The current body of literature concerning cervical conization and its effect on subsequent pregnancy outcome is conflicting. Depending on the type of conization procedure that is examined and the quality of the control group, the results and conclusions vary widely. Because treatment for cervical intraepithelial neoplasia is commonplace among women of reproductive age, it is imperative that practitioners have an understanding of the issues surrounding the treatment. Therefore, this review will summarize the published literature that addresses excisional procedures of the uterine cervix and the risk of preterm delivery in subsequent pregnancies and provide reasonable treatment recommendations for women with cervical abnormalities and a desire for future fertility.
Since inception, screening programs that use Papanicolaou smear tests have decreased the incidence of cervical cancer in the United States by >50%. The unprecedented success of this program hinges not only on the sensitivity of the Papanicolaou smear test, but also on the ability to eliminate successfully the precancerous lesions that are detected by the screening test. Cervical intraepithelial neoplasia (CIN) is encountered most commonly among women of reproductive age; a peak incidence occurs among women in their twenties. Because of the 5-12% chance of progression to squamous cell cancer, management guidelines recommend aggressive treatment for women with moderate-to-severe dysplasia. Because many women in this age group have not yet completed childbearing at the time of diagnosis, treatment for these cervical abnormalities has potentially significant reproductive consequences. Many reports that have investigated this issue have been uncontrolled observational studies with small sample sizes, which makes them difficult to interpret. Therefore, this review will summarize the published literature regarding the effects of cervical conization on the risk of preterm delivery (PTD) in future pregnancies and provide reasonable treatment recommendations for women with cervical dysplasia.
Methods
English-language studies in PubMed and Medline were identified by the search terms conization, preterm delivery, cervical dysplasia, pregnancy outcome, preterm birth , and cervical ablation . The references of the resulting articles were then searched manually for further pertinent publications. All study types were considered for inclusion, provided the subject matter was pertinent to the focus of this review.
Treatment modalities for CIN
Historically, the treatment of choice for moderate-to-severe CIN was the cold knife cone (CKC). Its application predated modern colposcopic practice and the widespread availability of electrocautery and laser technology. However, its modern applicability has been limited by high cost, significant intraoperative and postoperative bleeding, substantial perioperative infectious risk, a high level of technical difficulty, and a recognized association with postprocedure cervical stenosis. As a result of these limitations, alternative excisional and ablative procedures were developed that include the laser conization, the loop electrosurgical excisional procedure (LEEP), and various methods of ablation. The laser conization had the advantage of being performed under local anesthesia with less associated bleeding and more accurate tailoring of cone size. However, the thermal damage that was inflicted on the tissue specimen potentially could make pathologic evaluation of the margins impossible. With the advent of widely available electrocautery, the LEEP gradually replaced the CKC as the treatment of choice for CIN. Several studies have documented its advantages over CKC in that it is less expensive, technically easier, less painful, associated with less hemorrhage, and can be performed in an office setting with similar efficacy. Additionally, in contrast to the laser cone, the tissue specimen is more adequate for pathologic evaluation of the surgical margins.
Ablative techniques that are used to treat cervical dysplasia include laser ablation, cryotherapy, electrofulguration, and cold coagulation. Although these ablative techniques provide no tissue specimen for pathologic evaluation and can be applied only to a certain subset of patients, they appear to have similar efficacy with respect to the elimination of CIN and reduction of the risk of progression to cancer. A Cochrane Review about the surgical treatment of CIN reviewed 28 trials that compared the efficacy of both ablative and excisional treatment techniques and concluded that no method was more efficacious than any other. Therefore, the selection of ablative techniques vs excisional techniques should be based on the severity of disease, the adequacy of the colposcopic examination, the histologic findings of the biopsy, the appropriate correspondence of the cytologic and histologic evidence, and the desire for future childbearing.
