Study Design: 51 preterms-born healthy neonates, 62 term-born CHD neonates, and 54 term-born healthy neonates underwent a brain MRI with volumetric imaging. Cerebellar volumes were extracted through an automated segmentation pipeline that was developed in-house. Volumes were correlated with clinical growth parameters at both the birth and time of MRI. Results: The CHD cohort showed significantly lower cerebellar volumes when compared with both the control (p < 0.015) and preterm (p < 0.004) groups. Change in weight from birth to time of MRI showed a moderately strong correlation with cerebellar volume at time of MRI  in the preterms, but not in the CHD neonates . Changes in birth length and head circumference showed no significant correlation with cerebellar volume at time of MRI in either cohort. Conclusions: Cerebellar development in premature-born infants is associated with change in birth weight in the early post-natal period. This association is not observed in term-born neonates with CHD, suggesting differential mechanisms of aberrant cerebellar development in these perinatal at-risk populations.Aberrant cerebellar development and the associated neurocognitive deficits has been postulated in infants with congenital heart disease (CHD). Our objective is to investigate the effect of postnatal head and somatic growth on cerebellar development in neonates with CHD. We compared term-born neonates with a history of CHD with a cohort of preterm-born neonates, two cohorts at similar risk for neurodevelopment impairment, in order to determine if they are similarly affected in the early developmental period.  Infants diagnosed with congenital heart disease (CHD) are at a higher risk for neurodevelopment impairment, with particular predilection for executive function and motor deficits ,2,3,4,5.Poor intrauterine somatic growth has been widely studied as a predictor of neurocognitive outcomes in preterm populations ,14,15. AIn this work, we aim to explore the specific relationship between cerebellar development and somatic growth, as the cerebellum is a key structure that undergoes rapid development in the late gestation period, placing it at higher risk for injury . AberranThis work is an exploratory analysis of previously prospectively recruited neonates at our institution. We recruited 62 term-born CHD neonates, 54 term-born healthy neonates, and 51 preterm-born neonates as part of IRB-approved prospective studies. This dataset has been previously described in our prior work ,24,25. AThe mean gestation age for the control cohort was 41.2 (+/− 3.8), CHD cohort was 38.0 (+/− 2.9), and preterm cohort was 30.7 (+/− 3.8). Post-menstrual age (PMA) at time of imaging was 43.5 (+/− 5.5) for the control group, 42.4 (+/− 6.9) for the CHD group, and 40.5 (+/− 7.8) for the preterm group. Preoperative research brain imaging was conducted when the cardiothoracic intensive care unit (CTICU)/cardiology team determined the patient was stable for transport to the MRI scanner. A postoperative research scan was performed when the patient was younger than 3 months of postnatal age, either as an inpatient or outpatient. Most of our scans were research indicated and, as such, no additional sedation/anesthesia was given for the purpose of the scan. Most of the preoperative scans were performed on nonintubated, nonsedated patients; however, if a patient was intubated and sedated for clinical reasons at the time of the scan, their clinically indicated sedation continued under care of the primary CTICU team. Most of the postoperative scans were performed after the infant had stepped down from the CTICU and were done as “feed and bundle” scans without sedation.The CHD and preterm cohorts had head and somatic growth measures taken at both birth and time of MRI, which included weight (WT), length/height (LT), and head circumference (HC). From these measures, we also calculated the relative head growth (change in HC/change in WT), adjusted for the time interval between birth and MRI. Head and somatic growth measures were not available for the term neonates; therefore, they were excluded from the growth rate analysis.In order to account for the expected rapid growth in the preterm population , we converted the raw growth parameters into Z-Scores for age, following established WHO guidelines  and norm3, and matrix size 320 × 320; (2) volumetric T2 sampling perfection with application optimized contrasts using different flip angle evolution sequence at TE/TR: 2.56/2400 ms, 1.0 × 1.0 × 1.0 mm3, and matrix size 256 × 196; (3) axial T2 weighted fast spin echo (FSE) at TE/TR: 3/2400 ms, slice thickness 2.0 mm with 0 skip, and in-plane matrix