Human Reproduction vol.5 no.8 pp.1025- 1028, 1990
CASE REPORT
Rare ectopic pregnancies after in-vitro fertilization: one unilateral twin and four bilateral tubal pregnancies
Boum-Hallam Medical Centre, 112 Harley Street, London WIN 1AF, UK
Between 1985 and 1989, one unilateral twin and four bilateral tubal pregnancies were encountered among 124 extrauterine pregnancies and 1648 intrauterine pregnancies following in-vitro fertilization and embryo transfer. The two factors associated with this high incidence of single and multiple extrauterine pregnancies were tubal damage and multiple embryo transfer. Embryos at different stages of development appear to have the capacity to implant ectopkally. Despite advances in diagnostic capabilities, ectopic pregnancy remains a major cause of maternal mortality. Early diagnosis prior to rupture must be made if mortality and morbidity are to be abolished. The use of transvaginal sonography has improved the diagnosis of ectopic pregnancy and should be routinely used in all pregnancies following assisted conception. The identification of an intrauterine pregnancy should not be sufficient to rule out the possibility of an extrauterine pregnancy or even bilateral tubal pregnancies. Key words: bilateral/IVF — ET/tubal pregnancy/unilateral twin
The rarest form of binovular twin pregnancy is bilateral, simultaneous tuba] pregnancy (Fox and Mevs, 1963). Twin pregnancies in the same tube are more frequent and simultaneous extra- and intrauterine pregnancies are the most frequent (Norris, 1953). Such rare conditions occur more frequently during assisted human conception. We report one unilateral twin and four bilateral tuba! pregnancies after in-vitro fertilization and embryo transfer (TVF-ET). Case 1 A 28-year-old patient, para 0+0, conceived after IVF-ET. She was initially referred for donor insemination in view of her husband's severe oligoasthenozoospermia. Hysterosalpingography confirmed normal uterine countour and patent Fallopian tubes one year before her referral. She failed to conceive during 11 cycles of donor insemination and two cycles of intrauterine insemination with superovulation. Laparoscopic assessment during gamete intra-Fallopian transfer (GIFT) revealed that the left tube was distended and the fimbriae were clubbed with an occluded distal end. There were also fine adhesions between the © Oxford University Press
left tube and the bowel. The right tube was oedematous and the fimbriae blunted, but there were no peritubal adhesions and the distal end was not occluded. Seven oocytes were recovered by laparoscopy and four of them were replaced in the right tube. However, she did not conceive. She subsequently underwent FVF—ET. Multiple follicular development was induced with human menopausal gonadotrophin (HMG, Pergonal, Serono, Welwyn Garden City, UK) 225 IU daily after pituitary suppression with a luteinizing hormone releasing hormone agonist (LHRH-a, buserelin, Suprefact, Hoechst, Hounslow, UK) 0.2 mg subcutaneously daily. Human chorionic gonadotrophin (HCG, Profasi, Serono; 5000 IU) was administered intramuscularly on day 12. Transvaginal oocyte recovery was performed 35 h later under sonographic control. Six oocytes were recovered, two of which fertilized and two embryos, 4-cell and 2-cell, were replaced using a Wallace catheter (Wallace, Colchester, UK). Luteal phase support was given in the form of HCG 2000 IU on the day of transfer and 3 days later. Serum /3-HCG was positive 15 days after oocyte recovery. Twenty-five days after oocyte recovery, the patient complained of pain in the right iliac fossa and was admitted to the local hospital. Abdominal sonography did not identify an intrauterine or extrauterine pregnancy. The ultrasound scan was repeated 3 days later but did not identify a pregnancy. The abdominal pain became worse and she became faint. Ectopic pregnancy was suspected and emergency laparoscopy revealed a bilateral tubal pregnancy. The right ectopic pregnancy had ruptured and the left had incipient rupture. Laparotomy and bilateral salpingectomy was performed. Histological examination confirmed the presence of chorionic villi in both tubes. She made an uneventful recovery and is currently undergoing her second FVF cycle. Case 2 A 28-year-old woman was referred with a 4-year history of secondary infertility due to tubal damage. At the age of 20 she underwent an elective abortion and subsequently had an intrauterine contraceptive device fitted. It was removed 3 months later due to pelvic infection and thereafter she used oral contraceptives for 3 years. Laparoscopic assessment of the pelvis revealed bilateral tubal blockage and peritubal adhesions. Bilateral salpingostomy with ovariolysis and ventrosuspension was performed. Follow-up laparoscopy revealed a patent right Fallopian tube and healthy ovary but adhesions had redeveloped around the left ovary and the left oviduct filled with dye but there was no spill. In her first IVF cycle, she had four embryos replaced but did not conceive. In her second IVF cycle, multiple follicular 1025
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Botros Rizk, Samuel Morcos, Susan Avery, Kay Elder, Peter Brinsden, Bridgett Mason and Robert Edwards
B.Rizk et al.
