The importance of gynecological examination in adolescent girls and adult women with Prader-Willi syndrome.

Current published guidelines for routine care of women with Prader-Willi syndrome (PWS) do not include recommendations for gynecologic examinations. We describe our experience with gynecological examinations in women with PWS and offer recommendations for routine health care for these patients. Data were collected on all 41 PWS females ages ≥12 year, followed in our national Israeli multidisciplinary clinic between the years 2011 and 2022. Menstrual data and findings on external gynecological examination, including evaluation of the vulva and hymen were recorded at yearly visits. During the gynecological evaluation the topic of sexual education was discussed. Pelvic ultrasound, specifically for antral follicular count, was performed for those visiting the clinic during 2020-2022. Blood samples for luteinizing hormone (LH), follicular stimulating hormone (FSH), and estradiol were obtained routinely and DEXA scans for bone density were done when indicated. Of the 41 women, (median age at start of follow-up 17 years, range [12.3-39], BMI 30.4 kg/m2 [IQR 23.5-37.1]), 39 women agreed to external gynecological examination. Eleven women (27%) had spontaneous menses, with menarche at the age of 14 to as late as 31 years. The hymen was intact in all except one. Poor hygiene was observed in eight women, three women with vulvovaginitis, and five with irritated vulva related to poor hygiene. Gynecological ultrasound was performed in 27 women. In 22, endometrial thickness was less than 5 mm. The median antral follicular count (AFC) was 6 (<10th percentile for age). No correlation between AFC and menstruation or BMI was found. Mean FSH level was 5.7 ± 3.6 IU, LH was 2.29 ± 2.23, and estradiol was 128 ± 76 pmol/L. Data on DEXA measurements were available in 25 women aged 16-39. Median spine T score was -1.3 (range between 0.5 and -3.7), and hip T score was -1.2 (range between 0.8 and -3.3). A negative correlation was found between endometrial thickness and the presence of osteopenia or osteoporosis (r = -0.5, p = 0.013). Despite our recommendations, only eight of 14 women agreed to hormonal treatment or contraception. One woman who received treatment had a thromboembolic event. Routine health care for women with PWS should include gynecological examinations. The gynecological evaluation should include external genital examination, assessment of hygiene, obtaining a blood sample for hormone levels, and documenting a history of sexual experience or sexual abuse. Hormonal treatment or contraception should be offered when appropriate.

PGT pregnancies have a similar risk for post-partum complications as naturally conceived pregnancies.

RESEARCH QUESTION: Do preimplantation genetic testing (PGT) pregnancies have higher post-partum complications compared with naturally conceived pregnancies? DESIGN: Retrospective cohort study conducted in 2008-2020 at the Shaare Zedek Medical Center (SZMC), including all patients aged 18-45 years old who conceived following PGT with a singleton live birth >24 weeks. Data were collected from computerized hospital databases and patient files. There were two control groups: (i) pregnancies following IVF-ICSI (intracytoplasmic sperm injection); (ii) four neighbourhood controls for each case delivery (two women delivered before and two after) of women with naturally conceived pregnancies. RESULTS: Overall, 120 PGT, 779 IVF-ICSI and 3507 naturally conceived deliveries were included. Demographic variables were similar apart from slightly higher age in the PGT (P = 0.003) and ICSI (P = 0.002) groups (31.07 ± 4.38 PGT, 31.66 ± 5.03 ICSI, 28.77 ± 5.72 naturally conceived). Composite post-partum placental-related complications (manual lysis of placenta, revision of uterine cavity, haemoglobin drop ≥3 g/dl, post-partum haemorrhage, need for blood transfusion) were more prevalent in both the PGT and IVF-ICSI groups as opposed to naturally conceived (20.0% versus 18.9% versus 10.3%, respectively, P < 0.001, P = 0.007). In a multivariate regression model PGT was not found to be independently associated with composite post-partum placental-related complications (adjusted odds ratio [aOR] 1.44, 95% confidence interval [CI] 0.83-2.15), while IVF-ICSI pregnancies had increased risk (aOR 1.52, 95% CI 1.20-1.97) compared with natural conception. No difference was found between fresh and frozen cycles or between day 3 and day 5 embryo transfer. CONCLUSIONS: PGT pregnancies have a comparable risk of post-partum placental-related complications to naturally conceived pregnancies, unlike IVF-ICSI pregnancies. It is possible that infertility itself is the main mediator for post-partum complications in IVF-ICSI pregnancies.

