Introduction
An incremental in the detection rate of gynecological malignancies during pregnancy has been reported nowadays. Many plausible explanations have emerged: the increase of maternal age or higher compliance of the patients to the screening programs(1-3). Among all the malignancies encountered during pregnancy, cervical cancer is thought to be the most frequent and the second cause of death due to cancer(3,4). Approximately 3% of the cervical cancer cases are discovered during pregnancy, the incidence being estimated between 0.8 and 1.5 per 10,000 births(2,4). In contrast, the reported frequency of abnormal cytology results in pregnant women is about 5-8%, similar to nonpregnant women(1-5).
The chance of diagnosing an initial stage of cervical cancer is three times higher than in the general population(4). This might be explained by the particularities of the prenatal care system (in some countries the system is more permissive for otherwise uninsured low-income women) that includes mandatory inspection and cytologic or/and HPV sampling in patients not screened previously, and the fact that advanced stages can interfere in the conception process, therefore being rarely detected in pregnant women. Overall, after stratifying for stage, the prognosis of cervical cancer appears to be similar in pregnant and nonpregnant women(2,6-8).
The physiological changes that occur in the glands and stroma of the cervix during pregnancy – such as hyperplasia of the endocervical glands, decidualization, ectropion, degenerated decidual or trophoblastic cells – might lead to some overestimation of some possible lesions(9).
Clinical manifestations
The clinical manifestations of cervical cancer in pregnancy are dependent on the clinical stage and the size of the lesion. Most of the pregnant women with early cervical cancer have no symptoms. However, some symptomatic women show abnormal vaginal bleeding or vaginal discharge and even pelvic pain or chronic anemia in the late stages of cervical cancer, all these frequently being confused with a complication related to the pregnancy or the puerperium period. Therefore, all the abnormal bleedings during pregnancy or in postpartum patients should be evaluated very carefully, and all the cervical lesions should be biopsied(2,10).
Screening
The screening of cervical cancer in pregnancy is similar to that of nonpregnant women, and includes cervical cytology, colposcopy and cervical biopsy. Studies have shown that the incidence of the abnormal Pap tests in pregnant women is about 5-8%, similar to that of nonpregnant ones. However, changes that occur in pregnant women could easily be misdiagnosed as high-grade squamous intraepithelial lesions (HSIL) or even invasive cancer, which requires an experienced pathologist to examine the cervical cytology smears(11-14).
Taking into account the different parameters analyzed, pregnant women with abnormal cytological results or/and positive for human papillomavirus (HPV) should undergo further colposcopy evaluation with biopsy when necessary. Ideally, colposcopy should be performed in the first half of the pregnancy (in the first and second trimesters of pregnancy) and repeated after 20 weeks of pregnancy if required. The high rates of high-grade lesions found after an ASCUS smear encourage for such an attitude(3,14). If a HSIL CIN2 or CIN3 lesion is diagnosed at the first colposcopy performed during pregnancy, a reevaluation after 12-24 weeks is recommended(15-17). If the lesion is well visualized, a colposcopic follow-up will be offered every trimester, having the final management of the case only postpartum, if possible, after a complete reevaluation(15). On the other hand, if the colposcopy suggests a high-grade lesion that evolves to the endocervix or there is a suspicion of invasion, a biopsy or even an excisional procedure is indicated(15-17).
The therapeutic plan is challenging in case of invasive cancer detected during pregnancy. The patient should be informed about the risk and benefits of the therapeutic alternatives, but ultimately the fully informed patient takes the final decision. If a diagnosis of an advanced cervical cancer is made during the first two trimesters, the medical recommendation is to terminate pregnancy(6,8,10,11,18). In the more complicated case of a cervical cancer detected in the last trimester of pregnancy, the case should be managed by a complex team: oncologist, maternal and fetal medicine specialist and perinatologist(6,8,10,11,18). The recommended attitude is to deliver the fetus once the fetal maturity is achieved, choosing the caesarean section followed by radical hysterectomy and lymphadenectomy(6,8,10,11,18). The chemotherapy is also an option during pregnancy, but must be avoided in the first trimester, due to its teratogen effects, and also after 35 weeks of gestation, as delivery might occur during the period of fetal immunosuppression(1,20).