Case 3 A 29-year-old patient was referred for IV with a 4-year history of primary infertility because of tubal damage. Laparoscopic assessment revealed bilateral hydrosalpinges. Multiple follicular development was induced with buserelin 0.5 mg subcutaneously on days 2—4 and HMG 225 IU daily from day 3. Transvaginal oocyte recovery was performed under ultrasound control. Six oocytes were recoverd of which four fertilized and three embryos (6-cell, 4-cell and pronuclear) were replaced. Serum £-HCG levels were 40 and 488 IU/1 at 15 and 20 days after oocyte recovery, respectively. Twenty-eight days after oocyte recovery the patient was admitted to the local hospital complaining of abdominal pain and slight vaginal bleeding. The serum level of/3-HCG was 13 750 IU/1 at 30 days after oocyte recovery. Transvaginal sonography identified a right tubal pregnancy. Laparoscopy was performed which revealed bilateral tubal pregnancies and a bilateral salpingectomy was performed. Histological examination confirmed the diagnosis of bilateral tuba! pregnancy. Case 4 A 36-year-old woman had a 10-year history of primary infertility because of her husband's oligoasthenozoospermia. Hysterosalpingography showed a normal uterine outline and patent Fallopian tubes. The pelvis was normal at laparoscopic assessment. The 42-year-old husband had a sperm count that varied between 10 and 25 x lO^ml, motility 10-30% with poor progression and 50% abnormal forms. He underwent left 1026
varicocoele ligation and bilateral hydrocoele excision. The sperm count did not improve despite treatment with tamoxifen and mesterelone for one year. At that stage the couple were referred for IVF. She conceived following her second IVF attempt. Multiple follicular development was induced with clomiphene citrate 100 mg daily from day 2 to day 6 and HMG 150 IU daily from day 4 to day 9. Eighteen oocytes were recovered by laparoscopy. Two embryos (7-cell and 2-cell) were replaced 3 days after oocyte recovery. A pregnancy test was positive 15 days after oocyte recovery. Thirty-two days after oocyte recovery, the patient developed vaginal bleeding and bilateral lower abdominal pain. These symptoms were attributed to threatened abortion. Abdominal sonography performed at the local hospital, 38 days after oocyte recovery, did not identify an intrauterine gestation sac. The pregnancy test was still positive. The ultrasound scan was repeated one week later but did not identify a pregnancy. At that point, the abdominal pain became severe, vaginal bleeding recurred and she suffered from episodes of fainting and vomitting. Laparotomy revealed a ruptured left tubal pregnancy as well as a small gestation sac protruding from the fimbrial end of the right tube. Bilateral salpingectomy was performed. Histology confirmed the diagnosis of bilateral tubal pregnancies. Case 5 A 34-year-old woman was referred for assisted conception with a 5-year history of secondary infertility. At the age of 8 years she had an appendicular abscess which was drained. She had a 12 weeks spontaneous abortion 11 years prior to her referral. Laparoscopic assessment and hydrotubation revealed the left tube to be patent but the right tube was occluded with severe peritubal adhesions. She conceived after the third IVF treatment. Multiple follicular development was induced with clomiphene citrate 100 mg on days 2 - 6 and HMG 375 IU daily from day 4 to day 9. Oocyte recovery was performed under ultrasound control using the transabdominal transvesical route for the left ovary and the direct transabdominal route for the right ovary. Eight oocytes were retrieved and four embryos (three 4-cell and one 2-cell) were replaced. Luteal support was give in the form of progesterone vaginal pessaries of 400 mg twice daily. A pregnancy test was positive 15 days after oocyte recovery. The patient was asymptomatic when she attended for the ultrasound scan 35 days after the oocyte recovery. Abdominal sonography identified a viable unruptured tubal twin pregnancy. A left extrauterine gestation sac that measured 18 x 12 x 23 mm in which a fetal pole with 9 mm crown-rump length and beating fetal heart as well as a yolk sac was visible. The second gestation sac measured 20 x 21 x 19 mm and a fetal pole with a beating fetal heart and a yolk sac was identified in it. Laparotomy and salpingectomy was performed. The diagnosis was confirmed histologically. The patient subsequently adopted a baby. Discussion The occurrence of bilateral simultaneous tubal pregnancy is rare. Its incidence has been reported to range from 1/725 to 1/1580
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development was induced with buserelin 0.5 mg subcutaneously on days 1 - 3 and HMG 150 IU on days 3 - 7 , 300 IU on days 8 - 1 0 and 450 IU on days 11-13. Fourteen oocytes were recovered by the transvaginal route under sonographic control and four embryos (two 4-cell, one 2-cell and one pronuclear) were replaced. Luteal support was given in the form of HCG 2000 IU on the day of transfer and 3 days later. Serum jS-HCG 15 days after oocyte recovery was positive. Thirty-two days after oocyte recovery, slight vaginal loss occurred followed by mild abdominal pain which settled spontaneously. Abdominal ultrasound performed 37 days after oocyte recovery revealed an empty intrauterine gestation sac equivalent to 47—49 days gestation. Two days later, acute bilateral lower abdominal pain occurred and she was admitted to hospital. An abdominal ultrasound scan identified bilateral tubal pregnancies. Laparotomy confirmed bilateral ruptured tuba! pregnancies and a bilateral salpingectomy was performed. Evacuation of the uterus was not performed in accordance with the patient's request. Blood loss of 1000 ml was estimated and two units of blood were transfused. She subsequently developed vaginal bleeding and abdominal pain which were followed by passing a decidual cast. Histological examination confirmed chorionic villi in both Fallopian tubes and only decidual tissue from the uterine cast. However, histological examination was not performed on all the products of conception that were passed vaginally. She made a good recovery and subsequently underwent an unsuccessful IVF cycle.
