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Simultaneous ectopic pregnancy with intrauterine twin gestations after in vitro fertilization and embryo transfer
FERTILITY AND STERILITY Copyright © 1985 The American Fertility Society
Vol. 43, No.2, February 1985 Printed in U.s.A.
Simultaneous ectopic pregnancy with intrauterine twin gestations after in vitro fertilization and embryo transfer
Steven J. Sondheimer, M.D.*t Richard W. Tureck, M.D.* Luis Blasco, M.D. * Jerome Strauss III, M.D., Ph.D.*:j: Peter Arger, M.D.§ Michael Mennuti, M.D.* Hospital of the University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
The first successful pregnancy achieved through in vitro fertilization and embryo transfer OVF-ET) occurred in 1976 and was reported by Steptoe and Edwards. l This pregnancy was a right tubal ectopic pregnancy. Tubal ectopic pregnancies following IVF-ET continue to be reported. 2 A simultaneous intrauterine and ectopic pregnancy occurring spontaneously is a relatively rare event, occurring in approximately 1 in 30,000 pregnancies. Ovulation induction with clomiphene citrate or menotropins increases the incidence of multiple ovulation and thus may increase the risk of simultaneous intrauterine and ectopic pregnancy. We report a left tubal ectopic pregnancy with concomitant viable twin intrauterine gestations resulting from IVF-ET.
Received August 1, 1984; accepted October 15, 1984. *Department of Obstetrics and Gynecology. tReprint requests: Steven J. Sondheimer, M.D., Department of Obstetrics and Gynecology, Hospital of the University of Pennsylvania School of Medicine, 3400 Spruce Street, Philadelphia, Pennsylvania 19104. :j:Department of Pathology. §Department of Radiology. Vol. 43, No.2, February 1985
CASE REPORT
The patient is a 28-year-old married Caucasian woman with 4 years of primary infertility. Complete infertility evaluation discovered minimal pelvic endometriosis, presence of a diethylstilbestrol-exposed T-shaped uterus, and repeated poor postcoital tests because of scanty mucus production. In spite of intensive and complete therapy, pregnancy failed to occur, and IVF was considered. Ovulation stimulation was carried out with human menopausal gonadotropins (Pergonal, Serono Laboratories, Inc., Randolph, MA) starting on day 3 of the cycle. Ovum retrieval was achieved laparoscopically with seven follicles aspirated and five oocytes recovered. All five eggs successfully fertilized; and 49 hours after recovery, two of the concepti were 5 cells, one was 3 cells, one was 2 cells, and one was 1 cell (pronuclear). All were transferred transcervically in the knee-chest position. The concepti were deposited ~ 0.5 cm from the uterine fundus (as determined by previous sonographic measurements of the cavity) in 50 ILl of a viscous transfer medium consisting of 90% maternal serum and 10% Ham's F-10. At the time of transfer, no uterine cramping or bleeding occurred. The patient was treated with 12.5 mg Sondheimer et al. Communications-in-brief
313
Figure 1 Longitudinal real-time ultrasound shows a double gestational sac, indicating twins. On this single projection, notice the fetal pole in one of the sacs (arrow).
progesterone (P), intramuscularly daily, after transfer. In the week following transfer, the patient complained of mild cramping and very light vaginal bleeding. Seventeen days after transfer, a positive test for serum beta-human chorionic gonadotropin (l3-hCG) was obtained. Thereafter, she received P vaginal suppositories, 25 mg, twice daily. Twenty-seven days after transfer, the patient noted mild uterine cramping with vaginal spotting. At that time, ultrasonography showed two gestational sacs within the uterus and two fetal poles, and serum l3-hCG was 18,800 mIU/ml. Four days later, a repeat ultrasonography confirmed two fetal poles. A definite heartbeat was seen associated with a fetal pole with a crown-rump length of 8.5 mm, correlating with a menstrual age of 6 weeks and 6 days (Figs. 1 and 2). The left ovary showed a lo8-cm cyst; the right ovary measured 5 cm in greatest dimension and had three small cysts. The patient then presented 10 days later, 41 days after transfer, with 1 day of increasing lower abdominal pain and a fainting episode at home. Her hematocrit was 30%, and her blood pressure was stable. Two weeks prior to this, her hematocrit had been 35%. Ultrasound showed two gestational sacs, a crown-rump length of 9 mm, compatible with 7 weeks' gestation, and fetal heart activity in both gestational sacs. Small cysts were present in both adnexa, and free fluid was identified in the abdomen. After observation in the hospital, the patient's discomfort initially improved, 314
Sondheimer et al.