There are only a few studies in the literature regarding the HPV testing in pregnant women. The current guidelines recommend that pregnant women should follow the same algorithms as nonpregnant patients(16,17). Some reports showed a similar or even higher prevalence of the high-risk HPV in the cohort of pregnant women(19,20). An isolated study has demonstrated that the presence of high-risk HPV during pregnancy might be predictive for an evolving risk(21).
Instead, the management of pregnant women with cervical disease differs from the one for the general population, because some maneuvers are considered to be unacceptable during pregnancy, such as endometrial biopsy, endocervical curettage and excisional treatment without biopsy(22).
One of the most challenging situations is represented by the management of atypical glandular cells (AGC) in pregnant patients. An expert-guided colposcopy is needed, taking into account directed biopsies of the transformation zone and also cytobrush biopsy of the endocervix, since the endocervical curettages are forbidden during pregnancy(23). If adenocarcinoma in situ is diagnosed during pregnancy, it is recommended the referral to a gynecologic oncologist. Also, an acceptable approach is the management of such a case by an expert colposcopist(22).
There are only a few studies that have enrolled pregnant women with adenocarcinoma in situ, the study of Lacour et al. being one of the largest(24). The aforementioned research was a retrospective study that had identify 11 pregnant women with adenocarcinoma in situ during pregnancy in a ten-year interval (from 1995 to 2004). The patients were managed differently: one group (n=5) underwent conization and cerclage in the early second trimester, between 14 and 19 gestational weeks, without any complications; the second group (n= 6), diagnosed later or after 24 weeks of pregnancy, was followed every 4 to 6 weeks (colposcopy and directed biopsy) and had their treatment only postpartum (five underwent conization and one hysterectomy). Interesting, all patients have delivered at term, eight of them vaginally and three by caesarean section. From the five patients treated antepartum, two had residual adenocarcinoma in situ (AIS) and the other three remained disease-free. Of the five women treated postpartum, undergoing conization, four had AIS and only one had stage IB1 cervical adenocarcinoma(24). The results suggested that the risk of residual AIS is higher if the conization in performed early in pregnancy and needs postpartum reassessment.
Colposcopy during pregnancy and postpartum
Well-known physiological changes occur in the cervix of pregnant patients that can have an important impact upon the interpretations of the cytology and colposcopy in inexperienced hands. During the first trimester, these changes are reduced and don’t interfere with the colposcopic evaluation. In the following months, the changes are more and more important: the eversion of the ectocervix, the softening of the cervix and the vaginal walls, the increased vascularization(25,26).
The unusual situation requires an experienced colposcopist which is able to distinguish between pregnancy-associated signs and cervical lesions. An unsatisfactory colposcopy of the transformation zone requires a reevaluation after 6-12 weeks, the most appropriate colposcopies (according to the current terminology) being done after 20 weeks of pregnancy; the squamocolumnar junction is 100% visualizable after 20 gestational weeks.
The eversion of the ectocervix generates a squamous metaplasia induced by the vaginal acidity. In addition, the hypervascularity of the cervix might exaggerate the reaction of the epithelium to acetic acid, creating a confusion between normal and severe lesions. There can be observed that the cervical volume, together with the stromal oedema and the hyperplasia of the glandular epithelium cause an increased mucus production(5,26). If there is any doubt between pregnancy changes and dysplastic lesions, a biopsy is imperative. These maneuvers are 100% safe, bleeding being frequently associated, but easily solved with Monsel’s solution and sutures, if necessary(3,5).
In the postpartum period, colposcopy is recommended only after four weeks from the delivery moment. If during pregnancy a patient was diagnosed with HSIL CIN2 or CIN3 and the current colposcopy reveals a lesion, a full examination or even an excisional treatment should be considered. If no lesion is detected on the postpartum colposcopy, a full examination is indicated(22).
