Reduced Intellectual Ability in Offspring of Ovarian Hyperstimulation Syndrome: A Cohort Study.
Xu Gu-Feng,Zhou Cheng-Liang,Xiong Yi-Meng,Li Jing-Yi,Yu Tian-Tian,Tian Shen,Lin Xian-Hua,Liao Yun,Lv Yuan,Zhang Fang-Hong,Liu Zhi-Wei,Shi Yin-Yin,Shen Yan,Sha Jin,Zhang Dan,Zhu Yi-Min,Sheng Jian-Zhong,Huang He-Feng
EBioMedicine
BACKGROUND:Ovarian hyperstimulation syndrome (OHSS), a complication of ovarian stimulation, has various adverse effects on both pregnant women and their offspring. However, whether OHSS will affect intellectual ability in offspring is still unknown. METHODS:We recruited 86 Chinese children born to OHSS women and 172 children conceived with non-OHSS In Vitro Fertilization (IVF) in this cohort study. Their intellectual ability was assessed according to the Revised Chinese Version of the Wechsler Intelligence Scale for Children (C-WISC). Verbal Intelligence Quotient (VIQ), Performance Intelligence Quotient (PIQ), and Full Intelligence Quotient (FIQ) were calculated. The investigation was registered in Chinese Clinical Trial Registry (ChiCTR-SOC-16009555). FINDINGS:OHSS offspring scored less on C-WISC (mean (standard deviation [SD]): (VIQ=92.7 (14.7), PIQ=108.9 (13.1), FIQ=100.6 (13.4)) compared with non-OHSS IVF offspring (VIQ=100.1 (13.2), PIQ=113.7 (10.8), FIQ=107.4 (11.5)). The prevalence of low IQ (<80) children was 4.7 times higher in OHSS offspring compared with non-OHSS offspring. Maternal estradiol level on hCG administration day was negatively associated with FIQ in offspring. INTERPRETATION:OHSS offspring displayed reduced intellectual ability. Prenatal estradiol exposure might be involved in underlying mechanism.
10.1016/j.ebiom.2017.05.020
Antimüllerian hormone to determine polycystic ovarian morphology.
Dietz de Loos Alexandra,Hund Martin,Buck Katharina,Meun Cindy,Sillman Johanna,Laven Joop S E
Fertility and sterility
OBJECTIVE:To determine a cutoff for the Elecsys AMH Plus immunoassay (Roche Diagnostics International Ltd, Rotkreuz, Switzerland) to identify polycystic ovarian morphology (PCOM), a polycystic ovary syndrome (PCOS) criterion. DESIGN:The AMH Protein in Humans for polycystic ovaRian mOrphology DIagnostic TEsting (APHRODITE) study was a retrospective, multicenter, case-control study. The serum antimüllerian hormone (AMH) level was measured using the Elecsys AMH Plus immunoassay. The antral follicle count was determined using transvaginal ultrasound. An AMH cutoff was derived and validated in separate cohorts with cases of PCOS with full phenotype A (oligo/anovulation, hyperandrogenism, and PCOM) versus that with controls. Exploratory analyses of age and PCOS phenotype were performed. SETTING:Not applicable. PATIENT(S):Polycystic ovary syndrome-positive (PCOS A-D per the Rotterdam criteria) and PCOS-negative women aged 25-45 years. INTERVENTION(S):None. MAIN OUTCOME MEASURE(S):A validated cutoff for AMH using the Elecsys AMH Plus assay for PCOM. RESULT(S):In the validation cohort (455 cases and 500 controls), an AMH cutoff of 3.2 ng/mL (23 pmol/L) resulted in a sensitivity of 88.6% (95% confidence interval [CI] 85.3-91.3) and specificity of 84.6% (95% CI 81.1-87.7) for PCOM diagnosis as well as an area under the receiver-operator characteristic curve of 93.6% (95% CI 92.2-95.1). In women aged 25-35 years, the sensitivity and specificity for the cutoff were 88.5% and 80.3%, respectively, versus 77.8% and 90.1%, respectively, in women aged 36-45 years. The results were consistent across PCOS phenotypes A-D. CONCLUSION(S):The Elecsys AMH Plus immunoassay, with a cutoff of 3.2 ng/mL (23 pmol/L), is a robust method for identifying PCOM to aid in PCOS diagnosis.
