Heterotopic pregnancies after in vitro fertilization and embryo transfer Botros Rizk, MD, Seang Lin Tan, MD, Samuel Morcos, MD, Andrew Riddle, MD, Peter Brinsden, MD, Bridgett A. Mason, MB, BS, and Robert G. Edwards, PhD, DSc London, England Seventeen cases of heterotopic pregnancies are reported among 1648 clinical pregnancies after in vitro fertilization. The high prevalence of tubal damage among IVF patients and the use of superovulation and multiple embryo transfer might predispose patients to the condition. Nine patients reported abdominal pain and vaginal bleeding, five patients did not have symptoms, and three had acute abdominal emergencies. Transvaginal ultrasonography was superior to transabdominal ultrasonography in the diagnosis of extrauterine pregnancies. The presence of an intrauterine gestation sac in a patient without symptoms should not exclude the diagnosis of a concomitant extrauterine pregnancy until the pelvis is carefully visualized. Early diagnoses of viable ectopic pregnancies before rupture abolishes mortality and morbidity and offers the chance of patient selection for conservative treatment. In two patients the extrauterine gestation sac was treated by transvaginal aspiration and injection of potassium chloride under ultrasonographic gUidance. The outcome of the intrauterine pregnancy was favorable regardless of the method of treatment of the ectopic pregnancy. (AM J OasTET GVNECOL 1991 ;164:161-4.)
Key words: Heterotopic pregnancy, in vitro fertilization, embryo transfer
The incidence of combined intrauterine and extrauterine pregnancy is evidently higher after in vitro fertilization (IVF) than in spontaneous pregnancies. Our data indicate a frequency of 1% in clinical pregnancies after IVF as compared with 1 in 3889 and 1 in 6778 after spontaneous conceptions. I, 2 Diagnosis of heterotopic pregnancy is difficult because symptoms of ectopic gestation may be attributed to complications of intrauterine pregnancy, and a patient without symptoms may not raise suspicions of ectopic gestation. Transvaginal ultrasonography helps in the diagnosis and should be used in suspected cases, but assays of l3-human chorionic gonadotropin (l3-hCG), which are usually low in ectopic pregnancies, can be unhelpful inasmuch as they might indicate normal ranges in combined pregnancies. Management of combined pregnancies presents another difficulty. Laparotomy during the first trimester might threaten the intrauterine pregnancy and ultrasonography-guided aspiration procedures have limitations, although they are valuable in properly selected cases. In the present study we discuss the factors From Bourn Hallam Medical Centre. Received for publication January 10,1990; revised July 30,1990; accepted August 3, 1990. Reprint requests: Botros Rizk, MD, Bourn Hallam Medical Centre, 112 Harley St., London, England WIN 1AF. 611/24438
responsible for the increased frequency of combined pregnancy after IVF, the variations in clinical presentation, and the value of transvaginal ultrasonography in early diagnosis and therapy.
Material and methods Seventeen cases of combined intrauterine and extrauterine pregnancies were encountered among 1648 clinical pregnancies after IVF at the Bourn Hallam Medical Centre between 1985 and 1989. The methods of ovarian stimulation, ultrasonographic and endocrine monitoring, oocyte retrieval, fertilization of 00cytes, and growth of embryos in vitro used in this period have been described previously.' Embryo replacements were mostly carried out 2 1/2 days after oocyte retrieval with a catheter (Wallace, Colchester, United Kingdom), and anesthetic agents were not administered to any of the 17 patients. A maximum of four embryos were replaced in 0.02 ml of culture medium deposited near the fundus. Urinary and serum l3-hCG levels were measured 15 days after oocyte recovery. Serial l3-hCG levels were measured at 5 days' interval. At Bourn Hall Clinic, transabdominal followed by transvaginal ultrasonography was performed 35 days after oocyte recovery; at Hallam Medical Centre, only transabdominal ultrasonography was performed. Patients returned to the referring obstetricians during the pregnancy and delivery. 161
162
Rizk at at.
