Obstetrics & Gynecology:
Time From Cervical Conization to Pregnancy and Preterm Birth
Himes, Katherine P. MD; Simhan, Hyagriv N. MD, MSCR
From the Department of Obstetrics, Gynecology, and Reproductive Sciences, Division of Maternal Fetal Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Corresponding author: Katherine Himes, MD, Department of Obstetrics, Gynecology, and Reproductive Sciences, 300 Halket Street, Pittsburgh, PA 15213; e-mail: firstname.lastname@example.org.
OBJECTIVE: To estimate whether the time interval between cervical conization and subsequent pregnancy is associated with risk of preterm birth.
METHODS: Our study is a case control study nested in a retrospective cohort. Women who underwent colposcopic biopsy or conization with loop electrosurgical excision procedure, large loop excision of the transformation zone, or cold knife cone and subsequently delivered at our hospital were identified with electronic databases. Variables considered as possible confounders included maternal race, age, marital status, payor status, years of education, self-reported tobacco use, history of preterm delivery, and dimensions of cone specimen.
RESULTS: Conization was not associated with preterm birth or any subtypes of preterm birth. Among women who underwent conization, those with a subsequent preterm birth had a shorter conization-to-pregnancy interval (337 days) than women with a subsequent term birth (581 days) (P=.004). The association between short conization-to-pregnancy interval and preterm birth remained significant when controlling for confounders including race and cone dimensions. The effect of short conization-to-pregnancy interval on subsequent preterm birth was more persistent among African Americans when compared with white women.
CONCLUSION: Women with a short conization-to-pregnancy interval are at increased risk for preterm birth. Women of reproductive age who must have a conization procedure can be counseled that conceiving within 2 to 3 months of the procedure may be associated with an increased risk of preterm birth.
LEVEL OF EVIDENCE: II
The incidence of cervical intraepithelial neoplasia (CIN) is highest among women in their reproductive years. Treatment for CIN depends upon the severity of the dysplasia as well as the patient's age and risk factors. Although low-grade lesions may be treated with expectant management, many high-grade lesions are treated with either ablative therapy or excision procedures. Commonly performed excision procedures include cold knife conization, loop electrosurgical excision procedure (LEEP), or large loop excision of the transformation zone.
Given the prevalence of CIN in reproductive-age women, researchers have investigated the impact that treatment of CIN has on subsequent obstetric outcomes.1–8 Although most studies suggest an association between treatment of cervical dysplasia and preterm birth, these studies have been small and often do not control for potential confounders of the relation between cervical conization and subsequent preterm birth. A recent meta-analysis by Kyrgiou et al9 pooled 27 studies to determine pooled relative risks for outcomes, including preterm delivery and low birth weight. In this study both cold knife conization and large loop excision of the transformation zone were significantly associated with preterm delivery (less than 37 weeks) (relative risk [RR] 2.59, 95% confidence interval [CI] 1.80–3.72, and RR 1.70, 95% CI 1.24–2.35, respectively).
Although conization procedures may be associated with an increased risk of preterm birth overall, it is possible that particular subgroups of women experience poor obstetric outcomes after conization procedures to a disproportionately greater degree. This would limit the ability of smaller studies to detect an overall difference. In this study, we seek to estimate whether the time interval between cervical conization and subsequent pregnancy is associated with risk of preterm birth. This may help clinicians identify a subset of women who are at higher risk for preterm birth after conization.
MATERIALS AND METHODS
Our primary study objective was to estimate the association between the time interval between cervical conization and subsequent pregnancy and preterm birth. To accomplish this we nested a case control study of women who delivered after a conization procedure—specifically LEEP, large loop excision of the transformation zone, or cold knife conization—in a larger retrospective cohort of women who were evaluated for cervical dysplasia and subsequently delivered a pregnancy of at least 20 weeks at our institution. Data from an obstetric and a pathological database were merged to create the retrospective cohort used in this study. After approval by the University of Pittsburgh Institutional Review Board, all women who underwent colposcopy with biopsy, LEEP, large loop excision of the transformation zone, or cold knife conization for cervical dysplasia between November 2001 and December 2004 were identified using a pathology database. The date of treatment procedure, the pathological diagnosis, and the dimensions of the pathological specimen (reported as height and width) were also extracted. In our final analysis, only women who underwent LEEP and large loop excision procedures were included because the number of cold knife conization procedures was small, and excluding them did not change the results of the analysis. Thus, conization in this paper specifically refers to either LEEP or large loop excision procedures.
