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Human albumin does not prevent ovarian hyperstimulation syndrome in assisted reproductive technology program: a prospective randomized placebo-controlled double blind study

2007; Elsevier BV; Volume: 88; Issue: 4 Linguagem: Inglês

10.1016/j.fertnstert.2006.11.170

1556-5653

Mete Işıkoğlu, Murat Berkkanoğlu, Zeliha Senturk, Kemal Özgür,

Systemic Sclerosis and Related Diseases

We aimed to clarify the efficiency of IV human albumin in the prevention of ovarian hyperstimulation syndrome (OHSS). We found that human albumin at the described strength does not seem to either prevent or reduce the incidence of severe OHSS in high risk patients undergoing intracytoplasmic sperm injection (ICSI). We aimed to clarify the efficiency of IV human albumin in the prevention of ovarian hyperstimulation syndrome (OHSS). We found that human albumin at the described strength does not seem to either prevent or reduce the incidence of severe OHSS in high risk patients undergoing intracytoplasmic sperm injection (ICSI). Ovarian hyperstimulation syndrome (OHSS) is a purely iatrogenic condition and the most serious complication of controlled ovarian hyperstimulation (COH) with gonadotropin preparations (1Shaker A.G. Zosmer A. Dean N. Berik J.S. Jacob H.S. Tan S.L. Comparison of intravenous albumin and transfer of fresh embryos with cryopreservation of all embryos for subsequent transfer in prevention of ovarian hyperstimulation syndrome.Fertil Steril. 1996; 65: 992-996Abstract Full Text PDF PubMed Scopus (72) Google Scholar). Severe forms complicate ∼1% of all IVF cycles (2Delbaere A. Smits G. Olatunbosun O. Pierson R. Vassart G. Costagliola S. New insights into the pathophysiology of ovarian hyperstimulation syndrome. What makes the difference between spontaneous and iatrogenic syndrome?.Hum Reprod. 2004; 19: 486-489Crossref PubMed Scopus (76) Google Scholar). The pathophysiology of the syndrome still remains obscure. Prostaglandins (3Balasch J. Arroyo V. Carmona F. Severe ovarian hyperstimulation syndrome: role of peripheral vasodilation.Fertil Steril. 1990; 56: 1077-1083Google Scholar), plasma renin activity, and aldosterone levels (4Navot D. Margalioth E.H. Laufer N. Direct correlation between plasma renin activity and severity of the ovarian hyperstimulation syndrome.Fertil Steril. 1987; 28: 141-143Google Scholar), and vascular endothelial growth factor (5McClure N. Healy D.L. Paw R. Vascular endothelial growth factor as a capillary permeability agent in ovarian hyperstimulation syndrome.Lancet. 1994; 344: 235-236Abstract PubMed Scopus (342) Google Scholar) have been studied to elucidate the mechanism of OHSS. Although IV human albumin (HA) seems to have some efficiency as a preventive measure, basic comparative studies have some methodological limitations. We designed a properly randomized, placebo-controlled double blind study to clarify the efficiency of IV HA in the prevention of OHSS. Patients entering the intracytoplasmic sperm injection (ICSI) program in Antalya IVF between January 2003 and December 2004 were evaluated for high risk factors of severe OHSS. High blood E2 level (>4,000 pg/mL) and >20 follicles ≥14 mm on the day of hCG administration have been defined as the basic risk factors for severe OHSS (6Navot D. Bergh P.A. Laufer N. Ovarian hyperstimulation syndrome in novel reproductive technologies: prevention and treatment.Fertil Steril. 