Sepsis in neonates carries a high morbidity and mortality rate and is among the most feared complications in the neonatal intensive care unit (NICU). Catheter-related bloodstream infections (CRBSI) are a common etiology of late-onset sepsis. The aim of this study was to compare risk factors and characteristics between patients according to the type of catheter that was utilized and according to birth weight classification. The study included 51 newborns with confirmed CRBSI, which were hospitalized in our level 3 NICU between January 2017 and December 2018. The study population was stratified according to the type of venous catheter utilized , and peripheral venous catheter). Infants with low birth weight and those who required prolonged parenteral nutrition were most likely to develop CRBSI in our study group. The type of venous catheter was not associated with blood culture results. Also, infants with a birth weight of < 1500 g and > 1500 g did not differ in sepsis etiology. Further research is required to assess venous catheters relative risk of causing sepsis and if the outcome can be traced back specifically to catheter type or patient characteristics. A frequently feared complication of venous catheters is catheter-related bloodstream infections (CRBSI). CRBSI is among the most common causes of late-onset sepsis (LOS) and is described as the development of bacteremia due to catheter placement intravenously2. Infants who develop CRBSI have an estimated mortality rate of 70% and may experience impairments in neurodevelopment and growth later in life3. Sepsis in neonates is variably classified as late-onset when signs appear at or following the third day until the seventh day of life5. Most commonly early-onset sepsis is defined as sepsis diagnosed before 72 h of life6. Such a classification helps the physician to make the best decision when it comes to starting an empirical antibiotic therapy due to the varying etiologies between these two types of sepsis. A better understanding of this multifactorial complication and its associated risk factors may help to initiate life-saving treatment earlier and to prevent its progression into further stages.Venous catheters are among the most commonly used medical tools in practice and are an essential component in the treatment and care of patients in intensive care units. In neonates, they are primarily used to administer medications, obtain blood tests as well as provide parenteral nutrition to vulnerable premature infants7. However, such progress might additionally expose neonates to the dangers of infection. CRBSI can be caused by either the patient's skin flora that gains access to the bloodstream or hospital-derived organism which could lead to nosocomial bacteremia2. Increasing signs of sepsis in patients with venous catheters, in the absence of other sources of infection, allows the physician to presume the source of the infection to be catheter-related8.Advancements in modern neonatology have led to greater survivability of infants that have been born preterm, which in turn increased the population that is at risk for LOS due to the increased need for invasive monitoring and support in this populationThe aim of this study was to compare risk factors as well as characteristics of neonates with CRBSI according to the type of venous catheter that was utilized and according to birth weight classification. Based on these findings we made conclusions about the pathogenesis of sepsis in our studied population, and how to optimize the treatment approach for patients with this complication.The study included infants with diagnosed septicemia at or after the 7th day of life (LOS) and had confirmed CRBSI. Each participant was allowed to have only one venous catheter at the time of diagnosis: a peripherally inserted central catheter ((PICC) VYGON GmbH & Co.KG), a central venous catheter ((CVC) BD Neoflon), or a peripheral venous catheter ((PVC) Arrow Medical). Infants that developed signs of sepsis before the 7th day of life or that developed septicemia due to factors other than catheter placement were excluded. To exclude urinary tract infections or pneumonia as the source of the infection, we only included patients with negative urine and bronchoscopic cultures.This cross-sectional study included 51 newborns, which were hospitalized between January 2017, and December 2018, at the Neonatal Intensive Care Unit of the Obstetrics & Gynecology Clinical Hospital of the Poznań University of Medical Sciences. During this time a total of 985 newborns were admitted to the level 3 NICU, and all of them were on a ventilator. Data from secondary sources was used for the study, which included the patient’s medical records from the moment of admission until discharge from the clinic. Informed consent about participation in the study has been obtained by the parent and/or legal guardian of all subjects involved in the study.Sepsis was diagnosed based on the presence of two clinical signs and two positive laboratory tests. Clinical signs of sepsis are reluctance to feed, gastrointestinal retention, flatulence, hyperbilirubinemia, loss of muscle tone, bradycardia or tachycardia, tachypnea or apnea, and hypothermia or hyperthermia without disturbance of peripheral perfusion. Laboratory signs of sepsis are increased serum procalcitonin, increased serum CRP, and leukocytosis.CRBSI was diagnosed when the same organisms grew from a percutaneous blood culture and from a culture from the tip of the venous catheter.Performing a blood culture was recognized as the gold standard in the diagnosis of sepsis and is considered a compulsory test on suspicion. Blood samples of 0.5–1 ml were drawn from a freshly placed venous access site to subsequently be analyzed with the bacT/ALERT 3D microbial identification system. The blood was cultured using the automatic incubation system as recommended by the manufacturer. Strict aseptic measures were taken to exclude any false contamination during blood sampling, i.e. with surgical washing of hands, wearing a sterile gown, and sterile gloves. The collection site is protected by surgical covers. The skin at the injection site was disinfected with antiseptic alcohol by making circular movements in a centrifugal direction. After aspirating the blood with a sterile syringe, the puncture site was disinfected, and covered with a sterile dressing. The blood was taken during a period at which the probability to isolate a pathogenic organism is the greatest. Generally, the blood sample is taken before antibiotic therapy is initiated, however, in certain cases where this approach was not possible, the sample was taken before the next antibiotic was given.The studied group was stratified based on two criteria. The first one is the type of venous catheter. Body weight was used as the second criterion and we differentiated between infants with a body weight of less than or more than 1500 g. Within each subpopulation, we assessed the child’s birth history and made divisions according to gender, birth weight, gestational age, type of pregnancy, mode of delivery, place of birth, and APGAR score at the first, third, and fifth minute of life. Of interest was also the day of life that the venous catheter was inserted, the duration of its use, type of antibiotic therapy, day of parenteral nutrition termination, day of life at which sepsis occurred, and hospitalization time. Laboratory parameters that were taken into account included C-reactive protein, procalcitonin, white blood cell count, and blood culture.The statistical analysis of the neonatal population was performed in two stages. In the first stage, the frequency by which certain parameters occurred was described with the use of descriptive analysis. Secondly, the correlation between certain variables was analyzed. Dispersion of data in relation to the center was represented using mean (standard deviation) in continuous variables. For categorical variables, median (interquartile range (IQR)) was utilized. Variables represented on a nominal scale were presented using modified number tables.9 and IBM SPSS Statistics Version 26.010.The Shapiro–Wilk test was used to test for compliance and data normality. To assess the correlations between certain variables, nonparametric tests such as Mann–Whitney test, Kruskal-Willis test, Dann post-hoc test, and the independent chi-square test were used. The level of significance was set at α = 0.05. Tables were used to present the collected data. All statistical calculations were performed with the help of R Statistics Version 4The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of Department of Neonatology of the Poznan University of Medical Sciences.Informed consent about the participation in the study has been obtained by the parent and/or legal guardian of all subjects involved in the study.The study included 29 males and 22 females, which had a mean birth weight of 1636.86 ± 896.17 g and a mean gestational age of 30.71 ± 4.37 weeks. The median and interquartile range of APGAR scores at the first, third, and fifth minute of life was 6 (4–6), 7 (5–8), and 8 (6.25–9), respectively. Thirty-eight children (74.51%) were born by cesarean section. Out of the 51 infants included in the study, the majority received a PICC (22/51–43.1%) or a CVC (16/51–31.4%), while 13/51 (25.5%) infants had a PVC.p = 0.001) and birth weight (p ≤ 0.001) between the infants. On average, preterm infants with higher gestational age (33.50 ± 4.59 weeks) were receiving a CVC.A significant difference was observed in gestational age (p = 0.001). The newborns that received a CVC had the highest birth weight at a mean of 2344.06 ± 1030.43 g followed by the patients with a PVC, which, on average, weighed 1590.0 ± 548.04 g. Patients with a PICC had the lowest birth weight at 1150.23 ± 616.90 g. The catheter was inserted at the earliest for PVC infants (1.69 ± 1.55 days of age) followed by PICC infants (4.95 ± 3.79 days of age), and CVC infants (10.06 ± 17.10 days of age) (p = 0.001). Termination of parenteral nutrition was latest for patients with a CVC (31.63 ± 20.64 days), while for patients with a PICC termination occurred at 29.0 ± 15.84 days of age. PVC patients were fed parenterally until they were 17.54 ± 8.03 days old (p = 0.031) and required the shortest course of