10 October 2024: Articles
Recurrent Heterotopic Pregnancy Following Frozen-Thawed Embryo Transfer: A Case Study and Comprehensive Literature Review
Mistake in diagnosis, Management of emergency care, Rare disease
Yonghuan Lv12ACDE, Wenyan Tian12ADG, Xueru Song12AD, Ye Tian12CDF, Kan Wang12BCF, Fengxia Xue12AG*DOI: 10.12659/AJCR.945053
Am J Case Rep 2024; 25:e945053
Abstract
BACKGROUND: Recurrent heterotopic pregnancy is a serious and rare pregnancy complication that occurs after in vitro fertilization and embryo transfer, posing a great threat to the safety of the mother and intrauterine fetus. We report a case of recurrent heterotopic pregnancy after in vitro fertilization and embryo transfer. We also reviewed the literature to explore the causes, diagnosis, treatment, and prevention of recurrent heterotopic pregnancy.
CASE REPORT: A 32-year-old woman with tubal factor infertility underwent in vitro fertilization and embryo transfer. Oocyte extraction was performed twice, while embryo transfer was performed 4 times, with 2 embryos transferred each time. No pregnancies occurred during the 2 fresh embryo transfer cycles; however, heterotopic pregnancies occurred during both frozen-thawed embryo transfer cycles. Ultrasonography detected only the first heterotopic pregnancy, at 6 weeks after embryo transfer. As the intrauterine embryo had stopped developing, laparoscopically monitored dilatation and curettage and removal of the affected fallopian tubes were performed. The second heterotopic pregnancy was detected 3 weeks after embryo transfer, guided by the ultrasound examination conducted earlier. After timely surgical treatment, a live birth occurred.
CONCLUSIONS: This case and review of the literature elucidates the importance of considering the possibility of a heterotopic pregnancy during ultrasound examinations, especially in patients who utilized assisted reproductive technology to transfer multiple embryos.
Keywords: Embryo Transfer, Fertilization in Vitro, Pregnancy, Heterotopic, Reproductive Techniques, Assisted
Introduction
A heterotopic pregnancy (HP), which relatively rarely occurs with natural conception, with an incidence of approximately 1 in 30 000 pregnancies, is defined as the simultaneous occurrence of intrauterine and ectopic pregnancy [1]. The incidence of HP has significantly increased from 1 in 100 to 1 in 1000 pregnancies with the widespread application of assisted reproductive technology (ART) [2,3]. The main clinical symptoms of HP are abdominal pain and vaginal bleeding [4]. Risk factors are primarily related to multiple embryo transfer and controlled ovarian stimulation during ART [5]. Other risk factors include oviduct patency impairment caused by history of chronic pelvic inflammation disease, fallopian tube surgery, ectopic pregnancy, and induced abortion [6]. Although HP has been widely reported, recurrent HP is extremely rare. We report the case of a patient who experienced recurrent HP during 2 cycles of frozen-thawed embryo transfer and achieved a live birth after surgical treatment. Additionally, we reviewed the literature to explore the characteristics and causes of HP recurrence.
Case Report
A 32-year-old woman underwent in vitro fertilization (IVF) because of abnormal oviduct patency. Seven years previously, she underwent an induced abortion during early pregnancy. The patient had no history of pelvic inflammatory disease, pelvic surgery, or fallopian tube surgery. Ultrasound salpingography revealed an unobstructed left fallopian tube; however, the right proximal fallopian tube was obstructed (Figure 1). Prior to IVF treatment, the patient’s transvaginal ultrasonography showed normal ovarian reserve function and no signs of endometriosis. Endometrial resectivity, endometrial microbiota testing, and immunohistochemistry were not performed prior to embryo transfer. During the first IVF embryo transfer cycle, 2 high-quality cleavage embryos were transferred; however, pregnancy was not achieved.
Three months later, the patient underwent hormone replacement therapy and frozen-thawed embryo transfer. Two high-quality 8-cell embryos were transferred. Serum β-human chorionic gonadotropin (β-HCG) levels at 14 and 16 days after embryo transfer were 896.42 mIU/mL and 1637.55 mIU/mL, respectively. Twenty-five days after embryo transfer (gestational age of 5 weeks, 4 days), transvaginal ultrasonography showed an intrauterine gestational sac without a fetal bud; 6 and 13 days later, no fetal bud was still observed. There were no abnormal echoes in the bilateral adnexal area during 3 ultrasonography examinations. After another week of observation, there were still no fetal buds. However, a small mass, an anechoic area, and the absence of a fetal bud were observed in the right adnexa (Figure 2). Therefore, an HP was diagnosed. Laparoscopically monitored dilatation and curettage and complete aspiration of the villi and decidual tissues were performed. Simultaneous laparoscopic surgery was performed, and no obvious abnormalities were observed in the left fallopian tube; thus, left fallopian tube resection was not performed to prevent ectopic pregnancy again. The right fallopian tube ampulla was enlarged to approximately 2×1.5 cm, without rupture. We removed the right fallopian tube from the root, and pathological examination revealed an ectopic pregnancy in the right fallopian tube. No chromosomal abnormalities or copy number variations were observed in the curetted intrauterine embryos.