resolution 200 × 256. This dataset has been described in further detail in a previous publication [Infants were scanned on a 3T Siemens Skyra MRI  without sedation. Effort was made to scan at close to term equivalent age, or when infants were deemed clinically stable. Where available, we chose the earliest pre-operative scan for CHD infants. When no pre-operative imaging was possible, or the pre-operative scan failed QC, we used the earliest post-operative time point. The imaging parameters were as follows: (1) volumetric T1 magnetization-prepared rapid gradient-echo at echo time (TE)/repetition time (TR): 418/3100 ms, 1.0 × 1.0 × 1.0 mmhttps://github.com/PIRCImagingTools/NeBSS (accessed on 5 July 2022).We developed a semi-automated neonatal brain segmentation pipeline . This piStatistical analysis was done in R  . We compThere was no significant difference in PMA between the three cohorts at the time of imaging. Of the 62 CHD subjects, 11 did not have imaging pre-surgical intervention, and post-surgical intervention imaging was used. There was no statistically significant difference between pre- and post-op in the cerebellar volumes or growth parameters.We looked at the standardized growth parameters for each cohort at both birth and time of MRI, comparing the CHD and preterm cohorts . Preterm3, compared with the term controls, mean 457.8 (+/−2064.2) mm3 and the CHD group, mean −683.8 (+/−2428.0) mm3. The preterm cerebellar volumes were significantly higher than the CHD group (p < 0.008), and the CHD group also demonstrated a reduced cerebellar volume compared with the controls. Change in weight from birth to time of MRI showed a moderately strong correlation with cerebellar volume at the time of MRI  in the preterms, but not the in the term-born CHD neonates , significant at p < 0.000  after birth . Here, wHead circumference and somatic growth are useful measures that have been thoroughly validated in preterm populations ,34, and While studies in CHD patients do show catch-up growth in height and, to a lesser extent, in weight and head circumference by 10 years of age, somatic growth can still remain impaired with respect to head circumference and overall weight z-scores below the norm for up to 10 years . The etiHere, we chose to focus specifically on cerebellar volumes and its correlation with growth parameters. Cerebellar abnormalities have strong associations with neurocognitive outcomes in both preterm and CHD populations . A potenThis work has some limitations. Due to the precarious condition of infants born with CHD, there is some variance in the time interval between birth and MR imaging. We attempted to mitigate this by calculating a growth rate measure, at a trade-off of the direct interpretability of these values. Furthermore, a convenience sample cannot be avoided, as patients not stable enough to image were excluded from the analysis. There may be bias due to the less-stable cases not getting pre-surgical MRI, but there are also uncorrelated reasons, including scheduling difficulties, motion artifacts/failed scans, or consent to study done only after surgery. We used the pre-operative time point for CHD infants whenever possible, and limited the time interval post-operative to mitigate as much of potential surgically related changes as we could. Unfortunately, it was not possible to image every neonate prior to surgery, but we feel that including post-operative infants within a short time frame would still primarily reflect pre-operative findings. We believe this is not directly detrimental to our overall hypothesis, as characterizing aberrant development in relatively healthy infants with CHD points to these deficits being implicit in CHD, independent of clinical condition at birth. Additionally, as this was a secondary analysis of a prospective study, we did not power recruitment to specifically look at growth changes from birth to MRI, and did not control for nutrient accretion. Similarly, we did not acquire growth data on the control population, and the reported gestational age of the controls  may be biased—where term-born infants may be defaulted to 40 weeks gestation. However, the primary purpose of this work was to contrast preterm and CHD infants, and comparisons to the control population were only used as a comparative baseline. We believe using normalized values and z-score conversions helps attenuate this shortcoming, but further investigation is necessary to confirm our findings.Future work aims to more granularly differentiate between serial pre-operative and post-operative MRI scans in infants with CHD. Additionally, we will incorporate socio-economic status, genetic