Ovarian hyperstimulation syndrome: review and new classification criteria for reporting in clinical trials.

STUDY QUESTION: What is an objective approach that employs measurable and reproducible physiologic changes as the basis for the classification of ovarian hyperstimulation syndrome (OHSS) in order to facilitate more accurate reporting of incidence rates within and across clinical trials? SUMMARY ANSWER: The OHSS flow diagram is an objective approach that will facilitate consistent capture, classification and reporting of OHSS within and across clinical trials. WHAT IS KNOWN ALREADY: OHSS is a potentially life-threatening iatrogenic complication of the early luteal phase and/or early pregnancy after ovulation induction (OI) or ovarian stimulation (OS). The clinical picture of OHSS (the constellation of symptoms associated with each stage of the disease) is highly variable, hampering its appropriate classification in clinical trials. Although some degree of ovarian hyperstimulation is normal after stimulation, the point at which symptoms transition from those anticipated to those of a disease state is nebulous. STUDY DESIGN, SIZE, DURATION: An OHSS working group, comprised of subject matter experts and clinical researchers who have significantly contributed to the field of fertility, was convened in April and November 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: The OHSS working group was tasked with reaching a consensus on the definition and the classification of OHSS for reporting in clinical trials. The group engaged in targeted discussion regarding the scientific background of OHSS, the criteria proposed for the definition and the rationale for universal adoption. An agreement was reached after discussion with all members. MAIN RESULTS AND THE ROLE OF CHANCE: One of the following conditions must be met prior to making the diagnosis of OHSS in the context of a clinical trial: (i) the subject has undergone OS (either controlled OS or OI) AND has received a trigger shot for final oocyte maturation (e.g. hCG, GnRH agonist [GnRHa] or kisspeptin) followed by either fresh transfer or segmentation (cryopreservation of embryos) or (ii) the subject has undergone OS or OI AND has a positive pregnancy test. All study patients who develop symptoms of OHSS should undergo a thorough examination. An OHSS flow diagram was designed to be implemented for all subjects with pelvic or abdominal complaints, such as lower abdominal discomfort or distention, nausea, vomiting and diarrhea, and/or for subjects suspected of having OHSS. The diagnosis of OHSS should be based on the flow diagram. LIMITATIONS, REASONS FOR CAUTION: This classification system is primarily intended to address the needs of the clinical investigator undertaking clinical trials in the field of OS and may not be applicable for the use in clinical practice or with OHSS occurring under natural circumstances. WIDER IMPLICATIONS OF THE FINDINGS: The proposed OHSS classification system will enable an accurate estimate of the incidence and severity of OHSS within and across clinical trials performed in women with infertility. STUDY FUNDING/COMPETING INTERESTS: Financial support for the advisory group meetings was provided by Merck & Co., Inc., Kenilworth, NJ, USA. P.H. reports unrestricted research grants from MSD, Merck and Ferring, and honoraria for lectures from MSD, Merck and IBSA. S.M.N. reports that he has received fees and grant support from the following companies (in alphabetic order): Beckman Coulter, Besins, EMD Serono, Ferring Pharmaceuticals, Finox, MSD and Roche Diagnostics over the previous 5 years. P.D., C.C.C., J.L.F., H.M.F., and P.L. report no relationships that present a potential conflict of interest. B.C.T. REPORTS: grants and honorarium from Merck Serono; unrestricted research grants, travel grants and honorarium, and participation in a company-sponsored speaker's bureau from Merck Sharp & Dohme; grants, travel grants, honoraria and advisory board membership from IBSA; travel grants from Ferring; and advisory board membership from Ovascience. L.B.S. reports current employment with Merck & Co, Inc., Kenilworth, NJ, USA, and owns stock in the company. K.G. and B.J.S. report prior employment with Merck & Co., Inc., Kenilworth, NJ, USA, and own stock in the company. All reported that competing interests are outside the submitted work. No other relationships or activities exist that could appear to have influenced the submitted work. TRIAL REGISTRATION NUMBER: Not applicable.