10.1016/j.fertnstert.2021.05.094
Luteal phase support with GnRH agonist does not eliminate the risk for ovarian hyperstimulation syndrome.
Friedler Shevach,Grin Leonti
Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology
This study aims to report a case of early, severe ovarian hyperstimulation syndrome (OHSS) following GnRH agonist trigger for final oocyte maturation despite luteal support with a GnRH agonist. Contrary to the claim that luteal support using a GnRH agonist eliminates the risk for OHSS in high-risk patients, this report alerts practitioners to the risk of severe OHSS development despite GnRH agonist luteal support in patients receiving GnRH antagonist protocol with GnRH agonist triggering and cautions the practitioners to consider other measures of OHSS prevention.
10.1080/09513590.2018.1548591
Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome.
The Cochrane database of systematic reviews
BACKGROUND:The use of insulin-sensitising agents, such as metformin, in women with polycystic ovary syndrome (PCOS) who are undergoing ovulation induction or in vitro fertilisation (IVF) cycles has been widely studied. Metformin reduces hyperinsulinaemia and suppresses the excessive ovarian production of androgens. It is suggested that as a consequence metformin could improve assisted reproductive techniques (ART) outcomes, such as ovarian hyperstimulation syndrome (OHSS), pregnancy, and live birth rates. OBJECTIVES:To determine the effectiveness and safety of metformin as a co-treatment during IVF or intracytoplasmic sperm injection (ICSI) in achieving pregnancy or live birth in women with PCOS. SEARCH METHODS:We searched the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL via the Cochrane Register of Studies Online (CRSO), MEDLINE, Embase, PsycINFO, LILACS, the trial registries for ongoing trials, and reference lists of articles (from inception to 13 February 2020). SELECTION CRITERIA:Types of studies: randomised controlled trials (RCTs) comparing metformin treatment with placebo or no treatment in women with PCOS who underwent IVF or ICSI treatment. TYPES OF PARTICIPANTS:women of reproductive age with anovulation due to PCOS with or without co-existing infertility factors. Types of interventions: metformin administered before and during IVF or ICSI treatment. PRIMARY OUTCOME MEASURES:live birth rate, incidence of ovarian hyperstimulation syndrome. DATA COLLECTION AND ANALYSIS:Two review authors independently selected the studies, extracted the data according to the protocol, and assessed study quality. We assessed the overall quality of the evidence using the GRADE approach. MAIN RESULTS:This updated review includes 13 RCTs involving a total of 1132 women with PCOS undergoing IVF/ICSI treatments. We stratified the analysis by type of ovarian stimulation protocol used (long gonadotrophin-releasing hormone agonist (GnRH-agonist) or short gonadotrophin-releasing hormone antagonist (GnRH-antagonist)) to determine whether the type of stimulation used influenced the outcomes. We did not perform meta-analysis on the overall (both ovarian stimulation protocols combined) data for the outcomes of live birth and clinical pregnancy rates per woman because of substantial heterogeneity. In the long protocol GnRH-agonist subgroup, the pooled evidence showed that we are uncertain of the effect of metformin on live birth rate per woman when compared with placebo/no treatment (risk ratio (RR) 1.30, 95% confidence interval (CI) 0.94 to 1.79; 6 RCTs; 651 women; I = 47%; low-quality evidence). This suggests that if the chance for live birth following placebo/no treatment is 28%, the chance following metformin would be between 27% and 51%. Only one study used short protocol GnRH-antagonist and reported live birth rate. Metformin may reduce live birth rate compared with placebo/no treatment (RR 0.48, 95% CI 0.29 to 0.79; 1 RCT; 153 women; low-quality evidence). This suggests that if the chance for live birth following placebo/no treatment is 43%, the chance following metformin would be between 13% and 34% (short GnRH-antagonist protocol). We found that metformin may reduce the incidence of OHSS (RR 0.46, 95% CI 0.29 to 0.72; 