Ectopfc pregnandts after IVF
to 0.8 per 1000 in 1980. However the number of ectopic pregnancies increased from 17 800 to 52 000 thus offsetting the reduction in fatality (Dorfinan, 1983). It therefore appears that the only effective way to abolish mortality and morbidity from ectopic pregnancy is by early diagnosis prior to rupture. In 1950, Stewart reviewed 139 reported cases of bilateral ectopic pregnancies and found that the diagnosis was not made before operation except in one case. Forty years later the diagnosis still remains a clinical challenge. In spontaneous conception one effective way to rule out extrauterine pregnancy is by diagnosing the intrauterine pregnancy because the frequency of heterotopic pregnancy in spontaneous conception ranges between 1 in 3889 to 1 in 6778 (Harm et al., 1984; Bello et al., 1986). This principle does not hold true for pregnancies after IVF-ET, since almost 1% of them are combined pregnancies (Rizk et al., 1989). In fact, the diagnosis of ectopic gestation in the second and fourth cases was delayed as the symptoms of pain and bleeding were attributed to threatened abortion of the intrauterine pregnancy, hi the second case, it was difficult to determine whether an intrauterine pregnancy ever existed or if the empty sac identified at ultrasound scan was a misinterpretation of the decidual reaction to the extrauterine pregnancies. The use of transvaginal sonography improved the diagnosis of ectopic pregnancy; the sensitivity varied from 82 to 100%, the specificity 98.2% and the positive predictive value 93 to 98% (Stiller et al., 1989; Timor-Tritsch et al., 1989a). The majority of the ectopic pregnancies were detected at an early stage prior to rupture. Recognizing the high risk of ectopic pregnancy after IVF-ET, transvaginal sonography should be implemented for all clinical FVF pregnancies. Furthermore, with the increased incidence of heterotopic pregnancy and bilateral tubal pregnancy, the identification of an intrauterine or ectopic pregnancy should not be sufficient to rule out a co-existent extrauterine pregnancy, as in the third case, and the pelvis should be visualized carefully. The predictive value of /3-HCG in diagnosing ectopic pregnancy after IVF —ET was addressed by Okamoto et al. (1987). The authors achieved a 100% sensitivity by taking a high cut-off limit of the 25th centile of ongoing intrauterine pregnancy to diagnose ectopic pregnancy. However, the /3-HCG levels in bilateral tubal pregnancies might be higher than the 25th centile of intrauterine pregnancies (as in the third case) and another cut off level should be determined. The concept of 'discriminatory /3-HCG zone' at which ultrasound detects the earliest normal intrauterine pregnancy was introduced by Kadar et al. (1981). One of the limitations of this approach was that 40% of patients at risk of ectopic pregnancy had initial /3-HCG below the discriminatory value (Romero et al., 1985). However as transvaginal sonography has improved the imaging of the pelvic structures, the intrauterine gestation sacs could be observed at lower discriminatory zones (Goldstein etal., 1988). Furthermore, the higher values of /3-HCG in bilateral ectopic pregnancy compared to unilateral ectopic pregnancy would make the diagnosis of extrauterine pregnancy easier when an intrauterine gestation sac could not be identified on ultrasound scan. It must be stressed, however, that a high index of suspicion of ectopic pregnancy is needed if delays in diagnosis are to be avoided. Tait (1884) was the first to perform salpingectomy for ruptured ectopic pregnancies. Over the last century, very little has changed 1027
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extrauterine pregnancies (Abrams and Kanter, 1948; Stewart, 1950). We have encountered four bilateral tubal pregnancies amongst 124 extrauterine pregnancies and 1648 intrauterine pregnancies. This gives an incidence of 1/30 extrauterine pregnancies and 1/412 intrauterine pregnancies. This calculation is open to considerable variation since the true incidence of unior bilateral ectopic pregnancies is unlikely to be known with any accuracy because many ectopic gestations undergoing early spontaneous resolution would not have been recorded. In 1939, Fishback laid down the principles for acceptance of an authentic case of simultaneous bilateral extrauterine pregnancy: 'there should be a description of the fetuses or any portion of them found, as well as of placental material. A microscopic examination may be necessary to confirm the diagnosis and to give criteria for fixing the pregnancy periods. Especially is this needed where only a haematosalpinx is present grossly'. Norris (1953) clarified this principle, stating that the presence of chorionic villi in each tube should be sufficient to justify the diagnosis. The first reported pregnancy after IVF — ET was an ectopic pregnancy (Steptoe and Edwards, 1976). In 1986, Cohen et al. found a 5% risk of ectopic pregnancy after IVF — ET in a large multicentre collaborative study. The first case of bilateral tubal pregnancy following IVF —ET was confirmed by Hewitt et al. (1985). A unilateral tuba! twin pregnancy occurred after IVF and the transfer of four embryos (Dor et al., 1984) and a combined twin ectopic pregnancy and intrauterine gestation was reported after the transfer of six embryos (Porter et al., 1986). Fifteen cases of heterotopic pregnancies encountered during 5 years were presented by Rizk et al. (1989). Two factors associated with this high incidence of single and multiple extrauterine pregnancies after IVF — ET are tubal damage and multiple embryo transfer. It was interesting to note in the first case that the tubal pregnancies occurred after the IVF-ET treatment and not the GIFT procedure. Of additional interest was the fact that the tubes were normal when assessed by hysterosalpingography but found to be damage during the GIFT after the unsuccessful inseminations. Contrary to expectation, the tubal twin prengnacy in the fifth case occurred in the patent tube rather than the damaged tube. The present cases also clarify the capacity of embryos to implant ectopically. In the fourth case, there were marked differences in the stage of development of the two replaced embryos (2-cell and 7-cell), yet both implanted. In the second and third cases, it is possible that the pronucleate embryos might have implanted ectopically. The fact that only two embryos were replaced in the first and the fourth case shows that there is no direct correlation between the number of embryos replaced and the risk of multiple extrauterine pregnancy. The same conclusion can be drawn from an analysis of heterotopic pregnancies (Rizk et al., 1991). The mortality rate from bilateral ectopic pregnancies in the first half of the twentieth century was 3.6%. This was considered surprisingly low as the mortality rate from unilateral ectopic pregnancies was 2.5% at that time (Stewart, 1950). The cause of death was always haemorrhage, early and late. Despite advances in diagnostic capabilities, ectopic pregnancy remains a leading cause of maternal mortality. In the USA, the death rate from ectopic pregnancy decreased from 3.5 per 1000 in 1970
B.Rizk et al.
References Abrams,R.A. and Kanter,A.E. (1948) Bilateral simultanous extra-uterine pregnancy. Am. J. Obstet. Gynecoi, 56, 1198-1200. Bello,G.V., Schonolz.D., Moshirpur.J., Jeng.D.Y. and Berkowitz.R. (1986) Combined pregnancy: the mount Sinai experience. Obstet.
