Journal of Assisted Reproduction and Genetics, Vol. 9, No. 5, 1992
CONTROVERSIES IN ASSISTED REPRODUCTION
IVF Versus GIFT
Gamete Intra-Fallopian transfer (GIFT) was popularized in 1985 when the in vitro fertilization/embryo transfer (IVF/ET) pregnancy rates varies between 5-15% with wide variations between different centers. The comparable pregnancy rate following GIFT was reported to be between 25-30%. The most recent US. national statistics reported a pregnancy and delivery rate of 25.4% and 19.4%, respectively, when the number of oocytes transferred was not limited. In the U.K., the clinical pregnancy and delivery rates with the transfer of a maximum of four oocytes were 19% and 12.2%. With tVF/ET, the clinical pregnancy and delivery rates in the U.S. and U.K. were 15.4% and 11.4% (1,2). One of the advantages of GIFT, over IVF, is that placing the gametes into the Fallopian tube allows fertilization to occur at its normal site so that embryo development will not be retarded as sometimes happen in the in vitro system. In addition, placing gametes or, indeed, pro-nucleate embryos or cleaved embryos into the Fallopian tube, ensures that the factors governing entry of the fertilized ovum into the uterus ensures a more synchronous entry 5-6 days after ovulation when the uterus may be more receptive for implantation as opposed to transferring embryos into the uterus usually 2 days following IVF. The controversy that surrounds GIFT being performed as a primary treatment option can be pursued in two directions: (a) does GIFT improve on no treatment or simpler forms of assisted conception treatment, e.g., IUl? (b) more importantly, does it offer advantages over IVF and ET? Unfortunately, no prospective randomized controlled studies were undertaken to answer these questions at the time that GIFT was introduced and popularized because of demands and expectations of the infertile patients and of fertility specialists to offer the most successful treatment. However, we will endeavor to respond to these ques-
tions on the future of GIFT in relation to IVF from our own experience and following a review of the literatu re.
GIFT VERSUS NO TREATMENT OR SIMPLER ASSISTED CONCEPTION TREATMENT, e.g., IUI A recent report on a contemporaneous study in a single group of patients has clearly shown that the fecundity rate and the chance of having a baby after one cycle of GIFT is significantly greater than the chance in a spontaneous cycle (3). The same investigators subsequently reported (4) their results of undertaking a randomized trial allocating women to one of three treatment protocols, i.e., (i) spontaneous cycle intrauterine insemination, (ii) superovulation and intrauterine insemination, or (iii) GIFT. The fecundability was significantly better with GIFT than either intrauterine insemination with superovulation or without. They further concluded that, in unexplained infertility, intrauterine insemination does not enhance pregnancy although they confirm the role of GIFT in this context. This conclusion was reached despite the fact that they accepted their pregnancy rate with GIFT was rather lower than would be expected in the latter part of the trial because of their initial learning curve with this method. These results corroborate those reported by others of the value of GIFT over superovulation and intrauterine insemination (5).
GIFT VERSUS IVF/ET IVF/ET is now a relatively simple treatment procedure, especially with the use of vaginal ultrasonography to both monitor the superovulation cycles and to guide vaginal ultrasound oocyte retrieval without the need for general anaesthesia. These aspects make it more imperative than ever to justify
The opinions presented in this column are those of its author(s) and do not necessarily reflect those of the journal and its editors, publisher, and advertisers, 1058-0468/92/1000-0424506.50/0 © 1992 Plenum Publishing Corporation
424
IVF VERSUS GIFT
425
GIFT treatment especially as IVF provides the most critical indication of the fertilizing competence of gametes. Unfortunately, there are only very few small prospective randomized trials comparing GIFT with IVF in the literature (6,7). These have included cases with male infertility which makes appraisal of the results difficult to evaluate especially when a limited number of oocytes are transferred since the GIFT pregnancy rate would be expected to be significantly reduced because of fewer embryos being generated, especially when it has been reported that transferring pronucleate embryos, or cleaved embryos, into the Fallopian tube achieves higher pregnancy rates than in utero transfer (8,9). It is therefore very important, when comparing the results between IVF/ET and GIFT, that male infertility factors should be excluded from the analysis especially when a limited number of oocytes are transferred into the GIFT treatment cycle. Even when male factors are excluded, limiting the number of oocytes transferred to a maximum of three with GIFT, as it is now in the U.K., is bound to have a negative effect on the outcome of treatment. We recently