data, and clinical factors associated with perinatal injury into our statistical models to further investigate the short- and long-term neurodevelopmental outcome correlates of our cerebellar morphological findings.Cerebellar development in premature-born infants is associated with change in birth weight in the early post-natal period. This association is not observed in term-born neonates with CHD, suggesting differential mechanisms of aberrant cerebellar development in these perinatal at-risk populations. Taken together, our findings are consistent with a body of work showing that somatic and head growth are important biomarkers that may reflect deeper mechanistic brain development in infants with CHD.


Preterm neonates display a high risk of postnatal malnutrition, especially at very low gestational ages, because nutritional stores are less in younger preterm infants. For this reason nutrition and growth in early life play a pivotal role in the establishment of the long-term health of premature infants. Nutritional care for preterm neonates remains a challenge in clinical practice. According to the recent and latest recommendations from ESPGHAN, at birth, water intake of 70–80 mL/kg/day is suggested, progressively increasing to 150 mL/kg/day by the end of the first week of life, along with a calorie intake of 120 kcal/kg/day and a minimum protein intake of 2.5–3 g/kg/day. Regarding glucose intake, an infusion rate of 3–5 mg/kg/min is recommended, but VLBW and ELBW preterm neonates may require up to 12 mg/kg/min. In preterm infants, lipid emulsions can be started immediately after birth at a dosage of 0.5–1 g/kg/day. However, some authors have recently shown that it is not always possible to achieve optimal and recommended nutrition, due to the complexity of the daily management of premature infants, especially if extremely preterm. It would be desirable if multicenter randomized controlled trials were designed to explore the effect of early nutrition and growth on long-term health. The incidence of preterm birth is on the rise: 11% of births worldwide occur before the 37th week of gestation. Survival of preterm infants continues to increase both in developed and developing countries, and in part reflects improvements in nutritional care. However, the preterm population presents a high risk of postnatal malnutrition, and this risk is higher for infants of low gestational age (GA) because nutritional reserves are lower in younger preterm infants. For this reason several studies continue to demonstrate the importance of nutrition and growth in early life.Preterm birth interrupts the physiological growth path of the fetus that occurs during the third trimester of pregnancy. Preterm infants are exposed to an environment which is different from the maternal uterus, hence requiring more energy to maintain thermal and metabolic homeostasis. Extremely preterm infants (less than 28 weeks’ gestation) also feature little or no subcutaneous fat and low stores of glycogen and key nutrients such as iron, zinc, calcium, and vitamins. Therefore, the nutritional care for preterm newborns remains a challenge in clinical practice since an inadequate nutrition in the first days of life could determine not only growth failure , but alsSome authors have recently shown that it is not always possible to achieve optimal and recommended nutrition, due to the complexity of the daily management of preterm infants, especially if extremely preterm. Infusion of drugs, maintenance of vascular access, and volume boluses to support blood pressure commonly result in administration of relatively large volumes of non-nutritional fluids .This narrative review was conducted by searching scientific databases for articles reporting on parenteral nutrition in preterm neonates and on correct macronutrient and micronutrient intake.To fully investigate the importance of parenteral nutrition in preterm neonates, an exhaustive search for eligible studies was performed in PubMed, Embase, Medline, Cochrane library and Web of Science databases.The following subject MeSH headings were used: “Parenteral nutrition” (MeSH), “Macronutrients” (MeSH), “Micronutrients” (MeSH), “Energy intake” (MeSH), “Infants, Newborn” (MeSH), “Premature Birth” (MeSH), and “Prematurity” (MeSH).To be as comprehensive as possible, proper Boolean operators such as “AND” and “OR” were also included. Additional studies were sought using references in articles retrieved from searches.We included all relevant articles  written in English, involving only human subjects, and published between January 2011 and November 2021.Preterm neonates are exposed to a high risk of faltering