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Predictive value of volume of cervical tissue removed during LLETZ on subsequent preterm delivery: a cohort study

European Journal of Obstetrics & Gynecology and Reproductive Biology, pages 51 - 55

Abstract

Objective

To evaluate the impact of volume of tissue removed during large loop excision of transformation zone on subsequent preterm birth rates.

Study design

A retrospective cohort study was carried out in a single, large tertiary referral unit in UK. A total of 556 women who delivered between January 2008 and December 2011 following a previous large loop excision of transformation zone procedure or punch biopsy were identified from the maternity and colposcopy databases. Demographic data, gestational age at delivery, birthweight, neonatal outcome and dimensions of excised cervical specimen were collected. Pregnancy outcomes for women who had a previous loop excision were compared to a matched control group who had undergone punch biopsies only.

Results

There was a significant increase in preterm birth rate in the large loop excision group compared to the control group (9.0% vs. 3.6%, respectively, RR 2.5, 95% CI 1.224–5.107). Women who had undergone at least one previous loop excision had more than a threefold increased risk of spontaneous preterm birth compared with their matched controls. However, no relationship between volume or depth of cervical tissue excised and subsequent gestation at delivery could be demonstrated.

Conclusions

Whilst LLETZ is associated with an increased rate of preterm birth, the volume of tissue removed does not appear to influence the subsequent gestational age at delivery. This should reassure clinicians who should continue to perform LLETZ with adequate tissue margins to ensure complete resection of disease.

Keywords: Large loop excision of transformation zone, Preterm birth, Volume, Prediction, Punch biopsy.

Introduction

Colposcopy services have been transformed in recent years in response to advances in HPV screening and vaccination. Increased public acceptance of screening following high profile media cases means that increasing numbers of women attend for screening and are recommended LLETZ procedures to treat CIN. The majority of affected women are of reproductive age and, therefore, the impact of treatment on future pregnancy outcomes must be considered. Concerns have been raised about an increased risk of preterm delivery, particularly when more than one LLETZ is performed. The published data, however, have failed to reach a unified conclusion [1], [2], [3], [4], [10], [12], and [13].

Recently attention has focussed on the impact of depth of tissue excised on subsequent preterm delivery risk, again with conflicting results [3], [5], [6], and [7]. Defining an appropriate control group for comparison in such studies has frequently proven to be difficult. Many consider cases following treatment of CIN by LLETZ to those of the untreated obstetric population as a whole without considering known influencing factors. CIN and preterm labour share many associated risk factors, such as smoking. Studies evaluating the impact of LLETZ on preterm birth rates, therefore, must take this into account.

The impact of LLETZ on cervical function is unlikely to be purely due to a reduction in length as demonstrated by the conflicting evidence in the literature discussing the predictive value of cervical length on the risk of preterm delivery [8] and [9]. The volume (or physical dimensions) of tissue removed at the time of LLETZ is commonly reported to clinicians. If this proved to be a useful predictor of pregnancy outcome, the quality of counselling given to women regarding the impact of their colposcopy treatment on future pregnancy risk would be significantly improved.

A study was, therefore, designed to evaluate the impact of prior LLETZ on the risk of subsequent preterm birth in singleton pregnancies compared to a control group matched for known risk factors for preterm birth and CIN. Secondary analysis was performed to investigate the predictive value of volume of tissue and depth of tissue removed during treatment on the risk of preterm birth.

