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Keywords:

  • Cervical intraepithelial neoplasia;
  • cervix;
  • incomplete excision;
  • large loop excision of the transformation zone;
  • loop treatment;
  • recurrence

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure of interests
  8. Contribution to authorship
  9. Details of ethics approval
  10. Funding
  11. Acknowledgements
  12. References
  13. Supporting Information

Please cite this paper as: Ang C, Mukhopadhyay A, Burnley C, Faulkner K, Cross P, Martin-Hirsch P, Naik R. Histological recurrence and depth of loop treatment of the cervix in women of reproductive age: incomplete excision versus adverse pregnancy outcome. BJOG 2011;118:685–692.

Objective  Recent meta-analyses have shown that loop treatment of the cervix of >10 mm depth may be associated with adverse outcomes in future pregnancies. The aim of this study is to assess the rate of incomplete excision and recurrent disease in relation to depth of excision in women of reproductive age undergoing loop treatment.

Design  Observational cohort study.

Setting  Colposcopy Clinic, Northern Gynaecological Oncology Centre, Gateshead, UK.

Population  In all, 1558 women undergoing loop treatment for high-grade cervical intraepithelial neoplasia (HGCIN) between 1998 and 2003.

Methods  Women were followed up until 2008. Recurrence was analysed using Kaplan–Meier plots.

Outcome measures  Incomplete excision rates and recurrence rates. Recurrence was defined as post-treatment disease with high-grade histology. Any dyskaryotic cytology on follow-up was also documented.

Results  Recurrent high-grade disease on histology was found in 57/1558 (3.7%) women. In women ≤35 years old, despite a greater rate of incomplete excision at the endocervical margin at loop depths <10 mm compared with ≥10 mm (24.4% versus 13.3%, P < 0.01), the recurrence rate was similar between the two groups (4.3% versus 3.4%, log-rank, P = 0.52). In contrast, a loop depth <10 mm was associated with a higher disease recurrence rate (7.5% versus 3.0%, log-rank, P = 0.05) in women >35 years.

Conclusion  In women of reproductive age requiring treatment for HGCIN, colposcopists performing loop excision should aim for <10 mm depth. This provides adequate treatment for HGCIN and minimises the potential risk of adverse outcomes in future pregnancies.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure of interests
  8. Contribution to authorship
  9. Details of ethics approval
  10. Funding
  11. Acknowledgements
  12. References
  13. Supporting Information

Recent meta-analyses relating to pregnancy outcome after loop treatment have resulted in considerable debate on the management of women of reproductive age suspected of having high-grade cervical intraepithelial neoplasia (HGCIN).1–3 A recent commentary suggested that some women may be best managed by reverting to a previously established technique of ablation that appears to be as effective in the successful treatment of HGCIN but without any evidence of adverse outcomes in subsequent pregnancies.4

This change in practice from loop excision to ablation has been met with some resistance from the colposcopy community who have become familiar with the use of loop treatment largely because of the many advantages associated with it including, (1) ease of use, (2) speed of treatment, (3) relatively cheap, (4) low risk of complications, (5) option of treatment at the first appointment (see and treat), (6) tissue, often in one piece, for histological analysis allowing better detection of occult cancers, and (7) ability to determine histological margin involvement to help guide further management especially in older women. Loop treatment continues to be the commonest mode of treatment for the management of HGCIN in the UK5 and in other developed countries.

In general, colposcopy practice has become more refined with increasing effort to avoid overtreatment in young nulliparous women by not performing loop treatment unless the likelihood of HGCIN is considered to be very high or has been confirmed by a previous histological biopsy.6 The colposcopist is always required to make a judgement as to the depth of loop treatment, and has to balance the potential sequelae of a shallow loop resulting in the risk of incomplete treatment and persistent disease with performing a deep loop and risking potential adverse outcomes in future pregnancies. To date, there are no convincing data or evidence to provide clear guidance to the colposcopist on the optimal depth of treatment in young women requiring excisional treatment.

