The incidence of both serious and minor complications in young women undergoing oocyte donation

The incidence of both serious and minor complications in young women undergoing oocyte donation Kara N. Maxwell, M.D., Ph.D., a Ina N. Cholst, M.D., b and Zev Rosenwaks, M.D. b a Department of Medicine, College of Physicians and Surgeons of Columbia University and b Center for Reproductive Medicine and Infertility, Weill Cornell Medical College, New York, New York Objective: To investigate the incidence of serious and minor complications experienced by women undergoing controlled ovarian hyperstimulation and oocyte retrieval for oocyte donation. Design: Retrospective study. Setting: University-based IVF center. Patient(s): Five hundred eighty-seven donors underwent 973 cycles of controlled ovarian hyperstimulation and 886 oocyte retrievals for anonymous or directed oocyte donation. Intervention(s): Controlled ovarian hyperstimulation; oocyte retrieval. Main Outcome Measure(s): Complications of the procedure. Result(s): The rate of serious complications, which included ovarian hyperstimulation syndrome, ovarian torsion, infection, and ruptured ovarian cyst, was 6 in 886 (0.7%) retrieval cycles. The rate of minor complications severe enough to prompt the donor to seek medical attention after retrieval was 8.5%. The cancellation rate after stimulation cycle initiation was approximately 9%, regardless of whether the donation was anonymous or directed. Conclusion(s): This study provides information on the incidence of serious complications experienced by oocyte donors after controlled ovarian hyperstimulation and oocyte retrieval. It provides evidence that with careful monitoring, and when a liberal cancellation policy is followed, oocyte donors experience lower rates of ovarian hyperstimulation syndrome, compared with infertile women undergoing IVF. Furthermore, the study provides the first set of data on the rate of symptomatic minor complications experienced by oocyte donors. This information will help clinicians administer appropriate informed consent to the young women who present themselves as potential oocyte donors. (Fertil Steril Ò 2008;90:2165 71. Ó2008 by American Society for Reproductive Medicine.) Key Words: Oocyte donation, egg donation, IVF, ART complications, informed consent Infertility is a common problem in the United States. Although the probability of conception after 1 year in young, healthy couples is approximately 90%, fertility declines and the rate of miscarriage increases as women age (1). Despite this, women in the United States and in the developed world generally may find their educational and career goals incompatible with youthful pregnancy. We see, therefore, increasing trends toward later childbearing. When coupled with the increased success and availability of infertility treatments, these facts have resulted in an increase in the use of such technology, particularly assisted reproductive technology (ART). In fact, in 2004, in the United States, 49,458 babies about 1% of American newborns were born as the result of >127,977 IVF cycles performed at 411 clinics (2, 3). Since its introduction in the early 1980s, oocyte donation has played an ever-increasingly important role in ART (4). A group of women for whom pregnancy previously was impossible are now conceiving, carrying, and delivering babies Received August 2, 2007; revised and accepted October 26, 2007. I.N.C. served on the speaker s bureau for Merck. All other authors have nothing to disclose. Reprint requests: Ina N. Cholst, M.D., Reproductive Medicine, The Center for Reproductive Medicine and Infertility, Weill Cornell Medical College, 1305 York Avenue, 7 th Floor, New York, New York 10021 (E-mail: icholst@med.cornell.edu). with high rates of success. This group includes women who have survived cancer treatment, women who are without ovarian function (because of surgery, premature menopause, gonadal agenesis, or for a variety of other reasons), women who carry serious inheritable diseases, women who are of advanced reproductive age, and women who have failed repeated IVF attempts (5, 6). Of the 127,977 ART procedures reported to the CDC in 2004, 15,175 (12%) used donated oocytes. Furthermore, of the 49,458 infants born as a result of ART in 2004, 6,564 (13%) were from donated oocytes (2, 3). Oocyte donation is an ethically complex area of ART. To donate eggs, young, healthy women undergo medical procedures for which they do not receive any health benefits (7 9). Informed consent in this case therefore is similar to informed consent for medical research and thus is subject to similar pitfalls, including misperception of risk and misconception of benefit to self (10). Thus, we, as the physicians caring for these young women, must provide the information and, specifically, the discussion of risks, with thoroughness if we are to have any hope of a truly informed consent (11). Furthermore, when risk is incurred in young healthy women undergoing procedures without medical benefit to themselves, it is especially incumbent upon us as clinicians to document these risks and to work assiduously to reduce their incidence. 0015-0282/08/$34.00 Fertility and Sterility â Vol. 90, No. 6, December 2008 2165 doi:10.1016/j.fertnstert.2007.10.065 Copyright ª2008 American Society for Reproductive Medicine, Published by Elsevier Inc.

