Excisional procedures are necessary for the diagnosis and treatment of high-grade cervical intraepithelial neoplasia (CIN),1 but they may lead to structural and functional changes of the cervix. The correct timing and successful execution of cervical remodeling is a critical component of parturition.2 The majority of published research on the effects of surgical excisional therapies, including cold-knife conization and loop electrosurgical excision procedure (LEEP), on pregnancy outcomes has focused on the gestational age of subsequent deliveries and prematurity-related neonatal outcomes.3–6 The ability of the cervix after an excisional procedure to undergo the dynamic intrapartum changes of dilation and effacement to result in a successful vaginal delivery has been inadequately studied.
As the current treatment of choice for CIN, LEEP is commonly performed in women of childbearing age.7–11 Like all excisional procedures, LEEP may result in loss of cervical tissue12 and can lead to scarring of the cervix,13 which, in theory, could influence the ability of the cervix to dilate in labor. Arrest of dilation is one of the most common indications for cesarean delivery in the United States.14 Thus, we hypothesized that LEEP could affect the risk of cesarean delivery in subsequent pregnancies. In this study, we estimated the effect of LEEP on risk of cesarean delivery in a large retrospective cohort and secondarily estimated the risk of cesarean delivery for arrest as well as the effect of specimen size and time from LEEP to delivery on risk of cesarean delivery.
MATERIALS AND METHODS
This study is a secondary analysis of a multicenter retrospective cohort study. In the parent study, women with prior LEEP were compared with age-matched control patients without prior cervical excisional procedure and control patients with prior cervical biopsy to assess the association of LEEP and spontaneous preterm birth before 34 weeks of gestation. Approval for the study was granted by the institutional review boards at each participating hospital. Women with LEEP performed between 1996 and 2006 as well as age-matched control patients with screening cervical cytology or cervical punch biopsy performed the same calendar year were identified from clinical databases of surgical pathology at nine participating hospitals by searching for the key words: “Pap (Papanicolaou) smear,” “cervical cytology,” “cervical biopsy,” and “LEEP.” Trained research nurses contacted the participants by telephone and collected information, including maternal demographics and details regarding all pregnancies both before and after the procedure. With informed consent, medical records were obtained from each pregnancy. Pathology and cytology reports were also acquired from all prior cervical procedures. In cases of inconsistencies between the patient recall and chart-obtained data, the medical records information was preferentially used. All research data were stored in a secure, central, electronic study database.
In the present study, risk of cesarean delivery among women with a prior LEEP was compared with risk in women without a prior surgical excisional procedure. There were two unexposed cohorts in this study, both of which were identified from the surgical pathology databases. The first unexposed group consisted of women with only prior screening cervical cytology (Pap test). Women in the second unexposed group had a prior cervical punch biopsy performed for evaluation of cervical dysplasia. The pregnancy evaluated in this analysis was the first pregnancy of a duration more than 20 weeks of gestation after the classifying procedure (LEEP, Pap test, or cervical biopsy). In the unexposed cohorts, women who reported any history of LEEP or other cervical excisional procedure were excluded. Women with a multiple gestation in the index pregnancy were also excluded. Those women with missing data regarding pregnancy history, mode of delivery in the index pregnancy, or the dates of the cervical procedure or delivery were excluded as were any women for whom medical records were unavailable.
Demographic information at the time of the index pregnancy was obtained during a structured phone interview and confirmed by inpatient medical records. Data collected included maternal age, parity, height, weight, race, and history of prior cesarean delivery. Documented gestational age at delivery, use of induction agents during labor, and neonate birth weight in the index pregnancy were extracted from the records. Preterm was defined as delivery less than 37 weeks of gestation. Medical history at the time of the index pregnancy was reviewed. Gestational diabetes was defined as glucose 140 g/dL or greater on a screening glucose tolerance test followed by at least two abnormal values on a 3-hour glucose test using the National Diabetes Data Group criteria.15 Pregestational diabetes was defined as the diagnosis of either type 1 or type 2 diabetes mellitus before pregnancy. Criteria used to identify women with preeclampsia or gestational hypertension included persistent blood pressure greater than 140 mm Hg systolic or greater than 90 mm Hg diastolic with or without proteinuria.16 Pathology reports were examined to determine the grade of cervical dysplasia on screening cytologic specimens for all women.
