Fertility and early pregnancy outcomes after treatment for cervical intraepithelial neoplasia: systematic review and meta-analysis

OBJECTIVE: To determine the impact of cervical excision for cervical intraepithelial neoplasia on fertility and early pregnancy outcomes. DESIGN: Systematic review and meta-analysis of cohort studies. DATA SOURCES: Medline and Embase. ELIGIBILITY CRITERIA: Studies assessing fertility and early pregnancy outcomes in women with a history of treatment for cervical intraepithelial neoplasia versus untreated women. We classified the included studies according to treatment type and fertility or early pregnancy endpoint. ANALYSIS: Pooled relative risks and 95% confidence intervals using a random effect model, and interstudy heterogeneity with I(2) statistics. RESULTS: 15 studies fulfilled the inclusion criteria and were included. The meta-analysis did not provide any evidence that treatment for cervical intraepithelial neoplasia adversely affected the chances of conception. The overall pregnancy rate was higher for treated women than for untreated women (four studies; 43% v 38%, pooled relative risk 1.29, 95% confidence interval 1.02 to 1.64), although the heterogeneity between studies was high (P<0.0001). Pregnancy rates did not differ between women with an intention to conceive (two studies; 88% v 95%, 0.93, 0.80 to 1.08) and the number requiring more than 12 months to conceive (three studies, 15% v 9%, 1.45, 0.89 to 2.37). Although the rates for total miscarriages (10 studies; 4.6% v 2.8%, 1.04, 0.90 to 1.21) and miscarriage in the first trimester (four studies; 9.8% v 8.4%, 1.16, 0.80 to 1.69) was similar for treated and untreated women, cervical treatment was associated with a significantly increased risk of miscarriage in the second trimester. The rate was higher for treated women than for untreated women (eight studies; 1.6% v 0.4%, 16,558 women; 2.60, 1.45 to 4.67). The number of ectopic pregnancies (1.6% v 0.8%; 1.89, 1.50 to 2.39) and terminations (12.2% v 7.4%; 1.71, 1.31 to 2.22) was also higher for treated women. CONCLUSION: There is no evidence suggesting that treatment for cervical intraepithelial neoplasia adversely affects fertility, although treatment was associated with a significantly increased risk of miscarriages in the second trimester. Research should explore mechanisms that may explain this increase in risk and stratify the impact that treatment may have on fertility and early pregnancy outcomes by the size of excision and treatment method used

Perinatal mortality and other severe adverse pregnancy outcomes associated with treatment of cervical intraepithelial neoplasia: meta-analysis

Objective To assess the relative risk of perinatal mortality, severe preterm delivery, and low birth weight associated with previous treatment for precursors of cervical cancer

Obstetric outcomes after conservative treatment for cervical intraepithelial lesions and early invasive disease.

