NIHR Signal Some treatments for abnormal cervical cells increase risk of preterm birth

Published on 15 November 2016

Women who receive the more radical treatments (like loop excisions) for abnormal cells on the cervix are more likely to experience preterm birth and other adverse pregnancy outcomes than those receiving more local treatments or those not needing treatment at all. Abnormal cells – termed cervical intraepithelial neoplasia (CIN) – can be picked up on cervical screening. These non-cancerous changes can develop into cancer in the future if left untreated. Various treatment options are available to either cut away or destroy the problem cells. The benefits of treatments need to be considered too.

This is the largest review to date of this topic and it aimed to see whether CIN treatment increases the risk of complications in future pregnancies as often thought and to estimate the extent of the risk. It found consistent evidence for a link with preterm birth, though the number of babies born very early (under 30 weeks) was low. The risk was higher for more aggressive techniques and those that involved cutting away a larger volume of cervical tissue. There were also links with newborn low birthweight, admission to a neonatal unit and neonatal mortality. Although risks were greater for those women receiving treatment, the overall chances for premature birth in either group were still quite small.

Women should be informed of the potential risks of CIN treatment, particularly those planning future pregnancies. This information should support the decisions about timing and type of treatment made by clinicians and patients together. Over time, it is hoped that HPV vaccination will reduce the need for these types of treatment.

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Why was this study needed?

More than 23,800 cervical treatments were carried out in England in 2013-14. The average age of women having treatment for abnormal cervical cells is similar to the age women have their first child. Treatment has been linked to an increased risk of poor maternal and newborn outcomes in pregnancy, including increased risk of preterm birth.

Media publicity has heightened public awareness of the potential pregnancy risks, resulting in increased patient inquiries to health professionals.

Since the first review on the topic a decade ago, more than 50 studies have been published with mixed findings. No comprehensive high quality synthesis has been performed and there is a need to give a clear message on the risks.

This review assessed the impact of treatment for abnormal cells on pregnancy outcomes and looked at how any identified risk could be modified by the depth of the biopsy.

What did this study do?

The review identified 71 studies (6,338,982 women) comparing pregnancy outcomes for women treated for abnormal cells to women with no treatment history. Treatments were grouped as excisional (abnormal cells removed) or ablative (abnormal cells destroyed). Excisional techniques included cone biopsy (by knife or laser) and large loop excision of the transformation zone (the area where abnormal cells are found). Ablative techniques included laser and freezing (cryotherapy).

Pregnancy outcomes (beyond 24 weeks) included spontaneous and threatened preterm birth, low birthweight, and type of labour and delivery. The researchers’ analyses looked at the influence of the number of cone biopsies, depth and volume.

Most studies were retrospective cohorts which are a less reliable study as they relied on questionnaires to collect some of the data. Adjustments were made for other factors that could be influencing the results and can limit interpretation.  For example it is difficult to know whether the added risk could be partly due to things such as human papillomavirus (HPV), smoking or socioeconomic differences between the groups.

What did it find?

  • All types of treatment for CIN significantly increased the risk of preterm birth (threatened and spontaneous) compared to no treatment:
    • overall preterm birth rate (less than 37 weeks): 10.7% among treated women vs. 5.4% among untreated (relative risk [RR] 1.78, 95% confidence interval [CI] 1.60 to 1.98, 60 studies)
    • severe preterm birth (less than 34 weeks): 3.5% vs. 1.4% (RR 2.40, 95% CI 1.92 to 2.99, 25 studies)
    • extreme preterm birth (less than 30 weeks): 1.0% vs. 0.3% (RR 2.54, 95% CI 1.77 to 3.63, 9 studies).
  • More than one previous treatment carried higher risk of preterm birth (13.2% vs. 4.1% for no treatment; RR 3.78, 95% CI 2.65 to 5.39), as did increasing cone biopsy depth or volume (for example, cone depth of 12mm or less, 7.1% vs. 3.4% for no treatment; RR 1.54, 95% CI 1.09 to 2.18).
  • More radical techniques, such as large loop excision of the transformation zone, carried increased risk. Rate of preterm in women who received this technique was 8.1% compared with 4.7% in untreated women (RR 1.56, 95% CI 1.36 to 1.79, 26 studies). Excisional techniques in general carried higher risk (RR 2.02, 95% CI 1.60 to 2.55, 15 studies) than ablative techniques (RR 1.46, 95% CI 1.27 to 1.66, 5 studies).
  • CIN treatment increased the risk of preterm rupture of membranes (6.1% vs. 3.4% for no treatment; RR 2.36, 95% CI 1.76 to 3.17, 21 studies); infection of membranes (3.5% vs. 1.1%; RR 3.43, 95% CI 1.36 to 8.64, 4 studies); and need for cervical stitches to prevent preterm birth (4.0% vs. 0.7%; RR 14.29, 95% CI 2.85 to 71.65, 8 studies).
  • CIN treatment also increased the risk of adverse new born outcomes compared to babies of women who did not undergo treatment. This included birthweight less than 2500g (7.9% vs. 3.7%; RR 1.81, 95% CI 1.58 to 2.07, 30 studies), admission to a neonatal intensive care unit (12.6% vs. 8.9%; RR 1.45, 95% CI 1.16 to 1.81, 8 studies), and infant mortality (0.9% vs. 0.7%; RR1.51, 95% CI 1.13 to 2.13, 23 studies).