The primary outcome assessed was mode of delivery. Secondarily, indication for cesarean delivery was evaluated in women who had a cesarean delivery in the index pregnancy. Indication for cesarean delivery was abstracted from the operative report. The indication was coded as arrest of labor if the documented reason for cesarean delivery included “arrest of dilation,” “failure to progress,” “failed induction of labor,” “cephalopelvic disproportion,” or “cervical stenosis,” or “scarring.” Failed operative vaginal delivery and “arrest of descent” were not classified as an arrest of labor. Cesarean deliveries performed for indications other than arrest of labor were classified as “other.” In cases in which multiple indications for delivery were documented, the indication was coded as arrest of labor if any one of the indications included one of the criteria used to define labor arrest.
Women with prior LEEP were compared with women with screening cytology only (Control Group 1) and women with a history of cervical punch biopsy (Control Group 2) in independent analyses. Baseline characteristics of the groups were compared using χ2 analysis. The distribution of all continuous variables in this study was assessed using the Kolmogorov-Smirnov test. Median maternal age was compared using the Mann-Whitney U test because the values were not normally distributed. Unadjusted relative risks and 95% confidence intervals for cesarean delivery after LEEP were calculated using each reference group. Stratified analyses were performed based on gestational age at delivery, history of cesarean delivery, and induction of labor. The indications for cesarean delivery in the exposed and unexposed groups were compared. Multivariable logistic regression was performed to adjust for confounders identified in the literature as risk factors for cesarean delivery as well as those factors found to be significant in bivariate analysis including neonate birth weight, parity, race, prior cesarean delivery, maternal diabetes, maternal body mass index (BMI, calculated as weight (kg)/[height (m)]2), and age.17–19 The final logistic regression model created using a backward, stepwise approach for the primary outcome, cesarean delivery, included parity, prior cesarean delivery, birth weight, maternal BMI, and maternal age. The likelihood ratio test was used to assess the effect of removal of covariates from the model.
In the group of women with prior LEEP, the relationship between LEEP specimen size and risk of cesarean delivery was examined. Using the dimensions of the specimens described in the pathology reports, total volumes for the specimens were calculated. Median specimen volumes were compared using the Mann-Whitney U test in women who had a cesarean delivery in the index pregnancy and those women who delivered vaginally because the volume data were not normally distributed.
The effect of time from procedure on delivery mode was also evaluated in the group of women with prior LEEP. Median length of time from LEEP to index pregnancy was compared in women who had a cesarean delivery and women delivered vaginally using the Mann-Whitney U test. Risk of cesarean delivery in women who delivered within 12 months of the LEEP was compared with risk of cesarean delivery in women who delivered greater than 12 months after the procedure. A similar comparison was conducted using delivery within 24 months of the LEEP.
The parent cohort study was powered to detect differences in preterm birth. All women enrolled in the study with a postprocedure pregnancy of more than 20 weeks of gestation were included in this secondary analysis, and a post hoc power analysis was performed. Tests with P<.05 were considered statistically significant. All statistical analyses were performed using STATA 10.0.
A total of 1,738 women in the initial cohort study met inclusion criteria for this secondary analysis. The exposed group consisted of 598 women with a history of a LEEP procedure. The unexposed groups were composed of 588 women with a history of only cytologic screening (Control Group 1) and 552 women with a prior cervical punch biopsy (Control Group 2). Baseline demographic characteristics were similar between the exposed cohort and the unexposed control groups in regard to parity, maternal BMI, history of prior cesarean delivery, rates of preeclampsia or gestational hypertension, and rates of gestational and pregestational diabetes at the time of the index pregnancy. Women with a prior LEEP were older than women in either control group. White women were more likely to have had a prior LEEP than women of other races, whereas control groups were comprised of a significantly higher percentage of black women. Gestational age at delivery, use of induction agents, and birth weight of the neonate in the index pregnancy were not significantly different among the groups. Women with a prior LEEP were more likely to have had cytology demonstrating high-grade cervical dysplasia before their procedure than women in the unexposed cohorts (Table 1).