antibiotic therapy (10.69 ± 2.18 days). Babies with a PICC and a CVC were treated for 12.64 ± 2.82 and 18.13 ± 9.05 days, respectively (p = 0.001). On average PICC patients were hospitalized the longest (86.36 ± 37.28 days), followed by CVC patients at a mean of 51.0 ± 27.76 days and PVC patients at 48.23 ± 28.72 days (p = 0.002).Subjects with a PICC and those with a PVC were born at 31.38 ± 3.66 weeks and 28.41 ± 3.32 weeks of gestation, respectively (p = 0.015).C-reactive protein was the only laboratory value that was significantly associated with the type of catheter used. The highest mean CRP was measured in the patients with the highest gestational age (those that received a CVC) (74.57 ± 40.47 µg/mL), while patients with a PVC had 59.31 ± 39.93 µg/mL, and PICC patients had 48.48 ± 62.52 µg/mL (p = 0.361).Staphylococcus epidermidis was the most commonly isolated pathogen from the blood of our subjects (16/51–31.37%) followed by staphylococcus haemolyticus that infected 15 (29.41%) subjects. Other bacteria isolated from the subject’s blood included enterococcus faecalis (6/51–11.76%), staphylococcus capitis (5/51–9.80%), staphylococcus aureus (3/51–5.88%), klebsiella pneumoniae (3/51–5.88%), escherichia coli (2/51–3.92%), staphylococcus hominis (2/51–3.92%), serratia marcescens (2/51–3.92%), staphylococcus saprophyticus (1/51–1.96%), staphylococcus warneri (1/51–1.96%), staphylococcus caprae (1/51–1.96%), klebsiella oxytoca (1/51–1.96%), and bacillus sporothermodurans (1/51–1.96%). The results from blood culture were not significantly correlated with the type of central line that has been used  infants that weighed less than 1500 g, while 24/51 (47.06%) weighed more than 1500 g.p = 0.001)), lower APGAR score at the first (5 (4–6) (p = 0.006)), and fifth minute (7 (6–8) (p = 0.010)) of life. Hospitalization time was comparatively longer in lower birth weight infants (79.96 ± 34.54 days (p = 0.003)). The most common catheter used in these newborns were PICCs (19/27 (70.38%)), whereas CVCs and PVCs were each used in 4/27 (14.81%) (p = 0.001).Infants with lower birth weight had a lower gestational age (27.77 ± 2.21 weeks (p = 0.006)) and fifth minute (8 (7–10) (p = 0.010)) of life. Hospitalization time was comparatively shorter in the higher birth population (51.29 ± 33.91 days (p = 0.003)). The most common catheter used in these newborns was a CVC (12/24 (50.00%)), whereas 9/24 (37.50%) used PVCs and 3/24 (12.5%) used PICCs (p = 0.001). The results from blood culture were not significantly correlated with the birth weight classification (p = 0.262).Infants with a higher birth weight had a higher APGAR score at the first (7.5 (5–9)  and tumor necrosis factor creates an environment advantageous for infections in preterms27. IL-6 in turn stimulates the production of acute-phase proteins. The former has been analyzed in a cohort study with 241 infants by Henrik Doellner et al., who found CRP to be significantly lower in preterm than in term neonates28. Similarly, it has been shown that term neonates are three times as likely to have a pronounced CRP response of 60 mg/l than neonates born at 24–27 weeks of gestation29. Serial CRP measurements are used to assess the course of an infection, the efficacy of initiated treatment, and the time at which treatment can be terminated30. However, since a CRP response by the preterm infants is likely premature, it is unclear whether the low CRP levels are a reliable marker of disease severity.Preterm infants suffer from quantitative deficits of immune cells as well as qualitative deficits in the efficiency of killing pathogens13. The prolonged hospitalization time in this group could possibly be explained solely by their physical immaturity.In our study infants with a higher gestational age also had a significantly higher level of CRP, as can be seen in the infants that received a CVC. As shown in Table After stratifying the infants by birth weight of less than or more than 1500 g, laboratory markers reflecting the severity of inflammatory processes like CRP, procalcitonin, and WBC count were not significantly elevated. Therefore, immune system immaturity may not be the only factor influencing elevated CRP in the CVC patient group, but possibly other factors like prolonged invasive care.The type of microorganism that has been isolated from blood culture was not significantly associated with the type of venous catheter that was used in the therapy and treatment of our infant population. Hence, not one specific type of catheter predisposed to a certain etiological agent causing CRBSI. Also, infants with a birth weight of < 1500 g and > 1500 g did not differ in sepsis etiology.Since our catheter groups significantly differed in birth weight and gestational age, it is difficult to assess the superiority of any one particular catheter type without physical maturity to act as a confounding factor. As for future directions, we suggest that future studies assess whether there is a correlation between the development of end organ damage consistent with the definition of severe sepsis in patients with CRBSI and the types of vascular catheters that have been used in the care of these patients.CRBSI is a serious complication in the NICU, where invasive support is inevitable to provide the best care for newborns. Infants with low birth weight and those who required prolonged parenteral nutrition were most likely to develop CRBSI in our study group. The type of venous catheter was not associated with blood culture results. Also, infants with a birth weight of < 1500 g and > 1500 g did not differ in sepsis etiology. Further research is required to assess venous catheters relative risk of causing sepsis and if the outcome can be traced back specifically to catheter type or patient characteristics.The data are not publicly available due to ethical and privacy restrictions.


Objective: To determine whether first- and second-trimester maternal serum biomarkers are useful for the prediction of pregnancy complications like preterm birth, intrauterine growth restriction (IUGR), and macrosomia.Methods: We conducted a retrospective analysis of 353 women having first- or second-trimester combined test for Down syndrome screening who delivered at our institution between January 2018 and December 2020. Associations between first- and second-trimester serum markers and adverse pregnancy outcomes among those who underwent prenatal screening for Down syndrome in our clinic were studied. The adverse pregnancy outcomes, serum levels of pregnancy-associated plasma protein-A (PAPP-A), β-human chorionic gonadotropin (β-hCG), and maternal serum alpha-fetoprotein (ms-AFP) were recorded and analyzed. Correlation analyses of PAPP-A, free βhCG, and ms-AFP with pregnancy outcomes were studied. We sought to predict the risks of preterm delivery , low birth weight  and macrosomia (>4000 grams).Results: A total of 353 women who had first- and second-trimester screening test for Down syndrome were included. Two hundred fifty (70.08%) of them had first-trimester and 103 (41.2%) had second-trimester test. Mean age of the patients who underwent screening test for Down syndrome was 29.3±5.9, mean maternal weight was 67.3±13.6, mean gestational weeks at birth was 38.6±2.1 weeks and mean birth weight was 3260.9±511.1, preterm birth rate was 40/353 (11.3%), IUGR rate was 21/353 (5.9%), macrosomia rate was 17/353 (4.8%), stillbirth rate was 3/353 (0.8%). When laboratory and clinical parameters affecting birth weight and birth weeks were analysed in correlation analysis, both birth week and birth weight were found to be positively correlated with maternal weight. Of first-trimester markers Papp-A MoM (Multiples of Median) was found to be positively correlated with fetal birth weight (p = 0.044). Of second-trimester biochemical parameters ms-AFP was found to be negatively correlated with fetal birth weight (p = 0.039).Conclusion: The study concluded that there is a relationship between serum markers and adverse pregnancy outcomes. Significant associations were found between the levels of first- and second-trimester serum markers PAPP-A, AFP and IUGR, macromia and additionally significant association was found between maternal weight and both delivery week and fetal weight. These results can highlight the pregnancies at risk and follow-up intervals may be arranged according to risk scala which may help at antenatal follow-up of high-risk patients. Down syndrome  is a genetic disorder that affects about 1/800 babies and causes both physical and mental health problems [To detect this disorder in pregnancy, noninvasive screening tests based on biochemical analysis of maternal serum can be performed, and are used alongside fetal ultrasound measurements and maternal age to estimate the Down syndrome risk and trisomy 13/18 risk. When this screening test is done during the first trimester, it involves maternal age, nuchal translucency, and maternal serum biochemical analytes pregnancy-associated plasma protein-A (PAPP-A) and free β-human chorionic gonadotropin (fβ-hCG). On the other hand, second-trimester serum screening includes maternal age and weight, and maternal serum biochemical analytes, including alpha-fetoprotein (AFP), fβ-hCG and unconjugated estriol (uE3) or inhibin A, combined with gestational age and sonographic fetal biparietal diameter (BPD) measurements [The combined first-trimester screening test can detect approximately 85% of Down syndrome cases with a 5% false-positive rate,while the second-trimester screening test yields an 81% detection rate and has a false-positive rate of 5% ,4. TheseIn this retrospective study, medical records of 353 pregnant women that had singleton pregnancies and underwent the first-trimester (n = 250) or second-trimester (n = 103) biochemical screening tests at our maternal clinic between January 2018 and December 2020 were reviewed. Maternal age, gravidity, parity, gestational week at birth, fetal weight, and birth records were analyzed. Exclusion criteria included incomplete screening tests, giving birth at another center, fetal structural or chromosomal anomalies, and multiple pregnancies.For first-trimester screening test, women had an ultrasound for NT and a blood sample taken for PAPP-A and free β-hCG between 11 weeks and 13 weeks 6 days of