CKC
It was recognized as early as 1938 that conization may have a negative impact on future pregnancy, with higher incidences of PTD and other complications. Early studies that investigated the association between CKC and obstetric complications were contradictory. Since that time, significant data have been published that has solidified the increased obstetric risk after CKC. A retrospective analysis by Klaritsch et al in 2006 evaluated the risk of PTD and obstetric complications in women with a history of cold knife conization of the cervix relative to the general obstetric population in Austria. The investigators reported PTD in 22.4% of 76 deliveries in the conization group compared with 6.6% of 29,711 deliveries in the general obstetric population (odds ratio [OR], 4.07; 95% confidence interval [CI], 2.22–7.10; P < .001). They further reported nearly an 8-fold increased risk of both preterm premature rupture of membranes (OR, 7.70; 95% CI, 3.87–14.21; P < .001) and cervical tears (OR, 7.53; 95% CI, 2.63–17.57; P < .001) but no significant increase in the risk of cesarean delivery, low birthweight, or duration of labor.
Because many confounding variables such as smoking, sexually transmitted diseases, maternal marital status, and socioeconomic status serve as important risk factors for both CIN and PTB, drawing conclusions from retrospective studies with the use of the general obstetric population as control subjects can be misleading. Kristensen et al attempted to address this issue by including patients with deliveries before conization. The investigators divided the cohort of 14,223 Danish women into 4 groups: those who had their conization before first delivery, those who had it between their first and second deliveries, those who had it after 2 deliveries, and those with no history of conization. The 170 women with a history of CKC, regardless of timing of the procedure, experienced a higher incidence of PTD. Although this risk was higher in women who underwent conization before pregnancy, women who underwent CKC subsequent to both deliveries also had a slightly increased risk of PTD in the precedent pregnancies, when compared with the general population. The authors therefore concluded that CKC was associated with a higher rate of PTB, but that factors other than surgical intervention may contribute to the observed risk. To further elucidate this issue, El-Bastawissi et al retrospectively compared women who had carcinoma in situ of the cervix who were not treated with conization with those women who received the prescribed therapy. Importantly, this study reported no increased risk of preterm birth or cesarean delivery in women with untreated carcinoma in situ over the general population. It did demonstrate, however, an increase in PTD and cesarean delivery among women with a history of conization (OR, 1.6; 95% CI, 1.2–2.0). Bruinsma et al also attempted to clarify the relationship between cervical dysplasia and PTD by reporting on women who underwent treatment for the precancerous changes and women who remained untreated. In contrast to the study just discussed, these authors reported an increased risk among women with untreated cervical dysplasia, compared with the general population (standardized prevalence ratio, 1.5; 95% CI, 1.4–1.7), with an even higher risk among those women who underwent treatment (OR, 2.0; (95% CI, 1.8–2.3). However, once the authors controlled for confounding factors that included marital status, history of multiple induced abortions or miscarriages, maternal age, major maternal medical condition, and illicit drug use, neither group had an increased risk. Despite multiple attempts to clarify this issue, it remains unclear which factors play the greatest role in the risk of PTD and adverse obstetric outcomes in women with cervical dysplasia.
A search of the published literature revealed 2 metaanalyses that addressed obstetric outcome after cervical surgery (ie, CKC, LEEP, laser ablation, laser conization). Both studies reported an increased risk of PTD (relative risk [RR], 2.59; 95% CI, 1.8–3.72; RR, 2.78; 95% CI, 1.72–4.51) and low birthweight (RR, 2.53; 95% CI, 1.19–5.36; RR, 2.86; 95% CI, 1.37–5.97) in patients with a history of CKC. The metaanalysis by Kyrgiou et al also reported a significantly increased rate of cesarean delivery (RR, 3.17; 95% CI, 1.07–9.40). The report published by Arbyn et al in 2008 evaluated the incidence of perinatal death, early PTD (<32-34 weeks of gestation), very early PTD (<28-30 weeks of gestation), and low birthweight (<2000 g) and reported that a history of CKC was associated with increased perinatal mortality rates, severe PTD, extreme PTD, and low birthweight. The results of studies that evaluated CKC and obstetric outcomes are summarized in Table 1 .