Communications-in-brief
her hematocrit remained stable, and the possibility of a self-limited bleed from the fragile corpus luteum was considered. However, her crampy lower abdominal pain recurred and worsened, and her hematocrit fell to 27%. A diagnostic laparoscopy was performed. An unruptured left ampullary ectopic pregnancy was found, with blood in the cul-de-sac. A left salpingectomy was performed. Corpora lutea were noted in both ovaries. At the time of surgery, the patient was treated with 100 mg P intramuscularly, to decrease uterine irritability. She had one episode of vaginal bleeding the day after surgery. At 13 weeks' gestation, McDonald cerclage was used because of cervical effacement. The patient remained at bed rest. She had recurrent premature labor requiring therapy with beta-mimetic agents and mild pregnancy-induced hypertension. Amniocentesis at 32 weeks was consistent with fetal pulmonary maturity. At 33 weeks' gestation, premature labor recurred and the patient was delivered of healthy male infants by cesarean section who are well at 2 months of age. The hCG titers are shown in Figure 3. Pathologic diagnosis op the removed tube showed mild, acute and chronic salpingitis and chorionic villi with decidual reaction. Chromosomal analysis was performed directly on chorionic villi of the ectopic pregnancy tissue with a modification of the method described by Gregson and Seabright. 3 A normal (46,XX) karyotype was observed.
Figure 2 Transverse section shows hypoechoic masses in each ovary, believed to be residual cysts. This shows the difficulty in diagnosing the presence of an ectopic gestation in these patients.
Fertility and Sterility
..
200,000 100,000 50,000
. -:
20,000 10,000 5,000
E .... =>
E
2,000 1,000 500 200 100 50 20 10 25
35
45
55
65
75
S5
95
105
115
125
135
DAYS POST LAST MENSTRUAL PERIOD
Figure 3 Serum hCG levels for this case ® and in normal singleton pregnancies; notice the day following surgery (arrow),
DISCUSSION
Serial quantitative hCG serum assays with judicious use of pelvic ultrasound has made the diagnosis of ectopic pregnancy much more reliable. The modern management of the pregnant patient with lower abdominal pain has greatly reduced the risk of ectopic pregnancy rupture. In many cases, ectopic pregnancy is diagnosed by attainment of a critical hCG level with failure to visualize an intrauterine gestational sac. However, si:multaneous intrauterine and ectopic pregnancies can occur and make the diagnosis more difficult, because precise ultrasonographic visualization of the pregnancy within th~ fallopian tube is often not possible. Theoretic factors that may predispose to ectopic pregnancies following ET include uterine cramping resulting in retrograde delivery of the conceptus to the fallopian tube and traumatic ET, which may be evidenced by immediate uterine bleeding. This patient did not have cramping or bleeding at Table 1. Pregnancy After lVF -ET (Hospital of the University of Pennsylvania) Embryos transferred (no. pregnant patients)
Singleton
Twin
Ectopic
2 (12) 3 (6)
10 6
2" 0
1
3
0 0 1 Ib
4 (5) 5 (3)
2
Ib
"One twin in the first trimester, The pregnancy continued to term as a singleton, ~he present case had both a twin and an ectopic pregnancy and is included twice. Vol. 43, No.2, February 1985