growth, mainly due to undernutrition. In order to limit growth retardation, current guidelines for preterm neonates recommend the administration of high doses of protein and energy intakes through parenteral nutrition (PN), starting soon after birth . Early pKashyap et al. showed that greater protein intakes would increase weight, length, and head circumference, whereas additional lipids only increased weight and subcutaneous fat. Such diets lead to fatter, shorter, less muscular infants, and perhaps to long-term neurological deficits. This issue is crucial for the smallest, most preterm infants who are fed far more energy and much less proteins than needed to meet appropriate growth rate and body composition. Boscarino et al.  in 2021 However, Bonsante et al. demonstrated in an observational study that high PN energy intake is associated with metabolic acidosis . MoreoveDespite the fact that hundreds of thousands of preterm infants receive parenteral fluids each year, study of optimal fluid and electrolyte management in this population is limited. Appropriate fluid and electrolyte management is critical for optimal care of low birth weight or sick infants, as fluid overload and electrolyte abnormalities pose significant morbidity threats. Water and electrolyte balance is influenced by different factors, such as insensible cutaneous and respiratory water loss, contraction of the extracellular compartment in the first days of life, renal immaturity, and needs related to growth. Therefore, water intake must compensate for ‘renal excretion and water loss through the skin and respiratory and digestive tracts, in order to ensure adequate growth .Nonetheless, the right and appropriate volume of fluids to administer to premature newborns is not yet fully defined. It is important to define the right fluid intake because an adequate intake in preterm newborns is essential to prevent deficits and promote growth, improving the potential outcome for the most fragile subjects.Restrictive fluid administration significantly decreases the risk of patent ductus arteriosus (PDA) and necrotizing enterocolitis (NEC) , albeit In the first days of life water intake should be individualized, considering changes in the neonate’s weight, serum sodium and urine output. Fluid needs in preterm neonates are postnatal and gestational age dependent. At birth, water intake is 70–80 mL/kg/day and progressively increases, reaching 150 mL/kg/day at the end of the first week of life . Water iFurther research is needed to clarify the optimal fluid regimen for preterm infants to ensure adequate hydration and nutrition without contributing to serious complications.Electrolytes intake is also very important for the adequate growth of preterm infants, in particular sodium balance, since wide variations in serum sodium are associated with a worse prognosis at 2 years of life . For anyAt birth there is a physiological loss of sodium because of the normal contraction of extracellular volume in the first days of life. Subsequently, after the initial relative oliguria, a diuretic phase occurs which can lead to sodium loss due to increased urine output. Hence, after a first restriction of Na intake (less than 2 mEq/kg/day at birth), a rapid increase in sodium intake  must be considered . CurrentPlasma potassium concentration is higher in preterm than in term neonates, and it typically falls in the first few days of life . For thiCalcium and phosphate (Ca-P) should be added from the first day; 60–80 mg/kg of elemental Ca, 45–60 mg/kg of phosphate per day should be given . During However, high aminoacidic and energy intake can also cause hypophosphatemia, hypercalcemia, and hypercalciuria . ChlorinProteins are the major structural and functional component of all cells in the body and consist of chains of amino acids joined together by peptide bonds.Providing adequate protein supply to preterm infants during the early postnatal period is critical to ensure proper growth and avoid early postnatal malnutrition, that may affect long-term neurodevelopmental outcome.A minimum intake of 1.5 g/kg/day intravenous protein is required to prevent a negative nitrogen balance in preterm babies and this forms the basis of current recommendations for intravenous amino acid intakes for VLBW babies (starting dose of 1.5 g/kg/day with progressive daily increases up to 2.5–3.5 g/kg/day in the first week of life)  Table 1Table 1.Brain growth and development depend on a high rate of protein synthesis because protein is essentially the structural scaffolding of the brain, as shown by the positive correlations between higher protein intakes, greater head circumference growth