We observed similar rates of cesarean delivery in women with a history of LEEP and women without a history of cervical biopsy or excisional procedure (Control Group 1) (31.6% compared with 29.3%, adjusted odds ratio [OR] 1.06, 95% confidence interval [CI] 0.79–1.41). Stratified analyses by gestational age at delivery, labor induction, and history of prior cesarean delivery demonstrated similar rates of cesarean delivery among LEEP-exposed and LEEP-unexposed women. Evaluation of indication for cesarean delivery demonstrated similar rates of cesarean delivery for arrest of labor in women with a prior LEEP and women in Control Group 1 after controlling for relevant confounders (Table 2).
In a comparison of women with a history of LEEP and those in the second unexposed group with a history of prior cervical biopsy, no difference in rate of cesarean delivery was seen (31.6% compared with 29.0%, adjusted OR 0.99, 95% CI 0.74–1.33, P=.98). Similar to the Control Group 1 analysis, stratified analyses based on gestational age at delivery, history of cesarean delivery, and induction of labor also revealed no association between prior cervical procedure and risk of cesarean delivery. Similar indications for cesarean delivery were documented in both groups (Table 3).
Among women with a history of prior LEEP, the size of the LEEP specimen was compared among women who had a cesarean delivery in the index pregnancy and those who delivered vaginally. No difference in median LEEP specimen volume was found (1.81 cm3 in the cesarean delivery group compared with 1.70 cm3 in the vaginal group, P=.71). Similarly, the specimen size did not significantly vary among women who underwent cesarean delivery for labor arrest in the index pregnancy compared with all women who did not require cesarean delivery for arrest (1.35 cm3 compared with 1.77 cm3, P=.10). The effect of specimen size was further examined by comparing rates of cesarean delivery among those women who had a prior LEEP with the smallest specimen volumes (less than 10th percentile) with other women with LEEP. Rates of cesarean delivery were statistically similar (37.3% compared with 31.1%, P=.36). Likewise, women with particularly large LEEP specimens (greater than 90th percentile) also did not have an increased rate of cesarean delivery (32.7% compared with 31.3%, P=.78).
The effect of interval of time between LEEP and subsequent pregnancy on cesarean delivery rate was assessed. No difference in median length of time from LEEP was demonstrated in women who subsequently had a cesarean delivery in the index pregnancy and those who delivered vaginally (33.4 months compared with 33.0 months, P=.42). There was also no difference in the time interval between the procedure and delivery in women who had a cesarean delivery for arrest and those who did not require cesarean delivery for arrest (25.7 months compared with 33.0 months, P=.82). Among women with a prior LEEP, delivery within 12 months of the procedure was not associated with increased cesarean delivery risk (29.8% compared with 31.8%, P=.78) nor was delivery within 24 months of the procedure (31.1% compared with 31.9%, P=.84).
A post hoc power analysis to estimate our ability to detect meaningful differences in rates of cesarean delivery in this secondary analysis was performed. Based on the sample sizes of the exposed and unexposed cohorts and assuming an α equal to 0.05, we would be able to detect a 1.5-fold difference in rates of cesarean deliveries among the groups with a 90% power.
In this study, we estimated the effect of LEEP on subsequent cesarean delivery. We found no statistically significant difference in rates of cesarean delivery in women with a prior LEEP compared with two control groups after controlling for relevant confounders. Furthermore, the indications for cesarean delivery, including arrest of labor, did not vary among the groups. The size of the LEEP specimen and the interval of time from the LEEP also did not affect the risk of cesarean delivery in the subsequent pregnancy.