Extended fertility at highly advanced reproductive age is not related to anti-Müllerian hormone concentrations.

RESEARCH QUESTION: Is extended fertility at the advanced reproductive age of 43-47 years associated with high anti-Müllerian hormone (AMH) concentrations? DESIGN: Prospective cohort study including 98 women aged 43-47 years old with a spontaneous conception who were tested for AMH concentrations 1-4 days and 3-11 months post-partum. AMH concentrations at 3-11 months post-partum were further compared with AMH concentrations in healthy age-matched controls that last gave birth at ≤42 years old. Women with current use of combined hormonal contraceptives (CHC), ovarian insult or polycystic ovary syndrome were excluded. Power analysis supported the number of participating women. RESULTS: Median AMH concentrations did not differ between the extended fertility (n = 40) and control (n = 58) groups (0.50 versus 0.45 ng/ml, P = 0.51). This remained when analysing by age (≥ or <45 years old). AMH concentrations and women's age did not correlate within the extended fertility group (r = 0.017, P = 0.92); a weak negative correlation was found within the control group (r = -0.23, P = 0.08). AMH was significantly higher 3-11 months post-partum (0.50 ng/ml [0.21-1.23]) than 1-4 days post-partum (0.18 ng/ml [0.06-0.40]), P < 0.001. The two results for each participant were highly correlated (r = 0.82, P < 0.001). The extended fertility and control groups were similar regarding age, age at menarche, past CHC use and history of fertility concern. Parity differed but showed no significant correlation with AMH. CONCLUSIONS: Serum AMH concentrations that reflect ovarian reserve do not seem to predict reproductive potential at highly advanced age. Thus, additional factors such as oocyte quality should also be considered in evaluating reproductive potential. AMH suppression that is associated with pregnancy at 1-4 days post-partum recovers at 3-11 months post-partum in women of highly advanced reproductive age.

Clinical outcome of planned oocyte cryopreservation at advanced age.

PURPOSE: To report outcome of planned oocyte cryopreservation (POC) in the first 8 years of this treatment in our center. METHODS: A retrospective study in a university-affiliated medical center. RESULTS: A total of 446 women underwent POC during 2011-2018. Fifty-seven (13%) women presented to use these oocytes during the study period (until June 2021). POC was performed at a mean age of 37.9 ± 2.0 (range 33-41). Age at thawing was 43.3 ± 2.1 (range 38-49). A total of 34 (60%) women transferred their oocytes for thawing at other units. Oocyte survival after thawing was significantly higher at our center than following shipping to ancillary sites (78 vs. 63%, p = 0.047). Forty-nine women completed their treatment, either depleting their cryopreserved oocytes without conceiving (36) or attaining a live birth (13)-27% live birth rate per woman. Only one of eleven women who cryopreserved oocytes aged 40 and older had a live birth using thawed oocytes. CONCLUSION: Women should be advised to complete planned oocyte cryopreservation before age 40, given low success rates in women who underwent cryopreservation at advanced reproductive age. In this study, oocyte shipping was associated with lower survival rate. These findings may be relevant for women considering POC and utilization of cryopreserved oocytes.

Expanded clinical validation of Haploseek for comprehensive preimplantation genetic testing.