What does current guidance say on this issue?

There is no specific NICE guideline on the treatment of CIN or invasive cervical cancer.

The UK Royal College of Obstetricians and Gynaecologists have produced an impact paper on reproductive outcomes after local treatment for preinvasive cervical disease that discusses the findings from this review.

NICE guidance on the recognition and referral of suspected cancer recommends a suspected cancer pathway referral for an appointment within two weeks if the appearance of the cervix is consistent with cervical cancer.

What are the implications?

Treatment for CIN seems to be clearly linked with a small increased risk of preterm birth and other adverse pregnancy outcomes. More radical techniques (e.g. large loop excision of the transformation zone) and increased size and volume of excision may carry highest risk.

It is useful to know more precisely the extent of the risk and this will enable clinicians to advise women better on their options for surgery. This is particularly important for those planning future pregnancies.

There is a hope that these procedures will be required less in the long-term as HPV vaccination begins to have an effect on the next generation.

Citation and Funding

Kyrgiou M, Athanasiou A, Paraskevaidi M, et al. 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:i3633.

This project was funded by the British Society of Colposcopy Cervical Pathology Jordan/Singer Award, the Imperial College Healthcare Charity, Genesis Research Trust, Sigrid Juselius Fellowship and the Imperial healthcare NHS Trust NIHR Biomedical Research Centre.

Bibliography

Kyrgiou M, Martin-Hirsch PL, Paraskevaidis EA, Bennett PR. Reproductive outcomes after local treatment for preinvasive cervical disease (scientific impact paper no.21). London: Royal College of Obstetricians and Gynaecologists; 2016.

NHS Choices. Cervical cancer . London. Department of Health; 2015.

NICE. Suspected cancer: recognition and referral. NG12. London. National Institute for Health and Care Excellence; 2015.

Why was this study needed?

More than 23,800 cervical treatments were carried out in England in 2013-14. The average age of women having treatment for abnormal cervical cells is similar to the age women have their first child. Treatment has been linked to an increased risk of poor maternal and newborn outcomes in pregnancy, including increased risk of preterm birth.

Media publicity has heightened public awareness of the potential pregnancy risks, resulting in increased patient inquiries to health professionals.

Since the first review on the topic a decade ago, more than 50 studies have been published with mixed findings. No comprehensive high quality synthesis has been performed and there is a need to give a clear message on the risks.

This review assessed the impact of treatment for abnormal cells on pregnancy outcomes and looked at how any identified risk could be modified by the depth of the biopsy.

What did this study do?

The review identified 71 studies (6,338,982 women) comparing pregnancy outcomes for women treated for abnormal cells to women with no treatment history. Treatments were grouped as excisional (abnormal cells removed) or ablative (abnormal cells destroyed). Excisional techniques included cone biopsy (by knife or laser) and large loop excision of the transformation zone (the area where abnormal cells are found). Ablative techniques included laser and freezing (cryotherapy).

Pregnancy outcomes (beyond 24 weeks) included spontaneous and threatened preterm birth, low birthweight, and type of labour and delivery. The researchers’ analyses looked at the influence of the number of cone biopsies, depth and volume.

Most studies were retrospective cohorts which are a less reliable study as they relied on questionnaires to collect some of the data. Adjustments were made for other factors that could be influencing the results and can limit interpretation.  For example it is difficult to know whether the added risk could be partly due to things such as human papillomavirus (HPV), smoking or socioeconomic differences between the groups.

What did it find?

