Exposure to per- and polyfluoroalkyl substances in early pregnancy and risk of cerebral palsy in children.

BACKGROUND: Most cerebral palsy (CP) cases have an unexplained etiology, but a role for environmental exposures has been suggested. One purported environmental risk factor is exposure to endocrine-disrupting pollutants specifically per- and polyfluoroalkyl substances (PFAS). OBJECTIVES: We investigated the association between prenatal PFAS exposures and CP in Swedish children. METHODS: In this case-control study, 322 CP cases, 343 population controls, and 258 preterm controls were identified from a birth registry in combination with a CP follow-up program from 1995 to 2014 and linked to a biobank which contains serum samples from week 10-14 of pregnancy. Maternal serum concentrations of four PFAS compounds: perfluorohexane sulfonate (PFHxS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorooctane sulfonate (PFOS) were analyzed using liquid chromatography-tandem-mass-spectrometry. We estimated odds ratios (ORs) and 95 % confidence intervals (CIs) for CP and each PFAS in quartiles and as continuous variables controlling for various sociodemographic and lifestyle factors. RESULTS: In crude and adjusted analyses, we did not find consistent evidence of associations between serum PFHxS, PFOA, PFNA, PFOS and concentrations in early pregnancy and CP, except in preterm infants. The ORs comparing the highest PFAS quartiles to the lowest were 1.05 (95 % CI: 0.63-1.76), 0.96 (95 % CI: 0.55-1.68), 0.71 (95 % CI: 0.41-1.25), and 1.17 (95 % CI: 0.61-2.26), for PFHxS, PFOA, PFNA, and PFOS, respectively. Some positive associations were observed for preterm infants, but the results were imprecise. Similar patterns were observed in analyses treating PFAS as continuous variables. CONCLUSIONS: In this study, we found little evidence that early pregnancy prenatal exposure to PFHxS, PFOA, PFNA, or PFOS increases the risk of CP. However, some positive associations were observed for preterm cases and warrant further investigation.

Catatonia and Neuroleptic Malignant Syndrome in Patients With Cerebral Palsy: Two Case Reports and a Systematic Review of the Literature.

BACKGROUND: Patients with cerebral palsy, a group of movement disorders with motor, and possibly communication and behavioral features that mimic catatonic signs, may benefit from efforts to improve the detection and treatment of comorbid catatonia. Given that cerebral palsy frequently co-occurs with conditions associated with catatonia, such as autism spectrum disorder, epilepsy, intellectual disability, and mood and psychotic disorders, lifetime prevalence of catatonia in this population may be high. OBJECTIVE: This study aimed to systematically review the literature on catatonia and the related condition of neuroleptic malignant syndrome (NMS) in patients with cerebral palsy while presenting 2 additional cases of catatonia. METHODS: We used the terms "cerebral palsy" in combination with "catatoni∗," related terms for catatonia, and "neuroleptic malignant syndrome" to query Ovid MEDLINE (1948 to November 28, 2022), PsycINFO, Cumulative Index to Nursing, and Allied Health Literature, and Embase for applicable case reports. The Neuroleptic Malignant Syndrome Information Service database was also manually searched. RESULTS: In addition to our 2 catatonia reports, we identified 10 reports of catatonia in patients with cerebral palsy, as well as 8 reports of NMS. Patients with both conditions responded well, and sometimes rapidly, to treatment. Notably, of the 5 patients with catatonia and cerebral palsy who received electroconvulsive therapy, 2 developed recurrent self-limited hyperthermia posttreatment. We also identified several cases of baclofen withdrawal, which can be life threatening because of seizure risk, presenting with NMS-like features in patients with cerebral palsy who had malfunctioning intrathecal baclofen pumps for spasticity management. CONCLUSIONS: Given frequent comorbidity of conditions associated with catatonia in patients with cerebral palsy, as well as routine treatment with medications that can induce NMS, such as metoclopramide and anticholinergics, catatonia and NMS may be underreported in the cerebral palsy patient population, despite being highly treatable. Possible underdiagnosis of catatonia in patients with cerebral palsy may be because of misattribution of overlapping features between the 2 conditions to cerebral palsy. Clinicians should be aware of possible recurrent self-limited fever when using electroconvulsive therapy to treat patients with catatonia and cerebral palsy while also being vigilant for intrathecal baclofen withdrawal when encountering NMS-like features in patients with cerebral palsy.

Prenatal tobacco smoke exposure and neurological impairment at 10 years of age among children born extremely preterm: a prospective cohort.

