Pregnancy incidence and outcome before and after cervical intraepithelial neoplasia: a retrospective cohort study

Introduction

Evidence linking cervical intraepithelial neoplasia (CIN) treatments, like cervical conization, to later increase in preterm deliveries, low birthweight, and perinatal mortality is extensive 1-3. Effects of the cervical conization itself on the incidence of pregnancies, live births, and other types of pregnancies are less clear. The largest study so far showed that the incidence of pregnancy or live birth was actually higher among the CIN-treated women compared to the age-matched reference population, and also the risk of induced abortion and extrauterine pregnancy was higher in CIN patients than the reference cohort 4.

Women with CIN differ from the general population in several significant ways: they smoke more, have more sexually transmitted infections, are more often multiparous, have more sexual partners during their lives, and they are younger at sexual debut 5—all these factors are capable of affecting fertility as well. Therefore, comparing the treated to healthy might only reflect differences in group-specific fertility patterns and hence dilute or even mask the direction and magnitude of the true effect of the intervention, CIN treatment, on the studied outcomes.

Our objective was to examine the effects of CIN treatment itself upon incidence of live births and other pregnancy outcomes—miscarriages, abortions, extrauterine pregnancies, and molar pregnancies—by comparing the CIN patients' pregnancy outcomes before and after CIN treatment with those within a cohort of CIN-treated women. The previous analysis 4 could not adequately take into account the above factors; there could have been residual confounding left in the results—they may not reflect merely the effect of CIN treatment itself on the outcomes studied, but rather the differences between women with and without CIN. The current study offers a more appropriate approach to study the effect of CIN treatment.

Material and Methods

To study the possible effect of CIN treatment on pregnancy outcome, we compared the incidence of different types of pregnancies before and after CIN treatment within a cohort of CIN-treated women. The initial study group comprised 7253 women treated for CIN with cold knife conization (CKC), cryocoagulation (cryo), laser conization or ablation, or with a loop electrosurgical excision procedure (LEEP), between 1974 and 2001 at Helsinki University Central Hospital, Finland, a reference center for colposcopy in the district.

In our data, median age at treatment was lower than at the first pregnancy, so women were more likely to be pregnant after than before the CIN treatment. Presenting results of a cohort where treated women serve as their own controls, adjusting only for age at treatment and age at endpoint does not sufficiently control for age, therefore we fitted all models for a matched reference cohort as well. For each woman treated, five individually age- and municipality-matched controls were selected from the Finnish Population Register, resulting in 36,265 women in the initial reference cohort.

Data covering all pregnancy outcomes were available only from the beginning of 1974. Hence, from the initial study population we included in the study only women turning 16 at the onset of nationwide registers or younger, 1974, that is, women born 1958 or later. After this exclusion, the final study population included 3530 women treated for CIN and the reference cohort was reduced to 17,451 women.

Birth dates of their live-born children (date of live singleton birth) and possible dates of emigration or death were retrieved from the population registry. Precise dates of all other pregnancy outcomes (miscarriage, extrauterine pregnancy, molar pregnancy, and termination of pregnancy [TOP]) and the date of possible sterilization were gathered from the THL's (National Institute for Health and Welfare) Care Registers for Social Welfare and Health, who have been shown to have high completeness and validity 6.

A live birth here means delivery of a live-born baby with over 24 weeks of gestation; miscarriages occurred before 24 gestational weeks; extrauterine pregnancy is pregnancy outside the uterus; molar pregnancy means benign gestational trophoblastic neoplasia; and TOP means a medically performed abortion, either by medication or by dilatation and curettage. Pregnancy incidence denotes incidence of all endpoints: live births, TOPs, extrauterine pregnancies, miscarriages, and molar pregnancies.

The incidence of the outcomes studied was calculated over consecutive follow-up periods for each woman in both cohorts to account for the changing values of explanatory variables over the whole follow-up time. We calculated the conception time of each pregnancy by median estimates of the duration of pregnancy for each outcome and were thus able to determine whether a pregnancy had started before or after the CIN treatment. (1) A live birth: 280 days before the actual birth. (2) Miscarriage or TOP: 63 days before. (3) Extrauterine pregnancy: 56 days. (4) Molar pregnancy: 77 days. All women were followed up until sterilization, turning 50, emigration, death, or at the end of 2004. The median age at treatment was 26 and age at first pregnancy among the 2637 treated women who became pregnant at least once was 24.

Results

Among the 3530 CIN-treated women with 76,162 woman-years of follow-up, we observed altogether 6535 pregnancies of which 4615 were live births, 1545 TOPs, 208 miscarriages, 97 extrauterine pregnancies, and 70 molar pregnancies (Table 1).

