Pregnancy outcomes following radical trachelectomy for early‐stage cervical cancer: A retrospective observational study in the Kanto area, Japan

The authors aimed to investigate the prevalence of pregnancy and obstetric outcomes in patients who underwent radical trachelectomy (RT) for early‐stage cervical cancer in the Kanto area, Japan.


| INTRODUC TI ON
Radical trachelectomy (RT) is a fertility-sparing surgical technique that shows the same treatment outcomes as radical hysterectomy for early-stage cervical cancer. 1 While the administration of the human papillomavirus (HPV) vaccine has reduced the incidence of cervical cancer, 2,3 the fear of adverse events (e.g., chronic pain and movement disorders) has hindered the HPV vaccination program in Japan. 4,5According to the Japanese Annual Patients Report for 2019, 42.6% of 7983 patients with cervical cancer were younger

| RE SULTS
Of the 113 institutions included in this survey, we received answers from 100 hospitals (88.5%).Fifteen institutions reported to have prior experience in managing pregnancies after RT, and we retrospectively collected maternal and perinatal data from 13 hospitals.
Of these 15 institutions, we could not obtain data from two institutions: one institution had an early miscarriage and another had five miscarriages and two deliveries; however, they were unable to acquire permission to provide disclosed data from their institution.
There were 135 pregnancies among the 115 female patients following RT during our study period.Of the 135 pregnancies, there were 32 miscarriages and 103 deliveries after 22 gestational weeks.The median number of pregnancies managed at each institution was two (range, 1-98).

| Oncologic characteristics
The oncological characteristics of the patients are shown in Table 1.

| Miscarriage
During the study period, 32 miscarriages occurred.Of these, 22 patients miscarried by 12 gestational weeks (early miscarriage) and 10 patients miscarried between 12 and 21 gestational weeks (late miscarriage).The characteristics of the early pregnancy miscarriages are presented in Table 2.The median age of the 22 patients with early miscarriage was 38.5 years (range, 30-42 years), and the median gestational age at miscarriage was 7.5 weeks (range, 5-11 weeks).Of the 18 patients who selected expectant management, four patients needed aspiration for treatment after waiting for 56 days (median range, 35-73 days).Two patients selected aspiration and the other two selected dilatation and curettage (D&C) without expectant management.These four patients did not have any complications (e.g., cervical laceration or intrauterine infection).The characteristics of the late miscarriages are listed in Table 3. Cesarean section (CS) was performed in seven patients.Two patients developed cervical laceration due to vaginal delivery since it was too late to perform emergency CS during labor onset with severe abdominal pain.Case 3 developed chorioamnionitis and massive bleeding and underwent aspiration after uterine artery embolism.Case 10 was terminated because of genetic abnormality (conjoined twins) at 21 gestational weeks.

| Birth after 22 gestational weeks
During the study period, 103 cases delivered after 22 gestational weeks via CS (Table 4).Approximately half of them were conceived via in vitro fertilization-embryo transfer (n = 48, 47%).The median midtrimester residual CL was 15 mm (range, 5-37 mm), and 38 cases had a short residual CL (<13 mm).Preterm PROM developed in 25 cases (24%), and abnormal bleeding from the varices at the site of the uterovaginal anastomosis was noted in 14 cases (14%).
The median duration of hospitalization, excluding the period of hospitalization for CS, was 11 days (range, 0-140 days).Sixty-nine cases received long-term tocolysis, performed for over 48 hours.
Furthermore, the median duration from preterm PROM to CS was 1 day (range, 0-38).The median gestational age at delivery was 36 weeks, and 65 patients had a preterm delivery (<37 weeks).The trend in gestational age at delivery is shown in Figure 1.The incidence of preterm delivery before 28 gestational weeks was 8.7% (n = 9) and that before 34 gestational weeks was 30.1% (n = 31).All patients underwent CS.
According to Spearman correlation coefficient, midtrimester residual CL was correlated with gestational weeks at delivery (r = 0.24, P = 0.010) (Figure 2).When examining the association between midtrimester residual CL and preterm delivery (<34 gestational weeks), patients in the short cervix group (<13 mm) had a significantly higher risk of preterm delivery than patients in the nonshort cervix group (P = 0.046).However, abnormal bleeding from the varices at the site of uterovaginal anastomosis was not associated with preterm delivery before 34 gestational weeks (P = 0.12).

