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Reproductive effects of cervical excisional and ablative procedures

Reproductive effects of cervical excisional and ablative procedures
Literature review current through: Jan 2024.
This topic last updated: Jul 10, 2023.

INTRODUCTION — Cervical cancer precursors (figure 1) (eg, cervical intraepithelial neoplasia 2,3 [CIN]; high-grade squamous intraepithelial lesions [HSIL]) are typically managed with an ablative or excisional procedure; surveillance (with cervical cytology and colposcopy) is an option for some patients. In excisional procedures (cold knife conization; loop electrosurgical excision procedure [LEEP], also called large loop excision of the transformation zone [LLETZ]; laser conization), a segment of the cervix is removed and examined histologically. In ablative procedures (cryotherapy, laser, cold coagulation, diathermy), the tissue is destroyed but remains in place; no histologic confirmation of the diagnosis is performed.

Treatment of CIN has been associated with subsequent cervical stenosis, second-trimester pregnancy loss, and preterm birth. These risks are higher with excisional compared with ablative procedures and increase with increasing weight and volume of tissue removed. This topic will review the potential reproductive consequences of prepregnancy treatment of cervical cancer precursors, which will be described by the term "CIN" in this topic.

General principles of management of these lesions and treatment techniques are discussed separately.

(See "Cervical intraepithelial neoplasia: Management".)

(See "Cervical intraepithelial neoplasia: Choosing excision versus ablation, and prognosis and follow-up after treatment".)

(See "Cervical intraepithelial neoplasia: Diagnostic excisional procedures".)

(See "Cervical intraepithelial neoplasia: Ablative therapies".)

POSSIBLE MECHANISMS FOR ADVERSE REPRODUCTIVE EFFECTS — Removal or destruction of cervical tissue may involve both the stroma and cervical glands. Hypotheses regarding how changes in cervical tissue potentially affect reproductive function have not been thoroughly investigated.

Removal/destruction of a large portion of the stroma may result in scarring and loss of cervical plasticity (cervical stenosis), which may affect cervical function. (See 'Cervical stenosis' below.)

Removal/destruction of a large portion of the stroma may also decrease the tensile strength of the cervix, either because of loss of stroma or differences in collagen expression in regenerated stroma during healing [1]. Normal tensile strength is likely important for maintaining a pregnancy until term. (See 'Second-trimester pregnancy loss' below and 'Preterm birth' below.)

Removal/destruction of cervical glands may alter the cervical mucus by reducing the quantity or decreasing the secretion of antimicrobial compounds into the mucus. Changes in cervical mucus, as well as decreased tensile strength of the stroma, may facilitate migration of cervicovaginal flora across the cervix and into the uterine cavity during pregnancy. (See 'Second-trimester pregnancy loss' below and 'Preterm birth' below.)

Theoretically, the integrity of the cervix is better preserved following ablation than excision, and some analyses have found a lower frequency of adverse obstetric outcomes after ablative procedures [2]. In one population-based cohort study examining pregnancy outcomes in patients with CIN 3 from 1973 to 2018, those performed later compared with earlier in the study period had lower rates of adverse pregnancy outcomes, likely because of changes in treatment practices (eg, a trend towards fewer cold knife conizations and more LEEPs, which can be associated with removal of less cervical tissue) [3].

However, cervical integrity is not the only factor. Some of the increased risk for adverse reproductive effects has been attributed to cervical intraepithelial neoplasia (CIN) itself or characteristics of patients who develop CIN (eg, smoking, bacterial vaginosis, low socioeconomic status, human papillomavirus [HPV] infection). This is discussed in more detail below. (See 'Preterm birth' below.)

ADVERSE REPRODUCTIVE EFFECTS OF PROCEDURES PERFORMED BEFORE PREGNANCY

Cervical stenosis — Cervical stenosis may impede menstrual flow, passage of instruments (eg, cannula) through the endocervical canal, and adequate visualization of the transformation zone. There is also a theoretical concern that migration of sperm into the uterine cavity will be impeded, although this risk is likely very small.

