Cervical cancer is the second most common cancer in women, diagnosed each year in nearly 500,000 women worldwide.1 Its incidence has been drastically reduced in the United States due to the widespread Pap smear screening, which has led to earlier detection of cervical intraepithelial neoplasia (CIN). CIN is a precursor to cervical cancer, and detection of it permits improved treatment outcomes resulting in an 80% reduction in cervical cancer progression.2
The treatment of CIN is dependent on lesion grading, with low-grade CIN often managed with watchful waiting and CIN grades II or higher requiring invasive treatments such as excisional or ablative destruction of the lesion.2 Excisional procedures, such as loop electrosurgical excision procedure (LEEP) and cold knife conization are more common due to their improved ability to treat higher CIN grades. Laser ablation and cryotherapy are reserved for lower-grade CIN.2,3
CIN treatment selection for women of childbearing age carries long-term consequences due to its potential association with future pregnancies.3-6 Studies have identified a link between cervical conization and preterm birth.2-12 Identifying cervical insufficiency as a risk factor for preterm labor after LEEP procedures is especially important.2,4,5,7 However, because cervical insufficiency lacks a well-accepted definition and its mechanism is poorly understood, many questions remain.
Research has demonstrated an increased risk of pregnancy complications in women who have undergone excisional procedures.8 These complications include preterm delivery (delivery at less than 37 weeks' gestation), low birth weight (less than 2,000 grams) and preterm premature rupture of membranes (PPROM; rupture of membranes at less than 37 weeks' gestation).2,3,8,10,11,13,14 The risk for preterm delivery is three times higher than average in women who have undergone LEEP.2,7 Yet limited research has examined the link between excisional CIN treatment and low birth weight or between excisional treatment and PPROM.2,8,9
Excisional vs. Ablative Procedures
Mainstay treatment choices for CIN are divided into two categories: excisional and ablative. Excisional procedures such as LEEP and cold knife conization are the most effective treatment for cervical neoplasia, especially those grade II or higher.2,5,7,10,14 LEEP utilizes a small wire loop charged with a high electrical current to remove all or part of the transformation zone (T-zone) of the cervix, the area where most cervical cancers arise.5,15 Alternatively, cold knife conization uses a scalpel to remove the cancerous lesion, resulting in more tissue removal and increased immediate risk compared to LEEP, due to greater blood loss and the occasional need for general anesthesia.3,5,15
A major benefit of both LEEP and cold knife conization is the ability for histologic examination of the tissue margin to grade the lesion and to ensure clean margins with removal of atypical tissue. Furthermore, because the lesion is completely excised, LEEP has a 91% to 98% cure rate and cold knife conization has a 90% to 94% cure rate.5,15
Ablative procedures such as cryotherapy and laser ablation use freezing or laser technology to destroy the lesion; the cure rate is 77% to 93% with cryotherapy and 95% with laser ablation.5,12,14,15 Ablative procedures are used for noninvasive low-grade lesions without glandular involvement.2,5,15 The main disadvantage to these procedures is the resulting surrounding tissue damage, which prevents histological sampling to determine treatment effectiveness. This results in a risk of incomplete treatment, leading to cancer recurrence in a small percentage of patients within 2 years of ablative treatment.15
Although histological analysis is lost, ablative procedures overall have a decreased risk of preterm labor and low birth weight compared to excisional procedures.2,9,16 Cold knife conization carries the greatest risk, including risk of severe preterm delivery (less than 32 to 34 weeks), extreme preterm delivery (less than 28 to 30 weeks), low birth weight, and second trimester pregnancy loss.2,4,5,16 LEEP is associated with an increased risk of preterm delivery but has no significant effect on severe or extreme preterm delivery.4,16,17 However, in women who undergo more than one LEEP procedure, preterm delivery risk increases almost fivefold.7 Due to the ability to examine the margins of the excised tissue, LEEP remains the standard of treatment for cervical dysplasia.2,4,5,7,10,12
Several hypotheses have been proposed about the cause of adverse pregnancy outcomes in women who have been treated for CIN.3-6,10,12 Whether using excisional or ablative procedures, the integrity of the cervix is compromised and results in disruption of normal cervical tissue and cervical shortening. The term for this phenomenon is cervical insufficiency, however, as stated earlier, there is no clear consensus about the definition of or parameters for diagnosing cervical insufficiency.
