Adverse Reproductive Outcomes After CIN Treatment. Similar results from other publications

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1 Adverse Reproductive Outcomes After CIN Treatment Similar results from other publications Maria Kyrgiou Senior Lecturer Consultant Gynaecologic Oncology Queen Charlotte s & Chelsea Hammersmith Hospital Imperial Healthcare NHS Trust Imperial College

2 Reproductive morbidity after CIN treatment

3 Cold Knife Conization Laser Ablation Laser Conization LLETZ Meta-analysis 1 Kyrgiou, Koliopoulos, Martin-Hirsch, Arbyn, Prendiville, Paraskevaidis Lancet 2006 Meta-analysis 2 Arbyn, Kyrgiou, Simoens, Raifu, Koliopoulos, Martin-Hirsch, Prendiville,Paraskevaidis BMJ Meta-analysis 3 Bruinsma, Quinn BJOG 2011 Meta-analysis 4 & 5 Conner et al. Jin et al. Obs Gyn 2014 Arch Obs Gyn

4 Well let s see their conclusions Kyrgiou Lancet 2006 Excisional treatment increases the risk of PTB Arbyn BMJ 2008 Excision increases the risk of severe adverse outcomes but NOT LLETZ Bruinsma BJOG 2011 Excisional treatment increases the risk of PTB but the risk is smaller Conner Obstet Gynecol 2014 LLETZ does not increase the risk of PTB as compared to CIN only Jin Arch Gynecol Obstet 2014 LLETZ increases the risk of PTB and SEVERE adverse outcomes

5 Are you confused?...

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7 2008 Excised Cx Volume: PD (<37/40) Severe PD (<32/40) Extreme PD (<28/40) PM CKC LC > LLETZ > LA - - x x x x x x x

8 2011

9 2014

10 c c 2014

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12 Majority of literature vs Recent Opposing data (58+ Studies) (5 Studies) Preterm delivery at <37 W (Excisional vs no Treatment) Study ID CKC Jones, 1979 Buller, 1982 Larsson, 1982 Ludviksson, 1982 Kristensen, 1985 Kuoppala, 1986 Lund, 1986 Lund, 1986 Kasum, 1991 Kristensen, 1993 Crane, 2006 Klaritsch, 2006 Bruinsma, 2007 Jakobsson, 2007 Ortoft, 2010 Subtotal (I-squared = 34.6%, p = 0.092). LC Hagen, 1993 Sagot, 1995 Spitzer, 1995 Bekassy, 1996 Raio, 1997 Andersen, 1999 Sadler, 2004 Subtotal (I-squared = 63.7%, p = 0.011). LLETZ Blomfield, 1993 Haffenden, 1993 Braet, 1994 Cruickshank, 1995 Paraskevaidis, 2002 Sadler, 2004 Tan, 2004 Acharya, 2005 Samson, 2005 Crane, 2006 Bruinsma, 2007 Jakobsson, 2007 Noerh, 2009 Ortoft, 2010 Werner, 2010 Subtotal (I-squared = 65.7%, p = 0.000). Excision (NOS) El-Bastawissi, 1999 Jakobsson, 2007 Sjoborg, 2007 Albrechtsen, 2008 Shanbhag, 2009 Van de Vijver, 2010 Jakobsson, 2007 Subtotal (I-squared = 92.0%, p = 0.000). Overall (I-squared = 83.1%, p = 0.000) NOTE: Weights are from random effects analysis RR (95% CI) 3.43 (1.66, 7.06) 12/ (0.13, 2.84) 2/ (1.92, 5.93) 33/ (1.01, 12.05) 11/ (0.82, 2.84) 9/ (0.46, 34.78) 4/ (2.24, 3.69) 87/ (2.33, 4.95) 87/ (0.64, 4.33) 10/ (2.40, 5.60) 19/ (1.82, ) 4/ (2.22, 5.16) 17/ (0.89, 2.72) 11/ (0.93, 3.50) 8/ (1.26, 5.13) 7/ (2.22, 3.28) 321/ (2.71, 13.26) 1.56 (0.53, 4.62) 0.44 (0.07, 2.84) 1.00 (0.55, 1.81) 2.00 (0.52, 7.65) 2.80 (1.31, 6.00) 1.56 (0.98, 2.50) 1.86 (1.10, 3.14) 1.43 (0.48, 4.22) 1.07 (0.54, 2.14) 2.50 (0.82, 7.63) 1.87 (0.93, 3.76) 3.67 (1.14, 11.75) 1.30 (0.89, 1.88) 1.18 (0.55, 2.53) 1.06 (0.49, 2.27) 3.14 (1.74, 5.67) (1.42, 82.35) 1.60 (0.92, 2.79) 1.61 (1.42, 1.84) 1.91 (1.75, 2.07) 2.34 (1.82, 3.02) 0.94 (0.69, 1.30) 1.66 (1.40, 1.97) 1.66 (1.39, 1.98) 2.10 (1.92, 2.30) 3.41 (2.36, 4.93) 2.66 (2.56, 2.76) 1.66 (1.41, 1.96) 7.00 (1.67, 29.36) 2.54 (2.24, 2.87) 2.25 (1.89, 2.68) 2.09 (1.87, 2.34) Events, Treated 21/56 7/53 2/34 20/250 6/64 14/75 20/105 90/637 5/40 15/152 10/78 14/149 11/28 44/278 13/119 9/79 44/558 10/75 11/69 209/ / /572 35/ / / / / / / /55 223/ / /39187 Events, Not treated 14/264 6/79 16/268 3/79 888/ /62 96/739 30/273 6/68 560/ / / / / / / /112 5/59 2/15 20/250 3/64 10/150 52/426 99/1076 7/80 14/152 4/78 15/298 3/28 52/426 11/119 17/158 14/558 1/81 217/ / / / / / / / / / / / / / / Shanbhag M Obstet Gynecol 2009 Werner C Obstet Gynecol 2009 Andia D Int J Gynaecol Obstet Reilly BJOG, 2012 Castanon BMJ Treatment increases the risk of PTB It is not the Treatment, it is the CIN

