OBJECTIVE: To estimate whether the severity of cervical intraepithelial neoplasia (CIN) and the loop electrosurgical excision procedure (LEEP) increase the risk for preterm delivery, and to evaluate the role of repeat LEEP and time interval since LEEP.
METHODS: This was a retrospective register-based study from Finland from 1997 to 2009. We linked Hospital Discharge Register and Finnish Medical Birth Register data. Case group women consisted of 20,011 women who underwent LEEP during the study period and their subsequent singleton deliveries in 1998–2009. Control population included women from the Medical Birth Register with no LEEP (n=430,975). The main outcome measure was preterm delivery before 37 weeks of gestation.
RESULTS: The risk for preterm delivery increased after LEEP. Women with previous LEEP had 547 (7.2%) preterm deliveries, whereas the control population had 30,151 (4.6%) preterm deliveries (odds ratio [OR] 1.61, confidence interval [CI] 1.47–1.75, number needed to harm 38.5). The overall preterm delivery rate in the study period was 4.6% for singleton deliveries. Repeat LEEP was associated with an almost threefold risk for preterm delivery (OR 2.80, CI 2.28–3.44). The severity of CIN did not increase the risk for preterm delivery. However, with LEEP for carcinoma in situ or microinvasive cancer, the risk for preterm delivery was higher (OR 2.55, CI 1.68–3.87). The increased risk also was associated with non-CIN lesions (OR 2.04, CI 1.46–2.87). Similarly, the risk was increased after diagnostic LEEP (OR 1.39, 95% CI 1.16–1.67). Time interval since LEEP was not associated with preterm delivery. Adjusting for maternal age, parity, socioeconomic or marital status, urbanism, and previous preterm deliveries did not change the results.
CONCLUSION: The risk for preterm delivery was increased after LEEP regardless of the histopathologic diagnosis. The risk was highest after repeat LEEP, which should be avoided, especially among women of reproductive age.
LEVEL OF EVIDENCE: II
The risk for preterm delivery is increased after loop electrosurgical excision procedure regardless of histopathology, and the risk was highest after repeat loop electrosurgical excision procedure.
Department of Obstetrics and Gynecology, Helsinki University Central Hospital, and the National Institute of Health and Welfare, Helsinki, Finland; and the Nordic School of Public Health, Gothenburg, Sweden.
Corresponding author: Annu Heinonen, MD, Women's Hospital, Helsinki University Hospital Haartmaninkatu 2, PL 140, 00029 HUS Finland; e-mail: firstname.lastname@example.org.
Supported by grants from the Research Foundation of the University of Helsinki, Helsinki, Finland.
Financial Disclosure The authors did not report any potential conflicts of interest.
Presented in abstract form at the EUROGIN Conference, May 8–11, 2011, Lisbon, Portugal, and as a poster at the 28th International Papillomavirus Conference, November 30–December 6, 2012San Juan, Puerto Rico,.
Cervical intraepithelial neoplasia (CIN) is a precancerous lesion common in women of reproductive age.1 Effective treatment of high-grade lesions is important to prevent cervical cancer. However, only a small proportion of low-grade lesions proceed to high-grade lesions or invasive cancer.2,3 The most common treatment for CIN is loop electrosurgical excision procedure (LEEP). Several studies have shown an association between all types of excisional treatments of the cervix, including LEEP, and the risk for preterm delivery.4–7 The risk for preterm delivery increases with the depth and volume of the excised cone.8 Before cancerous lesion, CIN itself also may increase the risk.9,10 Thus, it could be assumed that this risk increases with the increasing severity of CIN.
The objective was to estimate whether LEEP and the severity of CIN increase the risk for preterm delivery. Furthermore, we wanted to assess the effect of repeat LEEP. We hypothesized that a short time interval between LEEP and delivery further increases the risk for preterm delivery.
MATERIAL AND METHODS
We used Hospital Discharge Register to identify women of reproductive age (15–49 years) who had LEEP for cervical lesions from 1997 to 2009. We linked this information with Medical Birth Register data to identify subsequent singleton deliveries. The data linkage was performed by using the encrypted unique personal identification numbers of women in both registers. Both registers are controlled by the National Institute of Health and Welfare and include the whole population.
The Hospital Discharge Register collects information on all hospitalizations since 1967. According to the latest quality study, 95% of the hospitalizations were registered and 97% of main diagnoses concerning pregnancy, delivery, and puerperium were correctly reported. Increased use of electronic patient journals has further improved the completeness and validity of the Hospital Discharge Register.11 The Hospital Discharge Register includes all day surgical procedures since 1994 and also all outpatient visits in public hospitals since 1998. The medical procedures performed at hospitals are identified by surgical procedure codes (since 1997 based on the Finnish version of Nordic Classification on Surgical Procedures).
