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Treatment-independent, treatment-associated, and pregnancies after additional therapy in a program of in vitro fertilization and embryo transfer
r FERTILITY AND STERILITY Copyright ,to 1987 The American Fertility Society
Vol. 47, No.4, April 1987 Printed in UB.A.
Treatment-independent, treatment-associated, and pregnancies after additional therapy in a program of in vitro fertilization and embryo transfer
Arthur F. Haney, M.D.* Claude L. Hughes, Jr., M.D., Ph.D. Daniel B. Whitesides, M.D. William C. Dodson, M.D. Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina
Although the technique of in vitro fertilization and embryo transfer (lVF -ET) was developed for couples with untreatable tubal factor infertility, IVF -ET is now being applied to women with other causes of infertility and normal pelvic anatomy. In an effort to determine the treatment-independent pregnancy rate, we retrospectively reviewed the first 245 couples enrolled in the IVF-ET program at Duke University Medical Center. There were 19 treatment-independent pregnancies in 18 women and 3 treatment-associated pregnancies in cycles in which the oocyte retrieval was canceled (in 2 women washed intrauterine insemination was substituted for oocyte retrieval). Six pregnancies were established after an unsuccessful attempt at IVF -ET with additional non-IVF-ET therapy, including washed intrauterine insemination in three couples, and donor insemination in two couples. These observations suggest that (1) a significant number of treatment-independent pregnancies will occur in couples clinically deemed appropriate for IVF-ET, (2) pregnancies can be established in cycles of controlled hyperstimulation without oocyte retrieval, and (3) additional non-IVFET therapy can result in pregnancy despite failure of IVF -ET in selected couples. Fertil Steril 47:634, 1987
The technique of in vitro fertilization and embryo transfer (lVF-ET) was developed for couples with untreatable tubal factor infertility. As success rates for IVF-ET improved, the indications broadened to include couples without distorted pelvic anatomy having endometriosis, cervical factor, male factor, or unexplained infertility.1 IVF -ET has been considered the "final option" in infertility therapy, with little expectation that the couple will spontaneously conceive or that any additional therapy would prove rewarding. Received August 14, 1986; revised and accepted October 10, 1986. *Reprint requests: A. F. Haney, M.D., Box 2971, Duke University Medical Center, Durham, North Carolina 27710.
634
Haney et al. IVF -ET pregnancies
Despite this, it has long been observed that "spontaneous cures" of infertility (i.e., treatmentindependent pregnancies) can occur even after extended intervals of childlessness. 2 - 4 This has even been reported when tubal occlusion has been demonstrated. 5 Similarly, long-term follow-up after infertility treatment has demonstrated continuing conceptions up to 72 months, well after most clinical observers would have concluded the therapy a failure. 6 On the basis of these considerations, it is logical to assume that a portion of the pregnancies attributed to IVF-ET might be treatment-independent conceptions. Previous reports from IVF -ET programs have documented a number of treatment-independent pregnancies. 7 , 8 In an attempt to address the issue of treatmentFertility and Sterility
independent conceptions, we retrospectively evaluated our experience in the first 3 years of the IVF-ET program at Duke University Medical Center. MATERIALS AND METHODS
All couples enrolled in the IVF-ET program at Duke University Medical Center since 1983 were included in this retrospective analysis. Before enrollment, the gynecologic history was thoroughly reviewed and the previous infertility investigation critically evaluated to ensure that no other therapy options had been overlooked. Criteria for inclusion into the IVF-ET program were that a couple had to have been attempting pregnancy for a minimum of 2 years and that all other available treatment options had been attempted and were unsuccessful. In most cases the couples were infertile for substantially longer intervals of time. After the gynecologic history review and a physical examination, the couple viewed an audiovisual presentation, and a trial embryo transfer was performed with the same catheter used for the actual embryo transfer. A semen sample was then processed identically to the sperm preparation technique used for the actual IVF-ET cycle, and an additional semen sample was frozen