Some experts have suggested that cervical insufficiency cannot be diagnosed until a woman has had several spontaneous abortions or a previous preterm delivery.12,13 This is a particularly difficult definition when risk stratifying the primagravida patient. Some studies have examined the use of cervical sonography to measure second trimester cervical length as a predictor of risk for preterm birth.3,12,18 But published views about cervical length measurement during pregnancy are conflicting because the practice may lead to overuse of cervical cerclage placement.12 Cerclage, a French word meaning "encirclement," is a surgical procedure in which temporary sutures are applied at the cervicoisthmic junction during pregnancy to strengthen the cervix and prevent spontaneous abortion.13
Studies using cervical sonography between 14 and 28 weeks' gestation found that women who had undergone excisional procedures had short cervical lengths, defined as measurements less than 2.5 cm.3,19 Fischer et al measured cervical lengths in 85 women between 15 and 22 weeks' gestation who had undergone excisional procedures. Compared to controls, the researchers found a 0.6-cm difference in cervical length between the two groups.12 Women with no prior history of cervical dysplasia or excisional procedures had a mean cervical length of 3.9 cm and those with prior history of LEEP or cold knife conization had a mean cervical length of 3.3 cm, as well as greater incidence of preterm birth.12
The most studied mechanism explaining cervical compromise after excisional procedures was depth of cone size removed.3,4,7,10 Studies show a direct relationship between cone size removal and increased incidence of preterm delivery,3-5,7,12 and the removal of a cone size greater than 10 mm, leading to increased risk for preterm delivery.4-7 Noehr et al concluded that for each 1 mm of cone depth removed, the risk of premature delivery increased by 6%.4 Histological analysis of the excised tissue also demonstrated that lesion severity did not contribute to an increased risk for preterm delivery.4,5,7,12 These studies demonstrate that more cervical tissue excision during CIN treatment increases the risk for future preterm deliveries.
Controversy exists with regard to the effect of time between treatment and subsequent pregnancy.3,4,10,11 Noehr et al found that the amount of time after LEEP procedure and delivery did not demonstrate a strong correlation and concluded that the increased risk of preterm delivery is mainly attributed to the procedure itself (i.e., amount of tissue removed).4,10 However, two other studies disagreed and found that the length of time between the treatment procedure and pregnancy may correlate with adverse pregnancy outcomes.3,11 Himes and Simhan found that women who conceived within 2 to 3 months after an excisional procedure were at a higher risk for preterm delivery. This effect was attributed to functional difficulties of a cervix still undergoing healing inflammation from such procedures.11 Therefore, they recommended that women of reproductive age be thoroughly educated about the increased risk of preterm birth if conception occurs within 3 months of these procedures.5,11
It is important to remember the limitations of these two small retrospective studies. Clearly, more high-quality research is needed to determine the effect of timing between LEEP procedures and pregnancy. It may be prudent to delay pregnancy for a few extra months after CIN treatment to minimize the risk of a preterm delivery.
A small percentage of women decide against CIN treatment during pregnancy.10 Usually this is due to a diagnosis of low-grade CIN and the choice to utilize a "watch and wait" method since low-grade lesions have a high chance of spontaneously regressing.15 Little research has been done in this area, due to the difficulty of gathering sample populations and the ethical issues involved. One study found that although untreated women have a higher risk of preterm labor than the general population, in women who have received CIN treatment, a slightly higher risk of adverse pregnancy outcome exists.20 However, these results are inconclusive and merit further research.
Another factor that may contribute to cervical insufficiency after CIN treatment is that a shortened cervix can predispose women to vaginal infection, a well-established risk factor for preterm delivery.4,6,12 One theory is that disruption of the mucus plug from CIN treatment procedures leads to less protection against bacterial colonization.10 The bacterial colonization sets off an inflammation cascade, which could trigger PPROM and preterm labor. It is also important to consider that many risk factors for CIN development also increase the risk for premature birth.
Human papillomavirus (HPV), a sexually transmitted infection, is a cause of CIN. Lifestyle choice and risky sexual behavior may be the underlying risk factor for vaginal infections during pregnancy.4,6,7,10 The growing awareness of the link between HPV and cervical cancer and the recommendation for HPV vaccination for all adolescents may result in decreased CIN rates and therefore decreased adverse effects of its treatment.8 In light of this, the HPV vaccine should be considered as a preventive measure for CIN and subsequent pathways.2,6,15
Other risk factors are smoking during or before pregnancy, advanced maternal age, alcohol and drug use, and previous medical conditions that can increase the odds for contracting HPV and thus developing CIN.4,5,8,17 A few studies found that smokers and alcohol users were more frequently diagnosed with CIN than the general population.4,8,10 These may be the underlying reasons for increased preterm delivery and other adverse pregnancy outcomes in women who have received CIN treatment. Yet, most studies accounting for confounding factors such as maternal smoking and alcohol still demonstrate that excisional procedures lead to adverse pregnancy outcomes.2,6-10,17
Management of Cervical Insufficiency
For women who have already undergone excisional treatments for CIN, the question remains: What can be done to reduce the risk for a future adverse pregnancy outcome? Historically, placement of a cervical cerclage has been the treatment of choice for prevention of preterm birth. A cerclage procedure is most commonly performed via a transvaginal approach with use of antibiotics, such as an erythromycin and metronidazole combination, for 10 days postplacement to prevent bacterial vaginosis and preterm delivery.19,21,22 The transvaginal approach is generally preferred because it is associated with shorter operative duration and fewer perioperative complications.13 However, in women with a history of three or more pregnancy losses accompanied by a failure of the transvaginal cerclage, a transabdominal approach may be utilized.
