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STUDY QUESTION Is there a relationship between karyotype abnormalities in fetuses and children conceived by ICSI and their father’s semen parameters? SUMMARY ANSWER The de novo chromosomal abnormality rate in pre- and postnatal karyotypes of ICSI offspring was higher than in the general population and related to fathers’ sperm parameters. WHAT IS KNOWN ALREADY Several studies have reported a higher rate of de novo chromosomal anomalies in ICSI fetuses but recent data from large cohorts are limited. Overall, reported prevalences of non-inherited karyotype aberrations are increased in fetuses conceived after ICSI and vary between 1.6% and 4.2%. Only a few studies focus on the relation between karyotype anomalies in ICSI offspring and semen parameters of their fathers. Furthermore, an increased incidence of abnormal karyotypes in ICSI neonates has been described, but the rates vary widely across studies. STUDY DESIGN, SIZE, DURATION We report on karyotype results from prenatal testing by means of chorionic villus sampling and amniocentesis and results from postnatal blood sampling in offspring conceived by ICSI in a single center. Ongoing pregnancies resulting from an oocyte retrieval between January 2004 and December 2012 and after transfer of fresh ICSI embryos obtained using ejaculated or non-ejaculated sperm (fresh or frozen-thawed) were considered. Pregnancies following frozen embryo transfer, oocyte or sperm donation, IVF, preimplantation genetic testing and IVM were excluded. All abnormal prenatal results after sampling are reported irrespective of the outcome of the pregnancy. PARTICIPANTS/MATERIALS, SETTING, METHODS From the 4816 ongoing ICSI pregnancies, information on pregnancy outcome was available for 4267 pregnancies. Prenatal testing was performed in 22.3% of the pregnancies, resulting in a diagnosis in 1114 fetuses. A postnatal karyotype was obtained in 29.4% of the pregnancies in which no invasive prenatal diagnosis was performed, resulting in a total of 1391 neonates sampled. The prevalence of chromosomal anomalies according to maternal age and semen quality was analyzed with logistic regression. For definitions of normal semen quality, the World Health Organization reference values for human semen characteristics were adopted. MAIN RESULTS AND THE ROLE OF CHANCE An abnormal fetal karyotype was found in 29 singletons and 12 multiples (41/1114; 3.7%; 95% CI 2.7–4.9%): 36 anomalies were de novo (3.2%; 95% CI 2.3–4.4), either numerical (n = 25), sex (n = 6) or structural (n = 5), and five were inherited. Logistic regression analysis did not show a significant association between maternal age and a de novo chromosomal fetal abnormality (odds ratio (OR) 1.05; 95% CI 0.96–1.15; P = 0.24). In all but one case, fetuses with an abnormal karyotype were conceived by ICSI using ejaculated sperm. Abnormal karyotypes were found in 14 (1.0%; 95% CI 0.6–1.7) out of 1391 postnatal samples of children born after ICSI who were not tested prenatally: 12 were de novo anomalies and two were inherited balanced karyotypes. The 14 abnormal karyotypes were all found in children born after ICSI using ejaculated sperm. The odds of a de novo karyotype aberration increased with maternal age when combining pre- and postnatal data (OR 1.11; 95% CI 1.04–1.19). A higher rate of de novo chromosomal abnormalities was found in fetuses and children of couples with men having a sperm concentration LIMITATIONS, REASONS FOR CAUTION We cannot exclude that the observation of a higher prevalence of karyotype anomalies in ICSI offspring compared to literature data in the general population is due to enhanced surveillance after ART given the lack of a control group. Although we did not find more chromosomal anomalies after ICSI with non-ejaculated sperm, the small numbers do not allow firm conclusions. WIDER IMPLICATIONS OF THE FINDINGS The observed increased risk of a de novo karyotype anomaly after ICSI conception in couples with poor sperm warrants continued counseling toward prenatal testing. The current and widespread use of innovative non-invasive prenatal testing will result in larger datasets, adding to a balanced estimation of the prevalence of karyotype anomalies in ICSI offspring. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by the Methusalem grants issued by the Vrije Universiteit Brussel. All authors declared no conflict of interest related to this study. TRIAL REGISTRATION NUMBER N/A