and improved neurodevelopmental outcomes . Morgan The growth of head circumference, an index of brain growth correlated with neurodevelopment, between day 1 and day 28 was higher (with a gain of 0.37 Z-score) with high amino acid intake.In a randomized prospective study, Roelants et al. demonstrated that starting amino acid intake in the early hours of life does not result in hyperammonemia or acidosis, and improves the net amino acid balance as measured by perfusion of 13C-leucine. Compared to glucose alone, the initiation of amino acids (2.4 g/kg/day) in the first 2 h of life in 32 premature babies with an average weight of 923 g improved not only protein synthesis and nitrogen balance on the 2nd day of life, but also the synthesis of glutathione [Glucose is the primary source of non-protein energy in PN and is essential for the developing brain after birth because it is easily metabolized. Preterm neonates have low stores of glucose in the form of glycogen, hence an adequate source of exogenous glucose is mandatory to ensure satisfactory growth and neurological development .Glucose requirements in the neonatal period vary according to gestational age and the individual needs of the neonate. For most infants, a glucose infusion rate of 3–5 mg/kg/min is sufficient, but VLBW and ELBW preterm neonates may require up to 12 mg/kg/min to maintain enough energy for their metabolism. Correct glucose intake must be provided to guarantee adequate growth rates, in particular to support growth and protein synthesis from amino acids .In preterm neonates glucose production rates is 2–3 mg/kg/min, and glucose utilization rates can be as high as 7–9 mg/kg/min, for the brain but also for the heart. Term infants also produce 2–3 mg/kg/min of glucose, but their glucose utilization rates are lower (3–5 mg/kg/min)  Table 2Table 2.In preterm infants it is important to avoid not only hypoglycemia but also hyperglycemia which is a cause of hypoxia, acidosis, and various forms of toxicity inducing cellular and systemic inflammation .Glucose should be infused to meet needs, adjusting the glucose infusion rate (GIR) to maintain normal glucose concentrations (50–100 mg/dL). Maximum intravenous glucose infusion rates should not exceed 6–10 mg/kg/min .Recently the concept of “aggressive nutrition” has emerged, with early administration of lipids and a significant supply of protein along with high glucose from the first hours of life . In partEvidence has demonstrated that the introduction of amino acids within 4 h after birth diminishes insulin-treated hyperglycemia incidence in preterm infants.On the other hand, some studies have shown that decreasing carbohydrate intake to 7 mg/kg/min reduced the risk of neonatal hyperglycemia in preterm infants .More than half of preterm neonates require a continuous glucose infusion immediately after birth to maintain blood glucose levels .The GIR for preterm infants in PN should be maintained at 6–8 mg/kg/min to ascertain adequate glucose requirements . Some liEarly aggressive parenteral nutrition potentially increases the risk of hyperglycemia , especiaIn a recent study Angelika et al. showed that the GIR usage of <7 g/kg/day in PN in the first week of life for preterm neonates was an independent variable significantly increasing the risk of hypoglycemia while reducing the risk of sepsis . These fHowever, further research is needed to better define glucose administration in PN in ELBW preterm infants. How much glucose is optimal to provide a better outcome in preterm infants receiving parenteral nutrition is unclear and the results of related studies are conflicting.Lipids are a pivotal source of energy and calories for growth, but also provide essential fatty acids which are required for brain development. Hence, intravenous lipid emulsion in PN is crucial to prevent essential fatty acid deficiency, which is frequent in preterm babies due to the shortage of stores. Intravenous lipid emulsions are linked to critical outcomes such as neurodevelopment, anthropometric measures  and adverse effects of lipids, including sepsis and PN related liver disease .Pooled data revealed that no significant differences were found comparing high (3–3.5 g/kg/day) versus low (1 g/kg/day) target dose of lipids in terms of sepsis ,40, cholIn comparison with a lower dosage of lipids, higher target dosage of lipids was associated with increased mean weight gain in the first 28 days , and decStudies across the years have assessed two starting dosage thresholds: 0.5–1 g/kg/day was chosen as the lower starting dosage whereas 2 g/kg/day was selected as the upper starting dosage threshold .Slowly increasing lipids