reported (10) on a series of 349 GIFT treatment cycles in women of 40 years of age and over. When three oocytes were electively transferred, the pregnancy rate was 16.6% compared with a pregnancy rate of 22.4% when four oocytes were transferred with a delivery rate of 10.2% in this latter group. We have also noted that even in this older group of women, the pregnancy and delivery rate was 22.1% and 10.1%, respectively, in those women in whom 4-10 oocytes were retrieved, even though a maximum of four oocytes were transferred. This confirmed to us that the quality and quantity of oocytes transferred with GIFT are more important than each alone, especially in older aged women. In this study, 83% of deliveries were singleton, 17% were multiple with only two triplets and no high order multiple births resulted. We have previously
reported that the rate of high order multiple births was 2.7% (1:37 pregnancies) when more than four oocytes were transferred in women over 39 years of age (11,12). These factors, i.e., the quality of gametes and the age of the patient, emphasize how important it is to use flexible criteria as to how many oocytes should be transferred, otherwise some patients would be positively discriminated against with regard to their predicted outcome. To identify the value of GIFT vs. IVF/ET in our center, we have analyzed the first 6 months' results since January 1, 1991. This included 113 IVF/ET procedures and 152 GIFT procedures. Table I analyzes the results by age. The clinical pregnancy rate starts to decrease from the age of 35 onward in both types of treatment, but more so with IVF especially when the patient reaches over the age of 40. This has been confirmed by large national studies (1,2). Although this study was not controlled for etiological cause, it clearly shows the advantage of GIFT treatment in older aged, infertile women. The advantage of incorporating GIFT in assisted conception programs also undertaking IVF is that the supernumery oocytes may be subject to in vitro fertilization in order to assess gamete interaction. We have previously reported that the fertilization rate of supernumery oocytes in vitro in successful GIFT cycles is higher than those who were not successful with their treatment, i.e., 41.2% compared with 34.9%, respectively (P < 0.05) (11). In that same study, total failure of fertilization was high in non-pregnant cycles but not significantly so when compared with pregnant cycles. Analysis of more recent data from our Department in patients exclusively using the gonadotrophin-releasing hormone analogue and gonadotrophin superovulation induction protocol showed that total failure of fertilization was significantly lower in pregnant cycles when compared to non-pregnant cycles, i.e., 20% compared to 41.6%, respectively (P < 0.005). It is also interesting to note that women who were successful after GIFT were more likely to have frozen
Table I. Results of GIFT (n = 157 cycles) and IVF/ET (n = 113 cycles) in Relation to Women's Age
N (%) Age
CONTROVERSIES IN ASSISTED REPRODUCTION
IVF Versus GIFT
Gamete Intra-Fallopian transfer (GIFT) was popularized in 1985 when the in vitro fertilization/embryo transfer (IVF/ET) pregnancy rates varies between 5-15% with wide variations between different centers. The comparable pregnancy rate following GIFT was reported to be between 25-30%. The most recent US. national statistics reported a pregnancy and delivery rate of 25.4% and 19.4%, respectively, when the number of oocytes transferred was not limited. In the U.K., the clinical pregnancy and delivery rates with the transfer of a maximum of four oocytes were 19% and 12.2%. With tVF/ET, the clinical pregnancy and delivery rates in the U.S. and U.K. were 15.4% and 11.4% (1,2). One of the advantages of GIFT, over IVF, is that placing the gametes into the Fallopian tube allows fertilization to occur at its normal site so that embryo development will not be retarded as sometimes happen in the in vitro system. In addition, placing gametes or, indeed, pro-nucleate embryos or cleaved embryos into the Fallopian tube, ensures that the factors governing entry of the fertilized ovum into the uterus ensures a more synchronous entry 5-6 days after ovulation when the uterus may be more receptive for implantation as opposed to transferring embryos into the uterus usually 2 days following IVF. The controversy that surrounds GIFT being performed as a primary treatment option can be pursued in two directions: (a) does GIFT improve on no treatment or simpler forms of assisted conception treatment, e.g., IUl? (b) more importantly, does it offer advantages over IVF and ET? Unfortunately, no prospective randomized controlled studies were undertaken to answer these questions at the time that GIFT was introduced and popularized because of demands and expectations of the infertile patients and of fertility specialists to offer the most successful treatment. However, we will endeavor to respond to these ques-
tions on the future of GIFT in relation to IVF from our own experience and following a review of the literatu re.
