Department of Infertility, Instituto Valenciano de Infertilidad (IVI), Plaza de la Policía Local 3, 46015, Valencia, Spain
1 To whom correspondence should be addressed at: Instituto Valenciano de Infertilidad, Plaza de la Policía Local 3, 46015, Valencia, Spain. e-mail: jbellverp{at}sego.es
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Abstract |
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Key words: albumin/ovarian hyperstimulation syndrome/prevention/randomized
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Introduction |
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The pathophysiology of OHSS is still not well understood, but different factors related to an increased capillary permeability have been involved (Chen et al., 2000; Albert et al., 2002
; Gómez et al., 2002
), leading to a massive extravascular exudate accumulation combined with profound intravascular volume depletion and haemoconcentration (Schenker and Weinstein, 1978
; Navot et al., 1992
). OHSS is a self-limiting condition (Whelan and Vlahos, 2000
), especially when pregnancy is not achieved.
When a profile of high risk is recognized, preventive measures should be taken. Intravenous albumin administration has been described for many years as a debatable, but probably useful, measure (Asch et al., 1993; Shalev et al., 1995
; Aboulghar et al., 2000
). Albumin seems to have osmotic functions, as it contributes to around 75% of the plasma oncotic pressure, drawing extracellular fluid into the circulation, and possesses transport functions, binding and inactivating the vasoactive intermediates responsible for the pathogenesis of OHSS (McClelland, 1990
; Shalev et al., 1995
; Isik et al., 1996
; Aboulghar et al., 2002
). Recently, the benefits of preventive intravenous albumin administration have been discussed in a Cochrane review of five randomized controlled trials of albumin infusion versus placebo/no treatment for women at high risk of developing severe OHSS after COH (Aboulghar et al., 2002
). In those studies, in which the albumin doses ranged from 10 to 50 g and were administered 12 h before or immediately after oocyte retrieval, only 463 patients were considered. Since the prevention of OHSS is so important in assisted reproductive technologies, a broad prospective randomized controlled trial was designed to compare albumin infusion with no treatment in patients at high risk of moderate to severe OHSS after COH, in order to ascertain the actual preventive role of this protein.
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Materials and methods |
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Stimulation protocol
The protocol for COH consisted of pituitary desensitization with daily subcutaneous administration of 0.1 mg triptorelin (Decapeptyl 0.1; Lasa S.A., Barcelona, Spain) or 1 mg leuprolide acetate (Procrin; Abbott S.A., Madrid, Spain) beginning in the luteal phase of the previous menstrual cycle. This dose was continued until ovarian quiescence was demonstrated by vaginal ultrasound following menstruation. The standard protocol consisted of 225 IU/day highly purified or recombinant FSH (Neofertinorm or Gonal; Serono Laboratories, Madrid; or Puregon; Organon Española, S.A, Barcelona, Spain) plus 75 IU/day hMG (Lepori; Farma Laboratories, Barcelona, Spain) administered on days 1 and 2 of ovarian stimulation. This protocol was modified when the patient presented risk factors of hyperstimulation or poor response in her clinical history, ultrasound examination or hormonal assessment. Polycystic ovary syndrome (PCOS), defined as oligomenorrhoea and hyperandrogenism, was especially considered for COH. From day 3 of stimulation onwards, gonadotrophins were individualized according to serum estradiol levels and ultrasonographic ovarian response. hCG (10 000 IU; Profasi; Serono Laboratories, Madrid, Spain) was administered i.m. when at least two leading follicles reached a mean follicular diameter of 18 mm. GnRH agonist and gonadotrophin injections were discontinued on the day of hCG administration. Transvaginal oocyte retrieval was scheduled 36 h after hCG injection, at which time the treatment terminated for oocyte donors. In the remaining women, a luteal phase support of 400 mg/day micronized intravaginal progesterone (Progeffik; Laboratories Effik S.A., Madrid, Spain) was started the day after oocyte retrieval and maintained until a pregnancy test was performed, or until day 80 of pregnancy if the patient tested positive. Embryos were transferred on day 23 or 56 of development, according to the case, and always that cryopreservation was discarded because of the risk of OHSS. Serum -hCG levels were monitored 14 days after oocyte retrieval.