the time of transfer but did approximately 1 week later. Bleeding at some time during the first 2 weeks after transfer in patients who conceive is common, occurring in 50% of patients in our experience. The diethylstilbestrol-exposed uterus may have widening of the interstitial and isthmic portions of the oviducts, which may predispose to tubal pregnancy,4 This case illustrates that in the patient who has undergone ET with multiple oocytes, even the presence of an intrauterine gestational sac (or sacs) does not exclude the possibility of a simultaneous ectopic pregnancy. The optimal· number of oocytes transferred to maximize the conception rate has been evaluated. With increased numbers of oocytes transferred (at least up to four), the pregnancy rate appears to increase, but the incidence of multiple gestations may also increase. 5,6 Multiple gestations after· ovum transfer of multiple fertilized eggs have been reported to occur in as many as 35% of IVFET pregnancies. 5 In addition, reports of early evidence of triplet and twin pregnancies showing later regression of sacs and final progression as singleton pregnancies has been documented. 5, 6 Table 1 shows the relationship between ET and singleton pregnancies, multiple pregnancies, and ectopic gestations for the In Vitro Fertilization Program at the Hospital of the University of Pennsylvania. Although chromosomal abnormalities have been identified in as many as 30% of spontaneously occurring ectopic pregnancies, in this patient, chromosomal analysis was normal. 7 Another IVF-ET pregnancy of ours which ended in a firsttrimester spontaneous abortion also had a normal karyotype (46,XY). Normal karyotypes have been reported in two other spontaneous abortuses occurring after IVF-ET.5 Perhaps pregnancies after IVF-ET will be less likely than normal to have chromosomal abnormalities. The frequency of chromosomal abnormalities in spontaneous abortuses or ectopic pregnancies following IVF-ET will be important to determine. At present, the data are too limited to allow any interpretation of the chromosomal findings in our cases. We feel that this case reaffirms the need for close follow-up of pregnant patients after ovum transfer. It also illustrates the shortcomings of standard diagnostic techniques other than laparoscopy for diagnosing an ectopic pregnancy when faced with a simultaneous intrauterine pregnancy. Sondheimer et aI. Communications-in-brief
315
SUMMARY
A simultaneous ectopic tubal pregnancy with viable intrauterine twin gestations after IVF-ET of five fertilized eggs is presented. Pelvic ultrasound and serial quantitative hCG levels were not helpful in the diagnosis of the tubal pregnancy. The risk of multiple pregnancies and of concomitant intrauterine and extrauterine gestations increases with transfer of a greater number of embryos. Karyotype of the tubal pregnancy was normal (46,XX). REFERENCES 1. Steptoe PC, Edwards RG: Reimplantation of a human embryo with subsequent tubal pregnancy. Lancet 1:880, 1976
316
Sondheimer et al.
Communications-in-brief
2. Smith DH, Pike I, Tucker M, Sinosich MJ, Kemp JF, Picker RH, Saunders DM: Tubal pregnancy occurring after successful in vitro fertilization and embryo transfer. Fertil Steril 38:105, 1982 3. Gregson NM, Seabright M: Handling chorionic villi for direct chromosomal studies. Lancet 2:1491, 1983 4. Muasher SJ, Garcia JE, Jones HW Jr: Experience with diethylstilbestrol-exposed infertile women in a program of in vitro fertilization. Fertil Steril 42:20, 1984 5. Kerin J, Quinn P, Kirby C, Seamark R, Warnes G, Jeffry R, Matthews C, Cox L: Incidence of multiple pregnancy after in vitro fertilization and embryo transfer. Lancet 1:537,1983 6. Muasher S, Wilkes C, Garcia JE, Rosenwaks Z, Jones HW Jr: Benefits and risks of multiple transfer with in vitro fertilization. Lancet 1:570, 1984 7. Elias S, LeBeau M, Simpson JL, Martin AO: Chromosome analysis of ectopic human conceptuses. Am J Obstet Gynecol 141:698, 1981
Fertility and Sterility
Vol. 43, No.2, February 1985 Printed in U.s.A.