1992; 58: 249-261Abstract Full Text PDF PubMed Google Scholar). Patients having one of these factors were included in the study. Patients were randomized by third-party sealed envelope entry to receive either a 20% HA solution or an isotonic NaCl solution intravenously. Approval for the study was obtained from the institutional review board. Signed informed consent was also obtained from the patients before enrolling in the study. All patients underwent a down-regulation protocol with the GnRH agonist triptorelin 0.05 mg/day (Decapeptyl ErKim, Istanbul, Turkey), beginning from the 21st day of the cycle. After the assessment of pituitary down-regulation on the third day of the cycle with a blood E2 level <50 pg/mL, linear endometrium and suppressed ovaries, the dosage of triptorelin was reduced to half and gonadotropin stimulation including 75 IU FSH (Gonal F; Serono, Istanbul, Turkey) and 75 IU hMG (Pergonal; Organon, Istanbul, Turkey) was commenced. The dose was adjusted on day 6 and thereafter in accordance with the E2 level and number of developing follicles. Gonadotropin injections continued until at least two follicles of ≥18 mm were detected. The hCG (10,000 IU) was then administered, followed 35 hours later by oocte pickup. Embryo transfers were done 50 hours after oocte pickup. Progesterone in oil (50 mg/day) was administered intramuscularly for luteal phase support until the day of β-hCG assay. Clinically determined pregnancy was defined as the detection of an embryo with fetal cardiac activity by ultrasound 3 weeks after the embryo transfer. Immediately after oocte pickup, patients were admitted to the recovery room where they received either 20% HSA (50 cc, Human Albumin, Eczacibasi Baxter, Istanbul, Turkey) diluted in 100 mL 0.9% NaCl or 100 mL 0.9% NaCl. Solutions were infused IV during 1 hour, approximately 36 hours after the administration of hCG. Because the infusions were done in a separate location by one of the staff nurses, the outcome assessors were blind to the interventions. The patients were also blind to the infusions as both groups received the infusions as isotonic NaCl solutions. Blood was drawn on the day of hCG administration, 5 days and 12 days after embryo transfer for E2 assays, whole blood count, creatinine, and transaminases. On days 5 and 12 after embryo transfer, ultrasound examinations for ovarian size and detection of ascites were done as well as the assessment for other symptoms of severe OHSS. Diagnosis of severe OHSS was made according to the criteria of Navot et al. (6Navot D. Bergh P.A. Laufer N. Ovarian hyperstimulation syndrome in novel reproductive technologies: prevention and treatment.Fertil Steril. 1992; 58: 249-261Abstract Full Text PDF PubMed Google Scholar). Estradiol concentrations were determined from venous blood and measured by VIDAS 12 device (bioMerieux Vitek, Philadelphia, PA). Intra-assay and interassay coefficients of variation were less than 7.5% and 9.5%, respectively. Severe OHSS rate was the main outcome parameter and clinical pregnancy rates/embryo transfer and first trimester miscarriage rates were the main secondary outcome parameters. As previously reported, OHSS occurs as two distinct clinical entities depending on the timing of onset (7Mathur R.S. Akande V.A. Keay S.D. Hunt L.P. Jenkins J.M. Distinction between early and late ovarian hyperstimulation syndrome.Fertil Steril. 2000; 73: 901-907Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar). In accordance with this report, we classified OHSS as late onset (≥10 days after oocte pickup) or early onset. The χ2 test, Fisher's exact test, Mann Whitney U test, and Student's t-test were used for statistical analyses of the data. An α value <0.05 was considered significant. A total of 75 patients with high risk factors for severe OHSS were enrolled in the study on day of hCG administration. Group 1 patients (n = 38) received HA and group 2 patients (n = 37) received isotonic NaCl. Both groups were similar with regard to age of the women, the incidence of polycystic ovary syndrome (PCOS), and the number of patients with a history of severe OHSS (Table 1). The distribution