1. Obstetric outcome following cervical treatment for CIN By M Lokman, M DeLange

2. Aims and Objectives Aim:  To determine whether cervical conisation increases risk of preterm delivery and adverse obstetric outcome  To develop critical appraisal skills Objective:  To review current evidence in published studies, meta-analysis  To review RCOG advisory opinion  To critically appraise most current study  To discuss impact on clinical practice

3. The Clinical Question Does cervical conisation increase risk of preterm delivery and adverse obstetric outcomes? P(women of fertile age who have had cervical treatment) I (excisional cervical treatment) C (Cx conisation vs none) O (risk of preterm delivery and adverse obstetric outcome)

4. Literature search  Databases searched: RCOG, Cochrane, PubMed  Search terms: Cervical (MESH selecting subheadings treatment, surgery, complications) AND (obstetric morbidity OR perinatal mortality)  Results: 1 x RCOG advisory group opinion. 1 x cochrane protocol. 2 x current cohort studies. 2 x meta-analysis.

5. Guidelines (RCOG) Background – evidence show both ablative and excisional technique have equal efficacy and similar risk of invasive disease. 2 meta-analysis similar conclusion – excisional method increase risk of adverse pregnancy outcomes but not with laser ablation. biological mechanism – uncertain and confounding factors (age, smoking, socio-economic class) clinical practice: proportionally large excision/high grade lesion/multiple excision -> high risk pregnancy (serial TV scan/ffn). Intervention – cx cerclage, progesterone, steroids

6. Paper selected  Pregnancy outcome after cervical conisation: a retrospective cohort study in the Leuven University Hospital. Pregnancy outcome after cervical conisation: a retrospective cohort study in the Leuven University Hospital. van de Vijver A, Poppe W, Verguts J, Arbyn M. BJOG. 2010 Feb;117(3):268-73. Epub 2009 Nov 26. PMID: 19943824 [PubMed - indexed for MEDLINE] reason: the most relevant paper, up to date, good methodology.

7. Flow chart of the study 599 women had conisation (LLETZ, laser or cold knife) in 5 yr period (99-03) 17 miscarriages before 11/40 excluded 72 subsequent pregnancies identified (delivered before Jan 07) study group, n=55 in 43 women Note: 3 twin pregnancies in study gp and 1 twin pregnancy in the control gp Control group, 55 pregnancies in 54 women matched for age, parity and yr of delivery Had no intervention on cervix or CIN

8. Details of the study objective: verify strength of association between adverse obstetrical outcomes and prior excisional treatment for CIN study design: retrospective cohort study; setting university hosp population: 55 pregnancies in 34 women after conisation, 55 pregnancies in 54 women without history of conisation or CIN

9. Continued  Method: Study group - 55 pregnancies in 43 women with delivery after 22 weeks Control group - 55 pregnancies in 54 women with equal age, parity and year of delivery. (no intervention on cx or dx CIN) Data collection – patient files and questionnaire

10. Confounding factors - smoking, socio- economic status, education level, number of sexual partners Obstetric outcomes: duration of pregnancy, proportion of preterm deliveries (<37 weeks), proportion with PPROM. Use of induction or augmentation of labour, amniotic fluid, mode of delivery Neonatal outcomes: birthweight, length, hc, gender, apgar, pH, NICU

11. Data Analysis  43 women (study gp): 3 laser conisation (5 pregnancies), 40 with LLETZ (50 pregnancies). 2 of these had reconisation and delivered at term (4 pregnancies).

12. Table 1 Histological diagnosisNumber of patients (n=55) Chronic inflammation Squamous metaplasia CIN CIN 1 CIN 2 CIN 3 GIN GIN3 5 4 5 34 2

13. Table 2 : maternal characteristics VariableStudy group Mean SD Control group Mean SD P-value Maternal height (cm) Maternal weight at start (kg) Age at menarche (yr) Age at first sexual intercourse (yr) Number of sexual partners Ever smoked Smoked during pregnancy 166.1 6.2 63.9 12.2 12.9 1.5 17.7 1.9 4.6 3.4 Number % 26/52 50.0 12/51 23.5 167.0 5.6 67.5 14.8 13.2 1.5 18.6 2.6 2.5 Number % 11/54 20.4 5/54 9.3 0.44 0.28 0.41 0.12 0.01 0.002 0.057

14. Table 3: pregnancy outcome VariableStudy group Mean SD Control group Mean SD P-value Maternal characteristics Weight at end pregnancy(kg) Length of gestation(day) Neonatal characteristics Birthweight(g) Length(cm) HC (cm) pH UmA Apgar 1 min Apgar 5 min 78.6 11.8 266.0 21.2 3087.9 753.7 49.1 3.8 33.9 2.5 7.3 0.1 8.6 1.0 9.4 0.8 79.8 13.2 273.9 9.3 3380.5 430.0 50.2 2.0 34.6 1.2 7.3 0.1 8.6 1.1 9.5 0.8 0.62 0.01 0.07 0.04 0.82 0.98 0.56

15. Table 4: pregnancy outcome VariableStudy group Number % Control group Number % P- value Preterm delivery (<37wk) Severe preterm delivery(<34 wk) Complications in pregnancy PPROM Preterm contractions Oxytocin Prostaglandins Clear amniotic fl Primary C/S Secondary C/S Vacuum extraction Forceps NICU Sex of neonate Male Female 14/55 25.5 6/55 10.9 22/55 40 5/55 9.1 16/44 36.4 10/44 22.7 40/43 93.0 11/58 19.0 2/58 3.5 1/58 1.7 0/58 0 15/58 25.9 35/58 60.3 23/58 39.7 2/55 3.6 0/55 0 14/55 25.5 1/55 1.8 0/55 0 17/55 30.9 15/55 27.3 49/55 89.1 13/56 23.2 3/56 5.4 5/56 8.9 0/56 0 9/58 15.5 32/56 57.1 24/56 42.9 0.002 0.031 0.15 0.20 0.057 0.67 0.65 0.75 0.65 0.68 0.11 1 0.25 0.85

16. Discussion  Results largely confirm findings of meta-analysis  Relative risk 7.0, severe preterm significant (<34wks)  Limitations of retrospective cohort study. (confounding bias not always able to correct for, information bias, selection bias finding controls.)  Small number in study  Critical appraisal (see CASP ppt)

17. Summary and Conclusion  Current evidence – supports association between cervical excisional treatment and preterm delivery. However –confounding factors (technique, risk factors)  Women of fertile age with CIN – best balance between max treatment n minimal disturbance of anatomy. Need to reduce over-diagnosis n over-treatment  Inform patient of possible risk of excisional treatment

18.  Ideally: prospective RCT– 2 gps: ablative vs excisional n compared to untreated CIN.  More research area: dimension of cone, impact of CIN on pregnancy, perinatal mortality, pathophysiology  Preventative measures antenatally  Impact on current practice