in reserve for the active IVF-ET cycle. The couple were then considered "enrolled" as they awaited menses to begin the regimen of "controlled hyperstimulation" in the active IVF-ET cycle. This consisted of either a combination of clomiphene citrate and human menopausal gonadotropin (hMG) or hMG alone. If they were lost to follow-up after an IVFET cycle as of the time of this review, they were considered not to have conceived. Only clinical pregnancies that did not occur in a cycle in which embryos were transferred were considered for this review. Pregnancies were placed in one of three categories: (1) spontaneous treatment-independent pregnancies, defined as occurring either after enrollment while awaiting an IVF-ET cycle or after an IVF-ET attempt; (2) treatment-associated pregnancies, defined as occurring in an IVF-ET cycle in which the oocyte retrieval was canceled because of either a poor follicular response or detection of a spontaneous luteinizing hormone surge; and (3) pregnancies occurring subsequent to an IVF-ET cycle after additional therapy had been undertaken. Clinical pregnancies were defined by an ongoing pregnancy beyond 12 weeks, delivery of a fetus, or a histoVol. 47, No.4, April 1987
logically confirmed spontaneous abortion or ectopic pregnancy. RESULTS
A total of 245 couples were enrolled in the IVFET program at Duke University Medical Center since 1983. The length of follow-up obviously varies depending on the enrollment date. Nineteen spontaneous treatment-independent pregnancies in 18 women have occurred as of the preparation of this manuscript (Table 1). The mean length of infertility in this group was 5.7 ± 3.2 years (mean ± standard deviation). Four occurred after enrollment before an IVF-ET cycle, 12 after an unsuccessful IVF-ET attempt, and 2 after successful IVF-ET pregnancies. Three treatment-associated pregnancies occurred during IVF-ET cycles in which the retrieval of oocytes was not attempted (Table 2). In each of these cases the women had rising human chorionic gonadotropin (hCG) titers within 18 days of the last estradiol measurement, and hCG was not detected in the blood samples drawn during monitoring. Clinical pregnancies were established in every instance. In two women, the follicular stimulation was judged inadequate because fewer than two follicles reached 15 mm in diameter, and in the third woman a spontaneous luteinizing hormone surge was detected. One woman with inadequate follicular stimulation conceived despite discontinuance of the hMG and withholding of the hCG. In the remaining two women, washed intrauterine insemination (WIUn was substituted for oocyte retrieval 36 hours after the injection of hCG. In six couples pregnancies occurred with additional treatment after an attempt at IVF-ET failed to result in pregnancy (Table 3). The additional therapy consisted of WIUI after hMG/hCG stimulation in three women, artificial insemination by donor (AID) in two women, and removal of a previously unknown intrauterine device (IUD) in the remaining woman. Both women who conceived with WIUI did so on the first cycle of therapy. A previously undetected male factor was suspected in two couples after an IVF-ET attempt when the motility of the sperm declined rapidly in vitro. Both women established pregnancies on the third cycle of AID, one with fresh semen and one with frozen semen. The IUD was noted during ultrasonic follicular monitoring in the IVF-ET cycle. This had not been appreciated by her referHaney et al. IVF -ET pregnancies
635
Table 1. Summary of Treatment-Independent Pregnancies No.
Age
Parity
Length of infertility
Clinical diagnosis
Outcome
yr
4 5
Endometriosis PIDa
Spontaneous abortion Tubal pregnancy
0 1-0-1 0
3 8 5
Term delivery Term delivery Term delivery
31 35 31
0 0 0
6 9 5
39
1-0-1
7
Unexplained Endometriosis Endometriosis, adnexal adhesions Endometriosis Endometriosis, oligospermia Endometriosis, oligospermia, adnexal adhesions Unexplained PID Endometriosis, oligospermia PID Unexplained PID
Term delivery Spontaneous abortion Term delivery Term delivery Tubal pregnancy
.PID Endometriosis Unexplained
Term delivery Ongoing pregnancy Ongoing pregnancy
Endometriosis
Spontaneous abortion
1 2
28 29
3 4 5
32 35 36
6 7 8
0 2-2-0
(two tubal pregnancies)
9
Term delivery Spontaneous abortion Spontaneous abortion, ongoing pregnancy Term delivery
(previous IVF-ET pregnancy)
12 13 14
33 33 33 33 34
15 16 17
30 35 35
10 11
2-0-2 0 5-4-1 0 2-1-1
2 4 3 14 4
(one tubal pregnancy)
18
0 0 1-0-1
2 4
1-1-0
7
11 (previous IVF-ET pregnancy)
32
(tubal pregnancy) apelvic inflammatory disease.