Gynaecol. J., 41, 603-613. CohenJ., Mayaux,M.-J., Guihard-Moscato,M.-L. and Schwartz,D. (1986) In-vitro fertilization and embryo transfer: a collaborative study of 1163 pregnancies on the incidence and risk factors of ectopic pregnancies. Hum. Reprod., 1, 255—258. Dor,J., Rudak.E., Mashiach.S., Goldman.B. and Nebel.L. (1984) Unilateral tuba] twin pregnancy following in vitro fertilization and embryo transfer. Fertil. Steril., 42, 297-299. Dorfman,S.F. (1983) Deaths from ectopic pregnancy United States, 1979-1980. Obstet. Gynecoi., 62, 334-338. Feichtinger.W. and Kemeter.P. (1987) Conservative treatment of ectopic pregnancy by transvaginal aspiration under sonographic control and methotrexate injection. Lancet, 1, 381—382. Fishback.H.R. (1939) Bilateral simultaneous tubal pregnancy. Am. J.
Obstet. Gynecoi., 37, 1035-1037. Fox.E.J. and Mevs.F.F. (1963) Simultaneous bilateral tubal pregnancies.
Obstet. Gynecoi., 21, 499-501. Goldstein.S.R., Snyder.J.R., Watson,C. and Danon.M. (1988) Very early pregnancy detection with endovaginal ultrasound. Obstet. Gynecoi., 72, 200-204. Hann.L.E., Bachmann.D.M. and McArdle.C. (1984) Coexistent intrauterine and ectopic pregnancy in re-evaluation. Radiology, 152, 151-154. Hewitt,J., Martin,R., Steptoe.P., Rowland.G. and Webster.J. (1985) Bilateral tuba! ectopic pregnancy following in-vitro fertilisation and embryo transfer. Br. J. Obstet Gynaecol., 92, 850-852. Kadar.N., Devore.G. and Romero.R. (1981) Discriminatory HCG zone: its use in the sonographic evaluation of ectopic pregnancy. Obstet. Gynecoi., 66, 357-360. Lindblom,B. (1989) Management of ectopic pregnancy: what does the future hold? Hum. Reprod., 4, 855-857. Norris,S. (1953) Bilateral simultaneous tubal pregnancy. Can. Med. Assoc. J., 68, 379-381. Okamoto,S.H., Healy.D.L., Morrow,L.M., Rogers,P.A.W., Trounson,A.O. and Wood,E.C. (1987) Predictive value of plasma human chorionic gonadotrophin B subunit in diagnosing ectopic pregnancy after in vitro fertilisation and embryo transfer. Br. Med. J., 294, 667-670. Pouly,J.L., Manhes.H., Mage.G., Canis,M. and Bruhat,M.A. (1986) Conservative laparoscopic treatment of 321 ectopic pregnancies. Fertil. Steril, 46, 1093-1097. Porter.R., Smith.B., Ahuja.K., Tucker.M. and Craft.I. (1986) Combined twin ectopic pregnancy and intrauterine pregnancy following in-vitro fertilization. J. In Vitro Fertil. Embryo Transfer, 3, 330-332. Romero.R., Kadar.N., Jeanty,P., Copel,J.A., Chervenak.F.A., 1028 de Cherney,A. and Hobbins.J.C. (1985) Diagnosis of ectopic
pregnancy: value of the discriminatory human chorionk gonadotrophin zone. Obstet. Gynecoi, 66, 357-360. Rizk,B., Tan.S.L., Riddle,A., Morcos.S., Steer,C, Brinsden,P., Mason.B.A. and Edwards.R.G. (1989) Heterotopic pregnancy and IVF. Presented at the British Fertility Society Annual Meeting. The London Hospital, London, December 6 - 7 , 1989. Rizk.B., Tan.S.L., Morcos.S., Riddle,A., Brinsden.P., Mason.B.A. and Edwards.R.G. (1991) Heterotopic pregnancies after in vitro fertilization and embryo transfer. Am. J. Obstet. Gynecoi., 164, in press. Steptoe.P.C. and Edwards.R.G. (1976) Reimplantation of a human embryo with subsequent tubal pregnancy. Lancet, 1, 880—882. Stewart.H.L. (1950) Bilateral ectopic pregnancy. West J. Surg., 56, 648-656. Stiller.R.J., Haynes de Regt.R. and Blair.E. (1989) Transvaginal ultrasonography in patients at risk for ectopic pregnancy. Am. J.
Obstet. Gynecoi, 161, 930-933. Tait.L. (1884) Five cases of extrauterine pregnancy operated upon at the time of nipture. Br. Med. J., 1, 1250. Timor-Tritsch,I.E., Yeh.M.N., Peisner,D.B., Lesser.K.B. and Slavik.B.A. (1989a) The use of transvaginal ultrasonography in the diagnosis of ectopic pregnancy. Am. J. Obstet. Gynecoi, 161, 157-161. Timor-Tritsch.I.E., Baxi.L. and Peisner.D.B. (1989) Transvaginal salpingocentesis: a new technique for treating ectopic pregnancy. Am. J. Obstet Gynecoi, 160, 459-461. Received on February 5, 1990; accepted on June 19, 1990
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in the management of ectopic pregnancy. However, the early detection of ectopic pregnancy prior to rupture may have therapeutic implications (Lindblom, 1989). Conservative laparoscopic treatment of ectopic and heterotopic pregnancies is now widely performed (Pouly et al., 1986; Rizk and Brinsden, manuscript submitted). In carefully selected patients, local injection of methotrexate or potassium chloride and aspiration of the gestational sac could be successfully performed (Feichtinger and Kemeter, 1987; Rizk et al., 1989; Timor-Tritsch et al, 1989b).