An obstetric database was used to identify which of these women subsequently delivered a singleton, nonanomalous pregnancy of at least 20 weeks at Magee-Womens Hospital. The obstetric database also provided gestational age at delivery, estimated date of delivery (based on best obstetric estimate), social and demographic information, including race, payor status, years of education, self-reported tobacco use, and obstetric risk factors including prior preterm birth. Information about the type of preterm delivery—spontaneous preterm birth (births occurring after preterm labor or preterm premature rupture of membranes [PROM]) or indicated preterm birth—was also obtained. Accurate linkage between databases was assured by using unique patient identifier numbers given to all women at Magee-Womens Hospital.
For the purpose of this study, the interval from conization procedure to incident pregnancy (referred to as treatment interval in the paper) was defined as the accession date of the pathological cone specimen to the estimated date of delivery of the incident pregnancy. Height of the cone specimen was determined by examining the original pathology reports of cone dimensions. If multiple passes were made, the greatest height was taken from a single specimen. Preterm delivery was defined as delivery between 201/7 weeks and 366/7 weeks. No women who received cerclage were included.
The relation of preterm birth with treatment status in the cohort was determined by χ2 analysis. For these analyses, P<0.05 was considered significant. As this was not our primary objective, the study is not powered to detect a difference in preterm birth by treatment status. To assess our primary objective—the relationship between treatment interval and preterm birth—a ladder of powers was generated to determine whether any transformation of conization-to-pregnancy interval was necessary to achieve a Gaussian distribution.10 A reciprocal root transformation minimized the χ2 in this analysis, and thus, this transformation was undertaken for inclusion of interval into analyses that treated interval as a continuous variable. The relation of treatment interval to spontaneous preterm birth was then assessed with both Student t test and Mann-Whitney U test. The relation between treatment interval and spontaneous preterm birth was further explored using nonparametric regression smoothing with locally weighted regression.11,12 This analysis was done for all women who had a conization procedure and was stratified by race. Univariable and multivariable logistic regression was also used to explore the relation between treatment interval and spontaneous preterm birth. Variables considered for inclusion in the model included maternal race, age, marital status, payor status, years of education, tobacco use, history of preterm delivery, and height of the cone specimen. Confounders were included in the final model if they were found to be independently associated with preterm birth in the cohort. An odds ratio for the dichotomized exposure of “short” or “long” treatment interval (defined as less than or greater than 12 months, respectively) was also calculated using the same multivariable logistic regression model. All statistical analyses were performed using Stata 8.0 for Windows (Stata Corporation, College Station, TX).
A total of 1,079 women were identified for the retrospective cohort portion of this study—962 (89%) had biopsy alone and 117 (11%) had a LEEP or large loop excision. Conization occurred during pregnancy in 3 (2.6%) women, who were excluded from analysis. The overall frequency of preterm delivery was 12.7% (n=138): 61 preterm labor (5.6%), 22 preterm PROM (2%), and 55 indicated preterm birth (5.1%). Conization with LEEP or large loop excision was not associated with preterm birth overall or any of its subtypes. Demographic information on the two cohorts is given in Table 1, and Table 2 displays birth outcomes. Among women who had a LEEP, large loop excision, or cold knife conization, the median specimen height was 1.9 cm (range 0.8–4.6 cm).
With regard to the primary objective of the study, Table 3 shows the median treatment interval by spontaneous preterm birth status. As stated previously, interval was defined from the date of accession of the pathologic specimen to the estimated due date. For intuitive appeal, the treatment interval was converted into the time from conization to conception.
Using logistic regression, the relation of treatment interval and spontaneous preterm birth remained significant (P=.015) when adjusting for race and dimension of the excised cervical specimen. If treatment interval is dichotomized the odds ratio (OR) for spontaneous preterm birth is 20.2 (95% confidence interval 2.0–207.2). Treatment interval was dichotomized at 12 months, with short interval defined as less than 12 months and long interval as 12 months or more.
Figure 1 depicts the results of the mean-smoothed locally weighted regression analyses describing the relation between treatment interval and the probability of spontaneous preterm birth. Figures 2 and 3 depict these relationships stratified by self-reported race. These graphs suggest that incremental risk associated with treatment interval persists over a longer duration for African-American women than for white women.
Women undergoing treatment for cervical dysplasia are a heterogeneous group with different individual risk profiles for preterm birth. Identifying those factors associated with conization procedures that may place women at higher risk for preterm delivery is important for both patient counseling and risk modification. This idea was illustrated by a recent study published by Sadler et al,3 who reported birth outcomes among women treated for cervical dysplasia. This study did not show an association between treatment for cervical dysplasia and overall preterm birth. It did, however, find a statistically significant increased risk of preterm PROM in women who had laser conization or LEEP and showed an increasing risk of preterm PROM with increasing cone size. Thus, the subset of women with larger cervical excisions were at higher risk for preterm delivery after conization. The findings of our study identify another subset of women—those women who conceive within 2–3 months of LEEP or large loop excision of the transformation zone—who may be at higher risk for preterm delivery. This possible risk factor for preterm birth after LEEP or large loop excision is modifiable, making it a potentially important issue to discuss with patients.
