Pregnancy outcomes of prenatally diagnosed Turner syndrome: a French multicenter retrospective study including a series of 975 cases.

OBJECTIVES: The objectives of this study were to report pregnancy outcomes after prenatal diagnosis of Turner syndrome (TS) and to compare and assess termination of pregnancy rates during two periods. The intervals selected were before and after 1997 when multidisciplinary centers for prenatal diagnosis (MCPDs) were established in France. METHODS: A database of 975 cases of TS diagnosed between 1980 and 2012 was created from 21 French cytogenetics laboratories. For each case, the karyotype indication, maternal age, year of prenatal testing, sampling procedure, karyotype, associated ultrasound findings, and outcomes were recorded. RESULTS: Karyotypes were mainly performed because of abnormal sonographic findings (84%). Before 1997, there were no changes in the rate of termination (90%) of affected fetuses. After 1997, the rate fell to 80%. This decrease was mainly observed in cases of mosaicism, incidental diagnosis, and in later gestations. US abnormalities were more likely to be associated with a full 45,X karyotype. CONCLUSION: There was an evolution in the way genetic counseling was performed following prenatal diagnosis of Turner syndrome that coincided with the opening of MCPDs in France. This resulted in a decrease in the rate of termination of affected fetuses.

A French collaborative survey of 272 fetuses with 22q11.2 deletion: ultrasound findings, fetal autopsies and pregnancy outcomes.

OBJECTIVE: The 22q11.2 deletion (del22q11.2) is one of the most common microdeletions. We performed a collaborative, retrospective analysis in France of prenatal diagnoses and outcomes of fetuses carrying the del22q11.2. METHODS: A total of 272 fetuses were included. Data on prenatal diagnosis, ultrasound findings, pathological features, outcomes and inheritance were analyzed. RESULTS: The mean time of prenatal diagnosis was 25.6 ± 6 weeks of gestation. Most of the diagnoses (86.8%) were prompted by abnormal ultrasound findings [heart defects (HDs), in 83.8% of cases]. On fetal autopsy, HDs were again the most common disease feature, but thymus, kidney abnormalities and facial dysmorphism were also described. The deletion was inherited in 27% of cases. Termination of pregnancy (TOP) occurred in 68.9% of cases and did not appear to depend on the inheritance status. However, early diagnosis was associated with a higher TOP rate. CONCLUSION: This is the largest cohort of prenatal del22q11.2 diagnoses. As in postnatally diagnosed cases, HDs were the most frequently observed abnormalities. However, thymus and kidney abnormalities and polyhydramnios should also be screened for in the prenatal diagnosis of del22q11.2. Only the time of diagnosis appeared to be strongly associated with the pregnancy outcome: the earlier the diagnosis, the higher the TOP rate.

Emergency IVF for embryo freezing to preserve female fertility: a French multicentre cohort study.

