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Pregnancy outcome after cervical conisation: A 2nd retrospective cohort study in the Leuven University Hospital
Accepted Manuscript Title: Pregnancy outcome after cervical conisation: A 2nd retrospective cohort study in the Leuven University Hospital Authors: Kim van Velthoven, Willy Poppe, Hannah Verschuere, Marc Arbyn PII: DOI: Reference:
S0301-2115(17)30320-2 http://dx.doi.org/doi:10.1016/j.ejogrb.2017.06.043 EURO 9966
To appear in:
EURO
Received date: Revised date: Accepted date:
18-4-2017 24-6-2017 27-6-2017
Please cite this article as: van Velthoven Kim, Poppe Willy, Verschuere Hannah, Arbyn Marc.Pregnancy outcome after cervical conisation: A 2nd retrospective cohort study in the Leuven University Hospital.European Journal of Obstetrics and Gynecology and Reproductive Biology http://dx.doi.org/10.1016/j.ejogrb.2017.06.043 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Pregnancy outcome after cervical conisation: a 2nd retrospective cohort study in the Leuven University Hospital
Kim van Velthoven a, Willy Poppe a, Hannah Verschuere a, Marc Arbyn b Leuven, Belgium
Department of Obstetrics and Gynaecology, University Hospitals Leuven – Campus Gasthuisberg Leuven, Belgium b Unit of Cancer Epidemiology, Belgian Cancer Centre, Scientific Institute of Public Health, Brussels, Belgium\ a
Correspondence concerning manuscript: Kim van Velthoven, University Hospitals Leuven – Campus Gasthuisberg, Department of Obstetrics and Gynaecology, Herestraat 49, 3000 Leuven, Belgium E-mail address: [email protected]
CONDENSATION Our two successive studies show a significant trend towards smaller cones which is accompanied by a decrease in preterm birth after excisional treatment.
ABSTRACT
Objective: to evaluate whether the dimensions of the cones removed during large loop excision of the transformation zone have decreased over time. Secondly, whether these changes were associated with a lower risk of obstetrical harms on a subsequent pregnancy. Study design: A retrospective matched cohort study was performed in a tertiary referral unit in Belgium. A total of 97 women were identified from a database of women who underwent excisional treatment for cervical precancer between January 1st, 2004 and December 31st, 2012, and delivered before December 31st, 2014. The control group consisted of 120 non-treated women who had no history of cervical intra-epithelial
K. van Velthoven et al. / Pregnancy outcome after cervical conisation: a 2nd retrospective cohort study in the Leuven University Hospital
neoplasia. Data on smoking status; gestational age at delivery; number of conisations; time interval between treatment and pregnancy; dimensions of the cone; severity of the lesion; and the extra resection of endocervical tissue were collected. These data were compared with those from a previous similar study at the University Hospital of Leuven in 2009, which database we enriched with information on the cone dimensions. Main outcome variables were gestational age at delivery, birthweight and neonatal condition at birth. Results: Only a significant lower birthweight could be found in the treated group compared to the control group (3364 gram [95% CI 3094 – 3290] versus 3364 gram [95% CI 3253 – 3475], P = 0.023). The current study showed no increase in preterm birth rate after conisation and no relationship between volume or depth of the cone and preterm birth could be found. Over the period 1999-2014, a significant decrease in all dimensions was observed: on average -0.3mm, -0.3mm, -0.4 mm and -132mm3 per year, for the depth, anteroposterior and transverse diameter and the volume, respectively. Conclusions: Our two successive studies showed a significant trend towards smaller cones which was accompanied by a decrease in preterm birth after excisional treatment. The clinician could limit the size of the cone to avoid obstetrical harms, but needs to be aware of the oncological safety as well.
Keywords: Large loop excision of the transformation zone (LLETZ), cervical intraepithelial neoplasia (CIN), pregnancy duration, dimensions of the cone INTRODUCTION Large loop excision of the transformation zone (LLETZ) is the standard treatment for cervical intra-epithelial neoplasia (CIN) (1). The aim of this treatment is to remove the abnormal transformation zone. At the same time the cervical function needs to be 2
K. van Velthoven et al. / Pregnancy outcome after cervical conisation: a 2nd retrospective cohort study in the Leuven University Hospital
preserved. This is important since the peak incidence of CIN coincides with the reproductive age (2). The side effects associated with treatment of cervical precancer are preterm birth, premature rupture of the membranes and neonatal morbidity (3,4). In 2009, a study performed at the University Hospital of Leuven, Belgium demonstrated a significantly increased risk of preterm birth that was substantially higher than noted in two large meta-analyses (3 - 5). The causes of the obstetrical harm after excision of a CIN lesion are not fully clarified. However, the observation that larger cones are associated with a higher risk of preterm birth provides evidence for a causal relation (6,7). Awareness of the obstetrical harm may have generated a tendency to treat CIN lesions less aggressively to avoid risks of preterm birth (8,9). Therefore, the aim of our study was to verify whether the dimensions of the cones removed during LLETZ also have decreased over time in our clinic. Secondly, whether these changes were associated with lower risks of obstetrical harms on a subsequent pregnancy. METHODS A retrospective matched cohort study was performed in a university centre for obstetrical and gynaecological care (University Hospital of Leuven, Belgium). Patients were identified from a database of 1382 women who underwent excisional treatment for cervical precancer by LLETZ or cold knife conisation (CKC) between January 1st, 2004 and December 31st, 2012 and subsequently became pregnant and delivered before December 31st, 2014. Miscarriages were excluded. A control group was defined using the following matching criteria: parity, maternal age at delivery (birth year ± 1 year), year of delivery (± 1 year) and twin pregnancy. These women had no history of CIN or any surgical treatment of the cervix. Data were collected on: maternal smoking status before and during pregnancy; gestational age at delivery (in postmenstrual days and –weeks); number of conisations; severity of the treated lesion; time interval