Obstetric outcomes after cervical loop electrosurgical excision procedure

Objectives: This study aimed to investigate whether a history of loop electrosurgical excision procedure (i.e., conisation) affects obstetric and neonatal outcomes. Methods: A retrospective cohort study was carried out in V ¨ asternorrland county, Sweden. 57 nulliparous women with singleton pregnancies and previous conisation were compared with 100 age-matched pregnant controls without history of conisation. Results: There was significantly lower gestational age by delivery (p = 0.036), however, the premature delivery rate was not different. Caesarean section was also less frequent (OR: 0.29, 95% CI: 0.081 – 1.04, p = 0.047) in the conisation group than those in the control group. There were no differences in neonatal outcomes. Conclusions: Previous conisation does not affect the risk of prematurity or cervical dilatation during the first stage of labour. Women with history of conisation had a lower rate of caesarean section, and lower gestational age by delivery.


Introduction
Conisation is a standard procedure for the treatment of cervical dysplasia.Many women who undergo conisation are of reproductive age and may have future pregnancies.In Sweden, the standard conisation technique used to treat cervical dysplasia is the loop electrosurgical excision procedure (LEEP).Although the purpose of conisation is to excise the precancerous areas while preserving cervical function, some studies have shown that previous conisation may increase the risk of premature birth and low birthweight in subsequent pregnancies [1][2][3].According to several studies, this risk can increase with greater cone depth, and is dependent upon the excision technique used [3][4][5][6][7].
In contrast, many other studies found no differences in gestational age at delivery between women with or without a history of conisation [8][9][10].Two earlier meta-analyses showed that conisation did not increase the risk of caesarean section [3][4][5][6][7][8][9][10][11].However, Kyrgiou et al. demonstrated an increased risk of caesarean section after cold-knife conisation but not after LEEP [5], and the authors found no differences in the mode of delivery, duration of labour, rate of induction, cervical stenosis, or pre-or postpartum haemorrhage.The loss of cervical tissue by conisation may potentially shorten the dilatation phase of labour, or fibrous tissue that forms after excision may cause cervical stenosis, which may lead to prolonged labour due to a fibrous ring [12].
Given the higher prevalence of cervical precancerous lesions in reproductive-age women and the contradictory outcomes reported to date, we investigated whether a history of LEEP conisation affects the obstetric and neonatal outcomes in subsequent pregnancies.

