Impact of the COVID-19 Pandemic Regulations on the Health Status and Medical Care of Children with Trisomy 21.

BACKGROUND: While children are considered at low risk for COVID-19, little is known about the impact of SARS-CoV-2 on paediatric risk patients like children with Trisomy 21 (T21). As these children often need regular therapy and various medical appointments, this study aimed to investigate the possible impact of the COVID-19 pandemic on children with T21. PATIENTS AND METHODS: Parents of children with T21 in the age of 0-12 years in Saxony-Anhalt were interviewed via phone in June 2021 regarding the health status and medical care of their children during the past 15 months of pandemic. RESULTS: 37 children with mean age of 6.1 years (min 0; max 12) were included in the study. The majority did not have any additional congenital anomalies. Surveyed parents hardly reported adverse changes of health status during the pandemic, but rather improvements, such as decreased number of respiratory infections and more time spend with their children. Outpatient appointments and therapy were cancelled or postponed at the onset of the pandemic, but parents reported low impact on their child's health and development. The main concern seemed to be lack of childcare during school and day-care closures and uncertainty concerning possible health impacts of an infection on their children. CONCLUSION: There was low impact of the COVID-19 pandemic on health and medical care of children with T21 in our study population. Further research is needed to help weigh the child's individual risk of infection against the need for medical treatment and therapy when dealing with paediatric risk patients.

A very preterm infant born to mother of mirror syndrome secondary to fetomaternal hemorrhage: a case report.

BACKGROUND: Mirror syndrome (MS) is defined as maternal edema with fetal hydrops and placental edema with different etiologies, such as rhesus isoimmunization and twin-twin transfusion syndrome. Herein, we showcased a unique MS case secondary to fetomaternal hemorrhage (FMH). CASE PRESENTATION: A 32-year-old gravida 2 para 0 woman diagnosed with fetal hydrops was admitted to our hospital. Maternal laboratory tests revealed anemia, slightly increased creatinine and uric acid levels, hypoproteinemia, and significantly increased alpha-fetoprotein and hemoglobin-F levels. Therefore, FMH was diagnosed initially. Two days after admission, the woman had unexpectedly progressive anasarca and started to feel chest distress, palpitations, lethargy, and oliguria, and MS was suspected. An emergency cesarean section was performed to terminate the pregnancy. The maternal clinical symptoms and laboratory tests rapidly improved after delivery. A very preterm infant with a 2080-g birthweight at 31 weeks gestation survived after emergency cesarean section, active resuscitation, emergency blood transfusion, abdominocentesis, and advanced life support. CONCLUSIONS: FMH could develop into MS, providing new insights into the etiology of MS. Once MS is diagnosed, emergency cesarean section might be an alternative treatment. The very preterm infant survived with a favorable long-term outcome, and a well-trained perinatal work team is needed for such cases.

Practical Experience of Establishing German Standard Level 1 Perinatal Center in Chongqing Health Care for Women and Children.

Germany, as a western developed country, has an advanced medical level, especially in the health care of very immature premature infants. We trace the medical history of perinatology to understand the development of perinatal centers in Germany. After analyzing the classification and function, hierarchical management and quality control systems of German perinatal centers, we established a German standard level 1 perinatal center in the Chongqing Health Center for Women and Children (CHCWC). During more than two years of practice, we changed concepts, continuously updated clinical knowledge and skills, developed a series of high-quality work processes and supervision systems and introduced advanced medical equipment. We believe that the experience of establishing a German standard level 1 perinatal center and perinatal center network in Chongqing is worthy of being promoted to the Chinese maternal and child health care system.

Children From the Age of Three Show a Developmental Switch in T-Cell Differentiation.

