Ultrasound-guided local ethanol injection for fertility-preserving cervical pregnancy accompanied by fetal heartbeat:Two case reports

lNTRODUCTlON

Cervical pregnancies occur in approximately 1 in 9000 pregnancies[1,2]. They are believed to be more common in those with a history of abortion or cesarean delivery, and are more common with assisted reproductive technology than with natural pregnancies[3]. The cervix contains very little smooth muscle, and it is thought that the villi easily infiltrate the muscular layer and form a high degree of placenta accreta. Furthermore, careless intracervical curettage for cervical pregnancy may cause complicated massive bleeding. Therefore, hysterectomy should be considered for treatment.

However, the recent development of high-sensitivity human chorionic gonadotropin (hCG) testing and improved accuracy of transvaginal ultrasound imaging have allowed asymptomatic diagnosis and increased fertility preservation due to early intervention. Dilation and curettage with methotrexate(MTX) therapy[4] and uterine artery embolization (UAE)[5] have been reported as treatments for the preservation of fertility. However, in patients who wish to preserve fertility, MTX therapy poses problems that may include ovarian dysfunction and a delay in resumption of infertility treatment due to the washout period[6]. Furthermore, there are many reported cases of unsuccessful MTX administration in cases accompanied by fetal heartbeat or blood hCG concentration of ≥ 10000 mIU/mL[7]. Moreover,with UAE, the rate of preterm birth in subsequent pregnancies may increase, and placenta accreta may occur[8].

There have been reports on the efficacy and safety of ultrasound-guided local ethanol injection as an alternative to topical MTX therapy in ectopic pregnancy[9,10].This therapy has the potential to become a treatment option, as it does not require a washout period and has fewer complications than UAE therapy. Nevertheless, reports on this topic are scarce. In this report, we present two cases of cervical pregnancy with fetal heartbeat and elevated blood hCG concentration, in which fertility was preserved using local ethanol therapy.

CASE PRESENTATlON

Chief complaints

A 39-year-old nulliparous woman achieved pregnancyfertilization-embryo transfer(IVF-ET). Ultrasonographic images at 6 wk 2 d of gestation suggested cervical pregnancy; therefore, she was referred to our hospital for detailed examination and treatment.

How beautiful it must be to sit under that tree with the student, but that he could not do; he had to content himself with the key-hole and be happy there!There he stood out on the cold landing, the autumn wind blowing through the cracks of the floor

A 33-year-old woman, gravida 2, para 1 had achieved pregnancyIVF-ET. Ultrasound imaging results at 7 wk 6 d of gestation suggested cervical pregnancy; therefore, she was referred to our hospital for further examination and treatment.

History of present illness

The patients were asymptomatic aside from the ultrasonographic images suggesting cervical pregnancy.

History of past illness

The patients reported no notable past illness.

Personal and family history

No notable personal or family medical history.

Physical examination

Findings upon presentation included blood pressure of 128/72 mmHg, pulse rate of 72 beats/min, and body temperature of 36.8 ℃.

In both cases, based on the findings, cervical pregnancy was diagnosed.

Laboratory examinations

Blood testing revealed an elevated hCG concentration of 16346 mIU/mL and no other abnormalities noted.

On day 10, the blood hCG concentration had decreased to 116 mIU/mL, and only a small amount of vaginal bleeding was noted during follow-up. In addition, no complications due to local ethanol injection were noted. Two months after local ethanol therapy, menstruation had resumed, and infertility treatment was re-initiated.

Blood testing revealed an elevated hCG concentration of 26930 mIU/mL and no other noteworthy abnormalities.

And say to her that what I foretell8 shall come to pass, and if she does not come everything in the kingdom shall fall into ruin, and not one stone shall be left upon another

Imaging examinations

Then he would vex12 and fret13 himself because they did not laugh at the right time, or because they laughed in the wrong places; and so he fretted14 and worried himself till at last the unhappy man fretted himself into the grave

What he said to me is, I believe the key to his success and the reason I consider him the greatest quarterback of all time. He said, If you re not afraid of losing, then losing means nothing.

Transvaginal ultrasonography revealed a 30 mm cervical GS with fetal heartbeat, and blood flow was noted around the GS by color Doppler imaging (Figure 2).

FlNAL DlAGNOSlS

Findings upon presentation included a blood pressure of 104/79 mmHg, pulse rate of 78 beats/min, and body temperature of 36.9 ℃.