OBJECTIVE: To determine the association between prenatal tobacco smoke exposure and neurological impairment at 10 years of age among children born extremely preterm (<28 weeks of gestation). DESIGN: The Extremely Low Gestational Age Newborn (ELGAN) Study, a prospective cohort. SETTING: Ten-year follow-up of extremely preterm infants born at 14 US hospitals between 2002 and 2004. METHODS: Prenatal tobacco smoke exposure was defined as a mother's report at enrolment of active (i.e. maternal) and passive smoking during pregnancy. Poisson regression with generalized estimating equations was used. Models adjusted for mother's age, race/ethnicity, education, insurance, pre-pregnancy body mass index, US region, multiple gestation and infant's sex; and in sensitivity analysis, gestational age at delivery and clinical subtype of preterm birth, given their classification as intermediate and non-confounding variables. MAIN OUTCOMES: Neurological impairment at 10 years, epilepsy, cerebral palsy and cognitive impairment. RESULTS: Of 1200 ELGAN study survivors, 856 were assessed at 10 years of age with neurological outcomes, of whom 14% (118/856) had active tobacco exposure during pregnancy and 24% (207/852) had passive tobacco exposure. Compared with children who were not exposed prenatally to tobacco, children exposed to active tobacco use during pregnancy had a higher risk of epilepsy (14% versus 5%; adjusted relative risk: 1.68, 95% CI 1.45-1.92). This risk remained after adjustment for gestational age at delivery and clinical subtype of preterm birth. Prenatal tobacco smoke exposure was not associated with other assessed neurological outcomes, including cerebral palsy and multiple measures of cognitive impairment. CONCLUSIONS: Among children born extremely preterm, prenatal active tobacco smoke exposure was associated with an increased risk of epilepsy at 10 years of life. TWEETABLE ABSTRACT: Among infants born before 28 weeks of gestation, prenatal active tobacco smoke exposure was associated with an increased risk of epilepsy at 10 years of life.

Systemic dendrimer-drug nanomedicines for long-term treatment of mild-moderate cerebral palsy in a rabbit model.

BACKGROUND: Neuroinflammation mediated by microglia plays a central role in the pathogenesis of perinatal/neonatal brain injury, including cerebral palsy (CP). Therapeutics mitigating neuroinflammation potentially provide an effective strategy to slow the disease progression and rescue normal brain development. Building on our prior results which showed that a generation-4 hydroxyl poly(amidoamine) (PAMAM) dendrimer could deliver drugs specifically to activated glia from systemic circulation, we evaluated the sustained efficacy of a generation-6 (G6) hydroxyl-terminated PAMAM dendrimer that showed a longer blood circulation time and increased brain accumulation. N-acetyl-L-cysteine (NAC), an antioxidant and anti-inflammatory agent that has high plasma protein binding properties and poor brain penetration, was conjugated to G6-PAMAM dendrimer-NAC (G6D-NAC). The efficacy of microglia-targeted G6D-NAC conjugate was evaluated in a clinically relevant rabbit model of CP, with a mild/moderate CP phenotype to provide a longer survival of untreated CP kits, enabling the assessment of sustained efficacy over 15 days of life. METHODS: G6D-NAC was conjugated and characterized. Cytotoxicity and anti-inflammatory assays were performed in BV-2 microglial cells. The efficacy of G6D-NAC was evaluated in a rabbit model of CP. CP kits were randomly divided into 5 groups on postnatal day 1 (PND1) and received an intravenous injection of a single dose of PBS, or G6D-NAC (2 or 5 mg/kg), or NAC (2 or 5 mg/kg). Neurobehavioral tests, microglia morphology, and neuroinflammation were evaluated at postnatal day 5 (PND5) and day 15 (PND15). RESULTS: A single dose of systemic 'long circulating' G6D-NAC showed a significant penetration across the impaired blood-brain-barrier (BBB), delivered NAC specifically to activated microglia, and significantly reduced microglia-mediated neuroinflammation in both the cortex and cerebellum white matter areas. Moreover, G6D-NAC treatment significantly improved neonatal rabbit survival rate and rescued motor function to nearly healthy control levels at least up to 15 days after birth (PND15), while CP kits treated with free NAC died before PND9. CONCLUSIONS: Targeted delivery of therapeutics to activated microglia in neonatal brain injury can ameliorate pro-inflammatory microglial responses to injury, promote survival rate, and improve neurological outcomes that can be sustained for a long period. Appropriate manipulation of activated microglia enabled by G6D-NAC can impact the injury significantly beyond inflammation.

Associations between macrolide antibiotics prescribing during pregnancy and adverse child outcomes in the UK: population based cohort study.