Materials and methods

A retrospective cohort study was carried out in a large tertiary referral unit in the North East of England delivering over 7000 women annually. Women who had a previous LLETZ procedure performed between 2000 and 2010 and subsequently delivered a singleton pregnancy of at least 20 weeks gestation between January 2008 and December 2011 were identified from the pathology and maternity databases. Only those women for whom the index pregnancy was the first pregnancy occurring after the LLETZ procedure were included for analysis. A control group, matched as a cohort for age, parity and smoking status, delivering during the same time period and having had prior punch biopsies only were selected at random from the same databases. Data were collected on maternal age at delivery, parity, smoking status, gestational age at delivery, birth weight, mode of delivery, aetiology of preterm birth and neonatal outcome indicated by admission to neonatal intensive care unit. For those women who had had a previous LLETZ, data were also collected on number of prior procedures and dimensions of tissue excised, as measured by the pathology department receiving the specimen post fixation. In keeping with other studies, it was assumed that the cone of tissue removed during LLETZ approximated a hemiellipsoid shape [10] . The volume excised was, therefore, calculated using ½ × 4/3 × π × a/2 × b/2 × c where a = transverse diameter, b = longitudinal diameter and c = depth.

Gestational age was determined by ultrasound measurement of the crown-rump length performed between 10 and 13 + 6 weeks gestation and extended to the date of delivery.

A sample size of 266 women in each group was calculated as being required in order to determine a two fold increase in the preterm birth rate of the cohort compared with a control group rate of 7.8%, consistent with data from the WHO Born Too Soon report for the UK and estimates of effect size derived from previous studies [3], [7], [11], [12], and [22]. This sample size would give 80% power at a 5% significance level. A target sample size of 29 women was intended in order to perform a secondary analysis to evaluate the relationship between volume of tissue excised and subsequent gestational age at delivery. This sample size would give 80% power at a 5% significance level assuming at least a moderate degree of correlation between the two variables and a correlation coefficient of −0.5.

All clinical data collected were analysed using SPSS (software package version 19, Chicago, IL, USA). For all statistical tests a p-value of ≤0.05 was considered significant. Continuous variables were analysed using Student T-Test or if non-parametric, with Mann–Whitney U-test. Categorical variables were analysed with chi-square test. Difference in preterm delivery rates (<37 weeks and <34 weeks) between the LLETZ and control group was calculated using Chi-square test and relative risk with 95% confidence intervals. Fisher's exact test was used for analysing categorical data where the frequency was <5. Data on volume of tissue excised and gestational age at delivery was analysed using Pearson’s correlation.

Results

A total of 278 women were identified from the maternity and pathology databases having undergone at least one prior LLETZ procedure and had delivered a singleton pregnancy during the specified time interval. A corresponding control group of 278 women who had had previous punch biopsies only were selected from the same databases, matching as a cohort for age, parity and smoking status ( Table 1 ). A total of 30 (10.8%) women underwent two or more LLETZ procedures. The characteristics of this subgroup did not differ from those of the group of women who had undergone one LLETZ only. Table 2 shows the histology results for the two groups. As anticipated, women undergoing LLETZ biopsies were significantly more likely to have high grade disease than those having a punch biopsy alone. The mean gestational age at delivery was significantly earlier for the LLETZ group compared with the control group (274 ± 17.8 days vs. 279 ± 12.4 days p = 0.004 95% CI −7.7 to −2.6). This effect persisted when women who had undergone one previous LLETZ only were analysed separately (mean gestational age at delivery 274 ±17.5 days p = 0.01). The mean gestational age at delivery for women who had had two or more previous LLETZ procedures was significantly lower than the control group, but not different to the one LLETZ only group (268 ± 19.7 days, p = 0.005 and p = 0.082, respectively).

Table 1 Demographic data.

  Control group (278 women) LLETZ group (278 women) p-value
Median Age (range) 30 (24–43) 30 (23–45) 0.464
 
Parity (%)
0 136 (48.9%) 143 (51.4%) 0.358
1 65 (23.4%) 62 (22.3%)
2 41 (14.7%) 48 (17.3%)
3 17 (6.1%) 15 (5.4%)
≥4 19 (6.8%) 10 (3.6%)
 
Smoking status (%)
Yes 44 (15.8%) 62 (22.3%) 0.111
No 223 (80.2%) 209 (75.2%)
Not recorded 11 (4.0%) 7 (2.5%)

Table 2 Histology of punch and loop biopsies.