Preimplantation genetic testing-human leukocyte antigen '(PGT-HLA) only' refers to the HLA typing of single or few cells biopsied from in vitro fertilized preimplantation embryos. The aim of the procedure is to establish a pregnancy, in which the fetus is HLA compatible with an affected sibling in need of a hematopoietic stem cell transplantation (HSCT). During PGT-M-HLA, the identification of a HLA-compatible embryo is combined with the detection of mutation(s) underlying immunodeficiencies and hemoglobinopathies. We report a combined retrospective and prospective cohort analysis of PGT-(M-)HLA procedures carried out from 1998 until 2017, with follow-up of transplantations to 2019. During the study period, 234 couples from 22 countries were invited for a multidisciplinary consultation. Two couples were rejected and 70 couples declined (various reasons), leaving 162 couples for which 414 clinical cycles were carried out. Cleavage stage biopsy followed by single-cell multiplex PCR for short tandem repeat-based haplotyping was applied in most cases (98.7%). The diagnostic efficiency was high (94.8%) but only 16.5% of the embryos was genetically suitable for transfer. Fresh and frozen-thawed embryo transfer resulted in 67 clinical pregnancies, 63 deliveries, and 74 live births, of which 60 children were HLA compatible. This yielded a live birth delivery rate of 30.3% per transfer. Information on neonatal characteristics of the matching PGT-(M-)HLA children showed reassuring outcomes. So far, HSCT was carried out successfully for 25 out of 26 cases. In conclusion, our data show that PGT-(M-)HLA is a valuable procedure: the high complexity and limited delivery rate are balanced by the successful HSCT outcome and the positive impact on families.

STUDY QUESTION Does Day 3 embryo biopsy for pre-implantation genetic testing for monogenic (PGT-M) and structural chromosomal aberrations (PGT-SR) affect body composition and blood pressure readings of 6-year-old singletons? SUMMARY ANSWER This study of 87 PGT-M and PGT-SR conceived singletons showed no differences in anthropometric measurements and blood pressure readings in comparison with a matched cohort of peers born after ICSI without embryo biopsy. WHAT IS KNOWN ALREADY While neonatal outcomes after PGT conception have been found comparable to those after ICSI without embryo biopsy, only a few studies have reported outcomes after PGT at older ages. Moreover, embryo biopsy is also applied in couples who opt for PGT-M and PGT-SR and hence are not necessarily infertile. Health parameters and in particular body composition data in this group of children are lacking. STUDY DESIGN, SIZE, DURATION This single-centre matched-pair cohort study evaluated body composition of 6-year-old children born after fresh blastocyst embryo transfer with or without embryo biopsy performed at Day 3 for the purpose of PGT-M and PGT-SR. For each child born after embryo biopsy, a singleton born after transfer of a fresh ICSI embryo at the blastocyst stage and reaching the age of 6 years between May 2011 and June 2017 was matched as closely as possible for gender, age, maternal educational level and birth order. PARTICIPANTS/MATERIALS, SETTING, METHODS Anthropometry (weight, height, BMI, skinfold thickness, waist and mid-upper arm circumference) and blood pressure readings in a longitudinally followed cohort of 87 singletons conceived by PGT-M and PGT-SR and a pairwise matched sample of 87 children conceived by ICSI are described. Results are adjusted for current, neonatal and parental characteristics. MAIN RESULTS AND THE ROLE OF CHANCE From the 124 eligible PGT-M and PGT-SR families, 110 could be reached of whom 23 refused and 87 (87/110 = 79%) participated. All anthropometric measurements, including z-scores of BMI, waist and mid-upper arm circumference, were comparable between the PGT-M and PGT-SR (−0.23; 0.27; 0.17, respectively) and ICSI (−0.29; 0.11; 0.11, respectively) groups (all P > 0.05). Furthermore, indices of peripheral (triceps) and central (subscapular) adiposity derived from skinfold thickness were comparable (PGT-M and PGT-SR: 14.7 mm; 11.6 mm and ICSI: 15.5 mm; 11.5 mm) as well as the percentage total body fat mass derived from these (PGT-M and PGT-SR: 13.7% and ICSI: 13.9%) (all P > 0.05). Z-scores for blood pressure were also comparable between the PGT and ICSI groups (all P > 0.05). Results did not change when adjusted for neonatal (birthweight, birth order), current (age) and parental (smoking during pregnancy, parental BMI) characteristics. Hospitalization rate and surgical intervention rate were not different for PGT-M and PGT-SR children compared to matched peers born after ICSI. LIMITATIONS, REASONS FOR CAUTION Although our study describes the largest cohort of singletons born after embryo biopsy worldwide, we were only able to detect moderate differences in anthropometrics and blood pressure with our sample size. WIDER IMPLICATIONS OF THE FINDINGS Although Day 3 embryo biopsy followed by blastocyst transfer is not associated with adverse outcomes regarding anthropometry and blood pressure, future studies should focus on outcomes in children born after trophectoderm biopsy and/or transfer of warmed embryos after vitrification. STUDY FUNDING/COMPETING INTEREST(s) This study was supported by Methusalem grants and by grants from Wetenschappelijk Fonds Willy Gepts; all issued by the Vrije Universiteit Brussel (VUB). All co-authors, except M.B. declared no conflict of interest. M.B. has received consultancy fees from MSD, Serono Symposia and Merck. The Universitair Ziekenhuis Brussel (UZ Brussel) and the Centre for Medical Genetics have received several educational grants from IBSA, Ferring, Organon, Shering-Plough, Merck for establishing the database for follow-up research and organizing the data collection.