In 2004, the American Society for Reproductive Medicine published practice guidelines delineating the possible shortterm risks to oocyte donors, including ovarian hyperstimulation syndrome (OHSS), infection, bleeding, and anesthesia complications (12). The guidelines quote a 1% rate of OHSS experienced by women undergoing controlled ovarian hyperstimulation (COH) for IVF but note that the rate may actually be lower in oocyte donors because they do not become pregnant. We could speculate that the rate might actually be higher, given the high responder status of most donors. Clearly, more information is needed. However, little information is available on the actual rates of this and other complications, specifically in oocyte donors. To our knowledge, only one study has been performed on the rate of serious complications of COH and oocyte retrieval that specifically are experienced by oocyte donors (13), and no information exists concerning the rate of symptomatic minor complications. Although minor complications, by definition, do not result in hospitalization or increased long-term sequelae, we believe that they have particular significance for oocyte donors. Young, healthy women experiencing these minor complications may have anxiety, discomfort, or pain, and they may lose time from school, work, or the pleasures of daily life. Their informed-consent process thus should include discussion of both serious and minor complications. Furthermore, future research and technological advances should aim not just to improve the pregnancy rates associated with oocyte donation but also to decrease both major and minor risks to donors. This study therefore aims to further these goals by retrospectively investigating the rates of both serious and minor complications in oocyte donors at a New York City IVF center. MATERIALS AND METHODS This study consists of a retrospective analysis of all attempts at oocyte donation by anonymous and known directed donors at the New York Presbyterian Hospital Weill Cornell Medical School from April 1, 1991 to May 31, 2007. Charts were reviewed, and those donors who began at least one COH cycle were selected. Institutional review board approval was obtained. The charts of 587 donors (481 anonymous and 106 directed) were reviewed; these donors participated in 973 cycles. Donors were between 20 and 42 years of age. They were evaluated according to American Society for Reproductive Medicine guidelines and in accordance with US Food and Drug Administration and New York State Department of Health mandates, including infectious-disease, genetic, and psychological screening as well as general health and fertility assessment. Stimulation protocols were designed not only to maximize pregnancy rates but also to minimize complications, particularly OHSS. These protocols involved luteal-phase leuprolide acetate down-regulation and FSH, given in relatively low doses (75 to 225 miu/d) and adjusted according to a tapered, or step-down, protocol (14). A small number of donors received combined FSH and LH. Most, but not all, donors received oral contraceptive pills in the cycle preceding stimulation and overlapping with the leuprolide (15). Donors were evaluated by ultrasonogram and E 2 levels at baseline and then were evaluated daily from day 3 or 4 of stimulation. Decisions about dose were made individually, on the basis of daily follicular ultrasounds and serum E 2 concentrations. Coasting was used when deemed appropriate to decrease the incidence of OHSS (16). In addition, cycles that met criteria for cancellation because of increased risk of OHSS (E 2 of >4,000 pg/ml) were discontinued before administration of hcg. Human chorionic gonadotropin was given when two leading follicles reached 17 mm in average diameter. Ultrasound-guided retrieval was performed under intravenous sedation 34 to 36 hours after hcg administration (14). Before August of 2003, oral tetracycline was given for 4 days after retrieval. After August of 2003, an intravenous antibiotic (cefoxitin, 2 g) was administered to all donors perioperatively. Penicillin-allergic donors received clindamycin (900 mg). A nurse spoke on the phone to each donor 1 to 3 days after retrieval. Donors without complaints were not required to return to the clinic for