Adverse obstetrical outcomes after local treatment for cervical pre-invasive and early invasive disease according to the cone depth: a systematic review and meta-analysis

Abstract

Objective: To assess the effect of treatment for CIN on obstetric outcomes and to correlate this to the cone depth and comparison group used. Methods Design: Systematic review and meta-analysis Data Sources: CENTRAL, MEDLINE, EMBASE from 1948 to April 2016. Eligibility Criteria: Studies assessing obstetric outcomes in women with or without a previous local cervical treatment. Data Extraction & 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 (RR) were calculated using a random-effect model and inverse variance. Inter-study heterogeneity was assessed with I2 statistics. Main outcomes and measures: Obstetric outcomes; preterm birth (PTB) (spontaneous and threatened), premature rupture of the membranes (pPROM), chorioamnionitis, mode of delivery, length of labour, induction of delivery, oxytocin use, haemorrhage, analgesia, cervical cerclage & cervical stenosis. Neonatal outcomes; low birth weight (LBW), neonatal intensive care unit (NICU) admission, stillbirth, APGAR scores and perinatal mortality. Results: Seventy-one studies were included (6338982 participants: 65082 treated-6292563 untreated). Treatment significantly increased the risk of overall (<37weeks)(10.7 v 5.4%, RR=1.78[1.60 to 1.98]), severe (<34/32weeks)(3.5 v 1.4%, RR=2.40[1.92 to 2.99]) and extreme (<30/28weeks)(1.0 v 0.3%, RR=2.54[1.77 to 3.63]) PTB. The magnitude of the effect was higher for techniques removing or ablating more tissue (<37weeks: CKC (RR=2.70[2.14 to 3.40]), LC (RR=2.11[1.26 to 3.54)], excision not otherwise specified (NOS) (RR=2.02[1.60 to 2.55]), LLETZ (RR=1.56[1.36 to 1.79]), ablation NOS (RR=1.46[1.27 to 1.66]). The risk of PTB increased with repeat treatment (13.2 v 4.1%, RR=3.78[2.65 to 5.39]) and with increasing cone depth (≤12/10mm: 7.1 v 3.4%, RR=1.54[1.09 to 2.18]; ≥10/12mm: 9.8 v 3.4%, RR=1.93[1.62 to 2.31]; ≥15/17mm: 10.1 v 3.4%, RR=2.77[1.95 to 3.93]; ≥20mm: 10.2 v 3.4%, RR=4.91[2.06 to 11.68]), when compared to no treatment. The choice of comparison group affected the magnitude of effect that was higher for external, followed by internal comparators and ultimately women with disease but no treatment. The pregnancies of women with disease but no treatment and the pregnancies of treated women before treatment had higher risk of PTB than the general population (5.9 v 5.6%, RR=1.24[1.14 to 1.35]). Spontaneous PTB, pPROM, chorioamnionitis, LBW, NICU admission 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 it is for ablation.