Simultaneous ectopic pregnancy with intrauterine twin gestations after in vitro fertilization and embryo transfer
Steven J. Sondheimer, M.D.*t Richard W. Tureck, M.D.* Luis Blasco, M.D. * Jerome Strauss III, M.D., Ph.D.*:j: Peter Arger, M.D.§ Michael Mennuti, M.D.* Hospital of the University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
The first successful pregnancy achieved through in vitro fertilization and embryo transfer OVF-ET) occurred in 1976 and was reported by Steptoe and Edwards. l This pregnancy was a right tubal ectopic pregnancy. Tubal ectopic pregnancies following IVF-ET continue to be reported. 2 A simultaneous intrauterine and ectopic pregnancy occurring spontaneously is a relatively rare event, occurring in approximately 1 in 30,000 pregnancies. Ovulation induction with clomiphene citrate or menotropins increases the incidence of multiple ovulation and thus may increase the risk of simultaneous intrauterine and ectopic pregnancy. We report a left tubal ectopic pregnancy with concomitant viable twin intrauterine gestations resulting from IVF-ET.
Received August 1, 1984; accepted October 15, 1984. *Department of Obstetrics and Gynecology. tReprint requests: Steven J. Sondheimer, M.D., Department of Obstetrics and Gynecology, Hospital of the University of Pennsylvania School of Medicine, 3400 Spruce Street, Philadelphia, Pennsylvania 19104. :j:Department of Pathology. §Department of Radiology. Vol. 43, No.2, February 1985
CASE REPORT
The patient is a 28-year-old married Caucasian woman with 4 years of primary infertility. Complete infertility evaluation discovered minimal pelvic endometriosis, presence of a diethylstilbestrol-exposed T-shaped uterus, and repeated poor postcoital tests because of scanty mucus production. In spite of intensive and complete therapy, pregnancy failed to occur, and IVF was considered. Ovulation stimulation was carried out with human menopausal gonadotropins (Pergonal, Serono Laboratories, Inc., Randolph, MA) starting on day 3 of the cycle. Ovum retrieval was achieved laparoscopically with seven follicles aspirated and five oocytes recovered. All five eggs successfully fertilized; and 49 hours after recovery, two of the concepti were 5 cells, one was 3 cells, one was 2 cells, and one was 1 cell (pronuclear). All were transferred transcervically in the knee-chest position. The concepti were deposited ~ 0.5 cm from the uterine fundus (as determined by previous sonographic measurements of the cavity) in 50 ILl of a viscous transfer medium consisting of 90% maternal serum and 10% Ham's F-10. At the time of transfer, no uterine cramping or bleeding occurred. The patient was treated with 12.5 mg Sondheimer et al. Communications-in-brief
313
Figure 1 Longitudinal real-time ultrasound shows a double gestational sac, indicating twins. On this single projection, notice the fetal pole in one of the sacs (arrow).
progesterone (P), intramuscularly daily, after transfer. In the week following transfer, the patient complained of mild cramping and very light vaginal bleeding. Seventeen days after transfer, a positive test for serum beta-human chorionic gonadotropin (l3-hCG) was obtained. Thereafter, she received P vaginal suppositories, 25 mg, twice daily. Twenty-seven days after transfer, the patient noted mild uterine cramping with vaginal spotting. At that time, ultrasonography showed two gestational sacs within the uterus and two fetal poles, and serum l3-hCG was 18,800 mIU/ml. Four days later, a repeat ultrasonography confirmed two fetal poles. A definite heartbeat was seen associated with a fetal pole with a crown-rump length of 8.5 mm, correlating with a menstrual age of 6 weeks and 6 days (Figs. 1 and 2). The left ovary showed a lo8-cm cyst; the right ovary measured 5 cm in greatest dimension and had three small cysts. The patient then presented 10 days later, 41 days after transfer, with 1 day of increasing lower abdominal pain and a fainting episode at home. Her hematocrit was 30%, and her blood pressure was stable. Two weeks prior to this, her hematocrit had been 35%. Ultrasound showed two gestational sacs, a crown-rump length of 9 mm, compatible with 7 weeks' gestation, and fetal heart activity in both gestational sacs. Small cysts were present in both adnexa, and free fluid was identified in the abdomen. After observation in the hospital, the patient's discomfort initially improved, 314
Sondheimer et al.