between treatment and pregnancy; dimensions of the cone (measured post fixation in the pathology laboratory); and the presence of an endocervical recoupe (additional tissue removed from the endocervical canal if residual disease was suspected during treatment). Outcome variables were: duration of pregnancy; occurrence of preterm birth; birthweight; occurrence of low birth weight; and admission on neonatal intensive care unit (NICU). Patients with incomplete information regarding exposure or outcome variables were excluded. The volume of the excised cone was computed assuming a hemi-ellipsoid shape: volume = ½ x 4/3 x π x a/2 x b/2 x c, where a = transverse diameter, b = anteroposterior diameter and c = depth of the cone (10). In case of multiple conisations, only the volume of the first cone was measured. The volume of an endocervical recoupe was not quantified but taken into account as possible affecting qualitative variable. The dimensions and the volume of the cones were correlated with the gestational age at delivery and histopathological diagnosis. Data from the current study were compared with those from a similar study, conducted also in the University Hospital of Leuven, that enrolled women who had excisional treatment for cervical precancer between 1999 and 2003 (5). The two studies are 3
K. van Velthoven et al. / Pregnancy outcome after cervical conisation: a 2nd retrospective cohort study in the Leuven University Hospital
labelled as the current “Leuven-2” study and the prior “Leuven-1” study. The database from the Leuven-1 study was enriched with information on the cone dimensions by linkage with the pathology report. For differences between two continuous variables the student-t test was used, while the Chi-square test was used for associations between categorical variables. Trend analyses were performed by linear regression. Statistical significance was defined as a p-value of <0.05. RESULTS The treated group consisted of 120 pregnancies (delivery after 22 weeks of gestation) in 97 women. Nineteen women had two subsequent pregnancies and two women had three subsequent pregnancies. Table 1 shows the characteristics of the treated women. High-grade intraepithelial neoplasia (CIN2/3 or adenocarcinoma in situ (AIS)) was found in 75% and invasive cervical cancer in 5% of the treated cases. A matched control group consisted of 120 pregnancies in 120 women. There were significantly more ex-smokers in the treated group than in the control group (27.5% versus 15%, p =0.042). No significant difference in smoking status during pregnancy could be demonstrated. The treated group and the control group included two twin pregnancies. These women delivered at 30 and 36 weeks of gestation (treated group) and at 28 and 37 weeks of gestation (control group). The dimensions and the volume of the cone were plotted against the age of the women, the period of conisation and the histopathological diagnosis (Fig. 1, appendix fig. A-C). A significant decrease of the dimensions and the volume of the cone during the study period was demonstrated (p < 0.001). The mean gestational age at delivery did not differ significantly between the treated and the control group (38.2 weeks [95% CI 37.8 – 38.7] versus 38.6 weeks [95% CI 38.2 – 39.0], p = 0.236). Table 2 shows the differences in preterm birth rates (<37 weeks) between the treated versus control group, women with only one versus multiple conisations and women with versus without an endocervical recoupe. The risk of severe preterm birth (< 34 weeks) was higher in the treated than in the control group (6/120 [5.0%] versus 4/120 [3.3%]), but the difference was not significant (RR 1.50 [95% CI 0.4 – 5.18]) . No correlation between the dimensions or the volume of the cone and the pregnancy duration was demonstrated (Fig. 2). Similarly, there was no correlation between depth (less or more than 10mm) and proportion of preterm birth (Appendix table A). A significant lower birth weight was found in the treated group compared with the control group (3364 gram [95% CI 3094 – 3290] versus 3364 gram [95% CI 3253 – 3475], p = 0.023). In addition, the frequency of low birth weight (<2500 gram) was higher in the treated group compared to the control group (12/118 [10.2%] versus 7/116 [6.0%]), but the difference was not significant (RR 1.69 [95% CI 0.69 – 4.13], appendix table B). No significant difference regarding referral to NICU between the treated group and control group was observed (12/118 [10.2%] versus 10/118 [8.5%], RR 1.20 [95% CI 0.54 – 2.67]). 4
K. van Velthoven et al. / Pregnancy outcome after cervical conisation: a 2nd retrospective cohort study in the Leuven University Hospital
There was no significant difference neither in the rates of preterm birth nor in low birth weight for women with a short time interval between treatment and pregnancy (< 12 months) compared to women with a time interval > 12 months (respectively RR 0.68 [95% CI 0.29 – 1.60] and RR 1.20 [95% CI 0.45 – 3.22]). This was the same for a time interval less or more than 24 months (respectively RR 1.01 [95% CI 0.43 – 2.38] and RR 0.98 [95% CI 0.39 – 2.46]). Appendix table C compares the enrolled populations included in the two Leuven studies. Significantly more ex-smokers (p = 0.003) and nulliparous women (p = 0.016) were seen in the Leuven-2 study. The risk of preterm birth was significantly higher in the Leuven-2 control group compared with the Leuven-1 control group (p = 0.025). The dimensions of the cone were larger in the Leuven-1 study, but this was statistically significant only for the transverse diameter (p = 0.017). Over the period 1999-2014, a significant decrease in all dimensions was observed: on average -0.3mm, -0.3mm, 0.4 mm and -132mm3 per year, for the depth, anteroposterior diameter, transverse diameter and the volume respectively. Combining the two studies, preterm birth (<37 weeks of gestation) and severe preterm birth (<34 weeks) were more frequent among treated versus non-treated women (respectively 30/175 [17.1%] versus 15/175 [8.6%], RR 2.00 [95% CI 1.12 – 3.58] and 12/175 [6.9%] versus 4/175 [2.3%], RR 3.00 [95% CI 2.43 – 9.12]). There also was a trend towards a significant relation between cone depth and pregnancy duration (p = 0.077). A depth > 10mm significantly increased the risk of preterm birth compared with the non-treated women (13/57 [22.8%] versus 15/175 [8.6%], RR 2.66 [95% CI 1.35 – 5.25], appendix table A). This was similar for severe preterm birth (7/57 [12.3%] versus 4/175 [2.3%], RR 5.37 [95% CI 1.63 – 17.69]).