STUDY QUESTION: What are the outcomes of French emergency IVF procedures involving embryo freezing for fertility preservation before gonadotoxic treatment? SUMMARY ANSWER: Pregnancy rates after emergency IVF, cryopreservation of embryos, storage, thawing and embryo transfer (embryo transfer), in the specific context of the preservation of female fertility, seem to be similar to those reported for infertile couples undergoing ART. STUDY DESIGN, SIZE, DURATION: A French retrospective multicentre cohort study initiated by the GRECOT network-the French Study Group for Ovarian and Testicular Cryopreservation. We sent an e-mail survey to the 97 French centres performing the assisted reproduction technique in 2011, asking whether the centre performed emergency IVF and requesting information about the patients' characteristics, indications, IVF cycles and laboratory and follow-up data. The response rate was 53.6% (52/97). PARTICIPANTS/MATERIALS, SETTING, METHODS: Fourteen French centres reported that they performed emergency IVF (56 cycles in total) before gonadotoxic treatment, between 1999 and July 2011, in 52 patients. MAIN RESULTS AND THE ROLE OF CHANCE: The patients had a mean age of 28.9 ± 4.3 years, and a median length of relationship of 3 years (1 month-15 years). Emergency IVF was indicated for haematological cancer (42%), brain tumour (23%), sarcoma (3.8%), mesothelioma (n = 1) and bowel cancer (n = 1). Gynaecological problems accounted for 17% of indications. In 7.7% of cases, emergency IVF was performed for autoimmune diseases. Among the 52 patients concerned, 28% (n = 14) had undergone previous courses of chemotherapy before beginning controlled ovarian stimulation (COS). The initiation of gonadotoxic treatment had to be delayed in 34% of the patients (n = 19). In total, 56 cycles were initiated. The mean duration of stimulation was 11.2 ± 2.5 days, with a mean peak estradiol concentration on the day on which ovulation was triggered of 1640 ± 1028 pg/ml. Three cycles were cancelled due to ovarian hyperstimulation syndrome (n = 1), poor response (n = 1) and treatment error (n = 1). A mean of 8.2 ± 4.8 oocytes were retrieved, with 6.1 ± 4.2 mature oocytes and 4.4 ± 3.3 pronuclear-stage embryos per cycle. The mean number of embryos frozen per cycle was 4.2 ± 3.1. During follow-up, three patients died from the consequences of their disease. For the 49 surviving patients, 22.5% of the couples concerned (n = 11) requested embryo replacement. A total of 33 embryos were thawed with a post-thawing survival rate of 76%. Embryo replacement was finally performed for 10 couples with a total of 25 embryos transferred, leading to one biochemical pregnancy, one miscarriage and three live births. Clinical pregnancy rate and live birth per couple who wanted a pregnancy after cancer were, respectively, 36% (95% CI = 10.9-69.2%) and 27% (95% CI = 6.0-61%). LIMITATIONS, REASONS FOR CAUTION: The overall response rate for clinics was 53.6%. Therefore, it is not only that patients may not have been included, but also that those that were included were biased towards the University sector with a response rate of 83% (25/30) for a small number of patients. WIDER IMPLICATIONS OF THE FINDINGS: According to literature, malignant disease is a risk factor for a poor response to COS. However, patients having emergency IVF before gonadotoxic treatment have a reasonable chance of pregnancy after embryo replacement. Embryo freezing is a valuable approach that should be included among the strategies used to preserve fertility. STUDY FUNDING/COMPETING INTEREST(S): No external funding was sought for this study. None of the authors has any conflict of interest to declare.

Is intracytoplasmic morphologically selected sperm injection (IMSI) beneficial in the first ART cycle? a multicentric randomized controlled trial.

Intracytoplasmic morphologically selected sperm injection (IMSI), by selecting spermatozoa at high magnification improves the outcome of intracytoplasmic sperm injection (ICSI) mainly after several failures. However, only few monocentric randomized studies are available and they do not analyse results as a function of sperm characteristics. In 255 couples attempting their first assisted reproductive technology (ART) attempt for male infertility (motile sperm count <1×106 after sperm selection, but at least 3×106 spermatozoa per ejaculate to allow a detailed analysis of sperm characteristics), a prospective randomized trial was performed to compare the clinical outcomes of IMSI and ICSI and to evaluate the influence of sperm characteristics on these outcomes. IMSI did not provide any significant improvement in the clinical outcomes compared with ICSI neither for implantation (24% vs. 23%), nor clinical pregnancy (31% vs. 33%) nor live birth rates (27% vs. 30%). Moreover, the results of IMSI were similar to the ICSI ones whatever the degree of sperm DNA fragmentation, nuclear immaturity and sperm morphology. These results show that IMSI instead of ICSI has no advantage in the first ART attempts. However, this does not rule out IMSI completely and more randomized trials must be performed especially regarding patients carrying severe teratozoospermia, or high sperm DNA fragmentation levels or having previous ICSI failures.

Assisted oocyte activation overcomes fertilization failure in globozoospermic patients regardless of the DPY19L2 status.

