Scientific Impact Paper No. 21
June 2010
Obstetric Impact of Treatment for
Cervical Intraepithelial Neoplasia
Obstetric Impact of Treatment for Cervical Intraepithelial
Neoplasia
1.
Background
In countries like the UK, where a cervical screening programme has been successfully applied, the
incidence and mortality from cervical cancer has significantly decreased. However, there is increasing
evidence that resultant excisional procedures for treatment of cervical intraepithelial neoplasia (CIN) are
associated with preterm delivery1 and might be associated with perinatal mortality.2
2.
Current treatments for CIN
The mean age of women identified as having CIN and requiring treatment is around 30 years and it is
now common that this is before women are starting their families. Therefore, there is a need to consider
local treatment for CIN. Treatment of CIN should not be compromised in terms of efficacy and should
be as efficient as possible but should not lead to long-term effects on future fertility and pregnancy
outcome. Excisional techniques are usually performed under local anaesthesia in an outpatient setting
and are easy to perform.
The consensus view is that excisional techniques are superior to destructive ones, as they allow a
comprehensive histological evaluation of the excised tissue with precise evaluation of excision margins
and possible adjustment of follow up. Large-loop excision of the transformation zone (LLETZ) is by far
the most popular treatment. This is because LLETZ combines all the advantages of the excisional
techniques: a relatively short duration, low cost, good compliance, simplicity and an easier learning
curve. Destructive techniques have similar advantages, are usually performed under local anaesthesia in
an outpatient setting and are easy to perform. However, destructive techniques destroy the
transformation zone epithelium and preclude histological evaluation. Destructive techniques therefore
demand accurate pretreatment biopsy at a separate visit with all the disadvantages this implies: the
excision margins and the exact histology of the lesions following treatment are not known, leading in
several cases to a rather more intensive follow-up strategy. Despite the theoretical advantages of the
excisional techniques, the published evidence shows that all these methods, be they excisional or
destructive, have similar efficacy in terms of eradicating intraepithelial lesions.3,4 The current literature
also shows that the risk of invasive disease after the detection and treatment of intraepithelial lesions
remains four to five times higher than that of the general population5,6 and this risk remains stable for
20 years.7 It is notable that this risk is similar irrespective of the method used for the treatment of the
intraepithelial lesions.5,6 However, colposcopists need to be mindful that, in well-defined clinical
scenarios such as the management of glandular disease, incomplete colposcopy or suspected or
confirmed microinvasive disease, excisional treatment is mandatory. Coloscopists should always have
adequate clinical training to make such decisions.
3.
Obstetric complications following treatment for CIN
Since risk of invasive cervical cancer following treatment is similar whichever treatment method is used,
the question arises as to whether there are similarly clear and conclusive data regarding future fertility
and pregnancy outcomes.
A meta-analysis by Kyrgiou et al.1 analysed a total of 27 retrospective cohort studies of women with
CIN, published over the previous three decades. Cold-knife and laser conisation and LLETZ were all
significantly associated with increased risk of preterm birth and low birth weight, while no statistically
significant difference was found in perinatal mortality. This lack of effect on perinatal mortality was
thought to be due to low sample size.1 Cold-knife conisation was also found to be associated with an
increased rate of ceasarean section.1 In contrast, laser vaporisation was not associated with adverse
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obstetric outcomes. The surprising finding of this meta-analysis was the adverse effect of laser conisation
and LLETZ, which had not been seen in the individual small primary studies. Meta-analysis of three
studies revealed a consistent, significantly increased risk for preterm delivery if the depth of the excision
exceeded a cut-off point of 10 mm, while for less deep excisions the data of the individual studies were
contradictory and heterogeneous.1
Many large studies were consistent with this meta-analysis and strengthened these initial findings.8–10
This led to the question of whether the colposcopists actually dismissed ablative treatment too soon from
colposcopy practice.11 To answer this question, analysis of perinatal mortality, the most important of all
the outcomes clinically, was needed. A new meta-analysis revealed a significantly increased perinatal
mortality for excisional techniques that reflected the increased preterm delivery rate.2 The same analysis
on the ablative techniques did not reveal increased risk in perinatal mortality.2 A single treatment with
cold-knife conisation or laser conisation resulted in about one perinatal death in every 70 pregnancies.2
LLETZ was associated with a lesser risk of two perinatal deaths in 1000 pregnancies.2 Radical
diathermy, as opposed to tailored superficial destruction of the transformation zone performed by
inserting a ‘needle’ into the cervix to a distance greater than 1 cm, also seemed to cause adverse obstetric
outcomes.10 Severe and extreme preterm delivery (less than 32 weeks) and low birth weight (less than
2000 g) were common after cold-knife conisation and diathermy but rare after large-loop excision.2
Two further publications in 2009 studying large numbers of women also reported a two- to three-fold
increase in risk of preterm delivery associated with LLETZ.12,13 Thus, these two large meta-analyses
corroborate the conclusion that laser ablation does not affect obstetric outcomes.1,2 The differences in the
seriousness of adverse effects noted between cold-knife conisation and LLETZ might be related to
variations in the amount of tissue removed. Knife cones, by definition, excise more tissue than loop,
while loop cones might vary significantly from small to average or large. Something similar might
explain the differences in terms of premature birth between laser ablation and loop excision, as the laser
beam allows more accurate destruction with possibly less damage of redundant healthy cervical tissue.
