Fertility preservation issues in pediatric hematopoietic stem cell transplantation: practical approaches from the consensus of the Pediatric Diseases Working Party of the EBMT and the International BFM Study Group.

Fertility preservation is an urgent challenge in the transplant setting. A panel of transplanters and fertility specialists within the Pediatric Diseases Working Party of the European Society for Blood and Marrow Transplantation (EBMT) and the International BFM Study Group provides specific guidelines. Patients and families should be informed of possible gender- and age-specific cryopreservation strategies that should be tailored according to the underlying disease, clinical condition and previous exposure to chemotherapy. Semen collection should be routinely offered to all postpubertal boys at the diagnosis of any disease requiring therapy that could potentially impair fertility. Testicular tissue collection might be offered to postpubertal boys; nevertheless, its use has been unsuccessful to date. Oocyte collection after hormonal hyperstimulation should be offered to postpubertal girls facing gonadotoxic therapies that could be delayed for the 2 weeks required for the procedure. Ovarian tissue collection could be offered to pre-/post-pubertal girls. Pregnancies have been reported after postpubertal ovarian tissue reimplantation; however, to date, no pregnancy has been reported after the reimplantation of prepubertal ovarian tissue or in vitro maturation of pre-/post-pubertal ovarian tissue. Possible future advances in reproductive medicine could change this scenario. Health authorities should prioritize fertility preservation projects in pediatric transplantation to improve patient care and quality of life.

State-of-the-art fertility preservation in children and adolescents undergoing haematopoietic stem cell transplantation: a report on the expert meeting of the Paediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) in Baden, Austria, 29-30 September 2015.

Nowadays, allogeneic haematopoietic stem cell transplantation (allo-HSCT) is a well-established treatment procedure and often the only cure for many patients with malignant and non-malignant diseases. Decrease in short-term complications has substantially contributed to increased survival. Therefore long-term sequelae are reaching the focus of patient care. One of the most important risks of stem cell transplant survivors is infertility. As well as in the field of allo-HSCT also the field of reproductive medicine has achieved substantial advances to offer potential options for fertility preservation in both boys and girls. Access to these procedures as well as their financing differs significantly throughout Europe. As all European children and adolescents should have the same possibility, the Paediatric Diseases Working Party of the European Society for Blood and Marrow Transplantation organised an expert meeting in September 2015. This manuscript describes the recommendations for the diagnosis and pre-emptive procedures that should be offered to all children and adolescents in Europe who have to undergo an allo-HSCT.

Fertility preservation practices in pediatric and adolescent cancer patients undergoing HSCT in Europe: a population-based survey.

Chemotherapy and irradiation can affect the gonads, leading to impairment of pubertal development and/or infertility. Fertility preservation (FP) is therefore a crucial endeavor in hematopoietic stem cell transplantation (HSCT) because of the severe impact of infertility on the quality of life of long-term survivors. Despite the existence of different international guidelines, FP counseling and procedures are not routinely implemented as part of patient care. We present herein a survey conducted by the Pediatric Working Party of the European Society for Blood and Marrow Transplantation (EBMT), which aims to analyze and compare different FP practices for children and adolescents across EBMT centers in 2013. A total of 177 pediatric centers reporting to the EBMT were contacted; of this number, 38 centers (21%) located in 16 different countries responded. These centers reported 834 patients receiving HSCT in 2013 (73% prepubertal), corresponding to 22% of all children (n=3789) undergoing HSCT in EBMT reporting centers. Overall, 39% of the reported patients received counseling and 29% received an FP procedure. The increased need for FP programs, extended education for patient-care teams, and more personal resources and funding emerged from this survey as pivotal factors necessary to support and implement such programs.

Developmental changes in the electroencephalogram and responses to a noxious stimulus in anaesthetized tammar wallaby joeys (Macropus eugenii eugenii).

The tammar wallaby joey is born extremely immature and most of its neurological development occurs in the maternal pouch. It is not known at what in-pouch age functions such as conscious sensory perception commence. We determined the electroencephalographic (EEG) responses to noxious stimulation in lightly anaesthetized tammar wallaby joeys. Baseline median (F50) and spectral edge (F95) frequencies, total power (Ptot) and frequency spectra between 1 and 30 Hz of the EEG power spectrum were determined. Joeys aged less than 127 days showed little or no EEG activity. Prolonged periods of spontaneous EEG activity were present by 142 days. This activity increased, as did the power in all frequencies, while the duration of any intervening isoelectric periods decreased with increasing in-pouch age. EEG responses to a noxious stimulus (toe clamping) changed with increasing in-pouch age as there was no response from joeys aged 94-127 days (no EEG), a minimal decrease in the F50 in those aged between 142 and 181 days (P = 0.052) and a greater decrease in the F50 in those aged between 187 and 261 days (P < 0.001). The pattern of these changes, which presumably reflects anatomical and functional maturation of the cerebral cortex, is similar to, but develops more slowly than, that reported in the rat. The opening of the eyes and development of the pelage are discussed as markers of when brain development may be sufficient for joeys to consciously perceive noxious sensations including pain.

Electroencephalographic responses to tail clamping in anaesthetized rat pups.

