Neonatal erythropoietin mitigates impaired gait, social interaction and diffusion tensor imaging abnormalities in a rat model of prenatal brain injury.

Children who are born preterm are at risk for encephalopathy of prematurity, a leading cause of cerebral palsy, cognitive delay and behavioral disorders. Current interventions are limited and none have been shown to reverse cognitive and behavioral impairments, a primary determinant of poor quality of life for these children. Moreover, the mechanisms of perinatal brain injury that result in functional deficits and imaging abnormalities in the mature brain are poorly defined, limiting the potential to target interventions to those who may benefit most. To determine whether impairments are reversible after a prenatal insult, we investigated a spectrum of functional deficits and diffusion tensor imaging (DTI) abnormalities in young adult animals. We hypothesized that prenatal transient systemic hypoxia-ischemia (TSHI) would induce multiple functional deficits concomitant with reduced microstructural white and gray matter integrity, and tested whether these abnormalities could be ameliorated using postnatal erythropoietin (EPO), an emerging neurorestorative intervention. On embryonic day 18 uterine arteries were transiently occluded for 60min via laparotomy. Shams underwent anesthesia and laparotomy for 60min. Pups were born and TSHI pups were randomized to receive EPO or vehicle via intraperitoneal injection on postnatal days 1 to 5. Gait, social interaction, olfaction and open field testing was performed from postnatal day 25-35 before brains underwent ex vivo DTI to measure fractional anisotropy, axial diffusivity and radial diffusivity. Prenatal TSHI injury causes hyperactivity, impaired gait and poor social interaction in young adult rats that mimic the spectrum of deficits observed in children born preterm. Collectively, these data show for the first time in a model of encephalopathy of prematurity that postnatal EPO treatment mitigates impairments in social interaction, in addition to gait deficits. EPO also normalizes TSHI-induced microstructural abnormalities in fractional anisotropy and radial diffusivity in multiple regions, consistent with improved structural integrity and recovery of myelination. Taken together, these results show behavioral and memory deficits from perinatal brain injury are reversible. Furthermore, resolution of DTI abnormalities may predict responsiveness to emerging interventions, and serve as a biomarker of CNS injury and recovery.

High-risk behaviours for the fœtus in pregnant women: The medicolegal and judicial aspects.

Pregnancy is a period of psychological change which may lead to difficulties of adaptation and psychological suffering and give rise to high-risk behaviours for the fœtus in pregnant women. These risk behaviours, which are defined by certain authors as a form of "maltreatment" of the fœtus, usually spring from the psychological distress of the pregnant woman but are not recognised as a specific medical disorder. We illustrate the difficulties encountered in the identification of, and the specific intervention in, these situations through the clinical case of a pregnant drugs-dependent patient subjected to several stress factors who, in addition to consuming substances, developed high-risk behaviours for herself and her pregnancy: self-endangerment under the influence of substances, falls or refusals of treatment. In our first part, we discuss the medicolegal possibilities afforded by French law to protect the fœtus in the event of the future mother's high-risk behaviours. In our second part, we discuss the successive evolutions of the legal status of the fœtus and pregnancy, and their consequences for medical practice and the clinical situations concerned. The lack of an answer concerning the designation of these behaviours, as either medical, legal or social acts, will prompt perinatal practitioners to a certain medicolegal prudence.

Sex-specific and time-dependent effects of prenatal stress on the early behavioral symptoms of ADHD: a longitudinal study in China.

