Pregnancy is usually a joyful event and pregnant women and their families look forward to the future, but a diagnosis of cervical lesions during pregnancy can be devastating for the patient and her family. Cervical cancer is one of the most common malignancies in pregnancy, with 1.2 cases reported for every 10,000 pregnancies in the United States. And the incidence of cervical cytologic abnormalities during pregnancy is about 5%, similar to the incidence in non-pregnant women. This article reviews the management of cervical cytologic abnormalities, cervical intraepithelial neoplasia (CIN) and invasive carcinoma during pregnancy to provide some reference to guide clinical practice.
Classification system
The cytologic findings use the 2001 TBS terminology and include ASCUS (atypical squamous cells of undetermined significance), LSIL (low-grade intraepithelial lesions), HSIL (high-grade intraepithelial lesions), ASC-H (atypical squamous cells that do not exclude high-grade lesions, and AGC (atypical glandular cells).
Colposcopic diagnosis or biopsy diagnosis is made using a histological classification that includes CIN1 (cervical intraepithelial neoplasia grade 1), CIN2 (cervical intraepithelial neoplasia grade 2), and CIN3 (cervical intraepithelial neoplasia grade 3).
Importantly, cytological LSIL is not equivalent to CIN1 and HSIL is not equivalent to CIN2 and CIN3
Changes in the cervix during pregnancy
Normal physiologic changes in the cervix during pregnancy, such as cervical vascularity, cervical hypertrophy, and endocervical glandular hyperplasia, may complicate the accuracy of the cytologic diagnosis. Furthermore, multiple cell types specific to pregnancy, such as degenerating metaplastic cells (or A-S reaction) and trophoblasts may be shed from the endometrium. These cells have variable cytoplasmic staining and enlarged nuclei and, therefore, may resemble HSIL, leading to false-positive results on cytology.
During pregnancy, the transformation zone gradually moves outward and by 20 weeks of gestation, the squamocolumnar junction is fully visualized in most patients. Therefore, if colposcopy is considered unsatisfactory early in pregnancy when the entire transformation zone is not visualized, it can be repeated later in pregnancy when a satisfactory colposcopic examination is often obtained.
Natural history of abnormal cervical lesions in pregnancy
The chance of progression of abnormal cervical lesions to invasive carcinoma during pregnancy is low, about 0-0.4%, and it is common that the disease is stable or even regresses spontaneously (48%-70% of HSIL or CIN2,3 regress during pregnancy).
Whether the mode of delivery (vaginal or cesarean) is associated with regression rates remains controversial. It has been reported that cesarean delivery reduces the risk of cervical cancer, or that vaginal delivery has a higher regression rate, or even that disease progression is unrelated to the mode of delivery. In the absence of reliable evidence, the decision on the mode of delivery should be based on obstetric factors. Abnormal cervical lesions are not an indication for cesarean delivery.
Screening for cervical cytologic abnormalities during pregnancy
The current consensus recommendation is, in general, a conservative approach to the management of cytologic abnormalities in pregnancy in the absence of definite invasive cancer.
Evaluation methods
For ASCUS, high-risk HPV (human papillomavirus) testing can be used for triage during pregnancy. For HSIL, colposcopy is required and should preferably be performed by an experienced colposcopist. The results of colposcopy are not a substitute for direct colposcopic biopsy, which has been reported as CIN 1 or 2 in 54% of normal colposcopies and CIN 3 in 14% of colposcopies with CIN 1. However, this difference does not change the management options for most patients, as the management of cervical lesions in pregnancy is mostly observed conservatively, with the exception of invasive carcinoma.
Cervical biopsy is safe for the evaluation of cytologic abnormalities in pregnancy. To avoid spontaneous abortion due to cervical biopsy, it has been suggested to perform cervical biopsy in midtrimester, but at this time, biopsy increases the risk of bleeding, which can be stopped by compression. However, due to the abundance of cervical blood flow during pregnancy, most physicians are reluctant to perform a cervical biopsy due to concerns about the risk of hemorrhage and spontaneous abortion.
Intracervical curettage during pregnancy is contraindicated for fear of destroying the gestational sac, although there are no randomized trials evaluating the risk of intracervical curettage on pregnancy.
Diagnostic loop electrosurgery (LEEP) or conization should be considered only in patients with strongly suspected invasive carcinoma.
Negative cytology with high-risk HPV (+)
For pregnant women over 30 years of age, high-risk HPV testing is performed. If cytology (-) and high-risk HPV (+), repeat both tests at 6 weeks postpartum. If cytology remains (-) and high-risk HPV persists (+), colposcopy is performed. CIN2+ lesions have been reported in 4% of those with cytology (-) and high-risk HPV (+).
ASCUS and high-risk HPV (+)
The chance of finding invasive carcinoma after prenatal or postpartum ASCUS is <1%. in pregnant women over 21 years of age, testing with high-risk hpv is acceptable as a triage when there is ASCUS, and colposcopy can be delayed until 6 weeks after delivery. < p="">
ASCUS and high-risk HPV (-)
At 6 weeks postpartum, repeat both tests.
ASC-H
Colposcopy during pregnancy with or without cervical biopsy
LSIL
On biopsy, patients with cytologic LSIL are almost unlikely to have invasive carcinoma. Most LSIL regresses spontaneously or persists unchanged during pregnancy. In patients with prenatal LSIL, regression, persistence and progression to HSIL have been reported in 32%-62%, 32%-65% and 3%-6%, respectively, of patients with prenatal LSIL and no progression to invasive carcinoma when cytology is repeated at 6 weeks postpartum. Colposcopy is preferred in pregnant women with LSIL, but delaying colposcopy until 6 weeks postpartum is also feasible in pregnant women in whom neither cytology nor visual examination is suggestive of more advanced disease.
