Rare association of ovarian implantation site for patients with heterotopic and with primary ectopic pregnancies after ICSI and blastocyst transfer

Case report

Flávio Garcia Oliveira,1, Vicente Abdelmassih, André Luiz Eigenheer Costa, José Pedro Balmaceda, Soraya Abdelmassih and Roger Abdelmassih

Clínica e Centro de Pesquisa em Reprodução Humana `Roger Abdelmassih', Rua Maestro Elias Lobo, 805 01433–000, São Paulo, Brazil


    Abstract
 Top
 Abstract
 Introduction
 Case report
 Discussion
 References
 
Two cases of patients with ruptured ovarian pregnancies (P1 = ovarian heterotopic and P2 = primary ovarian ectopic) after intracytoplasmic sperm injection and blastocyst transfer are presented. Laparoscopy was performed on day 40 and day 27 after transfer in cases P1 and P2 respectively. In both cases the ectopic pregnancies were located on the left ovary and were successfully removed by laparoscopy preserving the ovaries. In case P1 the intrauterine pregnancy was not affected. A healthy boy was born after 37 weeks of pregnancy. In this way, potential fertility of the patients and the intrauterine pregnancy were maintained. These cases occurred during a series of blastocyst transfers in which 129 pregnancies were obtained. There were no cases of ovarian ectopic/heterotopic pregnancies from January 1996 to September 1999 in 814 pregnancies obtained from day 2 or day 3 embryo transfers. Because the ovarian ectopic pregnancies occurred in patients with day 5 embryo transfer who otherwise did not have any predisposing factors for ectopic pregnancy, it is advisable to conduct a large scale analysis of future data about the possible association between blastocyst-stage embryo transfer and the somewhat higher risk of unexpected complications of clinical outcome.

Key words: blastocyst/heterotopic pregnancy/ICSI/IVF/ovarian pregnancy


    Introduction
 Top
 Abstract
 Introduction
 Case report
 Discussion
 References
 
The incidence of natural primary ovarian ectopic pregnancy (OEP) ranges from ~1/60 000–1/1500 deliveries, accounting for up to 3.3% of all ectopic pregnancies (EP) (Einenkel et al., 2000Go). The incidence of all natural heterotopic pregnancies (HP) is about 1/30 000 pregnancies. Ovulation induction and controlled ovarian hyperstimulation for assisted reproductive technologies (ART) have dramatically increased the incidence of this condition (Tal et al.,1996Go). The incidence of HP ranges from 0.75 to 3% among the pregnancies from IVF and embryo transfer. However, ovarian heterotopic pregnancies (OHP) only accounted for up to 2.3% of all reported HP, in an extensive review performed by Tal et al. (Tal et al., 1996Go).

The ultrasonographic technologies, especially transvaginal probes, have facilitated earlier diagnosis of HP and EP. Laparoscopy has become the ideal form of diagnostic confirmation of EP and HP and a safe surgical resolution procedure (Pistofidis et al., 1995Go; Wang et al., 1998Go). However, the diagnosis and therapy of EP and HP following ovarian hyperstimulation are complicated by the co-existence of multiple luteal cysts in the hyperstimulated ovaries and an intrauterine pregnancy (IUP). This is especially true for OHP.

The aim of this report is to highlight the possibility of an association between blastocyst transfer and ovarian pregnancy, presenting two successfully treated ovarian pregnancies (a primary ectopic and a heterotopic) in infertile patients who underwent intracytoplasmic sperm injection (ICSI), prolonged in-vitro culture and embryo transfer at blastocyst stage.

Our cases differ from others previously reported in that both implantations occurred on the ovaries after ICSI and blastocyst transfer in two patients who otherwise had no predisposing factors for ectopic implantation.


    Case report
 Top
 Abstract
 Introduction
 Case report
 Discussion
 References
 
Relevant laboratory and clinical data about the two cases are presented in Table IGo. The routine general and gynaecological examination of the patients, including transvaginal ultrasonography (USG), failed to reveal any abnormalities. Hysterosalpingograms performed previously were also normal.


View this table:
[in this window]
[in a new window]
 
Table I. Summary of the most important laboratory and clinical data on the two cases.
 