The current practice of taking biopsies during colposcopy in pregnant women has proven to be safe in pregnancy, with minor adverse reactions. In selected cases with discrepancies or invasion suspicion, conization can be performed, but this procedure is associated with a higher risk of preterm birth(27). The largest study on the performance of biopsy in pregnancy was performed by Economos and collab.; they enrolled initially 612 pregnant women with abnormal cytology who had undergone colposcopy and during these procedure 449 biopsies have been taken. The study demonstrated a 95% concordance between cytology, colposcopy and biopsy, with no case of missed cervical cancer and minimal complications after the biopsies(27).
By contrast, the research conducted by Baldauf and collab. showed an acceptable concordance of only 72.6% between the cytology and the final diagnosis. The study had a case-control design and recruited 117 pregnant women and 234 controls. An overestimation was observed in 17.6% of cases, while an underestimation was present in 9.8% of cases. The study demonstrated that unsatisfactory colposcopies were less common during pregnancy, 12.8% versus 23.1% in the general population, and that the pregnancy-related changes don’t alter the performance of the biopsy(26).
Conization during pregnancy
The indications for cervical conization during the gestational period are different from the ones applicable in the nonpregnant women. The absolute indication for the procedure in pregnancy is in patients with HSIL Pap smear and unsatisfactory colposcopy and for those with suspicion or evidence of invasive disease, when this will alter the mode or timing of birth. Otherwise, conization should be postponed to the postpartum period.
The best period for conization is represented by 14 and 20 weeks of pregnancy. Due to the risk of hemorrhage, the procedure is not recommended four weeks prior to the estimated date of delivery(2,28,29).
The physiological changes associated to pregnancy lead to some particularities of this procedure in pregnancy. Therefore, in pregnant patients it is recommended to perform the excision much more extended in surface than in depth, making it a “cone-shaped” excision more than a “coin” one. This recommendation is possible due to the particularities of the pregnant cervix that enables the visualization of the squamocolumnar junction on the exocervix in the majority of pregnant women, thus facilitating the intervention. In case the conization is absolutely necessary, a prophylactic cervical cerclage should be done during the same surgery, to prevent a hemorrhage and premature delivery(3,30). It is well-known that the bigger the depth of the cone excision during the conization (the extent into the cervical canal), the higher the risk for preterm birth.
In spite of the conization’s diagnostic accuracy, this procedure has its limitations when it comes to complications if performed during pregnancy. The most frequent complications are related to the risk of hemorrhage, spontaneous abortion, preterm rupture of membranes, preterm labor and delivery and infection(5,29,31). The risk of significant hemorrhage increases with the trimester when the conization is done, from negligible to 5% in the first one, to 10% in the third trimester(5,29,31).
Robinson and collab., in a study conducted in 1997 on 20 patients between 8 and 34 weeks of pregnancy who underwent LOOP excision, have shown positive margins in 57% of cases, recurrent disease in 47% of cases and one intrauterine fetal demise at 36 weeks of pregnancy, four weeks postprocedure. The effects seem to be aggravated by the gestational age(28).
Prognosis
The management of dysplasia during pregnancy is based, in the majority of cases, on expectant observation, postponing its treatment after delivery, if possible. Some studies have shown that most of the lesions remain stable during pregnancy and even regress (from 0% to 69%). The factors that influence the regression rate might be related to the severity of the lesions, as the CIN1 is more likely to regress(32,33), and the type of delivery, the regression being associated frequently with the vaginal birth(34,35). On the other hand, there has also been reported some cases of progression, but at a lower rate (below 5%), which seem to be misdiagnosed during pregnancy(1).
Conclusions
The management of abnormal cytology results in pregnancy is challenging mainly due to the physiological particularities of the pregnant cervix, but also because of the difficulty of the colposcopy itself in this particular period. While managing an abnormal result in pregnancy, the fetal status and his prognosis must be also considered.
Therefore, colposcopy in pregnant women should be reserved for expert colposcopists. Biopsy taken has proven to be safe in the absence of significant complications. Conization should be performed only in particular situations (HSIL with no visible squamocolumnar junction or suspicion of invasion) due to the risk of preterm birth. In difficult cases, the decision should be made by a medical board, including oncologist, perinatologist, and specialist in maternal and fetal medicine. Last but not least, the couple’s option is a major component of the medical management.
Conflict of interests: The authors declare no conflict of interests.