Introduction: The effect of in vitro fertilization (IVF) on neurodevelopmental outcome is unclear. Probably, IVF does not affect traditional measures of neurological development in infancy, but little is known on long-term effects. Recently a new video-based instrument to evaluate neuromotor development was developed. The Infant Motor Profile (IMP) evaluates neuromotor condition in infants in terms of the quality of spontaneous motor behaviour. The IMP does not only assess traditional neuromotor domains, such as performance, symmetry and movement fluency, but also two novel domains: variation and variability. Movement variation denotes the size of the child's movement repertoire. Previous studies demonstrated that reduced movement variation is associated with early lesions of the periventricular white matter and - more generally - reflects the integrety of cortical connectivity. In addition, reduced variation during infancy is associated with neurodevelopmental disorders in later life and reduced intelligence at school age. Variability denotes the child's ability to select from the repertoire of movements the strategy that suits the situation best. In this prospective, assessor-blinded cohort study, we address the question whether ovarian hyperstimulation and/or the in vitro procedure affect movement variation during infancy. Material and Methods: Singletons born following IVF with conventional controlled ovarian hyperstimulation (COH-IVF, n = 68), following IVF in a modified natural cycle (MNC-IVF, n = 57) and following natural conception born to subfertile couples (Sub-NC, n = 90) were assessed with the IMP at 4, 10 and 18 months. The assessment resulted in a total IMP score and 5 domain scores: variation (i.e. the size of movement repertoire), variability (i.e. the ability to select motor strategies), symmetry, fluency and performance. Primary outcome was the domain score variation. Outcome variables were analyzed with a mixed effects model. Results: The mixed model indicated an overall effect of treatment on variation (p Conclusions: The preliminary data suggest that ovarian hyperstimulation may be associated with reduced movement variation in infancy. These findings stress the need to carefully monitor neurodevelopment in IVF offspring.