Cervical stenosis may also impede cervical dilation during labor or render the fetal membranes more vulnerable to shearing forces, potentially leading to preterm prelabor rupture of membranes (PPROM).

Following excisional procedures for cervical intraepithelial neoplasia (CIN), cervical stenosis has been reported in up to 8 percent of patients. Risk factors include the amount of tissue removed (eg, incision depth of ≥1 to 2 cm has been associated with cervical stenosis) and postmenopausal status [4-11]. (See "Cervical intraepithelial neoplasia: Diagnostic excisional procedures", section on 'Late complications'.)

After cryotherapy or laser ablation, cervical stenosis is much less common (≤1 percent). (See "Cervical intraepithelial neoplasia: Ablative therapies", section on 'Late complications'.)

Second-trimester pregnancy loss — A past history of treatment for CIN appears to be associated with an increased risk for second-trimester pregnancy loss, but not with ability to conceive or first-trimester pregnancy loss. In a meta-analysis of 15 studies, mostly retrospective, comparing outcomes of patients treated with any type of treatment for CIN versus no treatment, the risk for second-trimester pregnancy loss in treated and untreated patients was 1.6 and 0.4 percent, respectively (relative risk [RR] 2.60, 95% CI 1.45-4.67), and the risk for first-trimester pregnancy loss in treated and untreated patients was 9.8 and 8.4 percent, respectively (RR 1.16, 95% CI 0.80-1.69) [12]. Among patients with an intention to conceive, pregnancy rates were similar whether or not they had been treated for CIN. However, these findings need to be interpreted with caution given the low quality of the data. For example, the meta-analysis was not able to adjust for the size of excised cervical tissue and the outcomes for each individual technique.

Subsequently, a large population-based study based on Norwegian registry data evaluated pregnancy outcomes associated with specific treatments for CIN and found that prior excisional treatment, compared with no treatment, was associated with an increased risk of pregnancy loss between 16 and 22 weeks (0.5 versus 0.2 percent, hazard ratio [HR] 2.6, 95% CI 1.7-3.8), particularly after loop electrosurgical excision procedure (0.4 versus 0.2 percent, HR 3, 95% CI 1.8-5.3) or laser conization (0.6 versus 0.2 percent, HR 2.3, 95% CI 1.3-4) [13]. Increasing weight and volume of removed tissue increased the risk for pregnancy loss, although the trend was not statistically significant. First-trimester loss was not evaluated.

No data are available regarding second-trimester pregnancy loss in patients treated for CIN specifically with ablative methods. These data are limited since second-trimester pregnancy losses are uncommon and birth registries do not usually collect information on pregnancies terminating before 20 or 22 weeks of gestation.

Preterm birth — Meta-analyses have generally concluded that treatment of CIN is associated with an increased risk for spontaneous preterm birth (PTB) and its sequelae [2,14-17]. PTB is related, at least in part, to an increased risk for PPROM.

For example, a 2017 meta-analysis of retrospective studies of obstetric outcomes after excisional and ablative treatments for CIN (including microinvasive disease [stage IA1]) reported the following major findings for treated versus untreated patients; the quality of evidence was very low or low [15]:

PTB <37 weeks (9.5 versus 5.4 percent, RR 1.75, 95% CI 1.57-1.96)

PTB <32 to 34 weeks (3.2 versus 1.4 percent, RR 2.25, 95% CI 1.79-2.82)

PTB <28 to 30 weeks (0.7 versus 0.3 percent, RR 2.23, 95% CI 1.55-3.22)

PPROM (8 versus 3.4 percent, RR 2.36, 95% CI 1.76-3.17)

Neonatal intensive care unit admission (13 versus 8.9 percent, RR 1.45, 95% CI 1.16-1.18)

Perinatal mortality (1.1 versus 0.7 percent, RR 1.51, 95% CI 1.13-2.03)

In addition:

The overall risk for PTB was higher in patients who had excisional rather than ablative techniques (11.2 versus 7.7 percent) and who had repeat treatment (13.2 percent). All three groups had a higher risk of PTB than the no treatment groups (4.6 to 5.5 percent). A network meta-analysis was not performed.