of the etiology of infertility of the two groups was not different. Total units of gonadotropins used, length of stimulation, peak E2 levels, E2 levels on days 5 and 12 after embryo transfer, number of follicles ≥14 mm on the day of hCG administration, number of MII oocytes, and number of embryos replaced did not show any statistically significant difference (Table 1). The outcome variables are also shown in Table 1. Severe OHSS developed in eight women from group 1 and in six women from group 2. All patients with late onset severe OHSS (n = 4) and both early and late onset severe OHSS (n = 6) had clinical pregnancies. Only one women with early onset severe OHSS had a negative pregnancy test result. Clinical pregnancy rates/embryo transfer and rates of miscarriage during the first trimester were similar for both groups. One patient in group 2 had an ectopic pregnancy and underwent laparoscopic salpingectomy.Table 1Demographic characteristics, stimulation, and outcome data.AlbuminPlaceboP valueNo. of cycles3837NAAge of the patients (mean ± SD)29.3 ± 3.929.1 ± 4.1.87aStudent's t-test.PCOS15/38 (39.5%)8/37 (21.6%).09bχ2 test.History of severe OHSS4/38 (10.5%)4/37 (10.8%).96bχ2 test.FSH (IU) (mean ± SD)1,055 ± 1,100885 ± 1,081.50aStudent's t-test.hMG (IU) (mean ± SD)1,117 ± 7931,597 ± 1,232.12cMann Whitney U test.Total gonadotropin (IU) (mean ± SD)2,124 ± 8512,462 ± 1,069.20cMann Whitney U test.Length of stimulation (mean ± SD)9.5 ± 0.89.5 ± 1.5.54cMann Whitney U test.Peak E2 level (pg/mL) (mean ± SD)5,622 ± 1,3265,431 ± 1,363.54aStudent's t-test.E2 on day 5 after embryo transfer (pg/mL) (mean ± SD)2,447 ± 1,6832,274 ± 1,729.69aStudent's t-test.E2 on day 12 after embryo transfer (pg/mL) (mean ± SD)2,848 ± 2,5692,013 ± 2,594.23aStudent's t-test.No. of follicles ≥14 mm (mean ± SD)20.5 ± 5.219.3 ± 3.6.30aStudent's t-test.No. of MII oocytes (mean ± SD)22.6 ± 7.320.5 ± 6.3.17aStudent's t-test.No. of embryos transferred (mean ± SD)3.4 ± 0.83.2 ± 0.8.34aStudent's t-test.Severe OHSS8/38 (21.1%)6/37 (16.2%).59bEarly severe OHSS3 (7.9%)1 (2.7%).61dFisher's exact test.Late severe OHSS2 (5.3%)2 (5.4%)1.0dFisher's exact test.Combined severe OHSS3 (7.9%)3 (8.1%)1.0dFisher's exact test.Clinical pregnancy/embryo transfer21/38 (55.3%)23/37 (62.2%).54bχ2 test.Multiple pregnancy rate7/21 (33.3%)7/23 (30.4%).90bχ2 test.First trimester miscarriage rate1/20 (5%)4/23 (17.3%).35dFisher's exact test.Note: NA = not applicable; OHSS = ovarian hyperstimulation syndrome; PCOS = polycystic ovary syndrome.Isikoglu. Human albumin does not prevent OHSS in ART program. Fertil Steril 2007.a Student's t-test.b χ2 test.c Mann Whitney U test.d Fisher's exact test. Open table in a new tab Note: NA = not applicable; OHSS = ovarian hyperstimulation syndrome; PCOS = polycystic ovary syndrome. Isikoglu. Human albumin does not prevent OHSS in ART program. Fertil Steril 2007. None of the patients with severe OHSS had renal failure or any other life-threatening complications. Only one patient in the albumin group underwent paracentesis. All of the patients in the albumin group tolerated the infusions and we did not encounter any hypersensitivity reactions. Although the key to controlling severe OHSS is in its prophylaxis, complete prevention is not as yet possible. Various preventive measures have been suggested for avoiding severe OHSS in assisted reproductive technology (ART) cycles, most of which have had debatable success. One of the first measures used, other than merely cancelling the cycle, was the avoidance of hCG for luteal phase supplementation, as there has been virtually unanimous agreement that severe OHSS is strongly associated with endogenous or exogenous hCG. Other measures have focused on hCG trigger substitutes. The use of GnRH agonist as the trigger is, however, limited to gonadotrophin-only or GnRH antagonist cycles. Another substitute for the conventional hCG trigger has been recombinant LH (8European Recombinant LH Study Group Human recombinant luteinizing hormone is as effective as, but safer than, urinary human chorionic gonadotropin in inducing final follicular maturation and ovulation in in vitro fertilization procedures: results of a multicenter double-blind study.J Clin Endocrinol Metab. 