OBJECTIVE: To assess the association between macrolide antibiotics prescribing during pregnancy and major malformations, cerebral palsy, epilepsy, attention deficit hyperactivity disorder, and autism spectrum disorder in children. DESIGN: Population based cohort study. SETTING: The UK Clinical Practice Research Datalink. PARTICIPANTS: The study cohort included 104 605 children born from 1990 to 2016 whose mothers were prescribed one macrolide monotherapy (erythromycin, clarithromycin, or azithromycin) or one penicillin monotherapy from the fourth gestational week to delivery. Two negative control cohorts consisted of 82 314 children whose mothers were prescribed macrolides or penicillins before conception, and 53 735 children who were siblings of the children in the study cohort. MAIN OUTCOME MEASURES: Risks of any major malformations and system specific major malformations (nervous, cardiovascular, gastrointestinal, genital, and urinary) after macrolide or penicillin prescribing during the first trimester (four to 13 gestational weeks), second to third trimester (14 gestational weeks to birth), or any trimester of pregnancy. Additionally, risks of cerebral palsy, epilepsy, attention deficit hyperactivity disorder, and autism spectrum disorder. RESULTS: Major malformations were recorded in 186 of 8632 children (21.55 per 1000) whose mothers were prescribed macrolides and 1666 of 95 973 children (17.36 per 1000) whose mothers were prescribed penicillins during pregnancy. Macrolide prescribing during the first trimester was associated with an increased risk of any major malformation compared with penicillin (27.65 v 17.65 per 1000, adjusted risk ratio 1.55, 95% confidence interval 1.19 to 2.03) and specifically cardiovascular malformations (10.60 v 6.61 per 1000, 1.62, 1.05 to 2.51). Macrolide prescribing in any trimester was associated with an increased risk of genital malformations (4.75 v 3.07 per 1000, 1.58, 1.14 to 2.19, mainly hypospadias). Erythromycin in the first trimester was associated with an increased risk of any major malformation (27.39 v 17.65 per 1000, 1.50, 1.13 to 1.99). No statistically significant associations were found for other system specific malformations or for neurodevelopmental disorders. Findings were robust to sensitivity analyses. CONCLUSIONS: Prescribing macrolide antibiotics during the first trimester of pregnancy was associated with an increased risk of any major malformation and specifically cardiovascular malformations compared with penicillin antibiotics. Macrolide prescribing in any trimester was associated with an increased risk of genital malformations. These findings show that macrolides should be used with caution during pregnancy and if feasible alternative antibiotics should be prescribed until further research is available. TRIAL REGISTRATION: ClinicalTrials.gov NCT03948620.

A Case-Control Study of Essential and Toxic Trace Elements and Minerals in Hair of 0-4-Year-Old Children with Cerebral Palsy.

The objective of the present study was to assess hair essential and toxic trace elements and minerals in children with cerebral palsy in relation to age of the examinees. A total of 70 children with cerebral palsy and 70 healthy controls aged 0-4 years old were enrolled in the present study. The examined children were also divided into two age groups of those younger and older than 2 years old. Hair trace element content was assessed using ICP-MS at NexION 300D (PerkinElmer, USA). The obtained data demonstrate that hair boron was more than 2-fold lower in CP children as compared with the control group. At the same time, hair Na, Se, and V levels were 21%, 12%, and 20% lower when compared with healthy controls, respectively. It is also notable that a 9% and 28% decrease in hair Fe and Li levels respectively were nearly significant. The observed alterations were more profound in a younger group of patients. No significant group difference in hair toxic metal and metalloid levels was observed between the general cohorts of children with and without CP. In regression models, only hair Al and Ca contents were significantly associated with the presence of cerebral palsy, whereas hair Mg, Na, Ni, and Se levels were characterized as significant negative predictors. The observed alteration in trace element metabolism may also provide an additional link between cerebral palsy, psychomotor delay, and certain diseases, including diabetes, epilepsy, and osteoporosis. However, further studies using other substrates (blood, urine) or biomarkers are required.

Associations between use of macrolide antibiotics during pregnancy and adverse child outcomes: A systematic review and meta-analysis.

BACKGROUND: Evidence on adverse effects of maternal macrolide use during pregnancy is inconsistent. We conducted a systematic review and meta-analysis to investigate the association between macrolide use during pregnancy and adverse fetal and child outcomes. METHODS AND FINDINGS: We included observational studies and randomised controlled trials (RCTs) that recorded macrolide use during pregnancy and child outcomes. We prioritized comparisons of macrolides with alternative antibiotics (mainly penicillins or cephalosporins) for comparability of indication and effect. Random effects meta-analysis was used to derive pooled odds ratios (OR) for each outcome. Subgroup analyses were performed according to specific types (generic forms) of macrolide. Of 11,186 citations identified, 19 (10 observational, 9 RCTs) studies were included (21 articles including 228,556 participants). Macrolide prescribing during pregnancy was associated with an increased risk of miscarriage (pooled ORobs 1·82, 95% CI 1·57-2·11, three studies, I2 = 0%), cerebral palsy and/or epilepsy (ORobs 1·78, 1·18-2·69; one study), epilepsy alone (ORobs 2·02, 1·30-3·14, one study; ORRCT 1.03, 0.79-1.35, two studies), and gastrointestinal malformations (ORobs 1·56, 1·05-2·32, two studies) compared with alternative antibiotics. We found no evidence of an adverse effect on 12 other malformations, stillbirth, or neonatal death. Results were robust to excluding studies with high risk of bias. CONCLUSIONS: Consistent evidence of an increased risk of miscarriage in observational studies and uncertain risks of cerebral palsy and epilepsy warrant cautious use of macrolide in pregnancy with warnings in drug safety leaflets and use of alternative antibiotics where appropriate. As macrolides are the third most commonly used class of antibiotics, it is important to confirm these results with high quality studies.