The risk of PTB increased with more radical excisional techniques (cold knife conization RR 2.70, 95% CI 2.14-3.40; laser conization RR 2.11, 95% CI 1.26-3.54; large loop excision of the transformation zone RR 1.58, 95% CI 1.37-1.81). A network meta-analysis was not performed.

The risk of PTB increased with increasing cone depth (<10 to 12 mm: 7.1 percent; >10 to 12 mm: 9.8 percent; >15 to 17 mm: 10.1 percent; ≥20 mm: 10.2 percent).

Of note, the rate of cerclage was higher in patients treated with excisional and ablative treatments than in untreated patients (4 versus 0.7 percent, RR 14.3, 95% CI 2.9-71.6). Among patients with multiple gestations, prior treatment was associated with a significant increase in risk of PTB <28 weeks, but not <37 or <32 to 34 weeks, compared with no prior treatment.

In a subsequent network meta-analysis including over 68,000 patients with CIN or stage IA1 cervical cancer from 29 randomized and observational studies, while patients treated with excisional techniques compared with no treatment had higher rates of PTB (cold knife cone: odds ratio [OR] 2.3, 95% CI 1.7-3; laser conization: OR 1.8, 95% CI 1.3-2.4; LLETZ: OR 1.4, 95% CI 1.2-1.6), rates of PTB were similar for patients undergoing ablation methods (ie, laser ablation, cryotherapy, cold coagulation) compared with no treatment [18]. However, rates of treatment failure (ie, continued abnormal histology or cytology) were higher with ablative methods. This is discussed in detail separately. (See "Cervical intraepithelial neoplasia: Choosing excision versus ablation, and prognosis and follow-up after treatment", section on 'Is excision more effective than ablation?'.)

Studies of the outcomes of CIN treatment that use patients with untreated CIN as a control group tend to report a lower relative risk of PTB than studies that use patients with no history of CIN as controls. In the meta-analysis discussed above, untreated patients with CIN and the pretreatment pregnancies of patients who were subsequently treated for CIN were at higher risk for PTB than the general population (5.9 versus 5.6 percent, RR 1.24, 95% CI 1.14-1.34) [15]. In a subsequent observational cohort study including over 31,000 females identified from a Dutch pathology registry, rates of spontaneous PTB were also higher among patients with treated CIN compared with untreated CIN (9.5 versus 6.9 percent, OR 1.5, 95% CI 1.3-1.8) and controls (9.5 versus 4.8 percent, OR 2.1, 95% CI 1.9-2.3) [19].

The increased risk for spontaneous PTB may also be related to CIN itself or characteristics of patients who develop CIN (eg, smoking, bacterial vaginosis, low socioeconomic status, high-risk human papillomavirus [HPV] subtypes) [15,20,21]. In one systematic review, maternal HPV infection was associated with an increased risk of PTB (OR 1.7, 95% CI 1.4-2.1, 22 observational studies), PPROM (adjusted OR 1.4, 95% CI 1.1-1.9, six observational studies), and other adverse pregnancy outcomes compared with maternal controls [22]. In a secondary analysis of a randomized trial analyzing effects of HPV vaccination, HPV-vaccinated compared with HPV-unvaccinated patients had lower rates of early PTB (<32 weeks gestation; 0 per 409 versus 20 per 1923 patients) [20]. While overall PTB (<37 weeks gestation) rates also trended lower for HPV-vaccinated patients, this was not statistically significant.

However, these factors do not explain the overall high global PTB rate, which is likely the result of multiple maternal and fetal factors and is discussed in detail separately. (See "Spontaneous preterm birth: Overview of risk factors and prognosis".)