The Medical Birth Register is nationwide and includes baseline data of pregnant women and all interventions during pregnancy and delivery. It also includes information on the outcomes of the newborns during the first 7 days. Data for less than 0.1% of all newborns are missing from the register, and information of such cases is routinely obtained from the Central Population Register and Cause-of-Death Register. The information in the Medical Birth Register is routinely controlled by the National Institute of Health and Welfare, and incorrect information is sent back to the birth hospital for revision in case of missing or obviously incorrect data. The data correspond well with the data in hospital records.11
Preterm delivery was defined as delivery before 37 weeks of gestation. Extremely preterm delivery (less than 28 weeks of gestation) was studied separately. We also analyzed the risk for small for gestational age based on sex-specific national standards,12 low birth weight (less than 2,500 g), and perinatal deaths (from 22 weeks of gestation until 1 week after birth). The socioeconomic status was based on the maternal occupation at the time of delivery and classified according to national standards kept by Statistics Finland (www.stat.fi/meta/kas/sosioekon_asema_en.html).
Our case group women consisted of 20,011 women with 25,101 LEEPs from 1997 to 2009. Of these women 5,114 had subsequent singleton deliveries according to the Medical Birth Register. The total number of deliveries was 7,636. Our control population consisted of 430,975 women in the Medical Birth Register with no previous LEEP and their subsequent 658,179 singleton deliveries from 1998 to 2009. No other exclusion criteria were used for the control population. The Finnish version of the Nordic Classification of Surgical Procedures uses LCD03 code for LEEP exclusively since 1997. We used this code to identify patients with LEEP treatment from the Hospital Discharge Register. Furthermore, women with repeat LEEP had this code at least twice at different time points. The severity of the CIN lesion was classified according to the latest version of the International Classification of Diseases (version 10). The codes to identify severity were as follows: R87.6 abnormal cytology; A63.0 condyloma accuminatum; N87.0 mild dysplasia (CIN 1); N87.1 moderate dysplasia (CIN 2); N87.2 severe dysplasia (CIN 3); N87.9 nonspecific dysplasia; D06.0, D06.1, D06.7, and D06.9 carcinoma in situ of cervix; and C53.00–C53.99 carcinoma of the cervix. For some LEEPs, no corresponding diagnosis was found and these were classified as nonspecific. The group formed by diagnosis A63.0 (condyloma accuminatum) was classified as having non-CIN lesions. The most severe diagnosis was recorded. We checked from the Hospital Discharge Register all diagnoses of women who had diagnostic LEEP without CIN. We further studied the time interval between the procedure and the delivery.
We calculated odd ratios (ORs), 95% confidence intervals (CIs), and number needed to harm (NNH) for preterm delivery. We adjusted these for maternal age, socioeconomic status, marital status, urbanity of woman's residence (urban, semi-rural, and rural as defined by Statistics Finland; www.stat.fi/meta/luokitukset/kuntaryhmitys/001-2008/1_en.html), and time since LEEP. In a second model, we adjusted the results for all of these and also for previous preterm deliveries. We used logistic regression to adjust for the confounding factors. To avoid clustering of preterm deliveries within individuals, we repeated the analyses including only the first deliveries after LEEP (n=5,114) and separately for primiparous deliveries (n=3,355).
The register-keeping organization, the National Institute of Health and Welfare, authorized the use of anonymous register data in scientific research. The ethical evaluation was performed by the register authorities and the data protection ombudsman who reviewed the study before the study permission was given, as required by the legislation.
Characteristics of the study population are presented in Table 1. The control population was slightly younger than the case population; the mean age of study population was 30.8 years (standard deviation [SD] 4.8) and 30.0 years (SD 5.5) for the control population. The number of previous deliveries was approximately the same in both populations; mean parity for study population was 1.0 (SD 1.2) and for the control population was 0.9 (SD 1.1). The majority of the study population (61%) belonged to socioeconomic status “other,” including stay-at-home mothers, students, and others for whom no specific socioeconomic status could be determined. Women with LEEP lived more often in cities and large towns, and these women were more often single. Women with LEEP were more often smokers. Up to 18% continued smoking after the first trimester. In the group of “other socioeconomic status,” stay-at-home mothers (17.6%), students (18.6%), and those with unknown occupations smoked more than parturients in general (15.2%).