Materials and methods
In this retrospective cohort study, we collected data from the medical records of pregnant nulliparous women with and without a history of LEEP conisation of the cervix who gave birth in Västernorrland county, Sweden, over a 5-year period (from January 1, 2013, to December 31, 2017) (see Fig. 1).This study was approved (Dnr 2021-00343) by the Ethical Review Board in Uppsala, Sweden The Swedish electronic medical record database for prenatal care and childbirth, Obstetrix (Siemens Corporation, Upplands Väsby, Sweden), and gynaecological medical records SYSteam Cross (EVRY Healthcare Systems AB, Eskilstuna, Sweden) were searched for women meeting the criteria defined below.
In Obstetrix, each pregnancy is followed in a logical and structured manner, from enrolment in the prenatal healthcare centre to arrival at the maternity unit and the time of delivery.The data on pregnancies fulfilling our criteria were compiled in an Excel file.Women aged < 18 or > 42 years and women with a stillborn foetus, multiple pregnancies, breech presentation, or elective caesarean section were excluded.However, premature births with breech presentation were included for the analysis of delivery method.Then, patients were identified by searching the personal medical record system SYSteam Cross for the procedure code for LEEP (LDC03), according to the International Statistical Classification of Diseases and Related Health Problem 10th revision (ICD-10).All patients underwent LEEP between January 1, 2012, and December 31, 2013.Women aged > 42 years at the time of conisation were excluded.The patients were then cross-linked with the information on pregnancies from the Obstetrix medical record system.
A control group of patients were identified by searching the Obstetrix journal records for all age-matched healthy women with no history of conisation, and who also underwent their first childbirth between January 2013 and December 2017, but not by elective caesarean section.The number of patients in the control group decreased as planned and was twice as many as in the patient group, after the women were randomised using the Microsoft Excel 'RAND' function (see Fig. 1).
The baseline characteristics of each woman at her first maternity visit (body mass index [BMI, kg/m 2 ], age, and earlier diseases) were registered.The gestational age at delivery was calculated according to an ultrasound examination in gestational weeks 18-20.The cervical dilation rate (mm/h) was calculated from the degree of cervical dilatation, measured with two vaginal examinations at two different times, when the uterine cervix was ≥ 4 cm.It was not possible to calculate the dilatation rate in some patients because the cervix had already dilated to more than 9 cm at the time of the first assessment.Similarly, it was not possible to measure the duration of the second stage of labour in some patients because no initial assessment was available, or the delivery ended with a caesarean section.
The primary maternal outcomes were the cervical dilation rate (mm/ Fig. 1.Flow chart of patient inclusion and exclusion in the study. E. Åström and S. Turkmen h) and the rate of prematurity (< 37 weeks) in the groups.The secondary outcomes were the duration of the second stage of labour (min), the type of labour onset (induced or not), the indication for labour induction, the use of oxytocin and amniotomy to treat a confirmed delayed labour, the mode of delivery (normal vaginal, caesarean section, or instrumental delivery), and the volume of postpartum bleeding.Alongside of the study outcomes, we also controlled the rate of any obstetric complication, the neonatal birth weight, Apgar score at 5 min after birth, and the umbilical cord arterial and venous blood gases.
The data for patients who gave birth prematurely at gestational age <37 weeks + 0 days were not included in the analysis for cervical dilatation rate (mm/h), the duration of second stage of labour or the use of oxytocin and amniotomy during first stage of labour.