2001; 86: 2607-2618Crossref PubMed Scopus (133) Google Scholar). Other measures that also have only gained limited acceptance as successful measures for the prevention of OHSS are coasting, GnRH antagonist protocols (9Aboulghar M.A. Mansour R.T. Ovarian hyperstimulation syndrome: classifications and critical analysis of preventive measures.Hum Reprod Update. 2003; 9: 275-289Crossref PubMed Scopus (231) Google Scholar), reducing the trigger dose, follicular reduction (10Golan A. Ron-El R. Herman A. Soffer Y. Weinraab Z. Caspi E. Ovarian hyperstimulation syndrome following D-Trp-6 luteinizing hormone-releasing hormone microcapsules and menotropin for in vitro ferttilization.Fertil Steril. 1988; 50: 912-916Abstract Full Text PDF PubMed Scopus (81) Google Scholar, 11Smitz J. Camus M. Devroey P. Erard P. Wisanto A. Van Steirteghem A.C. Incidence of severe ovarian hyperstimulation syndrome after GnRH agonist/hMG superovulation for in vitro fertilization.Hum Reprod. 1990; 5: 933-937PubMed Google Scholar, 12Laufer N. Grunfeld L. Garrisi G.J. In vitro fertilization.in: Leibel M.M. Infertility: a comprehensive text. Appleton-Lange, Norwalk, CT1990: 481-511Google Scholar), and freezing all cycles. The success of the latter measure is also highly dependent on the success of the laboratory's cryopreservation program. Histamine has been claimed to be mediator of OHSS in animal model (13Pride S.M. Yuen B.H. Moon Y.S. Clinical, endocrinological and intraovarian prostaglandin F responses to H-1 receptor blockade in the ovarian hyperstimulation syndrome: studies in the rabbit model.Am J Obstet Gynecol. 1984; 148: 670-674PubMed Google Scholar). However, studies failed to show any effect of H1 and H2 blockage on the syndrome (14Zaides I. Friedman M. Lindenbaum E.S. Serotonin and the ovarian hyperstimulation syndrome.Eur J Obstet Gynecol Reprod Biol. 1983; 15: 55-60Abstract Full Text PDF PubMed Scopus (25) Google Scholar, 15Erlik Y. Naot Y. Friedman M. Ben-David E. Paldi E. Histamin levels in ovarian hyperstimulation syndrome.Obstet Gynecol. 1979; 53: 580-582PubMed Google Scholar). Although, as with other measures described there has not been an absolute consensus, the IV administration of HA at the time of oocyte retrieval has been widely accepted as a measure that may facilitate the prevention of OHSS (16Aboulghar M. Evers J.H. Al-Inany H. Intravenous albumin for preventing severe ovarian hyperstimulation syndrome: a Cochrane review.Hum Reprod. 2002; 17: 3027-3032Crossref PubMed Scopus (53) Google Scholar). It has been suggested that the binding and transport properties of HA play a major role in the prevention of severe OHSS through the ability to bind and inactivate the vasoactive intermediates responsible for the pathogenesis of the syndrome. The osmotic properties of HA may also be responsible for maintaining the intravascular volume in the event of capillary leakage (17Shalev E. Giladi Y. Matilsky M. Ben-Ami M. Decreased incidence of severe ovarian hyperstimulation syndrome in high risk in-vitro fertilisation patients receiving intravenous albumin: a prospective study.Hum Reprod. 1995; 10: 1373-1376Crossref PubMed Scopus (64) Google Scholar). Asch et al. (18Asch R. Ivery G. Goldsman M. The use of intravenous albumin in patients at high risk for severe hyperstimulation syndrome.Hum Reprod. 