11 RCTs; 1091 women; I = 38%; low-quality evidence). This suggests that for a woman with a 20% risk of OHSS without metformin, the corresponding risk using metformin would be between 6% and 14%. Using long protocol GnRH-agonist stimulation, metformin may increase clinical pregnancy rate per woman compared with placebo/no treatment (RR 1.32, 95% CI 1.08 to 1.63; 10 RCTs; 915 women; I = 13%; low-quality evidence). Using short protocol GnRH-antagonist, we are uncertain of the effect of metformin on clinical pregnancy rate per woman compared with placebo/no treatment (RR 1.38, 95% CI 0.21 to 9.14; 2 RCTs; 177 women; I = 87%; very low-quality evidence). We are uncertain of the effect of metformin on miscarriage rate per woman when compared with placebo/no treatment (RR 0.86, 95% CI 0.56 to 1.32; 8 RCTs; 821 women; I = 0%; low-quality evidence). Metformin may result in an increase in side effects compared with placebo/no treatment (RR 3.35, 95% CI 2.34 to 4.79; 8 RCTs; 748 women; I = 0%; low-quality evidence). The overall quality of evidence ranged from very low to low. The main limitations were inconsistency, risk of bias, and imprecision. AUTHORS' CONCLUSIONS:This updated review on metformin versus placebo/no treatment before or during IVF/ICSI treatment in women with PCOS found no conclusive evidence that metformin improves live birth rates. In a long GnRH-agonist protocol, we are uncertain whether metformin improves live birth rates, but metformin may increase the clinical pregnancy rate. In a short GnRH-antagonist protocol, metformin may reduce live birth rates, although we are uncertain about the effect of metformin on clinical pregnancy rate. Metformin may reduce the incidence of OHSS but may result in a higher incidence of side effects. We are uncertain of the effect of metformin on miscarriage rate per woman.
10.1002/14651858.CD006105.pub4
Factors Associated with Ovarian Hyperstimulation Syndrome (OHSS) Severity in Women With Polycystic Ovary Syndrome Undergoing IVF/ICSI.
Sun Bo,Ma Yujia,Li Lu,Hu Linli,Wang Fang,Zhang Yile,Dai Shanjun,Sun Yingpu
Frontiers in endocrinology
Introduction:Age, polycystic ovary syndrome (PCOS), low body mass index (BMI), high antral follicle count (AFC), increased anti-Muller hormone (AMH) levels, and elevated serum estradiol (E2) concentrations are risk factors for ovarian hyperstimulation syndrome (OHSS). However, data on the relationship between risk factors and OHSS severity in patients with PCOS are rare. Objective:This retrospective study examined the risk factors for OHSS and their effect on OHSS severity in patients with PCOS undergoing fertilization (IVF)/intracytoplasmic sperm injection (ICSI). Method:The records of 2,699 women were reviewed and included in this study. These women were diagnosed with PCOS during their first IVF/ICSI cycle between January 2010 and December 2017. We analyzed the association between each of the interrogated risk factors (including female age, BMI, AFC, basal serum E2, and the number of oocytes retrieved) and OHSS. The effects of each risk factor on OHSS severity were further explored. Logistic regression was performed as part of the above analysis. Results:Of the 2,699 women with PCOS who underwent assisted reproductive technology (ART), 75.2% had a normal response to controlled ovarian hyperstimulation (COH), while 24.8% developed OHSS. All OHSS patients were younger and had lower BMIs and basal serum follicle-stimulating hormone (FSH) and E2 levels but higher AFCs than those in the normal group. AFC demonstrated a strong correlation with OHSS, with a cutoff value of 24 in patients with PCOS. A total of 19.5% of the patients had mild OHSS, while 80.5% had moderate OHSS. Compared with those in the moderate OHSS group, those in the mild OHSS group were older and had higher basal serum FSH levels and lower serum E2 and T levels. However, BMI and AFC were not different between the mild and moderate OHSS groups. Basal serum E2 showed a strong correlation with OHSS severity, with a cutoff value of 37.94 pg/ml. Conclusions:AFC is a strong marker of OHSS, and basal serum E2 is the best predictor of OHSS severity in women with PCOS undergoing IVF treatment.