PURPOSE: We previously developed Haploseek, a method for comprehensive preimplantation genetic testing (PGT). However, some key features were missing, and the method has not yet been systematically validated. METHODS: We extended Haploseek to incorporate DNA from embryo grandparents and to allow testing of variants on chromosome X or in regions where parents share common haplotypes. We then validated Haploseek on 151 embryo biopsies from 27 clinical PGT cases. We sequenced all biopsies to low coverage (0.2×), and performed single-nucleotide polymorphism (SNP) microarray genotyping on the embryos' parents and siblings/grandparents. We used the extended Haploseek to predict chromosome copy-number variants (CNVs) and relevant variant-flanking haplotypes in each embryo. We validated haplotype predictions for each clinical sample against polymerase chain reaction (PCR)-based PGT case results, and CNV predictions against established commercial kits. RESULTS: For each of the 151 embryo biopsies, all Haploseek-derived haplotypes and CNVs were concordant with clinical PGT results. The cases included 17 autosomal dominant, 5 autosomal recessive, and 3 X-linked monogenic disorders. In addition, we evaluated 1 Robertsonian and 2 reciprocal translocations, and 17 cases of chromosome copy-number counting were performed. CONCLUSION: Our results demonstrate that Haploseek is clinically accurate and fit for all standard clinical PGT applications.

Preimplantation genetic testing (PGT) for copy number variants of uncertain significance (CNV- VUS) in the genomic era: to do or not to do?

PURPOSE: To review cases of couples presented to our PGT-unit with copy number variants (CNVs) classified as variants of uncertain significance (VUS) in order to better understand their needs. METHODS: Retrospective cohort study conducted in a tertiary medical-center, 2014-2019. We reviewed files of all couples applying for genetic counseling with CNVs classified as VUS. The main outcomes measured: number of VUS findings and their description, PGT-M procedures planned and performed, IVF cycles, clinical pregnancy, and live birth rates (LBR). VUS were classified according to the American-College of Medical-Genetics and Genomics classification at time of first consultation, and updated-December 2018. RESULTS: Twenty-four couples presented with a total of 30 VUS. Twelve couples (50%) had isolated VUS and 12 (50%) had VUS diagnosed in addition to a pathogenic mutation. Initially, nine findings (30%) were defined as VUS; eight (27%) as likely benign (b-VUS); and 13 (43%) as likely pathogenic (p-VUS). PGT-M was recommended for 17/30 CNVs (56.6%), 12 (70%) of which, isolated VUS. No couple had other indications for IVF. To date, nine couples performed PGT-M for isolated VUS; LBR per-couple-55.5%. Five couples performed PGT-M for both pathogenic findings and VUS, LBR-80%. After reviewing VUS classifications, 30% remained unchanged, 20% were more severely defined, and 50% less severely defined. CONCLUSION: The genomic era enables detection of VUS whose definition is subject to change as additional information becomes available. The uncertainty of variants' clinical significance and changes in VUS definition over time complicates genetic counseling. Revised guidelines for VUS interpretation and reevaluation of patient counseling before each pregnancy must be practiced when counseling them regarding the justification of PGT-M for their diagnosed VUS.

Cancer in IVF patients treated at age 40 years and older: long term follow-up.

RESEARCH QUESTION: Current knowledge of cancer risk among women who undergo IVF is based mainly on studies of women treated in their thirties, frequently with short follow-up periods. Therefore, information about cancer risk among infertile menopausal women is limited. We aimed to evaluate the risk of cancer among IVF patients treated at age 40 years and older, followed up for an extended period. DESIGN: Historical cohort study of all IVF patients treated at the age of 40 years or older at two university-affiliated IVF units in Jerusalem, Israel, between 1994 and 2002. Data were cross-linked with the Israel National Cancer Registry to 2016. Standardized incidence ratios (SIR) and 95% confidence intervals were computed by comparing the observed number of cancer cases with the expected cancer rate in the general Israeli population adjusted for age and year of birth. In addition, Kaplan-Meier analysis was conducted to account for the length of follow-up. RESULTS: A total of 501 patients were included in the analysis, with mean follow-up of 16.7 ± 3.7 years (range 2-22 years). Mean age at first IVF cycle was 42.3 years (±2.1). Mean number of IVF cycles was 3.2 ± 2.6 (range 1-15). Thirty-six women (7.2%) developed invasive cancer, compared with 47.2 expected cases; SIR 0.76 (95% CI 0.53 to 1.06); 22 women were diagnosed with invasive breast cancer, compared with 19.84 expected; SIR 1.11 (95% CI 0.69 to 1.68). CONCLUSIONS: Older women undergoing IVF treatment were not significantly associated with an excess risk of cancer at long-term follow up. Further studies, however, are needed to confirm these findings.