Few studies have previously examined the relationship between prior LEEP and cesarean delivery.12,13,20–24 Of these studies, many have small sample sizes and thus may not be adequately powered to evaluate mode of delivery,13,20–22 and in some studies, cesarean delivery data have been presented without accounting for possible confounders.20,22–24 In addition, few studies13,23 have reported the indication for cesarean delivery, thus restricting the ability to draw meaningful conclusions from the reported data. Lastly, the published data on the effect of cervical procedures on rates of cesarean delivery are inconsistent. Although at least one publication reported a decreased rate of cesarean delivery24 after LEEP and others have found higher rates of cesarean delivery after cervical conization,25,26 most studies have reported no significant association between prior cervical excisional procedure and mode of delivery. 12,20–23,26–28
The major limitation of the present study is the retrospective design. The available data for analysis were limited to that which was collected as part of the initial study designed to evaluate preterm birth as the primary outcome. Details regarding labor and indication for cesarean delivery in the index pregnancy were restricted to that which could be extracted from the medical record. In cases of multiple indications for surgery, the data were coded in a manner that favored the classification of arrest of labor over other indications. This methodology was used because an alteration in the ability of the cervix to dilate was considered the most biologically plausible link between LEEP and cesarean delivery. However, possible heterogeneity among the women classified as having arrest of labor may have diminished the observed effect of cervical excisional procedures on cervical dilation in labor.
Although this study was retrospective, the amount of data collected was substantial. Our study is one of only a few to examine the indication for cesarean delivery,13,23 which is an essential step in understanding whether a link between prior LEEP and cesarean delivery exists. In addition, there were minimal missing data particularly in regard to indication for cesarean delivery (8.5%). All data collected during a structured telephone interview with the study participant were confirmed in medical records that were obtained for each pregnancy before and after the enrollment procedure, thus minimizing recall bias and improving the completeness of the data. Our use of two unexposed cohorts also enhanced the ability to draw conclusions from our results because it provided a better opportunity to assess confounding and selection bias. Furthermore, information from pathology reports was used to assess the effect of LEEP specimen size on risk of cesarean delivery. The lack of association between specimen size and cesarean delivery, even at the smallest and largest extremes, reinforces our conclusion that LEEP does not affect the risk of cesarean delivery.
Loop electrosurgical excision procedure has become the primary procedure used in the United States for the diagnosis and treatment of high-grade CIN. Although LEEP has been associated with cervical stenosis,13 our study indicates that a history of LEEP does not increase the risk of cesarean delivery in the subsequent pregnancy regardless of the size of the LEEP specimen or interval of time since the procedure was performed. Additionally, the evaluation of the indications for cesarean delivery suggests that LEEP does not significantly impair the ability of the cervix to dilate during labor.
1. Wright TC Jr, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D; 2006 American Society for Colposcopy and Cervical Pathology-sponsored Consensus Conference. 2006 consensus guidelines for the management of women with cervical intraepithelial neoplasia or adenocarcinoma in situ. Am J Obstet Gynecol 2007;197:340–5.
2. Word RA, Li XH, Hnat M, Carrick K. Dynamics of cervical remodeling during pregnancy and parturition: mechanisms and current concepts. Semin Reprod Med 2007;25:69–79.
3. Sadler L, Saftlas A, Wang W, Exeter M, Whittaker J, McCowan L. Treatment for cervical intraepithelial neoplasia and risk of preterm delivery. JAMA 2004;291:2100–6.
4. Kristensen J, Langhoff-Roos J, Kristensen FB. Increased risk of preterm birth in women with cervical conization. Obstet Gynecol 1993;81:1005–8.
5. Ortoft G, Henriksen T, Hansen E, Petersen L. After conisation of the cervix, the perinatal mortality as a result of preterm delivery increases in subsequent pregnancy. BJOG 2010;117:258–67.
6. Werner CL, Lo JY, Heffernan T, Griffith WF, McIntire DD, Leveno KJ. Loop electrosurgical excision procedure and risk of preterm birth. Obstet Gynecol 2010;115:605–8.
7. Bevis KS, Biggio JR. Cervical conization and the risk of preterm delivery. Am J Obstet Gynecol 2011;205:19–27.
8. Duggan BD, Felix JC, Muderspach LI, Gebhardt JA, Groshen S, Morrow CP, et al.. Cold-knife conization versus conization by the loop electrosurgical excision procedure: a randomized, prospective study. Am J Obstet Gynecol 1999;180:276–82.