Pathological analyses have suggested that crypt depths may extend up to 8 mm from the epithelial surface7 and general guidance has been that treatment should be at least to this depth. In addition, a recent meta-analysis relating to histological/cytological outcomes after loop treatment has shown that if the HGCIN is incompletely excised at the deep margin then there is a significant increased risk of recurrent disease.8 This meta-analysis did not provide any information relating to the depth of treatment required to ensure completeness of excision and has resulted in the practice by some colposcopists to treat/excise as deep as is feasible in the possibility that HGCIN may extend deep into the endocervical canal. The meta-analysis1 relating to future pregnancy outcome, however, has suggested that there is increased risk of preterm delivery after loop treatments >10 mm in depth. General opinion therefore is that in women of reproductive age who require treatment for HGCIN a loop treatment aiming for between 8 and 10 mm in depth would appear to be the optimal management on the basis that this should result in a low-risk of incomplete excision and therefore recurrent disease without adversely affecting future pregnancy outcome.

In the absence of any published data relating to depth of treatment and its association with histological outcomes, this current study was devised to provide the colposcopist with some guidance on the optimal depth of treatment/excision in women of reproductive age. In addition, it was hypothesised that if treatment <10 mm in depth in women of reproductive age was associated with an unacceptably high rate of recurrent disease then this would provide additional weight in support of the arguments for treatment by ablation in the management of this group of women.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure of interests
  8. Contribution to authorship
  9. Details of ethics approval
  10. Funding
  11. Acknowledgements
  12. References
  13. Supporting Information

This was a cohort study of women who underwent cervical loop excision for HGCIN treated at the Northern Gynaecological Oncology Centre, Gateshead, between January 1998 and December 2003. Women with histologically confirmed CIN 2 or CIN 3 were identified from the histopathology and colposcopy databases. Demographics such as age, previous cervical loop history, cervical loop measurements including depth, surface area (a*b*π; small <500 mm2, medium 500–1000 mm2 and large >1000 mm2), completeness of excision at both endocervical and ectocervical margins (defined as histologically confirmed CIN of any grade at excision margins), subsequent smears and histological outcome were recorded. Participants were excluded for: loop histology confirming the presence of benign or inflammatory disease, low-grade disease, intraepithelial glandular neoplasia or invasive disease or uncertain excision margins because of fragmented specimen or diathermy artefact. Women in whom the loop depth was not recorded, or who did not have at least one follow-up smear were also excluded from the analyses. Information on follow-up and cytological/histological outcomes were obtained until December 2008. Women were followed up predominantly in primary care according to local and National guidelines.6 The smear history was obtained from the National Cervical Screening Database using the Exeter System® to ensure completeness of follow-up. Women with abnormal smears were referred back for colposcopic assessment, and biopsy if necessary. Recurrent disease was defined in this study as histologically confirmed post-treatment HGCIN or worse and included early recurrence ‘persistent’ disease in the first 2 years and recurrent disease thereafter during follow-up. Cytological recurrence was defined as a subsequent smear showing mild dyskaryosis or worse.

Statistical analysis was carried out using SPSS® version 15 (SPSS Inc. Chicago, IL, USA). Kaplan–Meier statistics and log-rank (Mantel–Cox) test were used to determine time to recurrence. Data were censored for women who did not complete 5 years of follow-up and who did not have any disease recurrence within that time. Chi-square/Fisher’s exact statistics and odds ratio were used for analysing categorical data. Multivariate Cox regression analysis was performed using age, depth, surface area and endo/ectocervical margin status as predictors of recurrence. A P value <0.05 was accepted as being statistically significant.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure of interests
  8. Contribution to authorship
  9. Details of ethics approval
  10. Funding
  11. Acknowledgements
  12. References
  13. Supporting Information