Histology Punch biopsy (%) LLETZ biopsy (%)
Negative 13 (4.7) 5 (1.8)
Low grade 261 (93.9) 46 (16.5)
High grade 1 (0.4) 224 (80.6)
Carcinoma 0 (0) 2 (0.7)
CGIN 1 (0.4) 0 (0)
Not documented 2 (0.7) 1 (0.4)

p = 0.000.

The volume of tissue excised during LLETZ was plotted against the gestational age at delivery ( Fig. 1 ). No relationship between the two variables was demonstrated (p = 0.303). This was similarly the case when women who had one LLETZ and two or more LLETZ procedures were analysed separately. No correlation was noted between volume of tissue excised and gestational age at delivery (p = 0.123). Similarly, there was no correlation between depth of tissue excised and gestational age at delivery ( Fig. 2 , p = 0.301).

gr1

Fig. 1 Volume of cervical tissue excised versus gestational age at delivery.

gr2

Fig. 2 Depth of cervical tissue excised and gestation age at delivery.

The preterm birth rate <37 weeks, however, was significantly increased in the LLETZ group overall in contrast to the control group (25/278 [90%] and 10/278 [36%] respectively). This resulted in a relative risk of preterm birth at <37 weeks of 2.5 (95% CI 1.2–5.1). A similar increase in number of preterm births <34 weeks was also noted in the LLETZ group (15/278 [54%] vs. 4/278 [14%]), although included only a small number of cases. The relative risk of preterm birth at <34 weeks was 3.7 for the LLETZ group (95% CI 1.3–11.2). As demonstrated in Table 3 , the commonest reason for preterm birth was preterm pre-labour rupture of the membranes (14/25 [56%] LLETZ group vs. 5/10 [50%] control group). Preterm pre-labour rupture of the membranes (PPROM) was defined as spontaneous rupture of the membranes occurring prior to 37 weeks and before the start of contractions. There was an increased rate of spontaneous preterm birth in the LLETZ group compared with the control group (p = 0.004). This included deliveries occurring following PPROM as well as spontaneous preterm labour with intact membranes. The rate of PPROM was significantly higher in those women who had had a previous LLETZ procedure compared with those who had not (p = 0.036). The relative risk of spontaneous preterm birth following at least one LLEZ was 3.1 (95% CI 1.4–7.2) and of PPROM was 2.8 (95% CI 1.0–7.7).

Table 3 Reason for preterm birth.

Reason for preterm birth Control group (%) LLETZ group (%)
Preterm prelabour rupture of membranes 5 (50%) 14 (56%)
Spontaneous preterm labour (without PPROM) 2 (20%) 8 (32%)
PV bleeding (placenta praevia/abruption) 2 (20%) 1 (4%)
Medically indicated 1 (10%) 2 (8%)

p = 0.03.

The mean birth weight for babies born to women who had had previous LLETZ procedures was significantly lower than that of babies born to women in the control group (3263 ± 625 g vs. 3423 ± 557 g, p = 0.002, 95% CI 60.7–258.0). However, no difference was noted in the proportion of low birth weight babies in each group, as defined by birth weight <2500 g (24/278 [86%] vs. 14/278 [50%] p = 0.093). There was no difference in mode of delivery in each group (167/278 [601%] vs. 173/278 [622%] spontaneous vaginal delivery, 46/278 [165%] vs. 52/278 [187%] vaginal operative delivery, 62/278 [223%] vs. 53/278 [191%] caesarean section p = 0.836). There was no difference in mean gestational age at delivery for those women having LLETZ procedures performed pre-2008 with those performed in 2008–2010 suggesting that time from LLETZ to delivery does not influence the risk of preterm birth.

Admission to the neonatal intensive care unit (NICU) was used as a marker of neonatal morbidity. There was a significant increase in neonatal morbidity in the LLETZ group compared with the control group with 16/278 [58%] of babies requiring admission in contrast to 5/278 [18%] (p = 0.014, RR 3.2, 95% CI 1.2–8.6).