Communications-in-brief
her hematocrit remained stable, and the possibility of a self-limited bleed from the fragile corpus luteum was considered. However, her crampy lower abdominal pain recurred and worsened, and her hematocrit fell to 27%. A diagnostic laparoscopy was performed. An unruptured left ampullary ectopic pregnancy was found, with blood in the cul-de-sac. A left salpingectomy was performed. Corpora lutea were noted in both ovaries. At the time of surgery, the patient was treated with 100 mg P intramuscularly, to decrease uterine irritability. She had one episode of vaginal bleeding the day after surgery. At 13 weeks' gestation, McDonald cerclage was used because of cervical effacement. The patient remained at bed rest. She had recurrent premature labor requiring therapy with beta-mimetic agents and mild pregnancy-induced hypertension. Amniocentesis at 32 weeks was consistent with fetal pulmonary maturity. At 33 weeks' gestation, premature labor recurred and the patient was delivered of healthy male infants by cesarean section who are well at 2 months of age. The hCG titers are shown in Figure 3. Pathologic diagnosis op the removed tube showed mild, acute and chronic salpingitis and chorionic villi with decidual reaction. Chromosomal analysis was performed directly on chorionic villi of the ectopic pregnancy tissue with a modification of the method described by Gregson and Seabright. 3 A normal (46,XX) karyotype was observed.
Figure 2 Transverse section shows hypoechoic masses in each ovary, believed to be residual cysts. This shows the difficulty in diagnosing the presence of an ectopic gestation in these patients.
Fertility and Sterility
..
200,000 100,000 50,000
. -:
20,000 10,000 5,000
E .... =>
E
2,000 1,000 500 200 100 50 20 10 25
35
45
55
65
75
S5
95
105
115
125
135
DAYS POST LAST MENSTRUAL PERIOD
Figure 3 Serum hCG levels for this case ® and in normal singleton pregnancies; notice the day following surgery (arrow),
DISCUSSION
Serial quantitative hCG serum assays with judicious use of pelvic ultrasound has made the diagnosis of ectopic pregnancy much more reliable. The modern management of the pregnant patient with lower abdominal pain has greatly reduced the risk of ectopic pregnancy rupture. In many cases, ectopic pregnancy is diagnosed by attainment of a critical hCG level with failure to visualize an intrauterine gestational sac. However, si:multaneous intrauterine and ectopic pregnancies can occur and make the diagnosis more difficult, because precise ultrasonographic visualization of the pregnancy within th~ fallopian tube is often not possible. Theoretic factors that may predispose to ectopic pregnancies following ET include uterine cramping resulting in retrograde delivery of the conceptus to the fallopian tube and traumatic ET, which may be evidenced by immediate uterine bleeding. This patient did not have cramping or bleeding at Table 1. Pregnancy After lVF -ET (Hospital of the University of Pennsylvania) Embryos transferred (no. pregnant patients)
Singleton
Twin
Ectopic
2 (12) 3 (6)
10 6
2" 0
1
3
0 0 1 Ib
4 (5) 5 (3)
2
Ib
"One twin in the first trimester, The pregnancy continued to term as a singleton, ~he present case had both a twin and an ectopic pregnancy and is included twice. Vol. 43, No.2, February 1985
