Conner, Shayna N. MD; Cahill, Alison G. MD, MSCI; Tuuli, Methodius G. MD, MPH; Stamilio, David M. MD, MSCE; Odibo, Anthony O. MD, MSCE; Roehl, Kimberly A. MPH; Macones, George A. MD, MSCE
Department of Obstetrics and Gynecology, Washington University, St. Louis, Missouri.
Corresponding author: Shayna N. Conner, MD, Department of Obstetrics and Gynecology, Washington University School of Medicine, 4911 Barnes Jewish Hospital Plaza, Campus Box 8064, St. Louis, MO 63110; e-mail: email@example.com.
Supported by National Institutes of Health grant (5R01CA10918604 to G.A.M.). Dr. Conner is supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development T32 grant (22-3125-77026E) and the Washington University Institute of Clinical and Translational Sciences grant (UL1TR000448).
Presented as a poster at the annual meeting of the Society of Maternal Fetal Medicine, February 11–16, 2013, San Francisco, California.
Financial Disclosure The authors did not report any potential conflicts of interest.
Cervical excision procedures for diagnosis and treatment of cervical dysplasia are becoming increasingly common among women of reproductive age because of the prevalence of the human papillomavirus.1 Loop electrosurgical excision procedure (LEEP) is the most common cervical excision procedure currently used.2–4 The depth and breadth of the portion of cervix removed vary based on individual characteristics of the lesion; however, in most cases part of the cervical body, the complete transformation zone, and a portion of the endocervical canal are removed.2–4 Removing a portion of the cervix theoretically leaves future pregnancies at higher risk for complications related to cervical integrity.5,6 In addition, given that healing and remodeling from a LEEP occurs over time, it is biologically plausible that the time interval from LEEP to pregnancy is an important factor in determining risk for complications.
Previous studies have investigated the link between time interval from LEEP to pregnancy and pregnancy complications, with most relating to preterm delivery, with conflicting results.7–12 However, evidence of an association between time interval from LEEP to pregnancy and the effect on risk of spontaneous abortion is lacking.
In this study, we aimed to estimate the effect of length of time between LEEP and subsequent pregnancy on risk of preterm delivery and spontaneous abortion. This could potentially provide health practitioners with an evidenced-based guide to counseling women regarding the optimal timing of pregnancy after LEEP to optimize subsequent pregnancy outcomes.
MATERIALS AND METHODS
This study was a secondary analysis of a 10-year, multicenter, retrospective cohort study. Patients included in the primary study were women who underwent LEEP, a Pap test, or a cervical biopsy in one of nine centers (both tertiary and community) from 1996 to 2006. The parent study compared women with a previous LEEP to women in two age-matched control groups, women without a history of cervical dysplasia, and women with a history of cervical biopsy without LEEP for the primary outcome of preterm birth before 34 weeks of gestation. After approval by the Institutional Review Boards at each center, patients were identified through review of pathology records through a search of clinical databases of surgical pathology. All pathology records and medical records were obtained and reviewed in detail. Trained obstetric research nurses conducted structured closed-ended telephone interviews with each patient to complete demographic, historical, and obstetric data unavailable in the medical record. Data obtained included information regarding patient medical and surgical history, obstetric and gynecology history, prenatal history, antepartum records, and delivery records.
In this study, all women who had undergone LEEP and had a subsequent pregnancy during the study period were included. The pregnancy evaluated in this analysis was the first pregnancy after LEEP. Women were excluded from analysis if the index pregnancy was a multiple gestation, if medical records were missing, or if the date of LEEP or delivery was unknown. Pregnancies were dated by the woman's last menstrual period if that date was within 7 days of a first-trimester ultrasound examination or within 10 days of a second-trimester ultrasound examination. Pregnancies were dated by ultrasonography if the last menstrual period was unknown or if the ultrasound dating was outside the aforementioned parameters. Spontaneous abortion was defined as a spontaneous pregnancy loss at less than 20 weeks postmenstrual age. All diagnoses of spontaneous abortion were confirmed by review of medical records including positive human chorionic gonadotropin or ultrasound documentation. If a discrepancy was found between patient report of spontaneous abortion and the medical records, the medical record was used. Induced abortions were excluded. Two study groups were defined by time interval from LEEP to pregnancy: women with an interval less than 12 months compared with an interval of 12 months or longer. The 12-month time interval was chosen based on results from a previous study.7 Outcomes compared between groups were spontaneous abortion before 20 weeks of gestation and preterm delivery before 37 weeks of gestation and before 34 weeks of gestation. We performed secondary analyses for time interval strata of less than 6 months, 6–11 months, 12–23 months, and 24 months or more.