Between 1998 and 2003, 2531 loop excisions were carried out (Figure 1). Data were available for 1690 women who met the inclusion criteria and had histologically proven HGCIN in the loop specimen. Of these women, 16 (0.9%) had had a previous loop excision and were excluded. Another 54 women were excluded because they did not have at least one follow-up smear and 62 women were excluded because of uncertain histological margins (ectocervical, endocervical or both). The final cohort analysed in this study comprised 1558 women with a median follow-up time of 77 months (range 3–132 months); 482 women (31%) had CIN2 and 1076 (69%) had CIN3. The median number of follow-up smears per woman was six (range 1–15), and the mean was 5.9 (SD 2.6). Of the women, 1145 (73.5%) were ≤35 years of age. Distribution of age groups and loop depths are presented in Table 1. Fifty-seven women (3.65%) had histological recurrence of HGCIN; age ≤35 years, n = 41 (3.6%) and age >35 years, n = 16 (3.9%). A total of 176 (11.2%) women had cytological recurrence (mild dyskaryosis or worse) on follow-up smears of whom 112 (7.2%) had high-grade dyskaryosis. In univariate analyses, neither age >35 years or margin status at the ectocervix was associated with disease recurrence. Mean age in women with histological disease recurrence was 31.72 ± 10.77 years compared with 31.49 ± 8.51 years in women who did not have recurrent disease. In multivariate Cox regression analyses, margin status at the endocervix was an independent prognostic factor for disease recurrence (hazard ratio 0.42, 95% CI 0.24–0.74; P = 0.003), but not age, depth/surface area of loop, severity of lesion or incomplete excision at ectocervical margin. (see Table S1). Table 2 represents the relation of margin status with disease recurrence in univariate analysis. Margin status and recurrence rate in relation to loop surface area is presented in Table S2.

image

Figure 1.  Flow diagram of inclusion and exclusion criteria.

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Table 1.   Distribution of age groups and loop depths
 Age ≤35 years (n = 1145) n (% of total)Age >35 years (n = 413) n (% of total)P value
Age group
≤25 years423 (27.2)  
26–30 years397 (25.5) 
31–35 years325 (20.9) 
36–40 years 218 (14.0)
>40 years 195 (12.5)
Loop depth
≤5 mm75 (6.6)25 (6.1)0.51
6–8 mm139 (12.1)46 (11.1)
9–10 mm356 (31.1)122 (29.5)
11–15 mm419 (36.6)166 (40.2)
>15 mm156 (13.6)54 (13.1)
Surface area of loop
≤500 mm220 (1.7)9 (2.2)0.81
500–1000 mm2304 (26.6)106 (25.7)
>1000 mm2821 (71.7)298 (72.2)
Severity of CIN
CIN2365 (32)117 (28)0.67
CIN3780 (68)296 (72)
Table 2.   Incomplete excision margins and histological disease recurrence
 Age ≤35 years (n = 1145)Age >35 years (n = 413)
nRec* (%)OR (CI)nRec* (%)OR (CI)
  1. *Rec, histological recurrence.

  2. **P value obtained from Fisher’s Exact test (two-sided).

Endocervical margin
Incomplete1786.22.05 (1.01–4.18)1187.63.39 (1.23–9.36)
Complete9673.12952.4
P value** 0.042 0.017
Ectocervical margin
Incomplete4343.00.75 (0.36–1.47)1294.71.33 (0.47–3.76)
Complete7113.92843.5
P value** 0.512 0.589
Both margins
Incomplete837.22.28 (0.93–5.60)3910.33.44 (1.05–11.26)
Others10623.33743.2
P value** 0.113 0.054

Disease recurrence at various loop depths

Histological recurrence across different loop depths is shown in Figure 2(A). In women ≤35 years, there was no difference in the recurrence rate across various loop depths. However, in women >35 years old, there was a significantly higher (odds ratio 2.89, 95% CI 1.08–7.69) recurrence rate at loop depths ≤8 mm compared with >8 mm (log-rank, P = 0.02). A 10-mm loop depth or greater was not associated with any increase in disease recurrence (log-rank, P = 0.78; Figure 3). A similar trend was observed in both age group categories with cytologically high-grade disease recurrence (Figure 2B). However, the difference was not statistically significant.

image

Figure 2.  Histological and cytological recurrence rates at various loop depths in women ≤35 and >35 years of age; *P < 0.05.

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image

Figure 3.  Kaplan–Meier survival curves for histological recurrence at different loop depths in women ≤35 years versus >35 years of age. Higher recurrence seen at lower depths in older women, but no difference in younger women.

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Overall mean time to recurrence was 48 months (interquartile range 14–79) and was not different in women aged ≤35 years (mean 48 months, 95% CI 38–59) compared with women >35 years (mean 48 months, 95% CI 26–69). Twenty of the 57 women had an early disease recurrence. Early (n = 15 of 41, 36.6%) and late recurrence (n = 26 of 41, 63.4%) rates were not significantly different in women aged ≤35 years compared with women aged >35 years (early recurrence n = 5 of 16, 31.3% versus late recurrence n = 11 of 16, 68.8%) across all loop depths (P = 0.767). However, in women >35 years old, four of the five early recurrences were seen in women with loop depths of ≤8 mm (P = 0.036). In contrast, in women ≤35 years, 76.9% of early recurrences were seen at loop depths >8 mm.

