Any effect of adjuvant low dose prednisolone on follicular development and embryo implantation may be masked by the concomitant use of aspirin

Stephen D. Keay1,4, Patrick Vandekerckhove2 and Julian M. Jenkins3

1 Department of Biological Sciences, University of Warwick, Coventry CV4 7AL 2 Centre for Reproductive Medicine, University Hospitals Coventry and Warwickshire, Coventry CV2 2DX 3 and Division of Obstetrics and Gynaecology, University of Bristol, St Michael’s Hospital, Bristol BS2 8EG, UK 4 To whom correspondence should be addressed. E-mail: skeay{at}bio.warwick.ac.uk

Dear Sir,

We read the paper by Ubaldi and colleagues addressing the potential effect of exogenous prednisolone on ICSI outcome with interest but would like to comment on some of the methodological and clinical aspects of the study (Ubaldi et al., 2002Go).

The randomization procedure is an important issue in assessing the potential bias of randomized trials (Schulz and Grimes, 2002Go). The authors state randomization took place on the day of oocyte retrieval. We cannot understand how the stated timing of randomization fits with the commencement of prednisolone on day 1 of ovarian hyperstimulation. The lack of a placebo in the control arm is another potential source of bias and it would have been technically feasible to include a placebo within the trial. The absence of a power calculation makes it difficult to interpret the study findings. Using traditional levels of significance, the numbers studied in the trial yield it sufficient power to demonstrate an increase in pregnancy rate of 11% in the treatment compared with control groups (i.e. an ongoing/delivery rate of 48%). Smaller beneficial effects (an increase in pregnancy rate of <11%) are still of clinical significance but could not be demonstrated in a trial of this size. The authors’ conclusion that there is no benefit from prednisolone should be qualified. In addition, the pregnancy rate in the control group was high, even allowing for up to four embryos being replaced reflecting the very favourable prognosis of the study cohort.

Glucocorticoids have been used as adjunctive treatment during IVF/ICSI either to enhance follicular development or as an immunosuppressant. Studies addressing ovarian response and follicular development have continued steroid administration until the ovulation inducing dose of hCG or until oocyte retrieval (Bider et al., 1996Go; Rein et al., 1996Go). Trials focusing on immunosuppression have used high dose steroids to encourage embryo implantation (particularly where micromanipulated embryos are used) around embryo transfer, typically for 4 days from oocyte retrieval (Cohen et al., 1990Go; Polak de Fried et al., 1993Go; Lee et al., 1994Go). In this trial low dose glucocorticoid was given for 4 weeks commencing with ovarian stimulation and hence covers both time-spans. The authors focus on implantation but cortisol appears to have a physiological role in oocyte maturation from studies of unstimulated (Keay et al., 2002Go) and stimulated IVF cycles (Michael et al., 1999Go).

We have previously reported a reduction in cycle cancellation for poor ovarian response in a standard long protocol IVF programme with 1 mg dexamethasone administered throughout gonadotrophin stimulation but discontinued prior to oocyte retrieval (Keay et al., 2001Go). It is therefore disappointing, that poor responders and women with single embryo transfers were excluded from analysis after randomization.

The use of prednisolone for a fixed 4-week period implies that prompt responders may have continued taking prednisolone into early pregnancy, for at least a few days—it is not clear whether the authors intended this.

Aspirin was used routinely in their standard protocol in both treatment and control arms. Aspirin co-treatment is not standard management. Although a trial (Urman et al., 2000Go) failed to demonstrate a benefit of aspirin use during ICSI effects on ovarian responsiveness and endometrial development have been suggested ( Rubenstein et al., 1999Go). In effect this study was comparing aspirin +/– prednisolone in a highly selected group of patients.

Because of the problems identified above, the authors’ conclusion that low dose prednisolone used as an immunosuppressant does not improve pregnancy and implantation rates cannot be justified on the basis of the presented data. Furthermore, the authors overlooked the possible benefits of corticosteroids on ovarian response to gonadotrophin stimulation.

References

Bider, D., Amoday, I., Tur-Kaspa, I., Livshits, A. and Dor, J. (1996) The addition of a glucocorticoid to the protocol of programmed oocyte retrieval for in-vitro fertilization—a randomized study. Hum. Reprod., 11, 1606–1608.[Abstract]

Cohen, J., Malter, H. and Elsner, C. (1990) Immunosuppression supports implantation of zona pellucida dissected human embryos. Fertil. Steril., 53, 662–665.[ISI][Medline]

Keay, S.D., Lenton, E.A., Cooke, I.D., Hull, M.G.R. and Jenkins, J.M. (2001) Low-dose dexamethasone augments the ovarian response to exogenous gonadotrophins leading to a reduction in cycle cancellation rate in a standard IVF programme. Hum. Reprod., 16, 1861–1865.[Abstract/Free Full Text]

Keay, S.D., Harlow, C.R., Wood, P., Jenkins, J.M. and Cahill, D.J. (2002) Higher Cortisol:Cortisone ratios in the preovulatory follicle of completely unstimulated IVF cycles indicate oocytes with increased pregnancy potential. Hum. Reprod., 17, 2410–2414.[Abstract/Free Full Text]

Lee, K.A., Koo, J.J., Yoon, T.K., Do, B.R., Ko, J.J. and Cha, K.Y. (1994) Immunosuppression by corticosteroid has no effect on the pregnancy rate inroutine in-vitro fertilization/embryo transfer patients. Hum. Reprod., 1832–1835.

Michael, A.E., Collins, T.D., Norgate, D.P., Gregory, L., Wood, P.J. and Cooke, B.A. (1999) Relationship between ovarian cortisol:cortisone ratios and the clinical outcome of in vitro fertilization and embryo transfer (IVF-ET). Clin. Endocrinol., 51, 535–540.[CrossRef][ISI][Medline]

Polak de Fried, E., Blanco, L., Lancuba, S. and Asch, R.H. (1993) Improvement of clinical pregnancy rate and implantation rate of in-vitro fertilization-embryo transfer patients by using methylprednisolone. Hum. Reprod., 8, 393–395.[Abstract]

Rein, M.S., Jackson, K.V., Sable, D.B., Thomas, P.P. and Hornstein, M.D. (1996) Dexamethasone during ovulation induction for in-vitro fertilization: a pilot study. Hum. Reprod., 11, 253–255.[Abstract]

Rubenstein, M., Marrazi, A. and Polak de Fried, E. (1999) Low-dose aspirin treatment improves ovarian responsiveness, uterine and ovarian blood flow velocity, implantation and pregnancy rates in patients undergoing in vitro fertilization: a prospective, randomized, double-blind placebo controlled assay. Fertil. Steril., 71, 825–829.[CrossRef][ISI][Medline]

Schulz, K.F. and Grimes, D.A. (2002) Generation of allocation sequences in randomised trials: chance, not choice. Lancet, 359, 515–519.[CrossRef][ISI][Medline]

Ubaldi, F., Rienzi, L., Ferrero, S., Anniballo, R., Iacobelli, M., Cobellis, L. and Greco, E. (2002) Low dose prednisolone administration in routine ICSI patients does not improve pregnancy and implantation rates. Hum. Reprod., 17, 1544–1547.[Abstract/Free Full Text]

Urman, B., Mercan, R., Alatas, C., Balaban, B., Isiklar, A. and Nuhoglu, A. (2000) Low-dose aspirin does not increase implantation rates in patients undergoing intracytoplasmic sperm injection: a prospective randomized study. J. Ass. Reprod. Genet., 17, 586–590.[CrossRef][ISI][Medline]





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