 The Working Group
also acknowledged that their statement
does not meet the overall net public health
outcome, be this of a beneficial or ad-
verse effect other than cancer, and there
is no reason to change the current clini-
cal practice, particularly when the risks of
unwanted pregnancy are taken into con-
sideration.18
For BRCA mutation carriers, who al-
ready have a 50–80% increase in risk of
breast cancer, the use of COC will be of
concern. Among BRCA1 mutation carriers,
those who first used COC before 1975,
who used them before age 30, or who
used for 5 years or more might have an
increased risk of breast cancer. COC do not
appear to be associated with risk of breast
cancer in BRCA2 carriers; however, data to
support this are limited.19
On the use of depot medroxyproges-
terone acetate (MPA), pooled analysis of
two major case-control studies (one in
New Zealand20 and the other under the
auspices of the WHO21) found no increase
in risk for breast cancer. A currently unex-
plained pattern of increased risk in recent
users mimics that seen with COC.22
In a study involving completed ques-
Hormonal contraceptive use increases the relative risk of having breast cancer.
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tionnaires from 17,360 levonorgestrel-
releasing intrauterine system (LNG-IUS)
users, there was no apparent associa-
tion between the length of time elapsed
from the LNG-IUS insertion up to 10 years
and yearly incidence of breast cancer in
the Finnish female population (data from
the Finnish Cancer Registry). A causal
relationship between LNG-IUS use and
occurrence of breast cancer was not sup-
ported.23
CARCINOMA OF THE UTERINE CORPUS
A meta-analysis of 10 case-control stud-
ies (published up to 1996; 1,728 cases and
6,243 controls) and another cohort study
(440,000 woman-years of observation)
both showed statistically reduced RR for
carcinoma of endometrium in COC users.
This RR was negatively associated with
the duration of COC use; the risk reduction
was 56% with 4 years’ use, 67% with 8
years’ use, and 72% with 12 years’ use.24
The Oxford-Family Planning Asso-
ciation (Oxford-FPA) contraceptive study,
which took place in 1968–2004, involved
540,000 woman-years of observation.
There were 50 women with carcinoma of
the uterine corpus in the control group and
27 women in the COC user group. The RR
for ever-users versus never-users was 0.3
(95% CI, 0.2–0.6). The risk was further
found to be negatively related to the du-
ration of COC use, ie, a RR of 0.6 (95%
CI, 0.3–1.1) for up to 48 months’ use, 0.4
(95% CI, 0.2–0.5) for 49–96 months’ use,
and 0.1 (95% CI, 0.0–0.4) for > 97 months’
use.25 The Royal College of General Prac-
titioners oral contraceptive study also
showed similar findings.17
Another meta-analysis of 11 epide-
miological studies found that the more
recent the use of COC, the lower the risk
for carcinoma of the uterine corpus. Such
protective effect from the previous use of
COC would attenuate with time after dis-
continuation. The RR was 0.33, 0.41 and
0.51 for 5, 10, and 20 years of ceasing, re-
spectively. Even after more than 20 years
of cessation of use, the protective effect
is still significant, ie, at 50% less than
non-users.24
Prolonged and unremitting mitotic
activity of the endometrium due to unop-
posed oestrogenic stimulation has been
proposed to be the cause of development
of the majority of cases of endometrial ad-
enocarcinoma. COC suppress endometrial
mitotic activity, leading to apoptosis, thus
reducing the risk of endometrial cancer.
The use of depot MPA is associated
with an 80% risk reduction of endometrial
adenocarcinoma, a level of protection even
greater than that observed with COC. The
effect was also found to be long-term.22
CARCINOMA OF THE OVARY
The Collaborative Group on Epidemiologi-
cal Studies of Ovarian Cancer published a
collaborative reanalysis of data from 45
epidemiological cohort and case-control
The protective effect of combined oral contraceptives against ovarian carcinoma is long-lasting.