pregnancy, with an estimated risk detected on the basis of these combined markers and maternal age. Women undertaking second-trimester screening test had blood samples taken for the AFP, uE3 and f-βhCG measurements between 15 weeks and 20 weeks of gestation, which were combined with sonographic BPD measurements. The values of all serum markers were expressed as multiples of the median levels (MoM) of unaffected pregnancies at a given gestation [Premature birth is defined as any birth before 37 completed weeks of gestation, whereas small for gestational age (SGA)/IUGR is defined as <2,500 grams infant weight at term. SGA is often considered synonymous with IUGR, respectively defined as fetuses with birthweight below the 10th and 3rd percentile for the gestational age. IUGR is one of the main outcomes of high-risk pregnancy, and is associated with increased perinatal morbidity and mortality as well as abnormal neurodevelopment.This study was conducted with the ethical approval of the Institutional Review Board  and fully adhered to the Declaration of Helsinki principles. Informed consent was obtained from each research participant. The statistical procedures were undertaken using the Statistical Package for the Social Sciences (SPSS), Version 19.0 for Windows . For continuous variables mean ± SD was calculated, while n (%) was reported for categorical variables. The correlations between adverse pregnancy outcomes  and maternal biomarkers  were determined by conducting Pearson correlation analysis, while logistic regression analysis was performed to determine the maternal weight cutoff.During the study period, 353 women  underwent first-semester  and second-trimester  screening for Down syndrome at our clinic. The mean number of pregnancies was 2.0 ± 1.3, the mean gestational duration at birth was 38.6 ± 2.1 weeks, and the mean fetal birth weight was 3260.9 ± 511.1 grams., Our analyses revealed 40/353 (11.3%) preterm births, 21/353 (5.9%) cases of IUGR, 17/353 (4.8%) cases of macrosomia, and 3/353 (0.8%) stillbirths  as well as with maternal weight . However, gestational age at birth was negatively correlated with maternal age .As shown in Table In extended research, maternal serum analytes used in the first- and second-trimester screening tests, such as PAPP-A and βhCG, have been found to be related to poor pregnancy outcomes, such as preterm labor, preeclampsia, antenatal bleeding, gestational diabetes, low birth weight, stillbirth, and fetal loss ,7. PAPP-Guided by these findings, we examined the levels of these analytes in the pregnant women who gave birth at our clinic to uncover any associations with pregnancy complications. In our cohort, PAPP-A MoM was positively correlated with fetal birthweight (p = 0.044), as confirmed by other studies ,9 linkinThe second-trimester levels of maternal serum markers for aneuploidy  have also been shown to be associated with adverse obstetric outcomes mostly due to disturbances in the placental function. Elevated AFP and hCG have been associated with low birthweight, IUGR, preeclampsia, as well as fetal stillbirth and preterm birth -14. On tIn the present study, only second-trimester msAFP values were found to be negatively correlated with fetal birthweight (p = 0.039), as confirmed by other authors ,14. ThesAs hCG is produced by placenta, it is the first hormone detected in pregnancy ,3. HowevGiven the growing incidence of overweight status and obesity in pregnancy, our finding that greater maternal weight was associated with greater fetal weight is relevant but an interesting finding in this study is increased maternal weight was associated with increased pregnancy duration. This is supported by the results reported by Halloran et al., who recommended restricting maternal weight gain in order to reduce fetal postmaturity .A limitation of this study is that the study sample is small, so deriving strict conclusions is difficult, but similar studies we outlined above have large numbers and our results are consistent with them.Although abnormal first-trimester serum PAPP-A and second-trimester AFP levels were associated with adverse pregnancy outcomes in this study, the sensitivity of these tests is relatively low, limiting their clinical relevance. Nonetheless, these tests can be used to identify at-risk pregnancies and determine follow-up intervals that would allow adequate monitoring of both mother and the fetus.


Prematurity represents 10.6% of all births, and although preterm infants usually show adequate neurodevelopmental outcomes, some may develop significant and long-lasting neurological sequelae. Many studies have analyzed predictive factors for developing severe neurodevelopmental impairments . In this study, 148 preterm infants were enrolled to investigate the neurodevelopmental trajectories in a population of low-risk premature infants using standardized assessment methods. Significant correlations were found between the general movements, the Hammersmith Infant Neurological Examination, and the Griffiths Mental and Development Scales. Moreover, this study showed their validity and predictivity for adverse neurodevelopmental outcomes even in low-risk infants. Preterm birth is defined by the WHO as a live birth before 37 completed weeks of gestation and, recently, it has been considered a matter of utmost importance, representing the leading cause of death in children aged under 5 years . The exaPrematurity is considered a risk factor both for short- and long-term complications. Short-term complications usually occur in the first days of life. They include neonatal respiratory conditions (such as respiratory distress syndrome and bronchopulmonary dysplasia), necrotizing enterocolitis, sepsis, neurological conditions , feeding difficulties, and visual and hearing problems , 3, 5, 6+0-36+6 weeks). These children are considered a low-risk population because they appear less likely to develop pathological developmental trajectories compared to extremely and very preterm infants  and late-preterm babies should not be excluded from the usual follow-up programs , 21. MorCaucasian preterm infants (born before 37 weeks of pregnancy) were recruited at the Unit of Child Neurology and Psychiatry at the University Hospital “G. Martino” of Messina, Italy, between September 2018 and October 2020, and were enrolled in a follow-up prospective research program.+0-36+6 weeks; (2) weight appropriate for GA, considering appropriate a weight between 10th and 90th percentile; (3) normal cranial ultrasound (cUS) or mild abnormal findings such as transient flares (lasting < 2 weeks) or germinal layer hemorrhages grade 1 (IVH I) according to Volpe (The population has been selected according to the following inclusion criteria: (1) GA comprised between 28to Volpe ; (4) abs+0 and 33+6 weeks) and late preterm (GA between 34+0 and 36+6 weeks).According to GA, the preterm cohort was divided into two subgroups: early preterm , and pathological otoacoustic emissions were also considered.To identify the presence of cerebral lesions, cUS evaluations were performed on preterm infants within the first week of life and always around term-equivalent age. If an abnormal finding was recorded, weekly monitoring was performed. According to Volpe , transieAs part of the follow-up program, a video recording of General Movements (GMs) was performed during the visit. The subjects were recorded during the inter-feeding time, in the supine position, in a nappy. The videos were analyzed by a certified evaluator (GD) according to the standard methodological principles of Prechtl's method .General Movements are part of a complex spontaneous movement repertoire that already appears in early fetal life. They are fluent movements that occur frequently, have a gradual beginning and end, and involve the whole body in variable sequences . Two disThe Hammersmith Infant Neurological Examination (HINE) is a simple and scorable neurological assessment for infants between 2 and 24 months of age. It comprises 26 items that evaluate cranial nerves, posture, movements, tone, and reflex reactions. Each item is given a score from zero to three, and the sum of the individual scores determines a global score that can range from a minimum of 0 to a maximum score of 78. Based on the frequency distribution of the scores in the normal population, an optimality score has been developed for research purposes. Global scores are reported as optimal if they are ≥67 at 3 months, ≥70 at 6 months, and ≥73 at 9 to 12 months . HINE waThe neurodevelopmental evaluation was performed between 12 and 36 months of life with the validated Italian translations of the Griffiths Mental Development Scales Revised (GMDS-R) for children aged 0–24 months and the Griffiths Mental Development Scales Extended Revised (GMDS-ER) for children 2–8 years of age . The assThe general development quotient and the sub-quotients were calculated for CA and chronological age. The scales were always performed by the same examiner (RM).Data were securely stored and managed using an electronic data capture tool hosted at Unit of Child Neurology and Psychiatry at the University Hospital “G. Martino” of Messina. Missing demographic data and other clinical characteristics of the enrolled subjects were also collected using telephonic interviews. Data on family and personal medical history, presence of comorbidities, and drug use were also collected.The Institutional Review Board of the University of Messina approved the study. A written informed consent was obtained from the parents of the infants.Categorical variables were expressed as absolute and percentage frequencies and numerical variables as mean and standard deviation.The Kolmogorov–Smirnov test was applied to verify the normality of the distribution of the variables examined. The application of the test made it possible to ascertain the condition of normality for most of the variables considered; consequently, it was decided to use the parametric approach for the statistical analysis of the data.t-test was applied to identify the existence of statistically significant differences between two groups of patients (early preterm vs. late preterm) regarding the numerical variables, with reference to the categorical variables; on the contrary, the comparison between the two groups