Case Reports

Patient 1 was 33 years old (G1,P1) with a long history of secondary infertility because of endometriosis and tubal factor (bilateral hydrosalpinges diagnosed by hysterosalpingography). She had a history of multiple abdominal procedures because of endometriosis and a cesarean section delivery that had been complicated by a pelvic abscess; based on previous operative reports, she was believed not to be a good candidate for laparoscopic salpingectomy. Once IVF-ET was proposed as the treatment of choice for her infertility, she was stimulated with a long leuprolide acetate protocol that was associated with a combination of recombinant follicle-stimulating hormone and human menopausal gonadotropin and the administration of luteal progesterone. At the time of human chorionic gonadotropin (HCG) trigger, a 20-mm hydrosalpinx was documented by ultrasound scanning. During retrieval, 25 oocytes were aspirated, which resulted in 20 embryos. After extended culture, a total of 8 expanded blastocysts were obtained, 2 of which were transferred on day 5 uneventfully. She did not conceive and returned 3 months later for a frozen ET cycle. The patient was monitored by ultrasound scans during a natural cycle; when the lead follicle reached 17 mm, HCG was administered as per our protocol. At that time, no hydrosalpinx was visible by ultrasound scanning. Two blastocysts were thawed and transferred 5 days after ovulation. The patient received progesterone supplementation of 200 mg twice daily vaginally starting 4 days after HCG administration. The patient conceived and delivered twins by cesarean section delivery. Three years later, she underwent a second frozen ET, during which time no hydrosalpinx was visible by ultrasound scanning. She had 1 blastocyst transferred, which also resulted in a successful pregnancy and delivery.

Patient 2 was 25 years old (G1,P0010,SAB1) with a 1-year history of secondary infertility because of bilateral hydrosalpinges that had been documented on hysterosalpingography. The patient had been involved in a serious motor vehicle accident several years earlier and had required multiple abdominal surgeries at that time. Once IVF-ET was proposed as the treatment of choice for her infertility, she was offered and declined further treatment of her tubal disease before her IVF cycle. She had controlled ovarian hyperstimulation (COH) similar to the previous case; a total of 14 oocytes were obtained, 7 of which were fertilized. The patient underwent a transfer of two 8-cell embryos on day 3 without complications. There were 2 expanded blastocysts that were frozen 2 days later. She did not conceive and returned 3 months later for another fresh IVF cycle, despite having frozen embryos. At that time, she was given a similar stimulation protocol. At the time of retrieval, 25 oocytes were aspirated, and 15 of these were fertilized. She underwent transfer of 2 expanded blastocysts that were transferred on day 5; 6 others were frozen, and again no pregnancy was achieved. Subsequently, she underwent monitoring of a natural cycle, and 2 blastocysts were thawed and transferred 5 days after ovulation. The patient also received progesterone vaginally; she conceived, which resulted in a twin intrauterine gestation. One of the gestational sacs did not progress, and the patient went on to deliver a singleton pregnancy without complications.

Patient 3 was 32 years old (G0) with a 5-year history of primary infertility. She had a history of peritoneal tuberculosis status after treatment for 1 year and an appendectomy and a laparoscopy, which was done abroad and showed extensive pelvic adhesions and a right hydrosalpinx. She decided to proceed with IVF. She was given COH, which was similar to the previous cases; at the time of HCG injection a 24-mm hydrosalpinx was noted by ultrasound scanning. The retrieval resulted in 23 oocytes, of which 20 were fertilized, and a single hatching blastocyst was transferred. A total of 11 blastocysts were frozen. She did not conceive and returned 3 months later for a frozen ET cycle; there was no documentation of hydrosalpinx. A single blastocyst was thawed and transferred and again did not produce a pregnancy. The following month, she underwent another frozen ET, also during a natural cycle with HCG and progesterone supplementation. At the time of HCG administration, an 11.6-mm hydrosalpinx was documented. Two blastocysts were thawed and transferred, which resulted in a twin gestation that was delivered by cesarean section at 35.5 weeks.