1993; 8: 1015-1020PubMed Google Scholar) were the first to suggest that IV albumin may prevent the development of severe OHSS. This was followed by several clinical studies with conflicting results. At present there have been eight published randomized controlled trials exploring the use of HA in preventing severe OHSS (1Shaker A.G. Zosmer A. Dean N. Berik J.S. Jacob H.S. Tan S.L. Comparison of intravenous albumin and transfer of fresh embryos with cryopreservation of all embryos for subsequent transfer in prevention of ovarian hyperstimulation syndrome.Fertil Steril. 1996; 65: 992-996Abstract Full Text PDF PubMed Scopus (72) Google Scholar, 19Isik A.Z. Gokmen O. Zeyneloglu H.B. Kara S. Keles G. Gulekli B. Intravenous albumin prevents moderate-severe ovarian hyperstimulation in in vitro fertilisation patients: a prospective randomized and controlled study.Eur J Obstet Gynecol Reprod Biol. 1996; 70: 170-183Abstract Full Text PDF Scopus (38) Google Scholar, 20Gokmen O. Ugur M. Ekin M. Keles G. Turan C. Oral H. Intravenous albumin versus hydroxyethyl starch for the prevention of ovarian hyperstimulation in an in-vitro fertilisation programme: a prospective randomised placebo controlled study.Eur J Obstet Gynecol Reprod Biol. 2001; 96: 187-192Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 21Shoham Z. Weissman A. Barash A. Borenstein R. Schachter M. Insler V. Intravenous albumin for the prevention of severe ovarian hyperstimulation syndrome in an in vitro fertilisation program: a prospective, randomized, placebo-controlled study.Fertil Steril. 1994; 62: 137-142Abstract Full Text PDF PubMed Scopus (105) Google Scholar, 22Ben-Chetrit A. Eldar-Geva T. Gal M. Huerta M. Mimon T. Algur N. et al.The questionable use of albumin for the prevention of ovarian hyperstimulation syndrome in an IVF programme: a randomized placebo-controlled trial.Hum Reprod. 2001; 16: 1880-1884Crossref PubMed Scopus (49) Google Scholar, 23Costabile L. Unfer V. Manna C. Gerli S. Rossetti S. Di Renzo G.C. Use of intramuscular progesterone versus intravenous albumin for the prevention of ovarian hyperstimulation syndrome.Gynecol Obstet Invest. 2000; 50: 182-185Crossref PubMed Scopus (17) Google Scholar, 24Bellver J. Munoz E.A. Ballesteros A. Soares S.R. Bosch E. Simon C. et al.Intravenous albumin does not prevent moderate–severe ovarian hyperstimulation syndrome in high-risk IVF patients: a randomized controlled study.Hum Reprod. 2003; 18: 2283-2288Crossref PubMed Scopus (65) Google Scholar). A recent Cochrane review, based on five of these randomized controlled studies in which 378 patients were involved, showed definite benefit from the administration of IV albumin at the time of oocyte pickup in high risk patients (16Aboulghar M. Evers J.H. Al-Inany H. Intravenous albumin for preventing severe ovarian hyperstimulation syndrome: a Cochrane review.Hum Reprod. 2002; 17: 3027-3032Crossref PubMed Scopus (53) Google Scholar). However, in all but one of these trials, the exception being the study by Ben-Cherit et al. (22Ben-Chetrit A. Eldar-Geva T. Gal M. Huerta M. Mimon T. Algur N. et al.The questionable use of albumin for the prevention of ovarian hyperstimulation syndrome in an IVF programme: a randomized placebo-controlled trial.Hum Reprod. 2001; 16: 1880-1884Crossref PubMed Scopus (49) Google Scholar), the outcome assessors were not blind to the intervention (19Isik A.Z. Gokmen O. Zeyneloglu H.B. Kara S. Keles G. Gulekli B. Intravenous albumin prevents moderate-severe ovarian hyperstimulation in in vitro fertilisation patients: a prospective randomized and controlled study.Eur J Obstet Gynecol Reprod Biol. 1996; 70: 170-183Abstract Full Text PDF Scopus (38) Google Scholar, 20Gokmen O. Ugur M. Ekin M. Keles G. Turan C. Oral H. Intravenous albumin versus hydroxyethyl starch for the prevention of ovarian hyperstimulation in an in-vitro fertilisation programme: a prospective randomised placebo controlled study.Eur J Obstet Gynecol Reprod Biol. 2001; 96: 187-192Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 21Shoham Z. Weissman A. Barash A. Borenstein R. Schachter M. Insler V. Intravenous albumin for the prevention of severe ovarian hyperstimulation syndrome in an in vitro fertilisation program: a prospective, randomized, placebo-controlled study.Fertil Steril. 