Comment

This study demonstrates a significant increase in the preterm birth rate for women delivering singleton pregnancies following a previous LLETZ procedure, compared to a matched cohort. This effect was seen in deliveries pre-37 weeks and at the more significant level of pre-34 weeks gestation and included those that had undergone only one prior LLETZ as well as those who had experienced two or more procedures. This was associated with a lower mean birth weight and an increase in neonatal morbidity, as measured by admission to the neonatal intensive care unit. The commonest reason for preterm delivery was PPROM. This further supports the conclusions of the systematic reviews published in The Lancet in 2006 and the up dated meta-analysis in 2011 [3] and [12]. However, our results are at odds with the largest UK study performed by Castanon et al. who noted no increase in preterm birth rate in their cohort of 12,937 singleton births occurring following punch biopsy or LLETZ [13] . As in our study they appreciated the importance of an internal control group in performing appropriate analysis, which takes into account shared, and possibly as yet unknown, risk factors. The differing conclusions reached by their study in contrast to ours are difficult to explain as both studies were performed within the same quality assured national colposcopy programme. The difference may represent an unintentional selection bias on our behalf of our smaller, local population and the fact that we separately compared spontaneous preterm birth rates in preference to overall deliveries before 37 weeks. However, without further demographic information supplied by the Castanon group, in particular on smoking status and number of previous treatments, it is not possible to draw any direct comparisons between the two cohorts.

We did not, however, find an association between volume of tissue excised during LLETZ and subsequent gestational age at delivery. This is in concordance with the Danish study performed by Ortoft et al. [14] . They also demonstrated a higher perinatal morality rate due to severe prematurity in women undergoing one or two previous conisations compared to controls from both the general obstetric population and a group who had cervical dysplasia but had not had any previous treatment but could not correlate this with the volume of the conus removed. In contrast, Khalid et al. published their study in the BJOG in May 2012 and showed a preterm delivery rate at <37 weeks of 9.1% and a threefold increase in the risk of preterm labour when >6 cm3 of cervical tissue was excised [15] . There was no difference in the rate of preterm labour when the volume of tissue removed was below this threshold They had reviewed the obstetric outcomes for 321 women who had undergone LLETZ between 1999 and 2002 and who subsequently delivered at their hospital. The Dublin group performed their volume measurement on open LLETZ specimens post fixation in formalin and used a simpler calculation treating the specimen as a rectangular box. In our study population only 6 women had >6 cm3 of cervical tissue excised during their LLETZ, with four of these patients having had two loop procedures performed. In fact 91% of women in our cohort had <4 cm3 of cervical tissue removed. Ortoft's study similarly had a mean conisation volume of 0.634 cm3 when performed by LLETZ [12] . There has been a general trend towards performing smaller loops in women of reproductive age with an aim of achieving a depth of 8–10 mm. The rationale behind this practice is that the crypt depths extend up to 8 mm from the epithelial surface, therefore, limiting the thickness of excised tissue to 10 mm would ensure elimination of the disease whilst minimising the volume of tissue removed [16] . Ang et al. followed up women who had undergone LLETZ treatment for CIN between 1998 and 2003 and found that in women ≤35 years excision to a depth of <10 mm was associated with no increase in recurrence of disease compared with those who had ≥10 mm of tissue excised [17] . The fact that we, on the whole, used much smaller loops to achieve treatment of CIN in our study in line with these recommendations is likely to account for the lack of correlation demonstrated.