ring physician on either a hysterosalpingogram or two diagnostic laparoscopies. The IVF-ET cycle was abandoned and the IUD removed. DISCUSSION
When therapy for infertility is undertaken, it is typically assumed that any conceptions that follow are attributable to the treatment without regard to the "background" or treatment-independent pregnancy rate in the population under study. Unless circumstances absolutely precluding pregnancy are present (e.g., an absent uterus, azoospermia), a small but definable pregnancy rate is present in any infertile population. 2 - 4 This is true despite prolonged intervals without conception and even when tubal obstruction has been demonstrated by traditional diagnostic methods. 5 The group of women with treatment-independent pregnancies may not be representative of the overall IVF-ET candidate pool, because the number with severe anatomic distortion ofthe adnexa is small. It is likely that there will be fewer treatment-independent pregnancies in a population ofIVF-ET candidates with chronic pelvic inflammatory disease than those undergoing IVFET for other causes of infertility with proportionately less anatomic distortion of the pelvic vis636
Haney et al. IVF -ET pregnancies
cera. Only randomized prospective clinical trials can define the true treatment-independent conception rate in a given clinical situation. Because of considerations of cost and patient acceptance, it is unlikely that prospective controlled trials will be performed in programs of IVF-ET. Two previous reports 7 , 8 suggest that the number of treatment-independent pregnancies in the 24 months after IVF-ET is approximately equivalent to the success rate for a single cycle of IVF-ET. Our experience confirms that treatment-independent conceptions will occur in a program of IVF -ET despite long-standing childlessness, extensive and repetitive infertility investigations, and multiple therapeutic efforts. The total number of treatment-independent pregnancies can be expected to increase with a lengthening follow"up interval. The treatment-associated pregnancies form a unique group. Although they may simply represent treatment-independent pregnancies that occurred by chance in the stimulated cycle, there are several other intriguing possibilities. First, IVF-ET involves "controlled hyperstimulation" by a variety of techniques to increase the number of preovulatory oocytes for retrieval. The regimens include clomiphene citrate alone and in combination with hMG, or hMG alone. These Fertility and Sterility
Table 2. Summary of Treatment-Associated Pregnancies Length of infertility
No.
Age
Parity
Clinical diagnosis
1
30
2-2-0
8
Endometriosis
Term delivery
2
37
0
6
Endometri{)sis
Ongoing pregnancy
3
32
0
4
PID b
Ongoing pregnancy
Comments
Outcome
yr
Spontaneous luteinizing hormone surge, WIUla substituted for oocyte retrieval Inadequate follicular stimulation, IVF-ET cycle abandoned, hMG stopped, and heG withheld Inadequate follicular stimulation, WIUIa substituted for oocyte retrieval
aWIUI was performed 36 hours after injection of heG in a cycle of "controlled hyperstimulation" using hMG. bpelvic inflammatory disease.