the time of transfer but did approximately 1 week later. Bleeding at some time during the first 2 weeks after transfer in patients who conceive is common, occurring in 50% of patients in our experience. The diethylstilbestrol-exposed uterus may have widening of the interstitial and isthmic portions of the oviducts, which may predispose to tubal pregnancy,4 This case illustrates that in the patient who has undergone ET with multiple oocytes, even the presence of an intrauterine gestational sac (or sacs) does not exclude the possibility of a simultaneous ectopic pregnancy. The optimal· number of oocytes transferred to maximize the conception rate has been evaluated. With increased numbers of oocytes transferred (at least up to four), the pregnancy rate appears to increase, but the incidence of multiple gestations may also increase. 5,6 Multiple gestations after· ovum transfer of multiple fertilized eggs have been reported to occur in as many as 35% of IVFET pregnancies. 5 In addition, reports of early evidence of triplet and twin pregnancies showing later regression of sacs and final progression as singleton pregnancies has been documented. 5, 6 Table 1 shows the relationship between ET and singleton pregnancies, multiple pregnancies, and ectopic gestations for the In Vitro Fertilization Program at the Hospital of the University of Pennsylvania. Although chromosomal abnormalities have been identified in as many as 30% of spontaneously occurring ectopic pregnancies, in this patient, chromosomal analysis was normal. 7 Another IVF-ET pregnancy of ours which ended in a firsttrimester spontaneous abortion also had a normal karyotype (46,XY). Normal karyotypes have been reported in two other spontaneous abortuses occurring after IVF-ET.5 Perhaps pregnancies after IVF-ET will be less likely than normal to have chromosomal abnormalities. The frequency of chromosomal abnormalities in spontaneous abortuses or ectopic pregnancies following IVF-ET will be important to determine. At present, the data are too limited to allow any interpretation of the chromosomal findings in our cases. We feel that this case reaffirms the need for close follow-up of pregnant patients after ovum transfer. It also illustrates the shortcomings of standard diagnostic techniques other than laparoscopy for diagnosing an ectopic pregnancy when faced with a simultaneous intrauterine pregnancy. Sondheimer et aI. Communications-in-brief
315
SUMMARY
A simultaneous ectopic tubal pregnancy with viable intrauterine twin gestations after IVF-ET of five fertilized eggs is presented. Pelvic ultrasound and serial quantitative hCG levels were not helpful in the diagnosis of the tubal pregnancy. The risk of multiple pregnancies and of concomitant intrauterine and extrauterine gestations increases with transfer of a greater number of embryos. Karyotype of the tubal pregnancy was normal (46,XX). REFERENCES 1. Steptoe PC, Edwards RG: Reimplantation of a human embryo with subsequent tubal pregnancy. Lancet 1:880, 1976
316
Sondheimer et al.
Communications-in-brief
2. Smith DH, Pike I, Tucker M, Sinosich MJ, Kemp JF, Picker RH, Saunders DM: Tubal pregnancy occurring after successful in vitro fertilization and embryo transfer. Fertil Steril 38:105, 1982 3. Gregson NM, Seabright M: Handling chorionic villi for direct chromosomal studies. Lancet 2:1491, 1983 4. Muasher SJ, Garcia JE, Jones HW Jr: Experience with diethylstilbestrol-exposed infertile women in a program of in vitro fertilization. Fertil Steril 42:20, 1984 5. Kerin J, Quinn P, Kirby C, Seamark R, Warnes G, Jeffry R, Matthews C, Cox L: Incidence of multiple pregnancy after in vitro fertilization and embryo transfer. Lancet 1:537,1983 6. Muasher S, Wilkes C, Garcia JE, Rosenwaks Z, Jones HW Jr: Benefits and risks of multiple transfer with in vitro fertilization. Lancet 1:570, 1984 7. Elias S, LeBeau M, Simpson JL, Martin AO: Chromosome analysis of ectopic human conceptuses. Am J Obstet Gynecol 141:698, 1981
Fertility and Sterility