DISCUSSION This study could not demonstrate a significant correlation between conisation of the cervix and preterm birth. However, babies had a lower birth weight in the treated group than in the control group. This is in contrast with the Leuven-1 study in 2009, which observed a significantly increased risk for preterm birth after conisation (5). Furthermore, no correlation between volume or depth of the cone and pregnancy duration was demonstrated. There was no higher risk of preterm birth for women with multiple conisations. However, only eight pregnancies occurred after multiple conisations. This is partly in concordance with British findings (11). Kitson et al. found an increased risk of preterm birth in women with a history of one or more conisations, but could not correlate this with the volume nor the depth of the cone. In contrast, a recent large meta-analysis confirmed a correlation between depth or volume of the cone and the risk of preterm birth (4). In the Leuven-1 study, also a minimal effect of depth was observed. However, there was a significant decrease of all dimensions over the period 1999-2014, possibly due to awareness of the obstetric risks. These findings suggest that the tendency to excise smaller cones in the Leuven-2 study may have resulted in a lower risk of preterm birth. A recent Norwegian study demonstrated this 5
K. van Velthoven et al. / Pregnancy outcome after cervical conisation: a 2nd retrospective cohort study in the Leuven University Hospital
clearly in a nationwide study linking the birth registry data and treatment databases from the whole of the country (8). In our Leuven-2 study no significant treatment effect was found anymore. Nevertheless, there still is an effect. This was considerably lower in magnitude compared to the Leuven-1 study and in addition became insignificant. So by combining our previous and current findings, we rather confirm findings of the Kyrgiou meta-analyses than the opposite (4). Additionally, one could expect smaller cones in younger women due to the decision of the clinician to resect less tissue in patients who might have a desire for future pregnancy. In the Leuven-2 study, however, we could not confirm those expectations. Papoutsis et al. earlier work supports this conclusion, as no differences were found in the percentage of positive section margins of the cone between older and younger women (12). Despite both studies separately considered for known risk factors for preterm birth (such as maternal age, smoking status and parity) another explanation for the heterogeneity between the Leuven-1 and Leuven-2 study is the different study population. Indeed, there were significant more non-smokers and nulliparous women in the Leuven-2 study. Unfortunately, it was impossible to come to any conclusions about a possible increased risk for multiparous women due to the lack of information on the obstetric history (especially earlier preterm birth). Furthermore, there were significantly more preterm births in the control group of the Leuven-2 study (10.8%) compared with the control group of the Leuven-1 study (3.6%). For comparison, the mean rate of preterm births in the whole Flemish population during the study period was 7.3% (13,14). So probably due to selection bias, the Leuven-2 control group represented a falsely high risk of preterm birth, whereas the risk in the control group of the Leuven-1 study probably was too low. Logically, this lead to an underestimation and overestimation of the risk of excisional treatment on preterm birth in the Leuven-2 and Leuven-1 study, respectively. In the future, we recommend nation- or region wide linkage of databases containing treatment data with birth registries. Such populationbased linkage studies, avoids selection biases that are inherent to small centre-based studies with manually performed matching. The risk of preterm birth might increase with a short conisation-to-pregnancy interval, especially when shorter than 2-3 months (15). Although the mechanism of this relation is not clear, this might be due to changes in the structural integrity of the cervix, limiting its ability to support a pregnancy. With time, the cervix may scar or regenerate, minimizing the structural weakness of the cervix (15). In the Leuven-2 study, there was a tendency for lower risk of preterm birth when the interval was > 12 months compared to < 12 months. The outcomes from our two Leuven studies are mainly based on LLETZ. Given the rather small study size, we have allowed also other excisional procedures. This was justified by evidence derived from the literature concluding that cone dimensions, in particular the relative size of the cone compared to the size of the cervix, determine obstetrical harm rather than the technique (16). This study is a retrospective study, and therefore some limitations needs to be mentioned, such as possible confounding factors and the risk of information and selection bias. Another limitation is the imprecision of the cone measurements and the 6
K. van Velthoven et al. / Pregnancy outcome after cervical conisation: a 2nd retrospective cohort study in the Leuven University Hospital
calculation of the actual volume (12). Ideally this should be performed by the water replacement technique. It remains difficult to find the right balance between adequate treatment and maintaining the cervical function. For oncological safety, the depth of the cone should be at least 8mm due to the depth of the cervical crypts (17). The aim is to achieve negative section margins. However, positive section margins do not mean that treatment is not successful (12). Indeed, residual abnormal tissue may be destroyed by the coagulation effects during LLETZ or may disappear by healing. A recent study by Ang et al. concluded no risk for residual disease in women younger than 35 years when the cone had a depth of less than 10mm (18). In the Leuven-2 study, it was impossible to report data on the follow up of our patients. We found a significant lower birthweight in the treated group than in the control group. However, the frequency of low birthweight was not significantly increased probably due to the small study size. Moreover, low birth weight may be caused by the gestational age at delivery. Therefore, it would be better to evaluate low birthweight as a birthweight below the 10th percentile for the gestational age (19). In the Leuven-2 study, only low birthweight less than 2500g was taken into account.
CONCLUSION Our two successive studies on pregnancy outcome after cervical conisation showed a significant trend towards smaller cones with time. This was related to a decrease in obstetrical harms, as no higher risk of preterm birth after excisional treatment could be demonstrate. Our current data could not correlate the dimensions nor the volume of the cone with a higher risk of preterm birth. However, the reduction of the dimensions with time in association with the lower risk, does suggest a relationship. The clinician could limit the size of the cone to avoid obstetrical harms, but needs to be aware of the oncological safety as well.
ACKNOWLEDGEMENTS Marc Arbyn has received support from the seventh framework program of DG Research of the European Commission, through the COHEAHR Network (grant No 603019 and from the Institut national du Cancer (Paris, France) through the COSPCC study (Conséquences obstétricales du (sur)traitement des précurseurs du cancer du col utérin) coordinated by the University of Amiens (France).
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REFERENCES (1) Prendiville W, Davies R, Berry PJ. A low voltage diathermy loop for taking cervical biopsies: a qualititative comparison with punch biopsy forceps. Br J Obstet Gynaecol 1986; 93: 773-6. (2) Arbyn M, Simoens C, Van Oyen H, et al. Analysis of 13 million individual patient records pertaining to Pap smears, colposcopies, biopsies and surgery on the uterine cervix (Belgium, 1996-2000). Prev Med 2009; 48: 438-43. (3) Arbyn M, Kyrgiou M, Simoens C, et al. Perinatal mortality and other severe adverse pregnancy outcomes associated with treatment of cervical intraepithelial neoplasia: meta-analysis. BMJ 2008;337:a1284-a1284. (4) Kyrgiou M, Athanasiou A, Paraskevaidi M, et al. Adverse obstetric outcomes after local treatment for cervical preinvasive and early invasive disease according to cone depth: systematic review and meta-analysis. BMJ 2016;354:i3633 (5) van de Vijver A, Poppe W, Verguts J, Arbyn M. Pregnancy outcome after cervical conisation: a retrospective cohort study in the Leuven University Hospital. BJOG 2010;117(3):268-273 (6) Noehr B, Jensen A, Frederiksen K, Tabor A, Kjaer S. Depth of cervical cone removed by loop electrosurgical excision procedure and subsequent risk of spontaneous preterm delivery. Obstet Gynecol 2009;114(6):1232-1238. (7) Castanon A, Landy R, Brocklehurst P, et al. Risk of preterm delivery with increasing depth of excision for cervical intraepithelial neoplasia in England: nested case-control study. BMJ 2014; 349: g6223. (8) Bjorge T, Skare GB, Bjorge L, Trope A, Lonnberg S. Adverse Pregnancy Outcomes After Treatment for Cervical Intraepithelial Neoplasia. Obstet Gynecol 2016. (9) Arbyn M, Kyrgiou M, Gondry J, Petry KU, Paraskevaidis E. Long term outcomes for women treated for cervical precancer. BMJ 2014; 348: f7700. (10) Phadnis SV, Atilade A, Young MPA, Evans H, Walker PG. The volume perspective: a comparison of two excisional treatments for cervical intraepithelial neoplasia (laser versus LLETZ). BJOG 2010;117(5):615-619. (11) Kitson S, Greig E, Michael E, Smith M. Predictive value of volume of cervical tissue removed during LLETZ on subsequent preterm delivery: a cohort study. Eur J Obstet Gynecol Reprod Biol 2014;180:51-55.