Controlled ovarian hyperstimulation was achieved using pituitary suppression with leuprolide acetate-long protocol (Lupron®; Abott, São Paulo, Brazil) and recombinant FSH (Puregon®; Organon, São Paulo, Brazil). Patients received human chorionic gonadotrophin (HCG) (Pregnyl®; Organon, São Paulo, Brazil) when at least two follicles of 18 mm (median diameter) were detected. Oocytes were recovered by transvaginal sonographic aspiration. They were injected 3 h after retrieval and cultured in sequential culture media IVF 20, G1.1 and G2.2 (Scandinavian IVF Science, Gothenburg, Sweden) until blastocyst stage. On day 5 of culture, both patients had two blastocysts transferred to the uterus, in 10 µl of culture medium, using an Edwards-Wallace catheter (H.G.Wallace Ltd., Colchester, UK). The luteal phase support was performed with micronized progesterone (Utrogestan®; Laboratories Besins-Iscovesco, Paris, France), 800 mg/day—oral administration—starting on the day of the retrieval. Twelve days after the transfer the serum ß-HCG values (fluorimmunoassay; Delfia; Wallac Oy, Turku, Finland) were measured. Early follow-up ultrasound was performed once a week starting on day 24 after transfer in the case of the ovarian heterotopic pregnancy (P1), who was asymptomatic in this period. Follow-up ultrasound was also performed once a week for the primary ovarian ectopic pregnancy (P2), starting on day 17 after transfer. In this period P2 was asymptomatic and the ultrasound examination did not reveal any intrauterine gestational sac. In both cases a diagnostic laparoscopy was done to complete the diagnosis and it was also a therapeutic intervention.


    Discussion
 Top
 Abstract
 Introduction
 Case report
 Discussion
 References
 
During the period from January 1996 to September 1999, 14 out of 814 (1.7%) gestations that occurred after ICSI and transfer of 2- to 8-cell stage embryos resulted in ectopic pregnancies, 12 of these being in women with predisposing tubal pathologies (adhesions). Day 5 transfers were introduced in our centre in September 1998. From that date until September 1999, 2 out of 129 (1.5%) gestations resulting from ICSI and blastocyst stage embryo transfers were complicated with ectopic pregnancies. There was no increase in the incidence of ectopic pregnancies. However, from January 1996 to September 1999 there were no cases of primary ovarian ectopic nor heterotopic pregnancies in those 814 gestations obtained from day 2 or day 3 embryo transfer, whereas the two ectopic pregnancies out of 129 gestations obtained from blastocyst transfers were both ovarian ectopies (one primary and one heterotopic).

There were two expanded blastocysts transferred to each patient and an ovarian HP and ovarian EP occurred. For such conditions to occur, at least one of the transferred embryos must find its way from the uterine cavity to the ectopic location either during the procedure or shortly thereafter (Tal et al., 1996Go). This is especially true in the cases presented here as the embryos were transferred at the expanded blastocyst stage only a few hours before hatching and attaching to the recipients.

In our ovarian ectopic cases there were no predisposing factors for HP or EP. The volume of transfer was small. There was no pelvic pathology, a predisposing factor for EP (Verhulst et al., 1993Go), and only two embryos were transferred to each patient (Tummon et al., 1994Go).

On day 27 and day 40 after transfer in the cases of OEP and OHP respectively, the patients reported to our centre presenting moderate to severe abdominal pain, abdominal distension and peritoneal irritation signs. Both OHP and ovarian OEP are frequently asymptomatic and clinical presentation is highly variable.

The most common symptom is abdominal pain. Vaginal bleeding is a rare sign in OHP cases, probably due to the co-existence of the IUP. During a USG examination, an OHP is easily misdiagnosed with a luteal cyst, especially because the concurrent presence of an IUP is reassuring.

In the cases presented here, echographic diagnosis was clearly complicated by preceding ovarian stimulation that resulted in the formation of multiple `corpora lutea', making the identification of the ectopic sac extremely difficult. The association of HP or EP with hyperstimulated ovaries is a factor that may retard this diagnosis, even in those cases where an ultrasound scan is performed early (Wang et al., 1998Go). De Muylder et al. reported that presurgical USG diagnosis was not conclusive in a case of OHP (De Muylder et al., 1994Go). In our cases ultrasonographic findings, such as moderate quantity of echogenic fluid in the pouch of Douglas and hypoechogenic masses on the left uterine adnexa, and the values of serum ß-HCG on day 12 after transfer, led us to suspect ectopic implantations.

A diagnostic laparoscopy was necessary, which was also therapeutic, for the definitive diagnosis in both cases. The excellent results of the procedures allowed us to preserve the ovaries. In a recently reported case of primary ovarian pregnancy there was also preservation of the ovary during the laparoscopy (Einenkel et al., 2000Go), although oophorectomy was performed in most previously reported cases (De Muylder et al., 1994Go; Ranieri et al., 1994Go).

The IUP outcome until term is ~66% of all the HP cases including tubal, cervical, cornual, abdominal and ovarian implantations. Early use of diagnostic laparoscopy has also been useful in improving the IUP outcome of HP cases (Pistofidis et al., 1995Go).

Non-surgical procedures have also been reported in the literature, especially selective embryo reduction using KCl injection by transvaginal sonography guidance to resolve tubal and cervical HP (Baker et al., 1997Go; Honey et al., 1999Go). This approach needs a perfect identification of the boundaries of the ectopic gestation so it may be difficult to apply in cases of ovarian pregnancies.