HSIL
Only about 1% of patients with HSIL will be found to have invasive cancer. For colposcopy in pregnant women with HSIL, any suspected CIN2+ is biopsied under direct vision, but no endocervical curettage is performed. Diagnostic excision (LEEP, conization) is not acceptable unless invasive cancer is suspected. Since 11% of patients with prenatal HSIL have been reported to progress to microinfiltrative carcinoma (stage IA1) at the time of postpartum conization, it is recommended that colposcopy should be repeated every 12 weeks.
AGC or AIS
Whenever AGC or AIS (adenocarcinoma in situ) is detected cytologically, a thorough evaluation should be performed at any stage of pregnancy, including direct colposcopic biopsy and, if indicated, conization or LEEP.
Management of biopsy-proven CIN2,3
Overall, treatment of CIN lesions during pregnancy should be observed unless there is strong suspicion of microinfiltrative or invasive cancer.
CIN1: No treatment is required, with postpartum follow-up cytology. However, repeat cytology and colposcopy postpartum if prenatal cytology is HSIL, and repeat testing for high-risk HPV after 12 months if prenatal cytology is ASC-H.
CIN2,3: repeat cytology and colposcopy at 12-week intervals; consider repeat biopsy only if there is progression in the appearance of the lesion or if repeat cytology suggests invasive cancer. Postponing re-evaluation until 6 weeks postpartum is acceptable. Diagnostic excision (LEEP or conization) is recommended only if infiltrating cancer is suspected. Therapeutic excision (LEEP or conization) is not acceptable for CIN grade 2,3 lesions during pregnancy unless infiltrative cancer has been diagnosed.
Follow-up of postpartum pre-infiltrative disease
Any patient with abnormal cytology or histology of CIN lesions during pregnancy should be re-evaluated by cytology and colposcopy at 6-8 weeks postpartum. The choice of 6-8 weeks postpartum is based on the belief that the inflammatory response associated with pregnancy subsides significantly around 6-8 weeks postpartum, thus reducing the likelihood of false positive results.
Management of infiltrating carcinoma
A multidisciplinary consultation is required to assist in the development of a management plan. The treatment plan depends on the patient’s wishes regarding the continuation or termination of the pregnancy, in addition to the clinical stage and the week of gestation at the time of diagnosis.
Stage IA1 (microinfiltrative disease)
For those who wish to terminate the pregnancy, the treatment is termination followed by conization or simple hysterectomy, or simple removal of the pregnant uterus. For those with a large gestational week or those who desire to continue the pregnancy despite a small gestational week, conization may be performed if the margins are clean, followed by vaginal delivery at full term. Only conization during pregnancy is associated with a significantly increased risk of bleeding. Delaying treatment until postpartum may also not affect overall survival, due to the low likelihood of significant disease progression during pregnancy.
Stages IA2, IB1, IIA (early disease)
Treatment planning depends on the viability of the fetus and the patient’s decision to continue or terminate the pregnancy. If the fetus is not viable at the time of disease diagnosis and the patient decides to terminate the pregnancy, extensive hysterectomy and pelvic lymph node dissection with the fetus right in the uterus is recommended. In patients with a large gestational age or who desire to continue the pregnancy despite a small gestational age, the pregnancy can be conserved until fetal lung maturity, followed by a classical cesarean section with extensive hysterectomy and pelvic lymph node dissection. Some studies have found that cesarean delivery is superior to vaginal delivery in terms of reducing the recurrence rate of invasive cancer. After extensive hysterectomy, adjuvant treatment depends on the presence of risk factors (i.e., depth of interstitial infiltration, parametrial involvement, vascular lymphatic vessel infiltration, etc.).
Stages IB2 to IV (macrosomia or advanced disease)
If the fetus is not viable and does not wish to proceed with pregnancy, it should receive external pelvic irradiation with concurrent chemotherapy while the fetus remains in the uterus. Expect radiotherapy to cause spontaneous abortion. For complete termination of pregnancy and control of bleeding, curettage or hysterectomy may be indicated.
Neoadjuvant chemotherapy may be considered until fetal lung maturity for those with a large gestational age or those who desire to continue the pregnancy despite a small gestational age, provided there is no massive bleeding due to a giant tumor. Delaying treatment for 6-8 weeks does not alter maternal survival, but the absence improves fetal outcome. When the fetal lung is mature, delivery should be ended by classical cesarean section and radical chemoradiotherapy should be started as early as possible.
Neoadjuvant chemotherapy
The data are experimental and are not supported by large samples. Chemotherapy administered in mid- or late pregnancy may not increase the incidence of congenital malformations in the fetus, although there is no literature to confirm its long-term outcome. The most used regimen is the DDP (cisplatin)-based regimen.
In conclusion, the treatment of cervical lesions during pregnancy is based on conservative observation, mainly to exclude invasive carcinoma. Treatment during pregnancy is only necessary in case of invasive cancer. For those with low risk of invasive cancer, it is reasonable to delay colposcopy. In addition, intracervical scraping should be avoided during pregnancy. Regarding the treatment of invasive carcinoma during pregnancy, it should be individualized, weighing the risks to mother and child.