We investigated electroencephalographic (EEG) responses to tail clamping in lightly anaesthetized rat pups (5-22 days) in order to determine the ontogeny of EEG activity and at what age they may be capable of experiencing pain. Median frequency (F50) and spectral edge frequency (F95) of the power spectrum in the range of 1-30 Hz were determined before and after the application of a noxious stimulus and power spectra were compared by multivariate analysis. There was a postnatal increase in EEG power as, before clamping, pups aged 5-7 days exhibited isoelectric traces, whereas those aged 12-14 days and 21-22 days had intermittent EEG activity where the power in all frequencies was significantly lower at the former than at the latter age. Pups aged 5-7 days exhibited no EEG response to clamping in view of their isoelectric traces. Pups aged 12-14 days showed a significant decrease in F95 (P=0.002), whereas those aged 21-22 days showed highly significant reduction in F50 and F95 (P=0.028 and P<0.001, respectively) as well as changes in EEG power of specific frequencies after clamping. The results and related literature suggest that rat pups aged 5-7 days and younger are not likely to perceive pain and that the ability to perceive pain develops gradually between postnatal ages 12-14 days and 21-22 days.

Birth and hatching: key events in the onset of awareness in the lamb and chick.

The neuroanatomical and neurophysiological development of the embryo and fetus and unique features of the physiological environment of the fetal brain, features which are lost at birth, support recent conclusions that under normal circumstances awareness (or consciousness) is probably not exhibited by the ovine embryo-fetus before birth and that it appears for the first time only after birth. However, there has apparently been no evaluation of whether or not similar mechanisms modulate awareness-related functions in domestic chicks before and after hatching. This comparative review, in seeking to rectify this, arrived at the following conclusions. First, the neural apparatus of both lambs and chicks appears to be too immature to support any states resembling awareness during at least the first half of pregnancy or incubation. Second, electroencephalographic (EEG) activity, which evolves subsequently, shows that states of sleep-like unconsciousness are likely to be continuously present in lambs until after birth, and that such states at least predominate in chicks until after hatching. Third, as in fetal lambs, epochs of so-called 'wakefulness' previously reported in chick embryos do not seem likely to represent short periods of awareness in ovo. Fourth, several neurosuppressive mechanisms, with some unique features, also operate or have the potential to operate in chicks before hatching, but a dearth of published information currently hinders a full comparison with those demonstrated to operate in fetal lambs. Fifth, contradicting the intuitive perception that vocalisation pre-hatching by the chick indicates the presence of awareness, published evidence suggests that vocalisation before and during hatching occurs mostly during EEG states indicating sleep-like unconsciousness. Sixth, as seems to be the case for newborn lambs after birth, it is possible that demonstrable awareness may appear for the first time only after hatching in chicks, presumably through waning neurosuppression and burgeoning neuroactivation, but such awareness seems to take longer to manifest itself. However, additional research in chicks is recommended to further assess this suggestion. Particular attention should be given to the status of vocal interactions between hen and chick which begin several days before hatching, and to the operation of neurosuppressive and neuroactivating mechanisms throughout the last 40% of incubation and during and after hatching.

The physiological and physical status of single calves at birth in a dairy herd in New Zealand.

AIM: To determine the physiological status of calves at birth and the perinatal factors that might predispose newborn calves to debility and death, using criteria previously established for newborn lambs. METHODS: Friesian mixed-aged cows and heifers on a dairy farm in New Zealand that were close to calving were separated from the main herd and observed 24 h a day until they calved. Cows in which labour did not progress for over 1 h or which were in distress were assisted. About 12-13 min after birth, rectal temperature was measured and a blood sample was taken from each calf. The packed cell volume (PCV) and plasma lactate, glucose and fructose concentrations were determined. The time to stand for each calf and the air temperature and weather conditions at birth were recorded. RESULTS: The parameters measured were within normal ranges for newborns for the majority of calves. Calves sired by an Angus bull and born to heifers (AngusX) had significantly higher plasma lactate and fructose concentrations than Friesian calves born to cows, but there were no significant differences between the two breeds in any of the other parameters measured. Calves of both breeds born with assistance had significantly higher plasma lactate concentrations than those born without. Friesian calves that were assisted at birth had significantly lower PCVs and took significantly longer to stand than calves born without assistance. Assisted AngusX calves were significantly heavier than their unassisted counterparts. Calves born during windy and wet weather and when air temperatures were below 10 degrees C had lower rectal temperatures, took longer to stand and had higher plasma glucose concentrations than those born in dry weather and when air temperatures were above 10 degrees C. CONCLUSIONS: Calves with physiological parameters outside the normal range had experienced difficult labour and/or intrapartum hypoxaemia. Placental insufficiency and maternal undernutrition during late pregnancy did not apparently contribute to neonatal problems in the present study.

Blood metabolites and body temperature of single calves between 1 and 4 days of age in a dairy herd in New Zealand.

AIM: Using specified indices, to determine the nutritional and thermal status of calves between 1 and 4 days of age. METHODS: After birth, calves (n=106) were collected daily, according to farm practice. Over the following 4 days a jugular blood sample and rectal temperature were taken twice daily before feeding. Plasma concentrations of glucose, beta-hydroxybutyrate and urea, and gamma-glutamyl transferase (GGT) activities were determined. The significance of differences in plasma composition and rectal temperature between calves whose birth had been assisted or unassisted, and between calves with low and high plasma GGT activities 24 h after birth, was determined using repeated measures analysis of variance. RESULTS: There were no marked differences in plasma metabolite levels or body temperature of assisted and unassisted calves. Calves that had high plasma GGT activities 24 h after birth had higher plasma glucose concentrations over the 4 days than calves that had low plasma GGT activities (p<0.001). Overall, compared to published data on poorly-fed and hypothermic calves, calves in this study were normoglycaemic, their plasma beta-hydroxybutyrate and urea concentrations were low and their rectal temperatures were normal, indicating that they were well fed and did not become hypothermic. CONCLUSIONS: The nutritional and thermal status of at least 90% of the calves was compatible with good health and survival during the first 4 days after birth.