1994; 62: 137-142Abstract Full Text PDF PubMed Scopus (105) Google Scholar). A potential for outcome bias therefore exists. Bellver et al. (24Bellver J. Munoz E.A. Ballesteros A. Soares S.R. Bosch E. Simon C. et al.Intravenous albumin does not prevent moderate–severe ovarian hyperstimulation syndrome in high-risk IVF patients: a randomized controlled study.Hum Reprod. 2003; 18: 2283-2288Crossref PubMed Scopus (65) Google Scholar) published the largest prospective single-centered study. They compared 40 g of HA with no treatment in a total of 976 patients and concluded that albumin infusion is not useful in the prevention of moderate-to-severe OHSS. In this study, similarly, the outcome assessors were not blind to the intervention. In addition, two kinds of GnRH agonist were used and only early OHSS was assessed. Placebo was not used in their control group, which eliminates the placebo effect of albumin administration. Serum E2, level which was previously reported as an independent risk factor for severe OHSS, was not considered high risk factor in this study. In our study, both the patients and the outcome assessors were blind to the interventions and the results of our study are in accordance with those of Bellver et al. (24Bellver J. Munoz E.A. Ballesteros A. Soares S.R. Bosch E. Simon C. et al.Intravenous albumin does not prevent moderate–severe ovarian hyperstimulation syndrome in high-risk IVF patients: a randomized controlled study.Hum Reprod. 2003; 18: 2283-2288Crossref PubMed Scopus (65) Google Scholar). Various HA concentrations between 10 g (19Isik A.Z. Gokmen O. Zeyneloglu H.B. Kara S. Keles G. Gulekli B. Intravenous albumin prevents moderate-severe ovarian hyperstimulation in in vitro fertilisation patients: a prospective randomized and controlled study.Eur J Obstet Gynecol Reprod Biol. 1996; 70: 170-183Abstract Full Text PDF Scopus (38) Google Scholar, 20Gokmen O. Ugur M. Ekin M. Keles G. Turan C. Oral H. Intravenous albumin versus hydroxyethyl starch for the prevention of ovarian hyperstimulation in an in-vitro fertilisation programme: a prospective randomised placebo controlled study.Eur J Obstet Gynecol Reprod Biol. 2001; 96: 187-192Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar) and 50 g (21Shoham Z. Weissman A. Barash A. Borenstein R. Schachter M. Insler V. Intravenous albumin for the prevention of severe ovarian hyperstimulation syndrome in an in vitro fertilisation program: a prospective, randomized, placebo-controlled study.Fertil Steril. 1994; 62: 137-142Abstract Full Text PDF PubMed Scopus (105) Google Scholar, 22Ben-Chetrit A. Eldar-Geva T. Gal M. Huerta M. Mimon T. Algur N. et al.The questionable use of albumin for the prevention of ovarian hyperstimulation syndrome in an IVF programme: a randomized placebo-controlled trial.Hum Reprod. 2001; 16: 1880-1884Crossref PubMed Scopus (49) Google Scholar) were also used in these randomized studies. In the present study we assessed the efficacy of 10 g of HA and found that it does not seem to either prevent or reduce the risk of severe OHSS in high risk patients. The incidence of severe OHSS in patients undergoing ART during the study period in our center was 1.95%, which is consistent with previous reports (2Delbaere A. Smits G. Olatunbosun O. Pierson R. Vassart G. Costagliola S. New insights into the pathophysiology of ovarian hyperstimulation syndrome. What makes the difference between spontaneous and iatrogenic syndrome?.Hum Reprod. 