agents may produce qualitatively improved ovulatory function, and with at least one patent fallopian tube, a pregnancy may occur if this regimen corrects a previously undetected ovulatory defect. Second, unidentified fertility-reducing factors may be present, and an increase in the monthly fecundity rate could be anticipated simply by multiple ovulations in a single cycle (e.g., the probability of a conception over six ovulatory cycles compressed in a single cycle with six ovulations). Third, two women conceived with WIUI. The sperm washing procedure and/or the intrauterine placement of sperm may have a beneficial effect on fertility in selected couples. Whatever the specific mechanisms, the "controlled hyperstimulation" used in IVF-ET may have some therapeutic benefit, and WIUI should be considered when oocyte retrieval is canceled because of inadequate follicular stimulation or when a spontaneous LH surge is detected. Most physicians and patients consider IVF-ET the "final option" for the treatment of infertility because virtually all other therapeutic modalities have been attempted and the procedure is technically difficult and expensive. It should be appreciated that human sperm-egg interaction can currently be assessed only by direct observation of
the gametes in vitro. Occasionally, an unsuspected male factor may only be identified when IVFET is undertaken, particularly when other poten~ tial infertility factors are present in the female partner. Two women in this series conceived promptly with AID after a male factor was identified during an IVF-ET attempt. One of these women had severe endometriosis, and the infertility could easily have been attributable to that factor. Three women conceived with the additional therapy of WIUI in which hMGlhCG was used to provide "controlled hyperstimulation" in a manner similar to the IVF-ET cycles. All three couples had no obvious male factor. This might be considered a therapeutic option antecedent to IVF-ET in women without distorted anatomy including those with endometriosis, cervical factor, or idiopathic infertility. Similarly, a portion of the conceptions attributed to IVF-ET might be considered to have occurred because of the follicular stimulation, particularly in programs that place sperm in the genital tract before oocyte retrieval as part of their regimen. 9 This is also true for the gamete intra-fallopian tube transfer procedure in which a control group of stimulated but nontransferred patients has not been included. 10
Table 3. Summary of the Pregnancies Occurring with Additional Treatment After a Failed Attempt at IVF -ET No.
Age
Parity
Length of infertility
Clinical diagnosis
Additional therapy
Outcome
yr
1 2 3 4 5 6
36 30 37 35 29 32
0 0 0 2-2-0 0 2-0-2
8 7 10 7 4 4
Endometriosis Endometriosis Unexplained Endometriosis Endometriosis PID b
WIUIa WIUIa IUD removal AID AID WIUIa
Term delivery Term delivery Term delivery Term delivery Term delivery Ongoing pregnancy
aperformed 36 hours after injection of heG in a cycle of "controlled hyperstimulation" using hMG. bpelvic inflammatory disease. Vol. 47, No.4, April 1987
Haney et a1. IVF -ET pregnancies
637
r REFERENCES 1. Mahadevan MM, Trounson AO, Leeton JF: The relation-
ship of tubal blockage, infertility of unknown cause, suspected male infertility, and endometriosis to success of in vitro fertilization and embryo transfer. Fertil Steril 40: 755, 1983 2. Grant A: The spontaneous cure rate of various infertility factors or post hoc and propter hoc. Aust NZ J Ohstet Gynaecol 9:224, 1969 3. Bernstein D, Levin S, Amsterdam E, Insler V: Is conception in infertility couples t:r:eatment related? a survey of 309 pregnancies. Int J Fertil 24:65, 1979 4. Collins JA, Wrixon W, Janes LB, Wilson EH: Treatmentindependent pregnancy among infertile couples. N Engl J Med 309:1201, 1983 5. Gomel V, McComb P: Unexpected pregnancies in women afflicted by occlusive tubal disease. Fertil Steril 36:529, 1981
6. Russell JB, DeCherney AH, Laufer N, Polan ML, Naftolin F: Neosalpingostomy: comparison of 24- and 72-month follow-up time shows increased pregnancy rate. Fertil Steril 45:296, 1986 7. Jarrell J, Gwatkin R, Lumsden B, Lamont KG, Boulter G, Daya S, Collins J: An in vitro fertilization and embryo transfer pilot study: treatment-dependent and treatmentindependent pregnancies. Am J Obstet Gynecol 154:231, 1986 8. Ben-Rafel Z, Mashiach S, Dor J, Rudak E, Goldman B: Treatment-independent pregnancy after in vitro fertilization and embryo transfer trial. Fertil Steril 45:564, 1986 9. Sher G, Knutzen V, Stratton CJ, Montakhab MM, Allenson SG, Mayville J, Rubenstein J A, Glass MJ, Bilach SM: The development of a successful non-university-based ambulatory in vitro fertilization/embryo transfer program: Phase I. Fertil Steril 41:511, 1984 10. Asch RH, Ellsworth LR, Balmaceda JP, Wong PC: Pregnancy after translaparoscopic gamete intrafallopian transfer. Lancet 2:1034, 1984
Fertility and Sterility 638
Haney et al. IVF -ET pregnancies
Vol. 47, No.4, April 1987 Printed in UB.A.
