1 The Fertility Clinic, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100 Copenhagen and 2 The Fertility Clinic, Braedstrup Hospital, 8740 Braedstrup, Denmark
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key words: abortion/early pregnancy/ICSI/IVF/progesterone supplementation
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
An earlier meta-analysis (Soliman et al., 1994) indicated that after IVF, it is of value to give luteal support, using either HCG or progesterone, during the luteal phase itself. The luteal phase has been defined as the time span from the day of transfer of embryos until measurement of HCG 2 weeks later. Using the long protocol and down-regulation with GnRH agonists, LH secretion may not have completely recovered during the luteal phase. Therefore, progesterone supplementation could be of benefit in order to `cover the gap' between the disappearance of exogenous HCG and the rise of endogenous HCG during early implantation.
However, there is no rationale for the generally accepted practice of prolonging progesterone supplementation during early pregnancy. The purpose of the present study was to substantiate the recent findings (Schmidt et al., 2001) through a randomized controlled trial.
![]() |
Patients and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
All patients were treated with the long protocol using either Synarela® (nafarelin; Pharmacia, Copenhagen, Denmark) 600 µg/day or Suprefact® (buserelin; Hoechst, Copenhagen) 0.5 mg/day for down-regulation. The duration of down-regulation was at least 14 days. Ovarian stimulation was achieved by recombinant FSH (rFSH), either Puregon® (Organon, Copenhagen) or Gonal-F® (Serono, Copenhagen). IVF or ICSI were carried out using standard procedures. Following transfer, all patients were treated with vaginal progesterone (Progestan®; Organon) 200 mg three times a day from the day of embryo transfer until HCG measurement 14 days (range 1315) later.
A total of 303 patients became pregnant and fulfilled the criteria for randomization: a serum or urinary HCG >25 IU/l 14 days after transfer and absence or presence of slight vaginal bleeding. Pregnant patients who had vaginal bleeding of an intensity similar to menstruation prior to or on the day of HCG were excluded. The randomization was done by secretaries and was independent of the team who managed the treatment. A computer-generated randomization list using clusters of 10 was used for the procedure. Upon contacting the clinic, in order to hear the result of the pregnancy test, the patients were randomized. The number of patients who agreed to participate in the study in case of a pregnancy was achieved was not recorded, but it was ~900 couples. The ongoing pregnancy rate during the time period of the study was 30.2% per embryo transfer.
The study group consisted of 150 patients who were randomized to withdraw all progesterone at the day of a positive HCG test. The control group consisted of those 153 who were randomized to continue progesterone (Progestan®, 200 mg three times a day) for another 3 weeks.
All patients were asked to record daily the presence and intensity of any vaginal bleeding during the 3 weeks from randomization until ultrasonography. The recording of bleeding was done on a special bleeding chart. No hormones were measured apart from HCG.
After 3 weeks a transvaginal ultrasonography was performed, in order to assess the status of the pregnancy. If there was a normal ongoing pregnancy 3 weeks after a positive pregnancy test then no further controls were made at the Fertility Clinic, but the patient followed the normal antenatal care at her regional hospital. The study does not include data on possible later treatments with progesterone given by the patient's own physician or obstetricians. Those patients who had signs of imminent abortion prior to the scheduled ultrasonography had repeated determinations of serum HCG. If the serum HCG concentration was falling then progesterone was withdrawn in the control group. In both groups the HCG concentration was followed until it became negative. If serum HCG increased, the ultrasonography was done prior to week 7.
Further follow-up of pregnancy outcome was based on a standard reporting document, i.e. a pregnancy outcome form. All Danish women achieving pregnancy after assisted reproductive techniques are asked to return such a document to the clinic after delivery or miscarriage. According to Danish law it is compulsory to report all pregnancy outcomes after IVF or ICSI to the Danish IVF Registry at the National Board of Health (Andersen et al., 1999). All 303 pregnancies have been followed until pregnancy loss or delivery. The data does not include information on karyotyping of abortions.
The study was approved by the regional Ethical Committees in Copenhagen Municipality and Vejle County.
Statistical analysis
The original sample size calculations were based on the findings in our earlier uncontrolled study (Schmidt et al., 2001) where it was assumed that 66% of all patients with a positive HCG test would finally deliver. Using 80% power, randomization of 300 patients would give a confidence interval of 95% to show a difference in delivery rates of 10.7%. The t-test of unpaired observations and the
2 test were used as appropriate.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
|
Finally, it is seen that 118 (78.7%) patients delivered in the study group given no progesterone versus 126 (82.4%) in the control group who continued with progesterone. The difference was not significant.
