Risks for adverse pregnancy outcomes and infections in daycare workers: an overview of current epidemiological evidence and implications for primary prevention.

Childcare providers are overwhelmingly women of childbearing age. Occupational risks in this sector include exposure to biological (infectious) or physical (standing, carrying loads) hazards, many of which are associated with adverse pregnancy outcomes such as children with congenital infections, low birth weight or prematurity. Here, the authors examined literature on pregnancy outcomes and infectious hazards related to employment in daycare settings. Overall, 33 original studies (10 reporting pregnancy issues, 23 focusing on infectious risks) published in 1980-2018 were retained following a Medline search. Pregnancy issues in daycare workers have rarely been studied, and inconsistent risks of spontaneous abortion, congenital malformations and fetal growth retardation have been reported. Literature pertaining to infectious risks in daycare settings is extensive. The risk of a primary cytomegalovirus infection during pregnancy was increased for daycare workers caring for >6 children and younger children, changing diapers ≥3 days/week, not wearing gloves when changing diapers, and having employment in daycare for ≤2 years. Personal factors (nulliparity, ethnicity) were also independent risk factors. Parvovirus B19 (B19V) infections appear to be related to employment in daycare, but also to having one's own children and an increased number of siblings. Consequently, the risk of a primary B19V infection during an outbreak is of most concern among younger nulliparous workers caring for large numbers of young infected children. Since the main occupational hazard is viral infection, feasible prevention strategies include improving workers' awareness, serological monitoring during pregnancy, educating on appropriate preventive measures, and ensuring age-appropriate immunization of children and staff in childcare facilities. Int J Occup Med Environ Health. 2020;33(6):733-56.

Learned defense response to hypoxia in newborn mice.

In newborns, hypoxia elicits defensive behaviors including awakening from sleep, body movements and crying. An inability to produce this defense response is a risk factor for sudden infant death syndrome and other respiratory control disorders. In this study, we examined the possibility that the defense response to hypoxia in newborns is partly determined by early exposure to hypoxia. We explored this possibility in 6-day-old mice, which resemble human preterm infants of approximately 25-30 weeks' gestational age. Ultrasonic vocalizations (USVs) were recorded as a marker for the defense response to hypoxia. In a conditioning experiment, newborn mice were exposed to two artificial odors (conditioned stimuli, CS). For acquisition (two trials), pups were exposed to one odor (CS+) in a hypoxic gas mixture (10% O2, which was the unconditioned stimulus, US) and to another odor (CS-) in air. Then, the pups were exposed to each odor while breathing air. Newborn mice produced significantly more USVs when exposed to the odor previously paired with hypoxia than to the control odor. Thus, associative learning may shape the defense response to hypoxia in newborns.

Corrigendum: Protective effects of intermittent hypoxia on brain and memory in a mouse model of apnea of prematurity.

[This corrects the article on p. 313 in vol. 6, PMID: 26582992.].

Olfactory classical conditioning in newborn mice.

Determining the behavioural phenotype of genetically altered mice is a valuable approach for elucidating the function of genes and their role in cognitive disorders. Methods for phenotyping newborn mice are scarce and generally confined to sensorimotor reflexes. Here, we describe a simple method for assessing associative abilities in newborn mice. We used a two-odour-choice classical conditioning paradigm in mice from the day of birth (post-natal age 0, P0) to P6. Acquisition required 20 trials: 10 trials during which the pups were placed over the conditioned stimulus (CS+) odour (lemon or peppermint) for 30s and simultaneously stroked gently with a paintbrush and 10 trials during which the pups were placed over the other odour (CS-) for 30s, without stroking. Then, the pups were subjected to five odour-preference trials to test for conditioning. This sequence of five trials was repeated after 5 and 24h to assess retention of the conditioned odour preference. During the immediate post-acquisition sequence, the pups spent significantly more time over the CS+ than over the CS- (p<0.0001). No extinction of the conditioned preference was observed during this test. No preference was observed after 5 or 24h, indicating that the conditioned response was promptly lost. Conditioning was effective as soon as P0-P1. Thus, conditioning may emerge in newborn mice sooner than previously reported. This paradigm is well suited to phenotyping of large samples of genetically altered mice and may shed light on the role for genes in paediatric cognitive impairments.

Protective effects of intermittent hypoxia on brain and memory in a mouse model of apnea of prematurity.