The volume of tissue excised as a proportion of the total cervical volume may be more critical than the actual loop measurements. Papoutsis et al. studied the cervical dimensions of 73 women preconisation and at 6 months following treatment by three-dimensional ultrasonogography. They noted that the greater the initial cone size as a proportion of total cervical volume the less regeneration had occurred by the follow up consultation. A cut-off value of >14% of initial cervical volume was established at which point <75% of the tissue was regenerated and >25% deficit remained [18] . Time is an essential prerequisite for regeneration to occur with at least six months appearing to be the optimal time interval [19] . Whether delaying pregnancy influences the subsequent gestational age at delivery is unknown. In our study time from LLETZ to delivery did not influence preterm birth risk. Unfortunately data was not available for our cohort regarding the relative reduction in cervical length following a LLETZ procedure.

These findings suggest that the increased pregnancy risks associated with previous LLETZ treatment cannot entirely be attributed to reduced cervical tissue mass. Understanding the physiological consequences of CIN and LLETZ is necessary to guide the development of effective interventions to reduce the risk of preterm birth in this group of women. Functional differences in newly formed scar tissue compared to native tissue should be considered, particularly with respect to immunological and matrix remodelling. Alterations in cervical immunological response during pregnancy may lead to an increased risk of ascending infection, contributing to premature rupture of the membranes. Our data is consistent with that of other studies which show that the rate of PPROM is particularly increased in women who have undergone previous LLETZ procedures [3], [6], and [7]. Compared with data from the general population where PPROM is associated with one third of preterm deliveries, our results demonstrated that a half of all preterm births in women attending our colposcopy clinics were associated with PPROM. Vaginal infections such as bacterial vaginosis (BV) have been shown to be positively associated with the development of CIN in a recent meta-analysis and are well established as a risk factor for PPROM [20] . Whether the prevalence of such infections is higher in women with a higher grade of premalignant cervical disease or are more likely to persist in women who have had a LLETZ performed remains to be established. Whilst women in our clinics are screened for BV if they have had a previous preterm birth, testing is not routinely performed in the colposcopy clinics, and, therefore, the prevalence of this infection in our cohort cannot be determined accurately. Similarly the presence of infection does not necessarily imply causation and may simply reflect female sexual activity. Emerging evidence certainly suggests that inflammatory mediators are important initiators of labour, however, further investigation is required to determine the potential interaction between vaginal infection, CIN development and risk of PPROM and, if proven, may offer exciting opportunities for pharmacological manipulation [21] .

A strength of our study is that we have included a control group who were matched for age, parity and smoking status, factors all known to influence preterm birth rate. By including women who had CIN, albeit of a lower grade, we were also able to correct for any as yet unidentified features of the disease process itself which influence the preterm delivery rate. Sadler et al. observed a similar increase in preterm birth rate in a group of women who had treated disease compared with those who were untreated and found that the height of the cone excised influenced this risk (aRR 3.6 for a cone ≥1.7 cm, 95% CI 1.8–7.5) [6] . However, their group included women treated by laser conisation and ablation as well as LLETZ. By including only LLETZ procedures in our study we are able to study the effects of this treatment in isolation and provide data of greater applicability to the general population attending colposcopy services that are more likely to undergo LLETZ than other procedures. Our work also differs from previously published data in classifying preterm birth by the underlying aetiology. This allows a more clinically relevant assessment of the impact of LLETZ on PPROM and preterm labour.

A disadvantage of our study was our inability to correct for socioeconomic, ethnic and marital status, as this information was not available to us in the databases used. However, the population studied consists of a predominantly uniform white British community with a lower employment rate than the national average and a high level of deprivation. Information regarding a history of preterm birth would have been beneficial, however, as the database only commenced in 2008 this data was not provided. Women who have had pregnancies both pre and post LLETZ constitute the most informative control group, as it can be assumed that the only new risk factor for preterm delivery is cervical surgery. There is limited published data available investigating this group of women. A Finish study by Jakobsson et al. found an increase in preterm delivery rate following treatment with a relative risk of 1.94 (6.5% vs. 12%) [22] . Of the population of women who had had a previous term delivery, 10.8% went on to have a preterm delivery following LLETZ. This risk was increased further following a repeat LLETZ, with a relative risk of 5.15. The Castanon group alternatively found no increase in preterm birth rate following LLETZ with a RR 0.94 (95% CI 0.62–1.43). They managed to include 372 women in their analysis, but were unable to differentiate women who had had previous treatment. They propose that their results are a reflection of a more standardised colposcopy programme within the UK setting. In order to be able to expand upon the existing evidence base a larger, probably national, study population would be required to include sufficient numbers of women who have delivered both prior to and following LLETZ treatment.