10.3389/fendo.2020.615957
Ovarian hyperstimulation syndrome: review and new classification criteria for reporting in clinical trials.
Humaidan P,Nelson S M,Devroey P,Coddington C C,Schwartz L B,Gordon K,Frattarelli J L,Tarlatzis B C,Fatemi H M,Lutjen P,Stegmann B J
Human reproduction (Oxford, England)
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.
10.1093/humrep/dew149
Meta-analysis of GnRH antagonist protocols: do they reduce the risk of OHSS in PCOS?
Pundir Jyotsna,Sunkara Sesh Kamal,El-Toukhy Tarek,Khalaf Yacoub
Reproductive biomedicine online
This systematic review and meta-analysis investigated whether gonadotrophin-releasing hormone (GnRH) antagonist protocols reduce the risk of ovarian hyperstimulation syndrome (OHSS) in women with polycystic ovary syndrome undergoing IVF compared with the long agonist protocol. Searches were conducted on MEDLINE, EMBASE, Cochrane Library, National Research Register and ISI Conference Proceedings. Primary outcome was OHSS incidence. Secondary outcomes were total duration and dose of gonadotrophin, number of oocytes retrieved and clinical pregnancy and miscarriage rates. A total of 966 women were included in nine randomized controlled trials. There was inconsistency in definition, classification of severity and reporting of the OHSS rate. There was no difference in the incidence of severe OHSS in the antagonist group compared with the long agonist group (relative risk 0.61; 95% CI 0.23 to 1.64). However, when all moderate and severe OHSS cases were pooled, the antagonist protocol was associated with significantly lower risk of OHSS (relative risk 0.60; 95% CI 0.48-0.76; P<0.0001). A possible reduction in the incidence of severe OHSS with the GnRH antagonist protocol should be viewed with caution since the data is inconclusive. Larger randomized trials with adequate sample size and standardized definition, classification and diagnosis of OHSS remain necessary.
10.1016/j.rbmo.2011.09.017
Ultrasound and hematological changes during early luteal phase in women at high risk for developing ovarian hyperstimulation syndrome.
Lainas G T,Lainas T G,Venetis C A,Sfontouris I A,Zorzovilis I Z,Alexopoulou E,Tarlatzis B C,Kolibianakis E M
Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology
OBJECTIVE:To assess ultrasound and hematological changes during the early luteal phase following triggering of final oocyte maturation with human chorionic gonadotropin (hCG) in women at high risk for developing ovarian hyperstimulation syndrome (OHSS). METHODS:This was a retrospective cohort study of 319 women undergoing in-vitro fertilization who were at high risk for OHSS following administration of hCG for the triggering of final oocyte maturation. Patients were treated with a gonadotropin-releasing hormone agonist or antagonist protocol and were monitored for 5 days post-oocyte retrieval (early luteal phase). Severe OHSS was diagnosed in the presence of at least moderate ascites and two or more of the following: maximum ovarian diameter (MOD) > 100 mm, hematocrit (Ht) > 45%, white blood cell count (WBC) > 15 000/mm , hydrothorax, dyspnea and oliguria. Outcome measures included change in Ht, ascites grade, WBC and MOD, as well as the association between these changes during the early luteal phase. RESULTS:Ascites grade, Ht and WBC increased significantly (P ≤ 0.001) during the early luteal phase, both in patients who developed and in those who did not develop severe early OHSS. MOD increased significantly (P = 0.001) only in patients who developed severe early OHSS. On multivariable analysis, both time following oocyte retrieval and whether severe early OHSS developed were significantly associated with ascites grade, Ht, WBC and MOD; furthermore, there was also a significant interaction between time and development of severe early OHSS for all four variables (P ≤ 0.001). CONCLUSIONS:In women at high risk of OHSS, ascites grade, Ht and WBC significantly increased with time over the 5-day observation period, in line with the pathophysiology of the syndrome. Our data support the use of MOD in the diagnosis of severe early OHSS, and provide novel evidence for the role of change in Ht as a patient-specific hemoconcentration marker during development of OHSS. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.
10.1002/uog.18949