Apnea of prematurity (AOP) is considered a risk factor for neurodevelopmental disorders in children based on epidemiological studies. This idea is supported by studies in newborn rodents in which exposure to intermittent hypoxia (IH) as a model of AOP significantly impairs development. However, the severe IH used in these studies may not fully reflect the broad spectrum of AOP severity. Considering that hypoxia appears neuroprotective under various conditions, we hypothesized that moderate IH would protect the neonatal mouse brain against behavioral stressors and brain damage. On P6, each pup in each litter was randomly assigned to one of three groups: a group exposed to IH while separated from the mother (IH group), a control group exposed to normoxia while separated from the mother (AIR group), and a group of untreated unmanipulated pups left continuously with their mother until weaning (UNT group). Exposure to moderate IH (8% O2) consisted of 20 hypoxic events/hour, 6 h per day from postnatal day 6 (P6) to P10. The stress generated by maternal separation in newborn rodents is known to impair brain development, and we expected this effect to be smaller in the IH group compared to the AIR group. In a separate experiment, we combined maternal separation with excitotoxic brain lesions mimicking those seen in preterm infants. We analyzed memory, angiogenesis, neurogenesis and brain lesion size. In non-lesioned mice, IH stimulated hippocampal angiogenesis and neurogenesis and improved short-term memory indices. In brain-lesioned mice, IH decreased lesion size and prevented memory impairments. Contrary to common perception, IH mimicking moderate apnea may offer neuroprotection, at least in part, against brain lesions and cognitive dysfunctions related to prematurity. AOP may therefore have beneficial effects in some preterm infants. These results support the need for stratification based on AOP severity in clinical trials of treatments for AOP, to determine whether in patients with moderate AOP, these treatments are beneficial or deleterious.

Reproductive disorders in hairdressers and cosmetologists: a meta-analytical approach.

OBJECTIVES: The aim of this study was to perform a systematic review and to use a meta-analytical approach to assess quantitatively the risk of adverse pregnancy outcomes in hairdressers and cosmetologists. METHODS: A systematic literature search up to 1 February 2012 was carried out using major bibliographic databases, grey literature, contacts with research teams working on the subject, review papers and reference lists of selected articles. Observational studies reporting measures of effects in relation with body care (hairdressers, cosmetologists, etc.) and reproductive disorders were included. Study quality was assessed by three reviewers. The estimated risk ratios (RR) from all studies reporting on identical outcomes were combined using an average of logarithm transformation of estimated RR weighted by their inverted variance. Statistical heterogeneity across studies was assessed using Cochran's Q test. To explore the sources of heterogeneity, several sensitivity analyses and subgroup analyses were conducted based on study quality, country, study period, alcohol consumption, smoking habit, jobs and control populations. RESULTS: Nineteen studies were selected and reviewed in-depth. The combined risk ratios (RRcs) of five reproductive outcomes were calculated and found to be significantly increased for four outcomes: time to pregnancy, which had an RRc of 1.11 (95% CI: 1.03-1.19); premature birth, which had an RRc of 1.05 (95% CI: 0.99-1.11); small for gestational age, which had an RRc of 1.24 (95 CI%: 1.10-1.41); low birth weight, which had an RRc of 1.21 (95% CI: 1.06-1.39); and embryonic and fetal losses, which had an RRc of 1.19 (95% CI: 1.03-1.38). CONCLUSIONS: This work confirms a weak increase in risk of some reproductive disorders in female hairdressers/cosmetologists. However, the evidence level is rather weak, and a causal association between job and reproductive outcomes cannot be asserted.

Bench to cribside: the path for developing a neuroprotectant.

The consequences of perinatal brain injury include immeasurable anguish for families and substantial ongoing costs for care and support of effected children. Factors associated with perinatal brain injury in the preterm infant include inflammation and infection, and with increasing gestational age, a higher proportion is related to hypoxic-ischemic events, such as stroke and placental abruption. Over the past decade, we have acquired new insights in the mechanisms underpinning injury and many new tools to monitor outcome in perinatal brain injury in our experimental models. By embracing these new technologies, we can expedite the screening of novel therapies. This is critical as despite enormous efforts of the research community, hypothermia is the only viable neurotherapeutic, and this procedure is limited to term birth and postcardiac arrest hypoxic-ischemic events. Importantly, experimental and preliminary data in humans also indicate a considerable therapeutic potential for melatonin against perinatal brain injury. However, even if this suggested potential is proven, the complexity of the human condition means we are likely to need additional neuroprotective and regenerative strategies. Thus, within this review, we will outline what we consider the key stages of preclinical testing and development for a neuroprotectant or regenerative neurotherapy for perinatal brain injury. We will also highlight examples of novel small animal physiological and behavioral testing that gives small animal preclinical models greater clinical relevance. We hope these new tools and an integrated bench to cribside strategic plan will facilitate the fulfillment of our overarching goal, improving the long-term brain health and quality of life for infants suffering perinatal brain injury.

