Consequences of Superovulation and ART Procedures
Complications from ART in women who conceive include multiple gestations and early pregnancy complications, including ectopic and heterotopic pregnancy.
Multiple gestations and the accompanying increase in perinatal morbidity and mortality remain a significant complication of ovulation induction and IVF. Although the incidence of higher-order multiple gestations have been decreasing in IVF, the triplet and twin rates remain significant. A review of the ART data from 2003 found that 24.8% of fresh embryo transfers resulted in twin pregnancies and 2.0% in triplet pregnancies. Multiple gestation pregnancies are at increased risk of perinatal complications including premature delivery, intrauterine growth restriction, low birthweight, and increased perinatal mortality. Recent efforts to decrease the multiple pregnancy rate have focused on reducing the number of embryos transferred during IVF. The review of the 2003 ART data showed a significant correlation between number of embryos transferred and the triplet or higher rate. At our institution, a programmatic implantation of blastocyst transfer resulted in a significant decrease in the number of higher-order gestations. Studies evaluating elective single embryo transfer have found a significant reduction in twin pregnancies without sacrificing pregnancy rates, particularly in younger populations. Current research focusing on ways to identify the single best embryo for transfer, whether by morphology, chromosomal, or DNA analysis, may help to further increase pregnancy rates while reducing multiple gestations in IVF.
Ectopic pregnancy, defined as any pregnancy implanting outside of the endometrial cavity, is a potentially dangerous complication of early pregnancy following IVF. Although the ectopic pregnancy rate in spontaneous conceptions is 1.2 to 1.4%, the rate quoted for IVF is generally three to five times higher and has been quoted as ~5% in multicenter studies ( Table 3 ). Recent Society for Assisted Reproductive Technologies (SART) data have shown a lower rate for clinics in the United States, at ~2.1 to 2.2%. Tubal disease and history of pelvic infection have been identified as the main risk factors for ectopic pregnancy following IVF. Previous history of ectopic pregnancy, previous tubal surgery, and smoking are all risk factors as well. Other factors thought to be related to the risk of ectopic pregnancy include volume of transfer media and technique of embryo transfer. Knutzen et al and Azem et al both suggest that using 40 μL of media when transferring embryos increases the risk of ectopic pregnancy by allowing media possibly containing embryos to flush into the fallopian tubes. Knutzen used radio-opaque dye to demonstrate that dye progressed to the tubes in 38% of transfers when 40 μL of media was used. General clinical practice has established a transfer media volume of 15 to 20 μL. Other studies suggest that embryos may routinely be flushed into the fallopian tubes during transfer; it is only with abnormal tubal anatomy or transport that these then implant in the fallopian tubes, becoming ectopic pregnancies.
Transfer technique and its relationship to ectopic pregnancy has been an area of some controversy. Some studies suggest that deep fundal transfer results in increased rates of ectopic pregnancy compared with mid-fundal transfer. This is thought to occur because contact with the fundus can stimulate uterine contractions that can expel the embryo from the endometrial cavity. Ultrasound-guided embryo transfer has become common in many centers and might be expected to decrease the rate of ectopic pregnancy; however, published reviews have yet to find evidence of a reduced ectopic rate. A retrospective analysis by Ali et al found increased implantation and clinical pregnancy rates with ultrasound-guided embryo transfer but no difference in ectopic pregnancy rates, although the number of ectopic pregnancies in the study and control groups was small. A retrospective study by Flisser et al comparing ultrasound-guided embryo transfer to a "clinical touch" technique found no differences in clinical outcomes, including the presence of a gestational sac, implantation rate, and clinical pregnancy rate between the groups. The number of ectopic pregnancies in the study was too small to reach statistical significance data. However, a recent large retrospective review of the data from our institution did show a decrease in ectopic and heterotopic pregnancy with the routine use of ultrasound-guided transfer. Larger studies aiming specifically to study ectopic pregnancy and ultrasound-guided embryo transfer are needed to confirm these results.