Treatment-independent, treatment-associated, and pregnancies after additional therapy in a program of in vitro fertilization and embryo transfer
Arthur F. Haney, M.D.* Claude L. Hughes, Jr., M.D., Ph.D. Daniel B. Whitesides, M.D. William C. Dodson, M.D. Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina
Although the technique of in vitro fertilization and embryo transfer (lVF -ET) was developed for couples with untreatable tubal factor infertility, IVF -ET is now being applied to women with other causes of infertility and normal pelvic anatomy. In an effort to determine the treatment-independent pregnancy rate, we retrospectively reviewed the first 245 couples enrolled in the IVF-ET program at Duke University Medical Center. There were 19 treatment-independent pregnancies in 18 women and 3 treatment-associated pregnancies in cycles in which the oocyte retrieval was canceled (in 2 women washed intrauterine insemination was substituted for oocyte retrieval). Six pregnancies were established after an unsuccessful attempt at IVF -ET with additional non-IVF-ET therapy, including washed intrauterine insemination in three couples, and donor insemination in two couples. These observations suggest that (1) a significant number of treatment-independent pregnancies will occur in couples clinically deemed appropriate for IVF-ET, (2) pregnancies can be established in cycles of controlled hyperstimulation without oocyte retrieval, and (3) additional non-IVFET therapy can result in pregnancy despite failure of IVF -ET in selected couples. Fertil Steril 47:634, 1987
The technique of in vitro fertilization and embryo transfer (lVF-ET) was developed for couples with untreatable tubal factor infertility. As success rates for IVF-ET improved, the indications broadened to include couples without distorted pelvic anatomy having endometriosis, cervical factor, male factor, or unexplained infertility.1 IVF -ET has been considered the "final option" in infertility therapy, with little expectation that the couple will spontaneously conceive or that any additional therapy would prove rewarding. Received August 14, 1986; revised and accepted October 10, 1986. *Reprint requests: A. F. Haney, M.D., Box 2971, Duke University Medical Center, Durham, North Carolina 27710.
634
Haney et al. IVF -ET pregnancies
Despite this, it has long been observed that "spontaneous cures" of infertility (i.e., treatmentindependent pregnancies) can occur even after extended intervals of childlessness. 2 - 4 This has even been reported when tubal occlusion has been demonstrated. 5 Similarly, long-term follow-up after infertility treatment has demonstrated continuing conceptions up to 72 months, well after most clinical observers would have concluded the therapy a failure. 6 On the basis of these considerations, it is logical to assume that a portion of the pregnancies attributed to IVF-ET might be treatment-independent conceptions. Previous reports from IVF -ET programs have documented a number of treatment-independent pregnancies. 7 , 8 In an attempt to address the issue of treatmentFertility and Sterility
independent conceptions, we retrospectively evaluated our experience in the first 3 years of the IVF-ET program at Duke University Medical Center. MATERIALS AND METHODS
All couples enrolled in the IVF-ET program at Duke University Medical Center since 1983 were included in this retrospective analysis. Before enrollment, the gynecologic history was thoroughly reviewed and the previous infertility investigation critically evaluated to ensure that no other therapy options had been overlooked. Criteria for inclusion into the IVF-ET program were that a couple had to have been attempting pregnancy for a minimum of 2 years and that all other available treatment options had been attempted and were unsuccessful. In most cases the couples were infertile for substantially longer intervals of time. After the gynecologic history review and a physical examination, the couple viewed an audiovisual presentation, and a trial embryo transfer was performed with the same catheter used for the actual embryo transfer. A semen sample was then processed identically to the sperm preparation technique used for the actual IVF-ET cycle, and an additional semen sample was frozen in reserve for the active IVF-ET cycle. The couple were then considered "enrolled" as they awaited menses to begin the regimen of "controlled hyperstimulation" in