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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 doi: (Published 28 July 2016) Cite this as: BMJ 2016;354:i3633
  1. Maria Kyrgiou, senior lecturer1 2,
  2. Antonios Athanasiou, medical student3,
  3. Maria Paraskevaidi, research fellow1,
  4. Anita Mitra, clinical research fellow1 2,
  5. Ilkka Kalliala, clinical postdoctoral fellow1,
  6. Pierre Martin-Hirsch, professor45,
  7. Marc Arbyn, coordinator of unit6,
  8. Phillip Bennett, professor1 2,
  9. Evangelos Paraskevaidis, professor3
  1. 1Institute of Reproductive and Developmental Biology, Department of Surgery and Cancer, Faculty of Medicine, Imperial College, London, UK
  2. 2Queen Charlotte’s and Chelsea-Hammersmith Hospital, Imperial Healthcare NHS Trust, London, UK
  3. 3University Hospital of Ioannina, Ioannina, Greece
  4. 4Department of Gynaecological Oncology, Lancashire Teaching Hospitals, Preston, UK
  5. 5Department of Biophotonics, Lancaster University, Lancaster, UK
  6. 6Unit of Cancer Epidemiology, Scientific Institute of Public Health, Brussels, Belgium
  1. Correspondence to: M Kyrgiou m.kyrgiou{at}
  • Accepted 26 June 2016


Objective To assess the effect of treatment for cervical intraepithelial neoplasia (CIN) on obstetric outcomes and to correlate this with cone depth and comparison group used.

Design Systematic review and meta-analysis.

Data sources CENTRAL, Medline, Embase from 1948 to April 2016 were searched for studies assessing obstetric outcomes in women with or without previous local cervical treatment.

Data extraction and synthesis Independent reviewers extracted the data and performed quality assessment using the Newcastle-Ottawa criteria. Studies were classified according to method and obstetric endpoint. Pooled risk ratios were calculated with a random effect model and inverse variance. Heterogeneity between studies was assessed with I2 statistics.

Main outcome measures Obstetric outcomes comprised preterm birth (including spontaneous and threatened), premature rupture of the membranes, chorioamnionitis, mode of delivery, length of labour, induction of delivery, oxytocin use, haemorrhage, analgesia, cervical cerclage, and cervical stenosis. Neonatal outcomes comprised low birth weight, admission to neonatal intensive care, stillbirth, APGAR scores, and perinatal mortality.

Results 71 studies were included (6 338 982 participants: 65 082 treated/6 292 563 untreated). Treatment significantly increased the risk of overall (<37 weeks; 10.7% v 5.4%; relative risk 1.78, 95% confidence interval 1.60 to 1.98), severe (<32-34 weeks; 3.5% v 1.4%; 2.40, 1.92 to 2.99), and extreme (<28-30 weeks; 1.0% v 0.3%; 2.54, 1.77 to 3.63) preterm birth. Techniques removing or ablating more tissue were associated with worse outcomes. Relative risks for delivery at <37 weeks were 2.70 (2.14 to 3.40) for cold knife conisation, 2.11 (1.26 to 3.54) for laser conisation, 2.02 (1.60 to 2.55) for excision not otherwise specified, 1.56 (1.36 to 1.79) for large loop excision of the transformation zone, and 1.46 (1.27 to 1.66) for ablation not otherwise specified. Compared with no treatment, the risk of preterm birth was higher in women who had undergone more than one treatment (13.2% v 4.1%; 3.78, 2.65 to 5.39) and with increasing cone depth (≤10-12 mm; 7.1% v 3.4%; 1.54, 1.09 to 2.18; ≥10-12 mm: 9.8% v 3.4%, 1.93, 1.62 to 2.31; ≥15-17 mm: 10.1% v 3.4%; 2.77, 1.95 to 3.93; ≥20 mm: 10.2% v 3.4%; 4.91, 2.06 to 11.68). The choice of comparison group affected the magnitude of effect. This was higher for external comparators, followed by internal comparators, and ultimately women with disease who did not undergo treatment. In women with untreated CIN and in pregnancies before treatment, the risk of preterm birth was higher than the risk in the general population (5.9% v 5.6%; 1.24, 1.14 to 1.35). Spontaneous preterm birth, premature rupture of the membranes, chorioamnionitis, low birth weight, admission to neonatal intensive care, and perinatal mortality were also significantly increased after treatment.

Conclusions Women with CIN have a higher baseline risk for prematurity. Excisional and ablative treatment further increases that risk. The frequency and severity of adverse sequelae increases with increasing cone depth and is higher for excision than for ablation.


  • Contributors: The study was conceived and designed by MK, MA, PB, and EP. MK, AA, and MP acquired the data, which were collated and analysed by MK, AA, IK, and MA. All authors drafted and critically revised the manuscript for important intellectual content. MA, PB, and EP are joint senior authors. All authors gave final approval of the version to be published and have contributed to the manuscript. MK is guarantor.

  • Funding: This work was supported by the British Society of Colposcopy Cervical Pathology Jordan/Singer Award (P47773) (MK); the Imperial College Healthcare Charity (P47907) (AM and MK); Genesis Research Trust (P55549) (MK); Sigrid Jusélius Fellowship (P52483 to IK and MK), and the Imperial Healthcare NHS Trust NIHR Biomedical Research Centre (P45272) (MK, PRB). MA received support from the COHEAHR Network (grant No 603019), funded by Seventh Framework Programme of DG Research of the European Commission (Brussels); Institut National du Cancer (Paris) through the COSPCC study (Conséquences obstétricales du (sur)traitement des précurseurs du cancer du col); the European Federation of Colposcopy (Birmingham); and the Joint Action CANCON. None of the funders has any influence on the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: Not required.

  • Data sharing: No additional data available.

  • Transparency: The lead author affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.

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