Cervical intraepithelial neoplasia and the risk of spontaneous preterm birth: A Dutch population-based cohort study with 45,259 pregnancy outcomes

Background

Excisional procedures of cervical intraepithelial neoplasia (CIN) may increase the risk of preterm birth. It is unknown whether this increased risk is due to the excision procedure itself, to the underlying CIN, or to secondary risk factors that are associated with both preterm birth and CIN. The aim of this study is to assess the risk of spontaneous preterm birth in women with treated and untreated CIN and examine possible associations by making a distinction between the excised volume of cervical tissue and having cervical disease.

Methods and findings

This Dutch population-based observational cohort study identified women aged 29 to 41 years with CIN between 2005 and 2015 from the Dutch pathology registry (PALGA) and frequency matched them with a control group without any cervical abnormality based on age at and year of pathology outcome (i.e., CIN or normal cytology) and urbanization (= 100,000 inhabitants). All their 45,259 subsequent singleton pregnancies with a gestational age >= 16 weeks between 2010 and 2017 were identified from the Dutch perinatal database (Perined). Nineteen potential confounders for preterm birth were identified. Adjusted odds ratios (ORs) were calculated for preterm birth comparing the 3 different groups of women: (1) women without CIN diagnosis; (2) women with untreated CIN; and (3) women with treated CIN prior to each childbirth.

In total, 29,907, 5,940, and 9,412 pregnancies were included in the control, untreated CIN, and treated CIN group, respectively. The control group showed a 4.8% (1,002/20,969) proportion of spontaneous preterm birth, which increased to 6.9% (271/3,940) in the untreated CIN group, 9.5% (600/6,315) in the treated CIN group, and 15.6% (50/321) in the group with multiple treatments. Women with untreated CIN had a 1.38 times greater odds of preterm birth compared to women without CIN (95% confidence interval (CI) 1.19 to 1.60; P < 0.001). For women with treated CIN, these odds 2.07 times increased compared to the control group (95% CI 1.85 to 2.33; P < 0.001). Treated women had a 1.51 times increased odds of preterm birth compared to women with untreated CIN (95% CI 1.29 to 1.76; P < 0.001). Independent from cervical disease, a volume excised from the cervix of 0.5 to 0.9 cc increased the odds of preterm birth 2.20 times (37/379 versus 1,002/20,969; 95% CI 1.52 to 3.20; P < 0.001). These odds further increased 3.13 times and 5.93 times for women with an excised volume of 4 to 8.9 cc (90/724 versus 1,002/20,969; 95% CI 2.44 to 4.01; P < 0.001) and >= 9 cc (30/139 versus 1,002/20,969; 95% CI 3.86 to 9.13; P < 0.001), respectively. Limitations of the study include the retrospective nature, lack of sufficient information to calculate odds of preterm birth

Conclusions

In this study, we observed a strong correlation between preterm birth and a volume of >= 0.5 cc excised cervical tissue, regardless of the severity of CIN. Caution should be taken when performing excisional treatment in women of reproductive age as well as prudence in case of multiple biopsies. Fertile women with a history of performing multiple biopsies or excisional treatment for CIN may benefit from close surveillance during pregnancy.

Author summary

Why was this study done?

Women who are treated for a precancerous cervical lesion may have an increased risk of preterm birth.

It is unknown whether this increased risk is due to the treatment itself, to the cervical disease, or to secondary risk factors that are associated with both preterm birth and cervical disease.

What did the researchers do and find?

We identified women with untreated and treated cervical disease and matched them with a control group through the Dutch pathology registry and compared their pregnancy outcomes through the Dutch perinatal database.

The control group (29,907 pregnancies) showed a 4.8% proportion of preterm birth, which increased to 6.9% in the untreated cervical disease group (5,940 pregnancies), 9.5% in the treated cervical disease group (9,412 pregnancies), and 15.6% in the group with multiple treatments (505 pregnancies).

After adjustment for 19 potential confounders for preterm birth, women with untreated cervical disease had a 1.4 times and women with treated cervical disease had a more than 2 times increased odds of preterm birth compared to the control group.

Independent from cervical disease, a volume excised from the cervix of 0.5 cc or more was associated with an approximately 2 times greater odds of preterm birth.

What do these findings mean?

We observed a strong association between women with a 0.5 cc or more excised cervical tissue volume (through biopsy and/or treatment) and the odds of preterm birth, regardless of severity of cervical disease or secondary risk factors associated with both preterm birth and cervical disease.

Our findings suggest that caution should be taken when performing multiple biopsies or treatment for CIN in women of reproductive age and that women with such a history may benefit from close surveillance during pregnancy.