STUDY QUESTION: Does DPY19L2 status influence intracytoplasmic sperm injection (ICSI) outcomes with or without assisted oocyte activation (AOA)? SUMMARY ANSWER: DPY19L2 mutations have no major impact on ICSI outcomes in globozoospermic patients. WHAT IS KNOWN ALREADY: Globozoospermia is a rare and severe teratozoospermia characterized by round-headed spermatozoa lacking an acrosome. Recently, it has been shown that DPY19L2 mutations can be found in a vast majority of, but not all, globozoospermic patients (66.7%). These patients suffer from primary infertility due to a sperm-related oocyte activation deficiency secondary to the absence of an acrosome that can be overcome by the application of AOA. STUDY DESIGN, SIZE, DURATION: Cohort study, retrospective, 34 patients, 83 cycles. MATERIALS, SETTING, METHODS: Clinical and biologic data were collected from 29 patients mutated for DPY19L2 and 5 non-mutated patients. In total, 35 ICSI cycles using AOA and 48 conventional ICSI cycles were included in the analysis. Patients were divided into groups according to whether or not they were mutated for DPY19L2 and whether or not they received AOA. MAIN RESULTS AND THE ROLE OF CHANCE: Regardless of the presence of a DPY19L2 mutation, the fertilization rates with AOA are restored to normal when compared with conventional ICSI in our cohort of globozoospermic patients. Also, when performing ICSI plus AOA, both mutated and non-mutated cases have similar positive hCG rates, ongoing pregnancy rates and live birth rates per transfer. On the contrary, the fertilization rate in globozoospermic patients using conventional ICSI is correlated with the presence of a DPY19L2 mutation, with slightly better, although still very low, fertilization rates in patients carrying a DPY19L2 mutation. Nevertheless, when performing conventional ICSI, both mutated and non-mutated cases have similar very low positive hCG rates, ongoing pregnancy rates and live birth rates per transfer. LIMITATIONS: A limitation of this study is the low number of included non-mutated cases. WIDER IMPLICATIONS OF THE FINDINGS: We propose a pathway for the clinical management of globozoospermic patients depending on the phenotype that includes several diagnostic and therapeutic steps. STUDY FUNDING/COMPETING INTEREST(S): None.

[Conventional IVF versus ICSI in sibling oocytes: a French experience analysis for BLEFCO]. / FIV conventionnelle versus ICSI sur une même cohorte ovocytaire: analyse de l'expérience française pour les BLEFCO.

Assisted Reproductive Techniques (ART) separating oocytes in sibling oocytes treated either by conventional IVF or ICSI is called mid-IVF/ICSI. We sum up here 487 attempts of this kind from six French ART centers. The mid-IVF/ICSI technique was performed in 5.6% of cases. The fertilization rate by micro-injected oocytes was significantly higher (P<0.01) than oocytes inseminated conventionally, 72.6% versus 53.4%. A failure of fertilization was observed only in mid-IVF in 21.6% of cases, which prevented a complete fertilization failure when we decided to propose to the couples concerned the mid-IVF/ICSI technique. Conversely, in 75.2% of cases, fertilization was found for the two batches of oocytes. The overall pregnancy rate has improved since the use of the mid-IVF/ICSI technique (33.1% versus 28.9%, P=0.013) and the fertilization failures decreased (10.4% versus 14.3%, P=0. 019). The pregnancy rate in only mid-IVF/ICSI cases is very high at 39.8% but for a selected population. The indications for mid-IVF/ICSI remain to be clarified especially with regard to male and idiopathic indications.

[Female fertility preservation in autoimmune diseases: possibilities and practises in France]. / Demande de préservation de la fertilité chez la femme en cas de maladie auto-immune: possibilités et pratiques en France.

Cancer is not the only disease where the question of the female fertility preservation is asked. In autoimmune diseases, alkylating agents are also used and it is now established that 20 g as a cumulative dose of cyclophosphamide is associated with premature ovarian failure in 50% of 20-year-old patients. Several strategies are discussed and offered to these patients to prevent the ovarian failure: GnRH agonist treatment, in vitro fertilization and embryos cryopreservation, oocytes cryopreservation and ovarian cortex cryopreservation. These techniques might also be associated one with the other. A survey was conducted in France in order to assess the practices realised in these diseases. Four centres were asked for these diseases, concerning 17 patients (mean age: 26.2 +/- 1.8 SEM [15-43]) and systemic lupus erythematosus was the most frequent disease (7/17). Ovarian cortex cryopreservation was realised for 6 patients. Embryos or oocytes cryopreservation was realised for 2 patients including one where ovarian cortex cryopreservation was associated. In 10 cases, considering the treatment and the patient's wish no fertility preservation was realised. Female fertility preservation in autoimmune diseases is a difficult question and a national registry, such as the one conducted by the GRECOT, can help to answer this question.

Prenatal diagnosis in monozygotic twins with Down syndrome who had different phenotypes.