Morphofunctional characteristics of skeletal muscle in rats with cerebral palsy.

Knowledge of skeletal muscle adaptations is important to understand the functional deficits in cerebral palsy (CP). This study aimed to investigate the morphofunctional characteristics of skeletal muscle in a CP animal model. Initially, pregnant Wistar rats were injected intraperitoneally with saline or lipopolysaccharide over the last five days of pregnancy. The control group (n = 8) consisted of male pups born to females injected with saline. The CP group (n = 8) consisted of male pups born to females injected with lipopolysaccharide, which were submitted to perinatal anoxia [day of birth, postnatal day 0 (P0)] and sensorimotor restriction (P1-P30). The open-field test was undertaken on P29 and P45. On P48, the animals were weighed, and the plantaris muscle was collected and its weight and length were measured. Transverse sections were stained with haematoxylin-eosin, NADH-TR, Masson's trichrome and non-specific esterase reaction for analysis. and transmission electron microscopy was performed. In the CP group, reductions were observed in mobility time, number of crossings and rearing frequency, body weight, muscle weight and length, and nucleus-to-fibre and capillary-to-fibre ratios. There was a statistically significant increase in the percentage area of the muscle section occupied by collagen; reduction in the area and increase in the number of type I muscle fibres; increase in myofibrillar disorganization and Z-line disorganization and dissolution; and reduction in the area and largest and smallest diameters of neuromuscular junctions. Thus this animal model of CP produced morphofunctional alterations in skeletal muscle, that were associated with evidence of motor deficits as demonstrated by the open-field test.

Use of paracetamol, ibuprofen or aspirin in pregnancy and risk of cerebral palsy in the child.

Background: It has been debated whether mild analgesics, mainly paracetamol, adversely affect aspects of neurodevelopment. We examined whether mother's use of paracetamol, aspirin or ibuprofen in pregnancy is associated with increased risk of cerebral palsy (CP) in the child. Method: We included 185 617 mother-child pairs from the Danish National Birth Cohort and the Norwegian Mother and Child Cohort Study. We created harmonized definitions of analgesic use in pregnancy, as well as indications for analgesic use and other potential confounders. Children with CP were identified in nationwide registers. We estimated the average causal effect of analgesics on risk of CP using marginal structural models with stabilized inverse probability weights. Results: Paracetamol use was reported in 49% of all pregnancies, aspirin in 3% and ibuprofen in 4%. Prenatal exposure to paracetamol ever in pregnancy was associated with increased risk of overall CP [adjusted odds ratio (aOR) 1.3, 95% confidence interval (CI): 1.0-1.7] and unilateral spastic CP (aOR 1.5, 95% CI: 1.0-2.2). The association appeared to be driven by an increased risk of unilateral spastic CP in children exposed in second trimester (aOR 1.6, 95% CI: 1.0-2.5). Children ever prenatally exposed to aspirin in pregnancy had an elevated risk of bilateral spastic CP (aOR 2.4, 95% CI: 1.1-5.3) compared with unexposed. Conclusion: We observed an increased risk of spastic CP in children prenatally exposed to paracetamol and aspirin. Although we controlled for several important indications for analgesic use, we cannot exclude the possibility of confounding by underlying diseases.

Adverse events in women and children who have received intrapartum antibiotic prophylaxis treatment: a systematic review.

BACKGROUND: Adverse events from intrapartum antibiotic prophylaxis (IAP) are poorly documented yet essential to inform clinical practice for neonatal group B Streptococcus (GBS) disease prevention. In this systematic review, we appraised and synthesised the evidence on the adverse events of IAP in the mother and/or her child. METHODS: We searched MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Cochrane, and Science Citation Index from date of inception until October 16th 2016. Reference lists of included studies and relevant systematic reviews were hand-searched. We included primary studies in English that reported any adverse events from intrapartum antibiotics for any prophylactic purpose compared to controls. The search was not restricted to prophylaxis for GBS but excluded women with symptoms of infection or undergoing caesarean section. Two reviewers assessed the methodological quality of studies, using the Cochrane Risk of Bias tool, and the Risk of Bias Assessment Tool for Nonrandomised Studies. Results were synthesised narratively and displayed in text and tables. RESULTS: From 2364 unique records, 30 studies were included. Despite a wide range of adverse events reported in 17 observational studies and 13 randomised controlled trials (RCTs), the evidence was inconsistent and at high risk of bias. Only one RCT investigated the long-term effects of IAP reporting potentially serious outcomes such as cerebral palsy; however, it had limited applicability and unclear biological plausibility. Seven observational studies showed that IAP for maternal GBS colonisation alters the infant microbiome. However, study populations were not followed through to clinical outcomes, therefore clinical significance is unknown. There was also observational evidence for increased antimicrobial resistance, however studies were at high or unclear risk of bias. CONCLUSIONS: The evidence base to determine the frequency of adverse events from intrapartum antibiotic prophylaxis for neonatal GBS disease prevention is limited. As RCTs may not be possible, large, better quality, and longitudinal observational studies across countries with widespread IAP could fill this gap. TRIAL REGISTRATION: CRD42016037195 .