Women with previous LEEP had 547 (7.2%) preterm deliveries, whereas the corresponding figure among control population was 30,151 (4.6%; OR 1.61, 95% CI 1.47–1.75, NNH 38.5) (Table 2). The overall preterm delivery rate in the study period was 5.3% for all deliveries and 4.6% for singleton deliveries. The severity of CIN did not increase the risk for preterm delivery. Loop electrosurgical excision procedure performed for non-CIN lesions increased the risk twofold (OR 2.04, 95% CI 1.46–2.87). However, for cancerous lesions this risk was somewhat higher (OR 2.55, 95% CI 1.68–3.87). Repeat LEEP increased the risk almost threefold (OR 2.80, 95% CI 2.28–3.44). The risk for having low birth weight was similarly increased (OR 1.50, 95% CI 1.30–1.73). The risks for extremely preterm delivery (OR 1.27, 95% CI 0.75–2.16), small for gestational age (OR 0.27, 95% CI 0.70–1.31), and perinatal death (OR 1.25, 95% CI 0.76–1.89) were not increased.
Adjustment for maternal age, socioeconomic status, marital status, and urbanism did not change the results. Time interval since LEEP had no effect (OR 0.98, 95% CI 0.96–1.00). We repeated the analyses separately for the first delivery after LEEP and for primiparous women, but it did not change the results (Table 3). Even adjusting for previous preterm deliveries did not change the results.
Our study shows that LEEP is associated with increased risk for preterm delivery. The increasing severity of CIN did not increase the risk for preterm delivery. This risk also was increased after LEEPs performed for non-CIN lesions. Repeat LEEP was a strong risk factor for preterm birth. The so-called diagnostic LEEP was strikingly common during the study period and also increased the risk for preterm delivery. These procedures peaked in 1999–2000 (n=859) but have been gradually declining since then (n=282 in 2009; data not shown).
Our study has several strengths. We used high-quality population-based data from the Finnish Medical Birth Register and Hospital Discharge Register with high coverage and proven quality. We obtained data from more than 7,000 deliveries including 547 preterm deliveries. The large study population and the absence of reporting, recall, and participation bias improve the credibility of our results. We were able to adjust for several important variables, such as maternal age, socioeconomic status, marital status, and urbanism. Adjusting for previous preterm deliveries, which is known to be the main risk factor for preterm delivery,13 did not change the results. In addition, we had information about maternal smoking recorded during the first antenatal visit. Women with LEEP smoked more often during pregnancy than other women. We did not adjust specifically by smoking status because socioeconomic status and smoking are known to be strongly correlated in Finland.14 We chose to adjust for socioeconomic status rather than smoking, because the data of socioeconomic status are more accurate.
This study also has some limitations. The risk for preterm delivery increases with the depth and volume of the excised cone,8 and those performing colposcopies attempt to tailor cones to be less than 10 mm in depth.15 We could not determine the cone size because this information is not available in the register. However, the risk for preterm delivery was higher after LEEP performed for high-grade CIN or cancer than after LEEP preformed for low-grade CIN. Deeper cones are undoubtedly performed for such lesions. Some LEEPs may have been performed in private clinics not captured by the registers. In Finland, however, only few LEEP procedures are performed outside hospitals. Therefore, it is unlikely that a small number of missing cases would have changed our results.
When using national register data, the comparison group consists of a population of normal pregnant women, which might exaggerate the risk for preterm birth. However, in a study by Sadler et al16 the comparison group was formed by untreated colposcopy patients, and the risk associated with LEEP was still significant. Thus, we have no reason to believe that changing our comparison group would change the results.
Previous meta-analyses1,4,6 and many single studies5,16–18 have demonstrated increased risk for preterm delivery after LEEP. The risk was again observed in recent studies from Belgium7 and England, although in the latter to a smaller degree than in previous studies.19 The study from Belgium consisted of a small study population (n=97); however, the study from England was large, with 4,776 deliveries after cervical treatment, although the methods of treatment included other treatment as well as LEEP. The new finding in our study was that the severity of CIN lesion did not correlate with the risk for preterm delivery. This is in accordance with a Danish register-based study.17 In one study the risk for preterm birth was increased among women with untreated CIN 3 lesions.10 Women who had poor compliance with treatment for CIN 3 may, in fact, have other risk factors for preterm delivery such as poor education, lower socioeconomic class, sexually transmitted diseases, or smoking. Reilly et al20 found that the risk for preterm birth was increased among colposcopy patients regardless of treatment. However, the reason for colposcopy referral or severity of lesions was not reported.