Loop depth and excision margins

The association between incomplete excision margin and different loop depths along with histological disease recurrence rates are presented in Table 3. There was no difference in the rate of incomplete excision at the ectocervical margin across different loop depths in both age groups. The main question we wanted to ask in this study was whether disease recurrence was higher at loop depths <10 mm in women ≤35 years. Therefore we calculated incomplete excision and disease recurrence rates at this cut-off (Table 4 and Figure 3). In women ≤35 years, despite a greater rate of incomplete excision at the endocervical margin at loop depths of <10 mm compared with ≥10 mm (24.4% versus 13.3%, odds ratio 1.83, 95% CI 1.38–2.42, P < 0.01), the recurrence rate was not significantly different at these loop depth categories (4.3% versus 3.4%, log–rank = 0.52).

Table 3.   Incomplete endocervical and ectocervical excision margins and histological disease recurrence rates at different loop depths
Loop depth (mm)≤35 years (n = 1145)>35 years (n = 413)
n+ecto+endo+bothRecn+ecto+endo+bothRec
n (%)n (%)n (%)n (%)n (%)n (%)n (%)n (%)
  1. ecto, ectocervical; endo, endocervical; Rec, recurrence.

1–57541.3 (31)24.0 (18)10.7 (8)2.7 (2)2548.0 (12)52.0 (13)28.0 (7)4.0 (1)
6–813943.9 (61)25.2 (35)13.7 (19)5.8 (8)4637.0 (17)32.6 (15)17.4 (8)10.9 (5)
9–1035637.6 (130)13.2 (47)4.5 (16)3.4 (12)12240.2 (49)33.6 (41)9.8 (12)1.6 (2)
11–1213932.4 (45)9.4 (13)3.6 (50)1.4 (2)6412.5 (8)26.6 (17)4.7 (3)0
>1243637.4 (163)14.9 (65)8.0 (35)3.9 (17)15631.2 (48)20.5 (32)5.8 (9)5.1 (8)
Table 4.   Margin positivity and histological recurrence at loop depth <10 mm vs ≥10 mm
Loop depthTotalEndo +Ecto +Recurrence
nn (%)n (%)n (%)
  1. ecto, ectocervical; endo, endocervical.

Age ≤35 years1145178 (15.5)434 (37.9)41 (3.6)
<10 mm23457 (24.4)99 (42.3)10 (4.3)
≥10 mm911121 (13.3)335 (36.8)31 (3.4)
Odds ratio (95% CI)1.83 (1.38–2.42)1.15 (0.96–1.36)1.25 (0.62–2.52) 
P value<0.0010.1310.554 
Age >35 years413118 (28.6)129 (31.2)16 (3.9)
<10 mm8033 (41.3)34 (42.5)6 (7.5)
≥10 mm33385 (25.5)95 (28.5)10 (3.0)
Odds ratio (95% CI)1.61 (1.17–2.22)1.49 (1.09–2.02)2.49 (0.93–6.67) 
P value0.0080.0220.061 

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure of interests
  8. Contribution to authorship
  9. Details of ethics approval
  10. Funding
  11. Acknowledgements
  12. References
  13. Supporting Information

The results of this study of loop treatment in over 1000 women ≤35 years of age show that there are no significant increases in the risk of post-treatment high-grade disease recurrence rates with loop depths <10 mm, which provides reassurance that there is no need to perform loop treatment >10 mm in depth in women of reproductive age. The impact of this result is that colposcopists should aim to perform loop treatments of <10 mm in depth in women of reproductive age to avoid potential adverse outcomes in future pregnancies and without fear of increasing the risk of recurrent disease in this group of women.

To our knowledge, this is the first study to investigate the risk of recurrent disease in women of reproductive age based on depth of loop treatment. The finding that loop treatment <10 mm in depth results in excellent outcomes with no increase in risk of recurrence is highly supportive of the continuation of loop treatment as an ideal mode of treatment of HGCIN in women of reproductive age where previous studies have shown lower risk of adverse outcomes in future pregnancies when loop treatment does not exceed 10 mm in depth.