Results Patients and stimulation. The mean age of the 17 patients was 30.5 years (range, 20 to 37 years). Fifteen of them had tubal damage, one had endometriosis with patent tubes, and one had not conceived after repeated donor insemination. Five patients had previous tubal surgery and two had previous ectopic pregnancies. Ovarian stimulation was achieved by the use of clomiphene citrate (Serophene, Serono Laboratories, Welwyn Garden City, United Kingdom) and human menopausal gonadotropin (hMG; Pergonal, Serono) in 10 patients. Purified follicle-stimulating hormone (FSH; Metrodin, Serono) was added to this regime in two patients. The gonadotropin-releasing hormone (GnRH) agonist (Suprefact, Hoechst, Hounslow, United Kingdom), and hMG were used for stimulation in five patients. The number of oocytes retrieved varied between three and 16, and four embryos were replaced in eight patients, three in seven patients, and two in two patients. Symptoms and diagnoses. The symptoms at first examination in the 17 patients were quite variable, with abdominal pain and vaginal bleeding in nine patients, acute surgical abdominal emergencies in three, and no symptoms in the remaining five patients (Table I). Fifteen patients had ultrasonographic scans before the definitive management of the extrauterine pregnancy began and the ectopic pregnancy ruptured before ultrasonography in two patients. In 10 patients who had abdominal scans, a correct diagnosis was made in only five and was strongly suspected in one (50%). Each of the five patients who had abdominal and transvaginal scans had a correct diagnosis. Overall there was a 66.6% diagnostic accuracy rate. The earliest diagnosis of an extrauterine gestation sac was made at 6 weeks' gestation. Levels of plasma l3-hCG 15 days after oocyte recovery ranged from 141 to 2710 IU fL, and serial assays over 20 days were frequently within the normal range for normal intrauterine pregnancies. Outcome of pregnancies. The extrauterine gestation sac ruptured spontaneously in eight patients. Surgical excision was performed in 14 patients. Unilateral salpingectomy was performed in 10 patients, bilateral salpingectomy in two patients, and salpingooophorectomy in two patients. A local irtiection of potassium chloride in the fetal heart followed by aspiration of the gestation sac was performed in two patients under transvaginal ultrasonographic control. One extrauterine gestation sac resolved spontaneously. At the time of the initial diagnosis, the viable intrauterine pregnancy was present in seven patients and twin intrauterine sacs were present in three others. One patient miscarried and the others progressed uneventfully with seven singleton deliveries, one twin, and one on-going pregnancy.
January 1991 Am J Obstet Gynecol
Case reports and series of heterotopic pregnancy after IVG-embryo transfer are presented in Table II.
Comment There is a high incidence of combined heterotopic pregnancy after IVF, reaching 1% of all clinical pregnancies in our clinics between 1985 and 1989. Another recent series reported nine cases among 312 clinical IVF pregnancies (2.9%)4 and a multicenter study that incorporated large IVF centers in the United Kingdom had 30 cases among 2234 clinical pregnancies (1.3%).5 In comparison, the reported frequency of heterotopic pregnancies in spontaneous conception include 1 in 6778 from IsraeV 1 in 4112 from Belgium,6 and 1 in 3889 from New York.' These estimates replace the oftquoted theoretical incidence of the condition (e.g., 1 in 30,000 7) determined on the basis of an assumed incidence of 0.37% ectopic pregnancy, and 1 in 15,600 8 on the basis of a 0.8% incidence of ectopic pregnancy. Therefore the risk of a combined pregnancy after IVFembryo transfer seems to be 30 to 60 times higher than that after spontaneous conception. The etiologic factors associated with ectopic and heterotopic pregnancies include previous pelvic inflammatory disease, pelvic surgery, associated uterine malformation, use of ovarian hyperstimulation drugs, and multiple embryo transfer. Pelvic inflammatory disease with attendant postinfection tubal damage is evidently a potential etiologic factor in approximately 45% of ectopic pregnancies, raising the incidence by tenfold and even up to 4% of all pregnancies when laparoscopy was used for diagnosis. A 1% incidence of combined intrauterine and extrauterine gestation was found among patients who took ovarian hyperstimulation drugs. 9 The incidence of heterotopic pregnancies would be expected to be high in IVF patients because many have pelvic inflammatory disease, stimulation is used routinely, and multiple embryo transfers are common. The difference in the incidence between our center (l %) and other units (2.9%) could be attributed to the high prevalence of tubal damage and microsurgery among their patients, as discussed by the authors.' The procedure for embryo replacement could raise the chances of combined gestation (e.g., through the direct extrusion of embryos through the tubal ostium by hydrostatic forces).10 A small volume (50 to 100 1J.1) of radiopaque dye placed high in the uterus during mock embryo transfer can move into the fallopian tube after a few minutes, then subsequently disappear, possibly by spilling into the peritoneal cavity. II Dye was totally or partially transferred into the fallopian tubes in 44% of patients who had a mock embryo transfer in the cycle before IVF. A higher rate of ectopic pregnancy arises if the transfer catheter passes beyond the midcavity, and a routine measurement of the uterine length by
Heterotopic pregnancy after IVF and embryo transfer
Volume 164 Number I, Parl I
163
Table I. Clinical presentation and ultrasonographic diagnosis Duration of pregnancy at time of diagnosis
Ultrasonographu findings Patient no. I
2 3 4 5 6 7 8 9 10 II
12 13 14 15 16 17
Clinical
Gestational sac in utero
Type