the active IVF-ET cycle. This consisted of either a combination of clomiphene citrate and human menopausal gonadotropin (hMG) or hMG alone. If they were lost to follow-up after an IVFET cycle as of the time of this review, they were considered not to have conceived. Only clinical pregnancies that did not occur in a cycle in which embryos were transferred were considered for this review. Pregnancies were placed in one of three categories: (1) spontaneous treatment-independent pregnancies, defined as occurring either after enrollment while awaiting an IVF-ET cycle or after an IVF-ET attempt; (2) treatment-associated pregnancies, defined as occurring in an IVF-ET cycle in which the oocyte retrieval was canceled because of either a poor follicular response or detection of a spontaneous luteinizing hormone surge; and (3) pregnancies occurring subsequent to an IVF-ET cycle after additional therapy had been undertaken. Clinical pregnancies were defined by an ongoing pregnancy beyond 12 weeks, delivery of a fetus, or a histoVol. 47, No.4, April 1987
logically confirmed spontaneous abortion or ectopic pregnancy. RESULTS
A total of 245 couples were enrolled in the IVFET program at Duke University Medical Center since 1983. The length of follow-up obviously varies depending on the enrollment date. Nineteen spontaneous treatment-independent pregnancies in 18 women have occurred as of the preparation of this manuscript (Table 1). The mean length of infertility in this group was 5.7 ± 3.2 years (mean ± standard deviation). Four occurred after enrollment before an IVF-ET cycle, 12 after an unsuccessful IVF-ET attempt, and 2 after successful IVF-ET pregnancies. Three treatment-associated pregnancies occurred during IVF-ET cycles in which the retrieval of oocytes was not attempted (Table 2). In each of these cases the women had rising human chorionic gonadotropin (hCG) titers within 18 days of the last estradiol measurement, and hCG was not detected in the blood samples drawn during monitoring. Clinical pregnancies were established in every instance. In two women, the follicular stimulation was judged inadequate because fewer than two follicles reached 15 mm in diameter, and in the third woman a spontaneous luteinizing hormone surge was detected. One woman with inadequate follicular stimulation conceived despite discontinuance of the hMG and withholding of the hCG. In the remaining two women, washed intrauterine insemination (WIUn was substituted for oocyte retrieval 36 hours after the injection of hCG. In six couples pregnancies occurred with additional treatment after an attempt at IVF-ET failed to result in pregnancy (Table 3). The additional therapy consisted of WIUI after hMG/hCG stimulation in three women, artificial insemination by donor (AID) in two women, and removal of a previously unknown intrauterine device (IUD) in the remaining woman. Both women who conceived with WIUI did so on the first cycle of therapy. A previously undetected male factor was suspected in two couples after an IVF-ET attempt when the motility of the sperm declined rapidly in vitro. Both women established pregnancies on the third cycle of AID, one with fresh semen and one with frozen semen. The IUD was noted during ultrasonic follicular monitoring in the IVF-ET cycle. This had not been appreciated by her referHaney et al. IVF -ET pregnancies
635
Table 1. Summary of Treatment-Independent Pregnancies No.
Age
Parity
Length of infertility
Clinical diagnosis
Outcome
yr
4 5
Endometriosis PIDa
Spontaneous abortion Tubal pregnancy
0 1-0-1 0
3 8 5
Term delivery Term delivery Term delivery
31 35 31
0 0 0
6 9 5
39
1-0-1
7
Unexplained Endometriosis Endometriosis, adnexal adhesions Endometriosis Endometriosis, oligospermia Endometriosis, oligospermia, adnexal adhesions Unexplained PID Endometriosis, oligospermia PID Unexplained PID
Term delivery Spontaneous abortion Term delivery Term delivery Tubal pregnancy
.PID Endometriosis Unexplained
Term delivery Ongoing pregnancy Ongoing pregnancy
Endometriosis
Spontaneous abortion
1 2
28 29
3 4 5
32 35 36
6 7 8
0 2-2-0
(two tubal pregnancies)
9
Term delivery Spontaneous abortion Spontaneous abortion, ongoing pregnancy Term delivery
(previous IVF-ET pregnancy)
12 13 14
33 33 33 33 34
15 16 17
30 35 35
10 11
2-0-2 0 5-4-1 0 2-1-1
2 4 3 14 4
(one tubal pregnancy)
18
0 0 1-0-1
2 4
1-1-0
7
11 (previous IVF-ET pregnancy)
32
(tubal pregnancy) apelvic inflammatory disease.