Although the recent meta-analysis did not confirm a significant increase of more severe outcomes with
LLETZ, it is important to consider that even non-severe prematurity has implications in terms of
admission to special care units, health resources and cost, and maternal anxiety.14
4.
Biological mechanism
The mechanism by which the association between treatment for CIN and preterm delivery occurs is not
yet clarified. Women with previous excisional cervical treatment were found to have a shorter midtrimester mean cervical lengths9 but a length below 2.5 cm occurred in only 28% of women with previous
cervical surgery,15 suggesting that more subtle mechanisms than mechanical weakness are involved.
A potential problem with the reported association between cervical surgery for CIN and preterm birth
is that of confounding factors since both preterm birth and CIN are known to be more prevalent in
smokers and women of poor social economic class.16 A recent publication accounted for these
confounding factors in a regression analysis but found that the association between conisation and
preterm delivery remained.17 The same authors compared pregnancy outcomes in the same women
before and after cervical treatment and still found an increased risk of preterm birth after surgery, again
attributing the association with preterm birth to the treatment rather than any confounding factors.17
Ascending infection, from the vagina into the fetoplacental unit is commonly seen and presumed to be
causative in preterm labour. The cervix is thought to be an important physical and immunological barrier
to ascending infection,18 hence any weakening of the cervical barrier could increase the risk of infection
and preterm labour and delivery. The association of LLETZ with preterm prelabour premature rupture
of the membranes12 supports the concept of a weakened defence against infection as the pathophysiological basis for the reported association.
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5.
Obstetric management of women with a history of treatment for CIN
Until different research aspects are investigated and new data published, women receiving treatment for
high-grade lesions with a proportionally large excision should be alerted by their colposcopist that in the
event of a future pregnancy, they should be considered at high risk of preterm delivery. This is
particularly relevant for women who have had two excision treatments, as they are particularly at risk
of preterm delivery (estimated to be up to ten times the background risk)17 and for those who have had
treatment by knife conisation. Warning women of an increased risk of preterm birth may increase their
anxiety but may also increase the likelihood that they seek medical help should symptoms of preterm
labour occur.
The question arises as to how obstetricians should manage the subsequent pregnancies of women who
have had excisional cervical treatment for CIN. The increased risk of preterm delivery in women who
have had destructive treatment for CIN is very similar to that of women with a past history of previous
preterm birth.19 In current UK obstetric practice, women with a past history of preterm birth are treated
as high-risk patients and referred to high-risk antenatal clinics. The clinics provide a package of care that
can include serial transvaginal cervical scanning and/or fetal fibronectin screening and, if the woman
screens positive, preventative treatments such as cervical cerclage, progesterone and antenatal
corticosteroid therapy. The problem with this ‘screen and treat’ approach is that it has not been shown
to improve pregnancy outcome20 and is probably not cost effective.19 Further research in this area has
been recommended.19
Mid-trimester cervical shortening was found to predict preterm birth in women with previous excisional
cervical surgery.15 Furthermore, progesterone, but not cervical cerclage, was found to reduce the rate of
preterm birth in women with a short cervix.21,22 However, the issue of trying to prolong pregnancy is
complicated by the lack of trials of preterm labour prevention that include long-term paediatric
outcomes. There is a concern that prolonging pregnancy in women at risk of preterm delivery may
simply keep the fetus in an unfavourable intrauterine environment and thereby increase paediatric
morbidity. Hence, further research is required to determine the optimal management of pregnancy in
women with a history of excisional cervical surgery for CIN.
6.
Health services and organisational implications
Treatment for CIN has obstetric consequences that should be considered in young women. Policies of
‘see and treat’ may have been attractive in organisational terms as they involve the minimum number of
outpatient attendances. However, a more conservative approach should be the best way forward if we
are to minimise the damage to future pregnancy outcomes. This conservative approach could include
observational management of low-grade disease in young women, adoption of ‘select and treat’
management protocols and consideration of ablative techniques in histologically proven persistent lowgrade disease, in preference to excisional treatment, and possible consideration of ablative treatment in
high-grade squamous disease when there is no evidence of invasive disease when colposcopy has been
performed by experienced practitioners.
7.
Opinion
Colposcopists need to be mindful when planning treatment to the cervix for preinvasive disease that
excessive excisional treatment might result in higher risks of obstetric morbidity in subsequent
pregnancies. Treatment should always be conducted not only to minimise failure rates but to minimise
possible subsequent obstetric morbidity. Gynaecologists should give additional information to the
patient as to the amount of cervical tissue removed and the damage to the endocervical canal. Further
research is required to predict which women are at risk in subsequent pregnancies and to define antenatal
interventions that might reduce such risks.
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References
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This Scientific Impact Paper was produced on behalf of the Royal College of Obstetricians and Gynaecologists by
Professor SM Quenby FRCOG, Warwick, and Dr PL Martin-Hirsch FRCOG, Lancashire.
It was peer reviewed by: RCOG Consumers’ Forum; Dr RG Hughes FRCOG, Edinburgh; Dr TBR Freeman-Wang MRCOG,
London; Dr ME Cruickshank FRCOG, Aberdeen.
The Scientific Advisory Committee lead reviewer was Mr CWE Redman FRCOG, Staffordshire.
At the time of publication, the Chair of the Scientific Advisory Committee was Professor S Thornton FRCOG and the Vice Chair
was Professor R Anderson FRCOG.
The final version is the responsibility of the Scientific Advisory Committee of the RCOG.
The review process will commence in 2013 unless otherwise indicated.
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