Study protocol and randomization
The study was both prospective and randomized in nature. A computer-based randomization (Sigmastat for Windows, version 2.0; Jandel Scientific Corporation, San Rafael, CA, USA) was used to allocate the patients to two groups immediately after confirmation of retrieval of >20 oocytes. The first group received 40 g human albumin (Albúmina humana Grifols 20%; Grifols, Barcelona, Spain), infused i.v. at a slow rate during 30 min, immediately after oocyte retrieval. The second group did not receive any albumin treatment. All patients allocated by randomization to the albumin group received this protein, whereas in those of the control group albumin was always avoided. Randomization was strictly followed over the study period.
The incidence in the studied groups (albumin versus no treatment) of moderate and severe OHSS and biochemical serum changes were the primary outcome measures considered to assess the preventive role of albumin. The implantation and pregnancy rates in patients, and the clinical evolution of the hyperstimulated women were the secondary outcome measures.
In both groups, subjects were weighed and haematological tests performed immediately following oocyte retrieval and again 7 days later. Haemoglobin, haematocrit and leukocyte count and renal (creatinine) and liver [transaminases: aspartate aminotransferase (AST); alanine aminotransferase (ALT)] functions were analysed. Women were monitored on a non-rigid outpatient basis via phone contact and visits until menstruation occurred or until fetal heart activity was detected in pregnant patients. Cases of OHSS were classified according to previously published criteria (Golan et al., 1989)
The present study followed the CONSORT guidelines for the reporting of randomized control trials (Moher et al., 2001)
Hormone assay
Serum estradiol was measured using microparticle enzyme immunoassay (MEIA) technology and employing the Axsym System (Abbot Laboratories, Illinois, USA). The intra- and inter-assay coefficients of variation (CVs) were <13.9%. Haemoglobin, haematocrit and leukocytes were measured using the Cell-Dine 3200 (Abbot Laboratories), with intra- and inter-assay CVs <2.1, 6.0 and 5.7% respectively. Creatinine, AST and ALT were measured using the Alcyon 300i (Abbot Laboratories), with intra- and inter-assay CVs <10.4, 7.2 and 7.7% respectively.
Statistical analysis
Statistical analyses were performed using the Statistical Package for Social Science version 10.0 (SPSS Inc., Chicago, IL, USA). Categorical data were expressed as number and percentage, and numerical data as mean ± SD. Students t-test, chi-square test and Fishers exact test were used when appropriate. Statistical significance was assumed when P was < 0.05.
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Results |
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Discussion |
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Several non-randomized trials were initially performed to determine the preventive role of albumin in high-risk patients. The prevention of severe OHSS with human albumin administration was first demonstrated during the early 1990s (Asch et al., 1993). None of the 36 women who received 50 g albumin on the day of oocyte retrieval developed severe OHSS; however, embryo transfer was not carried out in 58% of the women, thereby reducing the risk of severe OHSS. In the same year, others (Ng et al., 1993
) found no statistical difference in the incidence of OHSS between a group of high-risk IVF patients who received 50 g albumin on the day of oocyte retrieval and another group that was not administered this protein. Further case reports (Orvieto et al., 1995
; Moutos et al., 1997
) and retrospective studies (Ng et al., 1995
; Ndukwe et al., 1997
) have described the ineffectiveness of prophylactic albumin in the prevention of severe OHSS.
Until now, there have existed only seven published randomized controlled trials exploring the intravenous use of albumin in preventing severe OHSS (Shoham et al., 1994; Shalev et al., 1995
; Isik et al., 1996
; Shaker et al., 1996
; Costabile et al., 2000
; Ben-Chetrit et al., 2001
; Gokmen et al., 2001
). One of these groups (Shaker et al., 1996
) compared the efficacy of i.v. infusion of albumin for preventing OHSS in high-risk patients with a standard policy of cryopreservation of all embryos, including 26 patients as a whole (13 in each group). The albumin group did not show any advantage in preventing OHSS, but presented lower pregnancy rates. Others (Costabile et al., 2000
) compared the effectiveness of i.m. progesterone with that of i.v. albumin in the prevention of OHSS in 96 high-risk patients, and showed a clear benefit of high-dose progesterone. A recent Cochrane review analysed the remaining five randomized controlled trials of the effect of albumin infusion versus placebo or no treatment in the prevention of severe OHSS after ovarian hyperstimulation (Shoham et al., 1994
; Shalev et al., 1995
; Isik et al., 1996
; Ben-Chetrit et al., 2001
; Gokmen et al., 2001
). These trials, all of which were single-centre, each involved between 31 and 250 participants (n = 463 in total). The preventive therapy consisted of doses of i.v. albumin ranging from 10 to 50 g, administered 12 h before or just after oocyte retrieval, and infused for periods of 3060 min. In three studies the control group received a saline infusion (Shoham et al., 1994
; Ben-Chetrit et al., 2001
; Gokmen et al., 2001
), while in the other two trials the controls received no treatment (Shalev et al., 1995
; Isik et al., 1996
). One group (Gokmen et al., 2001
) administered a hydroxyethyl starch solution to a third patient group. Four out of these five studies suggested a preventive role for albumin in OHSS. The Cochrane review highlighted a clear benefit of administration of i.v. albumin at the time of oocyte retrieval for preventing severe OHSS in high-risk cases, with an absolute risk reduction of 5.5%, and one case saved due to albumin infusion for every 18 women at risk of severe OHSS. Moreover, there was no evidence of an increase in the pregnancy rate (Aboulghar et al., 2002
).
