Pgd As a Tool in Ivf

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Pgd As a Tool in Ivf

PREIMPLANTATION GENETIC DIAGNOSIS (PGD) AS BOTH A THERAPEUTIC AND DIAGNOSTIC TOOL IN ASSISTED REPRODUCTIVE TECHNOLOGY

Lawrence Werlin, MD a

Ingrid Rodi, MD a

Alan DeCherney, MD a

Ellen Marello, BS b

David Hill, Ph.D. c

Santiago Munne, Ph.D. d

a.) Genesis Network for Reproductive Health

b.) Coastal Fertility Medical Center, Irvine, CA

c.) ART Reproductive Center, Beverly Hills, CA

d.) St. Barnabas Medical Center, Orange, NJ

Financial Support – Organon Pharmaceuticals, Inc., West Orange, NJ

Reprint Requests – Lawrence Werlin, MD Coastal Fertility Medical Center 4900 Barranca Parkway, Suite 103 Irvine, CA 92604

- Page 1 of 6 - CAPSULE

PGD is beneficial in patients with recurrent pregnancy loss. In view of the large number of abnormal embryos in all groups, couples may consider alternative options earlier.

- Page 2 of 6 - MANUSCRIPT

Cytogenetic analyses have shown that more than half of all human preimplantation embryos contain aneuploidic cells (1-4). Upon reviewing the literature, it appears that three groups of patients are at higher risk for aneuploidic embryos; (1) Recurrent

Pregnancy Loss (RPL) which we define as  2 spontaneous pregnancy losses, (2)

Advanced Maternal Age (AMA) which we define as >38 years of age, and (3) Repeated failed IVF cycles (FC), defined as >2 failed cycles (5,6). Thus far, there have been no published prospective studies evaluating the benefit of PGD. We now present the first

IRB approved, randomized, prospective study, evaluating the three high-risk groups.

A total of 57 patients have been enrolled in phase one of the study from 8/1/01 –

8/30/02. All patients were randomized into either control or PGD. All underwent stimulation protocols utilizing Follistim and Antagon (Organon, West Orange, NJ). At the appropriate time, Pregnyl (hCG) 10,000 IU (Organon, West Orange, NJ) was administered. Approximately 34-36 hours post hCG, ultrasound guided oocyte retrieval was performed. Intracytoplasmic sperm injection (ICSI) was performed on all mature oocytes.

In the PGD group, embryo biopsy and blastomere fixation, as previously described (1-4), was done on day #3 post retrieval on all 6-8 cell embryos. Slides were then sent to St. Barnabas for FISH analysis for chromosomes 13, 15, 16, 17, 18, 21, 22,

X and Y. Results were received on Day #4-5 post retrieval. Embryo transfer of only the chromosomally normal embryos was done on Day #5 post retrieval.

In the control group, embryo transfer was performed on Day #3 or Day #5 post retrieval based on physician preference.

- Page 3 of 6 - In both groups, corticosteroids, low dose aspirin (80-81 mg) and progestational

supplementation were utilized. Serum B-hCG levels were obtained 12 days post

embryo transfer. Pregnancy was confirmed by demonstrating at least 2 appropriate,

consecutively, rising B-hCG levels.

The results can be seen in table 1.

Table 1 – Results

A.) RPL AMA FC TOTAL # Pts Enrolled 19 19 19 57 # Pts PGD/Control 11/8 7/12 10/9 28/29 # Embryos Biopsied 44 41 28 113 # Abnormal Embryos 30/44 (68.2%) 22/41 (53.7%) 19/28 (67.9%) 71/113 (63%) # No Transfer 3/11 (27.3%) 1/7 (14.3%) 4/10 (40%) 8/28 (28.6%) # Pregnancy – PGD 7/11 (63.6%) 3/7 (43%) 2/10 (20%) 12/28 (43%) # Pregnancy – Control 3/8 (37.5%) 3/12 (25%) 0/9 (0%) 6/29 (20.7%)

There was an even distribution of patients in each of the 3 groups. In all control patients

an embryo transfer was performed. However in the PGD group, 28.6% of patients had

no normal embryos to transfer.

- Page 4 of 6 - Utilizing Chi Square analysis, it appears that the overall pregnancy rate between the PGD vs the control groups approach statistical significance with a “P” value of 0.07.

In each individual group the numbers are still too small to show statistical significance.

In conclusion, a number of findings were evident. (1) PGD confirms that aneuploidy is a common cause of RPL. (2) It appears that in patients with RPL, the trend indicates that PGD may be beneficial. (3) It is not clear as yet, whether PGD is beneficial in the AMA group. (4) PGD clearly offered no benefit in the FC group. (5) In view of the large numbers of abnormal embryos in each group, couples may consider alternative options earlier, such as donor oocytes, donor embryos and/or adoption.

- Page 5 of 6 - References

1.) Munne S Lee A, Rosenwaks Z, Griffo J, Cohen J. Diagnosis of major chromosome aneuploidies in human Preimplantation embryos. Hum Reprod 1993;8:2185-92

2.) Delhanty JDA, Griffin DK, Handyside AH, Harper J, Atkinson GHG, Pieters MHE, et al. Detection of aneuploidy and chromosomal mosaicism in human embryos during Preimplantation sex determination by florescent in situ hybridization (FISH). Hum Mol Genet 1993;2:1183-5

3.) Delhanty JD, Harper JC, Ao A, Handyside AH, Winston RM. Multi-colour FISH detects frequent chromosomal mosaicism and chaotic division in normal Preimplantation embryos from fertile patients. Hum Genet 1997;99:755-60.

4.) Munne S, Magli C. Bahce M, Fung J, Legator MS, Morrison LE, et al. Preimplantation diagnosis of the aneuploidies most commonly found in spontaneous abortions and live births: XY, 13, 14, 15, 16, 18, 21, 22. Prenat Diag 1998;18:1459-66.

5.) Verlinsky Y, Cieslak J, Frieidine M, Ivakhnenko V, Wolf G, Kovalinskaya I, et al. Pregnancies following pre-conception diagnosis of common aneuploidies by florescence in situ hybridization. Hum Reprod 1995;10:1923-7

6.) Gianaroli L, Magli MC, Munne S, Fiorentino A, Montanaro N, Ferraretti AP. Will Preimplantation genetic diagnosis assist patients with a poor prognosis to achieve pregnancy? Hum Reprod 1997;12:1762-7.

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