CASE REPORT
Rare ectopic pregnancies after in-vitro fertilization: one unilateral twin and four bilateral tubal pregnancies
Boum-Hallam Medical Centre, 112 Harley Street, London WIN 1AF, UK
Between 1985 and 1989, one unilateral twin and four bilateral tubal pregnancies were encountered among 124 extrauterine pregnancies and 1648 intrauterine pregnancies following in-vitro fertilization and embryo transfer. The two factors associated with this high incidence of single and multiple extrauterine pregnancies were tubal damage and multiple embryo transfer. Embryos at different stages of development appear to have the capacity to implant ectopkally. Despite advances in diagnostic capabilities, ectopic pregnancy remains a major cause of maternal mortality. Early diagnosis prior to rupture must be made if mortality and morbidity are to be abolished. The use of transvaginal sonography has improved the diagnosis of ectopic pregnancy and should be routinely used in all pregnancies following assisted conception. The identification of an intrauterine pregnancy should not be sufficient to rule out the possibility of an extrauterine pregnancy or even bilateral tubal pregnancies. Key words: bilateral/IVF — ET/tubal pregnancy/unilateral twin
The rarest form of binovular twin pregnancy is bilateral, simultaneous tuba] pregnancy (Fox and Mevs, 1963). Twin pregnancies in the same tube are more frequent and simultaneous extra- and intrauterine pregnancies are the most frequent (Norris, 1953). Such rare conditions occur more frequently during assisted human conception. We report one unilateral twin and four bilateral tuba! pregnancies after in-vitro fertilization and embryo transfer (TVF-ET). Case 1 A 28-year-old patient, para 0+0, conceived after IVF-ET. She was initially referred for donor insemination in view of her husband's severe oligoasthenozoospermia. Hysterosalpingography confirmed normal uterine countour and patent Fallopian tubes one year before her referral. She failed to conceive during 11 cycles of donor insemination and two cycles of intrauterine insemination with superovulation. Laparoscopic assessment during gamete intra-Fallopian transfer (GIFT) revealed that the left tube was distended and the fimbriae were clubbed with an occluded distal end. There were also fine adhesions between the © Oxford University Press
left tube and the bowel. The right tube was oedematous and the fimbriae blunted, but there were no peritubal adhesions and the distal end was not occluded. Seven oocytes were recovered by laparoscopy and four of them were replaced in the right tube. However, she did not conceive. She subsequently underwent FVF—ET. Multiple follicular development was induced with human menopausal gonadotrophin (HMG, Pergonal, Serono, Welwyn Garden City, UK) 225 IU daily after pituitary suppression with a luteinizing hormone releasing hormone agonist (LHRH-a, buserelin, Suprefact, Hoechst, Hounslow, UK) 0.2 mg subcutaneously daily. Human chorionic gonadotrophin (HCG, Profasi, Serono; 5000 IU) was administered intramuscularly on day 12. Transvaginal oocyte recovery was performed 35 h later under sonographic control. Six oocytes were recovered, two of which fertilized and two embryos, 4-cell and 2-cell, were replaced using a Wallace catheter (Wallace, Colchester, UK). Luteal phase support was given in the form of HCG 2000 IU on the day of transfer and 3 days later. Serum /3-HCG was positive 15 days after oocyte recovery. Twenty-five days after oocyte recovery, the patient complained of pain in the right iliac fossa and was admitted to the local hospital. Abdominal sonography did not identify an intrauterine or extrauterine pregnancy. The ultrasound scan was repeated 3 days later but did not identify a pregnancy. The abdominal pain became worse and she became faint. Ectopic pregnancy was suspected and emergency laparoscopy revealed a bilateral tubal pregnancy. The right ectopic pregnancy had ruptured and the left had incipient rupture. Laparotomy and bilateral salpingectomy was performed. Histological examination confirmed the presence of chorionic villi in both tubes. She made an uneventful recovery and is currently undergoing her second FVF cycle. Case 2 A 28-year-old woman was referred with a 4-year history of secondary infertility due to tubal damage. At the age of 20 she underwent an elective abortion and subsequently had an intrauterine contraceptive device fitted. It was removed 3 months later due to pelvic infection and thereafter she used oral contraceptives for 3 years. Laparoscopic assessment of the pelvis revealed bilateral tubal blockage and peritubal adhesions. Bilateral salpingostomy with ovariolysis and ventrosuspension was performed. Follow-up laparoscopy revealed a patent right Fallopian tube and healthy ovary but adhesions had redeveloped around the left ovary and the left oviduct filled with dye but there was no spill. In her first IVF cycle, she had four embryos replaced but did not conceive. In her second IVF cycle, multiple follicular 1025
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Botros Rizk, Samuel Morcos, Susan Avery, Kay Elder, Peter Brinsden, Bridgett Mason and Robert Edwards
B.Rizk et al.