ring physician on either a hysterosalpingogram or two diagnostic laparoscopies. The IVF-ET cycle was abandoned and the IUD removed. DISCUSSION
When therapy for infertility is undertaken, it is typically assumed that any conceptions that follow are attributable to the treatment without regard to the "background" or treatment-independent pregnancy rate in the population under study. Unless circumstances absolutely precluding pregnancy are present (e.g., an absent uterus, azoospermia), a small but definable pregnancy rate is present in any infertile population. 2 - 4 This is true despite prolonged intervals without conception and even when tubal obstruction has been demonstrated by traditional diagnostic methods. 5 The group of women with treatment-independent pregnancies may not be representative of the overall IVF-ET candidate pool, because the number with severe anatomic distortion ofthe adnexa is small. It is likely that there will be fewer treatment-independent pregnancies in a population ofIVF-ET candidates with chronic pelvic inflammatory disease than those undergoing IVFET for other causes of infertility with proportionately less anatomic distortion of the pelvic vis636
Haney et al. IVF -ET pregnancies
cera. Only randomized prospective clinical trials can define the true treatment-independent conception rate in a given clinical situation. Because of considerations of cost and patient acceptance, it is unlikely that prospective controlled trials will be performed in programs of IVF-ET. Two previous reports 7 , 8 suggest that the number of treatment-independent pregnancies in the 24 months after IVF-ET is approximately equivalent to the success rate for a single cycle of IVF-ET. Our experience confirms that treatment-independent conceptions will occur in a program of IVF -ET despite long-standing childlessness, extensive and repetitive infertility investigations, and multiple therapeutic efforts. The total number of treatment-independent pregnancies can be expected to increase with a lengthening follow"up interval. The treatment-associated pregnancies form a unique group. Although they may simply represent treatment-independent pregnancies that occurred by chance in the stimulated cycle, there are several other intriguing possibilities. First, IVF-ET involves "controlled hyperstimulation" by a variety of techniques to increase the number of preovulatory oocytes for retrieval. The regimens include clomiphene citrate alone and in combination with hMG, or hMG alone. These Fertility and Sterility
Table 2. Summary of Treatment-Associated Pregnancies Length of infertility
No.
Age
Parity
Clinical diagnosis
1
30
2-2-0
8
Endometriosis
Term delivery
2
37
0
6
Endometri{)sis
Ongoing pregnancy
3
32
0
4
PID b
Ongoing pregnancy
Comments
Outcome
yr
Spontaneous luteinizing hormone surge, WIUla substituted for oocyte retrieval Inadequate follicular stimulation, IVF-ET cycle abandoned, hMG stopped, and heG withheld Inadequate follicular stimulation, WIUIa substituted for oocyte retrieval
aWIUI was performed 36 hours after injection of heG in a cycle of "controlled hyperstimulation" using hMG. bpelvic inflammatory disease.