Characterization of a cerebral palsy-like model in rats: Analysis of gait pattern and of brain and spinal cord motor areas.

In an attempt to propose an animal model that reproduces in rats the phenotype of cerebral palsy, this study evaluated the effects of maternal exposure to bacterial endotoxin associated with perinatal asphyxia and sensorimotor restriction on gait pattern, brain and spinal cord morphology. Two experimental groups were used: Control Group (CTG) - offspring of rats injected with saline during pregnancy and Cerebral Palsy Group (CPG) - offspring of rats injected with lipopolysaccharide during pregnancy, submitted to perinatal asphyxia and sensorimotor restriction for 30days. At 29days of age, the CPG exhibited coordination between limbs, weight-supported dorsal steps or weight-supported plantar steps with paw rotation. At 45days of age, CPG exhibited plantar stepping with the paw rotated in the balance phase. An increase in the number of glial cells in the primary somatosensory cortex and dorsal striatum were observed in the CPG, but the corpus callosum thickness and cross-sectional area of lateral ventricle were similar between studied groups. No changes were found in the number of motoneurons, glial cells and soma area of the motoneurons in the ventral horn of spinal cord. The combination of insults in the pre, peri and postnatal periods produced changes in hindlimbs gait pattern of animals similar to those observed in diplegic patients, but motor impairments were attenuated over time. Besides, the greater number of glial cells observed seems to be related to the formation of a glial scar in important sensorimotor brain areas.

Systemic corticosteroid regimens for prevention of bronchopulmonary dysplasia in preterm infants.

BACKGROUND: Cochrane systematic reviews show that systemic postnatal corticosteroids reduce the risk of bronchopulmonary dysplasia (BPD) in preterm infants. However, corticosteroids have also been associated with an increased risk of neurodevelopmental impairment. It is unknown whether these beneficial and adverse effects are modulated by differences in corticosteroid treatment regimens. OBJECTIVES: To assess the effects of different corticosteroid treatment regimens on mortality, pulmonary morbidity, and neurodevelopmental outcome in very low birth weight (VLBW) infants. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 2) in the Cochrane Library (searched 21 March 2016), MEDLINE via PubMed (1966 to 21 March 2016), Embase (1980 to 21 March 2016), and CINAHL (1982 to 21 March 2016). We also searched clinical trials' databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing two or more different treatment regimens of systemic postnatal corticosteroids in preterm infants at risk for BPD, as defined by the original trialists. Studies investigating one treatment regimen of systemic corticosteroids to a placebo or studies using inhalation corticosteroids were excluded. DATA COLLECTION AND ANALYSIS: Two authors independently assessed eligibility and quality of trials and extracted data on study design, participant characteristics and the relevant outcomes. We asked the original investigators to verify if data extraction was correct and, if possible, to provide any missing data. The primary outcomes to be assessed were: mortality at 36 weeks' postmenstrual age (PMA) or at hospital discharge; BPD defined as oxygen dependency at 36 weeks' PMA; long-term neurodevelopmental sequelae, including cerebral palsy, measured by the Bayley Mental Developmental Index (MDI); and blindness or poor vision. Secondary outcomes were: duration of mechanical ventilation and failure to extubate at day 3 and 7 after initiating therapy; rescue treatment with corticosteroids outside the study period; and the incidence of hypertension, sepsis and hyperglycemia during hospitalizations. Data were analyzed using Review Manager 5 (RevMan 5). We used the GRADE approach to assess the quality of evidence. MAIN RESULTS: Fourteen studies were included in this review. Only RCTs investigating dexamethasone were identified. Eight studies enrolling a total of 303 participants investigated the cumulative dosage administered; three studies contrasted a high versus a moderate and five studies a moderate versus a low cumulative dexamethasone dose.Analysis of the studies investigating a moderate dexamethasone dose versus a high-dosage regimen showed an increased risk of BPD (typical risk ratio (RR) 1.50, 95% confidence interval (CI) 1.01 to 2.22; typical risk difference (RD) 0.26, 95% CI 0.03 to 0.49; number needed to treat for an additional harmful outcome (NNTH) 4, 95% CI 1.9 to 23.3; I² = 0%, 2 studies, 55 infants) as well as an increased risk of abnormal neurodevelopmental outcome (typical RR 8.33, 95% CI 1.63 to 42.48; RD 0.30, 95% CI 0.14 to 0.46; NNTH 4, 95% CI 2.2 to 7.3; I² = 68%, 2 studies, 74 infants) when using a moderate cumulative-dosage regimen. The composite outcomes of death or BPD and death or abnormal neurodevelopmental outcome showed similar results although the former only reached borderline significance.There were no differences in outcomes between a moderate- and a low-dosage regimen.Four other studies enrolling 762 infants investigated early initiation of dexamethasone therapy versus a moderately early or delayed initiation and showed no significant differences in the primary outcomes. The two RCTs investigating a continuous versus a pulse dexamethasone regimen showed an increased risk of the combined outcome death or BPD when using the pulse therapy. Finally, two trials investigating a standard regimen versus a participant-individualized course of dexamethasone showed no difference in the primary outcome and long-term neurodevelopmental outcomes.The quality of evidence for all comparisons discussed above was assessed as low or very low, because the validity of all comparisons is hampered by small samples of randomized infants, heterogeneity in study population and design, non-protocolized use of 'rescue' corticosteroids and lack of long-term neurodevelopmental data in most studies. AUTHORS' CONCLUSIONS: Despite the fact that some studies reported a modulating effect of treatment regimens in favor of higher-dosage regimens on the incidence of BPD and neurodevelopmental impairment, recommendations on the optimal type of corticosteroid, the optimal dosage, or the optimal timing of initiation for the prevention of BPD in preterm infants cannot be made based on current level of evidence. A well-designed large RCT is urgently needed to establish the optimal systemic postnatal corticosteroid dosage regimen.