follow-up examination; donors with complaints symptomatic enough to prompt them to seek medical attention, as well as those who were discovered to have significant complaints in the course of the routine follow-up phone conversation, were scheduled for office visits. Charts were reviewed for any events that occurred during or after the completion of a stimulation cycle, including cancellations, phone calls made to the office by the donor, office visits, and hospitalizations. The following complications were categorized as being serious: severe OHSS, moderate OHSS requiring hospitalization, infection requiring IV antibiotics, intraperitoneal bleeding, ovarian torsion, or any other complication necessitating hospitalization. Minor complications included the following: mild or moderate OHSS necessitating one or more office visits or any other symptoms resulting in an office visit. Ovarian hyperstimulation syndrome was defined according to the classification of Golan et al. (17). Specifically, mild OHSS was defined as abdominal distention and/or pain, with ovaries not enlarged beyond 5 cm in diameter. Moderate OHSS was defined as abdominal distension, nausea, vomiting, and/or diarrhea, with ovaries usually measuring between 5 and 12 cm in diameter. Severe OHSS was defined when the ovaries measured >12 cm in diameter and/or one or more of the following occurred: shortness of breath, coagulation abnormalities, or decreased renal function (17). RESULTS Demographics of Oocyte Donor Patient Population We report the rate of both minor and serious complications experienced by a group of women in an oocyte donation program in New York City between April 1991 and May 2007. This study analyzed the donation cycles of 587 women who participated in 973 cycles and 886 retrievals. The majority of women, 481 (82%), participated in anonymous donations; the remaining 106 (18%) participated in directed 2166 Maxwell et al. Complications of oocyte donation Vol. 90, No. 6, December 2008

donations to sisters or cousins. The women who participated in anonymous donation were younger, with an average age of 27 years (range, 20 37 y; there was only one donor who was 20 y of age and one donor who was 37 y of age, and both occurred before 1996), compared with those participating in directed donations, whose average age was 34 years (range, 25 42 y), P<.001 by two-tailed t-test. Finally, anonymous donors participated in a greater number of cycles; 481 women participated in 847 anonymous cycles (1.8 cycles per donor), compared with 106 women who participated in 126 directed cycles (1.2 cycles per donor). Rare Occurrence of Serious Complications After COH and Oocyte Retrieval for Oocyte Donation Charts were examined for the following serious complications: severe or moderate OHSS requiring hospitalization, infection requiring IVantibiotics, ovarian torsion, and any other complication requiring hospitalization. As shown in Table 1, there were six serious complications (0.7% of cycles). There was one case of moderate OHSS requiring hospitalization (0.1%), two ovarian torsions (0.2%), two significant infections (0.2%), and one case of ruptured ovarian cyst necessitating hospitalization (0.1%). The patient with moderate OHSS was admitted to the hospital with complaints of lower abdominal pain. Her right ovary measured 7.6 by 5.2 cm; her left ovary measured 7.0 by 6.2 cm. Renal, hepatic, and coagulation parameters were normal. She was treated with IV hydration and prophylactic SC heparin and was discharged after 48 hours of observation. No paracentesis was required. Both women with ovarian torsion presented with sharp abdominal pain in addition to symptoms of OHSS; both underwent laparoscopy, and the ovaries were detorsed. The two women with infection responded promptly to IV antibiotics, defervescing within 24 hours. Both were discharged within 72 hours on oral antibiotics, without subsequent sequelae. Finally, the patient with ovarian cyst rupture was admitted to the hospital with abdominal pain 1 week after retrieval. No surgical intervention was required, and she was discharged after 2 days of observation. Of note is that all serious complications occurred in anonymous donors. Incidence of Minor Complications After COH and Oocyte Retrieval for Oocyte Donation