Assisted Conception Unit, Guy's and St Thomas' Assisted Conception Unit, St Thomas' Hospital, Lambeth Palace Rd, London SE1 7EH, UK
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Abstract |
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Key words: embryo cryopreservation/IVF/ovarian hyperstimulation syndrome/renal transplant
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Introduction |
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Case report |
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In 1996 she conceived spontaneously but suffered an early miscarriage. Following this pregnancy she was treated empirically with clomiphene citrate but developed mild OHSS on a daily dose of 100 mg but did not require hospital admission. The next year a diagnostic laparoscopy demonstrated bilaterally blocked Fallopian tubes, pelvic endometriosis and a right ovarian endometrioma. Her endometriosis was initially treated conservatively with a subcutaneous implant of goserelin depot (3.6 mg; Zoladex, AstraZeneca, Cheshire, UK) every 28 days for three cycles. However, she subsequently required a laparotomy and right ovarian cystectomy to remove a 6x6 cm endometrioma. Basal hormonal profile showed an elevated LH of 18.5 IU/l, FSH of 5.1 IU/l and her mid-luteal progesterone was suggestive of anovulation. A baseline transvaginal ultrasound scan demonstrated polycystic ovarian morphology.
In 1998, she was referred to our unit for IVF treatment. She underwent mid-luteal pituitary down-regulation with a transnasal buserelin (Suprefact; Hoechst, Middlesex, UK) 200 µg four times daily followed by ovarian stimulation with a daily dose 225 IU of recombinant FSH (Gonal F; Serono, Middlesex, UK) for 8 days. On day 9 of stimulation, her serum oestradiol concentration was 4086 pg/ml and a transvaginal ultrasound scan revealed the presence of 23 pre-ovulatory follicles. HCG (10000 IU Profasi; Serono) was administered subsequently and a standard transvaginal oocyte retrieval under ultrasound guidance with prophylactic antibiotic was carried out 36 h later. A total of 22 oocytes was retrieved of which 12 fertilized normally following insemination.
Fresh embryo transfer was postponed because the patient had developed symptoms and signs suggestive of ovarian hyperstimulation syndrome (OHSS). These included pelvic pain, abdominal distension and nausea. A transvaginal ultrasound examination confirmed that both ovaries were enlarged (right 8x6 cm, left 7x6 cm), although there was no obvious ascites. A total of 11 good quality embryos was cryopreserved for future use.
The following day she was admitted to hospital with increasing pelvic pain, nausea and vomiting. On examination, she did not appear to be dehydrated; her abdomen was mildly distended and tender on palpation, particularly over her right pelvic kidney. Transvaginal ultrasound showed her ovaries to be further enlarged, the right (7x11 cm) filling the pelvis and the left (8x12 cm) displaced abdominally. Her urea was 9.0 mmol/l but her creatinine had risen to 166 µmol/l. Her white blood cell count was also elevated at 16.1x109/l. Her haematocrit (0.358), serum electrolytes, liver function tests and blood clotting tests were all normal.
During hospital admission her renal function deteriorated as shown by oliguria and serum urea and creatinine rising to a maximum of 16.0 mmol/l and 230 µmol/l respectively. The clinical picture was not typical of OHSS in that she was not intravascularly depleted, with a positive fluid balance and a normal haematocrit value (0.289). Her ovaries remained enlarged but at no time did she develop hypoalbuminaemia, ascites or a pleural effusion.
The differential diagnosis of the deterioration in function of her transplanted kidney included renal obstruction caused by the enlarged ovaries, urinary tract infection, acute rejection or cyclosporin toxicity. An abdominal ultrasound of her pelvic kidney showed a normal-sized kidney with mild pelvicalyceal dilatation. Bacterial culture of a mid-stream specimen of urine was negative. The cyclosporin concentration was 176 µg/l (therapeutic range 70180mµg/l). A diethylene-triaminepent-acetate (DTPA) renal scan showed prompt appearance of contrast but delayed clearance, indicative of renal obstruction, interstitial inflammation or poor hydration.
She was treated symptomatically with analgesics for pain and did not receive intravenous fluids because although oliguric, she was not intravascularly depleted and had a positive fluid balance.