from a low starting dose  to a target dose , using an infusion rate of 0.5 g/kg/day, may be associated with a reduced number of babies with retinopathy of prematurity and hypertriglyceridemia compared with those who start at a higher dosage (2 g/kg/day) and reach the same target dosage in a shorter time. Conversely, a benefit for the number of babies who are equal to or greater than the 10th percentile for weight was found in the higher starting dosage and shorter time to target dosage .Kao et al. showed reduced rates of sepsis in preterm babies with continuous lipid delivery  compared to intermittent delivery  at a starting dose of 0.5 g/kg/day, increasing incrementally by 0.5 g/kg/day to either 3 g/kg/day or until fat contributed to 40% of daily calories) .Therefore, it is recommended to start lipids from a low starting dose  and slowly increase to a target dose in the maintenance range , according to the baby PN tolerance. It is advisable to increment by 0.5 g/kg/day and favor continuous infusions ,43.As for timing of delivering lipids, current practice is to start infusion soon after birth. When comparing preterm babies started early  versus late  on lipid emulsions, Vlaardingerbroek et al. showed no significant differences in anthropometric measures at discharge, nor late onset sepsis, necrotizing enterocolitis, retinopathy of prematurity and mortality rates .However, delaying lipids causes fatty acid deficiency within the first two days of life in the vulnerable preterm population. Although some authors have shown an increased risk of cholestasis when lipids are started soon after birth , there wTherefore, it is currently recommended to start lipid emulsions soon after birth ,43.In case of babies starting PN after the first 4 days of life, lipids and other macronutrients should be started, based on the recommended maintenance range and adjusted according to enteral feed intake and tolerance .Lipid 20% emulsions are better tolerated than 10% due to the lower phospholipid concentration, with the same content of triglycerides. The excess of phospholipids leads to the formation of liposomes which, by accumulating free cholesterol, albumin and apoproteins, form the Lipoprotein X capable of interfering with the action of lipoprotein lipase by competition with triglycerides and LDL ,49,50,51Heparin frees endothelial lipoprotein lipase, significantly increasing its circulating levels; however, it also causes an increase in triglycerides, cholesterol and fatty acids, most of which are not used. Currently, there are no convincing elements to suggest the use of heparin with the aim of improving the clearance of lipids .Carnitine facilitates the transport of long-chain fatty acids across the mitochondrial membrane, improving the possibility of oxidation. Premature babies feature carnitine low deposits and limited synthesis capacity; however, in vitro studies have shown that β-oxidation of fatty acids is impaired only when tissue carnitine levels are below 10% of normal values .Moreover, a systematic review of six randomized controlled trials in which carnitine was added to parenteral nutrition in doses ranging from 8 to 24 mg/kg/day, for a period ranging from 6 days to 40 weeks of post-conceptional age, showed no difference compared to the control group in terms of weight growth and lipid tolerance .It is possible that greater intakes of carnitine are required, taking into account that a dosage of 48 mg/ kg/day has been associated with an increased metabolism with reduced storage of fats and proteins .The administration of carnitine could be useful in particular conditions such as in subjects in prolonged total PN and in SGA infants, generally excluded from the populations studied.There are numerous reports of the potential damage of lipid emulsions in the lungs of the preterm infant. Most of these observations, however, are based on weak study methodology, or far from clinical routine ,58,59,60The use of lipids during jaundice has been much debated: the fatty acids released during hydrolysis could displace bilirubin from the albumin carrier, increasing the risk of nuclear jaundice. In vivo studies have shown that a molar ratio of less than 6 between free fatty acids (FFA) and albumin is not associated with bilirubin displacement . In clinLipid emulsions, containing a high proportion of polyunsaturated fatty acids, are highly susceptible to peroxidation, the products of which can in theory trigger tissue damage from free radicals ,67,68, sInfants born prematurely are at increased risk of trace-mineral deficiencies because of low stores at birth, very rapid postnatal growth and variable intake. Although