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studies, which included 23,257 women
with ovarian cancer and 87,303 controls
from 21 countries. It was found that 7,308
(31%) of the women with ovarian cancer
and 32,717 (37%) of the controls had used
COC, and the average duration of use was
4.4 and 5.0 years, respectively. The over-
all RR for ever-users versus never-users
was 0.73 (95% CI, 0.70–0.76). The longer
the duration of use, the lower the risk for
ovarian cancer development. The overall
RR decreased by 20% for each 5 years of
use. For women who had used COC for 15
years, the risk was almost halved. The pro-
tective effect started after at least 1 year
of COC use. The RR for < 1 year, 1–4 years,
5–9 years, 10–14 years, and ≥ 15 years of
use were 1.0, 0.78, 0.64, 0.56, and 0.42,
respectively.26
This reanalysis also found that the
more recent the use of COC, the lower the
RR of ovarian cancer. The proportional de-
cline in RR per 5 years of COC use was
29% for < 10 years of cessation of use,
19% for 10–19 years, and 15% for 20–29
years. The longer the duration of use, the
higher the protective effect irrespective
of the time elapsed from ceasing. The
start age of COC use and age of last use
seemed to have no effect on the protec-
tion. Low-dose pill use was found to have
an identical RR compared with high-dose
pill use.26
The Oxford-FPA contraceptive study,
which included 17,032 women aged 25–39
recruited at 17 family planning clinics in
England and Scotland between 1968–1974
with a long follow-up till 2004, analyzed
a total of 540,000 woman-years of ob-
servation and 58 ovarian cancer cases in
the control group and 48 cases in the COC
group.25 The overall ovarian cancer RR for
ever-users versus never-users was 0.5
(95% CI, 0.3–0.7). The risk of ovarian can-
cer was significantly lower in women on
oral contraceptives for more than 4 years.
The Royal College of General Prac-
titioners oral contraceptive study, which
started in 1968, collected data from
23,377 COC users and 23,796 never-users
over a period of 14 months, with 339,000
woman-years of observation for never-
users and 744,000 woman-years for ever-
users.17 It was found that the RR was 0.51
for ever-users as compared with never-
users. Similarly, a statistically significant
gradual decrease in risk with increasing
duration of COC use was observed. The
protective effect was found to last for at
least 15 years after stopping COC.
In the early 1970s, it was proposed
that defective cellular repair after ovula-
tion represents the major risk factor for
ovarian cancer development.27 More re-
cent theories assume that ovarian can-
cer development is attributed to either
activated proto-oncogenes or inactivated
tumour-suppressor genes,27,28 which seem
to point to abnormalities of genomic DNA
quantity and quality, with the resulting de-
fects in post-ovulatory ovarian cellular re-
pair being the causative factor for ovarian
cancer. Thus, the protective effect of COC
against ovarian cancer may be attributed
to the resulting anovulation during their
use, which prevents genetic predisposing
cellular repair defects to be expressed.
Although depot MPA also suppresses
ovulation and would theoretically lower
the risk of ovarian cancer, a hospital-based
WHO case-control study failed to uncover
such a protective effect.22
CARCINOMA OF THE CERVIX
There is evidence suggesting that long-
term use of COC for 5 years or more may
be associated with an increased risk of
cervical cancer.29 A meta-analysis of 28
studies, involving 12,531 women with
cervical cancer, suggested that the risk of
cervical cancer may decrease after stop-
ping the use of COC.30 Another IARC analy-
sis which included eight studies found a
fourfold increase in risk among women
with over 5 years of COC use. The risk was
also increased in women who started us-
ing COC before the age of 20 and in those
who had used COC within the previous 5
years.31
The mechanism for increased risk of
cervical cancer in COC users is uncertain.
Human papillomavirus (HPV) has been
recognized to be the major cause of carci-
noma of the cervix. Steroid contraception
has been postulated to be able to bind to
specific DNA sequences within transcrip-
tional regulatory regions on the HPV DNA,
either to increase or suppress the tran-
The protective effect of
COC against ovarian cancer
may be attributed to the
resulting anovulation
during their use
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JPOG JUL/AUG 2013 • 174
scription of various genes. It was suggest-
ed that the regulatory region of HPV type
16 viral genome indicates transcriptional
control of the HPV genome and might con-
tain enhancer elements that are activated
by steroid hormones.32
In COC users, the cervical mucus be-
comes scanty, thick, and highly viscous. It
has been hypothesized that such mucus
may modulate and prolong the effect of
carcinogenic agents and pathogens (in-
cluding HPV), which might have been car-
ried by coitus, on the cervical squamoco-
lumnar junction, causing them to become
difficult to be removed.33
However, the majority of studies did
not analyse the HPV status of COC users
and controls. Moreover, early use of COC
might be related to early onset of sexual
activity, which is itself a significant risk
factor for HPV infection and development
of cervical cancer. The lower use of the
barrier method of contraception in COC
users might be another accountable fac-
tor for the increase in risk of HPV infec-
tion. However, with the development of
HPV vaccines, the observed association
of increased risk of cervical cancer in COC
users might be changed, and fear of cervi-
cal cancer should not be a reason to avoid
COC use.