Caracterização de um modelo de paralisia cerebral em ratos: cognição e estrutura do hipocampo e amígdala / Characterization of a model of cerebral palsy in rats: cognition and structureof the hippocampus and amygdala

FUNDAMENTO: A paralisia cerebral (PC) é caracterizada por distúrbios do movimento e da postura, que podem estar associados a déficits cognitivos. Tais comprometimentos são atribuídos a lesões não progressivas ao encéfalo em desenvolvimento. No âmbito experimental, modelos animais dessa condição clínica capazes de reproduzir o fenótipo e as alterações estruturais vistas em humanos são escassos. OBJETICO: Investigar as repercussões da indução de um modelo de PC sobre a função cognitiva e estrutura do hipocampo e amígdala em ratos Wistar. MÉTODOS: Dois grupos experimentais foram utilizados: 1) Controle - filhotes de ratas injetadas com solução salina durante a gestação (n=8) e 2) Paralisia cerebral - filhotes de ratas injetadas com Lipopolissacarídeo (LPS) durante a gestação (n=8), submetidos à anóxia perinatal e restrição sensório-motora durante 30 dias. A memória espacial dos animais foi avaliada pela tarefa de reconhecimento da localização de objetos, enquanto o comportamento do tipo ansioso foi verificado pelo teste de labirinto em cruz elevado. Após a avaliação comportamental, os animais foram eutanasiados e os encéfalos dissecados para posterior processamento histológico. RESULTADOS: O grupo PC apresentou déficits de memória espacial e uma redução do número de neurônios granulares no giro denteado. Entretanto o comportamento do tipo ansioso e a histologia do núcleo central e complexo basolateral da amígdala foram semelhantes entre os grupos. CONCLUSÃO: Como observado em parte dos pacientes com PC, este modelo experimental prejudica a memória dependente do hipocampo. Entretanto, a combinação de intervenções não alterou a ansiedade e estrutura da amígdala.

BASIS: Cerebral palsy (CP) is a disorder of movement and posture, which may be associated with cognitive impairments. Such clinical condition is caused by non progressive injuries ocurred during the brain development. In the experimental context, animal models of this condition that can reproduce the phenotype and the structural changes seen in humans are scarce. OBJECTIVE: The present study investigated cognitive function and hippocampus and amygdala structure in rats submitted to a CP model. METHODS: Two experimental groups were used: 1) Control - offspring of rats injected with saline during pregnancy (n = 8) and 2) Cerebral Palsy - offspring of rats injected with lipopolysaccharide (LPS) during pregnancy (n = 8), submitted to perinatal anoxia and sensorimotor restriction for 30 days. The spatial memory was evaluated by the object-placement recog- nition task and anxiety like-behavior by elevated plus maze test. After the behavioral assessment, animals were euthanized and brains dissected for histological processing. RESULTS: The PC group showed spatial memory deficits and a reduction of granule neurons in the dentate gyrus. However, the anxiety like-behavior and the number of neurons in central nucleus and basolateral complex of the amygdala were similar between studied groups. CONCLUSION: This animal model affects the hippocampus dependent memory, a deficit seen in part of CP patients. However, the interventions used did not alter the anxiety like-behavior and amygdala structure.