Study question Does the type of in vitro culture medium or the duration of in vitro culture influence singleton birthweight after IVF/ICSI treatment? Summary answer In a comparison of two culture media, neither the medium nor the duration of culture (Day 3 versus Day 5 blastocyst transfer) had any effect on mean singleton birthweight. What is known already Previous studies indicated that in vitro culture of human embryos may affect birthweight of live born singletons. Both the type of culture medium and the duration of culture may be implicated. However, these studies are small and report conflicting results. Study design, size, duration A large retrospective analysis was performed including all singleton live births after transferring fresh Day 3 or Day 5 embryos. IVF and ICSI cycles performed between April 2004 and December 2009 at a tertiary care centre were included for analysis. Participants/materials, setting, methods A total of 2098 singleton live births resulting from singleton pregnancies were included for analysis. Two different sequential embryo culture media were concurrently used in an alternating way: Medicult (n = 1388) and Vitrolife (n = 710). Maternal age, maternal and paternal BMI, maternal parity, maternal smoking, main cause of infertility, cycle rank, stimulation protocol, method of fertilization (IVF or ICSI), time in culture and number of embryos transferred were taken into account. Embryo transfers were performed either on Day 3 (n = 1234) or on Day 5 (n = 864). Singleton birthweight was the primary outcome parameter. Gestational age and gender of the newborn were accounted for in the multiple regression analysis. Main results and the role of chance No significant differences in mean singleton birthweight were observed between the two culture media: Medicult 3222 g (±15 SE) and Vitrolife 3251 g (±21 SE) (P = 0.264). The mean singleton birthweight was not different between Day 3 embryo transfers (3219 ± 16 g) and Day 5 blastocyst transfers (3250 ± 19 g; P = 0.209). Multiple regression analysis controlling for potential maternal, paternal, treatment and newborn confounders confirmed the non-significant differences in mean singleton birthweight between the two culture media. Likewise, the adjusted mean singleton birthweight was not different according to the duration of in vitro culture (P = 0.521). Limitations, reasons for caution The conclusions are limited by its retrospective design; however, the two different sequential culture systems were used in an alternating way during the same time period. Pregnancy-associated factors possibly influencing birthweight (such as diabetes, hypertension, pre-eclampsia) were not included in the analysis. Wider implications of the findings This large retrospective study does not support earlier concerns that both the type of culture medium and the duration of embryo culture influence singleton birthweight. However, a continuous surveillance of human embryo culture procedures (medium type, culture duration and other culture conditions) should remain a priority within assisted reproduction technology. Study funding/competing interests None.

Charles Edouard Brown-Sequard was an influential nineteenth-century neuroscientist who studied numerous areas of neuroanatomy and neurophysiology. His erratic behavior and extensive moving from country to country led to a fluctuating rhythm of scientific work. His most long-lasting contribution was his historic description of the clinical syndrome of spinal cord hemisection.

We report a case of a patient with congenital aortic stenosis previously repaired using the Ross procedure, who presented to our unit for urgent caesarean delivery. Management was complicated by moderate residual cardiac disease and the presence of a suprapubic femoro-femoral crossover graft. Following application of five-lead electrocardiogram and invasive blood pressure monitoring, anaesthesia was induced via combined spinal-epidural with epidural volume extension. A high transverse surgical approach avoided the course of the vascular graft, while further precautions included the immediate availability of vascular surgeons and cell salvage. Our anaesthetic technique was tailored to minimise disruption to cardiovascular function, and in particular to limit regurgitant flow across the pulmonary valve. This case highlights the value of early identification of high-risk parturients and multidisciplinary involvement at delivery. Risk stratification in the patient with grown-up congenital heart disease is based upon timely evaluation of the underlying congenital pathology, surgical history and subsequent functional status.

Gonadotrophin releasing hormone analogues (GnRH-A) suppress ovarian activity resulting in lowering of plasma oestrogens and androgens of ovarian origin, thus reducing androgen drive to target organs in the skin. They may be of value in the treatment of hirsuties. Sixteen female patients with mild idiopathic hirsuties and normal menstrual cycles were studied. Patients received depot implants of GnRH-A (goserelin) at 4-weekly intervals for 6 months initiated in early follicular phase as well as a single oestradiol implant at the time of the first goserelin implant. Hair measurements, by a global scoring system and microscopy (hair diameter, growth rate and presence of medulla), sebum excretion rates, and measurements of circulating testosterone, sex hormone binding globulin, and free androgen index were made at 8-weekly intervals throughout the trial. The treatment was well tolerated. Seven patients had amenorrhoea and the remaining nine had reduced menstrual bleeding. Only one patient complained of mild flushing. Patients did not notice significant improvement over the active study period. There was a 10-15% fall in sebum excretion rate compared with baseline during the treatment period (week 8 to 24) with a rebound 8 weeks after the last treatment, but these changes did not reach statistical significance. There was no consistent change in hair diameter or hair growth rate or in the numbers of hairs in which the medulla was intact, partially present or absent. There was a significant fall in Ferriman and Gallwey hirsuties score during the treatment period (p < 0.05). The study demonstrated that although the GnRH-A caused suppression of testosterone and free testosterone index, this effect was not sufficient to influence hair growth rate or hair diameter in a group of patients with mild idiopathic hirsuties. (J Dermatol Treat (1991) 1: 289-292)

A 21-year-old primigravida underwent caesarean section at term for failure-to-progress beyond 9 cm. The uterus was exteriorised and a right-sided lateral extension of the uterine incision was repai...