Case 3 A 29-year-old patient was referred for IV with a 4-year history of primary infertility because of tubal damage. Laparoscopic assessment revealed bilateral hydrosalpinges. Multiple follicular development was induced with buserelin 0.5 mg subcutaneously on days 2—4 and HMG 225 IU daily from day 3. Transvaginal oocyte recovery was performed under ultrasound control. Six oocytes were recoverd of which four fertilized and three embryos (6-cell, 4-cell and pronuclear) were replaced. Serum £-HCG levels were 40 and 488 IU/1 at 15 and 20 days after oocyte recovery, respectively. Twenty-eight days after oocyte recovery the patient was admitted to the local hospital complaining of abdominal pain and slight vaginal bleeding. The serum level of/3-HCG was 13 750 IU/1 at 30 days after oocyte recovery. Transvaginal sonography identified a right tubal pregnancy. Laparoscopy was performed which revealed bilateral tubal pregnancies and a bilateral salpingectomy was performed. Histological examination confirmed the diagnosis of bilateral tuba! pregnancy. Case 4 A 36-year-old woman had a 10-year history of primary infertility because of her husband's oligoasthenozoospermia. Hysterosalpingography showed a normal uterine outline and patent Fallopian tubes. The pelvis was normal at laparoscopic assessment. The 42-year-old husband had a sperm count that varied between 10 and 25 x lO^ml, motility 10-30% with poor progression and 50% abnormal forms. He underwent left 1026
varicocoele ligation and bilateral hydrocoele excision. The sperm count did not improve despite treatment with tamoxifen and mesterelone for one year. At that stage the couple were referred for IVF. She conceived following her second IVF attempt. Multiple follicular development was induced with clomiphene citrate 100 mg daily from day 2 to day 6 and HMG 150 IU daily from day 4 to day 9. Eighteen oocytes were recovered by laparoscopy. Two embryos (7-cell and 2-cell) were replaced 3 days after oocyte recovery. A pregnancy test was positive 15 days after oocyte recovery. Thirty-two days after oocyte recovery, the patient developed vaginal bleeding and bilateral lower abdominal pain. These symptoms were attributed to threatened abortion. Abdominal sonography performed at the local hospital, 38 days after oocyte recovery, did not identify an intrauterine gestation sac. The pregnancy test was still positive. The ultrasound scan was repeated one week later but did not identify a pregnancy. At that point, the abdominal pain became severe, vaginal bleeding recurred and she suffered from episodes of fainting and vomitting. Laparotomy revealed a ruptured left tubal pregnancy as well as a small gestation sac protruding from the fimbrial end of the right tube. Bilateral salpingectomy was performed. Histology confirmed the diagnosis of bilateral tubal pregnancies. Case 5 A 34-year-old woman was referred for assisted conception with a 5-year history of secondary infertility. At the age of 8 years she had an appendicular abscess which was drained. She had a 12 weeks spontaneous abortion 11 years prior to her referral. Laparoscopic assessment and hydrotubation revealed the left tube to be patent but the right tube was occluded with severe peritubal adhesions. She conceived after the third IVF treatment. Multiple follicular development was induced with clomiphene citrate 100 mg on days 2 - 6 and HMG 375 IU daily from day 4 to day 9. Oocyte recovery was performed under ultrasound control using the transabdominal transvesical route for the left ovary and the direct transabdominal route for the right ovary. Eight oocytes were retrieved and four embryos (three 4-cell and one 2-cell) were replaced. Luteal support was give in the form of progesterone vaginal pessaries of 400 mg twice daily. A pregnancy test was positive 15 days after oocyte recovery. The patient was asymptomatic when she attended for the ultrasound scan 35 days after the oocyte recovery. Abdominal sonography identified a viable unruptured tubal twin pregnancy. A left extrauterine gestation sac that measured 18 x 12 x 23 mm in which a fetal pole with 9 mm crown-rump length and beating fetal heart as well as a yolk sac was visible. The second gestation sac measured 20 x 21 x 19 mm and a fetal pole with a beating fetal heart and a yolk sac was identified in it. Laparotomy and salpingectomy was performed. The diagnosis was confirmed histologically. The patient subsequently adopted a baby. Discussion The occurrence of bilateral simultaneous tubal pregnancy is rare. Its incidence has been reported to range from 1/725 to 1/1580
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development was induced with buserelin 0.5 mg subcutaneously on days 1 - 3 and HMG 150 IU on days 3 - 7 , 300 IU on days 8 - 1 0 and 450 IU on days 11-13. Fourteen oocytes were recovered by the transvaginal route under sonographic control and four embryos (two 4-cell, one 2-cell and one pronuclear) were replaced. Luteal support was given in the form of HCG 2000 IU on the day of transfer and 3 days later. Serum jS-HCG 15 days after oocyte recovery was positive. Thirty-two days after oocyte recovery, slight vaginal loss occurred followed by mild abdominal pain which settled spontaneously. Abdominal ultrasound performed 37 days after oocyte recovery revealed an empty intrauterine gestation sac equivalent to 47—49 days gestation. Two days later, acute bilateral lower abdominal pain occurred and she was admitted to hospital. An abdominal ultrasound scan identified bilateral tubal pregnancies. Laparotomy confirmed bilateral ruptured tuba! pregnancies and a bilateral salpingectomy was performed. Evacuation of the uterus was not performed in accordance with the patient's request. Blood loss of 1000 ml was estimated and two units of blood were transfused. She subsequently developed vaginal bleeding and abdominal pain which were followed by passing a decidual cast. Histological examination confirmed chorionic villi in both Fallopian tubes and only decidual tissue from the uterine cast. However, histological examination was not performed on all the products of conception that were passed vaginally. She made a good recovery and subsequently underwent an unsuccessful IVF cycle.