In women over the age of 35 years, however, our results suggest that treatment should be at least 10 mm in depth to ensure adequate treatment and to reduce the risk of recurrent disease. This age-dependent difference in risk of recurrence is likely to be the result of the anatomical differences in the position of the squamo–columnar junction, with younger women being expected to have a Type 1 or 2 transformation zone (TZ) with the squamo–columnar junction closer to the outer aspects of the cervix and older women being expected to have a Type 2 or 3 TZ with the squamo–columnar junction further within the cervical canal. The limitation of our study was lack of complete information on squamo–columnar junction and lesion size; we would recommend that this be included in future studies.

In our study, loops with smaller surface area in women aged ≤35 years were not associated with disease recurrence, presumably because of complete excision of small lesions. However, in women aged >35 years, loops with a smaller surface area had a higher prevalence of incomplete excision at the endocervical margin (44.4%) and disease recurrence.

This result would appear to be consistent with previous reports relating to the required depth of excision of the cervical tissue to prevent residual HGCIN in the cervical crypts. Anderson and Hartley7 in 342 cone biopsies showed that the mean depth of involved crypts was 1.2 mm and of uninvolved crypts was 3.4 mm, and that destruction to a depth of 3.8 mm would eradicate 99.7% of all involved crypts. They also showed that the maximum depth of a normal cervical gland was 7.8 mm. Heatley9 in 280 consecutive loop specimens showed similar results and stated that almost 100% of CIN-involved crypts were within 4.8 mm of the epithelial surface. Milinovic et al. 10 in 218 cone specimens also showed that the mean endocervical crypt involvement was 1.2 mm and that excision deeper than 4 mm removed >99% of CIN. In the same study, the authors also showed that in nulliparous and multiparous women, respectively, cone lengths of 15 and 18 mm did not result in any endocervical margin involvement. Fadi et al. 11 in 319 cone specimens, in addition to investigating crypt depth involvement, also investigated the linear extent of CIN and the location of CIN on the cervix. They showed that to eradicate 95% of CIN 3, the treatment should be to a depth of 3.6 mm and for a distance of 16.0 mm; 87.2% of the lesions occurred in the TZ whereas 3.1% of lesions occurred on the ectocervix without connection to the TZ and 9.7% of lesions were located in the cervical canal (rising to 28.6% of lesions in women over the age of 51 years). Boonstra et al. 12 recorded similar results—eradication of over 99% of CIN required treatment of involved crypts to a depth of 3.6 mm, with a linear extent of 14.8 mm and extending from between 1 mm distally and 21 mm proximally from the most caudal point of the ectocervix.

Based on these data, the general advice, from the NHS Cervical Screening Programme guidance and European Guidelines on Colposcopy have been that loop treatment should be of at least 8 mm depth.6,13 Although in our study, women ≤35 years of age did not have an increased disease recurrence rate even at loop depths ≤8 mm, it would seem logical that a cervical loop biopsy should be at least this amount to ensure adequate removal of the cervical glands.

The literature relating to incomplete excision and recurrence rates of HGCIN, however, are more variable. In a meta-analysis by Ghaem-Maghami et al.,8 including 66 studies and involving 35 109 women, it was shown that after incomplete excision (any margin including uncertainty of margin status), the recurrence risk of any grade of post-treatment disease (histological or cytological) was 5.47. The median proportion of women with involved margins was 24% (interquartile range 16–33). The pooled prevalence (histological or cytological) of post-treatment disease was 21% (336/1589) in those with involved endocervical margins, 16% (213/1374) in those with involved ectocervical margins, and 23% (99/434) when both margins were involved. The combined (histological and cytological) high-grade post-treatment recurrence rate was 18% for women with incomplete excision (any margin including uncertainty of margin status) compared with 3% with complete excision (relative risk 6.09).