The incidence of any pregnancy was similar after and before the CIN treatment, HR 1.02 and 95% CI 0.97–1.08, but the incidence of the first-ever pregnancy was significantly elevated after treatment, HR 1.13 and 95% CI 1.03–1.23 (Table 2). The incidence of live births was significantly higher after overall treatment, HR 1.08 and 95% CI 1.01–1.15, in the first-ever pregnancy, HR 1.16 and 95% CI 1.04–1.28, and in pregnancies after one or two children (Table 2). Overall incidences of TOPs, miscarriages, molar pregnancies, and extrauterine pregnancies were not statistically significantly increased after CIN treatment (Table 2). Overall incidence of TOPs was slightly but not significantly elevated, HR 1.07 and 95% CI 0.95–1.20, and reached statistical significance when the first-ever pregnancy was TOP, HR 1.40 and 95% CI 1.15–1.72 (Table 2). Incidence of extrauterine pregnancies was constantly elevated after treatment, regardless of pregnancy history, but the difference was statistically significant only in pregnancies that began after one child HR 3.50 and 95% CI 1.36–9.03 (Table 2).

We did not observe significant differences between the grades of CIN in any of the outcomes studied (Table 3). Results of those women treated with LEEP did not significantly differ from those of the whole study population, although the incidence of TOPs was statistically significantly and higher after than before the treatment, HR 1.36 and 95% CI 1.15–1.60 (Table 3).

Discussion

Among over 3500 CIN-treated women with 76,000 woman-years of follow-up, we observed a significant increase in the incidence of live births after CIN treatment. Pregnancy incidence remained stable through the CIN treatment, but significantly more women became pregnant at least once after treatment.

In the current study, all comparisons before and after pregnancy were made within the cohort of treated women and reference cohort and all models are adjusted for all possible confounding factors retrievable from the registers used (parity, age, method of treatment, grade of CIN, place of residence, previous incidence of the outcome studied, and time of treatment). This setting allows for drawing broader conclusions about the direct effect of CIN treatment itself on later fertility than in a setting where the comparisons are made between the treated and a healthy reference group 4.

The number of miscarriages and extrauterine pregnancies in the data is small, and many results concerning these endpoints lack statistical power. This is most likely due to the fact that mainly those women who were taken as in-patients appeared in nationwide registers during the study period. This remained the same throughout the study period and hence does not systematically bias the results. As women treated for CIN were collected from the hospital register, some women might have been treated for CIN before the first treatment in our data or might have been treated again later. This phenomenon would rather dilute than exaggerate the results observed in this setting and as these events have been rare, these cannot therefore be considered to seriously bias the conclusions.

Pregnancy incidence and especially live birth incidence increased after CIN treatment. All results were adjusted for age-specific fertility patterns of general population, so a natural increase in reproductive activity with advancing age (median age at treatment was 26) does not explain this observation. Most likely the surgical procedure itself does not directly promote reproduction either. We know that CIN treatment causes anxiety and distress 5, 9. Even though the psychosocial consequences of CIN treatment was not studied here, we cannot rule out that a psychosocial effect of CIN treatment might increase rather than decrease the will to acquire children.

In our previous study, the incidence of different pregnancy types was compared between CIN-treated women and the healthy reference cohort. Incidences of TOPs and extrauterine pregnancy were significantly elevated among the treated women 4. In the current study, overall TOP incidence was not increased. However, among women treated with LEEP (66% of the study population) and in the first-ever pregnancy, TOPs were significantly more common after treatment. As LEEP is the dominating treatment method in the most recent periods (used in the current hospital settings since 1991), these two findings could correlate to each other. The CIN treatment may hence cause a small but significant increase in TOP incidence. As the majority, over 95%, of TOPs in Finland, is made due to social reasons 6, the psychological effects of CIN treatment might play a small role in the observed increase in TOPs incidence after treatment. However, supporting direct evidence was beyond the scope of our study setting.

Incidence of extrauterine pregnancies was slightly increased after treatment, but due to the small number of events in the data all but one result lacked statistical significance, and strong conclusions cannot therefore in our opinion be made.

The overall incidence of miscarriages was not increased, and a slight but not statistically significant increase was observed only among women with no previous pregnancy. If the CIN treatment was subject to miscarriages, the incidence should be elevated regardless of pregnancy history.

Cervical conization effectively prevents cervical cancer 10. A significant number of these procedures are made for women during their fertile years. Even though vast evidence links conization to preterm delivery, our findings are reassuring for physicians: the pregnancy incidence after CIN treatment did not decrease and adjusted livebirth incidence was higher after than before CIN treatment. As the results are based on a large data set with a nationwide follow-up of women treated in a public hospital, we consider our findings' generalisability as satisfactory for our country. We did observe a significant increase in TOP incidence after LEEP and in the first pregnancy as well, and increased reproductive activity after the treatment. In light of the findings of the current study, more research about the psychosocial consequences of CIN treatment is strongly encouraged in addition to countries and settings.

Conflict of Interest

Ilkka Kalliala has worked as a consultant for Roche Diagnostics and received payment for the same. Pekka Nieminen has been working as a consultant for GSK and Sanofi Pasteur-MSD and has received payment as a member of the endpoint committee for HPV-vaccination studies.