Patient 4 was 33 years old (G0) with a history of polycystic ovary syndrome that was treated with metformin. She had undergone previous fertility treatments with several ovulation induction cycles. She was undergoing her first IVF cycle with a long gonadotropin-releasing hormone agonist protocol, which was similar to the previous cases, when a large right hydrosalpinx (22.5 mm) was diagnosed by pelvic ultrasound scanning; the patient decided to continue with COH, despite a recommendation to undergo surgical management for her hydrosalpinx. At the time of retrieval, 18 oocytes were obtained; 2 day-5 expanded blastocysts were transferred, and 8 others were frozen. The cycle was unsuccessful, and 2 months later the patient underwent frozen ET similar to the previous cases. At that time, the hydrosalpinx was noted to be 14 mm. Per patient request, 3 blastocysts were thawed and transferred, which resulted in a chemical pregnancy. Subsequently, the patient underwent a second frozen ET with 2 blastocysts that resulted in a successful singleton pregnancy. During this second frozen cycle, the hydrosalpinx was documented to be 11 mm. Almost 2 years later, the patient returned for another fresh IVF cycle. Again she was given a long leuprolide acetate protocol, and during oocyte retrieval a large right hydrosalpinx (24 mm) was identified and aspirated. Two day-5 blastocysts were transferred, and 5 blastocysts were frozen, but no pregnancy resulted. Two months later, 2 blastocysts were thawed and transferred, at which time the hydrosalpinx was 5.6 mm. This resulted in a successful singleton gestation.

The cases reported here reveal a pattern of failed IVF-ET after fresh transfer of high-quality embryos, followed by successful pregnancies from FET, and in some cases more than once. Some of the patients were offered salpingectomy before IVF but declined treatment because of a history of multiple abdominal surgeries. Overall, there was no implantation in all 6 of the fresh cycles (0/11 embryos transferred), compared with a 60% implantation rate with the transfer of frozen embryos (9/15 blastocysts transferred).

It is likely that COH for IVF-ET results in the enlargement of the hydrosalpinx, which increases the deleterious effects on the transferred embryos. Data on the size of the hydrosalpinges was obtained in 3 of the 4 cases, and ultrasound documentation showed that these hydrosalpinges were present during the fresh cycles and smaller or not present during the frozen transfers. It has been shown that the increased tubal secretion, because of hormonal stimulation, causes a blocked tube to distend by the time of oocyte retrieval. Reaccumulation of fluid in the tube can occur even after aspiration of the hydrosalpinx at the time of retrieval, and the hydrometra itself, which is seen at the time of transfer, can reaccumulate very quickly after it is evacuated. In the 4 patients described in this report, no fluid was seen in the uterine cavity at the time of the fresh transfer. However, this does not exclude the possibility that a small amount of hydrosalpinx fluid, which was not clearly visible by ultrasound scanning, may be present in the uterine cavity and may have prevented implantation. It is also possible that the detrimental effect of the larger hydrosalpinx that is associated with COH may occur through a different mechanism, as discussed earlier. In any case, the transfer of cryopreserved blastocysts during a natural cycle could result in decreased fluid accumulation in the tube, with a resulting improvement in implantation rate.

Most of the studies in the literature that describe decreased implantation with hydrosalpinges in IVF-ET cycles are related to fresh ETs. A few studies include a subset of patients who underwent frozen ET, but these frozen ETs were not evaluated separately. One study that specifically looked at the effects of hydrosalpinx on the implantation of cryopreserved embryos was that of Akman et al, who evaluated transfers of cryopreserved embryos during a natural cycle in 14 patients; all of the patients had an untreated hydrosalpinx, which was documented by ultrasound scanning. They were compared with a control group that included patients without tubal disease, and the study group was found to have significantly lower implantation and pregnancy rates. Of note, the overall implantation rate in the study was rather low for both groups (5% and 10.38%, respectively). The embryos in this study were cryopreserved at the 2 pronuclei stage then thawed and transferred at the cleavage stage. The authors concluded that the presence of hydrosalpinges is associated with lower implantation and pregnancy rates during frozen ET cycles.

The high implantation rate that was seen in our patients who used frozen blastocysts, compared with the cleavage stage embryos in the study of Akman et al, may be related to the ability of a more advanced embryo to better tolerate an inhospitable intrauterine environment. Also, the shorter time interval from blastocyst transfer to implantation in comparison with the transfer of cleavage stage embryos, which creates less exposure to the intracavitary fluid/toxins, may contribute to the improved pregnancy rates that were observed in our study. In addition, the potential negative effects of hydrosalpinges during the window of implantation may have been overcome by the high implantation potential of frozen-thawed expanded blastocysts that was reported recently; the authors suggested enhanced synchronization between blastocyst and endometrial development in natural cycles.

In summary, this is the first case series to suggest a higher implantation rate with frozen ET than fresh ET in patients with untreated hydrosalpinx, in which patients served as their own controls. Although surgical ligation or tubal removal prior to IVF-ET should remain the standard recommendation, we recognize that all cases are not amenable to surgical correction. Based on our initial success, we recommend that further studies be performed to evaluate the pregnancy rates of frozen vs fresh blastocyst transfers in the setting of untreated and inoperable hydrosalpinges.