During pregnancy, maternal endocrine signals drive fetal development and program the offspring's physiology. A disruption of maternal glucocorticoid (GC) homeostasis increases the child's risk of developing psychiatric disorders later in life. We here show in mice, that the time of day of antenatal GC exposure predicts the behavioral phenotype of the adult offspring. Offspring of mothers receiving GCs out-of-phase compared to their endogenous circadian GC rhythm show elevated anxiety, impaired stress coping, and dysfunctional stressaxis regulation. The fetal circadian clock determines the vulnerability of the stress axis to GC treatment by controlling GC receptor (GR) availability in the hypothalamus. Similarly, a retrospective observational study indicates poorer stress compensatory capacity in 5-year old preterm infants whose mothers received antenatal GCs towards the evening. Our findings offer insights into the circadian physiology of feto-maternal crosstalk and assign a role to the fetal clock as a temporal gatekeeper of GC sensitivity.
Aim: To analyze short term outcomes of very low birth weight infants (VLBWI) born preterm after maternal preeclampsia and HELLP syndrome within the German Neonatal Network. Methods: The German Neonatal Network is a large population-based cohort study enrolling VLBWI since 2009. Two thousand six hundred and fifty two infants below 32 weeks of gestation born after maternal preeclampsia or HELLP syndrome and 13,383 infants born prematurely for other causes between 2009 and 2018 were included in our analysis. Descriptive statistics and multinomial regression models including preeclampsia and HELLP syndrome were performed for short-term outcome measures such as intracerebral hemorrhage, necrotizing enterocolitis requiring surgery, bronchopulmonary dysplasia, retinopathy of prematurity, periventricular leukomalacia, persistent ductus arteriosus requiring surgery, blood culture positive sepsis and death. Results: After adjustment for confounding variables, preterm birth due to preeclampsia or HELLP syndrome was associated with a reduced risk for intracerebral hemorrhage (OR 0.73, 95% CI 0.60–0.89), necrotizing enterocolitis requiring surgery (OR 0.35 95% CI 0.15–0.82), periventricular leukomalacia (OR 0.61 95% CI 0.40–0.92), and death (OR 0.72 95% CI 0.55–0.96) as compared to other causes of preterm birth. Conclusions: The indication for preterm birth has an impact on neonatal outcome in preterm infants born below 32 weeks. This notion should be included when counseling the families.
the German neonatal network (Gnn) † Gastrointestinal complications during the neonatal period, i.e. necrotizing enterocolitis (nec) and spontaneous intestinal perforation (Sip), are associated with adverse short-term outcome in very-lowbirthweight infants (VLBWi, <1500 g birth weight). However, little is known about the neurological outcome of survivors at school age. We analysed data of 2241 infants followed-up at the age of 6 years. To determine the effect of NEC and SIP on cognitive outcome in consideration of other important confounding factors, we used multivariable logistic regression models. in addition, infants with surgical diagnosis of nec (n = 43) or SIP (n = 41) were compared to NEC (n = 43) or SIP (n = 41) negative controls using Mahalanobis distance matching. infants with a history for nec had a three times increased risk (RR 3.0 [1.8-4.2], p < 0.001) to develop IQ scores <85 while history of surgical SIP did not increase the relative risk for lower IQs at school age (RR 1.0 [0.4-2.1], p = 1.000). In a matched-cohort analysis, we confirmed that infants with surgical NEC had lower mean IQ results than unaffected controls (±SD) (85±17 vs. 94±14, p = 0.023) while no differences were found for history of SIP. Our results reflect that the different aetiology and inflammatory extent of NEC and SIP may lead to disparate neurodevelopment trajectories. Hence, our data suggest a potential role of early gut-brain axis distortion in infants with nec which needs to be further explored. Necrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP) are typical gastrointestinal complications in very-low-birthweight infants (VLBWI) and have a remarkable impact on mortality and long-term morbidity in this vulnerable group 1-4. In VLBWI, NEC mainly occurs during day 14-28 of life 5 and seems to have multifactorial facets including genetic predisposition, intestinal immaturity, inflammation, oxidative stress, ischemia, nutritional aspects and gut dysbiosis 2,6,7. SIP usually occurs in the first 14 days of life 8 and is mainly associated with extreme prematurity, use of non-steroidal and steroidal anti-inflammatory drugs and prolonged evacuation of meconium 9,10. Recently, we noted an increased SIP risk in infants <25 weeks of gestation who were primarily managed with less invasive respiratory care 3. Epidemiological data of infants with NEC or SIP show delayed neurodevelopment in early childhood 2,9,11 , but little is known about outcome at school age. Roze et al. found an increased rate of reduced intelligence quotient (IQ) and motor testing scores among children at school age who suffered from NEC or SIP 11 compared to controls without these complications. However, the authors did not adjust for confounding variables such as gestational age or maternal education level and did not differentiate between NEC and SIP.