Recognizing the unique prenatal phenotype of Prader-Willi Syndrome (PWS) indicates the need for a diagnostic methylation test.

OBJECTIVES: Prader-Willi syndrome (PWS) is a neurogenetic disorder characterized by mental retardation, morbid obesity, and endocrine and behavior disorders. We previously showed in a small group of patients that PWS may have a unique prenatal phenotype. We aimed to characterize clinical and ultrasonic features in a larger series of pregnancies with a PWS fetus. METHODS: We retrospectively interviewed all mothers of children with PWS followed in the Israel national multidisciplinary PWS clinic. We compared details of the PWS pregnancy with the pregnancies of healthy siblings and with data from the general population. Medical records including ultrasound reports, obstetric records, and genetic results were analyzed. RESULTS: Distinct prenatal features of PWS pregnancies included abnormal fetal growth [fetal growth restriction (FGR) (37.3%), increased head to abdominal circumference ratio (44.8%), decreased abdominal circumference (49.2%)], markedly decreased fetal movements (DFM) (80.4%), and polyhydramnios (42.0%) (P < 0.001 for all). The combination of abnormal growth accompanied by polyhydramnios or DFM was highly suggestive for PWS. CONCLUSIONS: Recognition of the unique PWS phenotype should alert obstetricians to consider the possibility of PWS, perform the diagnostic methylation test, provide appropriate counseling, and plan optimal management of the affected pregnancy.

The effect of repeated biopsy on pre-implantation genetic testing for monogenic diseases (PGT-M) treatment outcome.

PURPOSE: To study the outcome of repeated biopsy for pre-implantation genetic testing in case of failed genetic diagnosis in the first biopsy. METHODS: The study group included 81 cycles where embryos underwent re-biopsy because there were no transferable embryos after the first biopsy: in 55 cycles, the first procedure was polar body biopsy (PBs) and the second cleavage-stage (BB); in 26 cycles, the first was BB and the second trophectoderm (BLAST) biopsy. The control group included 77 cycles where embryos underwent successful genetic diagnosis following the first biopsy, matched by maternal age, egg number, genetic inheritance type, and embryonic stage at the first biopsy. We measured genetic diagnosis rate, clinical pregnancy rates (PRs), live-birth rates (LBRs), gestational age, and birth weight. RESULTS: For repeated biopsy, genetic diagnosis was received in 67/81 cycles (82.7%); at a higher rate in PB + BB than in BB + BLAST (49/55, 89.1% and 18/26, 69.2% respectively, p = 0.055). Transferable embryos were found in 47 and 68 cycles in the study and the control groups. PRs/ET were 20/47 (42.6%) and 36/68 (52.9%) (p = 0.27), 16/36 (44.4%) following PB + BB, and 4/11 (36.4%) following BB + BLAST (p = 0.74). LBRs/ET were 13/47 (27.7%) in study group, and 28/68 (41.2%) in the controls (p = 0.14), 10/36 (27.8%) following PB + BB group, and 3/11 (27.3%) following BB + BLAST (p > 0.99). Gestational age and birth weight were similar in all groups. CONCLUSIONS: Re-biopsy of embryos when no genetic diagnosis could be reached following the first biopsy, achieved high rates of genetic diagnosis, pregnancies, and live births.

Preimplantation genetic testing for aneuploidy by microarray analysis of polar bodies in advanced maternal age: a randomized clinical trial.