TREATMENT

Case 1

MTX therapy was offered as a treatment option because of the patient's desire to preserve fertility. The patient declined MTX therapy after learning that side effects may include ovarian dysfunction and that a course of contraception was required during MTX washout. Dilation and curettage with UAE were also presented as options; however, the patient declined these after understanding that UAE may affect subsequent pregnancies. As such, the patient sought other fertility-preserving therapies. Therefore, we offered transvaginal ultrasound-guided local absolute ethanol injection because it allows early resumption of infertility treatment and has little effect on ovarian function and subsequent pregnancy.We also emphasized its efficacy and safety in patients with ectopic pregnancies. We explained that the use of local absolute ethanol injection for cervical pregnancy is an off-label and unestablished treatment at this time. Upon explaining the above, the patient and her family chose this treatment.

The treatment involved local injection of 2.5 mL absolute ethanol around the cervical GS using a 23-gauge percutaneous transhepatic cholangiography (PTC) needle under transvaginal ultrasonic guidance(Hakko Co., Ltd., Nagano, Japan). The blood hCG concentration 2 h after treatment was decreased by 20% from the pretreatment value; therefore, the therapeutic effect was confirmed. However, the blood hCG concentration increased the next day to 18087 mIU/mL; therefore, 2.5 mL absolute ethanol was injected again in the same manner. Thereafter, the blood hCG concentration decreased steadily, and spontaneous passage of the GS was observed 7 d after the second local injection of absolute ethanol.Histopathological examination revealed decidua and chorionic villi.

Case 2

The patient and her family sought fertility-preserving treatment. As in Case 1, the patient chose transvaginal ultrasound-guided local absolute ethanol injection among the available fertility-preserving treatments.

She stood on her tiptoes and scrutinized3（） the bowls of chopped pickles4, eggs, and onions. Her lips curled in disgust（，） . She pointed5 at the bowls. What s that? And that ... and that!

Using a 23-gauge PTC needle, 4.0 mL absolute ethanol was locally injected around the cervical GS under transvaginal ultrasonic guidance (Hakko Co., Ltd.). The blood hCG concentration 2 h after treatment was 20% less than the pretreatment value, verifying the therapeutic effect. Thereafter, the blood hCG concentration decreased steadily, and the GS spontaneously passed 6 d after the local injection of absolute ethanol. Histopathological examination revealed decidua and chorionic villi.

OUTCOME AND FOLLOW-UP

Case 1

On day 17, the blood hCG concentration had decreased to 198 mIU/mL, and no complications due to local ethanol injection were observed during follow-up. Two months after local ethanol therapy,menstruation had resumed, and infertility treatment was re-initiated.

Many years ago, I read that James A. Michener, who did not publish until he was forty years of age, advised young writers to do extensive research before trying to write a novel. He visited the countries and areas he was interested in writing about, interviewing countless1 people as well as reading more than two hundred books for back-ground material for each of his books -- Hawaii, Iberia, The Source, Texas, Poland, Alaska, Caribbean -- and for some forty other book projects, spanning2 a fifty-year writing career.

He found not a soul on board, but there was a very cosy80 little bed in the cabin, and an ample supply of all sorts of good things to eat and drink, which he made up his mind to enjoy until something new happened

Case 2

My mother was a vocal1 supporter of corporal punishment（） , but for all her talking she has never spanked2 my siblings3, and me only once. Instead she found ways of punishment that left a more lasting4 memory then the short sting of a swat on our rumps. One of the most memorable5 of these occasions occurred when I was four.

DlSCUSSlON

In this report, transvaginal ultrasound-guided local injection of absolute ethanol was performed as a new treatment method replacing MTX therapy and UAE. Previously, we reported the efficacy and safety of transvaginal ultrasound-guided local absolute ethanol injection in ectopic pregnancies[9,10].This treatment method involves the local injection of absolute ethanol around the implantation site under ultrasonic guidance. Its therapeutic effect can be determined earlier than in MTX therapy since a 10%-30% decrease in blood hCG concentration can be confirmed within 2 h of injection. We believe that absolute ethanol dehydrates and denatures the villous tissue, and that acute tissue changes reduce the blood hCG concentration within a short period of time. Therefore, we believe that these mechanisms are effective in patients such as ours, who had high blood hCG concentrations and fetal heartbeats—factors associated with unsuccessful MTX therapy. Furthermore, because no massive bleeding was observed after local injection of absolute ethanol, we believe that these mechanisms are hemostatic and may also be an effective treatment for cervical pregnancy accompanied by genital bleeding in patients who desire fertility preservation.