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(12) Papoutsis D, Rodolakis A, Mesogitis S, Sotiropoulou M, Antsaklis A. Appropriate cone dimensions to achieve negative excision margins after large loop excision of transformation zone in the uterine cervix for cervical intraepithelial neoplasia. Gynecol Obstet Invest 2013;75(3):163-168. (13) Cammu H, Martens G, Martens E, Van Mol C, Defoort P. Perinatale Activiteiten in Vlaanderen 2009. SPE, Brussel, 2010. (14) Devlieger R, Martens E, Martens G, Van Mol C, Cammu H. Perinatale Activiteiten in Vlaanderen 2014. SPE, Brussel, 2015. (15) Himes KP, Simhan HM. Time from cervical conization to pregnancy and preterm birth. Obstet Gynecol 2007;109(2):314-9 (16) Founta C, Arbyn M, Valasoulis G, et al. Proportion of excision and cervical healing after Large Loop Excision of the Transformation Zone (LLETZ) for CIN. BJOG 2010; 117: 1468-74. (17) Anderson MC, Hartley RB. Cervical crypt involvement by intraepithelial neoplasia. Obstet Gynecol 1980;55(5):546-550. (18) Ang C, Mukhopadhyay A, Burnley C, et al. Histological recurrence and depth of loop treatment of the cervix in women of reproductive age: incomplete excision versus adverse pregnancy outcome. BJOG 2011;118(6):685-692. (19) Simoens C, Goffin F, Simon P, et al. Adverse obstetrical outcomes after treatment of precancerous cervical lesions: a Belgian multicentre study. BJOG 2012;119(10):1247-1255.
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K. van Velthoven et al. / Pregnancy outcome after cervical conisation: a 2nd retrospective cohort study in the Leuven University Hospital
LEGENDS FOR FIGURES AND TABLES Figure 1. Age at conisation, period of the conisation and histological diagnosis versus depth of the cone. Figure 2. Dimensions and volume of the cone versus pregnancy duration (days).
Figure 1
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K. van Velthoven et al. / Pregnancy outcome after cervical conisation: a 2nd retrospective cohort study in the Leuven University Hospital
Figure 2
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K. van Velthoven et al. / Pregnancy outcome after cervical conisation: a 2nd retrospective cohort study in the Leuven University Hospital
Appendix Figure A. Age at conisation versus dimensions and volume of the cone. Figure B. Period of conisation versus dimensions and volume of the cone. Figure C. Histopathological diagnosis versus dimensions and volume of the cone.\
Appendix a
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K. van Velthoven et al. / Pregnancy outcome after cervical conisation: a 2nd retrospective cohort study in the Leuven University Hospital
Appendix b
13
K. van Velthoven et al. / Pregnancy outcome after cervical conisation: a 2nd retrospective cohort study in the Leuven University Hospital
Appendix c
14
Table 1. Characteristics of the treated women.LLETZ: Large loop excision of the transformation zone, CKC: cold knife conisation, CIN: cervical intra-epithelial neoplasia, AIS: adenocarcinoma in situ Values in bold are statistically significant differences (p < 0.05)
Maternal age (mean)
Smoking status Ever smoked Current smoker
Treated group
Control group
32.2
32.2
Number
%
Number
%
33/120 11/120
27.5 9.2
18/120 8/120
15.0 6.7
Number patients = 97)
of Number (N pregnancies (N = 120)
Type of conisation LLETZ CKC
95 2
117 3
Number of conisations 1 2 3
90 6 1
112 7 1
Endocervical recoupe
Pvalue
of
0.042 0.644
K. van Velthoven et al. / Pregnancy outcome after cervical conisation: a 2nd retrospective cohort study in the Leuven University Hospital
Yes No
25 72
Histopathological diagnosis Normal Metaplasia CIN 1 CIN 2 CIN 3 AIS CIN 3 + AIS Invasive squamous carcinoma Invasive adenocarcinoma
5 2 12 19 48 3 3 3 2
31 89
Mean (SD) Dimension of the cone Transverse diameter (cm) Anteroposterior diameter (cm) Depth (cm) Volume (cm3)
1.73 (0.50) 1.52 (0.44) 0.89 (0.43) 1.50 (1.87)
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K. van Velthoven et al. / Pregnancy outcome after cervical conisation: a 2nd retrospective cohort study in the Leuven University Hospital
Table 2. Proportion of preterm birth (<37 weeks) in Leuven-2 study.
Population Treated vs Control group All pregnancies
Treated group Number % 16/120 13.3
Twin pregnancies and multiple conisations 13/110 excluded Multiple vs one conisation All pregnancies With vs without recoupe All pregnancies
Control group Number % 13/120 10.8
11.8
12/118
10.2
Multiple conisations Number % 1/8 12.5
One conisation Number % 13/110 11.8
With recoupe Number % 4/29 13.8
Without recoupe Number % 12/91 13.2
17
RR (95% CI) 1.23 (0.62 - 2.45) 1.16 (0.55 - 2.44)
RR (95% CI) 1.06 (0.16 - 7.09) RR (95% CI) 1.05 (0.37 - 2.99)
K. van Velthoven et al. / Pregnancy outcome after cervical conisation: a 2nd retrospective cohort study in the Leuven University Hospital
Appendix Table A. Depth and proportion of preterm birth (<37 weeks). Values in bold are statistically significant differences (p < 0.05)
Population Depth > 10mm vs depth <10mm Leuven-2 study Both studies combined Depth >10mm vs no treatment Leuven-2 study Both studies combined
Depth >10mm Number 6/38 13/57 Depth >10mm Number 6/38 13/57
% 15.8 22.8
Depth <10mm Number 10/82 16/109
% 12.2 14.7
% 15,8 22.8
No treatment Number 13/120 15/175
% 10.8 8.6
18
RR (95% CI) 1.29 (0.51 - 3.30) 1.55 (0.80 - 3.00)
RR (95% CI) 1.46 (0.60 - 3.57) 2.66 (1.35 - 5.25)
K. van Velthoven et al. / Pregnancy outcome after cervical conisation: a 2nd retrospective cohort study in the Leuven University Hospital
Table B. Frequency of low birth weight (<2500 gram) in Leuven-2 study.
Population Treated vs control group All singleton pregnancies Deep excision vs control group All singleton pregnancies
Treated group Number 12/118 Deep excision Number 5/37
% 10.2
Control group Number 7/116
% 6.0
% 13.5
Control group Number 7/116
% 6
19
RR (95% CI) 1.69 (0.69 - 4.13) RR (95% CI) 2.24 (0.76 - 6.64)
K. van Velthoven et al. / Pregnancy outcome after cervical conisation: a 2nd retrospective cohort study in the Leuven University Hospital
Table C. Comparison Values in bold are statistically significant differences (p < 0.05)
Mean age (years)
both
study
Leuven-2 study
Leuven-1 study
P-value
32
33
0.418
Number
%
Number
%
Parity Nulliparous Multiparous
62 58
51.7 48.3
21 34
38.2 61.8
0.016
Ever smoked No Yes
86 33
71.7 27.5
26 26
47.3 47.3
0.003
Smoking during pregnancy No Yes
107 11
89.2 9.2
39 12
70.9 21.8
0.008
13
10.8
2
3.6
0.025
Preterm birth in the control group
20
populations.