was carried out using the chi-square test.Student's The possible correlations between all the variables were also investigated in the whole group by stratifying by group (early preterm and late preterm) using the Spearman test.p-value < 0.050 for two-tailed tests was considered statistically significant.The predetermined significance level is α = 0.050; therefore, Multiple linear regression models were estimated to identify significant predictors of the interest outcomes, such as general development quotient, locomotor scale, personal–social scale, hearing and language scale, eye–hand coordination scale, and performance scale, all considered for chronological age. Tested covariates were as follows: GMs, posture subsection (in the three timepoints), movement subsection (in the three timepoints), tone subsection (in the three timepoints), reflex reaction subsection (in the three timepoints), cranial nerve subsection (in the three timepoints), developmental milestones, and birthweight.The statistical analysis was performed using SPSS software version 22.0 .p-value = 0.018). The early preterm group had a mean birthweight of 1670.4 ± 439.1 g, while the late-preterm babies had a mean birthweight of 2319.1 ± 502.9 g. The mean 1-min and 5-min Apgar scores resulted significantly lower in the early preterm group than in the late-preterm group, being 7.0 ± 1.6 vs. 8.1 ± 1.4  and 8.4 ± 0.9 vs. 9.1 ± 0.9 , respectively. In 94.6% of the cases, a neonatal intensive care unit recovery was required, particularly in 97.7% of the early preterm babies and 90.3% of the late-preterm group. Eighty-eight patients  had acute respiratory distress syndrome (ARDS). It occurred more frequently in the early preterm group when compared to late-preterm group , requiring in 65.5% of cases a non-invasive ventilation  and in 19.6% of cases an invasive ventilation .A total of 148 infants were enrolled in the study, 85 males (57.4%) and 63 females (42.6%). The mean GA of the entire group was 33.2 ± 2.1 weeks, and the average birth weight was 1,944 ± 565 g. Pre-, peri-, and postnatal risk factors and cUS findings were collected for all the enrolled patients. About 10.1% of the total group have a history of placental abruption during the pregnancy, with a significantly higher percentage in the early preterm group than the late-preterm group  compared to the late-preterm group.Moreover, the early preterm group more frequently received blood transfusions  are summarized in General Movements assessment was performed for all groups of infants during the Fidgety period. HINE was performed at 3-, 6-, and 9-month CA on 67.6, 52, and 41% of the patients, respectively. Sixty-three infants  were subsequently evaluated with GMDS-R (82.5%) and GMDS-ER (17.5%). At the evaluation, the early preterm group had a mean of the chronological age of 18.4 ± 5.8 months (mean of corrected age 16.3 ± 5.8 months), while the late-preterm group had a mean chronological age of 18.7 ± 6.6 months (mean of corrected age 17.3 ± 6.6 months). During the follow-up, seven of the infants (4.7%), specifically five (5.8%) from the early preterm group and two (3.2%) from the late-preterm group, developed motor impairments, and they were excluded from further statistical analyses.General Movements were assessed in each infant during the Fidgety period: 68.1% of the population showed normal FMs (64.2% of the early preterm group vs. 73.3% of the late-preterm group), 27.7% presented abnormal FMs (29.6 vs. 25%), while the FMs were absent in 4.2% of the total group (6.2 vs. 1.7%). The differences between the two groups were not statistically significant. Data are summarized in Hammersmith Infant Neurological Examination was administered to 94 children  at 3 months CA, to 73 infants (51.8%) at 6 months CA, and 63 patients (44.7%) at 9-month CA. HINE scores are summarized in p-value = 0.004, <0.001, and <0.001, respectively) was evidenced. Better GMA significantly correlated with higher scores in the subsection movements  at 3-, 6-, and 9-month CA evaluations, with the subsection posture at 6- and 9-month CA evaluations , with the subsection tone at 3- and 6-month CA evaluations , and with the subsection reflex reactions at 3- and 9-month evaluations .A significant correlation between GMs scores and HINE global scores at 3-, 6-, and 9-month CA evaluations  between 12 and 36 months . Considering the chronological age, no significant differences were detected between the scores of the two groups: The mean general development quotient appeared to be slightly below the standard both in the early (86.5 ± 14.4) and the late-preterm babies (87.7 ± 17.5), whereas the subscales quotients resulted within the normal range in both groups. The only exception is represented by the hearing and language scale, in which the mean score resulted within the standards in the late-preterm babies (89.7 ± 24.2) and below the normal range in the early preterm infants (78.4 ± 20.4) and the total group (82.3 ± 22.6). All the quotients were assessed within the normal range of scores when assessed by CA, and data are summarized in p-value = 0.029) between GMA and the eye–hand coordination scale of the GMDS was detected.A significant correlation ; the subsection tone had a significant correlation with higher scores of general development score  and with personal–social  and eye–hand coordination  scales , the locomotor scale , the hearing and language scale , and the eye–hand coordination scale ; the subsection reflex reactions had a significant correlation with the performance scale   . The subMultiple linear regression showed significant correlations between the locomotor scale, the posture at 6 months (CA), and the movement subsection at 3- and 6-month (CA) evaluations. Moreover, the subsection posture at the 6-month CA evaluation significantly correlated with the personal–social scale and the general development quotient. Multiple linear regression data are shown in Nowadays, prematurity is considered a risk factor for both major and minor neuropsychological sequelae, driving the need for effective assessments that may be highly predictive of developmental outcomes in early life. GMA and HINE have been proven to be highly accurate tools, having together with neuroimaging, a sensitivity of >97% and a specificity of >97% in detecting significant neurological impairments . Therefore, they are considered the gold-standard tools in early diagnosis of children at high risk for neurological sequelae , 24.However, the interest in the early prediction of minor outcomes has increased, posing a new challenge to the scientific community , 29–31.This study aimed to analyze the predictivity of standardized early neurological assessments in a population of low-risk babies and to identify precocious neurological predictors of adverse neurodevelopmental outcomes.+6 weeks. However, Kwong et al.  of absent/abnormal FMs than the term-born low-risk population. In this cohort of patients, 15% of patients presenting abnormal/absent FMs at 12 weeks showed normal FMs at the 14-week observation, indicating a favorable GMs trajectory  demonstrates a similar development pathway, not significantly influenced by their GA. This study underlines the importance of including even these low-risk populations in the follow-up programs to early identify infants at risk for adverse long-term impairments and introduce early intervention therapies for optimizing neurodevelopmental outcomes.Therefore, it would be necessary to identify accurate tools to optimize the follow-up programs, allowing to continue monitoring low-risk premature infants up to 36 months of life. It would also be crucial to prove the predictivity of an early neurological assessment to identify abnormal development trajectories and realize an early intervention such as for high-risk babies.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Institutional Review Board of University of Messina. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.GR conceived, planned, and supervised the study and performed GMA and HINE. DD collected the data. DD and GS wrote the first draft of the manuscript and prepared the tables. GS and AN prepared the figures. AN revised the manuscript and supervised the study. RM performed the GMDS. AA performed the statistical analysis. All authors contributed to manuscript revision, read, and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


To leverage large scale genetic association data to investigate the interplay between circulating cytokines and cardiometabolic traits, and thus identifying potential therapeutic targets.Bi-directional Mendelian randomisation study.Genome-wide association studies from three Finnish cohorts , and genetic association summary statistics pooled from observational studies for expression quantitative trait loci and cardiometabolic traits.Data for 47 circulating cytokines in 13 365 individuals from genome-wide association studies, summary statistic data for up to 21 735 individuals on circulating cytokines, summary statistic gene expression data across 49 tissues in 838 individuals, and summary statistic data for up to 1 320 016 individuals on cardiometabolic traits.Relations between circulating cytokines and cardiovascular, anthropometric, lipid, or glycaemic traits .Genetic instrumental variables that are biologically plausible for the circulating cytokines were generated. The effects of cardiometabolic risk factors on concentrations of circulating cytokines, circulating cytokines on other circulating cytokines, and circulating cytokines on cardiometabolic outcomes were investigated.Genetic evidence (mendelian randomisation P<0.0011) suggests that higher body mass index, waist circumference, smoking, higher concentrations of lipids, and systolic blood pressure increase circulating concentrations of several inflammatory cytokines and C reactive protein. Evidence for causal relations (mendelian randomisation P<0.0011) were noted between circulating cytokines, including a key role of vascular endothelial growth factor on influencing the concentrations of 10 other cytokines. Both mendelian randomisation (P<0.05) and colocalisation (posterior probability >0.5) suggested that coronary artery disease risk is increased by higher concentrations of circulating tumour necrosis factor related