Every sixth child suffers from hypertrophy of the adenoid, a secondary lymphoid organ, at least once in childhood. Little is known about the impact of pathogen-provocation vs. developmental impact on T-cell responses after 1 year of age. Therefore, developmental and infection-driven influences on the formation of T-cell-compartments and -multifunctionality in adenoids were analyzed taking into account patient's history of age and inflammatory processes. Here, we show that in adenoids of 102 infants and children similar frequencies of naïve, effector, and memory T-cells were accumulated, whereby history of suffering from subsequent infection symptoms resulted in lower frequencies of CD4+ and CD8+ T-cells co-expressing several cytokines. While patients suffering from sole nasal obstruction had balanced Th1- and Th17-compartments, Th1 dominated in patients with concomitant upper airway infections. In addition, analysis of cytokine co-expressing CD4+ and CD8+ T-cells showed that children at the age of three or older differed significantly from those being 1- or 2-years old, implicating a developmental switch in T-cell differentiation at that age. Yet, dissecting age and infectious history of the patients revealed that while CD8+ T-cell differentiation seems to be triggered by development, CD4+ T-cell functionality is partly impaired by infections. However, this functionality recovers by the age of 3 years. Thus, 3 years of age seems to be a critical period in an infant's life to develop robust T-cell compartments of higher quality. These findings identify important areas for future research and distinguish an age period in early childhood when to consider adjusting the choice of treatment of infections.

Periconceptional folic acid supplement use among women of reproductive age and its determinants in central rural Germany: Results from a cross sectional study.

BACKGROUND: Prevalence of neural tube defects (NTD) has not decreased in Germany despite longstanding recommendations for folic acid supplementation. To examine the prevalence of periconceptional folic acid supplement use and associated factors among German women of reproductive age. METHODS: Cross-sectional survey was conducted in hospital-based maternity units in rural Germany. A sample of 1,004 women of reproductive age, either pregnant or in their early postpartum period, took interviewer/self-administered paper-based survey questionnaire. Prevalence of periconceptional folic acid supplement use was assessed, where periconception was defined as 1 month prior to and 3 months post-conception. Prevalence odds ratios (POR) and 95% confidence intervals (CI) using crude and adjusted logistic regression analysis were estimated to examine determinants of folic acid supplement use. RESULTS: Prevalence of folic acid supplement use was 41.5% (95% CI: 37.7%, 45.7%). Multivariable analysis showed lack of educational qualifications, unplanned pregnancy, later diagnosis of pregnancy, increased parity, and not having an awareness of importance of folic acid for optimal pregnancy outcomes were associated with not taking periconceptional folic acid supplements. Books, doctors, friends, media, were sources of information. CONCLUSION: Periconceptional folic acid is sub-optimal in rural Germany and thus failing to prevent NTDs. Targeted promotion of folic acid supplement use should be conducted periodically by gynecologists and primary care physicians during annual medical screenings. Mandatory folic acid fortification of staple foods is a complementary approach to overcome limitations of individual behaviors of folic acid supplement intake, and should be considered as it has been proven effective in multiple countries.

The impact of neuropsychiatric disease on fetal growth: a case-control study.

PURPOSE: To determine the impact of depression, epilepsy and drug abuse during pregnancy on delivery and fetal outcome. Due to the worldwide increasing prevalence of neurological and psychiatric diseases and drug abuse, the number of affected pregnant women is increasing. METHODS: A large-scale retrospective case-control analysis of pregnancies affected by depression, epilepsy or drug abuse with and without medication was conducted in two German perinatal centres between 2013 and 2017. The case group consisted of 706 pregnant women who had a diagnosis of depression, epilepsy or drug abuse vs. 12,574 pregnant women without neuropsychiatric diagnosis (control group). The analysis included the rate of intrauterine growth restriction, birth weight and length, neonatal head circumference. RESULTS: Significant differences in the subgroups were found in the parameters intrauterine growth restriction, birth weight, length and head circumference. Women with epilepsy were affected less often than women with depression and substance abuse. Major differences were found in the group of women with substance abuse. Negative associations were found within the non-pharmacologically managed disease group itself compared to women exposed to medication. CONCLUSION: The present results demonstrated a negative association between maternal neurological or psychiatric disease and pregnancy outcome in the examined parameters. However, the non-pharmacologically treated maternal disease was identified as a risk factor itself.

The prone sleeping position and SIDS. Historical aspects and possible pathomechanisms.