S0301-2115(17)30320-2 http://dx.doi.org/doi:10.1016/j.ejogrb.2017.06.043 EURO 9966
To appear in:
EURO
Received date: Revised date: Accepted date:
18-4-2017 24-6-2017 27-6-2017
Please cite this article as: van Velthoven Kim, Poppe Willy, Verschuere Hannah, Arbyn Marc.Pregnancy outcome after cervical conisation: A 2nd retrospective cohort study in the Leuven University Hospital.European Journal of Obstetrics and Gynecology and Reproductive Biology http://dx.doi.org/10.1016/j.ejogrb.2017.06.043 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Pregnancy outcome after cervical conisation: a 2nd retrospective cohort study in the Leuven University Hospital
Kim van Velthoven a, Willy Poppe a, Hannah Verschuere a, Marc Arbyn b Leuven, Belgium
Department of Obstetrics and Gynaecology, University Hospitals Leuven – Campus Gasthuisberg Leuven, Belgium b Unit of Cancer Epidemiology, Belgian Cancer Centre, Scientific Institute of Public Health, Brussels, Belgium\ a
Correspondence concerning manuscript: Kim van Velthoven, University Hospitals Leuven – Campus Gasthuisberg, Department of Obstetrics and Gynaecology, Herestraat 49, 3000 Leuven, Belgium E-mail address: [email protected]
CONDENSATION Our two successive studies show a significant trend towards smaller cones which is accompanied by a decrease in preterm birth after excisional treatment.
ABSTRACT
Objective: to evaluate whether the dimensions of the cones removed during large loop excision of the transformation zone have decreased over time. Secondly, whether these changes were associated with a lower risk of obstetrical harms on a subsequent pregnancy. Study design: A retrospective matched cohort study was performed in a tertiary referral unit in Belgium. A total of 97 women were identified from a database of women who underwent excisional treatment for cervical precancer between January 1st, 2004 and December 31st, 2012, and delivered before December 31st, 2014. The control group consisted of 120 non-treated women who had no history of cervical intra-epithelial
K. van Velthoven et al. / Pregnancy outcome after cervical conisation: a 2nd retrospective cohort study in the Leuven University Hospital
neoplasia. Data on smoking status; gestational age at delivery; number of conisations; time interval between treatment and pregnancy; dimensions of the cone; severity of the lesion; and the extra resection of endocervical tissue were collected. These data were compared with those from a previous similar study at the University Hospital of Leuven in 2009, which database we enriched with information on the cone dimensions. Main outcome variables were gestational age at delivery, birthweight and neonatal condition at birth. Results: Only a significant lower birthweight could be found in the treated group compared to the control group (3364 gram [95% CI 3094 – 3290] versus 3364 gram [95% CI 3253 – 3475], P = 0.023). The current study showed no increase in preterm birth rate after conisation and no relationship between volume or depth of the cone and preterm birth could be found. Over the period 1999-2014, a significant decrease in all dimensions was observed: on average -0.3mm, -0.3mm, -0.4 mm and -132mm3 per year, for the depth, anteroposterior and transverse diameter and the volume, respectively. Conclusions: Our two successive studies showed a significant trend towards smaller cones which was accompanied by a decrease in preterm birth after excisional treatment. The clinician could limit the size of the cone to avoid obstetrical harms, but needs to be aware of the oncological safety as well.
Keywords: Large loop excision of the transformation zone (LLETZ), cervical intraepithelial neoplasia (CIN), pregnancy duration, dimensions of the cone INTRODUCTION Large loop excision of the transformation zone (LLETZ) is the standard treatment for cervical intra-epithelial neoplasia (CIN) (1). The aim of this treatment is to remove the abnormal transformation zone. At the same time the cervical function needs to be 2
K. van Velthoven et al. / Pregnancy outcome after cervical conisation: a 2nd retrospective cohort study in the Leuven University Hospital
preserved. This is important since the peak incidence of CIN coincides with the reproductive age (2). The side effects associated with treatment of cervical precancer are preterm birth, premature rupture of the membranes and neonatal morbidity (3,4). In 2009, a study performed at the University Hospital of Leuven, Belgium demonstrated a significantly increased risk of preterm birth that was substantially higher than noted in two large meta-analyses (3 - 5). The causes of the obstetrical harm after excision of a CIN lesion are not fully clarified. However, the observation that larger cones are associated with a higher risk of preterm birth provides evidence for a causal relation (6,7). Awareness of the obstetrical harm may have generated a tendency to treat CIN lesions less aggressively to avoid risks of preterm birth (8,9). Therefore, the aim of our study was to verify whether the dimensions of the cones removed during LLETZ also have decreased over time in our clinic. Secondly, whether these changes were associated with lower risks of obstetrical harms on a subsequent pregnancy. METHODS A retrospective matched cohort study was performed in a university centre for obstetrical and gynaecological care (University Hospital of Leuven, Belgium). Patients were identified from a database of 1382 women who underwent excisional treatment for cervical precancer by LLETZ or cold knife conisation (CKC) between January 1st, 2004 and December 31st, 2012 and subsequently became pregnant and delivered before December 31st, 2014. Miscarriages were excluded. A control group was defined using the following matching criteria: parity, maternal age at delivery (birth year ± 1 year), year of delivery (± 1 year) and twin pregnancy. These women had no history of CIN or any surgical treatment of the cervix. Data were collected on: maternal smoking status before and during pregnancy; gestational age at delivery (in postmenstrual days and –weeks); number of conisations; severity of the treated lesion; time interval between treatment and pregnancy; dimensions of the cone (measured post fixation in the pathology laboratory); and the presence of an endocervical recoupe (additional tissue removed from the endocervical