Babies born after in vitro fertilisation (IVF) are increasing in number, and, although these babies are considered as very precious, no data are available regarding their risk for sudden infant death or apnoea. To evaluate the respiratory maturity of IVF babies, we evaluated the incidence of apnoea during an 8-h polysomnography in 50 consecutively presented IVF babies and in a group of 50 unselected naturally conceived babies. All infants were in good health and matched for term (born > 38 weeks of gestation), birth weight, sex and age at the time of investigation (6-11 weeks post term, median 8.0). There were 24 twins in the IVF and 6 twins in the control group. The incidence of obstructive and isolated central apnoea was comparable in the IVF and control group. However, IVF babies had significantly more periodic breathing episodes than control babies (median 2.30 (range 0-15.30) in IVF, and 1.02 (range 0-11.2) in control babies; P < 0.01). This difference was not related to the higher number of twins in theIVF group. Single IVF babies had significantly more short central apnoeas (5-10 s) than IVF twins (5-10 s) (mean 38.80 +/- 18.63 and 22.33 +/- 13.35; P < 0.001). This difference between single and twin babies was not found in the control group. Conclusion: IVF babies have more periodic breathing episodes indicating an immature respiratory pattern than normally conceived babies.

The present report covers the results of a 26-month period in which 1275 consecutive treatment cycles by intracytoplasmic sperm injection (ICSI) were performed in 919 couples. These couples were afflicted with male factor infertility and had had at least one previous failed conventional in vitro fertilization (IVF) treatment cycle. In other couples, the husband had semen parameters incompatible with conventional IVF or suffered from excretory azoospermia which required microsurgical epididymal sperm aspiration or testicular sperm retrieval. Overall, the 2 pronuclear (PN) fertilization rate was 47.7% per retrieved oocyte-cumulus complex and 66.4% per successfully injected metaphase II oocyte. Embryo transfer was performed in 90.8% of started cycles and 362 clinical pregnancies were recorded, giving a clinical pregnancy rate of 28.4% per started cycle or 31.3% per transfer. In addition, updated results on the outcome of pregnancies after microassisted fertilization are presented. As of 30 August 1994, 416 children have been born. Although 16 major congenital malformations have been observed (3.9%), there appears to be no reason for serious concern as regards the occurrence of major congenital anomalies after ICSI.

Hypophosphatasia is a rare inherited disorder characterized by defective bone mineralization and deficiency of serum and tissue liver/bone/kidney tissue alkaline phosphatase (L/B/K ALP) activity. We report here the characterization of tissue-nonspecific alkaline phosphatase (TNSALP) gene mutations in a series of 11 families affected by various forms of hypophosphatasia. Nineteen distinct mutations were found, 7 of which were previously reported. Eleven of the 12 new mutations were missense mutations (Y11C, A34V, R54H, R135H, N194D, G203V, E218G, D277Y, F310G, A382S, V406A), the last one (998-1G>T) was a mutation affecting acceptor splice site.