Egg retrieval was conducted 8 months after the HP. Prior to this embryo transfer, the patient was informed of the possibility of another ectopic pregnancy. It was recommended to transfer only 1 embryo, to avoid HP recurrence, but the patient requested 2 embryos. Considering that the patient did not have contraindications for twin pregnancy, 2 embryos were ultimately transferred; however, pregnancy was not achieved. Two months later, natural cycle frozen-thawed embryo transfer was performed. Owing to the previous embryo transfer not resulting in pregnancy, the patient still requested 2 embryos for this transfer; thus, 2 good-quality cleavage-stage embryos were then transferred. Serum β-HCG levels were 2180.47 mIU/mL and 5662.4 mIU/mL at 14 and 16 days after embryo transfer, respectively. As the β-HCG level was higher than it was previously, ultrasonography was performed 1 week earlier than usual. The intrauterine gestational sac and yolk sac were observed during the transvaginal ultrasound examination 24 days after embryo transfer (gestational age of 5 weeks, 3 days). An anechoic area and visible yolk sac were observed in the left adnexa (Figure 3); hence, HP was considered. One week later, an intrauterine gestational sac, visible fetal bud, and heartbeat were observed. Additionally, an anechoic area within a moderately echoic mass, fetal bud, and primitive heart tube pulsations were observed on the left side. Laparoscopy was performed because the ectopic gestational sac was significantly enlarged. The absence of the right fallopian tube and enlargement of the left fallopian tube ampulla were observed intraoperatively. Left salpingectomy was performed, and postoperative pathology results revealed placental villi and decidual tissues. A healthy male infant with a weight of 3600 g was born via cesarean delivery at 39 weeks of gestation. At 1 year of age, the infant exhibited normal physical and mental development.
Discussion
We report a case of recurrent HP after 2 frozen-thawed embryo transfer cycles. To the best of our knowledge, recurrent HP has been described by only 3 case reports (Table 1) [7–9]. When HP occurs, maternal safety is compromised, and the fetus can also be affected. Therefore, clinicians should be aware of recurrent HP and carefully manage such cases appropriately, particularly when patients have existing risk factors.
Fallopian tube abnormalities are the main cause of HP. Factors such as pelvic inflammatory disease and history of pelvic surgery, endometriosis, ectopic pregnancy, and fallopian tube resection can obstruct the fertilized eggs in the fallopian tubes, thus preventing them from returning to the uterine cavity, and increasing the risk of HP [4]. Our patient did not have any high-risk factors. However, combined with a history of induced abortion and right fallopian tube obstruction, the patient may have had a pelvic infection previously. Excluding potential infections, such as chronic endometritis, may help prevent the occurrence of HP. Unfortunately, the patient did not undergo analysis of the endometrial microbiota and was not subjected to immunohistochemical screening for chronic endometritis before transplantation.
In the present case, an obstructed fallopian tube may have been the cause of the first HP; however, HP occurred despite the absence of obvious abnormalities in the left fallopian tube. In 2006, Ben-Ami et al reported a patient with recurrent HP who underwent prophylactic resection of the contralateral damaged fallopian tube [9]. However, an HP comprising a residual-angle pregnancy occurred after the subsequent embryo transfer, indicating that salpingectomy could not completely prevent HP recurrence, and that embryos could still be implanted in the uterine horn, interstitial tube, fallopian tube stump, and other sites. In 1997, Raziel et al reported a case of recurrent HP in a patient with unobstructed bilateral fallopian tubes as confirmed by laparoscopy before IVF embryo transfer; however, recurrent HP occurred, suggesting that patients with unobstructed fallopian tubes could experience HP [8]. It is crucial to prevent ectopic pregnancy recurrence during treatment for the initial ectopic pregnancy. Salpingectomy can reduce the possibility of recurrent ectopic pregnancy, but it cannot completely avoid it, as the embryo can also implant in the interstitial tube/corner of the fallopian tube. Meanwhile, removing the interstitial tube/ corner of the fallopian tubes increases the risk of uterine rupture. Therefore, if the contralateral fallopian tube is damaged during the initial ectopic pregnancy surgery, preventive resection is feasible. However, if the contralateral fallopian tube is normal, and the patient still has the possibility of natural conception, the contralateral fallopian tube should be preserved [8].