A large, population-based, case-con-
trol study in Costa Rica, a hospital-based
WHO case-control study in Thailand, Mex-
ico and Kenya, and a study in New Zealand
found that the risk of cervical cancer did
not appear to be affected by depot MPA
use.22
CONCLUSION
The majority of studies on the relationship
between hormonal contraceptive use and
development of cancer have focused on
COC and breast cancer, albeit with con-
flicting results. From the cumulative expe-
rience and meta-analyses of large epide-
miological studies with a long follow-up
duration, the present evidence suggests
an increase in risk of breast cancer devel-
opment mainly in current COC users, with
Figure 1. Risks of cancer development with duration of oral contraceptive pill (OCP) use
10
1.0
0.1
Rela
tive
risk
for c
ance
r dev
elop
men
t
Duration of OCP use (mo)0–48 49–96 > 97
Increased risk (?) of cervical cancer(Decreased risk on stopping OCP)
Increased risk of breast cancer(Decreased risk on stopping OCP)
Decreased risk of ovary cancer
Decreased risk of endometrial cancer
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JPOG JUL/AUG 2013 • 175
REFERENCES
the risk decreased on stopping therapy.
By 10 years of cessation of use, the risk
is similar to that in never-users. Similar-
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found to be increased in current COC us-
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and prolonged protective effect against
carcinoma of the endometrium and ovary,
which will last even after over 20 years of
cessation of therapy (Figure 1).
Depot MPA was observed to cause
a plausible increased risk of breast can-
cer in current or recent users, similar to
that observed in COC users. It does not
seem to affect the overall breast cancer
risk. However, there is strong evidence of
prolonged decreased risk for carcinoma of
the uterine corpus. No strong association
has been noted for carcinoma of the cervix
and ovary.
When counselling women regarding
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to be included. However, its prescription
should be based on an individual risk-
benefit assessment, provided contraindi-
cations are taken into account and regular
visits to doctors or health-care profession-
als are made.
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About the Author
Dr Wong is Consultant in the Department of Obstetrics and Gynaecology, Kwong Wah Hospital, Hong Kong.
JPOG_JulAug_2013_CME_PH_Final_Hormonal Contraception and Cancers.indd 175 8/5/13 2:13 PM
This continuing medical education service is brought to you by MIMS. Read the article ‘Hormonal Contraception and Cancers’ and answer the following questions. Answers are shown at the bottom of this page. We hope you enjoy learning with JPOG.
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Hormonal Contraception and Cancers
Answer True or False to the questions below.
1. Combined oral contraceptives (COC) are classified by IARC as ‘carcinogenic’ to humans.
2. There is strong evidence for COC to cause a rise in epithelial cell proliferation of the glandular breast, leading to increase in genetic error and resulting in malignant transformation and breast cancer development.
3. The results of COC toxicity studies using animal models can accurately reflect the effects in humans.
4. The Collaborative Group on Hormonal Factors in Breast Cancer concluded that there was a small increase in the relative risk of having breast cancer in current and recent COC users.
5. Depot medroxyprogesterone acetate (MPA) users have decreased risk of carcinoma of the breast.
6. The protective effect of COC against carcinoma of the uterine corpus disappears after 10 years of stopping.
7. Low-dose COC has been shown to have a similar protective effect against carcinoma of the ovary compared with high-dose COC.
8. There is good evidence for the protective effect of depot MPA against carcinoma of the ovary.
9. There is evidence suggesting that long-term use of COC increases the risk of cervical cancer.
10. The carcinogenic potential of hormonal therapy should not be discussed during contraceptive counselling.
True False
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JPOG_JulAug_2013_CME_PH_Final_Hormonal Contraception and Cancers.indd 176 8/5/13 2:13 PM