some trace elements (TE) may not be required for short-term PN therapy, all patients requiring long-term parenteral nutrition should be provided with TEs .Zinc (Zn) is an essential nutrient, involved in the metabolism of energy, proteins, carbohydrates, lipids and nucleic acids and is crucial for tissue accretion. Infants on long term PN may commonly have zinc deficiency and may have growth retardation, infections and a typical skin rash . ChildreCopper (Cu) is an essential nutrient, and is a functional component of several enzymes, including cytochrome oxidase, superoxide dismutase, monoamine oxidase and lysyl oxidase. Cu deficiency, which is associated with pancytopenia and osteoporosis, has occasionally been reported in children on long term PN . ParentePediatric recommendations for selenium provision in PN, except for preterm infants, are consistent across publications at 2–3 µg/kg/day with a maximum of 60 to 100 µg/day . CriticaAlthough there are no reports of selenium toxicity in children , cautionEuropean and Australian, unlike American, trace element commercial solutions usually contain iodine. A parenteral dose of 1 µg/kg/day of iodine is suggested for children by most nutrition societies. There are pediatric reports of iodine deficiency and hypothyroidism described with iodine-free PN use , highligInformation on fluoride provision in PN in children is scarce, perhaps because fluoride deficiency has not been described in children on PN. Fluoride is not considered as an essential element, although it may contribute to bone strength and prevention of dental caries. ESPGHAN/ESPEN guidelines do not recommend fluoride supplementation of PN for children .-the pharmacological addition of vitamins is not required, e.g., high doses of vitamins A and E are not proven as effective in minimizing oxidative phenomena or incidence and severity of chronic lung diseases, retinopathies and other diseases.-vitamins should be used in adequate doses to meet normal needs, avoiding both deficiencies and potentially harmful excesses.Vitamins are essential for growth and development especially in premature infants on parenteral nutrition. The needs and biological role of individual vitamins in preterm infants have been the subject of various critical reviews and some studies, which generally agree on the following points:A physiological vitamin intake must be guaranteed early to all preterm VLBWs, possibly already within the first week of life. It is advisable to use specifically designed products for parenteral administration in pediatric age, carefully following the manufacturer’s recommendations regarding timing and methods of preparation of bags for PN .Parenteral vitamins are usually administered as a mixture of different vitamins. Therefore, the actual dose of vitamins delivered to the patient may be much lower than the intended dose, particularly in the case of retinol (vitamin A) and in premature infants who receive solutions with slow infusion rates.Currently only a few multivitamin preparations are commercially available for infants and preterm infants. Liposoluble vitamin  deficiencies are quite common in preterm infants due to low lipid and fat-soluble vitamins stores and low levels of protein and lipoprotein transport.Estimates of the vitamin needs of preterm infants are approximate due to lack of adequate studies and the difficulty in adapting the needs of individual cases, which may be affected by many variables, such as gestational age, weight, pre- and postnatal nutritional status , clinical conditions, and relationship between parenteral and enteral nutrition .In this review much attention has been focused on enhancing the nutritional support of very preterm (less than 32 weeks) and extremely preterm (less than 28 weeks) infants. However, it is important to remember that late and moderately preterm (LMPT) infants, that represent the largest population of preterm infants, have specific nutritional requirements, sometimes different from those of the very preterm infant . FurtherA few special considerations are warranted regarding the nutritional management of preterm infants in case of common complications of prematurity, such as PDA, RDS requiring ventilatory support and BPD.The definition of restrictive or liberal fluid intake varies widely. Evidence suggests that fluid balance in the first days to weeks of life is an important factor influencing neonatal morbidity. Although some authors have recommended restricting the amount of fluid given to preterm infants to allow for a negative water balance in the first few days of life, recently it has been shown that adequate nutrition and caloric intake are