apoptosis-inducing ligand (TRAIL), interleukin-1 receptor antagonist (IL1RA), and macrophage colony-stimulating factor (MCSF).This study offers insight into inflammatory mediators of cardiometabolic risk factors, cytokine signalling cascades, and effects of circulating cytokines on different cardiometabolic outcomes. Inflammation contributes to the development of cardiovascular disease but the role of circulating cytokines in cardiovascular disease cause is not fully understoodNovel evidence shows the effects of body mass index, smoking, blood lipids, and systolic blood pressure on the concentrations of several circulating cytokinesThe findings provide support for complex causal relations between cytokinesIncreased concentrations of tumour necrosis factor related apoptosis-inducing ligand (TRAIL), interleukin-1 receptor antagonist (IL1RA), and macrophage colony-stimulating factor (MCSF) increase coronary artery disease riskThe findings on TRAIL, IL1RA, and MCSF suggest their prioritisation in further research into putative pharmacological targets for coronary artery diseaseInflammation contributes to the development of cardiovascular disease. has been increasing rapidly. By use of randomly allocated genetic variants that proxy the effect of altering a risk factor of interest, the causal effect of that risk factor on a given outcome in the mendelian randomisation framework can be investigated.Availability of large scale genetic association data relating to cardiometabolic phenotypesIn this study, we performed genome-wide association studies of circulating cytokines. Subsequently, we aimed to use mendelian randomisation to investigate the effect of cardiometabolic risk factors on the concentrations of these circulating cytokines. Then, we pooled data from these genome-wide association studies with publicly available summary statistics and further incorporated gene expression data. We sought to identify biologically plausible genetic variants to proxy the effect of varying circulating cytokine levels. We used mendelian randomisation to investigate cytokine cascades and pathways. Additionally, we aimed to use mendelian randomisation to study the effects of circulating cytokines on cardiometabolic outcomes to identify potential therapeutic targets.10.1136/bmjmed-2022-000157.supp1Supplementary dataTo obtain genetic association estimates for the cytokines considered, genome-wide association studies were conducted separately in each of the three Finnish studies , assuming an additive genetic model. The results were pooled via an inverse variance weighted fixed effects meta-analysis.-8 (P<1×10-6 for fasting insulin) and were uncorrelated (r2<0.001). The inverse variance weighted method was applied as the main mendelian randomisation analysis. We also conducted analyses using weighted median, MR-Egger, and MR-PRESSO methods that are more robust to violations of mendelian randomisation assumptions due to horizontal pleiotropy.The genetic associations for the cardiometabolic traits were obtained from the summary statistics derived from the large scale genome-wide association studies . Instrum-4, which we term cis-protein QTL (cis-pQTL) instruments. In the second approach, we chose variants within plus or minus 500 kilobases of the corresponding gene locus that associated with both gene expression aggregated across tissues at P<1×10-4, and circulating cytokine levels at P<0.05, which we term cis-expression QTL (cis-eQTL) instruments. The cross-tissue gene expression associations were further compared with blood expression associations.To define the instrumental variables for circulating cytokine levels modelled as exposures in a mendelian randomisation, we enhanced our genome-wide association studies data with additional publicly available summary statistics from the INTERVAL studyMendelian randomisation analyses investigated the effects of cardiometabolic traits on circulating cytokine concentrations, the effects of circulating cytokines to other cytokine concentrations, and the effects of circulating cytokine concentrations on cardiometabolic phenotypes.cis-pQTL and cis-eQTL). The ratio method (if one instrument available) or inverse variance weighted method (if two or more instruments available) was applied as the main mendelian randomisation analysis, complemented with weighted median, MR-Egger, and MR-PRESSO methods to investigate whether the results were driven by pleiotropic effects.2r<0.001) variants from across the genome, associating with the cytokine concentrations at P<5×10-8. The Pearson correlation coefficient estimated the similarity between mendelian randomisation estimates obtained for the same exposure and outcome associations as with the two main different instrument selection criteria (cis-pQTL and cis-eQTL). To account for multiple testing, we applied a Bonferroni correction for the number of outcomes, yielding a P value threshold of 0.05/47=0.0011 when cytokines were outcomes, and 0.05/15=0.0033 when the cardiometabolic phenotypes were outcomes.The mendelian randomisation analyses that had circulating cytokine concentrations as exposures were performed by use of the two sets of instruments (shared) with the exposure and outcome cytokine concentrations at the exposure gene locus, and thus, any evidence for colocalisation would further support a causal association.distinct) would suggest genetic confounding. PPshared+PPdistinct >0.5 and PPshared /(PPshared+PPdistinct) >0.5 was considered as evidence for colocalising signals. Similar colocalisation analysis was done for the cytokine and cardiometabolic phenotype pairs with nominal evidence for association in mendelian randomisation (P<0.05).For cytokines that generated mendelian randomisation evidence of having causal effects on concentrations of other cytokines, we conducted colocalisation. Specifically, we investigated the posterior probability (PP) of a shared causal variant  for genetically proxied body mass index, waist circumference, systolic blood pressure, high and low density lipoprotein cholesterol concentrations, total cholesterol levels, triglycerides, and smoking liability with circulating concentrations of at least one cytokine . The abs10.1136/bmjmed-2022-000157.supp2Supplementary datacis-pQTL instruments were available for 30 cytokines and cis-eQTL instruments for 20 cytokines, with both types of instruments available for 19 cytokines   . Mendeli to 1.71 . The mos to 1.71 . When coshared /(PPshared+PPdistinct) >0.5) for 20 exposure-outcome pairs of cytokines (VEGF gene) with levels of seven other cytokines: interferon gamma (IFNγ), IL5, IL7, IL10, IL12p70, IL13, and macrophage inflammatory protein-1-alpha (MIP1α).Colocalisation provided further evidence supporting causality  for genetically increased IL1RA concentrations with decreased CRP concentrations ; cis-eQTL β=−0.13 (−0.17 to −0.09)) and increased total cholesterol concentrations (cis-pQTL β=0.05 (0.04 to 0.06); cis-eQTL β=0.05 (0.02 to 0.08)); additionally, for genetically increased macrophage migration inhibitory factor (MIF) concentrations with decreased CRP levels (cis-pQTL β=−0.08 (−0.12 to −0.04); cis-eQTL β=−0.07 (−0.10 to −0.04)), increased high density lipoprotein cholesterol (cis-pQTL β=0.03 (0.01 to 0.04); cis-eQTL β=0.03 (0.01 to 0.05)), and increased triglycerides concentrations (cis-pQTL β=0.06 (0.04 to 0.08); cis-eQTL β=0.07 (0.05 to 0.08)). For the 15 cytokines where three or more genetic instrumental variables were available  >0.5) for 19 cytokine and outcome pairs. Notably, IL1RA colocalised with five cardiometabolic traits , and coronary artery disease risk colocalised with MCSF and TRAIL (shared /(PPshared+PPdistinct) >0.99). Although colocalisation of IL1RA and coronary artery disease risk showed stronger support for shared causal variant than distinct variants (PPshared /(PPshared+PPdistinct) >0.91), the statistical power was insufficient to show conclusive evidence against genetic confounding .Obesity, hypertension, and smoking are leading preventable threats to global health.To better understand cytokine regulatory networks, we also examined the associations of genetically predicted circulating cytokines with levels of other cytokines. Our approach suggests complex relations between circulating cytokines, with VEGF appearing as a master regulator. Indeed, VEGF signalling is already targeted clinically in the treatment of certain cancers and ophthalmic conditions.IL1RN gene that increase IL1RA are positively associated with total cholesterol, low density lipoprotein cholesterol, and glucose, but negatively with CRP concentrations,Considering the cardiometabolic outcomes under study, we identified consistent mendelian randomisation and colocalisation evidence for circulating TRAIL increasing coronary artery disease risk; IL1RA and MIF decreasing CRP levels; and IL1RA increasing circulating low density lipoprotein cholesterol, total cholesterol, and glucose concentrations. TRAIL is a ligand involved in initiating apoptosis that has previously been implicated in atherosclerosis.ABO locus.trans-QTL proxies for cytokines. However, this strategy is also likely to include variants that are not specific only to the relevant cytokine, therefore, potentially mis-specifying the exposure and introducing pleiotropic effects violating the mendelian randomisation assumptions.The mendelian randomisation results using genome-wide selection for instruments provided distinct results to the main results. In particular, genetically proxied circulating soluble E-selectin levels were associated with eight cardiometabolic traits, mostly driven by strong associations in the In our analyses, we aimed to maximise the validity of instruments selected to proxy levels of circulating cytokines by considering only variants that were located at the corresponding gene locus, an established strategy for selecting instruments when investigating drug effects.By leveraging large scale genetic data, this work offers deeper insight into causal relations between cardiometabolic traits, circulating cytokines, and cardiovascular disease. Our findings replicate previously described therapeutic targets and further identify potential pharmacological opportunities, including perturbation of circulating TRAIL, IL1RA, and MCSF for reducing coronary artery disease risk.