Although it is most important to inform potential oocyte donors about the incidence of serious complications associated with COH and oocyte retrieval, it is also important to inform them of other possible complications. To this end, we analyzed 886 donor retrieval cycles to determine the frequency of symptoms significant enough to warrant one or more office visits after retrieval. As shown in Table 2, in 75 (8.5%) of 886 cycles, donors had sufficient symptoms to justify one or more office visits. There were 40 cases (4.5%) of mild or moderate OHSS requiring one office visit; 12 cases (1.4%) of mild or moderate OHSS requiring two office visits; four donors (0.5%) with moderate OHSS requiring three to four office visits; and one case of mild, self-limiting intraperitoneal bleeding (0.1%). Eighteen other patients presented with miscellaneous symptoms, including ovarian cysts, hematomas, urinary tract infections, yeast infections or other symptoms (2.0%). In all, the incidences of mild and moderate OHSS symptomatic enough to warrant medical attention in this series were 2.8% and 3.7%, respectively; there was no occurrence of severe OHSS. Overall Complication Rates After COH and Oocyte Retrieval for Oocyte Donation In addition to information on serious and minor complications necessitating office visits, data were collected on the TABLE 1 Serious complications that occurred in 886 retrieval cycles. Complication Moderate OHSS requiring hospitalization No. of donor cycles (% of retrieval cycles) Course 1 (0.1) a One patient admitted to hospital for observation, IV hydration, and prophylactic subcutaneous heparin. No paracentesis or other interventions required. Ovarian torsion 2 (0.2) a Admitted to hospital for laparoscopy, ovary preserved. Infection 2 (0.2) Admitted to hospital for IV antibiotics. Ruptured ovarian cyst 1 (0.1) Admitted to outside hospital. Total 6 (0.7) a Two patients experienced both moderate OHSS and ovarian torsion. Because moderate OHSS did not require hospitalization, these patients were considered to have one serious complication. Fertility and Sterility â 2167

TABLE 2 Incidence of all symptomatic complications requiring office visits in 886 retrieval cycles. Complication No. of office visits No. of donor cycles (% of retrieval cycles) Mild and 1 40 (4.5) moderate OHSS Mild and 2 12 (1.4) moderate OHSS Moderate 3 or 4 4 (0.5) OHSS Intraabdominal 2 1 (0.1) bleeding Other 1 or 2 18 (2.0) (cyst, hematoma, UTI, yeast infection, vague symptoms) Total 75 (8.5) Note: UTI ¼ urinary tract infection. frequency with which donors expressed symptoms in a phone call to the office. Thirty-seven symptom-related phone calls were made by donors after retrieval cycles (4.2%). In summary, serious complications occurred in 0.7% of cycles, minor complications requiring at least one office visit occurred in 8.5% of cycles, and 4.2% of cycles were associated with phone calls related to symptoms but not necessitating an office visit. Thus, 87% (768/886) of donors had no apparent concerns or complications. Cancellation of Donor Cycles Of 973 initiated cycles, 886 underwent oocyte retrieval; therefore, the cancellation rate was 8.9% among all donors. Table 3 shows the reasons for cancellation. Of the 973 initiated cycles, 38 were canceled as a result of poor ovarian response (3.9%), 16 were canceled to avoid the risk of OHSS (1.6%), and 8 were canceled because of a positive drug screen (0.8%). In addition, 25 cycles were canceled for miscellaneous reasons. These included donor withdrawal, donor illness, pregnancy, or medication errors. As shown in Table 3, cancellation rates were similar among anonymous and directed donors (8.9% vs. 9.5%); however, the reasons for cancellation differed between anonymous and directed donors. For example, cancellation to avoid the risk of OHSS occurred in 1.8% of anonymous donors and 0.8% of directed donors; in comparison, cancellation as a result of poor response occurred in 3.3% of anonymous donors but 7.9% of directed donors. DISCUSSION As physicians, we have a particular responsibility to provide detailed informed consent along with the safest possible care to young, healthy women who intend to become oocyte donors. Despite this, and despite the large numbers of young women currently undergoing