It has become apparent in recent years, however, that use of cervical cerclage for cervical insufficiency is not warranted except in specific circumstances,5,6,8,12,14,21,22 generally in women with a history of more than two second-trimester pregnancy losses or premature births.14,21,22 This small subset may include women who have undergone LEEP or a similar procedure.
Although cerclage placement has not been proven universally beneficial, the use of cerclage to treat cervical insufficiency continues to be widespread.3,13,19,21 This is concerning because the risks of cerclage placement itself include increased incidence of PPROM, very early preterm birth, chorioamnionitis, placental abruption and premature uterine contractions.3,5,13,16 Indomethacin and other tocolytics are often used after cerclage placement to try to forestall preterm birth, but their effectiveness is not well studied.19,22 It seems the continued, probably unwarranted, use of cervical cerclage today is driven by confusion over the definition of cervical insufficiency combined with lack of clinician awareness about valid and current indications for cerclage.19,22
Another factor contributing to the continued use of cerclage is the population with prior history of cerclage use in pregnancy. When these patients become pregnant again, clinicians are reluctant to withhold the subsequent cerclage.19 Thought and education are needed for both the clinician and patient when cerclage is under consideration as a possible treatment option for cervical insufficiency, and caution is advised when presenting this option to primagravida women with a history of CIN treatment.
Several alternative treatments to cerclage placement exist. Two are ultrasound surveillance and expectant management.21 Cervical ultrasound surveillance may reduce the amount of unnecessary cerclage by better identifying patients most likely to benefit from the procedure.19 However, as previously mentioned, cervical ultrasonography continues to be controversial.6,12 Again, simply increasing the time between cervical procedure and pregnancy is another method that may help decrease risk of adverse pregnancy outcomes.3 Whether considered an alternative or an adjunctive therapy, screening and treatment for vaginal infection early in the second trimester may also be useful in reducing preterm delivery risk. However, there is no official recommendation to do so for any patient, regardless of cervical status.
A newer alternative treatment is the use of intramuscular progesterone (17-alpha-hydroxyprogesterone caproate or 17P) starting between 16 and 18 weeks' gestation and continuing throughout the pregnancy.5,6,13,14,19 One trial of 250 women demonstrated that the use of 17P halved the risk of preterm delivery.14 Another randomized controlled trial conducted by Hassan et al (465 women) demonstrated that vaginal progesterone gel reduced the risk of preterm birth in women with a shortened cervix (less than 28 mm) by 45%. The same study also showed that in the case of preterm delivery, the risk for adverse neonatal events such as respiratory distress syndrome and low birth weight was reduced with the use of prophylactic progesterone treatment.23 Therefore, providers should consider progesterone and other alternatives before cerclage placement, given the recent findings against liberal cerclage use.
Thorough Education Needed
Clinicians should thoroughly educate patients with CIN about treatment options and possible adverse outcomes; a majority of women diagnosed with CIN are of childbearing age. Future research is needed to define cervical insufficiency and the mechanisms behind it, as well as alternatives to cerclage, use of transabdominal cerclage,22 use of indomethacin,19 and the use and ideal formulation of progesterone as a treatment option for pregnant patients with short cervixes.14,19 Better understanding would also come from larger population studies conducted on treatment of cervical insufficiency, especially after an invasive CIN procedure.
There are proven links between excisional procedures used to treat CIN and subsequent adverse effects on pregnancy. In light of the plethora of research addressing this issue, questions have been raised about whether medical providers are overtreating CIN, especially in cases of low-grade dysplasia. Therefore, it is prudent to exercise caution when managing patients of childbearing age diagnosed with low-grade CIN. For patients who must receive excisional treatment for CIN, better education about consequent effects on pregnancy is necessary, including available options to help combat subsequent cervical insufficiency.
Megan Schmittdiel, Catherine Chen and Adria Brzenk are students in the physician assistant program at Pace University in New York City. Ellen D. Mandel is a clinical associate professor at Pace University.
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