GIFT VERSUS NO TREATMENT OR SIMPLER ASSISTED CONCEPTION TREATMENT, e.g., IUI A recent report on a contemporaneous study in a single group of patients has clearly shown that the fecundity rate and the chance of having a baby after one cycle of GIFT is significantly greater than the chance in a spontaneous cycle (3). The same investigators subsequently reported (4) their results of undertaking a randomized trial allocating women to one of three treatment protocols, i.e., (i) spontaneous cycle intrauterine insemination, (ii) superovulation and intrauterine insemination, or (iii) GIFT. The fecundability was significantly better with GIFT than either intrauterine insemination with superovulation or without. They further concluded that, in unexplained infertility, intrauterine insemination does not enhance pregnancy although they confirm the role of GIFT in this context. This conclusion was reached despite the fact that they accepted their pregnancy rate with GIFT was rather lower than would be expected in the latter part of the trial because of their initial learning curve with this method. These results corroborate those reported by others of the value of GIFT over superovulation and intrauterine insemination (5).
GIFT VERSUS IVF/ET IVF/ET is now a relatively simple treatment procedure, especially with the use of vaginal ultrasonography to both monitor the superovulation cycles and to guide vaginal ultrasound oocyte retrieval without the need for general anaesthesia. These aspects make it more imperative than ever to justify
The opinions presented in this column are those of its author(s) and do not necessarily reflect those of the journal and its editors, publisher, and advertisers, 1058-0468/92/1000-0424506.50/0 © 1992 Plenum Publishing Corporation
424
IVF VERSUS GIFT
425
GIFT treatment especially as IVF provides the most critical indication of the fertilizing competence of gametes. Unfortunately, there are only very few small prospective randomized trials comparing GIFT with IVF in the literature (6,7). These have included cases with male infertility which makes appraisal of the results difficult to evaluate especially when a limited number of oocytes are transferred since the GIFT pregnancy rate would be expected to be significantly reduced because of fewer embryos being generated, especially when it has been reported that transferring pronucleate embryos, or cleaved embryos, into the Fallopian tube achieves higher pregnancy rates than in utero transfer (8,9). It is therefore very important, when comparing the results between IVF/ET and GIFT, that male infertility factors should be excluded from the analysis especially when a limited number of oocytes are transferred into the GIFT treatment cycle. Even when male factors are excluded, limiting the number of oocytes transferred to a maximum of three with GIFT, as it is now in the U.K., is bound to have a negative effect on the outcome of treatment. We recently reported (10) on a series of 349 GIFT treatment cycles in women of 40 years of age and over. When three oocytes were electively transferred, the pregnancy rate was 16.6% compared with a pregnancy rate of 22.4% when four oocytes were transferred with a delivery rate of 10.2% in this latter group. We have also noted that even in this older group of women, the pregnancy and delivery rate was 22.1% and 10.1%, respectively, in those women in whom 4-10 oocytes were retrieved, even though a maximum of four oocytes were transferred. This confirmed to us that the quality and quantity of oocytes transferred with GIFT are more important than each alone, especially in older aged women. In this study, 83% of deliveries were singleton, 17% were multiple with only two triplets and no high order multiple births resulted. We have previously
reported that the rate of high order multiple births was 2.7% (1:37 pregnancies) when more than four oocytes were transferred in women over 39 years of age (11,12). These factors, i.e., the quality of gametes and the age of the patient, emphasize how important it is to use flexible criteria as to how many oocytes should be transferred, otherwise some patients would be positively discriminated against with regard to their predicted outcome. To identify the value of GIFT vs. IVF/ET in our center, we have analyzed the first 6 months' results since January 1, 1991. This included 113 IVF/ET procedures and 152 GIFT procedures. Table I analyzes the results by age. The clinical pregnancy rate starts to decrease from the age of 35 onward in both types of treatment, but more so with IVF especially when the patient reaches over the age of 40. This has been confirmed by large national studies (1,2). Although this study was not controlled for etiological cause, it clearly shows the advantage of GIFT treatment in older aged, infertile women. The advantage of incorporating GIFT in assisted conception programs also undertaking IVF is that the supernumery oocytes may be subject to in vitro fertilization in order to assess gamete interaction. We have previously reported that the fertilization rate of supernumery oocytes in vitro in successful GIFT cycles is higher than those who were not successful with their treatment, i.e., 41.2% compared with 34.9%, respectively (P < 0.05) (11). In that same study, total failure of fertilization was high in non-pregnant cycles but not significantly so when compared with pregnant cycles. Analysis of more recent data from our Department in patients exclusively using the gonadotrophin-releasing hormone analogue and gonadotrophin superovulation induction protocol showed that total failure of fertilization was significantly lower in pregnant cycles when compared to non-pregnant cycles, i.e., 20% compared to 41.6%, respectively (P < 0.005). It is also interesting to note that women who were successful after GIFT were more likely to have frozen
Table I. Results of GIFT (n = 157 cycles) and IVF/ET (n = 113 cycles) in Relation to Women's Age
N (%) Age
