Risk Factors of Preterm Birth in Women After Local Treatment of Cervical Intraepithelial Neoplasia – a Retrospective Cohort Study

Abstract

Purpose A previous cervical intraepithelial neoplasia is associated with an increased obstetrical risk. It was the aim of the study to identify risk factors of preterm birth in patients with cervical intraepithelial neoplasia in dependence of the treatment modality (excisional vs. ablative).

Methods Women with treated cervical intraepithelial neoplasia and subsequent pregnancy (n = 155) were included in this retrospective study. Methods of treatment were either conization by large loop excision of the transformation zone (LLETZ) or ablative laser vaporization.

Results Of the total population 60.6% (n = 94) had a conization and 39.4% (n = 61) a laser vaporization alone. The frequency of preterm birth < 37 weeks was 9.7% (n = 15) without differences between conization and laser (11.7 vs. 6.7%, p = 0.407) with an odds ratio (OR) of 1.9 (95% confidence interval [CI] 0.6–6.2). Preterm birth < 34 weeks was found in 2.6% (n = 4), of which all had a conization (4.3 vs. 0%, p = 0.157). Risk factors for preterm birth were repeated cervical intervention (OR 4.7 [95% CI 1.5–14.3]), especially a combination of conization and laser ablation (OR 14.9 [95% CI 4.0–55.6]), age at intervention < 30 years (OR 6.0 [95% CI 1.3–27.4]), a history of preterm birth (OR 4.7 [95% CI 1.3–17.6]) and age at delivery < 28 years (OR 4.7 [95% CI 1.5–14.3]).

Conclusion The large loop excision of the transformation zone as a modern, less invasive ablative treatment did not obviously increase the risk of preterm birth compared to laser vaporization. The most important risk factor for preterm delivery was the need of a repeated intervention, especially at younger age. We assume that the persistence or recurrence of the cervical intraepithelial neoplasia following a high-risk human papillomavirus infection is mainly responsible for the observed effect.

Zusammenfassung

Zielsetzung Eine frühere intraepitheliale Neoplasie der Zervix wird mit einem höheren geburtshilflichen Risiko assoziiert. Ziel dieser Studie war es, die Risikofaktoren für eine Frühgeburt bei Patientinnen mit einer zervikalen intraepithelialen Neoplasie in der Anamnese zu identifizieren in Abhängigkeit von der Behandlungsmodalität (Exzision vs. ablative Behandlung).

Methoden In dieser retrospektiven Studie wurden Frauen aufgenommen, die zuvor wegen einer zervikalen intraepithelialen Neoplasie behandelt worden waren und danach schwanger wurden (n = 155). Die Behandlungsmethode bestand entweder aus Konisation mittels Schlingenexzision der Transformationszone (LLETZ) oder ablativer Laservaporisation.

Ergebnisse Von der Gesamtkohorte erhielten 60,6% (n = 94) eine Konisation und 39,4% (n = 61) eine Laservaporisation. Die Frequenz der Frühgeburten vor der 37. Schwangerschaftswoche betrug 9,7% (n = 15). Es gab keinen Unterschied zwischen Konisation und Laserbehandlung (11,7 vs. 6,7%, p = 0,407) mit einer Odds Ratio (OR) von 1,9 (95%-Konfidenzintervall [KI] 0,6–6,2). Eine Frühgeburt vor der 34. Schwangerschaftswoche trat bei 2,6% (n = 4) auf, und alle Betroffenen hatten zuvor eine Konisation erhalten (4,3 vs. 0%, p = 0,157). Risikofaktoren für eine Frühgeburt waren wiederholte zervikale Prozeduren (OR 4,7 [95%-KI 1,5–14,3]), vor allem eine Kombination aus Konisation und Laserablation (OR 14,9 [95%-KI 4,0–55,6]), Alter beim Eingriff < 30 Jahre (OR 6,0 [95%-KI 1,3–27,4]), Frühgeburt in der Anamnese (OR 4,7 [95%-KI 1,3–17,6]) sowie Alter bei der Entbindung < 28 Jahre (OR 4,7 [95%-KI 1,5–14,3]).

Schlussfolgerung Die Schlingenexzision der Transformationszone stellt eine moderne, weniger invasive ablative Behandlung dar, die offenkundig nicht das Risiko einer Frühgeburt erhöht verglichen mit der Laservaporisation. Der wichtigste Risikofaktor für eine frühgeburtliche Entbindung waren wiederholte Prozeduren zur Behandlung von Neoplasien, vor allem in jüngeren Jahren. Wir nehmen an, dass die Persistenz bzw. das Wiederauftreten einer zervikalen intraepithelialen Neoplasie nach einer Infektion mit einem Hochrisikoform des humanen Papillomavirus maßgeblich verantwortlich für die beobachtete Wirkung ist.