Statistical analysis: SPSS version 25 (SPSS Inc., Chicago, IL, USA) was used for all analyses.The normality of the data was determined with the Shapiro-Wilks test.No variables, except for foetal blood pH and base excess (BE), were normally distributed.Therefore, a nonparametric test was used for their analysis.We analysed continuous variables with the Mann-Whitney U test and categorical variables with Pearson's χ 2 test.
Descriptive statistics are presented as medians and interquartile ranges (IQRs) or as percentages.The risk of complications and caesarean section was estimated as a crude odds ratio (OR) with the 95% confidence interval (CI).Spearman's test was used to analyse correlations between parameters.In all tests, the level of significance was set at p < 0.05.
According to an earlier study, the duration of childbirth in pregnant women with a history of conization are shorter than those women in the control group.The duration in the patient group was 330 + 132 min and in the control group 426 + 162 min [10].To detect a difference between 80% of patients (power) and the probability of false positivity (alpha) at a level of 0.05, we need at least 30 patients in each group.

Results
Data were available for 12,720 pregnancies in the study period.Seven hundred conisations were performed between 2012 and 2013.After applying the exclusion criteria, 57 patients qualified for the conisation group and 100 women for the control group (see flow chart, Fig. 1).
The median age did not differ between the conisation group (28.0 years [IQR: 27.0-30.5])and the control group (28.0 years [IQR: 26.0-31.0];p > 0.05).The body mass index in the two groups also did not differ (24.0 [IQR: 22.0-27.0]and 24-0 [IQR: 21.0-27.0],respectively, p > 0.05).The proportion of patients with a history of at least one miscarriage before or after conisation did not differ between the conisation group (14%, n = 8) and the control group (11%, n = 10).The gestational age at delivery was significantly lower in the conisation group than in the control group (p = 0.036), but the gestational age at birth was in the mature period (i.e., > 37 weeks) in both groups (Table 1).
Although the rate of prematurity was not significantly different between the two groups and there was no association between conisation and prematurity, the number of premature labours was twice as high in the conisation group than in the control group.The rate of cervical dilatation in the first stage of labour, the duration of the second stage of labour, the volume of postpartum bleeding, and the foetal birth weight, Apgar score, and umbilical artery pH and BE did not differ between the two groups (Table 1).
The rate of caesarean section was significantly lower in the conisation group than in the control group (OR: 0.29, 95% CI: 0.081-1.04,p = 0.047).However, the rate of spontaneous vaginal delivery or instrument-assisted delivery did not differ between the two groups.Furthermore, there were no differences in the other secondary outcomes: the number of labours that were induced and the number of patients who used amniotomy or required oxytocin infusion during the first stage of labour (Table 1).
The patients in the conisation group had a significantly higher rate of at least one obstetric complication during their pregnancies than those in the control group (32% vs 13%, respectively, OR: 3.09, 95% CI: 1.37-6.92,p = 0.005).The complications observed were polyhydramnios, oligohydramnios, gestational hypertension, gestational diabetes, pre-eclampsia, prematurity, immune thrombocytopenic purpura, and amnionitis.There was no significant difference in the rate of induction between the two groups.However, the rate of post-term pregnancies in the control group was 13% of deliveries in the control group compared with 1.7% in the conization group.The indications for induction included post-term pregnancy, pregnancy-induced hypertension and preeclampsia, membrane rupture, and oligohydramnios.
The correlations between different parameters were examined with the Spearman test.In the conisation group, the duration of the second stage of labour also correlated positively with the patient BMI (r = 0.28, p = 0.03), and negatively with the BE value in the umbilical artery blood (r = 0.36, p = 0.02).