From their first trimester until delivery, intervention participants received education about eating balanced meals to meet daily dietary requirements with diverse food groups. The primary outcome of mean birth weight was 127.5 g higher in the intervention compared to control women, and the intervention reduced the risk of LBW by 57%. Post hoc analyses showed a significantly higher birth weight and a greater reduction in LBW amongst adolescent mothers. The mean number of food groups consumed was significantly higher in the intervention from the third month of pregnancy than in the control. A community-based balanced plate nutrition education intervention effectively increased mean birth weight and reduced LBW, and improved dietary diversity in rural Bangladeshi women.Low birth weight (LBW) is a global public health problem with the highest prevalence in South Asia. It is strongly associated with maternal undernutrition. In South Asia, intra-household food distribution is inequitable, with lower dietary adequacy in women. Evidence that nutrition education improves diet during pregnancy and reduces LBW is weak. We assessed the impact of nutrition education for pregnant women on birth weight in rural Bangladesh. We conducted a parallel, two-arm, cluster-randomised controlled trial, with 36 clusters allocated equally to intervention ( Birth weight is a powerful predictor of infant survival . Low birLBW is strongly associated with maternal undernutrition , which iThere is little data on nutrition education’s effects on birth weight in low or middle-income countries, although four meta-analyses have assessed impacts. The first, in 1993, found that nutrition education significantly increased the consumption of protein and vitamins and the birth weight of infants by 300 g. However, the studies lacked statistical power or did not report effect size estimates . The secThus, the evidence for nutrition education to improve diet and maternal and neonatal health indicators, including birth weight, remains weak. Most evidence comes from trials with design or analysis limitations  and in hWe conducted a two-arm, parallel, cluster-randomised controlled trial (cRCT) and have previously described the design . In brieShasthya Kormi. One Shasthya Kormi serves an area of ~10,000 people, along with ten health volunteers (Shasthya Shebika). The Shasthya Kormi are village women who have basic 10-years schooling and have received training on health, nutrition, and sanitation issues for six weeks, followed by bi-monthly refreshers.Sherpur has five sub-districts: Jhenaigati , Nakla , Nalitabari , Sherpur Sadar  and Sreebardi . Pregnant women, self-reporting to a hospital or formal practitioner , receive nutrition education as part of antenatal care (ANC). BRAC  implements a community-based Maternal, Neonatal, and Child Health (MNCH) program characterised by prospective pregnancy surveillance and basic ANC led by community health workers (CHW) known as Shasthya Kormi, which provided logistical convenience and minimised intervention spills into the control group. Shasthya Kormi, with at least six months of experience in MNCH, were eligible. Participants were pregnant women 15–49 years, with gestation 12 weeks or less, permanently residing in the area, and not expecting to move from the usual residence until birth. We used the established BRAC pregnancy detection system for monthly menstrual surveillance to identify new pregnancies. Women with delayed menstruation for six weeks or more underwent a urine test. We excluded pregnant women with self-reported chronic disease. All women excluded from the study continued to receive standard care and counselling as in the control clusters. A Shasthya Kormi visited each confirmed pregnant woman, screened for eligibility, and obtained verbal informed consent. Recruitment took place from 1 October–31 December 2016. In our study, a cluster was the catchment area of one Shasthya Kormi a single BRAC supervisor could oversee. We randomly allocated the treatments to clusters in a 1:1 ratio by conducting a lottery. We wrote each cluster number onto 36 pieces of paper and put them into five different jars, one for each sub-district, based on the cluster selection made in the first step. The treatment sequence alternated between A (intervention) and B (control), starting with A. We invited a blindfolded volunteer not linked to the study to choose the pieces of paper from each of the jars. We have described this process in more detail in the protocol paper [Shasthya Kormi received the intervention or standard care per the random assignment.Sherpur district is divided into five sub-districts: Jhenaigati, Nakla, Nalitabari, Sherpur Sadar and Sreebardi, containing 16, 19, 25, 49 and 26 clusters, respectively. We used the stratified proportionate to population size sampling method to obtain 4, 5, 7, 13 and 7 clusters, respectively, from each of the five sub-districts. The clusters were dispersed across the sub-districts and sufficiently separated to minimise the risk of contamination. We selected 36 as the maximum number of ol paper . All eliWe could not mask families or the research team to group allocation; however, we blinded researchers assessing primary and secondary outcomes to the study hypotheses. We also used an objective outcome (birth weight) that is less prone to ascertainment bias.Shasthya Kormi received two days of nutrition training, including a balanced diet and counselling techniques. They also practised community counselling skills under supervision and received one-day training on taking consent and data collection. Enrolled participants were visited monthly to provide ANC that included standard nutrition advice. In intervention clusters, balanced plate intervention replaced the standard nutrition advice using a culturally appropriate diet for Bangladeshi pregnant women [Intervention nt women . This coWe delivered the intervention individually. Initially, participants received information on a balanced diet and the maternal and fetal health benefits. Then, they learned to prepare a “balanced plate” by demonstrating the right proportions of food groups using the prescribed menu . The comDelivering the intervention took 45 min: 10 for individual counselling, 10 for household counselling, and 25 for demonstration. To help recall messages, we provided a pictorial food chart and a written menu . The comHome visits continued until birth or the end of the pregnancy; ANC from other sources was not discouraged. Husbands were encouraged to reallocate family budgets to purchase nutritious food and mothers-in-law to re-distribute family food to increase their daughter-in-law’s share.In the control group, pregnant women received the same frequency of home and standard nutrition advice except for the balanced plate demonstrations. Standard advice recommended consuming all food groups and taking iron-folic acid and calcium supplements. More details about the intervention and standard care can be found in the published protocol paper .Shasthya Kormi collected demographic, socio-economic, and reproductive data at enrolment plus birth weight measurements within 72 h of birth. Families immediately notified births or pregnancy losses  to their nearby Shasthya Shebika.Shasthya Kormi, recorded field activities, and conducted follow-up interviews with 5% of participants to confirm visits and measure protocol adherence.One field supervisor oversaw the 36 Shasthya Kormi had many years of experience measuring birth weight, but we retrained them with their standard equipment, a 5 kg Salter spring balance scale with an accuracy of 100 g. They calibrated the scales with a standard weight every week. We also checked the scales monthly during refresher training. For mothers birthed in health facilities, we recorded the birth weight measured at the facility.Primary outcomes were the mean birth weight of live-born infants and the proportion of newborns with a birth weight less than 2500 g. The Shasthya Kormi used structured forms to record fetal loss during pregnancy, birth outcome, delivery information, and neonatal or maternal death. They also used monthly semi-structured questionnaires to collect dietary data, with the food list adapted from Food and Nutrition Technical Assistance II Project (FANTA-2) [For secondary outcomes, the FANTA-2) . These qFANTA-2)  and compWe required 720 pregnant women to achieve 80% power to detect a difference of 100 g in birth weight between groups. We assumed a mean birth weight of 2531 g (standard deviation (SD) 415 g) in the control group based on the findings from a similar trial in Bangladesh . We set lincom command to estimate the intervention effect at each gestational month.We analysed the data with Stata version 17 and conducted intention-to-treat analyses. We assigned the intervention randomly at the cluster level but assessed outcomes at the individual level. We estimated the mean between-group difference in birth weight using linear regression and the relative risk for LBW using binomial regression. We included the study group as a covariate and adjusted for cluster randomisation using Generalised Estimating Equations (GEE) . We estiWe conducted post hoc subgroup analyses for the modifying effects of age, education, family income, and place of delivery on the primary outcome, low birth weight. We added an interaction term to assess whether there was a difference in intervention effect for any sub-group, using a significance level of 0.01.We identified 2154 newly pregnant women from August 2015 to February 2016 in the selected clusters. Of these women, 937 did not meet the eligibility criteria , and 324 declined to participate. We recruited 893 participants, 445 in 18 intervention clusters and 448 in 18 control clusters, and we lost 44 participants during follow-up, 25 (5.6%) intervention, and 19 (4.2%) control. Birth weight was missing for 22 participants . There wThere were no important differences in baseline characteristics between the groups . There wSupervisors attended 5% of balanced plate demonstrations to observe the appropriateness of message delivery, the use of the menu and food chart, demonstration, problem-solving, and counselling. Approximately 6–7 of 8 messages were delivered to 80% of the participants. The time taken for the demonstrations gradually decreased with increasing numbers of visits. Counselling family members largely depended on availability; husbands were present at 15–20% of visits, and other family members at >80% of visits.p = 0.032) adjusted for clustering. The estimated relative risk (RR) of LBW was 57% lower in the intervention group  adjusted for clustering.We found a statistically significant difference in mean birth weight and LBW . The meap = 0.003; vs 95.6 g; 95% CI: −17.3, 208.4; p = 0.097)  as was the reduction in LBW , although this was not statistically significant . There was no evidence of treatment modification by the mother’s education or family income .To assess bias in ascertaining birth weight, we stratified by participants birthed in a facility whose babies were weighed by independent observers and those birthed at home and found no evidence of treatment modification (p = 0.030), which is 5.7 g less than the unadjusted analysis (p = 0.042), which was smaller than the unadjusted relative risk in After adjustment for ANC, using iron and folic acid, and clustering, the reduction in mean birth weight and LBW was smaller in the intervention group . The adjanalysis . The adjThe mean number of food groups consumed increased in the intervention group and was significantly higher from the third month of pregnancy . The larThe relative consumption rate of beans, legumes and nuts, dairy food and other fruits and vegetables was significantly higher in the intervention than in the comparison group after the third or fourth gestational month . The larWe demonstrated that antenatal nutrition education with practical demonstrations of preparing a balanced diet increases infant birth weight and reduces LBW in rural Bangladesh. After adjustment for ANC, using iron and folic acid, and clustering, there was a higher mean birth weight in the intervention group of public health significance (121.8 g) than in the control group. The effect of the intervention was greater in adolescent mothers. The findings provide strong evidence of the effectiveness of a sustainable intervention suitable for implementation in community-based healthcare systems. They demonstrate the potential impact of nutrition education to improve intrahousehold food distribution as a tool to reduce low birth weight in Bangladesh and across South Asia.The process evaluation of the trial  providedOur intervention appears more effective than interventions using micronutrients or food supplements. A large cluster RCT  in Bangladesh assessed the impact of antenatal micronutrient supplementation and found a 54 g  increase in birth weight and a 12% reduction  in LBW . AnotherProviding micronutrient supplements, even with additional food energy, is unlikely to address the fundamental problems of insufficient food intake in pregnancy related to food taboos and inequitable intra-household food distribution. The earlier MINIMat RCT (3267 singleton newborns) , which tAdolescent pregnancy increases the risk of adverse birth outcomes, including LBW . If seveThe balanced-plate intervention significantly increased maternal dietary diversity . Change p = <0.0001). This evidence supports our findings that an improved and more diverse dietary intake reduces LBW.There was a significant six-fold increase in the adjusted odds of LBW with an inadequate minimum dietary diversity score . A cross-sectional study  from GhaParticipants in the intervention group consumed more animal-sourced protein foods, reaching a peak at eight months of gestation of approximately two animal-sourced foods/day. A large cross-sectional study of pregnant women in Shaanxi province, northwestern China, reported an average weekly consumption of five animal-sourced foods . As the Despite earlier evidence of the positive impact of nutrition education on pregnancy outcomes, the delivery method has received little attention. It is particularly important in low-literate and poor self-efficacy populations, such as rural Bangladesh, where women require dietary counselling to be accessible, feasible, and sanctioned by the community. A review of over 300 studies found that nutrition education is more likely to be effective when focusing on behaviour and action than knowledge alone. And it is also expected to be more effective if grounded in theory . FishbeiIn Bangladesh, the main source of nutrition education for pregnant women is through ANC, but the contact time is insufficient to affect nutrition change . Thus, WThe evidence presented from this trial is robust. Key strengths are the cluster, randomised controlled trial design with sufficient statistical power to detect clinically important changes in outcomes. The delivery of the trial treatments through an established home-based antenatal care service led to a balance between the treatment groups in the level of antenatal contact with community health workers. The unblinded intervention was counterbalanced by objective outcomes and blinding participants and data collectors to the aims and hypotheses. The trial had a very high follow-up (93%), and we used intention-to-treat analyses and adjusted for unbalanced baseline factors and clustering. Our intervention was logistically simple and culturally appropriate based on well-designed qualitative formative research. The key to our success was conducting the trial within existing ANC frameworks. The delivery strategy resonates with maternal and child nutrition recommendations to achieve adequate coverage of nutrition-specific interventions by reaching needy populations . Shasthya Kormi, who delivered the intervention, collected birth weight data. Measuring birth weight and providing nutrition counselling are routine tasks for these staff. By blinding the SK to the study outcome, we would expect non-differential bias. Also, we found no difference in the effects between women who had birth weight measured by hospital staff versus those who were birthed at home with birth weight measured by the SK. Secondly, using catchment areas as clusters might introduce contamination, with the possibility of Shasthya Kormi exchanging information. However, this would have biased results towards a null effect. To prevent this, we trained the intervention and control group Shasthya Kormi separately at regular refresher sessions. Thirdly, we could not quantify food intake and intra-household food distribution, which might have provided further evidence of pathways to the observed impact. Fourthly, we could not assess the modifying effects of seasonality on the response to the intervention because we did not collect detailed information about seasonality or food security. Further, the study recruitment period was short, and few women were impacted by seasonal food insecurity. Fifthly, we could not measure pre-pregnancy BMI, which is a potential confounder and might also modify the responses to the nutrition education intervention. Also, we did not measure the mother’s gestational weight gain, which might have provided more information about mechanisms leading to improved birth weight in the intervention arm. Finally, we excluded over 30% of pregnant women who identified because they were already in the second or third trimester when we detected their pregnancy. There is no information about the characteristics of these excluded women, and thus no way to compare them to those included in the trial. This lack of data limits our assessments of the external validity of the trial findings.However, we acknowledge the study’s limitations. First, Our results indicate that a balanced plate nutrition education during pregnancy increases birth weight and reduces LBW. Our trial offers a pragmatic food-based strategy for resource-poor environments, especially where there is gender-biased intrahousehold food allocation. The CHW-led intervention is simple, feasible, and easy to implement in settings with an existing community nutrition outreach program. The intervention can be implemented in Bangladesh through the existing community health infrastructure.