canal if residual disease was suspected during treatment). Outcome variables were: duration of pregnancy; occurrence of preterm birth; birthweight; occurrence of low birth weight; and admission on neonatal intensive care unit (NICU). Patients with incomplete information regarding exposure or outcome variables were excluded. The volume of the excised cone was computed assuming a hemi-ellipsoid shape: volume = ½ x 4/3 x π x a/2 x b/2 x c, where a = transverse diameter, b = anteroposterior diameter and c = depth of the cone (10). In case of multiple conisations, only the volume of the first cone was measured. The volume of an endocervical recoupe was not quantified but taken into account as possible affecting qualitative variable. The dimensions and the volume of the cones were correlated with the gestational age at delivery and histopathological diagnosis. Data from the current study were compared with those from a similar study, conducted also in the University Hospital of Leuven, that enrolled women who had excisional treatment for cervical precancer between 1999 and 2003 (5). The two studies are 3
K. van Velthoven et al. / Pregnancy outcome after cervical conisation: a 2nd retrospective cohort study in the Leuven University Hospital
labelled as the current “Leuven-2” study and the prior “Leuven-1” study. The database from the Leuven-1 study was enriched with information on the cone dimensions by linkage with the pathology report. For differences between two continuous variables the student-t test was used, while the Chi-square test was used for associations between categorical variables. Trend analyses were performed by linear regression. Statistical significance was defined as a p-value of <0.05. RESULTS The treated group consisted of 120 pregnancies (delivery after 22 weeks of gestation) in 97 women. Nineteen women had two subsequent pregnancies and two women had three subsequent pregnancies. Table 1 shows the characteristics of the treated women. High-grade intraepithelial neoplasia (CIN2/3 or adenocarcinoma in situ (AIS)) was found in 75% and invasive cervical cancer in 5% of the treated cases. A matched control group consisted of 120 pregnancies in 120 women. There were significantly more ex-smokers in the treated group than in the control group (27.5% versus 15%, p =0.042). No significant difference in smoking status during pregnancy could be demonstrated. The treated group and the control group included two twin pregnancies. These women delivered at 30 and 36 weeks of gestation (treated group) and at 28 and 37 weeks of gestation (control group). The dimensions and the volume of the cone were plotted against the age of the women, the period of conisation and the histopathological diagnosis (Fig. 1, appendix fig. A-C). A significant decrease of the dimensions and the volume of the cone during the study period was demonstrated (p < 0.001). The mean gestational age at delivery did not differ significantly between the treated and the control group (38.2 weeks [95% CI 37.8 – 38.7] versus 38.6 weeks [95% CI 38.2 – 39.0], p = 0.236). Table 2 shows the differences in preterm birth rates (<37 weeks) between the treated versus control group, women with only one versus multiple conisations and women with versus without an endocervical recoupe. The risk of severe preterm birth (< 34 weeks) was higher in the treated than in the control group (6/120 [5.0%] versus 4/120 [3.3%]), but the difference was not significant (RR 1.50 [95% CI 0.4 – 5.18]) . No correlation between the dimensions or the volume of the cone and the pregnancy duration was demonstrated (Fig. 2). Similarly, there was no correlation between depth (less or more than 10mm) and proportion of preterm birth (Appendix table A). A significant lower birth weight was found in the treated group compared with the control group (3364 gram [95% CI 3094 – 3290] versus 3364 gram [95% CI 3253 – 3475], p = 0.023). In addition, the frequency of low birth weight (<2500 gram) was higher in the treated group compared to the control group (12/118 [10.2%] versus 7/116 [6.0%]), but the difference was not significant (RR 1.69 [95% CI 0.69 – 4.13], appendix table B). No significant difference regarding referral to NICU between the treated group and control group was observed (12/118 [10.2%] versus 10/118 [8.5%], RR 1.20 [95% CI 0.54 – 2.67]). 4
K. van Velthoven et al. / Pregnancy outcome after cervical conisation: a 2nd retrospective cohort study in the Leuven University Hospital
There was no significant difference neither in the rates of preterm birth nor in low birth weight for women with a short time interval between treatment and pregnancy (< 12 months) compared to women with a time interval > 12 months (respectively RR 0.68 [95% CI 0.29 – 1.60] and RR 1.20 [95% CI 0.45 – 3.22]). This was the same for a time interval less or more than 24 months (respectively RR 1.01 [95% CI 0.43 – 2.38] and RR 0.98 [95% CI 0.39 – 2.46]). Appendix table C compares the enrolled populations included in the two Leuven studies. Significantly more ex-smokers (p = 0.003) and nulliparous women (p = 0.016) were seen in the Leuven-2 study. The risk of preterm birth was significantly higher in the Leuven-2 control group compared with the Leuven-1 control group (p = 0.025). The dimensions of the cone were larger in the Leuven-1 study, but this was statistically significant only for the transverse diameter (p = 0.017). Over the period 1999-2014, a significant decrease in all dimensions was observed: on average -0.3mm, -0.3mm, 0.4 mm and -132mm3 per year, for the depth, anteroposterior diameter, transverse diameter and the volume respectively. Combining the two studies, preterm birth (<37 weeks of gestation) and severe preterm birth (<34 weeks) were more frequent among treated versus non-treated women (respectively 30/175 [17.1%] versus 15/175 [8.6%], RR 2.00 [95% CI 1.12 – 3.58] and 12/175 [6.9%] versus 4/175 [2.3%], RR 3.00 [95% CI 2.43 – 9.12]). There also was a trend towards a significant relation between cone depth and pregnancy duration (p = 0.077). A depth > 10mm significantly increased the risk of preterm birth compared with the non-treated women (13/57 [22.8%] versus 15/175 [8.6%], RR 2.66 [95% CI 1.35 – 5.25], appendix table A). This was similar for severe preterm birth (7/57 [12.3%] versus 4/175 [2.3%], RR 5.37 [95% CI 1.63 – 17.69]).