Median time elapsed from LEEP to pregnancy was calculated and compared for women with a spontaneous abortion and no spontaneous abortion and women with preterm birth before 37 weeks of gestation and before 34 weeks of gestation compared with term birth. Women with spontaneous abortion were further stratified by gestational age at time of spontaneous abortion: those who were before 12 weeks of gestation and those who were 12–19 weeks of gestation compared with women without a spontaneous abortion. Baseline characteristics were compared between groups using χ2 or Fisher exact test for categorical variables, and Student t test or Mann–Whitney U test was used for continuous variables as appropriate. Normality was tested with the Kolmogorov–Smirnov test. Stratified analyses were performed to identify potentially confounding variables. Incidence, crude relative risk, and 95% confidence interval (CI) for each of the primary outcomes were calculated. Multivariable logistic regression was used to adjust for confounding factors identified through the results of the univariable and stratified analyses. Backwards stepwise selection was used to reduce the number of variables. Fits of the final models were tested with the Hosmer and Lemeshow goodness of fit test. Tests with P<.05 were considered statistically significant. All statistical analyses were completed using STATA software 10.0.
In all, 596 women who underwent LEEP and who had subsequent pregnancy during the study period met inclusion criteria. The interval from LEEP to pregnancy was less than 12 months for 56 women (9.4%) and was 12 months or more for 540 women (90.6%). The overall rates of the primary outcomes were 6% for spontaneous abortion, 8.7% for preterm birth before 34 weeks of gestation, and 18.1% for preterm birth before 37 weeks of gestation. Baseline characteristics of the study groups were only significantly different with respect to age and body mass index. Women with a LEEP-to-pregnancy interval of less than 12 months were younger and thinner compared with those with an interval of 12 months or more. Rates of previous preterm birth, smoking, and African American race were not significantly different between the two groups (Table 1).
The median time to pregnancy for the entire cohort was 30.8 months (interquartile range 18.4–50.7). Overall, women with spontaneous abortion had a shorter median time interval from LEEP to pregnancy compared with women without spontaneous abortion (20.3 months [interquartile range 11.2–40.9] compared with 31.2 months [interquartile range 18.7–51.2]; P=.01). There were 35 reported and confirmed spontaneous abortions before 20 weeks of gestation: 30 before 12 weeks of gestation and 5 at 12–19 weeks of gestation. When we stratified the analysis by these two gestational age range categories, we continued to find a significantly shorter LEEP-to-pregnancy median time interval for women with spontaneous abortion before 12 weeks of gestation (17.9 months [interquartile range 8.9–40.9] compared with 31.2 months [interquartile range 18.7–51.2]; P<.01). However, there was no difference in time interval for women with spontaneous abortion at 12–19 weeks of gestation compared with women without spontaneous abortion (33.0 months [interquartile range 23.4–40.6] compared with 31.2 months [interquartile range 18.7–51.2]; P=.85). However, median time intervals were not significantly different for preterm birth before 37 weeks of gestation and before 34 weeks of gestation compared with term births (Table 2).
Compared with women with a LEEP-to-pregnancy interval of 12 months or more, a time interval of less than 12 months was associated with an increased risk for spontaneous abortion of more than five-fold (17.9% compared with 4.6%; adjusted odds ratio [OR] 5.6; 95% CI 2.5–12.7), but not with preterm birth before 37 weeks of gestation (26.2% compared with 19.1%; adjusted OR 1.5; 95% CI 0.7–3.1) or before 34 weeks of gestation (16.2% compared with 9.7%; adjusted OR 1.8; 95% CI 0.7–4.5). The initial logistic regression models for spontaneous abortion and preterm birth were adjusted for age, body mass index, previous spontaneous abortion (or previous preterm birth), race (for preterm birth only), and smoking. However, only age remained significant for adjustment in the final regression models (Table 3).
In secondary analyses, women were further stratified into interval strata of less than 6 months, 6–11 months, 12–23 months, and they were compared with those women with a LEEP-to-pregnancy interval of 24 months or more. There was an inverse dose–response relationship between category of LEEP-to-pregnancy interval and spontaneous abortion (P for trend ≤.01). Women with a time interval less than 6 months from LEEP to pregnancy were at significantly increased risk for spontaneous abortion (42.9% compared with 4.3%; OR 16.8; 95% CI 3.5–81.6), but not preterm birth. Similarly, women with a time interval of 6–11 months were also found to be at increased risk for spontaneous abortion compared with those with the reference interval of 24 months or more (14.3% compared with 4.3%; OR 3.7; 95% CI 1.4–9.6). However, the increased risk of spontaneous abortion in women with a time interval of 12–23 months compared with those with an interval of 24 months or more was not statistically significant (5.5% compared with 4.3%; OR 1.3; 95% CI 0.6–3.0) (Table 4).
We found that women with a time interval from LEEP to subsequent pregnancy occurring in less than 12 months are at significantly increased risk for spontaneous abortion, but not preterm birth. Women who became pregnant within 12 months of the LEEP procedure were at more than five-fold increased risk compared with those who became pregnant after 12 months, even after adjusting for potential confounding factors.