Obstetric fractures usually occur after complicated births and are sent to paediatric orthopaedics for treatment and follow-up. Clavicle fractures represent the most common orthopaedic birth injury, involving approximately 0.2 to 3.5% of births.Caesarean delivery, elective or necessary, along with the type of presentation, may play a determinant role in the aetiology of obstetric fractures.We chose to do a retrospective study to determine possible risk factors for this type of injury that may manifest in either delivery. Our aim was to deepen our knowledge in order to have a better prediction and a better management of this condition. Data gathered included parity, gestity, type of delivery, presentation, shoulder dystocia, type of fracture, birth weight, and APGAR score.We followed 136 patients that were diagnosed with Allman type I clavicle fracture, 32 of them also having brachial plexus birth palsy (BPBP) type 1 (Duchenne-Erb). Natural birth with a pelvic presentation imposes a relative risk of 6.2 of associated pathology compared to cranial presentation. Caesarean delivery and cranial presentation increase the risk of related pathology by 5.04 compared to natural birth. Statistically, pelvic presentation is 5.54 times more likely to develop related pathology than cranial presentation. Type of delivery and presentation correlate with associated pathology of clavicle fractures.Caesarean delivery brings risks for the newborn and should be practiced only when necessary. Predictive modeling in obstetrics in third-trimester evaluations may statistically predict risks of birth complications like fracture and BPBP. Although they occur more often during vaginal delivery, most probably due to compression of the anterior fetal shoulder against maternal symphysis pubis after delivery of the head (shoulder dystocia), they can also occur in cesarean deliveries [Obstetric fractures are fractures that newborns suffer during the delivery or birth process. The most commonly affected bones are the clavicle, the humerus, the femur, and the skull , 2. Clavliveries . The mosliveries , and theliveries . On the liveries . Relatedliveries .Allman classifies fractures of the clavicle in three groups . Group IClavicular fractures usually heal without complications or late sequelae . The litThe decisive role of the type of birth and the presentation in the etiology of neonatal clavicle fractures is well known. Our study aims to determine possible risk factors for this type of injury that may manifest in either delivery to predict better and manage this condition.We set out a retrospective study regarding children who presented to the Paediatric Orthopaedic ward of “Grigore Alexandrescu” Children’s Emergency Clinical Hospital of Bucharest from 2018 to 2020 with obstetric fractures. The ethics committee of “Grigore Alexandrescu” Children’s Emergency Clinical Hospital of Bucharest approved this study on 14 December 2021. The identification number of the survey is 34/14 December 2021. Informed consent was obtained from the parents of all the participants when they presented initially.The main keywords we searched in our database were “obstetrical fracture” and “brachial plexus lesion” on infants under one year of age. The inclusion criteria were positive diagnosis of an obstetrical fracture with clinical and radiological findings, neurological examination of the affected limb, parental consent, and complete patient history. Exclusion criteria were non-obstetrical fractures , lack of data regarding delivery and labour, lack of radiological examination that might confirm the diagnostic, and lack of parental consent.From the initial group of 161 patients, 20 patients lacked a complete patient history. Three patients did not have the parental consent to be included in the study, and two patients had inconclusive radiological exams. Only 136 patients met the inclusion criteria . Birth weight did not correlate with gender statistically significantly, with a mean girls’ weight of 3418 g and a mean boys’ weight of 3510 g .Out of 136 patients, 68 were boys and 68 were girls. All of them were diagnosed with Allman I clavicle fracture; 32 children  were also diagnosed with brachial plexus birth palsy (BPBP) type 1 (Duchenne-Erb) involving C5 and C6 nerves. Restitutio ad integrum was the outcome of every patient with BPBP until 2. Our study affirms that gender was not a risk factor for obstetrical fractures , preeclampsia and maternal hypertension (1), maternal thrombocytopenia (4), and postmaturity (3) . Thus, cesarean delivery increases the risk of birth-related complications 4.75-fold compared to natural birth. This result only considers the type of birth and no other possible risk factors.We built a logistic regression model to assess the causality relationship between these two variables. According to the logistic regression, the type of delivery correlates with fracture complications statistically . We discovered that pelvic presentation is 5.54 times more likely to develop related pathology than cranial presentation.There were 124 children with the cranial presentation, from which 99 had no associated pathologies and 25 developed related pathology. There were 12 children with the pelvic display, and seven had associated pathology. After performing logistic regression, we found that presentation correlates with associated pathology statistically  instead of birth weight.Next, we assessed maternal age and birth weight in correlation with the risk of fractures. We classified the neonates into four groups according to their birth weight: small (< 3000 g), average (3000–3800 g), large (3800–4200 g), and huge (> 4200 g). In our study, maternal age did not represent a statistically significant variable . According to our analysis, the risk of associated pathology increases by 6% for each increment in maternal BMI during pregnancy for a particular child’s weight. We also found that for a certain maternal BMI, the risk of associated pathology decreases by 83% for each kilogram over the minimum birth weight in our group of children. Increased birth weight has proven to be a protective factor against the associated pathology.After conducting a logistical regression with birth weight and type of delivery as variables, we found that they correlate statistically. Caesarean delivery imposes a relative risk of 9.6 of associated pathology compared to vaginal delivery for a certain birth weight.The model based on birth weight and type of delivery varies according to the confidence intervals that we choose. For example, for a newborn with a weight of 3.46 kg, delivered vaginally, there is a probability of 9% of associated pathology. In contrast, for a newborn with the same weight provided through the caesarean section, the chance is 51.9%.The following table and figures Table  show theFollowing a logistic regression between parity as a variable and the presence of a fracture/associated pathology, we found that multiparae have a 90% lower risk of newborn injuries than primiparae.p-value of 0.0089).Following the logistic regression with associated pathology as a variable and also birth weight, parity, and type of delivery, we found that all three quotients are statistically significant , and the head to chest circumference ratio was considerably lower. They also note that APGAR scores at 1 and 5 min are significantly lower in the fracture group [Their ten year retrospective study about clavicle fractures among vaginally delivered babies reported that the birthweight of the infants that suffered clavicle fractures was significantly higher . Likewise, age does not have a considerable impact on primigravid women. Therefore, the main effect is that parity and increasing age jointly result in a higher fracture incidence. Thus, fractures are more likely to occur if the mother is older and parous. Our study suggests that nulliparity is a risk factor for obstetric clavicular fractures compared to their results. According to our statistic analysis, multiparae have a 90% lower risk of newborn trauma than primiparae. In our study, maternal age did not represent a statistically significant variable in infant injury .A study suggests that breech births are three times more common in the fracture group compared with the whole population. This type of presentation is a risk factor in our present study and already published literature. Furthermore, we found that pelvic presentation is 5.54 times more likely to develop pathology associated with the clavicle fracture than cranial presentation. Orthopaedic examination of breech newborns should obligatory include hip ultrasound, knowing that this condition is associated with developmental dysplasia of the hip .Kalk et al. on the impact of maternal BMI on neonatal outcome note that overweight and obese mothers exhibit an increased risk of delivering via caesarean section compared to healthy weight mothers. In contrast, for underweight mothers, no such association is detected. Caesarean section can also be technically more difficult in obese women, and there is a higher risk of anaesthetic and postpartum complications than in normal-weight mothers. Also, overweight or obese mothers have a significantly increased risk of macrosomic (birth weight > 4000 g) children (OR about 1.5 and 2), whereas underweight mothers are not at risk. Furthermore, elevated maternal BMI is associated with increased admission to neonatal care and with a lower APGAR score at one and five minutes, according to Mansart et al. Our results support maternal BMI as an independent risk factor for newborn fractures and associated complications, raising the risk with 6% per each BMI increment .The strength of this manuscript is a thorough statistical analysis, both univariate and multivariate. The study limitations were our sample size, which may undergo “The law of small numbers,” our complete lack of data about the obstetricians’ extraction manoeuvres, and their expertise  .In summary, the results of our study agree with other reports concerning obstetric trauma , 24. ForCaesarean delivery brings risks for the newborn and should be practiced only when necessary. It is possible to use predictive modeling in obstetrics in third-trimester evaluations. One may statistically predict risks of birth complications like fracture and BPBP. More data is needed, from larger study samples, to find new risk factors and validate our logistic regression models.