The incidence of SIDS decreased during the previous 25 years significantly. This is mainly due to epidemiological research identifying important risk factors such as prone sleeping position and subsequent campaigns to reduce this risk factor.Originally, the prone sleeping position for babies had been strongly recommended in the sixties and seventies despite previous publications pointed to the associated risk. Worldwide, many infants died of SIDS whose deaths could have been avoided. Today, the recommendation that infants should sleep in supine position has been scientifically verified. In supine sleeping position, pathophysiological mechanisms can be avoided which may lead to hypoxia and death in prone position. Such mechanisms could be occlusion of airways (in particularly associated with face-down position), elevated diaphragm, positional cerebral hypoxia caused by constriction of arteries, rebreathing CO2, and overheating.Irrespective of the specific pathomechanism leading to death in individual cases, it has been established that the prone position is the most important risk factor for SIDS and therefore should be incorporated in the definition of the term SIDS.

T Cells of Infants Are Mature, but Hyporeactive Due to Limited Ca2+ Influx.

CD4 T cells in human infants and adults differ in the initiation and strength of their responses. The molecular basis for these differences is not yet understood. To address this the principle key molecular events of TCR- and CD28-induced signaling in naive CD4 T cells, such as Ca2+ influx, NFAT expression, phosphorylation and translocation into the nucleus, ERK activation and IL-2 response, were analyzed over at least the first 3 years of life. We report dramatically reduced IL-2 and TNFα responses in naive CD31+ T cells during infancy. Looking at the obligatory Ca2+ influx required to induce T cell activation and proliferation, we demonstrate characteristic patterns of impairment for each stage of infancy that are partly due to the differential usage of Ca2+ stores. Consistent with those findings, translocation of NFATc2 is limited, but still dependent on Ca2+ influx as demonstrated by sensitivity to cyclosporin A (CsA) treatment. Thus weak Ca2+ influx functions as a catalyst for the implementation of restricted IL-2 response in T cells during infancy. Our studies also define limited mobilization of Ca2+ ions as a characteristic property of T cells during infancy. This work adds to our understanding of infants' poor T cell responsiveness against pathogens.

CTLA-4 (CD152) enhances the Tc17 differentiation program.

Although CD8(+) T cells that produce IL-17 (Tc17 cells) have been linked to host defense, Tc17 cells show reduced cytotoxic activity, which is the characteristic function of CD8(+) T cells. Here, we show that CTLA-4 enhances the frequency of IL-17 in CD8(+) T cells, indicating that CTLA-4 (CD152) specifically promotes Tc17 differentiation. Simultaneous stimulation of CTLA-4(+/+) and CTLA-4(-/-) T cells in cocultures and agonistic CTLA-4 stimulation unambiguously revealed a cell-intrinsic mechanism for IL-17 control by CTLA-4. The quality of CTLA-4-induced Tc17 cells was tested in vivo, utilizing infection with the facultative intracellular bacterium Listeria monocytogenes (LM). Unlike CTLA-4(+/+) Tc17 cells, CTLA-4(-/-) were nearly as efficient as Tc1 CTLA-4(+/+) cells in LM clearance. Additionally, adoptively transferred CTLA-4(-/-) Tc17 cells expressed granzyme B after rechallenge, and produced Tc1 cytokines such as IFN-γ and TNF-α, which strongly correlate with bacterial clearance. CTLA-4(+/+) Tc17 cells demonstrated a high-quality Tc17 differentiation program ex vivo, which was also evident in isolated IL-17-secreting Tc17 cells, with CTLA-4-mediated enhanced upregulation of Tc17-related molecules such as IL-17A, RORγt, and IRF-4. Our results show that CTLA-4 promotes Tc17 differentiation that results in robust Tc17 responses. Its inactivation might therefore represent a central therapeutic target to enhance clearance of infection.

CD4+ T cells from human neonates and infants are poised spontaneously to run a nonclassical IL-4 program.