Background and Purpose: Associations of APOE genotypes with intracerebral hemorrhage (ICH) in preterm infants were previously described. In adults, APOE-ε4 genotype has been proposed as susceptibility factor for impaired recovery after cerebral insult. We here aim to determine APOE genotype-specific neurological consequences of neonatal ICH at school age. Methods: In this multicenter observational cohort study, very low birth weight (<1500 g, <32 weeks gestational age) children were studied for cerebral palsy (CP) after ultrasound diagnosed ICH stratified by APOE genotype. Follow-up examination was done at the age of 5 to 6 years. Study personnel were blinded for perinatal information and complications. Participants were born between January 1, 2009 and December 31, 2013 and enrolled in the German Neonatal Network. Of 8022 infants primarily enrolled, 2467 children were invited for follow-up between January 1, 2014 and December 31, 2019. Univariate analyses and multivariate logistic regression models were used to assess the impact of APOE genotype (APOE-ε2, APOE-ε3, APOE-ε4) on CP after ICH. Results: Two thousand two hundred fifteen children participated at follow-up, including 363 children with ultrasound diagnosed neonatal ICH. In univariate analyses of children with a history of ICH, APOE-ε3 carriers had lower frequencies of CP (n=33/250; 13.2 [95% CI, 9.4%–17.8%]), as compared to APOE-ε2 (n=15/63; 23.8 [14.6%–35.3%], P =0.037) and –ε4 carriers (n=31/107; 29.0 [21.0%–38.0%], P <0.001), respectively. Regression models revealed an association of APOE-ε4 genotype and CP development (odds ratio, 2.77 [1.44–5.32], P =0.002) after ICH. Notably, at low-grade ICH (grade I) APOE-ε4 expression resulted in an increased rate of CP (n=6/39; 15.4 [6.7–29.0]) in comparison to APOE-ε3 (n=2/105; 1.9 [0.4%–6.0%], P =0.002). Conclusions: APOE-ε4 carriers have an increased risk for long-term motor deficits after ICH. We assume an effect even after low-grade neonatal ICH, but more data are needed to clarify this issue.
Preterm infants are at particularly high risk for infectious diseases. As this vulnerability extends beyond the neonatal period into childhood and adolescence, preterm infants benefit greatly from infection-preventive measures such as immunizations. However, there is an ongoing discussion about vaccine safety and efficacy due to preterm infants’ distinct immunological features. A significant proportion of infants remains un- or under-immunized when discharged from primary hospital stay. Educating health care professionals and parents, promoting maternal immunization and evaluating the potential of new vaccination tools are important means to reduce the overall burden from infectious diseases in preterm infants. In this narrative review, we summarize the current knowledge about vaccinations in premature infants. We discuss the specificities of early life immunity and memory function, including the role of polyreactive B cells, restricted B cell receptor diversity and heterologous immunity mediated by a cross-reactive T cell repertoire. Recently, mechanistic studies indicated that tissue-resident memory (Trm) cell populations including T cells, B cells and macrophages are already established in the fetus. Their role in human early life immunity, however, is not yet understood. Tissue-resident memory T cells, for example, are diminished in airway tissues in neonates as compared to older children or adults. Hence, the ability to make specific recall responses after secondary infectious stimulus is hampered, a phenomenon that is transcriptionally regulated by enhanced expression of T-bet. Furthermore, the microbiome establishment is a dominant factor to shape resident immunity at mucosal surfaces, but it is often disturbed in the context of preterm birth. The proposed function of Trm T cells to remember benign interactions with the microbiome might therefore be reduced which would contribute to an increased risk for sustained inflammation. An improved understanding of Trm interactions may determine novel targets of vaccination, e.g., modulation of T-bet responses and facilitate more individualized approaches to protect preterm babies in the future.
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