DISCUSSION This study could not demonstrate a significant correlation between conisation of the cervix and preterm birth. However, babies had a lower birth weight in the treated group than in the control group. This is in contrast with the Leuven-1 study in 2009, which observed a significantly increased risk for preterm birth after conisation (5). Furthermore, no correlation between volume or depth of the cone and pregnancy duration was demonstrated. There was no higher risk of preterm birth for women with multiple conisations. However, only eight pregnancies occurred after multiple conisations. This is partly in concordance with British findings (11). Kitson et al. found an increased risk of preterm birth in women with a history of one or more conisations, but could not correlate this with the volume nor the depth of the cone. In contrast, a recent large meta-analysis confirmed a correlation between depth or volume of the cone and the risk of preterm birth (4). In the Leuven-1 study, also a minimal effect of depth was observed. However, there was a significant decrease of all dimensions over the period 1999-2014, possibly due to awareness of the obstetric risks. These findings suggest that the tendency to excise smaller cones in the Leuven-2 study may have resulted in a lower risk of preterm birth. A recent Norwegian study demonstrated this 5
K. van Velthoven et al. / Pregnancy outcome after cervical conisation: a 2nd retrospective cohort study in the Leuven University Hospital
clearly in a nationwide study linking the birth registry data and treatment databases from the whole of the country (8). In our Leuven-2 study no significant treatment effect was found anymore. Nevertheless, there still is an effect. This was considerably lower in magnitude compared to the Leuven-1 study and in addition became insignificant. So by combining our previous and current findings, we rather confirm findings of the Kyrgiou meta-analyses than the opposite (4). Additionally, one could expect smaller cones in younger women due to the decision of the clinician to resect less tissue in patients who might have a desire for future pregnancy. In the Leuven-2 study, however, we could not confirm those expectations. Papoutsis et al. earlier work supports this conclusion, as no differences were found in the percentage of positive section margins of the cone between older and younger women (12). Despite both studies separately considered for known risk factors for preterm birth (such as maternal age, smoking status and parity) another explanation for the heterogeneity between the Leuven-1 and Leuven-2 study is the different study population. Indeed, there were significant more non-smokers and nulliparous women in the Leuven-2 study. Unfortunately, it was impossible to come to any conclusions about a possible increased risk for multiparous women due to the lack of information on the obstetric history (especially earlier preterm birth). Furthermore, there were significantly more preterm births in the control group of the Leuven-2 study (10.8%) compared with the control group of the Leuven-1 study (3.6%). For comparison, the mean rate of preterm births in the whole Flemish population during the study period was 7.3% (13,14). So probably due to selection bias, the Leuven-2 control group represented a falsely high risk of preterm birth, whereas the risk in the control group of the Leuven-1 study probably was too low. Logically, this lead to an underestimation and overestimation of the risk of excisional treatment on preterm birth in the Leuven-2 and Leuven-1 study, respectively. In the future, we recommend nation- or region wide linkage of databases containing treatment data with birth registries. Such populationbased linkage studies, avoids selection biases that are inherent to small centre-based studies with manually performed matching. The risk of preterm birth might increase with a short conisation-to-pregnancy interval, especially when shorter than 2-3 months (15). Although the mechanism of this relation is not clear, this might be due to changes in the structural integrity of the cervix, limiting its ability to support a pregnancy. With time, the cervix may scar or regenerate, minimizing the structural weakness of the cervix (15). In the Leuven-2 study, there was a tendency for lower risk of preterm birth when the interval was > 12 months compared to < 12 months. The outcomes from our two Leuven studies are mainly based on LLETZ. Given the rather small study size, we have allowed also other excisional procedures. This was justified by evidence derived from the literature concluding that cone dimensions, in particular the relative size of the cone compared to the size of the cervix, determine obstetrical harm rather than the technique (16). This study is a retrospective study, and therefore some limitations needs to be mentioned, such as possible confounding factors and the risk of information and selection bias. Another limitation is the imprecision of the cone measurements and the 6
K. van Velthoven et al. / Pregnancy outcome after cervical conisation: a 2nd retrospective cohort study in the Leuven University Hospital
calculation of the actual volume (12). Ideally this should be performed by the water replacement technique. It remains difficult to find the right balance between adequate treatment and maintaining the cervical function. For oncological safety, the depth of the cone should be at least 8mm due to the depth of the cervical crypts (17). The aim is to achieve negative section margins. However, positive section margins do not mean that treatment is not successful (12). Indeed, residual abnormal tissue may be destroyed by the coagulation effects during LLETZ or may disappear by healing. A recent study by Ang et al. concluded no risk for residual disease in women younger than 35 years when the cone had a depth of less than 10mm (18). In the Leuven-2 study, it was impossible to report data on the follow up of our patients. We found a significant lower birthweight in the treated group than in the control group. However, the frequency of low birthweight was not significantly increased probably due to the small study size. Moreover, low birth weight may be caused by the gestational age at delivery. Therefore, it would be better to evaluate low birthweight as a birthweight below the 10th percentile for the gestational age (19). In the Leuven-2 study, only low birthweight less than 2500g was taken into account.
CONCLUSION Our two successive studies on pregnancy outcome after cervical conisation showed a significant trend towards smaller cones with time. This was related to a decrease in obstetrical harms, as no higher risk of preterm birth after excisional treatment could be demonstrate. Our current data could not correlate the dimensions nor the volume of the cone with a higher risk of preterm birth. However, the reduction of the dimensions with time in association with the lower risk, does suggest a relationship. The clinician could limit the size of the cone to avoid obstetrical harms, but needs to be aware of the oncological safety as well.
ACKNOWLEDGEMENTS Marc Arbyn has received support from the seventh framework program of DG Research of the European Commission, through the COHEAHR Network (grant No 603019 and from the Institut national du Cancer (Paris, France) through the COSPCC study (Conséquences obstétricales du (sur)traitement des précurseurs du cancer du col utérin) coordinated by the University of Amiens (France).
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REFERENCES (1) Prendiville W, Davies R, Berry PJ. A low voltage diathermy loop for taking cervical biopsies: a qualititative comparison with punch biopsy forceps. Br J Obstet Gynaecol 1986; 93: 773-6. (2) Arbyn M, Simoens C, Van Oyen H, et al. Analysis of 13 million individual patient records pertaining to Pap smears, colposcopies, biopsies and surgery on the uterine cervix (Belgium, 1996-2000). Prev Med 2009; 48: 438-43. (3) Arbyn M, Kyrgiou M, Simoens C, et al. Perinatal mortality and other severe adverse pregnancy outcomes associated with treatment of cervical intraepithelial neoplasia: meta-analysis. BMJ 2008;337:a1284-a1284. (4) Kyrgiou M, Athanasiou A, Paraskevaidi M, et al. Adverse obstetric outcomes after local treatment for cervical preinvasive and early invasive disease according to cone depth: systematic review and meta-analysis. BMJ 2016;354:i3633 (5) van de Vijver A, Poppe W, Verguts J, Arbyn M. Pregnancy outcome after cervical conisation: a retrospective cohort study in the Leuven University Hospital. BJOG 2010;117(3):268-273 (6) Noehr B, Jensen A, Frederiksen K, Tabor A, Kjaer S. Depth of cervical cone removed by loop electrosurgical excision procedure and subsequent risk of spontaneous preterm delivery. Obstet Gynecol 2009;114(6):1232-1238. (7) Castanon A, Landy R, Brocklehurst P, et al. Risk of preterm delivery with increasing depth of excision for cervical intraepithelial neoplasia in England: nested case-control study. BMJ 2014; 349: g6223. (8) Bjorge T, Skare GB, Bjorge L, Trope A, Lonnberg S. Adverse Pregnancy Outcomes After Treatment for Cervical Intraepithelial Neoplasia. Obstet Gynecol 2016. (9) Arbyn M, Kyrgiou M, Gondry J, Petry KU, Paraskevaidis E. Long term outcomes for women treated for cervical precancer. BMJ 2014; 348: f7700. (10) Phadnis SV, Atilade A, Young MPA, Evans H, Walker PG. The volume perspective: a comparison of two excisional treatments for cervical intraepithelial neoplasia (laser versus LLETZ). BJOG 2010;117(5):615-619. (11) Kitson S, Greig E, Michael E, Smith M. Predictive value of volume of cervical tissue removed during LLETZ on subsequent preterm delivery: a cohort study. Eur J Obstet Gynecol Reprod Biol 2014;180:51-55.