STUDY QUESTION: Does preimplantation genetic testing for aneuploidy (PGT-A) by comprehensive chromosome screening (CCS) of the first and second polar body to select embryos for transfer increase the likelihood of a live birth within 1 year in advanced maternal age women aged 36-40 years planning an ICSI cycle, compared to ICSI without chromosome analysis? SUMMARY ANSWER: PGT-A by CCS in the first and second polar body to select euploid embryos for transfer does not substantially increase the live birth rate in women aged 36-40 years. WHAT IS KNOWN ALREADY: PGT-A has been used widely to select embryos for transfer in ICSI treatment, with the aim of improving treatment effectiveness. Whether PGT-A improves ICSI outcomes and is beneficial to the patients has remained controversial. STUDY DESIGN, SIZE, DURATION: This is a multinational, multicentre, pragmatic, randomized clinical trial with intention-to-treat analysis. Of 396 women enroled between June 2012 and December 2016, 205 were allocated to CCS of the first and second polar body (study group) as part of their ICSI treatment cycle and 191 were allocated to ICSI treatment without chromosome screening (control group). Block randomization was performed stratified for centre and age group. Participants and clinicians were blinded at the time of enrolment until the day after intervention. PARTICIPANTS/MATERIALS, SETTING, METHODS: Infertile couples in which the female partner was 36-40 years old and who were scheduled to undergo ICSI treatment were eligible. In those assigned to PGT-A, array comparative genomic hybridization (aCGH) analysis of the first and second polar bodies of the fertilized oocytes was performed using the 24sure array of Illumina. If in the first treatment cycle all oocytes were aneuploid, a second treatment with PB array CGH was offered. Participants in the control arm were planned for ICSI without PGT-A. Main exclusion criteria were three or more previous unsuccessful IVF or ICSI cycles, three or more clinical miscarriages, poor response or low ovarian reserve. The primary outcome was the cumulative live birth rate after fresh or frozen embryo transfer recorded over 1 year after the start of the intervention. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 205 participants in the chromosome screening group, 50 (24%) had a live birth with intervention within 1 year, compared to 45 of the 191 in the group without intervention (24%), a difference of 0.83% (95% CI: -7.60 to 9.18%). There were significantly fewer participants in the chromosome screening group with a transfer (relative risk (RR) = 0.81; 95% CI: 0.74-0.89) and fewer with a miscarriage (RR = 0.48; 95% CI: 0.26-0.90). LIMITATIONS, REASONS FOR CAUTION: The targeted sample size was not reached because of suboptimal recruitment; however, the included sample allowed a 90% power to detect the targeted increase. Cumulative outcome data were limited to 1 year. Only 11 patients out of 32 with exclusively aneuploid results underwent a second treatment cycle in the chromosome screening group. WIDER IMPLICATIONS OF THE FINDINGS: The observation that the similarity in birth rates was achieved with fewer transfers, less cryopreservation and fewer miscarriages points to a clinical benefit of PGT-A, and this form of embryo selection may, therefore, be considered to minimize the number of interventions while producing comparable outcomes. Whether these benefits outweigh drawbacks such as the cost for the patient, the higher workload for the IVF lab and the potential effect on the children born after prolonged culture and/or cryopreservation remains to be shown. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the European Society of Human Reproduction and Embryology. Illumina provided microarrays and other consumables necessary for aCGH testing of polar bodies. M.B.'s institution (UZBrussel) has received educational grants from IBSA, Ferring, Organon, Schering-Plough, Merck and Merck Belgium. M.B. has received consultancy and speakers' fees from Organon, Serono Symposia and Merck. G.G. has received personal fees and non-financial support from MSD, Ferring, Merck-Serono, Finox, TEVA, IBSA, Glycotope, Abbott and Gedeon-Richter as well as personal fees from VitroLife, NMC Healthcare, ReprodWissen, BioSilu and ZIVA. W.V., C.S., P.M.B., V.G., G.A., M.D., T.E.G., L.G., G.Ka., G.Ko., J.L., M.C.M., M.P., A.S., M.T., K.V., J.G. and K.S. declare no conflict of interest. TRIAL REGISTRATION NUMBER: NCT01532284. TRIAL REGISTRATION DATE: 7 February 2012. DATE OF FIRST PATIENT'S ENROLMENT: 25 June 2012.

Physical activity and maximal oxygen uptake in adults with Prader-Willi syndrome.

