Thatchers Thoughts: Assisted Reproductive Technologies (ART)

Thatchers Thoughts: Assisted Reproductive Technologies (ART)

Last Updated: October 16, 2006
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FSH as a marker of egg stores and IVF success

Title: IVF performance of women who have fluctuating early follicular FSH levels
Author: A. Lass, et al.
Address: Cambridge, England 
Source: Journal of Assisted Reproduction and Genetics 17:566-573 (November) 2000

Summary: In order to have a successful in vitro fertilization (IVF) treatment, it is of great importance that the ovary responds to gonadotropin stimulation and thus develop several follicles. Especially in older women, failure to respond to gonadotropin stimulation is common. Because researchers believe it would be clinically and economically beneficial to predict a poor response prior to treatment, they conducted this study to determine if women who have early follicular follicle stimulating hormone (FSH) levels >12 mIU/ml have reduced response to follicular stimulation for IVF in a following month, despite normal FSH levels. Subjects were 303 women > 38years old and/or who had previously had a poor response to superovulation for IVF. Blood samples were collected on day 2 of menstruation before beginning treatment and were tested for FSH, luteinizing hormone (LH) and estradiol (E2). In 38.6% of these women, FSH levels were >12 mIU/ml. Of these, 66 gave a further 130 blood samples for FSH measurement in the following months. Sixty percent of the tests showed raised FSH value >12 mIU/ml. Thirty women whose repeat FSH levels were less than 12mIU/ml underwent 41 IVF cycles. Sixty-three other women, older than 38 and/or who had a poor response to superovulation previously and whose FSH levels were less than 12 mIU/ml, made up the control group. There were no differences in the responses to superovulation and delivery rates between the two groups. Researchers concluded that women whose early follicular phase FSH levels were raised >12 mIU/ml had an increased risk (>50%) that in subsequent cycles levels would remain raised. They also found it was not possible to predict which individuals would have favorable FSH levels. If the cycle day 2 FSH level returns to a “normal” level of less than 12 mIU/ml, women >40 years had substantial cycle cancellation rates (43%). However, those patients who achieved the stage of embryo transfer had a good chance of conceiving, regardless of their age.

Comments: Success with in vitro fertilization therapy is directly correlated with the capacity to induce more than one follicle to preovulatory development. The capacity of the ovary to respond to gonadotropin stimulation is directly proportional to egg stores, and egg stores to age. It is of paramount clinical and economic importance to predict patients that will not respond well to stimulation, both to design the most effective stimulation protocol and to counsel about the chances of success. As egg stores dwindle FSH increases to compensate for the loss in order to protect normal ovulation as long as possible. Several methods, including early follicular phase FSH, estradiol, inhibin and the clomiphene challenge test, have all been proposed to access egg stores. Some believe that if the FSH level is ever elevated that the chances are markedly reduced for IVF pregnancies. Others believe that if stimulation is postponed until a cycle in which the FSH level is lower, that success is improved. It seems reasonable to both repeat FSH level and not start stimulation unless the level is under 12. We have found that women with an FSH level above 8 have significantly lower response to stimulation. In our practice, pregnancy after IVF with a day 2-3 FSH over 10 have been rare, however, there have been a substantial number of women who have conceived spontaneously with elevated FSH levels. An occasional spontaneous pregnancy has occurred with an FSH level over 20. I suggest that an estradiol level be drawn in addition to the FSH level. When the estradiol is over 50pg/mIU, FSH secretion has started to fall and the FSH measurement may not be as valid. I have not found that the clomiphene challenge (solely used as a test) or inhibin levels to have a particular advantage over the day 2-3 estradiol/ FSH determination.