Finally, the rates of ectopic pregnancy have been decreasing in IVF in recent years, likely due to the dual factors of decreased overall number of embryos being transferred as well as aggressive programs of salpingectomy prior to IVF for patients with known hydrosalpinx or other tubal disease. At our institution, patients with known hydrosalpinx almost uniformly undergo salpingectomy prior to IVF; this has resulted in an ectopic rate much lower than that quoted nationally by SART (2.1 to 2.2% per clinical pregnancy). Keegan et al reviewed the data and found 24 ectopic pregnancies of 2688 clinical pregnancies, for a rate of 0.9% between 1998 and 2003. Of note, although a previous analysis by Milki and Jun suggested that ectopic pregnancy rates were lower with day 5 blastocyst transfer, the ectopic rate in the study by Keegan et al was higher between 2000 and 2003 when the institution transitioned from day 3 embryo transfer to blastocyst transfer. A review from our institution comparing ectopic pregnancy rates in donor egg recipients to standard IVF patients found similar rates of ectopic pregnancy in the two populations despite the higher rate of tubal disease in the standard IVF population, a finding the authors attributed to the aggressive use of salpingectomy. Aside from salpingectomy, other means of tubal occlusion, including tubal embolization and placement of the Essure device, have been attempted as ways of preventing ectopic pregnancy in IVF (• Table 4 ).
Heterotopic pregnancy is another complication of IVF that, although rare, can be a diagnostic challenge and have potentially dangerous consequences. Although heterotopic pregnancy is rare in the general population, with an incidence of 1 in 15,000 to 1 in 30,000, the rate in IVF is significantly higher, up to 0.2 to 1%. In the study by Keegan et al, eight heterotopic pregnancies were identified out of 2688 clinical IVF pregnancies, for a heterotopic rate of 0.3%. Heterotopics accounted for 33% of all ectopic pregnancies identified. Heterotopic pregnancies pose a diagnostic and therapeutic challenge, although several case reports and our own experience have shown that surgical management of the ectopic pregnancy can be performed with continuation of the intrauterine pregnancy, at times leading to successful continuation of pregnancy and eventual live birth.
Pregnancy Complications
Complications from ART in women who conceive include multiple gestations and early pregnancy complications, including ectopic and heterotopic pregnancy.
Multiple Gestation
Multiple gestations and the accompanying increase in perinatal morbidity and mortality remain a significant complication of ovulation induction and IVF. Although the incidence of higher-order multiple gestations have been decreasing in IVF, the triplet and twin rates remain significant. A review of the ART data from 2003 found that 24.8% of fresh embryo transfers resulted in twin pregnancies and 2.0% in triplet pregnancies. Multiple gestation pregnancies are at increased risk of perinatal complications including premature delivery, intrauterine growth restriction, low birthweight, and increased perinatal mortality. Recent efforts to decrease the multiple pregnancy rate have focused on reducing the number of embryos transferred during IVF. The review of the 2003 ART data showed a significant correlation between number of embryos transferred and the triplet or higher rate. At our institution, a programmatic implantation of blastocyst transfer resulted in a significant decrease in the number of higher-order gestations. Studies evaluating elective single embryo transfer have found a significant reduction in twin pregnancies without sacrificing pregnancy rates, particularly in younger populations. Current research focusing on ways to identify the single best embryo for transfer, whether by morphology, chromosomal, or DNA analysis, may help to further increase pregnancy rates while reducing multiple gestations in IVF.
Ectopic Pregnancy
Ectopic pregnancy, defined as any pregnancy implanting outside of the endometrial cavity, is a potentially dangerous complication of early pregnancy following IVF. Although the ectopic pregnancy rate in spontaneous conceptions is 1.2 to 1.4%, the rate quoted for IVF is generally three to five times higher and has been quoted as ~5% in multicenter studies ( Table 3 ). Recent Society for Assisted Reproductive Technologies (SART) data have shown a lower rate for clinics in the United States, at ~2.1 to 2.2%. Tubal disease and history of pelvic infection have been identified as the main risk factors for ectopic pregnancy following IVF. Previous history of ectopic pregnancy, previous tubal surgery, and smoking are all risk factors as well. Other factors thought to be related to the risk of ectopic pregnancy include volume of transfer media and technique of embryo transfer. Knutzen et al and Azem et al both suggest that using 40 μL of media when transferring embryos increases the risk of ectopic pregnancy by allowing media possibly containing embryos to flush into the fallopian tubes. Knutzen used radio-opaque dye to demonstrate that dye progressed to the tubes in 38% of transfers when 40 μL of media was used. General clinical practice has established a transfer media volume of 15 to 20 μL. Other studies suggest that embryos may routinely be flushed into the fallopian tubes during transfer; it is only with abnormal tubal anatomy or transport that these then implant in the fallopian tubes, becoming ectopic pregnancies.