IVF cycles for the purpose of oocyte donation, the incidence of complications experienced by this group of women has been only rarely described. We therefore reviewed the incidence of both serious and minor complications experienced by all women undergoing COH for oocyte donation at our institution between 1991 and 2007. TABLE 3 Incidence of cycle cancellation among 973 donor cycles. Reason for cancellation Total no. of donor cycles (% of all cycles) Anonymous donors (% of anonymous cycles) Directed donors (% of directed cycles) Poor ovarian response 38 (3.9) 28 (3.3) 10 (7.9) Prevention of OHSS 16 (1.6) 15 (1.8) 1 (0.8) Positive drug screen 8 (0.8) 8 (0.9) 0 Other 25 (2.6) 24 (2.8) 1 (0.8) Donor withdrawal 5 4 1 Health reasons 5 5 0 Pregnancy 2 2 0 Chlamydia positive 2 2 0 Hepatitis B positive 2 2 0 Medication error 2 2 0 Total 87 (8.9) 75 (8.9) 12 (9.5) 2168 Maxwell et al. Complications of oocyte donation Vol. 90, No. 6, December 2008

This study determined that the rate of serious complications was 6/886 retrieval cycles, or 0.7%. Serious complications seen in this group of subjects included moderate OHSS requiring hospitalization, ovarian torsion, infection, and a ruptured ovarian cyst. Of note, after the second infection occurred in July 2003, we began using routine prophylactic antibiotics perioperatively. There have been no further infections since the new protocol was initiated (2 infections in 524 retrieval cycles before antibiotics were initiated and no infections in 362 retrieval cycles after antibiotics were initiated). Our analysis also determined that the rate of minor complications requiring at least one office visit after retrieval was 8.5%. A number of studies have investigated the incidence of complications, especially OHSS, experienced by women undergoing COH for IVF. In general, the rate of severe OHSS is considered to be approximately 1% (18). More specifically, analysis of a subset of these studies (Table 4) shows rates of all serious complications necessitating hospitalization in women undergoing IVF to be between 1.5% and 2.6% and shows the rates of OHSS necessitating hospitalization to be between 1.1% and 4.2% (19 22). Young donors often exhibit a high E 2 response to stimulation and thus are at increased risk for OHSS, compared with the larger pool of women undergoing IVF for infertility. Paradoxically, despite this, it generally is thought that donors have a lower risk of OHSS than IVF patients because they do not become pregnant (23). However, to our knowledge, only one study previously has investigated the rates of serious complications secondary to COH for oocyte donation. Sauer and Paulson (24) originally found no serious complications among 325 cycles; however, Sauer (13) later reported that the incidence of serious complications among 1,000 cycles was 0.7%, very similar to the incidence of 0.7% found in the present study. However, the types of complications were somewhat different. Sauer (13) found three cases of severe OHSS, two adverse anesthesia complications, and two bleeding complications. Regardless, the Sauer study (13) and the present study do confirm that donors experience a lower rate of serious complications than do infertile women undergoing IVF. This reduction in rate appears to be mostly a result of a lower rate of OHSS, because the incidence of other complications is similar to that in other published studies (Table 4). Sauer et al. (25) also investigated the rates of all forms of OHSS in women undergoing COH for oocyte donation. By using ultrasound to assess the degree of OHSS, the Sauer et al. (25) study found mild OHSS in 65%, moderate OHSS in 34%, and severe OHSS in 1.5% of cycles, rates significantly higher than those described in our study (2.8%, mild OHSS; 3.7%, moderate OHSS; and 0, severe OHSS). The reason for this apparent large discrepancy is that Sauer et al. (25) used postretrieval ultrasound to define OHSS (and, not surprisingly, discovered some degree of it in 100% of donors), whereas we reported only symptomatic OHSS specifically, OHSS that was significant enough for donors to comment on it in the standard follow-up phone call or to initiate an office visit. It is likely that our donors, if routinely ultrasounded postoperatively, would have been found to have had an incidence of asymptomatic mild and moderate OHSS similar to that reported by Sauer et al. TABLE 4 Comparison of incidence of serious complications among previous and current studies. Study first author (study location) (reference no.) No. of cycles Total Severe OHSS Moderate OHSS Infection Bleeding Torsion Other IVF Abramov (Israel) (19) Govaerts (Belgium) (20) Roest (The Netherlands) (21) Serour (Egypt) (22) Donors Sauer (New York) (23) Present (New York) Note: NA ¼ not applicable. 