Six days after admission her renal function began to improve; her urine output increased and serum urea and creatinine concentrations began to fall. She was discharged 8 days after admission and by the 10th day serum urea and creatinine concentrations had decreased to 8.3 mmol/l and 135 µmol/l respectively.
Three months later she had two frozenthawed embryos transferred that resulted in a twin pregnancy. This was complicated by pre-term labour at 30 weeks gestation culminating in a spontaneous vaginal delivery of live male and female infants.
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Discussion |
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There are several strategies to reduce the risk of OHSS (Amso et al., 1990; Navot et al., 1992
; Rizk and Smith, 1992; Asch et al., 1993
; Schenker, 1993
; Brinsden et al., 1995
; Sher et al., 1995
). However, only withholding HCG administration in down-regulated cycles may eliminate the risk of OHSS.
In this case, the cause of an exaggerated ovarian response to stimulation with recombinant FSH can be attributed to the sensitivity of the patient's polycystic ovaries to gonadotrophin stimulation. Other potential factors that may have contributed to the development of OHSS include the high daily dose of recombinant FSH, the altered metabolism of recombinant FSH secondary to the attendant impairment in renal function or the enhanced potency of recombinant FSH.
The reason for using such a relatively high dose for ovarian stimulation was the attempt to compensate for the anticipated poor ovarian response secondary to previous ovarian surgery and functional ovarian tissue damage caused by endometriosis. With the benefit of hindsight, a lower daily dose of gonadotrophins may have been appropriate to reduce the risk of OHSS.
The effect of renal impairment on metabolism of FSH is plausible as 10% of recombinant FSH is excreted into the urine. The delayed clearance of FSH from circulation may enhance the stimulatory effect of normal daily doses, although investigators (Ben-Rafael et al., 1995) have suggested that moderate renal impairment does not require dosage adjustments of FSH. The renal clearance for recombinant FSH (0.07 ± 0.04 l/h) is less than the glomerular filtration rate. This may indicate that human FSH is reabsorbed after filtration, or that high molecular weight glycosylated human FSH (~31 kDa) is too large to be excreted freely, or that a renal metabolism of the molecule may exist (Ben-Rafael et al., 1995
).
The currently available recombinant FSH preparations have proved safe in clinical trials, and despite their overall higher efficacy (Daya and Gunby, 1999) they have not been shown to be associated with increased risk of OHSS. In fact, some investigators have suggested that recombinant FSH may be safely used for ovarian stimulation of patients who previously experienced OHSS with the use of urinary gonadotrophins (Aboulghar et al., 1996
).
This case was not typical of severe OHSS since oliguria and deterioration in renal function occurred despite the patient being well hydrated, with no ascites, normal serum albumin concentration and other blood parameters. We believe that the most likely cause of the deterioration in renal function was secondary to obstruction of her pelvic transplanted kidney caused by ovarian enlargement. This diagnosis was supported by the ultrasound scan which showed mid-pelvicalyceal dilatation and the DTPA scan which demonstrated delayed clearance of contrast.
This patient had previously demonstrated an exaggerated response to clomiphene citrate and both her elevated basal LH concentration and ovarian morphology were consistent with polycystic ovaries. When she showed an exaggerated response to gonadotrophins it might have been appropriate to withhold HCG administration and restart ovarian stimulation later with a lower dose of gonadotrophins. This option, though safer, would have resulted in the loss of any chance of a pregnancy from that cycle with the attendant emotional and financial implications. Another management option that should have been considered is `coasting' ovarian stimulation until serum oestradiol falls to a safe level before HCG administration. This intervention in cases at risk of OHSS has been found to be safe and effective (Sher et al., 1995) and warrants consideration in future similar cases.
As the success of renal transplant increases, the number of women with transplants requesting assisted conception treatment is likely to increase. Our case demonstrates that such patients receiving gonadotrophins require very careful monitoring during treatment. Patients with a renal transplant seeking fertility treatment may well require gonadotrophins for ovulation induction for various forms of assisted conception with OHSS as a potential complication.
Our case demonstrates that great care is required when attempting ovarian stimulation with gonadotrophins in renal transplant patients. A more cautious approach than the one described here is advisable. We suggest that particular attention should be given to the medical disorders that may accentuate the systemic effects of OHSS, especially in patients at high risk of developing this serious complication.
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Notes |
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References |
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Submitted on January 10, 2000; accepted on March 10, 2000.