Schlüsselwörter

zervikale Dysplasie - LLETZ - Laservaporisation - Konisation - Frühgeburt - Risikoabwägung

Keywords

cervical dysplasia - LLETZ - laser vaporization - conization - preterm birth - risk assessment

• References

• 1 Albrechtsen S, Rasmussen S, Thoresen S. et al. Pregnancy outcome in women before and after cervical conisation: population based cohort study. BMJ 2008; 337: a1343
• 2 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: 1031-1041
• 3 Kyrgiou M, Athanasiou A, Kalliala IEJ. et al. Obstetric outcomes after conservative treatment for cervical intraepithelial lesions and early invasive disease. Cochrane Database Syst Rev 2017; (11) CD012847
• 4 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
• 5 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
• 6 Weinmann S, Naleway A, Swamy G. et al. Pregnancy Outcomes after Treatment for Cervical Cancer Precursor Lesions: An Observational Study. PLoS One 2017; 12: e0165276
• 7 Bruinsma F, Lumley J, Tan J. et al. Precancerous changes in the cervix and risk of subsequent preterm birth. BJOG 2007; 114: 70-80
• 8 Simoens C, Goffin F, Simon P. et al. Adverse obstetrical outcomes after treatment of precancerous cervical lesions: a Belgian multicentre study. BJOG 2012; 119: 1247-1255
• 9 Jar-Allah T, Karrberg C, Wiik J. et al. Abnormal cervical cytology is associated with preterm delivery: A population based study. Acta Obstet Gynecol Scand 2019; 98: 777-786
• 10 Castle PE, Giuliano AR. Chapter 4: Genital tract infections, cervical inflammation, and antioxidant nutrients--assessing their roles as human papillomavirus cofactors. J Natl Cancer Inst Monogr 2003; (31) 29-34
• 11 Khalid S, Dimitriou E, Conroy R. et al. The thickness and volume of LLETZ specimens can predict the relative risk of pregnancy-related morbidity. BJOG 2012; 119: 685-691
• 12 Voigt M, Rochow N, Hesse V. et al. Short communication about percentile values of body measures of newborn babies. Z Geburtshilfe Neonatol 2010; 214: 24-29
• 13 R Core Team. R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2020 Accessed May 14, 2022 at: http://www.R-project.org/
• 14 RStudio Team. RStudio: Integrated Development for R. Boston, MA: RStudio, Inc.; 2019 Accessed May 14, 2022 at: http://www.rstudio.com/
• 15 Heinonen A, Gissler M, Paavonen J. et al. Risk of preterm birth in women with cervical intraepithelial neoplasia grade one: a population-based cohort study. Acta Obstet Gynecol Scand 2018; 97: 135-141
• 16 Ortoft G, Henriksen T, Hansen E. et al. After conisation of the cervix, the perinatal mortality as a result of preterm delivery increases in subsequent pregnancy. BJOG 2010; 117: 258-267
• 17 Shanbhag S, Clark H, Timmaraju V. et al. Pregnancy outcome after treatment for cervical intraepithelial neoplasia. Obstet Gynecol 2009; 114: 727-735
• 18 El-Bastawissi AY, Becker TM, Daling JR. Effect of cervical carcinoma in situ and its management on pregnancy outcome. Obstet Gynecol 1999; 93: 207-212
• 19 Niyibizi J, Mayrand MH, Audibert F. et al. Association Between Human Papillomavirus Infection Among Pregnant Women and Preterm Birth. JAMA Netw Open 2021; 4: e2125308
• 20 Lasche M, Urban H, Gallwas J. et al. HPV and Other Microbiota; Who’s Good and Who’s Bad: Effects of the Microbial Environment on the Development of Cervical Cancer–A Non-Systematic Review. Cells 2021; 10: 714
• 21 Kumari S, Bhor VM. Association of cervicovaginal dysbiosis mediated HPV infection with cervical intraepithelial neoplasia. Microb Pathog 2021; 152: 104780
• 22 Plisko O, Zodzika J, Jermakova I. et al. Aerobic Vaginitis–Underestimated Risk Factor for Cervical Intraepithelial Neoplasia. Diagnostics (Basel) 2021; 11: 97
• 23 Usyk M, Zolnik CP, Castle PE. et al. Cervicovaginal microbiome and natural history of HPV in a longitudinal study. PLoS Pathog 2020; 16: e1008376
• 24 Wang H, Ma Y, Li R. et al. Associations of Cervicovaginal Lactobacilli With High-Risk Human Papillomavirus Infection, Cervical Intraepithelial Neoplasia, and Cancer: A Systematic Review and Meta-Analysis. J Infect Dis 2019; 220: 1243-1254
• 25 Donders GG, Van Calsteren K, Bellen G. et al. Predictive value for preterm birth of abnormal vaginal flora, bacterial vaginosis and aerobic vaginitis during the first trimester of pregnancy. BJOG 2009; 116: 1315-1324
• 26 Goldenberg RL, Culhane JF, Iams JD. et al. Epidemiology and causes of preterm birth. Lancet 2008; 371: 75-84
• 27 Hillemanns P, Friese K, Dannecker C. et al. Prevention of Cervical Cancer: Guideline of the DGGG and the DKG (S3 Level, AWMF Register Number 015/027OL, December 2017) – Part 1 with Introduction, Screening and the Pathology of Cervical Dysplasia. Geburtshilfe Frauenheilkd 2019; 79: 148-159