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(12) Papoutsis D, Rodolakis A, Mesogitis S, Sotiropoulou M, Antsaklis A. Appropriate cone dimensions to achieve negative excision margins after large loop excision of transformation zone in the uterine cervix for cervical intraepithelial neoplasia. Gynecol Obstet Invest 2013;75(3):163-168. (13) Cammu H, Martens G, Martens E, Van Mol C, Defoort P. Perinatale Activiteiten in Vlaanderen 2009. SPE, Brussel, 2010. (14) Devlieger R, Martens E, Martens G, Van Mol C, Cammu H. Perinatale Activiteiten in Vlaanderen 2014. SPE, Brussel, 2015. (15) Himes KP, Simhan HM. Time from cervical conization to pregnancy and preterm birth. Obstet Gynecol 2007;109(2):314-9 (16) Founta C, Arbyn M, Valasoulis G, et al. Proportion of excision and cervical healing after Large Loop Excision of the Transformation Zone (LLETZ) for CIN. BJOG 2010; 117: 1468-74. (17) Anderson MC, Hartley RB. Cervical crypt involvement by intraepithelial neoplasia. Obstet Gynecol 1980;55(5):546-550. (18) Ang C, Mukhopadhyay A, Burnley C, et al. Histological recurrence and depth of loop treatment of the cervix in women of reproductive age: incomplete excision versus adverse pregnancy outcome. BJOG 2011;118(6):685-692. (19) Simoens C, Goffin F, Simon P, et al. Adverse obstetrical outcomes after treatment of precancerous cervical lesions: a Belgian multicentre study. BJOG 2012;119(10):1247-1255.
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LEGENDS FOR FIGURES AND TABLES Figure 1. Age at conisation, period of the conisation and histological diagnosis versus depth of the cone. Figure 2. Dimensions and volume of the cone versus pregnancy duration (days).
Figure 1
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K. van Velthoven et al. / Pregnancy outcome after cervical conisation: a 2nd retrospective cohort study in the Leuven University Hospital
Figure 2
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K. van Velthoven et al. / Pregnancy outcome after cervical conisation: a 2nd retrospective cohort study in the Leuven University Hospital
Appendix Figure A. Age at conisation versus dimensions and volume of the cone. Figure B. Period of conisation versus dimensions and volume of the cone. Figure C. Histopathological diagnosis versus dimensions and volume of the cone.\
Appendix a
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K. van Velthoven et al. / Pregnancy outcome after cervical conisation: a 2nd retrospective cohort study in the Leuven University Hospital
Appendix b
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K. van Velthoven et al. / Pregnancy outcome after cervical conisation: a 2nd retrospective cohort study in the Leuven University Hospital
Appendix c
14
Table 1. Characteristics of the treated women.LLETZ: Large loop excision of the transformation zone, CKC: cold knife conisation, CIN: cervical intra-epithelial neoplasia, AIS: adenocarcinoma in situ Values in bold are statistically significant differences (p < 0.05)
Maternal age (mean)
Smoking status Ever smoked Current smoker
Treated group
Control group
32.2
32.2
Number
%
Number
%
33/120 11/120
27.5 9.2
18/120 8/120
15.0 6.7
Number patients = 97)
of Number (N pregnancies (N = 120)
Type of conisation LLETZ CKC
95 2
117 3
Number of conisations 1 2 3
90 6 1
112 7 1
Endocervical recoupe
Pvalue
of
0.042 0.644
K. van Velthoven et al. / Pregnancy outcome after cervical conisation: a 2nd retrospective cohort study in the Leuven University Hospital
Yes No
25 72
Histopathological diagnosis Normal Metaplasia CIN 1 CIN 2 CIN 3 AIS CIN 3 + AIS Invasive squamous carcinoma Invasive adenocarcinoma
5 2 12 19 48 3 3 3 2
31 89
Mean (SD) Dimension of the cone Transverse diameter (cm) Anteroposterior diameter (cm) Depth (cm) Volume (cm3)
1.73 (0.50) 1.52 (0.44) 0.89 (0.43) 1.50 (1.87)
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Table 2. Proportion of preterm birth (<37 weeks) in Leuven-2 study.
Population Treated vs Control group All pregnancies
Treated group Number % 16/120 13.3
Twin pregnancies and multiple conisations 13/110 excluded Multiple vs one conisation All pregnancies With vs without recoupe All pregnancies
Control group Number % 13/120 10.8
11.8
12/118
10.2
Multiple conisations Number % 1/8 12.5
One conisation Number % 13/110 11.8
With recoupe Number % 4/29 13.8
Without recoupe Number % 12/91 13.2
17
RR (95% CI) 1.23 (0.62 - 2.45) 1.16 (0.55 - 2.44)
RR (95% CI) 1.06 (0.16 - 7.09) RR (95% CI) 1.05 (0.37 - 2.99)
K. van Velthoven et al. / Pregnancy outcome after cervical conisation: a 2nd retrospective cohort study in the Leuven University Hospital
Appendix Table A. Depth and proportion of preterm birth (<37 weeks). Values in bold are statistically significant differences (p < 0.05)
Population Depth > 10mm vs depth <10mm Leuven-2 study Both studies combined Depth >10mm vs no treatment Leuven-2 study Both studies combined
Depth >10mm Number 6/38 13/57 Depth >10mm Number 6/38 13/57
% 15.8 22.8
Depth <10mm Number 10/82 16/109
% 12.2 14.7
% 15,8 22.8
No treatment Number 13/120 15/175
% 10.8 8.6
18
RR (95% CI) 1.29 (0.51 - 3.30) 1.55 (0.80 - 3.00)
RR (95% CI) 1.46 (0.60 - 3.57) 2.66 (1.35 - 5.25)
K. van Velthoven et al. / Pregnancy outcome after cervical conisation: a 2nd retrospective cohort study in the Leuven University Hospital
Table B. Frequency of low birth weight (<2500 gram) in Leuven-2 study.
Population Treated vs control group All singleton pregnancies Deep excision vs control group All singleton pregnancies
Treated group Number 12/118 Deep excision Number 5/37
% 10.2
Control group Number 7/116
% 6.0
% 13.5
Control group Number 7/116
% 6
19
RR (95% CI) 1.69 (0.69 - 4.13) RR (95% CI) 2.24 (0.76 - 6.64)
K. van Velthoven et al. / Pregnancy outcome after cervical conisation: a 2nd retrospective cohort study in the Leuven University Hospital
Table C. Comparison Values in bold are statistically significant differences (p < 0.05)
Mean age (years)
both
study
Leuven-2 study
Leuven-1 study
P-value
32
33
0.418
Number
%
Number
%
Parity Nulliparous Multiparous
62 58
51.7 48.3
21 34
38.2 61.8
0.016
Ever smoked No Yes
86 33
71.7 27.5
26 26
47.3 47.3
0.003
Smoking during pregnancy No Yes
107 11
89.2 9.2
39 12
70.9 21.8
0.008
13
10.8
2
3.6
0.025
Preterm birth in the control group
20
populations.