13 What makes those results so different? Well two (or perhaps three) things a. the comparison group b. the treatment methods analysed which really reflects the depth of excision c. THE QUALITY of the meta-analysis Kyrgiou et al. Editorial BMJ 2012

14 The Role of the Comparison Group... Sept 2012 EDITORIALS External Comparison Treated Women VS no CIN - no Tx controls ideally matched for known risk factors Internal Comparison Women who gave birth before VS after Tx Treated / Untreated Comparison Treated Women VS women in colposcopy/with CIN but no Tx Kyrgiou Editorial BMJ 2012

15 Depth of Excision < 10 mm > 10 mm Depth: > 10 mm < 10 mm RR: 2 6, 95% CI: RR: 1 5, 95% CI: Kyrgiou Lancet 2006

16 2008 Excised Cx Volume: PD (<37/40) Severe PD (<32/40) Extreme PD (<28/40) PM CKC LC > LLETZ > LA - - x x x x x x x

17 Series of publications Noehr et al. Obstet Gynecol 2009a Obstet Gynecol 2009b Am J Obstet Gynaecol 2009 Cone Volume Khalid BJOG fold increase in PTL risk if - Volume > 6cm 3 - Thickness > 12mm Repeat conisation Noehr AJOG 2009: x 4 PTB Ortoft BJOG 2010: eptb x5 PM x3

18 3 Proportion Relative risk (95% CI) 0.00 Punch before birth Small (<10mm) Medium (10-14mm) Large (15+mm) Multiple LLETZ 0 Case Control CASTANON et al. BSCCP GLASGOW 2013

19 Our Imperial - Hammersmith data The dose-effect relation 1440 women Treatment vs PB only

20 Why are the results different? Results depend on studies you analyse Retrospective: often no report on depth Tx Method analysed important CKC universally large cones LLETZ variety (small to large) Analysis that merges may mask the true effect Kyrgiou Editorial BMJ 2012

21 Are you confused?...

22 Fertility & Pregnancy outcomes after CIN treatment Kyrgiou M, Mitra A, Arbyn A, Stasinou M, Martin-Hirsch P, Bennett P, Paraskevaidis E Fertility outcomes: - no adverse effect - PR: treated (43%) > untreated (38%) Early pregnancy outcomes: - 2 nd trimester miscarriage: RR: 2.6 ( ) Treated 1.6% vs Untreated 0.4% Pregnancy outcomes: Ongoing BMJ 2014

23 women Loop depth </=35 yrs > 35 yrs </= 5 mm 75 (6.6%) 25 (6.1%) 6-8 mm 139 (12.1%) 46 (11.1%) 9-10 mm 356 (31.1%) 122 (29.5%) mm 419 (36.6%) 166 (40.2%) > 15 mm 156 (13.6%) 54 (13.1%)

24 What causes preterm birth after CIN treatment? Treatment CIN Intrinsic abnormality Mechanical integrity Founta BJOG 2010 Khalid BJOG 2011 Structure of cervix Phadnis BJOG 2011 HPV infection/cin: Immunological function Microbiome/metabonome Women HPV/CIN PTB: Impaired immunity (AMPs, leucocytes ) Woodham PLoS One 2012 Immunological function Paraskevaidis BJOG 2007 Vag microbiome/metabonome Castanon BMJ 2012 Kyrgiou BMJ 2012 (Editorial) Lee PLoS One 2013 Arbyn BMJ 2012 (Editorial) Microbiome/metabonome Lee PLoS One 2013

25 "which came first, the chicken or the egg?" To ancient philosophers, the question about the first chicken or egg also evoked the questions of how life and the universe in general began. Impaired. immunity, microbiome,. antimicrobial peptides, leucocytes

26 February 2014 Ghaem-Maghami S et al. Lancet Oncology 2007 Risk of recurrence ~ margins 18% vs 3% Increase in the risk of post-tx cervical cancer Optimal balance between risk of cancer & obstetric safety Arbyn, Kyrgiou, Gondry, Petry, Paraskevaidis BMJ Editorial 2014

27 The truth is somewhere in between Does Women Treatment with CIN increase higher PTB baseline risk & risk if yes when?? HPV affects microenvironment? Intrinsic abnormality Does CIN & other factors increase PTB risk? Treatment increases risk: large % excisions Experience is important How Balance does with less oncologic aggressive outcomes treatment affect the oncological outcomes? Epidemiological data to the laboratory Cause-directed treatments

28 Thank you