BACKGROUND: The mean age of women undergoing local treatment for pre-invasive cervical disease (cervical intra-epithelial neoplasia; CIN) or early cervical cancer (stage IA1) is around their 30s and similar to the age of women having their first child. Local cervical treatment has been correlated to adverse reproductive morbidity in a subsequent pregnancy, however, published studies and meta-analyses have reached contradictory conclusions. OBJECTIVES: To assess the effect of local cervical treatment for CIN and early cervical cancer on obstetric outcomes (after 24 weeks of gestation) and to correlate these to the cone depth and comparison group used. SEARCH METHODS: We searched the following databases: Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library, 2017, Issue 5), MEDLINE (up to June week 4, 2017) and Embase (up to week 26, 2017). In an attempt to identify articles missed by the search or unpublished data, we contacted experts in the field and we handsearched the references of the retrieved articles and conference proceedings. SELECTION CRITERIA: We included all studies reporting on obstetric outcomes (more than 24 weeks of gestation) in women with or without a previous local cervical treatment for any grade of CIN or early cervical cancer (stage IA1). Treatment included both excisional and ablative methods. We excluded studies that had no untreated reference population, reported outcomes in women who had undergone treatment during pregnancy or had a high-risk treated or comparison group, or both DATA COLLECTION AND ANALYSIS: We classified studies according to the type of treatment and the obstetric endpoint. Studies were classified according to method and obstetric endpoint. Pooled risk ratios (RR) and 95% confidence intervals (CIs) were calculated using a random-effects model and inverse variance. Inter-study heterogeneity was assessed with I2 statistics. We assessed maternal outcomes that included preterm birth (PTB) (spontaneous and threatened), preterm premature rupture of the membranes (pPROM), chorioamnionitis, mode of delivery, length of labour, induction of delivery, oxytocin use, haemorrhage, analgesia, cervical cerclage and cervical stenosis. The neonatal outcomes included low birth weight (LBW), neonatal intensive care unit (NICU) admission, stillbirth, perinatal mortality and Apgar scores. MAIN RESULTS: We included 69 studies (6,357,823 pregnancies: 65,098 pregnancies of treated and 6,292,725 pregnancies of untreated women). Many of the studies included only small numbers of women, were of heterogenous design and in their majority retrospective and therefore at high risk of bias. Many outcomes were assessed to be of low or very low quality (GRADE assessment) and therefore results should be interpreted with caution. Women who had treatment were at increased overall risk of preterm birth (PTB) (less than 37 weeks) (10.7% versus 5.4%, RR 1.75, 95% CI 1.57 to 1.96, 59 studies, 5,242,917 participants, very low quality), severe (less than 32 to 34 weeks) (3.5% versus 1.4%, RR 2.25, 95% CI 1.79 to 2.82), 24 studies, 3,793,874 participants, very low quality), and extreme prematurity (less than 28 to 30 weeks) (1.0% versus 0.3%, (RR 2.23, 95% CI 1.55 to 3.22, 8 studies, 3,910,629 participants, very low quality), as compared to women who had no treatment.The risk of overall prematurity was higher for excisional (excision versus no treatment: 11.2% versus 5.5%, RR 1.87, 95% CI 1.64 to 2.12, 53 studies, 4,599,416 participants) than ablative (ablation versus no treatment: 7.7% versus 4.6%, RR 1.35, 95% CI 1.20 to 1.52, 14 studies, 602,370 participants) treatments and the effect was higher for more radical excisional techniques (less than 37 weeks: cold knife conisation (CKC) (RR 2.70, 95% CI 2.14 to 3.40, 12 studies, 39,102 participants), laser conisation (LC) (RR 2.11, 95% CI 1.26 to 3.54, 9 studies, 1509 participants), large loop excision of the transformation zone (LLETZ) (RR 1.58, 95% CI 1.37 to 1.81, 25 studies, 1,445,104 participants). Repeat treatment multiplied the risk of overall prematurity (repeat versus no treatment: 13.2% versus 4.1%, RR 3.78, 95% CI 2.65 to 5.39, 11 studies, 1,317,284 participants, very low quality). The risk of overall prematurity increased with increasing cone depth (less than 10 mm to 12 mm versus no treatment: 7.1% versus 3.4%, RR 1.54, 95% CI 1.09 to 2.18, 8 studies, 550,929 participants, very low quality; more than 10 mm to 12 mm versus no treatment: 9.8% versus 3.4%, RR 1.93, 95% CI 1.62 to 2.31, 8 studies, 552,711 participants, low quality; more than 15 mm to 17 mm versus no treatment: 10.1 versus 3.4%, RR 2.77, 95% CI 1.95 to 3.93, 4 studies, 544,986 participants, very low quality; 20 mm or more versus no treatment: 10.2% versus 3.4%, RR 4.91, 95% CI 2.06 to 11.68, 3 studies, 543,750 participants, very low quality). The comparison group affected the magnitude of effect that was higher for external, followed by internal comparators and ultimately women with disease, but no treatment. Untreated women with disease and the pre-treatment pregnancies of the women who were treated subsequently had higher risk of overall prematurity than the general population (5.9% versus 5.6%, RR 1.24, 95% CI 1.14 to 1.34, 15 studies, 4,357,998 participants, very low quality).pPROM (6.1% versus 3.4%, RR 2.36, 95% CI 1.76 to 3.17, 21 studies, 477,011 participants, very low quality), low birth weight (7.9% versus 3.7%, RR 1.81, 95% CI 1.58 to 2.07, 30 studies, 1,348,206 participants, very low quality), NICU admission rate (12.6% versus 8.9%, RR 1.45, 95% CI 1.16 to 1.81, 8 studies, 2557 participants, low quality) and perinatal mortality (0.9% versus 0.7%, RR 1.51, 95% CI 1.13 to 2.03, 23 studies, 1,659,433 participants, low quality) were also increased after treatment. AUTHORS' CONCLUSIONS: Women with CIN have a higher baseline risk for prematurity. Excisional and ablative treatment appears to 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. However, the results should be interpreted with caution as they were based on low or very low quality (GRADE assessment) observational studies, most of which were retrospective

Immediate referral to colposcopy versus cytological surveillance for minor cervical cytological abnormalities in the absence of HPV test

A C K N O W L E D G E M E N T S The authors wish to acknowledge Jo Morrison for her clinical and editorial advice, Jane Hayes f or designing the search strategy and Gail Quinn, Clare Jess and Tracey Bishop for their contribution to the editorial process.This project was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to the Cochrane Gynaecological, Neuro-oncology and Orphan Cancer Group. The views and opinions expressed therein are those of the authors andd o not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health.Peer reviewedPublisher PD

Invasive cervical cancer following treatment of pre-invasive lesions: A potential theory based on a small case series

Peer reviewe

Incidence and mortality from cervical cancer and other malignancies after treatment of cervical intraepithelial neoplasia: a systematic review and meta-analysis of the literature