Transfer technique and its relationship to ectopic pregnancy has been an area of some controversy. Some studies suggest that deep fundal transfer results in increased rates of ectopic pregnancy compared with mid-fundal transfer. This is thought to occur because contact with the fundus can stimulate uterine contractions that can expel the embryo from the endometrial cavity. Ultrasound-guided embryo transfer has become common in many centers and might be expected to decrease the rate of ectopic pregnancy; however, published reviews have yet to find evidence of a reduced ectopic rate. A retrospective analysis by Ali et al found increased implantation and clinical pregnancy rates with ultrasound-guided embryo transfer but no difference in ectopic pregnancy rates, although the number of ectopic pregnancies in the study and control groups was small. A retrospective study by Flisser et al comparing ultrasound-guided embryo transfer to a "clinical touch" technique found no differences in clinical outcomes, including the presence of a gestational sac, implantation rate, and clinical pregnancy rate between the groups. The number of ectopic pregnancies in the study was too small to reach statistical significance data. However, a recent large retrospective review of the data from our institution did show a decrease in ectopic and heterotopic pregnancy with the routine use of ultrasound-guided transfer. Larger studies aiming specifically to study ectopic pregnancy and ultrasound-guided embryo transfer are needed to confirm these results.
Finally, the rates of ectopic pregnancy have been decreasing in IVF in recent years, likely due to the dual factors of decreased overall number of embryos being transferred as well as aggressive programs of salpingectomy prior to IVF for patients with known hydrosalpinx or other tubal disease. At our institution, patients with known hydrosalpinx almost uniformly undergo salpingectomy prior to IVF; this has resulted in an ectopic rate much lower than that quoted nationally by SART (2.1 to 2.2% per clinical pregnancy). Keegan et al reviewed the data and found 24 ectopic pregnancies of 2688 clinical pregnancies, for a rate of 0.9% between 1998 and 2003. Of note, although a previous analysis by Milki and Jun suggested that ectopic pregnancy rates were lower with day 5 blastocyst transfer, the ectopic rate in the study by Keegan et al was higher between 2000 and 2003 when the institution transitioned from day 3 embryo transfer to blastocyst transfer. A review from our institution comparing ectopic pregnancy rates in donor egg recipients to standard IVF patients found similar rates of ectopic pregnancy in the two populations despite the higher rate of tubal disease in the standard IVF population, a finding the authors attributed to the aggressive use of salpingectomy. Aside from salpingectomy, other means of tubal occlusion, including tubal embolization and placement of the Essure device, have been attempted as ways of preventing ectopic pregnancy in IVF (• Table 4 ).
Heterotopic Pregnancy
Heterotopic pregnancy is another complication of IVF that, although rare, can be a diagnostic challenge and have potentially dangerous consequences. Although heterotopic pregnancy is rare in the general population, with an incidence of 1 in 15,000 to 1 in 30,000, the rate in IVF is significantly higher, up to 0.2 to 1%. In the study by Keegan et al, eight heterotopic pregnancies were identified out of 2688 clinical IVF pregnancies, for a heterotopic rate of 0.3%. Heterotopics accounted for 33% of all ectopic pregnancies identified. Heterotopic pregnancies pose a diagnostic and therapeutic challenge, although several case reports and our own experience have shown that surgical management of the ectopic pregnancy can be performed with continuation of the intrauterine pregnancy, at times leading to successful continuation of pregnancy and eventual live birth.
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