The time interval between LEEP procedure and delivery had no effect on the risk for preterm delivery. In one study, the short interval between the treatment and delivery increased the risk for preterm delivery.21 This study, however, did not consider several confounding factors making the results difficult to interpret. Our results indicate that women do not need to postpone pregnancy after LEEP.
According to our study, the overall risk for preterm delivery is elevated after LEEP. Thus, careful consideration is important when treating women of reproductive age for CIN. In particular, repeat LEEP should be avoided if possible.
1. 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 RID B-6887-2009. Lancet 2006;367:489–98.
2. Moscicki A, Schiffman M, Kjaer S, Villa LL. Updating the natural history of HPV and anogenital cancer. Vaccine 2006;24:42–51.
3. Wright TC Jr, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D, et al.. 2006 consensus guidelines for the management of women with cervical intraepithelial neoplasia or adenocarcinoma in situ. Obstet Gynecol 2007;197:340–5.
4. Arbyn M, Kyrgiou M, Simoens C, Raifu AO, Koliopoulos G, Martin-Hirsch P, et al.. Perinatal mortality and other severe adverse pregnancy outcomes associated with treatment of cervical intraepithelial neoplasia: meta-analysis RID B-6887–2009. BMJ 2008;337:a1284.
5. Jakobsson M, Gissler M, Paavonen J, Tapper A. Loop electrosurgical excision procedure and the risk for preterm birth. Obstet Gynecol 2009;114:504–10.
6. Bruinsma FJ, Quinn MA. The risk of preterm birth following treatment for precancerous changes in the cervix: a systematic review and meta-analysis. BJOG 2011;118:1031–41.
7. Simoens C, Goffin F, Simon P, Barlow P, Antoine J, Foidart J, et al.. Adverse obstetrical outcomes after treatment of precancerous cervical lesions: a Belgian multicentre study. BJOG 2012;119:1247–55.
8. Noehr B, Jensen A, Frederiksen K, Tabor A, Kjaer SK. Depth of cervical cone removed by loop electrosurgical excision procedure and subsequent risk of spontaneous preterm delivery. Obstet Gynecol 2009;114:1232–8.
9. Bruinsma F, Lumley J, Tan J, Quinn M. Precancerous changes in the cervix and risk of subsequent preterm birth. BJOG 2007;114:70–80.
10. Shanbhag S, Clark H, Timmaraju V, Bhattachaya S, Cruickshank M. Pregnancy outcome after treatment for cervical intraepithelial neoplasia. Obstet Gynecol 2009;114:727–35.
11. Gissler M, Shelley J. Quality of data on subsequent events in a routine medical birth register. Med Inform Internet Med 2002;27:33–8.
12. Pihkala J, Hakala T, Voutilainen P, Raivio K. Characteristic of recent fetal growth curves in Finland. Duodecim 1989;105:1540–6.
13. Goldenberg RL, Culhane JF, Iams JD, Romero R. Preterm birth 1-epidemiology and causes of preterm birth. Lancet 2008;371:75–84.
14. Jaakkola N, Jaakkola M, Gissler M, Jaakkola J. Smoking during pregnancy in Finland: determinants and trends, 1987-1997. Am J Public Health 2001;91:284–6.
15. Ang C, Mukhopadhyay A, Burnley C, Faulkner K, Cross PA, Martin-Hirsch P, 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;118:685–92.
16. Sadler L, Saftlas A, Wang W, Exeter M, Whittaker J, McCowan L. Treatment for cervical intraepithelial neoplasia and risk of preterm delivery RID C-2215-2009. JAMA 2004;291:2100–6.
17. Noehr B, Jensen A, Frederiksen K, Tabor A, Kjaer SK. Loop electrosurgical excision of the cervix and subsequent risk for spontaneous preterm delivery: a population-based study of singleton deliveries during a 9-year period. Obstet Gynecol 2009;201:33.e1.
18. Albrechtsen S, Rasmussen S, Thoresen S, Irgens LM, Iversen OE. Pregnancy outcome in women before and after cervical conisation: population based cohort study. BMJ 2008;337:a1343.
19. Castanon A, Brocklehurst P, Evans H, Peebles D, Singh N, Walker P, et al.. Risk of preterm birth after treatment for cervical intraepithelial neoplasia among women attending colposcopy in England: retrospective-prospective cohort study. BMJ 2012;345:e5174.
20. Reilly R, Paranjothy S, Beer H, Brooks CJ, Fielder HM, Lyons RA. Birth outcomes following treatment for precancerous changes to the cervix: a population-based record linkage study. BJOG 2012;119:236–44.
21. Himes KP, Simhan HN. Time from cervical conization to pregnancy and preterm birth. Obstet Gynecol 2007;109:314–9.