Discussion
In this study, we found that the risk of premature labour and the cervical dilatation dynamics during the first stage of labour in women with a history of conisation did not differ from those of women in the control group, without history of conisation.The risk of caesarean section delivery was lower in women with a previous cervical conization for the treatment of CIN, while the risk of obstetric complications increased potentially.Although the neonates in the conisation group were mature (> 37 gestational weeks), they had a lower gestational age at birth than the control group.The number of premature births in the two groups did not differ significantly, although the percentage of premature births was two times higher in the conisation group (10.5%) than in the control group (5%).Several studies have suggested that conisation with the LEEP method increases the risk of premature birth [1,2,3], and that the volume of tissue removed can affect the results, because small excisions (< 10 mm) did not seem to increase the risk of premature labour [4].However, other studies found no difference in the risk of premature birth after LEEP [16,17,18].In the present study, unfortunately, no data on the dimensions of the conised tissues were available.
Consistent with our study, a meta-analysis by Kyrgiou et al. previously showed that the duration of labour in women with previous conisation did not differ from that in healthy women [3], although they analysed two extreme situations, precipitous and prolonged labour.Precipitous labour was defined as labour in which all three stages were completed within 2 h and prolonged labour as labour that exceeded 12 h.In our study, we analysed the rate of cervical dilatation during the first stage of labour, without classification of labour duration (e.g., precipitous or prolonged).Many studies have reported contradictory results.Kuoppala et al. showed that the duration of labour was shorter after conisation [19].Jones et al. reported prolonged labour in women with history of cold-knife conisation [20], but Klaritsch et al. found no difference in the duration of labour after cold-knife conisation [21].In our study, the conisation group only comprised women who had undergone LEEP, but the available studies of conisation using LEEP have also shown conflicting results.Paraskevaidis et al. analysed the duration of labour in women who underwent conisation with LEEP to treat microinvasive cervical cancer (stadium 1A1) and showed a shorter duration of labour in women with a history of conisation [10].Three studies analysed both the first and the second stages of labour after LEEP, but were unable to detect any difference in their duration in either nulliparous or multiparous women [9,22,23].
Our results, in line with previous studies, shows that the proportion of labours that commence with induction is not altered by conisation [3,19,24].When we analysed the indications for induction in the two groups, a greater number of patients required post-term induction in the control group than in the conisation group (13 versus one, respectively).This can be explained by the fact that the pregnancies of women with previous conisation rarely proceeded beyond the estimated time of labour, so they give birth earlier.
In this study, we calculated the rate of cervical dilatation instead of the total duration of the first stage of labour because the patients were admitted to the maternity ward in different stages of labour.According to a study by Zhang et al., the cervical dilatation rate is slower at the beginning and more rapid at the end of the first stage of the labour [25].Therefore, our results could have been affected by the timing of the first assessment.We report this as a limitation of our study.To our knowledge, none of the available studies investigated whether the rate of the cervical dilatation is altered by previous LEEP, and it is unclear how those studies have overcome this problem.In our study, all cervical assessments are documented in the patients` medical records, and all measurements were accurately made and carefully recorded, which was a strength in this study.
Physiologically, during the first stage of labour, the cervix dilates and effaces to allow the baby to move into the birth canal, but, there is a wide range in the normal duration of cervical effacement in labour [26].However, if the cervix is scarred from previous conisation, the length of the first stage of labour might be extended because scarring (cervical stenosis) may prevent dilatation.Cervical stenosis after conisation may present a mechanical obstacle to labour, and the incidence of cervical stenosis after LEEP varied between 4% and 10% in prior studies [12,13,14,15].However, Michelin et al. reported that LEEP is the procedure of choice among patients who wish to become pregnant because more miscarriages and preterm pregnancies occur after other procedures than after LEEP [27].In the present study, we only included women who underwent LEEP, and our results shows no differences in the cervical dilatation rate or the proportion of premature births between these women and women without a history of conisation.
On the other side, the numbers of deliveries completed by caesarean section was significantly lower in the conisation group, suggesting normal or even easier progress during labour.However, many of the available studies of pregnant women have also shown no change in the rate of caesarean section after LEEP conisation [8,9,11,24,28,29].Results of a meta-analysis concluded that the risk of caesarean section increases after cold-knife conisation, but not after LEEP conisation [5].Some study suggested that the volume of con tissue removed has a decisive effect on the development of cervical insufficiency and preterm delivery after conization [6].In that case, we can suggest that the smaller volume of cervical tissue present after previous conisation may cause faster dilatation and progress in the first stage of labour, which in turn could reduce the risk of caesarean section.
It is still unclear whether conisation among women with CIN is related to adverse pregnancy outcomes in subsequent pregnancies, but several studies have reported obstetric complications in these women, including premature birth, low-birthweight infants [1,2,3,5,11,30,31], incompetent cervix, and cervical stenosis [6,7,32].Similar to our study, Samson et al. analysed the rate of pregnancy complications and found a significantly higher incidence of gestational hypertension in the control group [31].Acharya et al. showed a higher rate of infection, cervical incompetence, premature contractions, pre-eclampsia, and gestational diabetes in women with previous conisation [8].Our results suggest that cervical conisation in women with CIN may entail an increased risk of complications during pregnancy, but there are no clear explanation how a conisation for the treatment of CIN can affect the risk of obstetric complication.Therefore, our findings need to be interpreted with caution.In our study, the number of patients with at least one complication during pregnancy was significantly higher in the conisation group, but the rate of premature births was the same in both groups.

Conclusion
The results of this study show that the cervical dilatation dynamics during labour, and the rate of premature birth in women with a history of conisation did not differ from those of women in the control group, without history of conisation.The number of previous studies that are exactly similar in design to this study is not many.A summary of previously published clinical trials with a study design almost similar to our study is presented in Table 2.However, our results, in the same line as other studies, show that the rate of obstetric complications increases among the group of women with a history of conization, future studies need to investigate whether there is a connection between cervical conization for the treatment of CIN and obstetric complications.On the other side, the proportion of caesarean deliveries can decrease after conisation, but this is probably not caused by the dysfunction of the cervical dynamics during the dilatation phase.Previous studies have reported inconsistent results, so those findings in this study must be confirmed in large prospective studies to clarify the effects of conisation on foetal and maternal outcomes.

Declaration of Competing Interest
The authors have no conflicts of interest to declare in relation to this article.

Table 1
Study outcomes.
BE: base excess; IQR: interquartile range; n = number of patients c aesarean vs vaginal delivery (including instrumental labour) a Fisher's exact test E. Åström and S. Turkmen

Table 2
Clinical trials of Loop Electrosurgical Excision Procedure (LEEP), and its impact on obstetrical outcomes.
E. Åström and S. Turkmen