Abdominal pain Abdominal pain Abdominal pain Abdominal pain Abdominal pain Abdominal pain Abdominal pain, bleeding Abdominal pain, bleeding Abdominal pain, bleeding Acute abdomen Acute abdomen Acute abdomen No symptoms No symplOms No symptoms No symptoms No symplOms
Abdominal Abdominal Abdominal Abdominal Abdominal Abdominal Abdominal Abdominal Abdominal Abdominal Abdominal Abdominal Abdominal Abdominal Abdominal Abdominal Abdominal
I
3 1 I I I
2
1 I I
2
+ + + + +
vaginal vaginal vaginal vaginal vaginal
I I
2 I I I
(wk)
Fetal hearts in utero 1
2 0 0 0 0
1
0 0 0 2 I I
2 I I I
Ect
Key words: Heterotopic pregnancy, in vitro fertilization, embryo transfer
The incidence of combined intrauterine and extrauterine pregnancy is evidently higher after in vitro fertilization (IVF) than in spontaneous pregnancies. Our data indicate a frequency of 1% in clinical pregnancies after IVF as compared with 1 in 3889 and 1 in 6778 after spontaneous conceptions. I, 2 Diagnosis of heterotopic pregnancy is difficult because symptoms of ectopic gestation may be attributed to complications of intrauterine pregnancy, and a patient without symptoms may not raise suspicions of ectopic gestation. Transvaginal ultrasonography helps in the diagnosis and should be used in suspected cases, but assays of l3-human chorionic gonadotropin (l3-hCG), which are usually low in ectopic pregnancies, can be unhelpful inasmuch as they might indicate normal ranges in combined pregnancies. Management of combined pregnancies presents another difficulty. Laparotomy during the first trimester might threaten the intrauterine pregnancy and ultrasonography-guided aspiration procedures have limitations, although they are valuable in properly selected cases. In the present study we discuss the factors From Bourn Hallam Medical Centre. Received for publication January 10,1990; revised July 30,1990; accepted August 3, 1990. Reprint requests: Botros Rizk, MD, Bourn Hallam Medical Centre, 112 Harley St., London, England WIN 1AF. 611/24438
responsible for the increased frequency of combined pregnancy after IVF, the variations in clinical presentation, and the value of transvaginal ultrasonography in early diagnosis and therapy.
Material and methods Seventeen cases of combined intrauterine and extrauterine pregnancies were encountered among 1648 clinical pregnancies after IVF at the Bourn Hallam Medical Centre between 1985 and 1989. The methods of ovarian stimulation, ultrasonographic and endocrine monitoring, oocyte retrieval, fertilization of 00cytes, and growth of embryos in vitro used in this period have been described previously.' Embryo replacements were mostly carried out 2 1/2 days after oocyte retrieval with a catheter (Wallace, Colchester, United Kingdom), and anesthetic agents were not administered to any of the 17 patients. A maximum of four embryos were replaced in 0.02 ml of culture medium deposited near the fundus. Urinary and serum l3-hCG levels were measured 15 days after oocyte recovery. Serial l3-hCG levels were measured at 5 days' interval. At Bourn Hall Clinic, transabdominal followed by transvaginal ultrasonography was performed 35 days after oocyte recovery; at Hallam Medical Centre, only transabdominal ultrasonography was performed. Patients returned to the referring obstetricians during the pregnancy and delivery. 161
162
Rizk at at.
Results Patients and stimulation. The mean age of the 17 patients was 30.5 years (range, 20 to 37 years). Fifteen of them had tubal damage, one had endometriosis with patent tubes, and one had not conceived after repeated donor insemination. Five patients had previous tubal surgery and two had previous ectopic pregnancies. Ovarian stimulation was achieved by the use of clomiphene citrate (Serophene, Serono Laboratories, Welwyn Garden City, United Kingdom) and human menopausal gonadotropin (hMG; Pergonal, Serono) in 10 patients. Purified follicle-stimulating hormone (FSH; Metrodin, Serono) was added to this regime in two patients. The gonadotropin-releasing hormone (GnRH) agonist (Suprefact, Hoechst, Hounslow, United Kingdom), and hMG were used for stimulation in five patients. The number of oocytes retrieved varied between three and 16, and four embryos were replaced in eight patients, three in seven patients, and two in two patients. Symptoms and diagnoses. The symptoms at first examination in the 17 patients were quite variable, with abdominal pain and vaginal bleeding in nine patients, acute surgical abdominal emergencies in three, and no symptoms in the remaining five patients (Table I). Fifteen patients had ultrasonographic scans before the definitive management of the extrauterine pregnancy began and the ectopic pregnancy ruptured before ultrasonography in two patients. In 10 patients who had abdominal scans, a correct diagnosis was made in only five and was strongly suspected in one (50%). Each of the five patients who had abdominal and transvaginal scans had a correct diagnosis. Overall there was a 66.6% diagnostic accuracy rate. The earliest diagnosis of an extrauterine gestation sac was made at 6 weeks' gestation. Levels of plasma l3-hCG 15 days after oocyte recovery ranged from 141 to 2710 IU fL, and serial assays over 20 days were frequently within the normal range for normal intrauterine pregnancies. Outcome of pregnancies. The extrauterine gestation sac ruptured spontaneously in eight patients. Surgical excision was performed in 14 patients. Unilateral salpingectomy was performed in 10 patients, bilateral salpingectomy in two patients, and salpingooophorectomy in two patients. A local irtiection of potassium chloride in the fetal heart followed by aspiration of the gestation sac was performed in two patients under transvaginal ultrasonographic control. One extrauterine gestation sac resolved spontaneously. At the time of the initial diagnosis, the viable intrauterine pregnancy was present in seven patients and twin intrauterine sacs were present in three others. One patient miscarried and the others progressed uneventfully with seven singleton deliveries, one twin, and one on-going pregnancy.