The patients in this report developed cervical pregnancy through assisted reproductive technology.Under these circumstances, many patients wish to preserve their fertility. Such patients often choose MTX therapy or UAE, both of which have high rates of treatment success[4,5] and postoperative pregnancy[11]. However, MTX therapy and UAE also have disadvantages for patients who desire fertility preservation. In a study of 35 patients with a history of MTX treatment for cervical pregnancy,oocyte yields duringfertilization were 10.1 ± 3.9 before treatment and 7.8 ± 3.6 after treatment,suggesting that MTX therapy caused a decrease in the number of oocytes. It has been reported that a decrease in oocyte count leads to a decrease in the number of collected eggs[6], and because MTX therapy affects the ovaries, it may also affect fertility preservation. Furthermore, when MTX is used, a 4–6-mo contraception period is required after surgery for washout[12,13], which delays the resumption of fertility treatment. Because patients under infertility treatment are becoming older, the best treatment method should allow early resumption of infertility treatment.

Absolute ethanol administration may also be effective in other transvaginal procedures, as there is a low possibility of iatrogenic infection. The therapy requires no anesthesia because the small needles cause less bleeding and pain, and the procedure is also more affordable than MTX therapy. This mitigates the physical and financial burdens of patients. In addition, when repeated administration is required for persistent ectopic pregnancy, side effects of anticancer drugs, such as MTX, also become a problem. However, injection of absolute ethanol causes only a local effect, which means that it can be repeated for persistent ectopic pregnancies. In Case 1, two local injections of absolute ethanol were administered for persistent ectopic pregnancy; however, no side effects were observed with this treatment.

In our two reported cases, blood hCG concentration was high and fetal heartbeat was present, which are risk factors for unsuccessful MTX therapy. However, the local injection of absolute ethanol was still able to preserve fertility. In both cases, local injection of absolute ethanol allowed resumption of menstruation 2 mo after treatment and early resumption of infertility treatment without any complications. Based on these results, we suggest that local injection of absolute ethanol for cervical pregnancy could be a safe and effective new treatment method.

CONCLUSlON

In this report, we presented two cases of cervical pregnancy with elevated blood hCG concentrations and fetal heartbeats. Each underwent fertility-preserving treatment with local ethanol injection. The outcomes suggested that this treatment method may avoid the complications of MTX therapy and UAE and may be an option for patients who desire fertility preservation.

Transvaginal ultrasonography revealed no gestational sac (GS) within the uterine body;however, a 21-mm GS-like mass with a fetal heartbeat was found within the cervix (Figure 1).

In UAE,postoperative fever is the most common complication,and pain,endometritis,intrauterine adhesions, uterine necrosis, and ovarian dysfunction may also occur[14-16]. According to Hardeman[17], 14 of 53 patients who underwent UAE for obstetrical bleeding desired subsequent pregnancy (all gelatin embolization cases), and 12 of these patients conceived and had successful delivery. These results indicate relatively high rates of postoperative fertility. However, in post-UAE pregnancies, there have been reports of significant increases in miscarriage rate, postpartum bleeding, preterm birth rate,and fetal position abnormalities, and there have been case reports of intrauterine growth restriction[8].This emphasizes the need for strict perinatal management in post-UAE pregnancies.

Kakinuma T designed the research study and wrote the manuscript; Kakinuma T, Kakinuma K,Ohwada M and Yanagida K performed the research; Matsuda Y and Kaijima H provided help and advice on the study protocol; All authors read and approved the final manuscript.

The study was approved by the Ethics Committee of the International University of Health and Welfare Hospital (Approval date:July 21, 2021; Approval number 21-B-8). The patients provided consent after receiving written and verbal explanation of the study protocol.

The authors declare no competing interests.

The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).

He walked down his block and found a lot of stores. He passed a CD store and looked through the front door for a second as he walked. He stopped and went back to look into the store. He saw a beautiful girl about his age and he knew it was love at first sight. He opened the door and walked in, not looking at anything else but her. He walked closer and closer until he was finally at the front desk where she sat.

This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BYNC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is noncommercial. See:https://creativecommons.org/Licenses/by-nc/4.0/

Japan

Toshiyuki Kakinuma 0000-0001-7853-4860; Kaoru Kakinuma 0000-0003-4647-9582; Yoshio Matsuda 0000-0002-2890-2802; Michitaka Ohwada 0000-0002-0396-6228; Kaoru Yanagida 0000-0002-5348-3603; Hirotsune Kaijima 0000-0002-1932-4780.

Gong ZM

A

For a while they just hung there to each other laughing and crying and saying things without meaning. She d say a few words like, It was the bus station I meant and he d kiss her speechless and tell her the many things he had done to find her. What apparently13 had happeded three years before was that May had come by bus, not by train, and in her telegram she meant bus station, not railroad station. She had waited at the bus station for days and had spent all her money trying to find Harry. Finally she got a job typing.，，，。“——”，。，3。“”“”。，。，。

Gong ZM