We report the case of monozygotic (MZ) male twin fetuses with different Down syndrome (DS) phenotypes. Prenatal fetal sonography showed a bichorial biamniotic pregnancy with increased nuchal translucency in twin A and a cervical cystic hygroma and heart defect in twin B. Cytogenetic analysis performed after double amniocentesis showed free and homogeneous trisomy 21 in both twins. Monozygosity was confirmed by molecular analysis. The pregnancy was terminated at 17 weeks of gestation (WG). Postmortem analysis confirmed the phenotypic discordance. To our knowledge, this is the first reported prenatal diagnosis of MZ male twins with different Down syndrome phenotypes but identical karyotypes. We discuss the mechanisms involved in phenotypic discordance of monozygotic twins and particularly the role of environmental factors.

[Male infertility: management strategies]. / Infertilité masculine: stratégie de la prise en charge.

Although the objective of the urologist is to correct the factors of male infertility and to favour natural procreation, the strategy must consider also the couple and the female aspects of infertility. Some types of male infertility require specific treatment. In severe cases, recent advances in medical assistance to procreation have changed the prognosis of male infertility. Pregnancy can be obtained by the means of gamet manipulation and spermatozoid selection. Nevertheless, such techniques expose to genetic disorders transmission. Subsequently, genetic assessment is required during male infertility management, especially for difficult cases.

[Male infertility: definition and pathophysiology]. / Infertilité masculine: définition et physiopathologie male infertility: definition and pathophysiology.

Male infertility is present in 50% of couple infertility. Diagnosis of infertility requires methodical and rigorous approach based upon knowledge of the pathophysiology and the causes of infertility.

[Psychometric properties of the Euroqol measure in patients with muscular dystrophy]. / Qualités métrologiques de l'outil de mesure Euroqol sur un échantillon de personnes myopathes.

OBJECTIVE: To analyse patient-reported outcome measures and to assess acceptability, test-retest reliability and responsiveness of the Euroqol measure (EQ), a conceptual health-related quality-of-life measure (HRQoL), for patients with muscular dystrophy. MATERIALS AND METHOD: One hundred and four consecutive outpatients completed the EQ in Reims university hospital between April 2002 and February 2005, and 60 patients were followed over 1 year. The acceptability of the EQ-5D and EQ-EVA measures was assessed by using the completion rate per dimension as an indicator; test-retest reliability was assessed with kappa and Spearman coefficients for qualitative data and the intraclass coefficient correlation (ICC) for quantitative data. Over the year, EQ-EVA score responsiveness was calculated according to the standardised response of the mean (SRM). RESULTS: Participation rate (96.3%) and EQ-5D completion rates were excellent, between 95.2 and 100%. Test-retest reliability after 15+/-7 days was excellent for the autonomy domain (kappa coefficient=0.81) and moderate for the other dimensions. EQ-EVA score stability was satisfactory (ICC=0.72). Global perceived health (EQ-EVA) was not associated with level of dependency but was associated with pain domain scores. EQ-EVA responsiveness was moderate (effect size=0.6) in the patients with a change in health status over 1 year and in reference to the relevant SF-36 item. CONCLUSION: EQ is a well-accepted tool for measuring HRQoL in this group of patients with muscular dystrophy. The prognostic interest of these subjective measures has yet to be demonstrated; however, these measures provide interesting additional information.

[Assessment of male infertility]. / Infertilité masculine: bilan.

The diagnosis of male infertility requires methodical approach which is primarily clinical, aimed at identifying all potential factors. Biological and radiological assessments allow diagnosis confirmation, and evaluation of both prognosis and therapeutic strategy.

[Kartagener's syndrome and infertility: observation, diagnosis and treatment]. / Syndrome de Kartagener et stérilité: observation, diagnostic et prise en charge.

Primary ciliary dyskinesia is a rare etiology of sterility in man (prevalence between 1/6000 and 1/40000). Kartagener's syndrome is an autosomal recessive disorder, characterized by total or partial dysfunction of the ciliary or flagellated cells. This syndrome associates situs inversus, sinusitis, bronchiectasis and occasionally sterility in males. We report a case of immotile cilia syndrome with male infertility and compare the data with four other couples reported in the literature (two couples in Germany, two in the United States). The difficulty is to select an alive sperm cell for ICSI.