| Study | Study type | Patients, n | Control subjects | Preterm deliveries | |
|---|---|---|---|---|---|
| Relative risk (95% CI) | Odds ratio (95% CI) | ||||
| Jones et al, 1979 | Retrospective | 66 | General population | 3.4 (1.7–7.1) | |
| Moinian et al, 1982 a | Retrospective | 414 | Internal/precedent pregnancies | 1.3 (0.4–4.4) | |
| Buller and Jones, 1982 a | Retrospective | 61 | Internal | NA | |
| Ludviksson and Sandstrom, 1982 | Retrospective | 79 | General population | NA | |
| Larsson et al, 1982 | Retrospective | 197 | Internal/precedent pregnancies | 3.0 (1.7–5.3) | |
| Kuoppala and Saarikoski, 1986 a | Retrospective | 77 | General population | 4.0 (0.5–35) | |
| Kristensen et al, 1993 | Retrospective | 170 | Internal + external | 4.13 (2.53–6.75) | |
| Klaritsch et al, 2006 | Retrospective | 65 | General population | 4.1 (2.22–7.10) | |
| Kyrgiou et al, 2006 | Metaanalysis | 704 | All | 2.59 (1.80–3.72) | |
| Arbyn et al, 2008 | Metaanalysis | 761 | All | 2.87(1.42–16.66) | |
Laser conization
Because of the growing concerns regarding CKC and technologic advances, laser conization became an increasingly popular alternative for the treatment of cervical dysplasia. Hagen and Skjeldestad in 1993 were the first investigators to report an increased rate of PTD in patients who underwent laser conization. In this series of 56 women with a history of laser conization who delivered after 22 weeks gestation, the authors demonstrated a 38% rate of PTD among cases, compared with 6% in matched control subjects (OR, 9.0; 95% CI, 3.7–21.7). Other investigators have demonstrated conflicting results. Sadler et al in 2004 reported an increased risk of preterm premature rupture of membranes among women who underwent laser conization with an adjusted RR of 2.7 (95% CI, 1.3–5.6) but failed to demonstrate an increase in spontaneous preterm deliveries (adjusted RR, 1.3; 95% CI, 0.8–2.2). Other studies found similar results including Sagot et al who examined 71 pregnancies in 54 women before laser conization and compared them with 82 pregnancies after the procedure. The authors reported no significant difference in the rate of PTD (13.2% vs 8.5%) or premature rupture of membranes (1.9% vs 0%) before and after treatment but detected a reduced rate of vaginal term deliveries after conization (90% vs 73.6%; P = .025). This study used patients as their own historic control subjects, thus strengthening the results by addressing many confounders that are associated with both cervical dysplasia and preterm birth.
Although studies by Raio et al and Sadler et al reported no overall increase in preterm birth after laser conization, both studies further analyzed outcomes based on cone height and independently detected increased risk for poor obstetric outcome with larger cone size. Raio et al demonstrated an increased risk of PTD in women with a cone height of ≥10 mm, whereas Sadler et al reported a 3-fold increase in risk of preterm premature rupture of membranes and subsequent PTD in women with a cone height of ≥1.7 cm. Finally, one retrospective study assessed the risk of low birthweight in 65 patients with a history of CO 2 laser conization and reported a 2.2 RR (95% CI, 1.04–4.5) for birthweight <2500 g, a 3.5 RR (95% CI, 1.02–12.0) for birthweight <2000 g, and a 10.0 RR (95% CI, 1.2–85.6) for weight <1500 g, which provides further, albeit different, supporting evidence to indicate poor obstetric outcomes in patients with a history of laser conization for cervical dysplasia.
LEEP
As mentioned earlier, the technical simplicity, decreased blood loss, and outpatient nature of the procedure have all contributed to LEEP becoming the treatment modality of choice for cervical dysplasia. Because of its widespread application, LEEP has the farthest reaching implications for public health impact and therefore should be considered most carefully. Despite the significant volume of data that are available, the effects of LEEP on pregnancy outcomes remain controversial, with evidence supporting both sides of the debate ( Table 2 ). Sjoborg et al published a multiinstitutional retrospective case-control study that evaluated the cases of 742 women with a history of either LEEP or laser conization. In this series, the authors reported the risk of giving birth before 37, 32, and 28 weeks of gestation after treatment with either laser conization or LEEP and compared those rates to control subjects in the general obstetric population. After adjustment for smoking habits, education level, and marital status, the ORs in the treatment group were 3.4 (95% CI, 2.3–5.1), 4.6 (95% CI, 1.7–12.5), and 12.4 (95% CI, 1.6–96.1) for each gestational age, respectively. The authors further reported increased rates of low birthweight and preterm rupture of membranes in women who underwent either excisional procedure relative to control subjects.