Each embryo has the potential to implant; therefore, the risk of HP increases with the increase in the number of transferred embryos [5]. However, the Chinese expert consensus on the numbers of embryos transferred in 2018 did not include HP as a contraindication for transferring multiple embryos. The consensus suggests that regardless of age or number of transfer cycles, the number of embryo transfer per cycle should be ≤2. Suggestions for single embryo transfer include uterine factors such as a scarred uterus and cervical dysfunction, which are unfavorable for twin pregnancy, individuals whose overall condition is not suitable for twin pregnancy, and pre-implantation genetic test cycles [10]. For the patient in the present case and the patients described in the 3 previous case reports of recurrent HP, 2 or more embryos were transferred. Recurrent HP may have been avoided if a single embryo transfer had been performed after the first HP. Because of the recent promotion of single embryo transfer strategies, complications associated with ART, such as multiple pregnancies and HP, have significantly decreased [11]. Therefore, single embryo transfer may minimize the risk of HP.
The diagnosis of HP mainly depends on ultrasonographic findings. Typically, patients who conceive with IVF undergo ultra-sonography at 4 weeks after embryo transfer (gestational age of 6 weeks). During the first HP of our patient, an ectopic pregnancy was not observed during 3 ultrasound examinations performed before 7 weeks of gestation; however, an ectopic pregnancy was detected at 8 weeks of gestation, likely because of its slow development. Therefore, we should be aware of the possibility of HP, especially among patients with characteristics that place them at high risk of HP after IVF embryo transfer and those who have undergone multiple embryo transfers. Furthermore, for these patients, ultrasound examinations can be performed 3 weeks rather than 5 weeks after embryo transfer.
Conclusions
This is the first report of recurrent HP after 2 frozen-thawed embryo transfer cycles. Additionally, this is the first review of previously published cases of recurrent HP. These findings highlight the need for increased vigilance of the possibility of HP recurrence. Ultrasound examinations should be performed as soon as possible after embryo transfer for patients who have undergone multiple embryo transfer.
Figures
References:
1.. DeVoe RW, Pratt JH, Simultaneous intrauterine and extrauterine pregnancy: Am J Obstet Gynecol, 1948; 56; 1119-26
2.. Perkins KM, Boulet SL, Kissin DM, Jamieson DJ, Risk of ectopic pregnancy associated with assisted reproductive technology in the United States, 2001–2011.: Obstet Gynecol., 2015; 125; 70-78
3.. Maleki A, Khalid N, Patel CR, El-Mahdi E, The rising incidence of heterotopic pregnancy: Current perspectives and associations with in-vitro fertilization: Eur J Obstet Gynecol Reprod Biol, 2021; 266; 138-44
4.. Reece EA, Petrie RH, Sirmans MF, Combined intrauterine and extra-uterine gestations: A review: Am J Obstet Gynecol, 1983; 146; 323-30
5.. Dor J, Seidman DS, Levran D, The incidence of combined intrauterine and extrauterine pregnancy after in vitro fertilization and embryo transfer: Fertil Steril, 1991; 55; 833-34
6.. Pi R, Liu Y, Zhao X, Tubal infertility and pelvic adhesion increase risk of heterotopic pregnancy after in vitro fertilization: A retrospective study.: Medicine (Baltimore)., 2020; 99; e23250
7.. Shavit T, Paz-Shalom E, Lachman E, Unusual case of recurrent heterotopic pregnancy after bilateral salpingectomy and literature review.: Reprod Biomed Online, 2013; 26; 59-61
8.. Raziel A, Friedler S, Herman A, Recurrent heterotopic pregnancy after repeated in-vitro fertilization treatment: Hum Reprod, 1997; 121; 810-12
9.. Ben-Ami I, Panski M, Ushakov F, Recurrent heterotopic pregnancy after bilateral salpingectomy in an IVF patient: Case report: J Assist Reprod Genet, 2006; 23; 333-35
10.. , Chinese expert consensus on numbers of embryos transferred.: J Reprod Med, 2018; 27(10); 940-45
11.. Li Z, Sullivan EA, Chapman M, Risk of ectopic pregnancy lowest with transfer of single frozen blastocyst: Hum Reprod, 2015; 30; 2048-54
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