title: Ovarian hyperstimulation syndrome: review and new classification criteria for reporting in clinical trials.
abstract: 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?
  
  
  
  The OHSS flow diagram is an objective approach that will facilitate consistent capture, classification and reporting of OHSS within and across clinical trials.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  Not applicable.
authors.affiliation: The Fertility Clinic, Fertility, Skive Regional Hospital, Faculty of Health, Aarhus University, Resenvej 25, 7800 Skive, Aarhus C, Denmark peter.humaidan@midt.rm.dk.
authors.forename: P
authors.initials: P
authors.lastname: Humaidan
authors.affiliation: University of Glasgow, School of Medicine, Glasgow, UK.
authors.forename: S M
authors.initials: SM
authors.lastname: Nelson
authors.affiliation: Centre for Reproductive Medicine Universitair Ziekenhuis Brussel, Fertility, Brussels, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Devroey
authors.affiliation: Mayo Clinic, Fertility, Rochester, MN, USA.
authors.forename: C C
authors.initials: CC
authors.lastname: Coddington
authors.affiliation: Merck & Co., Inc., Women's Health, Kenilworth, USA.
authors.forename: L B
authors.initials: LB
authors.lastname: Schwartz
authors.affiliation: Merck & Co., Inc., Women's Health, Kenilworth, USA.
authors.forename: K
authors.initials: K
authors.lastname: Gordon
authors.affiliation: Fertility Institute of Hawaii, Fertility, Honolulu, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Frattarelli
authors.affiliation: 1st Department of Obstetrics and Gynecology, Papageorgiou Hospital Medical School Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: B C
authors.initials: BC
authors.lastname: Tarlatzis
authors.affiliation: IVI-GCC, Abu Dhabi, UAE.
authors.forename: H M
authors.initials: HM
authors.lastname: Fatemi
authors.affiliation: Monash IVF, Clayton, Victoria, Australia.
authors.forename: P
authors.initials: P
authors.lastname: Lutjen
authors.affiliation: Merck & Co., Inc., Women's Health, Kenilworth, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Stegmann
mesh_terms: D002986:Clinical Trials as Topic; D005260:Female; D005307:Fertilization in Vitro / Q000379:methods; D006801:Humans; D015994:Incidence; D016471:Ovarian Hyperstimulation Syndrome / Q000145:classification* / Q000453:epidemiology* / Q000209:etiology; D010062:Ovulation Induction / Q000009:adverse effects*; D020554:Sperm Injections, Intracytoplasmic / Q000379:methods
keywords: OHSS flow diagram; assisted reproductive technology; classification criteria; clinical trials; in vitro fertilization; ovarian hyperstimulation syndrome; ovarian stimulation