Previous studies have been performed investigating the time interval from LEEP to pregnancy and the effect on preterm birth. Although some of the studies have reported an increased risk for preterm birth with a shorter interval,7–9 others have found no such association.10–12 Himes et al7 performed a retrospective study examining the effect of time interval from LEEP to pregnancy on spontaneous preterm birth. They found a significantly increased risk for spontaneous preterm birth for women with an interval less than 12 months compared with 12 months or more. However, this study had a limited sample size, reducing the precision of their risk estimates, and did not examine the risk of spontaneous abortion. Other studies that found a link between preterm birth and short interval from LEEP to pregnancy did not adjust for previous preterm birth, which could have confounded their results.8,9 In the most recent study that investigated the role of time interval in preterm birth risk, Heinonen et al12 found no association and their results were strengthened by their large numbers and adjusted analysis.
Although the effect of LEEP-to-pregnancy interval on risk of preterm birth has been investigated to an extent in the literature, only two studies, to our knowledge, reported rates of spontaneous abortion in women with a history of cervical excision.13,14 In 1979, Weber et al13 reported higher rates of spontaneous abortion in women with a history of a conization compared with women in an age-matched control group (20.4% compared with 9.0%). Later, Tan et al14 reported similar rates of spontaneous abortion in women with a history of LEEP compared with women in the control group. Despite these limited reports, there are no studies that investigate the risk of spontaneous abortion as it relates to the LEEP-to-pregnancy interval.
Compared with previous studies of this subject, our study offers unique strengths. Importantly, our study is the first to examine the effect of LEEP-to-pregnancy interval on risk of spontaneous abortion. Our study was a secondary analysis of a multicenter cohort that included both tertiary and community centers, increasing the generalizability and providing large numbers of women with a history of LEEP for analysis. In addition, the meticulous data gathering through patient interview and confirmation with medical records increased our the interval validity of our study by decreasing recall bias and allowed us to collect data regarding multiple confounding factors. By performing secondary analysis after further stratifying by time interval, we were able to more precisely identify the interval with the most risk for spontaneous abortion. Another strength of our study was the small amount of missing data; only 3% of our cohort was excluded for missing data regarding time interval from LEEP to pregnancy outcome.
The potential limitations of our study must be considered as well. By definition, the retrospective nature of our study limited the available data to that which were already collected. However, the data collected were robust and allowed us to evaluate relevant baseline maternal characteristics and to adjust for known confounders. Additionally, it is important to note that the number of spontaneous abortions in the group with an interval of 12 months or more was lower than expected. Patients with an interval of 12 months or more had a spontaneous abortion rate of 4.6%, which is much lower than would be anticipated in the general population, compared with the spontaneous abortion rate of 17.9% for patients with an interval of less than 12 months, possibly reflecting a degree of recall bias. Because of the relatively small number of women in the cohort with a LEEP-to-pregnancy interval of less than 6 months (n=7), although we were able to demonstrate a possible dose–response relationship with intervals less than 12 months, the CIs are wide and risk estimates should be interpreted with caution. Therefore, although women with an interval less than 12 months are at more than five-fold increased risk for spontaneous abortion, those with intervals less than 6 months may be at even higher risk. Another important consideration is that our negative findings with respect to preterm births as well as spontaneous abortions at 12–19 weeks of gestation may be secondary to inadequate power.
Our study found that women with a shorter LEEP-to-pregnancy interval are at increased risk for spontaneous abortion but not for preterm birth before 37 weeks of gestation or before 34 weeks of gestation. The exact mechanism that would lead to spontaneous abortion after LEEP is unknown but may be related to structural changes, and the pathogenesis deserves future study. The negative findings with respect to preterm birth are not unexpected and confirm previous rigorously performed studies on the subject.12 From the results of our study, we have identified multiple potential areas for further research. Some may question why interval from LEEP to pregnancy would influence risk of spontaneous abortion but not preterm delivery. We postulate that spontaneous abortion and preterm birth occur through different mechanisms and have differing risk factors; however, this hypothesis merits future research. In addition, by definition, the further a patient progresses in gestation, the more time the cervix has had to heal from the LEEP. Therefore, the pathogenesis could potentially be investigated as it relates to cervical length or inflammation. Another potential area for future investigation involves the relationship between size of LEEP specimen excised and risk for spontaneous abortion, given that previous studies have demonstrated that cervical regeneration after LEEP is dependent on size of previous excision.15,16 Our findings indicate that time interval from LEEP to pregnancy could potentially affect the risk of spontaneous abortion, and an interval of 12 months or more appears to be associated with the lowest risk. Additionally, if confirmed in other studies, patients can be reassured that the time interval from LEEP to pregnancy does not increase the risk for preterm delivery.
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© 2013 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.