Ectopfc pregnandts after IVF
to 0.8 per 1000 in 1980. However the number of ectopic pregnancies increased from 17 800 to 52 000 thus offsetting the reduction in fatality (Dorfinan, 1983). It therefore appears that the only effective way to abolish mortality and morbidity from ectopic pregnancy is by early diagnosis prior to rupture. In 1950, Stewart reviewed 139 reported cases of bilateral ectopic pregnancies and found that the diagnosis was not made before operation except in one case. Forty years later the diagnosis still remains a clinical challenge. In spontaneous conception one effective way to rule out extrauterine pregnancy is by diagnosing the intrauterine pregnancy because the frequency of heterotopic pregnancy in spontaneous conception ranges between 1 in 3889 to 1 in 6778 (Harm et al., 1984; Bello et al., 1986). This principle does not hold true for pregnancies after IVF-ET, since almost 1% of them are combined pregnancies (Rizk et al., 1989). In fact, the diagnosis of ectopic gestation in the second and fourth cases was delayed as the symptoms of pain and bleeding were attributed to threatened abortion of the intrauterine pregnancy, hi the second case, it was difficult to determine whether an intrauterine pregnancy ever existed or if the empty sac identified at ultrasound scan was a misinterpretation of the decidual reaction to the extrauterine pregnancies. The use of transvaginal sonography improved the diagnosis of ectopic pregnancy; the sensitivity varied from 82 to 100%, the specificity 98.2% and the positive predictive value 93 to 98% (Stiller et al., 1989; Timor-Tritsch et al., 1989a). The majority of the ectopic pregnancies were detected at an early stage prior to rupture. Recognizing the high risk of ectopic pregnancy after IVF-ET, transvaginal sonography should be implemented for all clinical FVF pregnancies. Furthermore, with the increased incidence of heterotopic pregnancy and bilateral tubal pregnancy, the identification of an intrauterine or ectopic pregnancy should not be sufficient to rule out a co-existent extrauterine pregnancy, as in the third case, and the pelvis should be visualized carefully. The predictive value of /3-HCG in diagnosing ectopic pregnancy after IVF —ET was addressed by Okamoto et al. (1987). The authors achieved a 100% sensitivity by taking a high cut-off limit of the 25th centile of ongoing intrauterine pregnancy to diagnose ectopic pregnancy. However, the /3-HCG levels in bilateral tubal pregnancies might be higher than the 25th centile of intrauterine pregnancies (as in the third case) and another cut off level should be determined. The concept of 'discriminatory /3-HCG zone' at which ultrasound detects the earliest normal intrauterine pregnancy was introduced by Kadar et al. (1981). One of the limitations of this approach was that 40% of patients at risk of ectopic pregnancy had initial /3-HCG below the discriminatory value (Romero et al., 1985). However as transvaginal sonography has improved the imaging of the pelvic structures, the intrauterine gestation sacs could be observed at lower discriminatory zones (Goldstein etal., 1988). Furthermore, the higher values of /3-HCG in bilateral ectopic pregnancy compared to unilateral ectopic pregnancy would make the diagnosis of extrauterine pregnancy easier when an intrauterine gestation sac could not be identified on ultrasound scan. It must be stressed, however, that a high index of suspicion of ectopic pregnancy is needed if delays in diagnosis are to be avoided. Tait (1884) was the first to perform salpingectomy for ruptured ectopic pregnancies. Over the last century, very little has changed 1027
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extrauterine pregnancies (Abrams and Kanter, 1948; Stewart, 1950). We have encountered four bilateral tubal pregnancies amongst 124 extrauterine pregnancies and 1648 intrauterine pregnancies. This gives an incidence of 1/30 extrauterine pregnancies and 1/412 intrauterine pregnancies. This calculation is open to considerable variation since the true incidence of unior bilateral ectopic pregnancies is unlikely to be known with any accuracy because many ectopic gestations undergoing early spontaneous resolution would not have been recorded. In 1939, Fishback laid down the principles for acceptance of an authentic case of simultaneous bilateral extrauterine pregnancy: 'there should be a description of the fetuses or any portion of them found, as well as of placental material. A microscopic examination may be necessary to confirm the diagnosis and to give criteria for fixing the pregnancy periods. Especially is this needed where only a haematosalpinx is present grossly'. Norris (1953) clarified this principle, stating that the presence of chorionic villi in each tube should be sufficient to justify the diagnosis. The first reported pregnancy after IVF — ET was an ectopic pregnancy (Steptoe and Edwards, 1976). In 1986, Cohen et al. found a 5% risk of ectopic pregnancy after IVF — ET in a large multicentre collaborative study. The first case of bilateral tubal pregnancy following IVF —ET was confirmed by Hewitt et al. (1985). A unilateral tuba! twin pregnancy occurred after IVF and the transfer of four embryos (Dor et al., 1984) and a combined twin ectopic pregnancy and intrauterine gestation was reported after the transfer of six embryos (Porter et al., 1986). Fifteen cases of heterotopic pregnancies encountered during 5 years were presented by Rizk et al. (1989). Two factors associated with this high incidence of single and multiple extrauterine pregnancies after IVF — ET are tubal damage and multiple embryo transfer. It was interesting to note in the first case that the tubal pregnancies occurred after the IVF-ET treatment and not the GIFT procedure. Of additional interest was the fact that the tubes were normal when assessed by hysterosalpingography but found to be damage during the GIFT after the unsuccessful inseminations. Contrary to expectation, the tubal twin prengnacy in the fifth case occurred in the patent tube rather than the damaged tube. The present cases also clarify the capacity of embryos to implant ectopically. In the fourth case, there were marked differences in the stage of development of the two replaced embryos (2-cell and 7-cell), yet both implanted. In the second and third cases, it is possible that the pronucleate embryos might have implanted ectopically. The fact that only two embryos were replaced in the first and the fourth case shows that there is no direct correlation between the number of embryos replaced and the risk of multiple extrauterine pregnancy. The same conclusion can be drawn from an analysis of heterotopic pregnancies (Rizk et al., 1991). The mortality rate from bilateral ectopic pregnancies in the first half of the twentieth century was 3.6%. This was considered surprisingly low as the mortality rate from unilateral ectopic pregnancies was 2.5% at that time (Stewart, 1950). The cause of death was always haemorrhage, early and late. Despite advances in diagnostic capabilities, ectopic pregnancy remains a leading cause of maternal mortality. In the USA, the death rate from ectopic pregnancy decreased from 3.5 per 1000 in 1970
B.Rizk et al.
References Abrams,R.A. and Kanter,A.E. (1948) Bilateral simultanous extra-uterine pregnancy. Am. J. Obstet. Gynecoi, 56, 1198-1200. Bello,G.V., Schonolz.D., Moshirpur.J., Jeng.D.Y. and Berkowitz.R. (1986) Combined pregnancy: the mount Sinai experience. Obstet.