| DISCUSS ION
The present study observed 103 deliveries among patients who had received RT, over a period of 11 years, from the Kanto area, Japan.There were 22 early miscarriages and 10 late miscarriages.Since we observed the incidence of preterm delivery before 34 gestational weeks to be 30.1%,pregnancies after RT are at a higher risk of preterm delivery.Furthermore, a midtrimester short residual cervix is a risk factor for preterm delivery in pregnancies following RT.Because the number of pregnancies after RT could be increasing in Japan, the perinatal management should be considered to prevent adverse outcomes.
0][21] Since there is a fear of cervical laceration or intrauterine infection due to aspiration or D&C, expectant management was recommended in our previous review. 11However, expectant management might be mentally difficult while waiting for natural discharge.In addition, aspiration or D&C might be safe for early pregnancy miscarriage after RT, based on our findings and other reports. 22e of the most difficult and important problems is the management of late miscarriages during pregnancy following RT.As RT is a childbearing surgery, prophylactic cerclage is performed at the time of RT to prevent preterm delivery.According to a previous report, when most patients with a second-trimester miscarriage selected expectant treatment, they could deliver vaginally without removal of the prophylactic cerclage. 23wever, cervical laceration was detected in two patients who underwent vaginal delivery in this study.Since none of the patients who received CS in the cohort of the second-trimester miscarriages after RT had any complications, we recommend that CS should be selected for patients with second-trimester miscarriage.
In this study, the incidence of preterm delivery (<37 gestational weeks) was 63.1%.According to a previous review, the incidence of preterm delivery was 41.8%, which was higher than that reported in previous data of pregnancy after RT. 7 Among the 34 patients who received CS between 34 and 36 gestational weeks in the present study, 18 were elective CSs.While one woman received elective CS at 34 gestational weeks due to placental previa, others did not have any complications.If these 17 patients were scheduled for CS after 37 gestational weeks, the incidence of preterm delivery was the same as that in the previous review.In women who have undergone RT, the cervixes are resected widely to treat early-stage cervical cancer.Therefore, we believe that this residual cervix will not be potent enough to support pregnancy, and the patients might be susceptible to infection owing to a lack of cervical glands.Therefore, a short residual cervix was reported as a risk factor for preterm delivery using transvaginal ultrasound or magnetic resonance imaging. 18,24Another noteworthy complication is the abnormal bleeding from the varices at the site of the uterovaginal anastomosis in pregnancies following RT. 8,10,25However, it was not associated with preterm delivery before 34 weeks of gestation in the present study.
This study is limited by its retrospective design.However, the sample size was larger than in previous reports.Moreover, this survey was performed in institutions that performed perinatal care for pregnancy after RT.Excluding our institution and another, many patients received RT or perinatal care at different institutions; hence, we did not have detailed oncologic information, such as adjuvant chemotherapy regimen, tumor size, and resected CL.Specifically, we did not know why the patients with adenocarcinoma in situ or cervical intraepithelial neoplasia grade 3 received trachelectomy.
Furthermore, although we explained the measurement of residual CL in some situations and described it in some reports, 10,18 the measurement of residual CL might differ between institutions because it is not very popular for clinicians.In addition, we could not centralize the review of residual CL, as this was a retrospective cohort study, and we could not obtain sonographic photos.Further research is required to determine the association between residual CL and preterm deliveries.

| CON CLUS ION
To the best of our knowledge, this is the first study to investigate the outcomes of pregnancies following RT in Japan.Since there were over 100 pregnancies after RT in the Kanto area, Japan, we anticipate that many physicians will have more opportunities to manage pregnancy after RT.Pregnancy after RT is associated with a higher risk of preterm delivery, and midtrimester short residual cervix is a good predictor of preterm delivery.Moreover, further dissemination

TA B L E 4 F I G U R E 1 F I G U R E 2
Abbreviations: IUI, intrauterine insemination; IVF-ET, in vitro fertilization-embryo transfer; OD, oocyte donation; PROM, premature rupture of membranes; RT, radical trachelectomy.
of information and development of useful management strategies to prevent preterm delivery are needed.AUTH O R CO NTR I B UTI O N SY.K. corrected data, performed statistical analysis, wrote the manuscript, contributed to discussion, and reviewed/edited the manuscript.K.H., K.T., K.A., A.H., Y.F., J.T., Y.T., and S.I. contributed to discussion and reviewed/edited the manuscript.M.T. reviewed/edited the manuscript and supervised research.FU N D I N G I N FO R M ATI O NThis study was supported by JSPS KAKENHI (grant number: 20 K18173) and Kanto Society of Obstetrics and Gynecology.