The Impact of Conservative Treatment for Cervical Intraepithelial Neoplasia and Early Cervical Cancer on Fertility and Early Pregnancy Outcomes
Maria Kyrgiou PhD1,2, Anita Mitra MBChB1,2, Evangelos Paraskevaidis PhD3
1Department of Surgery & Cancer, Faculty of Medicine, Imperial College, London, UK
2Queen Charlotte’s & Chelsea – Hammersmith Hospital, Imperial Healthcare NHS Trust, London, UK
3University Hospital of Ioannina, Greece
Corresponding author:
Maria Kyrgiou, MSc, PhD, MRCOG
3rd floor, Institute of Reproductive and Developmental Biology, Surgery and Cancer
Imperial College, Hammersmith Campus, Du Cane Road, W12 0NN, London
Email:
Tel: +44 2083833274
Word count: 808
Clinical Question: Does local conservative treatment for cervical intraepithelial neoplasia and early invasive cervical cancer adversely affect successful conception and early pregnancy outcomes in the first and second trimester (less than 24 weeks of gestation)?
Clinical Application: Local cervical treatment does not adversely affect fertility or first trimester miscarriage, although it is associated with a significant increase in the risk of second trimester miscarriages.
Introduction:
The mean age of women undergoing treatment for preinvasive cervical disease is similar to the age of women having their first child. Local conservative treatment for cervical intraepithelial neoplasia (CIN) and early invasive cervical cancer has been associated with increased risk of preterm birth, neonatal morbidiy and mortality [1, 2]. Although the impact of treatment on obstetric outcomes has been extensively assessed, there are relatively few studies exploring the impact of treatment on the ability to conceive and the early pregnancy outcomes. This JAMA Clinical Evidence Synopsis summarizes a Cochrane Systematic Review [3, 4] comparing the fertility and early pregnancy outcomes up to 24 weeks of gestation in women with a history of treatment versus those that have not received treatment.
Evidence Profile:
• No. of studies overall – 15
• No. of randomized controlled trials – 0
• Study years – 1948 to 2015 (Last search date: January 17th 2015)
• No. of patients – 2,223,440 women (25,008 treated - 2,198,432 untreated)
• Men - 0% Women - 100%
• Age – women of reproductive age
• Settings – colposcopy and general gynaecology clinics, national registries
• Countries – Denmark, England, Finland, France, Italy, Norway, Scotland, Sweden & United States
• Comparison – history of treatment (excisional or ablative) versus no previous treatment
• Primary outcomes – total pregnancy rate
• Secondary outcomes –
Fertility outcomes: pregnancy rates in women with an intention to conceive; conception rates within a given period: 0-3 months (m), 0-6m, 0-9m, 0-12m, 0-24m, >12m, >36m
Early pregnancy outcomes (less than 24 weeks of gestation): miscarriage (total, 1st trimester, 2nd trimester); ectopic pregnancy; molar pregnancy; termination of pregnancy rates
This manuscript summarizes an original Cochrane Collaboration review [3].
Summary of Findings:
Treated women have a higher rate of pregnancy compared to untreated controls (2946/6895 vs. 11906/31155 women; 43% vs. 38%; Relative risk (RR) 1.29, 95% confidence interval (CI) 1.02-1.64). There was no difference in the pregnancy rates in women with an intention to conceive (29/33 vs. 35/37 women; 88% vs. 95%; RR 0.93, 95%CI 0.8-1.08) or the number of women that took longer than 12 months to conceive (36/245 vs. 102/1103 women; 14% vs. 9%; RR 1.45, 95% CI 0.89-2.37).
Total miscarriage rates (350/7660 vs. 886/31844 women; 4.6% vs 2.8%; RR 1.04, 95%CI 0.9-1.21) and first trimester miscarriage (51/519 vs. 49/584 women; 9.8% vs 8.4%; RR 1.16, 95% CI 0.8-1.69) were not increased after treatment. The rate of second trimester miscarriages however was significant increased in the treated compared to untreated women (258/16558 vs. 8520/2165710; 1.6% vs. 0.4%; RR 2.6, 95%CI 1.45-4.67). There was a higher rate of ectopic pregnancies (114/6985 vs.239/31208; 1.6% vs. 0.8%; RR 1.89, 95%CI 1.5-2.39) and terminations (852/6990 vs. 2320/31218; 12.2% vs. 7.4%; RR 1.71, 95%CI 1.31-2.22) amongst treated women (Table).
Discussion:
Evidence from a meta-analysis of retrospective studies suggests that fertility is not affected by conservative treatment for CIN. There does appear to be an increased rate of mid-trimester loss and this may be a continuum of the effect seen relating to increased risk of preterm birth.
Limitations
The results should be interpreted with caution as the analysis included only a small number of retrospective studies that are prone to bias and therefore of low quality. Randomized controlled trials cannot be conducted in this setting. The number of participants was frequently low and the sources used for data extraction may have led to misclassification and recall bias. There was heterogeneity in the comparison groups used by studies, however it has not been possible to perform subgroup analyses for different comparison groups and individual treatment techniques due to the small number of studies. Stratification of the risk of mid trimester loss according to the depth of the excisional technique was also not feasible.
Comparison on Findings With Current Practice Guidelines
There are currently no clinical guidelines regarding this topic. Caution should prevail when clinicians consider treatment for women of childbearing age. Treatment should aim to ensure clear resection margins, while minimizing the removal of healthy cervical tissue. Women with infertility should be informed that it is unlikely that this relates to their cervical treatment and women undergoing treatment should be reassured about the impact of this in the ability to conceive.