Senescence or biological aging impacts a vast variety of molecular and cellular processes. To date, it is unknown whether CD4(+) Th cells display an age-dependent bias for development into specific subpopulations. In this study, we show the appearance of a distinct CD4(+) T cell subset expressing IL-4 at an early stage of development in infant adenoids and cord blood that is lost during aging. We identified by flow cytometric, fluorescent microscopic, immunoblot, and mass spectrometric analysis a population of CD4(+) T cells that expressed an unglycosylated isoform of IL-4. This T cell subpopulation was found in neonatal but not in adult CD4(+) T cells. Furthermore, we show that the mRNA of the Th2 master transcription factor GATA3 is preferentially expressed in neonatal CD4(+) T cells. The Th2 phenotype of the IL-4(+)CD4(+) T cells could be reinforced in the presence of TGF-ß. Although the IL-4(+)CD4(+) T cells most likely originate from CD31(+)CD4(+) T recent thymic emigrants, CD31 was downregulated prior to secretion of IL-4. Notably, the secretion of IL-4 requires a so far unidentified trigger in neonatal T cells. This emphasizes that cytokine expression and secretion are differentially regulated processes. Our data support the hypothesis of an endogenously poised cytokine profile in neonates and suggest a link between cytokine production and the developmental stage of an organism. The determination of the IL-4 isoform-expressing cells in humans might allow the identification of Th2 precursor cells, which could provide novel intervention strategies directed against Th2-driven immunopathologies such as allergies.

Risk for late-onset blood-culture proven sepsis in very-low-birth weight infants born small for gestational age: a large multicenter study from the German Neonatal Network.

BACKGROUND: It was the aim of this study to assess whether very-low-birth-weight (VLBW) infants born small for gestational age (SGA; birth weight less than 10th percentile) are at increased risk for late-onset sepsis. METHODS: This was a prospective, multicenter study of the German Neonatal Network including VLBW infants from 23 to < 32 weeks post menstrual age born 2009-2011. Outcomes were compared between VLBW infants born SGA (birth weight less than tenth percentile according to gestational age and gender) and non-SGA infants. The main outcome measure was at least 1 episode of late-onset sepsis defined as blood-culture-confirmed clinical sepsis occurring at ≥ 72 hours of age. RESULTS: 5886 VLBW infants were included. In SGA infants (n = 692), an increased incidence of late-onset sepsis was noted compared with non-SGA infants (20.1% vs. 14.3 %, P < 0.001). This difference was only observed among infants with a gestational age of 27 to < 32 weeks and attributed to sepsis episodes with coagulase-negative staphylococci (12.8% vs. 8.3%, P < 0.001). Different treatment modalities (eg more frequent use of central venous lines) and longer duration of invasive therapies (parenteral nutrition, mechanical ventilation, hospitalization) may account for the increased sepsis risk with coagulase-negative staphylococci in our SGA cohort. In a multivariate logistic regression analysis, higher gestational age [per week; odds ratio (OR): 0.75, 95% confidence interval (CI): 0.72-0.78, P< 0.0001], treatment with antenatal steroids (OR: 0.7, 95% CI: 0.53-0.92, P = 0.01), German descendance (OR: 0.76, 95% CI: 0.63-0.91, P = 0.003) and prophylaxis with glycopeptide antibiotics (OR: 0.64, 95% CI: 0.47-0.87, P = 0.005) were shown to be protective against late-onset sepsis. In contrast, longer duration of parenteral nutrition (per day; OR: 1.016, 95% CI: 1.011-1.021, P < 0.0001) and SGA were found to be risk factors (OR: 1.31, 95% CI: 1.02-1.68, P= 0.03). CONCLUSIONS: SGA contributes to the risk of late-onset sepsis in VLBW infants. Future studies are needed to investigate the underlying pathophysiology to guide individualized preventive measures in this vulnerable subgroup.

Neuroblastoma triggers an immunoevasive program involving galectin-1-dependent modulation of T cell and dendritic cell compartments.

The immunosuppressive strategies devised by neuroblastoma (NB), the most common solid extracranial childhood cancer, are poorly understood. Here, we identified an immunoevasive program triggered by NB through secretion of galectin-1 (Gal-1), a multifunctional glycan-binding protein. Human and mouse NB cells express and secrete Gal-1, which negatively regulates T cell and dendritic cell function. When injected subcutaneously in syngeneic A/J mice, knockdown transfectants expressing low amounts of Gal-1 (NXS2/L) showed reduction of primary tumor growth by 83-90% and prevented spontaneous liver metastases in contrast to NXS2 cell variants (NXS2/H, NXS2 wildtype) expressing high amounts of Gal-1. Splenocytes from mice receiving Gal-1 knockdown NXS2/L cells secreted higher amounts of IFN-γ and displayed enhanced cytotoxic T-cell function compared to NXS2/H or NXS2 controls. Immunohistochemical analysis revealed a six- to tenfold increase in the frequency of CD4+ and CD8+ T cells infiltrating tumors from mice receiving knockdown transfectants. This effect was confirmed by in vitro migration assays. Finally, supernatants of NXS2/H or NXS2 cells suppressed dendritic cell (DC) maturation and induce T cell apoptosis, whereas these effects were only marginal on DCs and T cells exposed to supernatants from NXS2/L cells. These results demonstrate a novel immunoinhibitory role of the Gal-1-glycan axis in NB, highlighting an alternative target for novel immunotherapeutic modalities.