Iatrogenic stenosis following suture-mediated closure device.

The use of percutaneous closure devices post arterial punctures has been introduced to reduce time to haemostasis, reduce haemorrhage, improve patient comfort and reduce time to ambulation. Their increased use has been a result of larger access sites for more complicated procedures, periprocedural anticoagulation and concomitant use of anti-platelet therapy. Although complication rates are not increased with their use as compared with mechanical compression, complications may be more severe and are an important consideration in their use. We report two cases of iatrogenic stenoses secondary to suture-mediated closure device. The first managed with open surgical repair and the second with cutting balloon angioplasty.

Oocyte maturation, follicle rupture and luteinization in human cryopreserved ovarian tissue following xenografting.

BACKGROUND: Previous studies have demonstrated development of antral follicles in cryopreserved human ovarian tissue after autografting and xenografting, thus indicating successful preservation of follicular function. The study aim was to assess whether these follicles could also undergo periovulatory changes in response to hCG. METHODS: Ovarian tissue from three patients were dehydrated in propanediol (PROH)/sucrose and cryopreserved using the slow cooling/rapid thaw procedure. Thawed tissue was placed under the kidney capsule in immunodeficient mice. Following growth (>20 weeks) in the presence of gonadotrophin, hCG was administered and ovarian tissue examined histologically. RESULTS: Thirty-two antral follicles (diameter range 0.6 to 5 mm) were examined. Histological evidence of a response to hCG was evident in all follicles. Disruption of the concentric layers of mural granulosa and theca cells was apparent in all antral cavities. In 17 (53%) follicles the exterior follicular wall had reduced to a few cells thick, and in eight (25%) the wall had ruptured. Mucified oocyte-cumulus cell complexes were present in 32 follicles, 17 of which had begun to detach from the pedicle. Resumption of meiosis had occurred in over half the oocytes (five metaphase II and seven metaphase I oocytes, eight germinal vesicle breakdown). Two corpora lutea were also detected. CONCLUSIONS: Follicles cryopreserved within human ovarian tissue using the PROH procedure, can develop to the antral stage and undergo periovulatory changes following xenografting and exposure to a luteinizing stimulus.

The maternal ovary is not the source of circulating inhibin levels during human pregnancy.

The concentration of immunoreactive inhibin in serum was measured in three pregnant women with premature ovarian failure involved in a donor oocyte in-vitro fertilization programme. Inhibin was not detectable in peripheral serum prior to conception but rose within 2-4 weeks of embryo transfer, whereafter levels rose gradually during pregnancy (less than 20 weeks 1.22 U/ml (0.85-1.76) versus greater than 20 weeks 2.28 U/ml (1.42-3.67), P less than 0.01; geometric mean +/- 67% confidence interval) and were similar to those observed in 24 normal pregnant women. hCG rose in parallel with inhibin during early gestation, but declined after 3 months. FSH levels were elevated before conception and were suppressed during pregnancy. In conclusion (i) immunoreactive inhibin is detectable from early gestation in women with no endogenous ovarian function indicating that the maternal ovary does not contribute significantly to inhibin secretion during pregnancy; (ii) the trophoblast is the likely source of inhibin during pregnancy; (iii) the regulation of hCG and inhibin secretion differs throughout gestation; and (iv) inhibin may have a role in FSH regulation during pregnancy and/or a local role within the feto-placental unit.

Monoclonal antibody against a sperm antigen Mr 95,000 inhibits attachment of human spermatozoa to the zona pellucida.

A murine monoclonal antibody raised against hamster spermatozoa was found to cross-react with human spermatozoa. By immunofluorescence, the antigen was visualized over the equatorial segment of human sperm heads. In the presence of antibody, sperm binding to the zona pellucida of salt-stored human oocytes was significantly inhibited (P less than or equal to 0.005) compared with other antibodies or control preparations. Using SDS-PAGE of whole spermatozoa and membrane preparations followed by Western blot analysis, the antigen was identified as a determinant with a relative molecular weight of 95,000.