Table IV shows the distribution of singleton, twin and triplet pregnancies and deliveries, and Table V
the gestational age and birthweight in relation to singleton and multiple pregnancies and deliveries. No significant differences were noted.
|
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
In the study group there was an insignificant trend towards more patients with vaginal bleeding prior to week 7, but this did not influence the number of ongoing pregnancies in week 7, and neither did it influence the number of deliveries. Progesterone may thus delay vaginal bleeding in some patients, but it does not prevent miscarriages.
Our two studies included a total of >700 pregnancies, and it is therefore suggested that the widespread practice of progesterone supplementation during early pregnancy should be abandoned. It has no clinical benefits in terms of increasing the live birth rates, it is costly and it is inconvenient for the patients. One possible but unlikely methodological concern of the present study is that the data do not incorporate information on additional supplementation with progesterone or other hormones after week 7 of pregnancy either by the patients' own physicians or obstetricians.
Apart from the present and earlier study (Schmidt et al., 2001) no trials have assessed whether progesterone should be used in early pregnancy at all, after the initial luteal support for 2 weeks after embryo transfer. There has been a single study by Prietl et al. where patients who had a positive HCG test were randomized to either no treatment or treatment with i.m. estradiol valerate and 17alpha-hydroxyprogesterone until week 12 of pregnancy (Prietl et al., 1992
). The treatment arm included 55 patients and the control arm 65 patients. A significant reduction in abortion rates was found in the estrogenhydroxyprogesterone treated women. In the study of Prietl et al. the pregnant patients were additionally supplemented with estradiol, making it different from the present study, and this may be of clinical importance. However, in that study the groups were small and heterogeneous, involving treatments with clomiphene, clomiphene HMG and also GnRH agonist and HMG (Prietl et al., 1992
).
Without firm evidence of any clinical benefits, the practice has been to extend progesterone supplementation until week 8 (Polson et al., 1992; Miles et al., 1994
; Mochtar et al., 1996
) or even week 12 (Smitz et al., 1988
; Smitz et al., 1992
; Van Steirteghem et al., 1998
; Sohn et al., 1999
; Schoolcraft et al., 2000
;Ludwig and Diedrich, 2001
) of pregnancy.
The duration of progesterone supplementation in early pregnancy has not been subjected to clinical trials, apart from a single study, where Stovall et al. showed that progesterone supplementation could safely be withdrawn at week 6 of pregnancy, in a subgroup of patients with high serum progesterone concentrations (Stovall et al. 1998). In the current study, the control group was supplemented with 3 weeks of progesterone. This was the duration that we and several other clinics used to practise. The duration of treatment was based on the fact that after this period placental steroid secretion would dominate, as recently reviewed (Ludwig and Diedrich, 2001).
In the present as well as in our earlier study (Schmidt et al., 2001) both groups of patients were treated with vaginal progesterone 600 mg/day for 2 weeks during the luteal phase. Supplementation was initiated on the day of embryo transfer and continued until the day of the pregnancy test, 14 days after embryo transfer. The clinical value of progesterone supplementation, during the luteal phase itself, has been subjected to a meta-analysis, showing that it is of clinical benefit (Soliman et al., 1994
). The cause of the short life-span of the corpus luteum in stimulated cycles has been attributed to both supraphysiological estrogen and progesterone concentrations immediately after ovulation due to the multifollicular maturation. In addition, patients treated with the long protocol may be deficient in progesterone secretion during the late luteal phase, due to the use of GnRH agonists that may cause an inability of the pituitary gland to secrete a sufficient amount of LH to maintain an adequate function and life span of the corpus luteum (Smitz et al., 1988
). During the first week after, transfer exogenous HCG given prior to oocyte retrieval will be present, but after clearance of HCG there may be a lack of both LH and HCG to support the luteal progesterone secretion. Additionally, aspiration and flushing of the follicles may deplete the granulosa cells, theoretically causing a further insufficiency of luteal progesterone secretion. In the present study, down-regulation was achieved by either buserelin or nafarelin. It is possible that the use of depot preparations may cause a further inhibition of luteal phase LH concentrations. This could be of clinical importance.
There were no differences between the study and control group regarding the number of singleton or twin pregnancies. Furthermore, no differences were found in the gestational age as well as birthweight. This gives further evidence that early placentation is not affected by lack of progesterone support.
As recently reviewed (Toner, 2001) it seems that there may be both a biological rationale and clinical evidence that the luteal phase itself should be supported by exogenous progesterone. However, if a pregnancy occurs, rising endogenous HCG should support luteal function. If follicular flushing depletes the granulosa cells, even sufficiently rising concentrations of endogenous HCG may not adequately support the multiple corpora lutea of early pregnancy. However, if such an effect exists, the present study shows that it cannot be overcome by supplementation with progesterone. As stated earlier (Schmidt et al., 2001), we believe that the common practice of extending progesterone supplementation in early pregnancy may be based on the reluctance among clinicians to withdraw progesterone, in order to be cautious and exert all efforts to achieve an ongoing pregnancy. However, we recommend that this practice should be abandoned.