BACKGROUND: Prader-Willi Syndrome (PWS) is the most common genetic syndrome causing life-threatening obesity. Strict adherence to a low-calorie diet and regular physical activity are needed to prevent weight gain. Direct measurement of maximal oxygen uptake (VO2 max), the "gold standard" for assessing aerobic exercise capacity, has not been previously described in PWS. OBJECTIVES: Assess aerobic capacity by direct measurement of VO2 max in adults with PWS, and in age and BMI-matched controls (OC), and compare the results with values obtained by indirect prediction methods. METHODS AND PATIENTS: Seventeen individuals (12 males) age: 19-35 (28.6 ± 4.9) years, BMI: 19.4-38.1 (27.8 ± 5) kg/m2 with genetically confirmed PWS who exercise daily, and 32 matched OC (22 males) age: 19-36 (29.3 ± 5.2) years, BMI: 21.1-48.1 (26.3 ± 4.9) kg/m2. All completed a medical questionnaire and performed strength and flexibility tests. VO2 max was determined by measuring oxygen consumption during a graded exercise test on a treadmill. RESULTS: VO2 max (24.6 ± 3.4 vs 46.5 ± 12.2 ml/kg/min, p < 0.001) and ventilatory threshold (20 ± 2 and 36.2 ± 10.5 ml/kg/min, p < 0.001), maximal strength of both hands (36 ± 4 vs 91.4 ± 21.2 kg, p < 0.001), and flexibility (15.2 ± 9.5 vs 26 ± 11.1 cm, p = 0.001) were all significantly lower for PWS compared to OC. Predicted estimates and direct measurements of VO2 max were almost identical for the OC group (p = 0.995), for the PWS group, both methods for estimating VO2 max gave values which were significantly greater (p < 0.001) than results obtained by direct measurements. CONCLUSIONS: Aerobic capacity, assessed by direct measurement of VO2 max, is significantly lower in PWS adults, even in those who exercise daily, compared to OCs. Indirect estimates of VO2 max are accurate for OC, but unreliable in PWS. Direct measurement of VO2 should be used for designing personal training programs and in clinical studies of exercise in PWS.

Cryopreserved embryo transfer: adjacent or non-adjacent to failed fresh long GnRH-agonist protocol IVF cycle.

The optimal time to perform cryopreserved embryo transfer (CET) after a failed oocyte retrieval-embryo transfer (OR-ET) cycle is unknown. Similar clinical pregnancy rates were recently reported in immediate and delayed CET, performed after failed fresh OR-ET, in cycles with the gonadotrophin-releasing hormone (GnRH) antagonist protocol. This study compared outcomes of CET performed adjacently (<50 days, n = 67) and non-adjacently (≥50 to 120 days, n = 62) to the last OR-day of cycles with the GnRH agonist down-regulation protocol. Additional inclusion criteria were patients' age 20-38 years, the transfer of only 1-2 cryopreserved embryos, one treatment cycle per patient and artificial preparation for CET. Significantly higher implantation, clinical pregnancy and live birth rates were found in the non-adjacent group than in the adjacent group: 30.5% versus 11.3% (P = 0.001), 41.9% versus 17.9% (P = 0.003) and 32.3% versus 13.4% (P = 0.01), respectively. These results support the postponement of CET after a failed OR-ET for at least one menstrual cycle, when a preceding long GnRH-agonist protocol is used.

Prediction value of anti-Mullerian hormone (AMH) serum levels and antral follicle count (AFC) in hormonal contraceptive (HC) users and non-HC users undergoing IVF-PGD treatment.

Use of hormone contraceptives (HC) is very popular in the reproductive age and, therefore, evaluation of ovarian reserve would be a useful tool to accurately evaluate the reproductive potential in HC users. We conducted a retrospective cohort study of 41 HC users compared to 57 non-HC users undergoing IVF-preimplantation genetic diagnosis (PGD) aiming to evaluate the effect of HC on the levels of anti-Mullerian hormone (AMH), small (2-5 mm), large (6-10 mm) and total antral follicle count (AFC) and the ability of these markers to predict IVF outcome. Significant differences in large AFC (p = 0.04) and ovarian volume (p < 0.0001) were seen, however, there were no significant differences in small and total AFC or in serum AMH and FSH levels. Oocyte number significantly correlated with AMH and total AFC in HC users (p < 0.001) while in non-HC users these correlations were weaker. In HC users, the significant predictors of achieving <6 and >18 oocytes were AFC (ROC-AUC; 0.958, p = 0.001 and 0.883, p = 0.001) and AMH (ROC-AUC-0.858, p = 0.01 and 0.878, p = 0.001), respectively. The predictive values were less significant in non-HC users. These findings are important in women treated for PGD, in ovum donors and for assessing the fertility prognosis in women using HC and wishing to postpone pregnancy.