Our study focused on high-grade disease recurrence and the overall post-treatment recurrence rates (histological 3.7%, cytological 7.2% and combined high-grade histological/cytological 7.8%), are comparable to some of the studies included in the above-mentioned meta-analysis and also in a meta-analysis by Arbyn et al.14 In a study by Paraskevaidis et al.,15 where only histological HGCIN was taken as an endpoint for post-treatment recurrence, 27% of women with involved margins (any margin) had recurrence. Although our incomplete excision rates at the endocervical and ectocervical margins were related to depth of excision, histological high-grade disease recurrence in women with involved margins was 6–7% with endocervical margins, 3–5% with ectocervical margins and 8–9% when both margins were involved. This result is similar to an earlier study from our department, which also showed no increased risk of disease recurrence with involved margins.16

In our study, the overall mean time to recurrence was 48 months regardless of age. Other studies have shown, however, that the highest rate of recurrent disease appears to occur in the first 2 years after treatment.17,18 A study by Flannelly et al.17 involving 3426 women showed that the maximum rate of recurrence occurred in the first 6 months following large loop excision of the TZ (LLETZ) but the rate remained constant thereafter up to 5 years. Chew et al.18 demonstrated that in women who required further treatment after their initial LLETZ, 52% were within the first 12 months and 71% within 24 months. This variation in outcomes relating to completeness of excision and subsequent recurrent disease may be partly explained by the practice of diathermy ball ablation of the loop base/crater following the loop excision. Although the indication for this is to induce haemostasis following the loop excision, it is presumed that the diathermy causes further damage to the remaining cervix and provides additional treatment to any residual HGCIN, which may not have been removed by the loop excision, resulting in a reduced likelihood of under treatment and therefore recurrence. Cervical craters that are more vascular may inadvertently receive a greater degree of diathermy and may result in greater damage to the residual cervix. This element of the treatment is not currently measured or graded and there are no data to determine whether it is the combined effect of the excision and the diathermy that influences not only disease recurrence but also the integrity of the cervix and its ability to provide adequate function during future pregnancies. For this reason, we would recommend that each LLETZ procedure is better described as ‘LLETZ without diathermy’ or ‘LLETZ with diathermy’ or alternatively ‘LLEATZ’ (i.e. large loop excision and ablation of the transformation zone) to highlight the potential damage that may occur to the cervix during the ablation after excision. This terminology would also emphasise the need to perform a loop excisional procedure in women of reproductive age that is <10 mm in depth and to apply minimal diathermy to the cervical base/crater to minimise any additional damage that may occur to the residual cervix and so help to safeguard any future pregnancies.

In conclusion, in women of reproductive age requiring treatment for HGCIN, colposcopists performing loop excision should aim for a depth between 8 and 10 mm. This provides adequate treatment for HGCIN without any evidence of adverse outcomes in future pregnancies. The procedure of LLETZ should be better described as LLETZ with or without ablation, or alternatively, LLETZ or LLEATZ, to highlight the need to minimise the use of diathermy associated with the procedure. Authorities preparing guidelines on colposcopy practice might consider revising descriptions of optimal excisional treatment in young women.

Contribution to authorship

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure of interests
  8. Contribution to authorship
  9. Details of ethics approval
  10. Funding
  11. Acknowledgements
  12. References
  13. Supporting Information

RN devised the study, supervised the data collection and analyses and contributed to the discussions. CA and AM collected the data, performed the analyses and contributed to the discussions. CB collected the data. PAC collected the data and contributed to the discussions. KF and PMH contributed to the discussions. All authors approved the final manuscript.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure of interests
  8. Contribution to authorship
  9. Details of ethics approval
  10. Funding
  11. Acknowledgements
  12. References
  13. Supporting Information
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  • 2
    Arbyn M, Kyrgiou M, Simoens C, Raifu AO, Koliopoulos G, Martin-Hirsch P, et al. Peri-natal mortality and other severe adverse pregnancy outcomes associated with treatment of cervical intraepithelial neoplasia: a meta-analysis. BMJ 2008;337:a1284.
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    Paraskevaidis E, Kalantaridou SN, Paschopoulos M, Zikopoulos K, Diakomanolis E, Dalkalitsis N, et al. Factors affecting outcome after incomplete excision of cervical intraepithelial neoplasia. Eur J Gynaecol Oncol 2003;24:5413.
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Supporting Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure of interests
  8. Contribution to authorship
  9. Details of ethics approval
  10. Funding
  11. Acknowledgements
  12. References
  13. Supporting Information

Table S1. Multivariate analysis of prognostic factors of histological recurrence (Cox regression).

Table S2. Histological recurrence and incomplete excision margins in relation to loop surface area.

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BJO_2929_sm_TableS1-2.doc26KSupporting info item

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