Areas in Need of Future Study
Further studies should aim to correlate these effects with the cone depth and proportion of excision, the treatment technique and compare outcomes to those of women with CIN but no treatment [5-7]. Looking beyond the structural mechanisms, research should also be conducted into the immune, biochemical and microbiological changes in the cervix with CIN and following treatment [8].
Acknowledgements
Author Affiliations: Department of Surgery & Cancer, Faculty of Medicine, Imperial College, London, UK (Kyrgiou, Mitra); Queen Charlotte’s & Chelsea – Hammersmith Hospital, Imperial Healthcare NHS Trust, London, UK (Kyrgiou, Mitra); University Hospital of Ioannina, Greece (Paraskevaidis)
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Additional contributions: We acknowledge Marc Arbyn MD (Scientific Institute for Public Health, Brussels), Maria Paraskeviaidi BSc (Imperial College London, UK), Antonis Athanasiou (University Hospital of Ioannina, Greece), Pierre Martin-Hirsch MBChB, MRCOG, MD (Lancaster University, UK) and Philip Bennett BSc, MBBS, MD, PhD, FRCOG (Imperial College London, UK) for their work on the original Cochrane review, and Clare Jess (Cochrane Collaboration) for her editorial support.
Funding: BSCCP Jordan/Singer Award (P47773); Imperial College Healthcare Charity (P47907); Imperial Healthcare NHS Trust NIHR BRC (P45272); Genesis Research Trust (P55549).
References:
1. Kyrgiou M, Koliopoulos G, Martin-Hirsch P, et al. Obstetric outcomes after conservative treatment for intraepithelial or early invasive cervical lesions: systematic review and meta-analysis. Lancet 2006;367(9509):489-98.
2. 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.
3. Kyrgiou M, Mitra A, Arbyn M, et al. Fertility and early pregnancy outcomes after conservative treatment for cervical intraepithelial neoplasia. Cochrane Database Syst Rev 2015;9:CD008478.
4. Kyrgiou M, Mitra A, Arbyn M, et al. Fertility and early pregnancy outcomes after treatment for cervical intraepithelial neoplasia: systematic review and meta-analysis. BMJ 2014;349:g6192.
5. Castanon A, Landy R, Brocklehurst P, et al. Risk of preterm delivery with increasing depth of excision for cervical intraepithelial neoplasia in England: nested case-control study. BMJ 2014;349:g6223.
6. Kyrgiou M, Valasoulis G, Stasinou SM, et al. Proportion of cervical excision for cervical intraepithelial neoplasia as a predictor of pregnancy outcomes. International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics 2015;128(2):141-7.
7. Kyrgiou M, Arbyn M, Martin-Hirsch P, et al. Increased risk of preterm birth after treatment for CIN. BMJ 2012;345:e5847.
8. Mitra A, MacIntyre DA, Lee YS, et al. Cervical intraepithelial neoplasia disease progression is associated with increased vaginal microbiome diversity. Sci Rep 2015;5:16865.
Table. Fertility and early pregnancy outcomes (<24 weeks of gestation) in women treated for CIN compared to untreated controls.
Outcomes / Studies / Total, N / Treated, n/N (%) / Untreated, n/N (%) / RR (95% CI)Fertility Outcomes
Total pregnancy rate / 4 / 38050 / 2946/6895 (42.7) / 11906/31155 (38.2) / 1.29 [1.02, 1.64]
Pregnancy rate in women with intention to conceive / 2 / 70 / 29/33 (87.9) / 35/37 (94.6) / 0.93 [0.80, 1.08]
Conception rates within given period
Conception within 0-3 m / 2 / 175 / 46/93 (49.5) / 45/82 (54.9) / 0.89 [0.67, 1.19]
Conception within 0-6 m / 2 / 175 / 73/93(78.5) / 62/82 (75.6) / 1.03 [0.89, 1.19]
Conception within 0-9 m / 1 / 41 / 14/21 (66.7) / 13/20 (65.0) / 1.03 [0.66, 1.59]
Conception within 0-12 m / 2 / 175 / 81/93 (87.1) / 69/82 (84.1) / 1.04 [0.94, 1.16]
Conception within 0-24 m / 1 / 41 / 18/21 (85.7) / 18/20 (90.0) / 0.95 [0.76, 1.20]
Conception >12 m / 3 / 1348 / 36/245 (14.7) / 102/1103 (9.2) / 1.45 [0.89, 2.37]
Conception >36 m / 1 / 134 / 4/72 (5.5) / 5/62 (8.0) / 0.69 [0.19, 2.45]
Early pregnancy outcomes
Miscarriage rates (total) / 10 / 39504 / 350/7660 (4.6) / 886/31844 (2.8) / 1.04 [0.90, 1.21]
Miscarriage (1st trimester) / 4 / 1103 / 51/519 (9.8) / 49/584 (8.4) / 1.16 [0.80, 1.69]
Miscarriage (2nd trimester) / 8 / 2182268 / 258/16558 (1.6) / 8520/2165710 (0.4) / 2.60 [1.45, 4.67]
Ectopic pregnancy / 6 / 38193 / 114/6985 (1.6) / 239/31208 (0.8) / 1.89 [1.50, 2.39]
Termination of pregnancy / 7 / 38208 / 852/6990 (12.2) / 2320/31218 (7.4) / 1.71 [1.31, 2.22]
NB. Analyses compare treated women (all types of treatment) versus untreated women or women that had colposcopy but no treatment