  • All types of treatment for CIN significantly increased the risk of preterm birth (threatened and spontaneous) compared to no treatment:
    • overall preterm birth rate (less than 37 weeks): 10.7% among treated women vs. 5.4% among untreated (relative risk [RR] 1.78, 95% confidence interval [CI] 1.60 to 1.98, 60 studies)
    • severe preterm birth (less than 34 weeks): 3.5% vs. 1.4% (RR 2.40, 95% CI 1.92 to 2.99, 25 studies)
    • extreme preterm birth (less than 30 weeks): 1.0% vs. 0.3% (RR 2.54, 95% CI 1.77 to 3.63, 9 studies).
  • More than one previous treatment carried higher risk of preterm birth (13.2% vs. 4.1% for no treatment; RR 3.78, 95% CI 2.65 to 5.39), as did increasing cone biopsy depth or volume (for example, cone depth of 12mm or less, 7.1% vs. 3.4% for no treatment; RR 1.54, 95% CI 1.09 to 2.18).
  • More radical techniques, such as large loop excision of the transformation zone, carried increased risk. Rate of preterm in women who received this technique was 8.1% compared with 4.7% in untreated women (RR 1.56, 95% CI 1.36 to 1.79, 26 studies). Excisional techniques in general carried higher risk (RR 2.02, 95% CI 1.60 to 2.55, 15 studies) than ablative techniques (RR 1.46, 95% CI 1.27 to 1.66, 5 studies).
  • CIN treatment increased the risk of preterm rupture of membranes (6.1% vs. 3.4% for no treatment; RR 2.36, 95% CI 1.76 to 3.17, 21 studies); infection of membranes (3.5% vs. 1.1%; RR 3.43, 95% CI 1.36 to 8.64, 4 studies); and need for cervical stitches to prevent preterm birth (4.0% vs. 0.7%; RR 14.29, 95% CI 2.85 to 71.65, 8 studies).
  • CIN treatment also increased the risk of adverse new born outcomes compared to babies of women who did not undergo treatment. This included birthweight less than 2500g (7.9% vs. 3.7%; RR 1.81, 95% CI 1.58 to 2.07, 30 studies), admission to a neonatal intensive care unit (12.6% vs. 8.9%; RR 1.45, 95% CI 1.16 to 1.81, 8 studies), and infant mortality (0.9% vs. 0.7%; RR1.51, 95% CI 1.13 to 2.13, 23 studies).

What does current guidance say on this issue?

There is no specific NICE guideline on the treatment of CIN or invasive cervical cancer.

The UK Royal College of Obstetricians and Gynaecologists have produced an impact paper on reproductive outcomes after local treatment for preinvasive cervical disease that discusses the findings from this review.

NICE guidance on the recognition and referral of suspected cancer recommends a suspected cancer pathway referral for an appointment within two weeks if the appearance of the cervix is consistent with cervical cancer.

What are the implications?

Treatment for CIN seems to be clearly linked with a small increased risk of preterm birth and other adverse pregnancy outcomes. More radical techniques (e.g. large loop excision of the transformation zone) and increased size and volume of excision may carry highest risk.

It is useful to know more precisely the extent of the risk and this will enable clinicians to advise women better on their options for surgery. This is particularly important for those planning future pregnancies.

There is a hope that these procedures will be required less in the long-term as HPV vaccination begins to have an effect on the next generation.

Citation and Funding

Kyrgiou M, Athanasiou A, Paraskevaidi M, et al. 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:i3633.

This project was funded by the British Society of Colposcopy Cervical Pathology Jordan/Singer Award, the Imperial College Healthcare Charity, Genesis Research Trust, Sigrid Juselius Fellowship and the Imperial healthcare NHS Trust NIHR Biomedical Research Centre.

Bibliography

Kyrgiou M, Martin-Hirsch PL, Paraskevaidis EA, Bennett PR. Reproductive outcomes after local treatment for preinvasive cervical disease (scientific impact paper no.21). London: Royal College of Obstetricians and Gynaecologists; 2016.

NHS Choices. Cervical cancer . London. Department of Health; 2015.

NICE. Suspected cancer: recognition and referral. NG12. London. National Institute for Health and Care Excellence; 2015.

Adverse obstetric outcomes after local treatment for cervical preinvasive and early invasive disease according to cone depth: systematic review and meta-analysis

Published on 30 July 2016

Kyrgiou, M.,Athanasiou, A.,Paraskevaidi, M.,Mitra, A.,Kalliala, I.,Martin-Hirsch, P.,Arbyn, M.,Bennett, P.,Paraskevaidis, E.

Bmj Volume 354 , 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 I(2) 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.

Cervical intraepithelial neoplasia (CIN) has three stages that indicate the depth of the abnormal cells. Mild abnormality or CIN 1 is when a third of the thickness of the cervix has abnormal cells. CIN 2 is when the depth is between one and two thirds. Severe abnormality or CIN 3 is when the full thickness of the cervix lining has abnormal cells. Treatment choice is decided based on the severity of CIN.

Expert commentary

Although the association between treatment to the cervix and an increased risk of preterm delivery has been described before, this analysis is the largest and most detailed to date and is therefore important in defining risk.

Even though the relative risks are increased for all procedures, the absolute risks remain small and have to be offset against the established benefits of treatment which have seen a huge decrease in the incidence of cervical cancer.

Nevertheless this should be seen as a further call to develop strategies to limit treatments to those patients at most risk of developing invasive disease.

Richard Edmondson, Professor of Gynaecological Oncology, University of Manchester