73,492 NA 0.3 3.9 NA NA NA NA 1,500 2.6 0.3 1.5 0.4 0.2 0.1 0 2,495 1.5 0.7 0.4 0.2 0 0.1 0.1 3,500 2.4 1.7 NA 0.3 0.1 0 0.3 1,000 0.7 0.3 0 0 0.2 0 0.2 886 0.7 0 0.1 0.2 0 0.2 0.1 Fertility and Sterility â 2169

(25). Of note, one other report of severe OHSS in an oocyte donor has been published elsewhere (26). Obviously, it is important that physicians discuss the rate of serious complications with potential donors during the informed consent process. It is, however, also important that we discuss the possibility of minor complications, especially those that might result in extra clinic visits, loss of time from work, or disruption of normal quality of life. These minor complications include mild and moderate OHSS, mild to moderate self-limited intraperitoneal bleeding, urinary tract infection, hematoma formation, ovarian cysts, and other annoying and sometimes temporarily disruptive events. The only previous information on the rates of minor complications in oocyte donors comes from two studies of questionnaires sent retrospectively to prior oocyte donors. Rosenberg and Epstein (27) analyzed questionnaires from 32 donors and found that 39.6% of women reported some negative physical reactions after the procedure. In addition, Kalfoglou and Gittelsohn (28) analyzed questionnaires from 33 donors who participated in 66 cycles and found that 27% of women reported significant abdominal discomfort. These rates are higher than our rate of 8.5% of cycles that were symptomatic enough to justify at least one postretrieval office visit and an additional 4.2% of cycles that resulted in symptoms serious enough to prompt the donor to place a phone call. Small sample size, differences in stimulation protocols, the passage of time, responder bias, and the structure of the questionnaires in the previous studies possibly could explain these discrepancies. A final important piece of information for donors during informed consent is the risk of long-term complications (11), which our study did not address; this would require further study. This study found that 16 (1.6%) of 973 cycles were canceled to avoid hyperstimulation; indeed, this cancellation policy may have contributed to the low incidence of symptomatic moderate OHSS and the absence of severe OHSS observed. We observed a cancellation rate of 8.9% among anonymous donors (75/847) and one of 9.5% among directed donors (12/126). Our data extend previous data from Sung et al. (29) on the differences in cancellation between anonymous and sister donors. In comparison to the present study, the Sung et al. (29) study found an increased cancellation rate in sister donors compared with anonymous donors (4/13 vs. 4/66). Similar to the present study, however, Sung et al. (29) found that all four sister donors were canceled as a result of poor ovarian response, vs. only two of four anonymous donors. The present study, although retrospective and specific to our IVF center, confirms data presented in another retrospective study at a different center by Sauer (13) on the incidence of serious complications experienced by young oocyte donors. We have supported previous evidence that when appropriate safeguards are in place, oocyte donors experience lower rates of OHSS than do infertile women undergoing IVF. Furthermore, we report on the incidence of minor complications experienced by these women. Minor complications do not, by definition, result in lasting consequences, but they may temporarily interfere with work, school, or the orderly progression of normal life. Therefore, as we care for these young women, it behooves us to make every effort to minimize the risks that they may experience and to be clear in providing informed consent concerning those risks. 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