agents may produce qualitatively improved ovulatory function, and with at least one patent fallopian tube, a pregnancy may occur if this regimen corrects a previously undetected ovulatory defect. Second, unidentified fertility-reducing factors may be present, and an increase in the monthly fecundity rate could be anticipated simply by multiple ovulations in a single cycle (e.g., the probability of a conception over six ovulatory cycles compressed in a single cycle with six ovulations). Third, two women conceived with WIUI. The sperm washing procedure and/or the intrauterine placement of sperm may have a beneficial effect on fertility in selected couples. Whatever the specific mechanisms, the "controlled hyperstimulation" used in IVF-ET may have some therapeutic benefit, and WIUI should be considered when oocyte retrieval is canceled because of inadequate follicular stimulation or when a spontaneous LH surge is detected. Most physicians and patients consider IVF-ET the "final option" for the treatment of infertility because virtually all other therapeutic modalities have been attempted and the procedure is technically difficult and expensive. It should be appreciated that human sperm-egg interaction can currently be assessed only by direct observation of
the gametes in vitro. Occasionally, an unsuspected male factor may only be identified when IVFET is undertaken, particularly when other poten~ tial infertility factors are present in the female partner. Two women in this series conceived promptly with AID after a male factor was identified during an IVF-ET attempt. One of these women had severe endometriosis, and the infertility could easily have been attributable to that factor. Three women conceived with the additional therapy of WIUI in which hMGlhCG was used to provide "controlled hyperstimulation" in a manner similar to the IVF-ET cycles. All three couples had no obvious male factor. This might be considered a therapeutic option antecedent to IVF-ET in women without distorted anatomy including those with endometriosis, cervical factor, or idiopathic infertility. Similarly, a portion of the conceptions attributed to IVF-ET might be considered to have occurred because of the follicular stimulation, particularly in programs that place sperm in the genital tract before oocyte retrieval as part of their regimen. 9 This is also true for the gamete intra-fallopian tube transfer procedure in which a control group of stimulated but nontransferred patients has not been included. 10
Table 3. Summary of the Pregnancies Occurring with Additional Treatment After a Failed Attempt at IVF -ET No.
Age
Parity
Length of infertility
Clinical diagnosis
Additional therapy
Outcome
yr
1 2 3 4 5 6
36 30 37 35 29 32
0 0 0 2-2-0 0 2-0-2
8 7 10 7 4 4
Endometriosis Endometriosis Unexplained Endometriosis Endometriosis PID b
WIUIa WIUIa IUD removal AID AID WIUIa
Term delivery Term delivery Term delivery Term delivery Term delivery Ongoing pregnancy
aperformed 36 hours after injection of heG in a cycle of "controlled hyperstimulation" using hMG. bpelvic inflammatory disease. Vol. 47, No.4, April 1987
Haney et a1. IVF -ET pregnancies
637
r REFERENCES 1. Mahadevan MM, Trounson AO, Leeton JF: The relation-
ship of tubal blockage, infertility of unknown cause, suspected male infertility, and endometriosis to success of in vitro fertilization and embryo transfer. Fertil Steril 40: 755, 1983 2. Grant A: The spontaneous cure rate of various infertility factors or post hoc and propter hoc. Aust NZ J Ohstet Gynaecol 9:224, 1969 3. Bernstein D, Levin S, Amsterdam E, Insler V: Is conception in infertility couples t:r:eatment related? a survey of 309 pregnancies. Int J Fertil 24:65, 1979 4. Collins JA, Wrixon W, Janes LB, Wilson EH: Treatmentindependent pregnancy among infertile couples. N Engl J Med 309:1201, 1983 5. Gomel V, McComb P: Unexpected pregnancies in women afflicted by occlusive tubal disease. Fertil Steril 36:529, 1981
6. Russell JB, DeCherney AH, Laufer N, Polan ML, Naftolin F: Neosalpingostomy: comparison of 24- and 72-month follow-up time shows increased pregnancy rate. Fertil Steril 45:296, 1986 7. Jarrell J, Gwatkin R, Lumsden B, Lamont KG, Boulter G, Daya S, Collins J: An in vitro fertilization and embryo transfer pilot study: treatment-dependent and treatmentindependent pregnancies. Am J Obstet Gynecol 154:231, 1986 8. Ben-Rafel Z, Mashiach S, Dor J, Rudak E, Goldman B: Treatment-independent pregnancy after in vitro fertilization and embryo transfer trial. Fertil Steril 45:564, 1986 9. Sher G, Knutzen V, Stratton CJ, Montakhab MM, Allenson SG, Mayville J, Rubenstein J A, Glass MJ, Bilach SM: The development of a successful non-university-based ambulatory in vitro fertilization/embryo transfer program: Phase I. Fertil Steril 41:511, 1984 10. Asch RH, Ellsworth LR, Balmaceda JP, Wong PC: Pregnancy after translaparoscopic gamete intrafallopian transfer. Lancet 2:1034, 1984
Fertility and Sterility 638
Haney et al. IVF -ET pregnancies