One of the most important aspects of this report is that, in both cases, ectopic implantation of embryos on the ovaries occurred after blastocyst transfer. Prolonged in-vitro culture of pre-implantation human embryos and blastocyst-stage transfer is only recently gaining more advocation and popularity to maintain or increase pregnancy rate and to decrease multiple pregnancies. However, possible complications associated with this approach are not yet studied or determined. Until now there was only one publication where a significantly higher incidence of monozygotic twin gestations was observed after blastocyst transfer in comparison with day 2 and day 3 embryo transfer, indicating new or altered pathological consequences of this technique (da Costa et al., 2001Go). The facts that (i) from 129 pregnancies after blastocyst transfer the two ectopic implantations were both on the ovary, while from 814 pregnancies after day 2 and day 3 transfer no ovarian implantation or heterotopic pregnancies occurred, and (ii) none of the two patients with ovarian ectopic/heterotopic pregnancies had any predisposing factors, while 12 of the 14 ectopic (tubal) pregnancies of day 2 and day 3 embryo transfer had predisposing tubal factors, indicate the possibility that blastocyst-stage embryo transfer may be associated with different complications.

These outcomes raise the possibility that prolonged embryo culture and blastocyst transfer may be associated with a somewhat higher risk of pathological outcome. By highlighting this experience we seek to raise awareness of this possibility, which may be confirmed or refuted by larger scale studies.

Further improvement in the clinical outcome of these cases will mainly come from increased clinician awareness and early invasive diagnostic techniques.


    Notes
 
1 To whom correspondence should be addressed at: Clínica e Centro de Pesquisa em Reprodução Humana `Roger Abdelmassih'. Rua Maestro Elias Lobo, 805 01433–000, São Paulo, Brazil. E-mail: flaviogo2{at}uol.com.br Back


    References
 Top
 Abstract
 Introduction
 Case report
 Discussion
 References
 
Baker, V.L., Givens, C.R. and Cadieux, M.C. (1997) Transvaginal reduction of an interstitial heterotopic pregnancy with preservation of the intrauterine gestation. Am. J. Obstet. Gynecol., 176, 1384–1385.[ISI][Medline]

da Costa, A.L.E., Abdelmassih, S., Oliveira, F.G. et al. (2001) Monozygotic twins and transfer at the blastocyst stage after ICSI. Hum. Reprod., 16, 333–336.[Abstract/Free Full Text]

De Muylder, X., De Loecker, P. and Campo, R. (1994) Heterotopic ovarian pregnancy after clomiphene ovulation induction. Eur. J. Obstet. Gynecol. Reprod. Biol., 53, 65–66.[ISI][Medline]

Einenkel, J., Baier, D., Horn, L.C. et al. (2000) Laparoscopic therapy of an intact primary ovarian pregnancy with ovarian hyperstimulation syndrome. Hum. Reprod., 15, 2037–2040.[Abstract/Free Full Text]

Honey, L., Leader, A. and Claman, P. (1999) Uterine artery embolization—a successful treatment to control bleeding cervical pregnancy with a simultaneous intrauterine gestation. Hum. Reprod., 14, 553–555.[Abstract/Free Full Text]

Pistofidis, G.A., Mastrominas, M.J. and Dimitropoulos, K. (1995) Laparoscopic management of heterotopic pregnancies. J. Am. Assoc. Gynecol. Laparosc., 2, S42–S43.

Ranieri, D.M., Vicino, M.G., Simonetti, S. et al. (1994) Heterotopic ovarian pregnancy after in vitro fertilization and embryo transfer and contralateral tubal pregnancy after gamete intrafallopian transfer. Minerva Ginecol., 46, 365–368.[Medline]

Tal, J., Haddad. S., Nina. G. et al. (1996) Heterotopic pregnancy after ovulation induction and assisted reproductive technologies: a literature review from 1971 to 1993. Fertil. Steril., 66, 1–12.[ISI][Medline]

Tummon, I.S., Whitmore, N.A., Daniel, A.S. et al. (1994) Transferring more embryos increases risk of heterotopic pregnancy. Fertil. Steril., 61, 1065–1067.[ISI][Medline]

Verhulst, G., Camus, M., Bollen, N. et al. (1993) Analysis of the risk factors with regard to the occurrence of ectopic pregnancy after medically assisted procreation. Hum. Reprod., 8, 1284–1287.[Abstract]

Wang, P.H., Chao, H.T., Tseng, J.Y. et al. (1998) Laparoscopic surgery for heterotopic pregnancies: a case report and a brief review. Eur. J. Obstet. Gynecol. Reprod. Biol., 80, 267–271.[ISI][Medline]

Submitted on April 17, 2001; accepted on June 24, 2001.





This Article
Abstract
FREE Full Text (PDF )
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Search for citing articles in:
ISI Web of Science (2)
Request Permissions
Google Scholar
Articles by Oliveira, F. G.
Articles by Abdelmassih, R.
PubMed
PubMed Citation
Articles by Oliveira, F. G.
Articles by Abdelmassih, R.