January 1991 Am J Obstet Gynecol
Case reports and series of heterotopic pregnancy after IVG-embryo transfer are presented in Table II.
Comment There is a high incidence of combined heterotopic pregnancy after IVF, reaching 1% of all clinical pregnancies in our clinics between 1985 and 1989. Another recent series reported nine cases among 312 clinical IVF pregnancies (2.9%)4 and a multicenter study that incorporated large IVF centers in the United Kingdom had 30 cases among 2234 clinical pregnancies (1.3%).5 In comparison, the reported frequency of heterotopic pregnancies in spontaneous conception include 1 in 6778 from IsraeV 1 in 4112 from Belgium,6 and 1 in 3889 from New York.' These estimates replace the oftquoted theoretical incidence of the condition (e.g., 1 in 30,000 7) determined on the basis of an assumed incidence of 0.37% ectopic pregnancy, and 1 in 15,600 8 on the basis of a 0.8% incidence of ectopic pregnancy. Therefore the risk of a combined pregnancy after IVFembryo transfer seems to be 30 to 60 times higher than that after spontaneous conception. The etiologic factors associated with ectopic and heterotopic pregnancies include previous pelvic inflammatory disease, pelvic surgery, associated uterine malformation, use of ovarian hyperstimulation drugs, and multiple embryo transfer. Pelvic inflammatory disease with attendant postinfection tubal damage is evidently a potential etiologic factor in approximately 45% of ectopic pregnancies, raising the incidence by tenfold and even up to 4% of all pregnancies when laparoscopy was used for diagnosis. A 1% incidence of combined intrauterine and extrauterine gestation was found among patients who took ovarian hyperstimulation drugs. 9 The incidence of heterotopic pregnancies would be expected to be high in IVF patients because many have pelvic inflammatory disease, stimulation is used routinely, and multiple embryo transfers are common. The difference in the incidence between our center (l %) and other units (2.9%) could be attributed to the high prevalence of tubal damage and microsurgery among their patients, as discussed by the authors.' The procedure for embryo replacement could raise the chances of combined gestation (e.g., through the direct extrusion of embryos through the tubal ostium by hydrostatic forces).10 A small volume (50 to 100 1J.1) of radiopaque dye placed high in the uterus during mock embryo transfer can move into the fallopian tube after a few minutes, then subsequently disappear, possibly by spilling into the peritoneal cavity. II Dye was totally or partially transferred into the fallopian tubes in 44% of patients who had a mock embryo transfer in the cycle before IVF. A higher rate of ectopic pregnancy arises if the transfer catheter passes beyond the midcavity, and a routine measurement of the uterine length by
Heterotopic pregnancy after IVF and embryo transfer
Volume 164 Number I, Parl I
163
Table I. Clinical presentation and ultrasonographic diagnosis Duration of pregnancy at time of diagnosis
Ultrasonographu findings Patient no. I
2 3 4 5 6 7 8 9 10 II
12 13 14 15 16 17
Clinical
Gestational sac in utero
Type
Abdominal pain Abdominal pain Abdominal pain Abdominal pain Abdominal pain Abdominal pain Abdominal pain, bleeding Abdominal pain, bleeding Abdominal pain, bleeding Acute abdomen Acute abdomen Acute abdomen No symptoms No symplOms No symptoms No symptoms No symplOms
Abdominal Abdominal Abdominal Abdominal Abdominal Abdominal Abdominal Abdominal Abdominal Abdominal Abdominal Abdominal Abdominal Abdominal Abdominal Abdominal Abdominal
I
3 1 I I I
2
1 I I
2
+ + + + +
vaginal vaginal vaginal vaginal vaginal
I I
2 I I I
(wk)
Fetal hearts in utero 1
2 0 0 0 0
1
0 0 0 2 I I
2 I I I
Ect