Interpreting risk as evidence of causality: lessons learned from a legal case to determine medical malpractice.

Translating risk estimates derived from epidemiologic study into evidence of causality for a particular patient is problematic. The difficulty of this process is not unique to the medical context; rather, courts are also challenged with the task of using risk estimates to infer evidence of cause in particular cases. Thus, an examination of how this is done in a legal context might provide insight into when and how it is appropriate to use risk information as evidence of cause in a medical context. A careful study of the case of Goodman v. Viljoen, a medical malpractice suit litigated in the Ontario Superior Court of Justice in 2011, reveals different approaches to how risk information is used as or might be considered a substitute for evidence of causation, and the pitfalls associated with these approaches. Achieving statistical thresholds, specifically minimizing the probability of falsely rejecting the null hypothesis, and exceeding a relative risk of 2, plays a significant role in establishing causality of the particular in the legal setting. However, providing a reasonable explanation or establishing "biological plausibility" of the causal association also seems important, and (to some) may even take precedent over statistical thresholds for a given context.

Adverse health effects in children of women exposed in utero to diethylstilbestrol (DES).

OBJECTIVE: Exposure to diethylstilbestrol (DES) in utero is associated with adverse health effects, including genital anomalies in women and men, and cancers in women. Animal studies showed birth defects and tumors in the offspring of DES exposed mice, revealing transgenerational transmission of DES effects. In humans, birth defects, such as hypospadias were observed in children of prenatally exposed women. The aim of this research was to further assess the health effects in children of prenatally exposed women. METHODS: In a retrospective cohort study, the reports of women exposed to DES in utero on their 4409 children were compared with those of unexposed women on their 6203 children. Comparisons used odd ratios (OR) between children of exposed and unexposed women and standardized incidence rate (SIR) with the general population. These cohorts were recruited on a voluntary basis to answer questionnaires. RESULTS: There was a global increase of defects in children born to exposed women when compared with those born to unexposed (OR 2.29, 95% CI: 1.80-2.79, P<0.001) and with the general population (SIR 2.39, 95% CI: 2.11-2.68). Increased defects were observed in male genital tract, esophagus, lip or palate, musculoskeletal and circulatory systems. For female genital tract anomalies, there was no significant increase. However, this cohort being relatively young, further follow-up is needed. An increase of cerebral palsy was revealed. The incidence of cancers was not increased, in particular for breast, uterus and ovary. CONCLUSION: Our results confirmed a transgenerational transmission of defects in male genital tract. With caution due to possible bias associated with this method, our data suggest an increase of defects for esophagus, lip or palate, musculoskeletal and circulatory system in children of exposed women.

The use of a physiologically-based extraction test to assess relationships between bioaccessible metals in urban soil and neurodevelopmental conditions in children.

Intellectual disability (ID) and cerebral palsy (CP) are serious neurodevelopment conditions and low birth weight (LBW) is correlated with both ID and CP. The actual causes and mechanisms for each of these child outcomes are not well understood. In this study, the relationship between bioaccessible metal concentrations in urban soil and these child conditions were investigated. A physiologically based extraction test (PBET) mimicking gastric and intestinal processes was applied to measure the bio-accessibility of four metals (cadmium (Cd), chromium (Cr), nickel (Ni), and lead (Pb)) in urban soil, and a Bayesian Kriging method was used to estimate metal concentrations in geocoded maternal residential sites. The results showed that bioaccessible metal concentrations of Cd, Ni, and Pb in the intestinal phase were statistically significantly associated with the child outcomes. Lead and nickel were associated with ID, lead and cadmium was associated with LBW, and cadmium was associated with CP. The total concentrations and stomach concentrations were not correlated to significant effects in any of the analyses. For lead, an estimated threshold value was found that was statistically significant in predicting low birth weight. The change point test was statistically significant (p value = 0.045) at an intestine threshold level of 9.2 mg/kg (95% confidence interval 8.9-9.4, p value = 0.0016), which corresponds to 130.6 mg/kg of total Pb concentration in the soil. This is a narrow confidence interval for an important relationship.

Diethylstilbestrol (DES): also harms the third generation.