TIMING OF CONCEPTION AFTER TREATMENT OF CIN — Intuitively, the cervix should be healed before the patient attempts to conceive; however, the appropriate period of time to allow for proper healing to optimize pregnancy outcome is unknown. We suggest that patients wait at least three months postprocedure, but this recommendation is based on limited data and expert opinion.

Maternal age should be taken into account since waiting may have a greater negative impact on fertility in patients in their mid to late 30s than among younger patients. It is not known whether other factors, such as the type of procedure (excision versus ablation) and the volume of tissue removed, should be considered in conception timing.

Several large or registry-based studies reported that the risk of preterm birth (PTB) was not associated with the time since loop electrosurgical excision procedure (LEEP) [13,23-25]. By comparison, a case-control study concluded that conceiving within 2 to 3 months of conization may be associated with an increased risk of PTB [26], and a population-based study noted that the risk of PTB was highest in patients who delivered <12 months from excisional surgery (risk ratio 3.26, 95% CI 1.41-7.53) [27].

In addition, two studies reported that patients with a LEEP-to-pregnancy interval <12 months were at increased risk for miscarriage compared with an interval >12 months (17.9 versus 4.6 percent, adjusted odds ratio [OR] 5.6, 95% CI 2.5-12.7 [24]; 28.2 versus 13.4 percent, adjusted OR 2.60, 95% CI 1.57-4.3 [28]).

OBSTETRIC MANAGEMENT IN PREGNANCIES AFTER TREATMENT OF CIN

General principles

Patients with a history of removal or destruction of cervical tissue for treatment of cervical intraepithelial neoplasia (CIN) should be counseled about their risks for preterm birth (PTB) and second-trimester pregnancy loss. Importantly, these risks increase as the weight and volume of removed or destroyed tissue increases; thus, the risks are highest in patients who have undergone an excisional procedure (cold knife conization, loop electrosurgical excision procedure [LEEP]/large loop excision of the transformation zone [LLETZ], laser conization). Ablative procedures (cryotherapy, laser, cold coagulation, diathermy) appear to have no or minimal increase in risk. (See 'Preterm birth' above and 'Second-trimester pregnancy loss' above.)

Prenatal care after treatment of CIN is routine, except we consider serial transvaginal sonographic monitoring of cervical length in patients who have had an excisional procedure because of their increased risk for pregnancy loss and PTB; guidelines for monitoring these pregnancies have not been published. Second-trimester transvaginal ultrasound examination identification of a short cervix is predictive of an increased risk of PTB whether or not the patient has had treatment of CIN [29,30]. (See 'Monitoring for cervical shortening' below.)

We would not perform a prophylactic cerclage based solely on a history of an excisional treatment of CIN as the utility of cerclage in this setting has not been well studied and its use is associated with perinatal risks. In one retrospective study of patients with a previous conization, the rate of PTB was similar in those with and without a prophylactic cerclage (23 versus 21 percent) [31]. However, we may place an ultrasound-indicated cerclage. (See 'Monitoring for cervical shortening' below.)

Similarly, we do not routinely prescribe progesterone supplements to reduce the risk for PTB based solely on a history of an excisional treatment of CIN. No data are available on the use of progesterone supplementation to prevent PTB in this specific population. However, we may offer vaginal progesterone supplementation to patients with a short cervix. (See 'Monitoring for cervical shortening' below.)

Persistent cervical stenosis may lead to dystocia in labor and, if neglected, uterine rupture [32]. Gentle digital dilation can be attempted; a forceful approach should be avoided as it may result in laceration of the cervix and lower uterine segment. Cesarean delivery is the best option if the cervix does not dilate.

Monitoring for cervical shortening

In patients who have undergone an ablative treatment of CIN, we monitor cervical length in the same way as in patients who have not undergone such procedures. A single baseline cervical length measurement at 16 to 20 weeks is sufficient for patients with no history of spontaneous PTB. (See "Short cervix before 24 weeks: Screening and management in singleton pregnancies".)