To the best of the present authors knowledge, herein is presented the largest prospective and single-centre study to date of the effects of prophylactic albumin in high-risk IVF patients. The sample size of the present study allowed the detection of a 50% decrease in the incidence of severe OHSS, with 95% confidence and a type II error of ±2.4%. Several known risk factors for severe OHSS, previous to and during COH, were considered including young age (Navot et al., 1988; Enskog et al., 1999
), body mass index (Navot et al., 1988
), serum estradiol level (Haning et al., 1983
; Navot et al., 1992
), number of retrieved oocytes (Enskog et al., 1999
) and evidence of PCOS (Buyalos and Lee, 1996
; Al-Ramahi, 1999
). More than 20 retrieved oocytes was chosen as inclusion criterion for the study, as this parameter was considered the best predictor for moderate and/or severe OHSS development. This would serve as an end-point of the other risk factors, and has been considered for the same purpose in previous studies (Ben-Chetrit et al., 2001
). Participants were studied first as a whole group, and then as patient and oocyte donor groups separately.
No difference was detected between the risk parameters of the albumin and control groups, and no predisposition of either of the groups to the development of OHSS was demonstrated. On the other hand, the cycle evolution did not vary, with similar implantation, pregnancy and on-going pregnancy rates and similar numbers of moderate and severe hyperstimulated cases (Table I). Hence, in agreement with the recent Cochrane review (Aboulghar et al., 2002) and other authors (Ben-Chetrit et al., 2001
), but in contrast to the suggestions of other authors (Shaker et al., 1996
), the outcome of the IVF cycle does not appear to be influenced by albumin administration. Therefore, the decision to use prophylactic albumin only must rest on the balance of benefits (prevention of OHSS) and risks (cost, undesirable side effects). In the present study, the cost of treatment (195 euros per patient) was the only drawback, as no side effects were detected. However, other authors have described the potential side effects of albumin infusion, such as nausea, vomiting, febrile reaction, allergic reaction, anaphylactic shock and risk of virus and prion transmission (Isik et al., 1996
; Ben-Chetrit et al., 2001
; Gokmen et al., 2001
).
When serum biochemical markers of haemoconcentration and renal or liver dysfunction were assessed at oocyte retrieval (baseline assessment) and 7 days later (hyperstimulated assessment), no significant difference was noted between the albumin and control groups (Table II). Hence, albumin did not improve the evolution of high-risk cases.
Blood samples were taken on the seventh day after oocyte retrieval because the early form of OHSS, related to the magnitude of the preceding ovarian response, is usually detected 37 days after the ovulatory dose of hCG (Lyons et al., 1994; Mathur et al., 2000
). Baseline blood samples were used to determine the predisposition of the studied groups to ovarian stimulation. Thus, when cases of moderate and severe OHSS were considered as a whole (n = 66), and when severe OHSS cases (n = 46) were evaluated separately, neither the baseline nor the hyperstimulated assessment showed differences between the albumin and the control groups. Moreover, variation of weight and blood parameters (Table III), and clinical evolution (Table IV) were similar in both groups. Therefore, no clinical or biochemical differences appeared in OHSS patients based on prior albumin administration.
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References |
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Submitted on February 14, 2003; resubmitted on May 13, 2003; accepted on July 15, 2003.