![]() |
Notes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Ludwig, M and Diedrich, K. (2001) Evaluation for an optimal luteal phase support protocol in IVF. Acta. Obstet. Gynecol. Scand., 80,452466.
Miles, R.A., Paulson, R.B., Lobo, R.A., Press M.F., Dahmoush, L. and Saner, M.V. (1994) Pharmacokinetics and endometrial tissue levels of progesterone after administration by intramuscular or vaginal routes: a comparative study. Fertil. Steril., 62, 485490.[ISI][Medline]
Mochtar, M.H., Hogerzeil, H.V. and Mol, B.W.J. (1996) Progesterone alone versus progesterone combined with HCG in GnRHa/hMG induced IVF cycles: a randomised clinical trial. Hum. Reprod., 11, 16021605.[Abstract]
Polson, D.W., Rogers, P.A.V., Krapez, J.A. and Leeton, J.F. (1992) Vaginal progesterone as luteal phase support in an IVF/GIFT programme. Eur. J. Obstet. Gynecol. Reprod. Biol., 46, 3538.[ISI][Medline]
Prietl, G, Diedrich, K, van der Ven, H.H., Luckhaus, J. and Krebs, D. (1992). The effect of 17alpha-hydroxyprogesterone caproate/oestradiol valerate on the development and outcome of early pregnancies following in vitro fertilization and embryo transfer: a prospective and randomised controlled trial. Hum. Reprod., 7 (suppl. 1), 15.[Abstract]
Roman, E., Aytoz, A., Smitz, J.E.J., Faguer, B., Camus, M., Van Steirteghem, A.C. and Devroey, P. (2000) Analysis of bleeding pattern in assisted reproduction cycles with luteal phase supplementation using vaginal micronized progesterone. Hum. Reprod., 15, 14351439.
Schoolcraft, W.B., Hesla, J.S and Gee, M.J. (2000) Experience with progesterone gel for luteal support in a highly successful IVF programme. Hum. Reprod., 15, 12841288.
Schmidt, K.L.T., Ziebe, S., Popovic, B., Lindhard, A., Loft, A. and Andersen, A.N. (2001) Progesterone supplementation during early gestation after IVF has no effect on the delivery rates. Fertil. Steril., 75, 337341.[ISI][Medline]
Smitz, J. Devroey, P., Camus, M., Deschacht, J., Khan, I., Stuessen, C., Van Waesberghe, L., Wisanto, A. and Van Steirteghem, A.C. (1988) The luteal phase and early pregnancy after combined GnRH-agonist/hMG treatment for superovulation in IVF or GIFT. Hum. Reprod., 3, 585590.[Abstract]
Smitz, J., Devroey, P., Faguer, B., Bourgain, C., Camus, M. and Van Steirteghem, A.C. (1992) A prospective randomised comparison of intramuscular or intravaginal natural progesterone as a luteal phase and early pregnancy supplement. Hum. Reprod., 7, 168175.[Abstract]
Sohn, S.H., Penzias, A.S., Emmi, A.M., Dubey, A.K., Layman, L.C., Reindollar, R.H. and De Cherney, A.H. (1999) Administration of progesterone before oocyte retrieval negatively affects the implantation rate. Fertil. Steril., 17, 1114.
Soliman, S., Daya, S., Collins, J. and Hughes, E.G. (1994) The role of luteal support in infertility treatments: a meta-analysis of randomised trials. Fertil. Steril., 61, 10681076.[ISI][Medline]
Stovall, D.W., Van Voorhis, B.J., Sparks, A.E.T., Adams, L.M. and Syrop, C.H. (1999) Selective early elimination of luteal support in assisted reproduction cycles using a gonadotropin-releasing hormone agonist during ovarian stimulation. Fertil. Steril., 70, 10561062.[ISI]
Toner, J.P. (2001) The luteal phase: luteal support protocols. In Gardner, D.K., Weissman, A., Howles, C.M. and Shoham, Z. (eds) Assisted Reproductive Techniques. Laboratory and Clinical Perspectives. Martin Dunitz, London, pp. 515525.
Van Steirteghem, A., Smitz, J., Camus, M., Van Waesberghe, L., Descacht, J., Khan, I., Stuessen C., Wisanto, A., Bourgain, C. and Devroey, P. (1998) The luteal phase after in-vitro fertilization and related procedures. Hum. Reprod., 3, 161164.[Abstract]
accepted on October 8, 2001.