There is increasing evidence that prenatal stressful life events (SLEs) may be a potential risk factor for attention-deficit hyperactivity disorder (ADHD), but the sex-specific and time-dependent effects of prenatal stress on ADHD are less clear. In this prospective longitudinal study, data on prenatal SLEs during different stages of gestation and indicators of buffers against stress, including maternal social support and avoidance coping, were obtained from 1765 pregnant women at 32 weeks of gestation. The behavioral symptoms of ADHD in children aged 48-54 months were evaluated by reports from the parents. There were 226 children (12.8%) above the clinically significant cutoff for ADHD. After adjusting for potential confounders, boys whose mother experienced severe SLEs in the second trimester had a significantly increased risk (OR = 2.41, 95% CI: 1.03-5.66) of developing ADHD symptoms compared with boys whose mothers did not experience severe SLEs at this time. However, no significantly increased risk of ADHD symptoms was observed in girls born to mothers experienced prenatal severe SLEs. Additionally, significant interaction effects of prenatal SLEs, social support and coping style on ADHD symptoms were found in males. Boys whose mothers experienced severe SLEs during the second trimester accompanied by a higher score for avoidance coping (OR = 3.31, 95% CI: 1.13-9.70) or a lower score for social support (OR = 4.39, 95% CI: 1.05-18.31) were likely to be at a higher risk for ADHD symptoms. The epidemiological evidence in this prospective follow-up study suggests that the effect of prenatal SLEs on ADHD symptoms in offspring may depend on the timing of prenatal stress and may vary according to the sex of the offspring.

Transmitting biological effects of stress in utero: implications for mother and offspring.

The developing foetus makes adaptations to an adverse in utero environment which may lead to permanent changes in structure and physiology, thus 'programming' the foetus to risk of ill health in later life. Epidemiological studies have shown associations between low birth weight, a surrogate marker of an adverse intrauterine environment, and a range of diseases in adult life including cardiometabolic and psychiatric disease. These associations do not apply exclusively to low birth weight babies but also to newborns within the normal birth weight range. Early life stress, including stressors in the prenatal and early postnatal period, is a key factor that can have long-term effects on offspring health. Animal studies show this is mediated through changes in the maternal and foetal hypothalamic-pituitary-adrenal axes resulting in foetal exposure to excess glucocorticoids. Data in humans are more limited but support that the biological effects of stress in utero may be transmitted through changes in glucocorticoid action or metabolism. Common contemporary physical and social stressors of maternal obesity and socio-economic deprivation impact on the maternal response to pregnancy and the prevailing hormonal milieu that the developing foetus will be exposed to. Prenatal stress may also be compounded by early postnatal stresses such as childhood maltreatment with resultant adverse effects for the offspring. Understanding of the mechanisms whereby these stressors are transmitted from mother to foetus will not only improve our knowledge of normal foetal development but will also help identify novel pathways for early intervention either in the periconceptional, pregnancy or the early postpartum period.

The association between developmental handicaps and traumatic brain injury during pregnancy: an issue that deserves more systematic evaluation.

AIMS: Trauma during pregnancy is commonly viewed as benign for the foetus when the delivery occurs normally. This study revisits that point of view. METHOD: We included eighteen patients having a neurological handicap with an anamnesis of an accident during pregnancy and a follow-up sufficient to determine a definite outcome. RESULTS: Pregnancy outcome and observed management. Foetal abnormalities were detected in six cases between the first and the thirteenth day after the trauma. Emergency delivery or rapid birth after signs of foetal distress occurred in five cases. One baby died soon after birth. One-third of cases were not submitted to any investigation. VARIOUS NEUROLOGICAL HANDICAPS WERE RECORDED: Congenital microcephaly (three patients), congenital hydrocephalus (three), Infantile cerebral hemiplegy (six), quadriplegy with severe encephalopathy (four), diplegy (one), clumsiness with cerebellar atrophy (one), Moebius syndrome (one), mental retardation with autistic features (two), learning disability (one) auditory agnosia (one). Cerebral imaging showed macroscopic abnormalities in fourteen patients, evoking various pathogenetic hypotheses. CONCLUSION: The association between maternal trauma and foetal brain lesions lacks sufficient investigation in many cases. Prospective studies are needed to clarify both medical and legal issues. Guidelines are proposed for obstetrical and paediatric management after significant maternal trauma.