Effect on plasma gonadotropins of cyclic steroid replacement in women with premature ovarian failure.

A sequential regimen of steroid replacement of oral estradiol valerate and progesterone (P) by intravaginal suppository was developed for women with premature ovarian failure or ovarian agenesis. The regimen, based on a 28-day cycle, resulted in peripheral plasma concentrations of estradiol and P within the normal range of the menstrual cycle and endometrial differentiation consistent with the normal secretory phase. Pregnancy has now been successfully established in four patients following this regimen of steroid treatment and transfer of donated embryos. Plasma concentrations of LH were within the normal range by the end of the first cycle of treatment with exogenous steroids. However, plasma FSH remained above the normal range, even during the third treatment cycle, consistent with the necessity of a gonadal feedback factor (inhibin?) other than estradiol and P for maintaining FSH in the normal range. Although 7/8 patients had a surge of LH at midcycle, only 3/8 patients had concomitant FSH surges, supporting a role for progesterone in facilitating the midcycle FSH surge.

Oocyte and embryo donation in IVF programmes.

We have described a cyclic steroid replacement regimen of oestradiol and progesterone which is able to produce physiological concentrations of these steroids in plasma indicative of a normal menstrual cycle. The stimulation of a secretory endometrium at the appropriate time in this artificial menstrual cycle bears testament to the suitability of the treatment and has led to the establishment of pregnancy in three women with complete ovarian failure or ovarian agenesis when used in combination with the established techniques of in vitro fertilization and embryo transfer. The steroid replacement regimen can easily be adjusted to maintain pregnancy until the time of luteoplacental shift, based on the close monitoring of the plasma steroid and hCG levels in the pregnant individual. The implications of this form of treatment for other disease states and for our understanding of the mechanisms involved in ovarian hormone action, pregnancy maintenance and parturition are immense.

Interaction between human cervical mucus and sperm surface antibodies.

The immunobead test was used to study the immunoglobulin class of antibodies on sperm before and after penetration through a microcolumn of cervical mucus. Sixteen men with positive sperm antibodies (positive sperm immobilization test) and sperm that penetrated cervical mucus in prior tests were selected for study. However, at the time of study, sperm from seven subjects could not be recovered from the microcolumn. The nine subjects from whom motile sperm were obtained after passage through the column had better sperm mucus penetration tests, lower proportions of sperm binding to anti-IgA immunobeads, and higher proportions of sperm with tail-tip-only binding. Sperm recovered after penetration through the mucus microcolumn displayed a greatly reduced binding to anti-IgA immunobeads in all nine subjects, whereas similar reductions in anti-IgG binding occurred only in four subjects. These results confirm that IgA and sperm-head-directed antibodies are more important than IgG and sperm tail-tip-directed antibodies in impairing sperm penetration of cervical mucus.

The establishment and maintenance of pregnancy using in vitro fertilization and embryo donation in a patient with primary ovarian failure.

Ovarian steroid replacement therapy in the ovariectomized ewe, given in the correct sequence to mimic endogenous steroid changes in the normal ovulatory cycle, allows the development of embryos transferred in utero. A similar type of sequential therapy was designed for steroid replacement in women with primary ovarian failure. This produces the histological changes in uterine endometrial morphology and plasma oestradiol and progesterone similar to those observed in the normal ovulatory cycle. We now report that in one of these women a donated oocyte, fertilized by her husband's spermatozoa and cultured to the two-cell stage in vitro, was transferred in utero, resulting in a normal pregnancy and the delivery of a healthy child. Oestrogen therapy was withdrawn at 12 weeks and progesterone at 19 weeks gestation. This technique allows the treatment of human infertility due to primary ovarian failure.