Implanted neurosphere-derived precursors promote recovery after neonatal excitotoxic brain injury.

Brain damage through excitotoxic mechanisms is a major cause of cerebral palsy in infants. This phenomenon usually occurs during the fetal period in human, and often leads to lifelong neurological morbidity with cognitive and sensorimotor impairment. However, there is currently no effective therapy. Significant recovery of brain function through neural stem cell implantation has been shown in several animal models of brain damage, but remains to be investigated in detail in neonates. In the present study, we evaluated the effect of cell therapy in a well-established neonatal mouse model of cerebral palsy induced by excitotoxicity (ibotenate treatment on postnatal day 5). Neurosphere-derived precursors or control cells (fibroblasts) were implanted into injured and control brains contralateral to the site of injury, and the fate of implanted cells was monitored by immunohistochemistry. Behavioral tests were performed in animals that received early (4 h after injury) or late (72 h after injury) cell implants. We show that neurosphere-derived precursors implanted into the injured brains of 5-day-old pups migrated to the lesion site, remained undifferentiated at day 10, and differentiated into oligodendrocyte and neurons at day 42. Although grafted cells finally die there few weeks later, this procedure triggered a reduction in lesion size and an improvement in memory performance compared with untreated animals, both 2 and 5 weeks after treatment. Although further studies are warranted, cell therapy could be a future therapeutic strategy for neonates with acute excitotoxic brain injury.

Cold stimulates the behavioral response to hypoxia in newborn mice.

In newborns, hypoxia elicits increased ventilation, arousal followed by defensive movements, and cries. Cold is known to affect the ventilatory response to hypoxia, but whether it affects the arousal response remains unknown. The aim of the present study was to assess the effects of cold on the ventilatory and arousal responses to hypoxia in newborn mice. We designed an original platform measuring noninvasively and simultaneously the breathing pattern by whole body plethysmography, body temperature by infrared thermography, as well as motor and ultrasonic vocal (USV) responses. Six-day-old mice were exposed twice to 10% O(2) for 3 min at either cold temperature (26 degrees C) or thermoneutrality (33 degrees C). At 33 degrees C, hypoxia elicited a marked increase in ventilation followed by a small ventilatory decline, small motor response, and almost no USVs. Body temperature was not influenced by hypoxia, and oxygen consumption (Vo(2)) displayed minimal changes. At 26 degrees C, hypoxia elicited a slight increase in ventilation with a large ventilatory decline and a large drop of Vo(2). This response was accompanied by marked USV and motor responses. Hypoxia elicited a small decrease in temperature after the return to normoxia, thus precluding any causal influence on the motor and USV responses to hypoxia. In conclusion, cold stimulated arousal and stress responses to hypoxia, while depressing hypoxic hyperpnea. Arousal is an important defense mechanism against sleep-disordered breathing. The dissociation between ventilatory and behavioral responses to hypoxia suggests that deficits in the arousal response associated with sleep breathing disorders cannot be attributed to a depressed hypoxic response.

Moderate growth restriction: deleterious and protective effects on white matter damage.

The role for growth restriction in the multifactorial pathophysiology of developing white-matter damage remains debated. We studied rat pups with prenatal growth restriction (GR) induced by unilateral ligation of the uterine artery. Pups with severe GR exhibited white-matter damage that persisted to adulthood [Olivier, P., Baud, O., Evrard, P., Gressens, P.,Verney, C., 2005. Prenatal ischemia and white matter damage in rats. J. Neuropathol. Exp. Neurol. 64, 998-1006]. Moderate GR was associated with diffuse white-matter lesions, microglial activation, and astrogliosis. Loss of pre-oligodendrocytes on postnatal day 7 was followed by a delay in myelination. Following a cortical excitotoxic insult on postnatal day 5, the size of the induced white-matter lesion was smaller in pups with moderate GR and larger in pups with severe GR, compared to normal pups. The increased pre-oligodendrocyte proliferation seen in the white matter of pups with moderate GR subjected to this "double-hit" injury may constitute a heretofore-undescribed neuroprotective mechanism of immature white matter.