In patients who have had an excisional procedure for treatment of CIN, a baseline cervical length measurement at 16 to 20 weeks can be offered and then repeated every 2 weeks until 28 weeks. There is no standard practice; the decision is a clinical judgment influenced by local practice and patient-specific factors (eg, past obstetric history of PT, size of excision and remaining cervix). Monitoring cervical length appears to be more common in countries where PTB rates are high and less common where these rates are low.

If performed, we use the same cutoff to define a short cervix as in the general obstetric population: ≤25 mm before 24 weeks. We repeat the cervical length measurement weekly if ≤25 mm, discuss the option of cerclage if cervical length is ≤20 mm before 24 weeks, and recommend cerclage if ≤15 mm before 24 weeks. Vaginal progesterone may be an alternative approach to management of patients with a short cervix, particularly those with cervical length >15 mm. (See "Short cervix before 24 weeks: Screening and management in singleton pregnancies" and "Cervical insufficiency", section on 'Ultrasound-based cervical insufficiency'.)

For patients with a short cervix at 24 to 28 weeks, we do not offer either cerclage or progesterone but use this information to individualize the frequency of follow-up visits and the timing of antenatal steroid administration. (See "Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery", section on 'Timing before delivery'.)

Route of delivery — The route of delivery should be based on standard obstetric indications. The type of previous CIN treatment is not a factor in our decision making and does not appear to significantly increase or decrease the cesarean delivery rate [15].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cervical cancer screening, prevention, and management".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Beyond the Basics topic (see "Patient education: Management of a cervical biopsy with precancerous cells (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Clinical significance – Cervical cancer precursors (eg, cervical intraepithelial neoplasia 2,3 [CIN]; high-grade squamous intraepithelial lesions [HSIL] (figure 1)) are typically managed with an ablative or excision procedure; surveillance (with cervical cytology and colposcopy) is an option for some patients. The choice of procedure is based primarily on the trade-offs between the risk of developing cervical cancer and the potential reproductive risks of treatment. (See 'Introduction' above and "Cervical intraepithelial neoplasia: Management".)

Adverse reproductive outcomes – Treatment of CIN has been associated with subsequent cervical stenosis, second-trimester pregnancy loss, and preterm birth (PTB). These risks are higher with excisional compared with ablative procedures and increase with increasing weight and volume of tissue removed. (See 'Adverse reproductive effects of procedures performed before pregnancy' above.)

Timing of conception – We suggest that patients wait at least three months after an excisional procedure before attempting to conceive. This recommendation is based on limited data and expert opinion. (See 'Timing of conception after treatment of CIN' above.)

Obstetric management

Role of cervical length monitoring – Prenatal care in patients with a history of treatment of CIN is routine, except serial transvaginal sonographic monitoring of cervical length can be considered in those who have had an excisional procedure. There is no standard practice; the decision is a clinical judgment influenced by local practice and patient-specific factors (eg, past obstetric history of PTB, size of excision and remaining cervix). (See 'Monitoring for cervical shortening' above.)

If cervical length monitoring is performed – If cervical length is monitored, we use the same cutoff to define a short cervix as in the general obstetric population: ≤25 mm before 24 weeks. We repeat the cervical length measurement weekly if ≤25 mm, discuss the option of cerclage if cervical length is ≤20 mm before 24 weeks, and recommend cerclage if ≤15 mm before 24 weeks. Vaginal progesterone may be an alternative approach to management of patients with a short cervix, particularly those with cervical length >15 mm. For patients with a short cervix at 24 to 28 weeks, we do not offer either cerclage or progesterone but use this information to individualize the frequency of follow-up visits and the timing of antenatal steroid administration. (See 'Monitoring for cervical shortening' above.)

Mode of delivery – Treatment of CIN does not impact choice of mode of delivery. Cesarean delivery is performed for standard obstetric indications. (See 'Route of delivery' above.)

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References

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