9. Kleinberg MJ, Straughn JM Jr, Stringer JS, Partridge EE. A cost-effectiveness analysis of management strategies for cervical intraepithelial neoplasia grades 2 and 3. Am J Obstet Gynecol 2003;188:1186–8.
10. Mathevet P, Dargent D, Roy M, Beau G. A randomized prospective study comparing three techniques of conization: cold knife, laser, and LEEP. Gynecol Oncol 1994;54:175–9.
11. Naumann RW, Bell MC, Alvarez RD, Edwards RP, Partridge EE, Helm CW, et al.. LLETZ is an acceptable alternative to diagnostic cold-knife conization. Gynecol Oncol 1994;55:224–8.
12. Crane JM. Pregnancy outcome after loop electrosurgical excision procedure: a systematic review. Obstet Gynecol 2003;102:1058–62.
13. Mathevet P, Chemali E, Roy M, Dargent D. Long-term outcome of a randomized study comparing three techniques of conization: cold knife, laser, and LEEP. Eur J Obstet Gynecol Reprod Biol 2003;106:214–8.
14. Barber EL, Lundsberg LS, Belanger K, Pettker CM, Funai EF, Illuzzi JL. Indications contributing to the increasing cesarean delivery rate. Obstet Gynecol 2011;118:29–38.
15. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 2003;26:S5–20.
16. Report of the National High Blood Pressure Education Program Working Group on high blood pressure in pregnancy. Am J Obstet Gynecol 2000;183:S1–S22.
17. Kaiser PS, Kirby RS. Obesity as a risk factor for cesarean in a low-risk population. Obstet Gynecol 2001;97:39–43.
18. Sokol RJ, Rosen MG, Bottoms SF, Chik L. Risks preceding increased primary cesarean birth rates. Obstet Gynecol 1982;59:340–6.
19. Wilkes PT, Wolf DM, Kronbach DW, Kunze M, Gibbs RS. Risk factors for cesarean delivery at presentation of nulliparous patients in labor. Obstet Gynecol 2003;102:1352–7.
20. Acharya G, Kjeldberg I, Hansen SM, Sorheim N, Jacobsen BK, Maltau JM. Pregnancy outcome after loop electrosurgical excision procedure for the management of cervical intraepithelial neoplasia. Arch Gynecol Obstet 2005;272:109–12.
21. Klaritsch P, Reich O, Giuliani A, Tamussino K, Haas J, Winter R. Delivery outcome after cold-knife conization of the uterine cervix. Gynecol Oncol 2006;103:604–7.
22. Paraskevaidis E, Koliopoulos G, Lolis E, Papanikou E, Malamou-Mitsi V, Agnantis NJ. Delivery outcomes following loop electrosurgical excision procedure for microinvasive (FIGO stage IA1) cervical cancer. Gynecol Oncol 2002;86:10–3.
23. Samson SL, Bentley JR, Fahey TJ, McKay DJ, Gill GH. The effect of loop electrosurgical excision procedure on future pregnancy outcome. Obstet Gynecol 2005;105:325–32.
24. Tan L, Pepra E, Haloob RK. The outcome of pregnancy after large loop excision of the transformation zone of the cervix. J Obstet Gynaecol 2004;24:25–7.
25. El-Bastawissi AY, Becker TM, Daling JR. Effect of cervical carcinoma in situ and its management on pregnancy outcome. Obstet Gynecol 1999;93:207–12.
26. Kyrgiou M, Koliopoulos G, Martin-Hirsch P, Arbyn M, Prendiville W, Paraskevaidis E. Obstetric outcomes after conservative treatment for intraepithelial or early invasive cervical lesions: systematic review and meta-analysis. Lancet 2006;367:489–98.
27. Kuoppala T, Saarikoski S. Pregnancy and delivery after cone biopsy of the cervix. Arch Gynecol 1986;237:149–54.
28. Cruickshank ME, Flannelly G, Campbell DM, Kitchener HC. Fertility and pregnancy outcome following large loop excision of the cervical transformation zone. Br J Obstet Gynaecol 1995;102:467–70.