Dependence of neonatal small and large for gestational age rates on maternal height and weight--an analysis of the German Perinatal Survey.

Neonatal anthropometric data reflect intrauterine development and correlate with postnatal outcome. Therefore, classification of neonates by body dimensions, using gestational age-adjusted population percentiles, is clinically practiced. However, neonatal anthropometric variables are also influenced by maternal constitution and the extent of this influence is currently unknown. We analyzed small for gestational age (SGA) and large for gestational age (LGA) rates according to maternal height and weight. We used data of about 2.3 million singleton pregnancies from the German Perinatal Survey of 1995-2000. A close correlation between maternal and neonatal anthropometric data was found; SGA rates were inversely proportional and LGA rates were directly proportional to maternal height, weight, and body mass index. Neonates of small and light mothers (<155 cm, <50 kg) had, according to the presently used classification scheme, an SGA rate of 25.3% and an LGA rate of 1.7%, respectively. Newborns to tall and heavy women (>179 cm, >89 kg) had a much lower SGA rate (3.1%) and a much higher LGA rate (30.6%). Neonatal body length and head circumference depended on maternal stature in a similar way. Some neonates who are "appropriate" for their gestational age in that they achieve their genetically determined growth potential are therefore apparently misclassified as SGA or LGA.

Birth weight percentile charts based on daily measurements for very preterm male and female infants at the age of 154-223 days.

OBJECTIVE: Birth weight percentiles based on weekly measurements are used to assess the nutritional status of preterm infants. However, as preterm infants exhibit a rapid growth rate (up to 20 g/kg/day), their body weight can increase by 15% per week. We calculated birth weight percentiles based on daily measurements, to more precisely classify very preterm infants (gestational age of 154-223 days). METHODS: Data of 23,864 (10,720 females and 13,144 males) very preterm singleton infants with a gestational age of 154-223 days (22-31 completed weeks) were retrieved from the German perinatal statistics of 1995-2000. Percentile curves based on the empirical birth weight data were subjected to three statistical smoothing procedures: cubic regression, local regression (LOESS smoothing), and the LMS method. RESULTS: Smoothing of the birth weight percentiles using cubic regression produced the smallest residual variance. CONCLUSION: Birth weight percentiles based on daily averages allow a more precise assessment of the somatic development of preterm infants.

Investigation of the association of Apgar score with maternal socio-economic and biological factors: an analysis of German perinatal statistics.

PURPOSE: To examine the relationship of 5-min Apgar score with maternal socio-economic and biological factors. METHODS: We analyzed data from 465,964 singleton pregnancies (37-41 weeks' gestation) from the German perinatal statistics of 1998-2000. Using a logistic regression model we analyzed the incidence of low (0-6) 5-min Apgar scores in relation to these maternal factors: body mass index (BMI), age, previous live births, country of origin, occupation, single mother status, working during pregnancy, and smoking. RESULTS: A low Apgar score was more common in overweight [adjusted odds ratio (OR) 1.24; 95% confidence interval (CI) 1.10-1.40; P < 0.001] and obese [OR 1.92 (95% CI 1.67-2.20); P < 0.001] compared to normal weight women. A low Apgar score was also more common for women aged >35 years compared to those aged 20-35 years [OR 1.35 (95% CI 1.16-1.58); P < 0.001]. Furthermore, odds of a low Apgar score were higher for women with no previous live births compared to those with one or more previous live births [OR 1.52 (95% CI 1.37-1.70); P < 0.001]. Socio-economic factors did not convincingly influence Apgar scores. CONCLUSIONS: There was an influence of the biological maternal factors age, BMI, and parity on the 5-min Apgar score. There was no convincing effect of socio-economic factors on Apgar score in our study population. Possible reasons for this are discussed.