Anti-Mullerian Hormone (AMH) Determinations in the Pediatric and Adolescent Endocrine Practice.

Anti-Mullerian hormone (AMH), secreted by immature testicular Sertoli-cells, triggers the regression of male fetal Mullerian ducts. During puberty, AMH is downregulated by intratesticular testosterone. In females, AMH is secreted from granulosa cells of immature ovarian follicles from late prenatal life until menopause; serum concentration is 5-20 times lower in females than in males through lifetime. In boys, AMH determination is useful in the clinical setting as a marker of Sertoli cell function. Serum AMH is low in infants with hypogonadotrophic hypogonadism (and increases with FSH treatment), in patients with primary hypogonadism from early postnatal life and in Klinefelter syndrome from midpuberty. In boys with nonpalpable gonads, AMH determination is useful to distinguish between cryptorchidism and anorchism, as well as differentiating the dysgenetic causes of disorders of sexual development from those due to defective androgen synthesis or action. AMH can be used as a marker of sertoli/granulosa cell tumors and primary ovarian insufficiency in girls with delayed puberty, Turner Syndrome and after treatment with gonadotoxic agents.

How Many Embryos should be Transferred? The Relevance of Parity and Obstetric History.

BACKGROUND: Fertility treatments are responsible for the rise in high order pregnancies in recent decades and their associated complications. Reducing the number of embryos returned to the uterus will reduce the rate of high order pregnancies. OBJECTIVES: To explore whether obstetric history and parity have a role in the clinician's decision making regarding the number of embryos transferred to the uterus during in vitro fertilization (IVF). METHODS: In a retrospective study for the period August 2005 to March 2012, data of twin deliveries > 24 weeks were collected, including parity, mode of conception (IVF vs. spontaneous), gestational age at delivery, preeclampsia, birth weight, admission to the neonatal intensive care unit (NICU), and Apgar scores. RESULTS: A total of 1651 twin deliveries > 24 weeks were record- ed, of which 959 (58%) were at term (> 37 weeks). The early preterm delivery (PTD) rate (< 32 weeks) was significantly lower with increased parity (12.6%, 8.5%, and 5.6%, in women with 0, 1, and ≥ 2 previous term deliveries, respectively). Risks for PTD (< 37 weeks), preeclampsia and NICU admission were significantly higher in primiparous women compared to those who had one or more previous term deliveries. Primiparity and preeclampsia, but not IVF, were significant risk factors for PTD. CONCLUSIONS: The risk for PTD in twin pregnancies is significantly lower in women who had a previous term delivery and decreases further after two or more previous term deliveries. This finding should be considered when deciding on the number of embryos to be transferred in IV.

Prader-Willi syndrome can be diagnosed prenatally.

The aim of this study was to characterize the fetal phenotype of a cohort of individuals with confirmed diagnoses of Prader-Willi syndrome (PWS), a severe multi-system genetic disorder, diagnosed by a specific methylation test. We interviewed mothers of 106 individuals with PWS to obtain information about the pregnancy of their affected child. For 47 pregnancies of children younger than 10 years, we also reviewed the obstetric ultrasound and detailed obstetric history from medical records. We compared the PWS pregnancies with those of the sibling closest in age and with the general population. McNemars, Chi-square and Fisher exact tests were used for statistical analyses. Decreased fetal movements, small for gestational age (SGA), asymmetrical intrauterine growth (increased head/abdomen circumferences ratio) and polyhydramnios were found in 88%, 65%, 43%, and 34%, respectively (P < 0.001 vs. siblings and P < 0.0001 vs. the general population for all measurements). No severe morphological abnormalities were found. A combination of 2, 3, and 4 abnormalities was found in 27%, 29%, and 24% of pregnancies, respectively. Fourteen out of 15 umbilical artery Doppler studies were within the normal range (93%). The rare combination of asymmetrical intrauterine growth and polyhydramnios was found in 34% of PWS pregnancies (P < 0.0001 vs. the general population). Prenatal genetic screening for PWS by methylation testing is indicated when any combination of polyhydramnios, SGA or asymmetric intrauterine growth, with normal Doppler studies is present, particularly when asymmetrical intrauterine growth and polyhydramnios coexist.