Chromosomal factors of infertility in candidate couples for ICSI: an equal risk of constitutional aberrations in women and men.

To assess the frequency of chromosomal aberrations in French candidates for intracytoplasmic sperm injection (ICSI), and to explore the existence of a female chromosomal factor in some cases of couple infertility, a collaborative retrospective clinical and cytogenetic study was performed, launched by the Association des Cytogénéticiens de Langue Franciaise (ACLF). The karyotypes of 3208 patients [2196 men (68.4%), 1012 (31.6%) women] included in ICSI programmes over a 3-year period in France were collected. A total of 183 aberrant karyotypes was diagnosed, corresponding to an abnormality frequency of 6.1% (134/2196) for men and 4.84% (49/1012) for women. The following frequencies of abnormalities were observed respectively for men and women: 1.23% (n = 27) and 0.69% (n = 7) for reciprocal translocations, 0.82% (n = 18) and 0.69% (n = 7) for Robertsonian translocations, 0.13% (n = 3) and 0.69% (n = 7) for inversions, 3.32% (n = 73) and 2.77% (n = 28) for numerical sex chromosome aberrations, and 0.59% (n = 13) and 0% for other structural aberrations. Among the male patients of this latter group, 0.40% (n = 9) had a Y chromosome abnormality. Among the male patients with numerical sex chromosome abnormalities, 2.23% (n = 49) were 47,XXY, 0.32% (n = 7) were 47,XYY, and 0.77% (n = 17) had a mosaicism for numerical sex chromosome anomalies. All the female patients with sex chromosome abnormalities (2.77%, n = 28) had mosaicism for numerical sex chromosome anomalies. Even if these cases-the significance of which was sometimes questioned-were disregarded in the analysis, 2.08% (21/1012) of abnormal karyotypes remained in women. An overall increased frequency of chromosomal aberrations was found, and this confirmed that in some cases of poor reproductive outcome there may be a contribution of maternal chromosome aberrations. Indeed, the existence of a chromosome abnormality in the female partner was associated with the group of infertile men in which there was no apparent cause of infertility.

Normal vas deferens in fetuses with cystic fibrosis.

PURPOSE: Infertility in patients with cystic fibrosis has been attributed to the congenital bilateral absence of the vas deferens. We studied the vas deferens in cystic fibrosis fetuses to determine whether this condition could be related to primary developmental abnormalities or to secondary obstructions. MATERIALS AND METHODS: Two cystic fibrosis male fetuses, with deltaF508+/+ and deltaF508/G542X genetic mutations, were examined after abortion at 12 and 18 weeks, respectively. The lumens of the vas deferens were measured using histological serial sections in the 2 cystic fibrosis fetuses and in 6 control fetuses. RESULTS: The vas deferens of cystic fibrosis and control fetuses showed a similar development. The diameters of the lumens were smaller at the extremities than in the medial part of the duct in cystic fibrosis and in control fetuses. No epithelial necrosis, focal dilatation or fibrous stenosis could be detected at any age. Secretions were observed in the lumen of the vas deferens of the homozygous fetus, but no obstruction was detected. CONCLUSIONS: The normal organogenesis of the vas deferens, the presence of secretions filling the lumen of the deltaF508 +/+ fetus and the high proportion of normal ducts reported in prepubertal male cystic fibrosis patients suggest a mechanism of luminal obstruction resulting in duct atrophy and infertility in male adults with cystic fibrosis. The term "atresia" or "inspissation" should be used in cases of congenital bilateral absence of the vas deferens associated with cystic fibrosis mutations, whereas the term "agenesis" should be used for cases of congenital bilateral absence of the vas deferens associated with urogenital abnormalities in which regional defects occur during organogenesis.

Fryns syndrome phenotype and trisomy 22.

Trisomy 22 was detected in a 32-week-old fetus born to an overweight mother with hypertension. Severe intrauterine growth retardation was associated with phenotypic manifestations of Fryns syndrome: diaphragmatic hernia, facial defects, and nail hypoplasia with short distal fifth phalanges. This is the second report of congenital diaphragmatic hernia in trisomy 22. This case demonstrates the importance of karyotyping malformed fetuses or newborns, even if a nonchromosome syndrome seems identifiable on clinical grounds. To date, at least 10 cases of Fryns syndrome have been reported without chromosome analysis.