Sleep environment risk factors for sudden infant death syndrome: the German Sudden Infant Death Syndrome Study.

OBJECTIVE: Our goal was to investigate the risk factors for sudden infant death syndrome in the infants' sleep environment for a population in which few infants sleep prone as a result of education campaigns. METHODS: This was a population-based sudden infant death syndrome case-control study over 3 years (1998-2001) in Germany. RESULTS: There were 333 sudden infant death syndrome cases and 998 matched controls. Although only 4.1% of the infants were placed prone to sleep, those infants were at a high risk of sudden infant death syndrome. Those who were unaccustomed to sleeping prone were at very high risk, as were those who turned to prone. Bed sharing (especially for infants younger than 13 weeks); duvets; sleeping prone on a sheepskin; sleeping in the house of a friend or a relative (compared with sleeping in the parental home); and sleeping in the living room (compared with sleeping in the parental bedroom) increased the risk for sudden infant death syndrome; pacifier use during the last sleep was associated with a significantly reduced risk of sudden infant death syndrome. CONCLUSIONS: This study has clarified the risk factors for sudden infant death syndrome in a population where few infants sleep prone. This study supports the current recommendations of the American Academy of Pediatrics. This study has identified several novel risk factors for sudden infant death syndrome: an increased risk if the infants sleeps outside the parental home, death in the living room, and the high risk when sleeping prone on a sheepskin; however, because the numbers of cases in these groups are small, additional studies are needed to confirm these findings.

Surface CD152 (CTLA-4) expression and signaling dictates longevity of CD28null T cells.

CD28(null) T cells are a highly enriched subset of proinflammatory T cells in patients with autoimmune diseases that are oligoclonal and autoreactive. In this study, we analyzed the role of CD152 signaling on the longevity of human CD28(null) T cells. Using a sensitive staining method for CD152, we show that human CD4(+)CD28(null) and CD8(+)CD28(null) T cells rapidly express surface CD152. Serological inactivation of CD152 using specific Fab or blockade of CD152 ligands using CTLA-4Ig in CD4(+)CD28(null) and CD8(+)CD28(null) T cells enhances apoptosis in a Fas/FasL-dependent manner. CD152 cross-linking on activated CD28(null) cells prevents activation-induced cell death as a result of reduced caspase activity. Apoptosis protection conferred by CD152 is mediated by phosphatidylinositol 3'-kinase-dependent activation of the kinase Akt, resulting in enhanced phosphorylation and thereby inhibition of the proapoptotic molecule Bad. We show that signals triggered by CD152 act directly on activated CD28(null) T lymphocytes and, due to its exclusive expression as a receptor for CD80/CD86 on CD28(null) T cells, prevention of CD152-mediated signaling is likely a target mechanism taking place during therapy with CTLA-4Ig. Our data imply strongly that antagonistic approaches using CD152 signals for chronic immune responses might be beneficial.

Head covering and the risk for SIDS: findings from the New Zealand and German SIDS case-control studies.

OBJECTIVES: The aim of this investigation was to identify risk factors for being found with the head covered in sudden infant death syndrome cases and determine whether head covering was likely to be an agonal event or potentially part of the causal pathway in some cases. By using the data from 2 sudden infant death syndrome case-control studies, consistency of the findings could be assessed. METHODS: Two case-control studies were assessed: (1) the New Zealand Cot Death Study (1987-1990, 393 sudden infant death syndrome cases) and (2) a German SIDS case-control study (1998-2001, 333 sudden infant death syndrome cases). RESULTS: The proportion of sudden infant death syndrome cases in which infants were found with their head covered was 15.6% in the New Zealand study and 28.1% in the German study. Being found with head covering was associated with older infant age. In both studies, being found with head covering was associated with being very sweaty when found. Head covering was also associated with the incidence and severity of thymic petechiae in both studies. Both the position in which the child was placed to sleep and the position in which the child was found were not associated with head covering. CONCLUSIONS: The finding that sudden infant death syndrome cases in which infants were found with their heads covered were often very sweaty suggests that head covering was not an agonal event and that it preceded the death and may have been causally related to the death. Infants who were found with their head covered were older, which probably reflects motor development.