Gynaecol. J., 41, 603-613. CohenJ., Mayaux,M.-J., Guihard-Moscato,M.-L. and Schwartz,D. (1986) In-vitro fertilization and embryo transfer: a collaborative study of 1163 pregnancies on the incidence and risk factors of ectopic pregnancies. Hum. Reprod., 1, 255—258. Dor,J., Rudak.E., Mashiach.S., Goldman.B. and Nebel.L. (1984) Unilateral tuba] twin pregnancy following in vitro fertilization and embryo transfer. Fertil. Steril., 42, 297-299. Dorfman,S.F. (1983) Deaths from ectopic pregnancy United States, 1979-1980. Obstet. Gynecoi., 62, 334-338. Feichtinger.W. and Kemeter.P. (1987) Conservative treatment of ectopic pregnancy by transvaginal aspiration under sonographic control and methotrexate injection. Lancet, 1, 381—382. Fishback.H.R. (1939) Bilateral simultaneous tubal pregnancy. Am. J.
Obstet. Gynecoi., 37, 1035-1037. Fox.E.J. and Mevs.F.F. (1963) Simultaneous bilateral tubal pregnancies.
Obstet. Gynecoi., 21, 499-501. Goldstein.S.R., Snyder.J.R., Watson,C. and Danon.M. (1988) Very early pregnancy detection with endovaginal ultrasound. Obstet. Gynecoi., 72, 200-204. Hann.L.E., Bachmann.D.M. and McArdle.C. (1984) Coexistent intrauterine and ectopic pregnancy in re-evaluation. Radiology, 152, 151-154. Hewitt,J., Martin,R., Steptoe.P., Rowland.G. and Webster.J. (1985) Bilateral tuba! ectopic pregnancy following in-vitro fertilisation and embryo transfer. Br. J. Obstet Gynaecol., 92, 850-852. Kadar.N., Devore.G. and Romero.R. (1981) Discriminatory HCG zone: its use in the sonographic evaluation of ectopic pregnancy. Obstet. Gynecoi., 66, 357-360. Lindblom,B. (1989) Management of ectopic pregnancy: what does the future hold? Hum. Reprod., 4, 855-857. Norris,S. (1953) Bilateral simultaneous tubal pregnancy. Can. Med. Assoc. J., 68, 379-381. Okamoto,S.H., Healy.D.L., Morrow,L.M., Rogers,P.A.W., Trounson,A.O. and Wood,E.C. (1987) Predictive value of plasma human chorionic gonadotrophin B subunit in diagnosing ectopic pregnancy after in vitro fertilisation and embryo transfer. Br. Med. J., 294, 667-670. Pouly,J.L., Manhes.H., Mage.G., Canis,M. and Bruhat,M.A. (1986) Conservative laparoscopic treatment of 321 ectopic pregnancies. Fertil. Steril, 46, 1093-1097. Porter.R., Smith.B., Ahuja.K., Tucker.M. and Craft.I. (1986) Combined twin ectopic pregnancy and intrauterine pregnancy following in-vitro fertilization. J. In Vitro Fertil. Embryo Transfer, 3, 330-332. Romero.R., Kadar.N., Jeanty,P., Copel,J.A., Chervenak.F.A., 1028 de Cherney,A. and Hobbins.J.C. (1985) Diagnosis of ectopic
pregnancy: value of the discriminatory human chorionk gonadotrophin zone. Obstet. Gynecoi, 66, 357-360. Rizk,B., Tan.S.L., Riddle,A., Morcos.S., Steer,C, Brinsden,P., Mason.B.A. and Edwards.R.G. (1989) Heterotopic pregnancy and IVF. Presented at the British Fertility Society Annual Meeting. The London Hospital, London, December 6 - 7 , 1989. Rizk.B., Tan.S.L., Morcos.S., Riddle,A., Brinsden.P., Mason.B.A. and Edwards.R.G. (1991) Heterotopic pregnancies after in vitro fertilization and embryo transfer. Am. J. Obstet. Gynecoi., 164, in press. Steptoe.P.C. and Edwards.R.G. (1976) Reimplantation of a human embryo with subsequent tubal pregnancy. Lancet, 1, 880—882. Stewart.H.L. (1950) Bilateral ectopic pregnancy. West J. Surg., 56, 648-656. Stiller.R.J., Haynes de Regt.R. and Blair.E. (1989) Transvaginal ultrasonography in patients at risk for ectopic pregnancy. Am. J.
Obstet. Gynecoi, 161, 930-933. Tait.L. (1884) Five cases of extrauterine pregnancy operated upon at the time of nipture. Br. Med. J., 1, 1250. Timor-Tritsch,I.E., Yeh.M.N., Peisner,D.B., Lesser.K.B. and Slavik.B.A. (1989a) The use of transvaginal ultrasonography in the diagnosis of ectopic pregnancy. Am. J. Obstet. Gynecoi, 161, 157-161. Timor-Tritsch.I.E., Baxi.L. and Peisner.D.B. (1989) Transvaginal salpingocentesis: a new technique for treating ectopic pregnancy. Am. J. Obstet Gynecoi, 160, 459-461. Received on February 5, 1990; accepted on June 19, 1990
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in the management of ectopic pregnancy. However, the early detection of ectopic pregnancy prior to rupture may have therapeutic implications (Lindblom, 1989). Conservative laparoscopic treatment of ectopic and heterotopic pregnancies is now widely performed (Pouly et al., 1986; Rizk and Brinsden, manuscript submitted). In carefully selected patients, local injection of methotrexate or potassium chloride and aspiration of the gestational sac could be successfully performed (Feichtinger and Kemeter, 1987; Rizk et al., 1989; Timor-Tritsch et al, 1989b).