IVF in women over age 41

Title: Outcome of assisted reproductive technology in women over the age of 41 
Author: R. Ron-El, et al.
Address: Zerifin, Israel 
Source: Fertility and Sterility 74:471-475 (September) 2000

Summary: This study of 431 IVF and intracytoplasmic sperm injection (ICSI) cycles was designed to analyze the results of ongoing pregnancies and deliveries after assisted reproductive technology in women aged greater than or equal to 41 years. Of the 431 cycles, 87% reached the oocyte retrieval stage. The average number of oocytes aspirated per patient was 5.4 ± 0.9 in the IVF cycles and 6.7 ± 1.2 in the ICSI cycles. In IVF cycles 2.3 ± 1.3 embryos were obtained and the number of these transferable was 2.0 ± 1.2; in the ICSI cycles 2.8 +1.6 embryos were obtained 2.5 ± 0.8 were transferable. The pregnancy rate per oocyte pickup (OPU) was 12.4% but the delivery rate per OPU was only 4.5%. The mean delivery rate per OPU among women 41-43 years was 2%-7%. There were no deliveries in women greater than or equal to 44 years and no pregnancies at the age of 45 years. Researchers concluded that ART performed with homologous oocytes (by IVF or ICSI) produced no clinical pregnancies among women greater than equal to 45 years and no deliveries in women greater than or equal to 44 years. The average delivery rate per oocyte retrieval among women aged 41-43 years varied between 2% and 7%.

Comment: Every time the statistics are figured for women over 41, it just keeps coming up the same. We just do not seem to get any better in treating this group of women, but we keep trying. 

Rest after IUI

Title:  A randomized study of the effect of 10 minutes of bed rest after intrauterine insemination 
Author: A. Saleh, et al. 
Address: Quebec, Canada
Source: Fertility and sterility 74:509-511 (September) 2000

Summary: This prospective randomized study evaluated the effects of 10 minutes of bed rest after intrauterine insemination on the pregnancy rate. Subjects were 95 couples with unexplained infertility. They were prospectively randomized either to immediate mobilization after IUI or to remain in a supine position for 10 minutes after the procedure. The first group was made up of 40 couples representing 90 cycles. The second group was made up of 55 couples representing 120 cycles. In the first group, the pregnancy rate per couple was significantly lower than in the second group (4 of 40 vs. 16 of 55). The pregnancy rate per cycle in the first group (4.4%) was also lower than in the second group (13.3%). Researchers concluded that a 10-minute interval of bed rest after IUI has a positive effect on the pregnancy rate. They recommend that mandatory bed rest for 10 minutes after IUI should be adopted into a standard practice.

Comment: I could understand this result when vaginal and cervical insemination was used. It seems illogical that the change in position after IUI would have much impact. Is it the rest or the position that makes the difference. Regardless, this is the second such report and we have changed or procedure accordingly. 
BMI and IVF success

Title: Clinical assisted reproduction: Does body mass index of infertile women have an impact on IVF procedure and outcome?

Author: C. Wittemer, et al. 
Address: Schiltigheim, France 
Source: Journal of Assisted Reproduction and Genetics 17:547-552 (November) 2000 
Summary: The purpose of this retrospective study was to determine if the body mass index (BMI) of patients related to the different parameters of the in vitro fertilization (IVF) procedure and outcome. Study participants were. Epidemiological features, characteristics of ovarian stimulation, number and quality of retrieved oocytes and pregnancy outcome were recorded in 398 couples divided in 3 groups. Group 1 was a BMI <20 (underweight), BMI from 20 to <25 (normal) and BMI >25 kg/m2 (overweight). Of the women, 21.8% were underweight and 22.3% were overweight. There was a significant increase in the FSH/LH ratio according to BMI. Group 3 used more gonadotropin ampoules together with a decrease in the number of collected oocytes. No significant difference was found in clinical pregnancy rates among underweight, normal weight and overweight patients. Miscarriage rate was increased in obese women.

Comment: A complicated issue. Is it weight or is it underlying ovarian dysfunction? Is it weight or is it PCOS? It would be curious to know more about those with spontaneous pregnancy loss. Weight alone is an overly simplistic, possibly prejudicial approach to the differences noted. 