Abstract #1042 Background: In a major proportion of breast cancer patients with a strong familial cancer history no BRCA1 or BRCA2 mutations are detected which prompted us to explore other proteins on the BRCA1/2 pathway. Previously we have identified BARD1 (De Brakeleer et al, SABC 2006) as a rare high penetrance breast cancer predisposing gene. Nucleophosmin (NPM1) is a multifunctional protein that is ubiquitylated and stabilized by the BRCA1-BARD1 complex and thus is part of the BRCA1 pathway. Somatic protein truncating mutations in NPM1 are frequent events in acute myeloid leukemia (AML). Aim: This study was aimed at determining whether NPM1 germline mutations may contribute to the breast cancer predisposition in families where no BRCA1 or BRCA2 mutation is found. Methods: NPM1 mutation analysis was performed on genomic DNA extracted from blood of 198 breast cancer patients with strong indications for a hereditary form of the disease and 110 controls. All the 11 exons of the NPM1 gene were separately amplified by PCR. Since a high number of processed NPM1 pseudogenes are dispersed throughout the human genome, PCR primers had to be designed carefully. The PCR products were subsequently analyzed by denaturing gradient gel electrophoresis (DGGE) and when an abnormal migration pattern occurred, sequencing analysis was performed to determine the exact nucleotide-sequence alteration which was verified against the pseudogene sequences. Results: Out of the six novel sequence variations, only one occurred in an exon: a duplication of thymidine located in the 3' non-coding sequence of exon 12 (c.1042dupT). The remaining 5 variants were located in intron sequences close to the exon borders. Two variants flanking exon7 (c.460-31G>A and c.524+42G>A) were always linked, and occurred at the same high frequency in breast cancer patients and controls. Two intron sequence variants were only found in one patient. One was a duplication of a sequence in intron 8 (c.582+52dupT) and the other a sequence deletion in intron 3 (c.139-9delT). One sequence variation located close to exon 11 (c.771-46C>A) was found in 7 familial breast cancer patients in 4 high incidence families but not in unaffected family members and in none of the control samples. This mutation leads to an alternative splicing of the NPM1 mRNA and is predicted to modify the carboxyterminal end of the protein, removing a nucleolar locating signal. Discussion: A germline mutation in NPM1 was found only in familial breast cancer cases. This mutation may result in the synthesis of a C-terminal truncated NPM1 protein conferring high susceptibility to breast cancer. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1042.

EDITOR, - As a Frenchman, I was delighted to read the article by Raymond Hierons commemorating the 100th anniversary of the death of Jean-Martin Charcot.1 Yet, as a rheumatologist, I was surprised that a large piece of Charcot's work was not mentioned. His medical thesis was devoted to rheumatoid arthritis, and in his famous book Lecons Cliniques sur les Maladies des Vieillards he is credited with the first description of both rheumatoid pericarditis and hand deformations. The latter is still quoted in recent rheumatology textbooks. As Charcot's links with Britain are the focus of Hieron's article, it is interesting …

The linkage relationships between the cystic fibrosis (CF) locus and four marker loci (MET-H, MET-D, D7S8 and D7S16), allelic associations between these loci and the extent of informativity at these marker loci were investigated in a sample of 206 families with at least one child affected by CF. The data were contributed by 11 laboratories from Europe and Israel. The maximum lod scores and recombination frequency estimates ( $$\hat \theta $$ ) (and confidence limits of θ) were: 18.3 at $$\hat \theta $$ =0.007(0.001−0.038) for CF vs. MET, 11.0 at $$\hat \theta $$ (0.001–0.068) for CF vs. D7S8, and 5.7 at $$\hat \theta $$ =0.0(0.0−0.064) for CF vs. D7S16. A gene order of CF-MET-D7S8 was best supported by the data, but its preference to the order D7S8-CF-MET is mainly based on one single family. There are significant allelic associations between CF, MET, D7S8 and D7S16; these allelic associations affect the risk of random individuals to be carriers of CF.

Summary. Prostacyclin and thromboxane have been implicated in the pathophysiology of several disorders of pregnancy, but there is little information on concentrations of these prostaglandins in normal pregnancy. The aim of our study was to determine the range of values throughout normal pregnancy and the puerperium and to compare this with concentrations in normal non-pregnant women. Measurement was by radioimmunoassay of prostacyclin and thromboxane metabolites. We observed a significant difference in prostacyclin metabolites in the first trimester. (mean 19·9, SEM 0·96 pg/ml) compared with the normal non-pregnant group (mean 15·9. SEM 0·68 pghl). There were no significant differences between values in the normal non-pregnant group and those in the second and third trimester or postnatally. The increase in prostacyclin in the first trimester may be associated with placentation and physiological vasodilation, and insencitivity to angiotensin It seen in early pregnancy. We noted a significant redaction in thromboxane metabolites in the second (mean 133, SEM 14·9 pg/ml) and third (mean 123, SEM 30·7 pg/ml) trimesters and the puerperium (mean 119, SEM 6·3 pg/ml) compared with the values in the normal non-pregnant group (mean 142, SEM 4·9 pg/ml). This may be due to increased platelet stability or decreased thromboxane synthesis.

no abstract available