The mechanism by which a short treatment interval predisposes to preterm birth is unclear. The structural integrity of the cervix may be diminished immediately after a cone procedure, limiting the ability of the cervix to support a pregnancy. With time, the cervix may scar or regenerate, minimizing the structural weakness of the cervix. Certainly, the association between shortened cervical length and preterm birth is well established.13,14 Additionally, there are numerous studies examining cervical length as determined by transvaginal ultrasonography after conization that reveal a shortened cervix after conization procedures.15,16 Mazouni et al16 found a mean cervical length after LEEP (within 7 days of procedure) of 24.3±6.7 mm. Interestingly, there are conflicting results about whether this shortening persists after LEEP. Some investigators have noted a trend toward cervical regeneration at 3–12 months after conization, which might minimize the risk of preterm birth after this period.17,18 The mechanisms by which a short cervix after conization might lead to subsequent preterm birth are not well understood. It is important to note that a short cervix by transvaginal ultrasonography is not unequivocally equivalent to a structurally weak cervix. A cervix that is short may be structurally quite sound. In fact, studies that have examined the efficacy of ultrasonography indicated that cerclage for shortened cervix has not shown benefit to cerclage.19,20
More plausibly, perhaps the immunologic milieu of the cervix is altered by a cone procedure. A cone procedure is associated with a significant inflammatory infiltrate. This inflammatory process may alter the cytokine environment early in pregnancy, predisposing a woman to ascending infection. Alternatively, perhaps the cone procedure itself introduces a low-grade infection that ultimately leads to an ascending infection. The cervix is not simply an anatomic barrier between the vagina and the uterus, but also an immunologic barrier that protects the uterus from ascending microbial invasion. A cervix that is surgically shortened may have an altered capacity to provide immune protection. Alternatively, a cervix that is surgically shortened may be more responsive to biochemical stimuli promoting preterm birth than a longer cervix. There are few data regarding the specific immunological and inflammatory processes involved in healing from conization, but, in general, wound healing, whether cutaneous or mucosal, is an intrinsically inflammatory process. Proinflammatory cytokines, matrix metalloproteinases, and prostaglandins are all increased in healing tissues. The nature and degree of inflammation in a healing wound abates over time.21,22 Perhaps establishing a pregnancy while the cervix is in the midst of healing inflammation has adverse functional consequences. Although the mechanism is not clear, there are biologically plausible reasons to support the idea that a short time interval from cone procedure to conception would increase a woman's risk for preterm delivery.
The disparity in preterm birth between white and African-American women is well established in the obstetric literature and remains poorly understood.23–26 Importantly, many confounders of preterm birth, such as prior preterm birth or tobacco use, were controlled for in our study, making the racial difference identified more compelling. Today's understanding of the biology of the racial disparity in preterm birth does not afford us the opportunity to explain this finding in our study. The persistence of risk for preterm birth among African-American women may have a real biological basis, or it may be an epiphenomenon with its underlying explanation in some other gene-environment interaction. To draw further conclusions in this regard would just be speculation.
The small number of women who underwent a cone procedure followed by a delivery is the most significant limitation of this study. Because of this small sample size, we are unable to characterize the magnitude of effect of a short treatment interval on subsequent pregnancy outcomes with as high a degree of precision as we would like. Consequently, we are unable to comment on whether there is a meaningful opportunity for intervention to decrease a woman's risk of preterm birth after LEEP or large loop excision by delaying her time to conception. Additionally, given the concern for second-trimester losses after cervical conization procedures, the inclusion of women after only 20 weeks gestation is another limitation of this study.
Finally, it is important to address the impact of short interpregnancy interval on preterm birth. The magnitude of increased risk of preterm birth with interpregnancy interval less than 6 months is estimated to be 30–60%.27–30 The relationship between short interpregnancy interval and preterm birth has been noted to be similar in magnitude and significance for African-Americans and white women.31,32 In the general obstetric population at low risk for adverse pregnancy outcomes, Adams et al33 found that short interpregnancy intervals are rare and are weak risk factors among low-risk women. In the segment of our cohort that did not undergo conization, there was no relation between short interval and subsequent preterm birth (data not shown). Thus, in this cohort short interpregnancy interval is unlikely to be a significant confounder of our finding of the relation between conization-to-conception interval and preterm birth.
In conclusion, this study identifies a subset of women who may be at higher risk of preterm delivery after their cone procedures. Future studies investigating the association between a short interval from conization to pregnancy would be helpful because this is a potentially modifiable risk factor for preterm birth.
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