The value of IUI in explained infertility

Title: Intrauterine insemination or in-vitro fertilization in idiopathic subfertility and male subfertility: a randomized trial and cost-effectiveness analysis
Author: A. Goverde, et al.
Address: Amsterdam, Netherlands 
Source: The Lancet 355: 13-18 (January) 2000

Summary: In a prospective, randomized, parallel trial, 258 couples with idiopathic subfertility or male subfertility were treated for a maximum of 6 cycles. 86 couples were assigned IUI alone, 85 IUI plus ovarian hyperstimulation, and 87 IVF. Although the pregnancy rate per cycle was higher in the IVF group than in the IUI groups (12.2% vs 7.4% and 8.7%, respectively), the cumulative pregnancy rate for IVF was not significantly better than that for IUI. Couples in the IVF group were more likely than those in the IUI groups to give up treatment before their maximum of 6 attempts. IUI was a more cost-effective treatment than IVF with the costs per pregnancy resulting in at least one live birth $4511-5710 for IUI vs $14679 for IVF. Researchers contend that couples with idiopathic or male subfertility should be counseled that IUI offers the same likelihood of successful pregnancy as IVF, and is a more cost-effective approach. IUI in the spontaneous cycle carries fewer health risks than does IUI after mild hormonal stimulation and is therefore the first-choice treatment.

Comment: This is getting a lot of press. These patients truly have unexplained infertility by the selection criteria. Many times this diagnosis is given with much less substantiation. Something just doesn’t seem to be quite right. Many other studies have been much less conclusive about the value of IUI in unexplained infertility. Most studies suggest that IUI is valuable only in the first 3 cycles. The low success with IVF is surprising; this is lower than most other studies and our experience. Maybe this group of Dutch is just not having intercourse.

Transfer of only two embryos

Title: Implantation rates after in vitro fertilization and transfer of a maximum of two embryos that have undergone three to five days of culture 
 G. Huisman, et al. 
Address: Roterdam, the Netherlands
Source: Fertility and sterility 73: 117-122 (January) 2000

Summary: This prospective study was conducted to evaluate implantation and pregnancy rates in patients undergoing IVF after the transfer of a maximum of 2 embryos that had been cultured for 3-5 days. Participants were 1,787 couples who underwent their first IVF cycle between 01/95-12/97. Overall implantation and pregnancy rates were not significantly different with different culture periods. 41% of all available embryos developed into blastocysts on day 5. The transfer of at least one good-quality blastocyst could be performed in 62% of patients. Blastocysts had an implantation rate of 26% per embryo, and the implantation rate of eight-cell embryos on day 3 was 18%. The transfer of embryos after 5 days as opposed to 3 days of embryo culture did not change the overall implantation and pregnancy rates. Researchers concluded that the implantation potential of embryos available for transfer can be assessed better after an extended culture period. Further, 5 days of culture allows the transfer of a reduced number of embryos without decreasing overall pregnancy rates.

Comment: Most in the US seem to equate the transfer of two embryos with the transfer of 2 good embryos. Nothing could be further from the truth. It is interesting that the authors fail to show an improvement with extended blastocyst culture. Transfer of two embryos makes a lot of sense on many grounds.


ICSI and sperm abnormalities

Title: Intracytoplasmic sperm injection in infertile patients with structural cytogenetic abnormalities 
Author: F. Causio, et al.
Address: Bari, Italy
Source: Journal of Reproductive Medicine 44: 859-863 (October) 1999

Summary: To evaluate the incidence of chromosomal aberration in men and women in an intracytoplasmic sperm injection (ICSI) program and in the conceptuses resulting from these treatments, researchers evaluated chromosomal analysis, outcome of ICSI and the conceptuses resulting from treatment of 301 couples included in an ICSI program. Cytogenetic evaluation demonstrated structural anomalies in 11 cases, all consisting of balanced chromosomal translocations. Embryo transfer led to a similar number of newborns per transferred embryo, without any correlation with parents’ chromosomes. In 63 fetuses conceived from couples without chromosomal abnormalities, 1 fetus affected by Patau syndrome was observed. Two of 4 fetuses conceived by couples with male balanced chromosomal defects were carriers of the chromosomal translocation inherited from their fathers. The 2 fetuses resulted in the birth of 2 infants observed to be normal at the 12-month pediatric visit. The offer of this treatment to infertile couples should be accompanied by proper information regarding the genetic risks of this treatment. ICSI remains a good therapeutic option for infertile patients, but prenatal diagnosis is mandatory because of the potential increased aneusomic risk for the offspring conceived. 

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