2004; 19: 486-489Crossref PubMed Scopus (76) Google Scholar, 25Papanikolaou E.G. Tournaye H. Verpoest W. Camus M. Vernaeve V. Steirteghem A.V. et al.Early and late ovarian hyperstimulation syndrome: early pregnancy outcome and profile.Hum Reprod. 2005; 20: 636-641Crossref PubMed Scopus (116) Google Scholar). The relatively high incidence of severe OHSS in our study population was mainly due to our sample selection criteria, as well as our aggressive COH policy. In our study, patients experiencing early severe OHSS and the resolution of the symptoms thereafter were all associated with a negative pregnancy result, whereas patients experiencing late severe OHSS with or without early severe OHSS were always associated with a positive pregnancy test result. The association between the late onset of OHSS and pregnancy has been previously reported to be a result of the endogenous hCG from the initiated pregnancy (6Navot D. Bergh P.A. Laufer N. Ovarian hyperstimulation syndrome in novel reproductive technologies: prevention and treatment.Fertil Steril. 1992; 58: 249-261Abstract Full Text PDF PubMed Google Scholar). Late OHSS is reported as being able to complicate a nonconception cycle only if additional hCG is given during the luteal phase (25Papanikolaou E.G. Tournaye H. Verpoest W. Camus M. Vernaeve V. Steirteghem A.V. et al.Early and late ovarian hyperstimulation syndrome: early pregnancy outcome and profile.Hum Reprod. 2005; 20: 636-641Crossref PubMed Scopus (116) Google Scholar). It has been shown that once a clinical pregnancy has been established in a patient with OHSS (both early and late OHSS), there is a normal risk of abortion (25Papanikolaou E.G. Tournaye H. Verpoest W. Camus M. Vernaeve V. Steirteghem A.V. et al.Early and late ovarian hyperstimulation syndrome: early pregnancy outcome and profile.Hum Reprod. 2005; 20: 636-641Crossref PubMed Scopus (116) Google Scholar). Our findings regarding first trimester abortion rates were consistent with previous reports. Although albumin is generally tolerated, hypersensitivity reactions such as urticaria (19Isik A.Z. Gokmen O. Zeyneloglu H.B. Kara S. Keles G. Gulekli B. Intravenous albumin prevents moderate-severe ovarian hyperstimulation in in vitro fertilisation patients: a prospective randomized and controlled study.Eur J Obstet Gynecol Reprod Biol. 1996; 70: 170-183Abstract Full Text PDF Scopus (38) Google Scholar) and even life-threatening anaphylactic reactions have been reported. The incidence of urticaria, fever, chills, or hypotension ranges from 0.47%–1.53% (26Tullis J.L. Albumin. Background and use.J Am Med Assoc. 1977; 237: 355-360Crossref PubMed Scopus (110) Google Scholar) and 0.011% for the incidence of allergic reactions (27Roberts J.S. Bratton S.L. Colloid volume expanders: problems, pitfalls, and possibilities.Drugs. 1998; 55: 621-630Crossref PubMed Scopus (101) Google Scholar). Despite the very low rate of life-threatening risks of HA, it is mandatory to prove a definite clinical benefit that outweighs the unnecessary risks before its routine use in clinical practice. In conclusion, the administration of 10 g of HA to high risk OHSS patients does not seem to either prevent or reduce the risk of severe OHSS. The efficacy of higher doses of HA needs to be clarified by future randomized studies with large study samples. We believe the results of the present study will assist other investigators in the decision to use HA as an OHSS preventative measure after COH for ART. We are grateful to Kevin Coetzee for the English proofreading of the article. We also thank to Dr. Levent Donmez for his valuable suggestions on statistical analyses.