Diethylstilbestrol(DES) is a synthet- ic nonsteroidal oestrogen and endo- crine disruptor that was used in the 1950s-1970s to prevent spontaneous abortion, despite its lack of proven efficacy. Millions of women worldwide took DES during pregnancy. In France, between 1951 and 1981, about 160 000 children were exposed to DES during the first trimester of their intrauterine life, and in some cases almost throughout the entire pregnancy. They are referred to as "DES daughters" and "DES sons". In 2010, in France, about 25 000 DES daughters were aged 33 to 40 years: pregnancies among these women are foreseeable until about 2020. In utero exposure to DES can have harmful effects. In particular, DES daughters have an increased risk of cancer and structural abnormalities of the uterus that can adversely affect their pregnancies. What are the consequences of tak- ing DES during pregnancy for the third generation, i.e. the children of DES children? To answer this question, we reviewed the available data in mid- 2016 using the standard Prescrire methodology. According to a retrospective study conducted in France by Réseau DES France, published in 2016, which included 4409 DES grandchildren (2228 girls and 2181 boys) and about 6000 controls, about one-quarter of DES grandchildren are born prematurely. Preterm delivery exposes neonates to serious neonatal complications, including neurosensory disorders, disabilities and increased neonatal mor- tality. The more premature the baby, the greater the risk of complications. In the Réseau DES France study, cerebral palsy was more frequent in the DES grandchildren group: 59/10 000, versus 6/10 000 in the control group. A study conducted in the United States in about 4500 DES daughters found that preterm delivery occurred at a frequency of about 26%, much higher than that reported in controls. Neonatal mortality was 8 times higher among DES grandchildren, and the risk of stillbirth was twice as high. Other smaller studies have also shown an increased risk of preterm birth. A cohort study conducted in about 5000 DES grandchildren found that the risk of malformations of any type was higher than in the unexposed control group. Epidemiological studies, conduct- ed in several countries, found an increased frequency of hypospadias in DES grandsons. The relative risk was about 5 in the largest study. Other, less robust studies found no statistically significant difference. Several studies in several countries have shown a twofold increase in the risk of oesophageal atresia or tracheo- oesophageal fistula in DES grandchildren. The data on congenital heart defects or musculoskeletal malformations are limited and uninformative. Epidemiological studies have not identified a significant increase in the risk of gynaecological anomalies or cancers in DES granddaughters. Limited data are available on the risk of malformations in the children of DES sons. The data obtained in rodents exposed to DES (and other endocrine disruptors) make it entirely plausible that in utero exposure to DES, in humans too, provokes epigenetic effects that are passed on to future generations not directly exposed to DES. In practice, these data should be discussed with DES daughters, their partners and healthcare teams so that appropriate monitoring, clinical man- agement and follow-up can be arranged for both mother and baby. The harms of taking DES during pregnancy last for decades and affect future generations.

Neuronal self-injury mediated by IL-1ß and MMP-9 in a cerebral palsy model of severe neonatal encephalopathy induced by immune activation plus hypoxia-ischemia.

BACKGROUND: Inflammation due to remote pathogen exposure combined to hypoxia/ischemia (HI) is one of the most common causes of neonatal encephalopathy affecting at-term or near-term human newborn, which will consequently develop cerebral palsy. Within term-equivalent rat brains exposed to systemic lipopolysaccharide (LPS) plus HI, it was previously showed that neurons produce IL-1ß earlier than do glial cells, and that blocking IL-1 was neuroprotective. To further define the mechanisms whereby IL-1 exerts its neurotoxic effect, we hypothesize that IL-1ß plays a pivotal role in a direct and/or indirect mechanistic loop of neuronal self-injury through matrix metalloproteinase (MMP)-9. METHODS: An established preclinical rat model of LPS+HI-induced neonatal encephalopathy was used. In situ hybridization, ELISA, and immunolabeling techniques were employed. Selective blocking compounds allowed addressing the respective roles of IL-1 and MMP-9. RESULTS: In LPS+HI-exposed forebrains, neuronal IL-1ß was first detected in infarcted neocortical and striatal areas and later in glial cells of the adjacent white matter. Neuronal IL-1ß played a key role: (i) in the early post-HI exacerbation of neuroinflammation and (ii) in generating both core and penumbral infarcted cerebral areas. Systemically administered IL-1 receptor antagonist (IL-1Ra) reached the brain and bound to the neocortical and deep gray neuronal membranes. Then, IL-1Ra down-regulated IL-1ß mRNA and MMP-9 neuronal synthesis. Immediately post-HI, neuronal IL-1ß up-regulated cytokine-induced neutrophil chemoattractant (CINC-1), monocyte chemoattractant protein-1 (MCP-1), and inducible nitric oxide synthase. MMP-9 would disrupt the blood-brain barrier, which, combined to CINC-1 up-regulation, would play a role in polymorphonuclear cell (PMN) infiltration into the LPS+HI-exposed brain. IL-1ß blockade prevented PMN infiltration and oriented the phenotype of macrophagic/microglial cells towards anti-inflammatory and neurotrophic M2 profile. IL-1ß increased the expression of activated caspase-3 and of receptor-interacting-protein (RIP)-3 within infarcted forebrain area. Such apoptotic and necroptotic pathway activations were prevented by IL-1Ra, as well as ensuing cerebral palsy-like brain damage and motor impairment. CONCLUSIONS: This work uncovered a new paradigm of neuronal self-injury orchestrated by neuronal synthesis of IL-1ß and MMP-9. In addition, it reinforced the translational neuroprotective potential of IL-1 blockers to alleviate human perinatal brain injuries.