Background Although local treatments for cervical intraepithelial neoplasia (CIN) are highly effective, it has been reported that treated women remain at increased risk of cervical and other cancers. Our aim is to explore the risk of developing or dying from cervical cancer and other human papillomavirus (HPV)- and non-HPV-related malignancies after CIN treatment and infer its magnitude compared with the general population. Materials and methods Design: Systematic review and meta-analysis. Eligibility criteria: Studies with registry-based follow-up reporting cancer incidence or mortality after CIN treatment. Data synthesis: Summary effects were estimated using random-effects models. Outcomes Incidence rate of cervical cancer among women treated for CIN (per 100 000 woman-years). Relative risk (RR) of cervical cancer, other HPV-related anogenital tract cancer (vagina, vulva, anus), any cancer, and mortality, for women treated for CIN versus the general population. Results Twenty-seven studies were eligible. The incidence rate for cervical cancer after CIN treatment was 39 per 100 000 woman-years (95% confidence interval 22–69). The RR of cervical cancer was elevated compared with the general population (3.30, 2.57–4.24; P <0.001). The RR was higher for women more than 50 years old and remained elevated for at least 20 years after treatment. The RR of vaginal (10.84, 5.58–21.10; P <0.001), vulvar (3.34, 2.39–4.67; P <0.001), and anal cancer (5.11, 2.73–9.55; P <0.001) was also higher. Mortality from cervical/vaginal cancer was elevated, but our estimate was more uncertain (RR 5.04, 0.69–36.94; P = 0.073). Conclusions Women treated for CIN have a considerably higher risk to be later diagnosed with cervical and other HPV-related cancers compared with the general population. The higher risk of cervical cancer lasts for at least 20 years after treatment and is higher for women more than 50 years of age. Prolonged follow-up beyond the last screening round may be warranted for previously treated women.Peer reviewe

Enoximone echocardiography: a novel test to evaluate left ventricular contractile reserve in patients with heart failure on chronic beta-blocker therapy

BACKGROUND: It has been suggested that an extensive contractile reserve identified recognised by means of dobutamine stress echocardiography may predict a better prognosis in patients with severe left ventricular dysfunction at rest. However, the clinical use of dobutamine stress echocardiography may be limited in patients with chronic heart failure by the substantial proportion of such patients treated with beta-blockers, since the inotropic response to adrenergic stimulation is known to be attenuated in patients receiving beta-adrenoceptor blockers. Enoximone is a positive inotropic agent that inhibits cyclic adenosine monophosphate-specific phosphosdiesterase. We therefore tested the hypothesis that enoximone may be an alternative to dobutamine in evaluating left ventricular contractile reserve in patients with systolic dysfunction on chronic beta-blocker therapy. METHODS: We studied 26 patients (21 males and five females) with a mean age of 58 ± 10 years: 11 were not receiving beta-blockers (noBB group); 15 were receiving carvedilol at a mean dose of 34 mg/day (BB group). Dobutamine was infused at doses of 5 and 10 micrograms/kg/min, and enoximone at a dose of 1.5 mg/kg. RESULTS: The ejection fraction in the noBB group increased by 9% with dobutamine and 8.73% with enoximone (p = 0.86); in the BB group, it increased by 6% with dobutamine and 8.94% with enoximone (p = 0.03). Regional peak systolic velocities were evaluated by means of tissue Doppler imaging in four basal and four medium level segments. In the noBB group, they increased more with dobutamine than with enoximone in three of the eight segments; no significant differences were found in the BB group. Dobutamine induced non-sustained ventricular tachycardia in three patients and supraventricular tachycardia in one, whereas enoximone did not induce any repetitive arrhythmias. CONCLUSIONS: Enoximone might be preferable to low-dose dobutamine for evaluating left ventricular contractile reserve in chronically beta-blocked heart failure patients as it is slightly more potent and has a better safety profile

Reference Force Field and CDW Amplitude of Mixed-Valence Halogen-Bridged Pt Complexes

The spectroscopic effects of electron-phonon coupling in mixed-valence chlorine-bridged Pt chains complexes are investigated through a parallel infrared and Raman study of three compounds with decreasing Pt-Pt distance along the chain. The e-ph interaction is analyzed in terms of the Herzberg-Teller coupling scheme. We take into account the quadratic term and define a precise reference state. The force field relevant to this state is constructed, whereas the electronic structure is analyzed in terms of a simple phenomenological model, singling out a trimeric unit along the chain. In this way we are able to account for all the available optical data of the three compounds, and to estimate the relevant microscopic parameters, such as the e-ph coupling constants and the CDW amplitude.Comment: 10 pages, compressed postscript, 6 Tables and 5 Figures also in a compressed ps.Z file. Revision is in the submission format only (postscript instead of tex