Preimplantation genetic risk reduction: a new dilemma in the era of chromosomal microarrays and exome sequencing.

New technologies are revealing genetic variants of unknown significance (VUS), raising questions about the indications that call for preimplanation genetic diagnosis (PGD). Two couples requesting PGD for VUS are presented. The first couple requested PGD for Lynch syndrome. Whole exome sequencing identified in a healthy male with a family history of Lynch-associated tumours, a MLH1 missense variant. The variant had not been reported as pathogenic, but was predicted as damaging by algorithms. The second couple had a child diagnosed with pervasive developmental disorder and intellectual disability, carrying a microduplication on chr:Xp.22.3, and a microdeletion on chr:17q21.31. The maternally inherited X linked microduplication was also present in the mother's healthy brother and daughter, whereas the chr17 microdeletion was a de-novo event. As chromosomal microarrays and whole-exome sequencing are becoming standard tests, couples are requesting PGD for these VUS. The risk of possible genetic diseases can be reduced by carrying out PGD for uncertain findings, yet will inevitably lead to the birth of affected children despite the transfer of embryos that are not carriers of the familial variants. Findings of unknown significance demand urgent discussion and guidelines for their use as a risk-reduction measure in the preimplantation setting.

Ovarian stimulation for oocyte cryopreservation for prevention of age-related fertility loss: one in five is a low responder.

Oocyte cryopreservation for age-related fertility loss is gaining interest considering the tendency to postpone motherhood in many societies. Little is currently known about the actual efficiency of this approach. We aimed to explore ovarian response of presumably fertile women undergoing in vitro fertilization for this indication. A total of 105 women underwent 151 stimulation cycles at mean age 37.7 ± 2.4. None had known infertility. Mean daily starting FSH dose was 371 ± 110 (225-600). Mean number of mature oocytes cryopreserved at the first completed cycle was 9.7 ± 7.5 (0-43). However, 21% of started cycles were either cancelled before egg retrieval or resulted in 0-3 mature oocytes retrieved. Therefore, women considering oocyte cryopreservation for prevention of age-related fertility decline should be encouraged to perform this procedure at younger age than, preferably before 35.

[The reproductive system in Prader-Willi syndrome].

Prader-Willi syndrome (PWS) is a genetic syndrome caused by the lack of expression of imprinted genes located on paternal chromosome 15q11-q13, characterized by endocrine defects, an insatiable appetite, short stature, cognitive and behavioral difficulties and dysmorphic features. Nearly all PWS males and most PWS women show clinical and/or laboratory evidence of hypogonadism, affecting their habitus, health and quality of life. Until recently, hypogonadism in PWS was generally considered to be of centrall, hypothalamic origin. However, recent studies have shown that primary gonadal dysfunction is the major contributor to hypogonadism in this condition, while severe gonadotropin deficiency is rare. Despite clinical and laboratory evidence of hypogonadism, young adult PWS men and women have sexual and romantic interests and aspirations. Pregnancies have been reported in a few women with genetically documented PWS. Fertility has not been reported in PWS men. Recognition of these interests is essential for physicians and caregivers in order to offer proper anticipatory guidance, psychological and sex education and counseling. Individual variations in pubertal development, reproductive hormone profiles, bone-mineral density and individual appeal need to be considered when recommending sex hormone replacement in this population. Testosterone should be considered in most hypogonadal PWS males, considering possible side effects. Hormone replacement may be indicated in PWS women with decreasing bone mineral density or in PWS women who wish to have regular menses. Contraception should be considered in women with normal inhibin B levels. Hormone replacement is likely to improve bone density, quality of life and body image.