An element of bias could have arisen in our data from the fact that our specimens were formalin fixed at the time of receipt in the pathology laboratory which is known to result in tissue retraction and hence a reduction in the measured dimensions. We also utilised the hemiellipsoid formula used by other groups in order to calculate the volume of tissue excised as the tissue had not had a formal volumetric assessment, this not being routinely performed by UK pathologists. The accuracy of volumetric calculations using the hemiellipsoid formula compared to the volume of a sample determined by fluid displacement has not been assessed and this, therefore, could have introduced an element of error into our results. Using the same formula consistently throughout the study would, however, help limit the size of any effect.

The preterm delivery rate observed in the control and cohort group was lower than anticipated from previous studies and epidemiological data. This may reflect the fact that the study was performed using patients treated in a tertiary unit with a large fetal medicine department and preterm birth clinic. Women undergoing one previous LLETZ are not managed any differently during their obstetric care to women who have only had cervical punch biopsies, therefore, the impact of any increased intervention is likely to have been the same in both groups, limiting the introduction of bias into the design methodology. The fact that our findings of an increased rate of preterm birth following a LLETZ procedure are consistent with other studies suggests that the results are applicable to a wider population including patients treated in smaller district general hospitals. The absence of a difference in the preterm birth rates of women who had one or more LLETZ procedures performed is likely to reflect the small number of cases included in the cohort (n = 30). The study was not powered to detect a difference between one and multiple LLETZ procedures; rather it was constructed to determine the effect of removing increasing volume of cervical tissue regardless of number of excisions performed.

Conclusion

Our study demonstrates an increased risk of preterm delivery and PPROM following LLETZ treatment compared with a matched control group. We did not, however, elucidate a relationship between the volume of cervical tissue excised and the subsequent gestational age at delivery. This further emphasises that reduction in cervical length is unlikely to be the sole contributing factor to the risk of preterm birth, rather complex interactions between the cervix, infectious agents and pro-inflammatory mediators may be of greater significance. Further work in this area is required to elucidate the underlying mechanisms behind preterm birth in order to generate potential treatments. Our data should provide some reassurance to clinicians who should continue to perform LLETZ with adequate tissue margins to ensure complete resection of disease in line with current UK guidance.

Conflict of interest

The authors have no conflicts of interest to disclose.

Contribution to authorship

SK designed the study, contributed to data collection, performed the analyses and drafted the manuscript. EG contributed to data collection and revision of the manuscript. EM contributed to revision of the manuscript. MS contributed to study design, discussion of analysis and revision of the manuscript. All authors contributed to the final manuscript.

Details of ethic approval

Approval for the study was obtained from the North East-Northern and Yorkshire research ethics committee. The Research Ethics Committee reference number is 12/NE/0252, dated 7th August 2012.

Funding

No financial support.

Acknowledgements

Special thanks to Jilly Goodfellow, nurse colposcopist, for her help with colposcopy data collection and James Summerton, IT manager, for his assistance in performing searches within the maternity database.

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Footnotes

a Department of Obstetrics and Gynaecology, Royal Lancaster Infirmary, Ashton Road, Lancaster LA1 4RP, United Kingdom

b Department of Obstetrics and Gynaecology, Royal Victoria Hospital, Newcastle-upon-Tyne, United Kingdom

lowast Corresponding author at: Department of Obstetrics and Gynaecology, Royal Lancaster Infirmary, Ashton Road, Lancaster LA1 4RP, United Kingdom. Tel.: +44 7905223064.