crucial in reducing the risk and severity of BPD.2. It is important to preserve protein anabolism, as amino acids are responsible for growth and repair of damaged tissues , and for the synthesis of proteins, such as hemoglobin, hormones, and enzymes. As for the recommended lipid mixtures, to date, it is known that long-chain fatty acids have important anti-inflammatory functions and are involved in pulmonary maturation processes [Sung et al. suggested a very restrictive approach with 60 mL/kg on the first day of life to <116 mL/kg/day during the first weeks in preterm infants at high risk of BPD . Other srocesses . Similarrocesses .Although early intravenous nutrition for very preterm infants has become standard care, many uncertainties persist about the ideal quantity and balance of single amino-acids, the optimal content of lipid emulsions, the best starting intake and the preferable increase rate of each macronutrient. The new concept of growth for preterm infants, based on growth trajectories of infants instead of fetuses, could have beneficial long-term effects on health. It would therefore be desirable that multicenter randomized controlled trials are designed to explore the effect of early nutrition and growth on long-term health.


Although preterm birth constitutes a risk factor for postpartum depressive symptomatology, perinatal depression (PND) has not been investigated extensively in fathers of very low (VLBW) and extremely low birth weight (ELBW) infants. This study explored paternal depression levels at 3, 9, and 12 months of infant corrected age, investigating also the predictive role played by the severity of prematurity, maternal and paternal PND levels, and parenting stress. We recruited 153 fathers of 33 ELBW, 42 VLBW, and 78 full-term (FT) infants, respectively. Depression was investigated by the Edinburgh Postnatal Depression Scale (EPDS) and distress by the Parenting Stress Index-Short Form-PSI-SF . ELBW fathers showed a significant decrease (improvement) in EPDS, total PSI-SF, and Parental Distress mean scores after 3 months. Paternal EPDS scores at 12 months were significantly predicted by VLBW and FT infants’ birth weight categories, fathers’ EPDS scores at 3 and 9 months, Parent–Child Dysfunctional Interaction subscale at 3 months, and Difficult Child subscale at 9 months. This study strengthens the relevance of including early routine screening and parenting support for fathers in perinatal health services, with particular attention to fathers who might be more vulnerable to mental health difficulties due to severely preterm birth. Preterm birth occurs when infants are born before the 37th gestational week  and consPrematurity represents a stressful and potentially traumatic event for parents, who might experience feelings of grief, guilt, anxiety, hopelessness, and persistent concerns about their infant’s condition . For thiMany studies have focused on the description of main psychological reactions in terms of distress, adjustment difficulties, depression, anxiety, and trauma-related symptoms ,7,8. AmoDepressive symptoms may interfere with the ability of the parent to be emotionally available and sensitive to the infant’s needs, therefore there is an increased risk of negative consequences on the parent–infant relationship and preterm infant’s development ,10.Several studies have investigated the presence of depressive symptoms in parents after preterm birth, mostly in mothers ,12. The Regarding the first postpartum weeks, which often correspond to the period of infant hospitalization, Petersen and Quinlivan  found noGlobally, these findings, given the differences among the studies in terms of research design and methodology (such as preterm samples including different grades of prematurity), as well as the paucity of research on fathers, call for further confirmation.Very few studies have further explored the depressive symptomatology in preterm infants’ fathers across the first postpartum year. Specifically, two studies have considered the first 6 months after birth. Pace et al.  longitudThree other studies longitudinally assessed paternal depressive symptomatology up to 12 months after birth. McMahon et al.  exploredAccording to those few studies, it emerges that depressive symptoms in preterm infants’ fathers have been poorly investigated over the first postpartum year. This trend is consistent with the more general literature on perinatal psychopathology on normative samples, that has extensively investigated maternal psychological states, while only recently showing a growing interest in the exploration of fathers’ emotional issues . Given tIn this sense, one of the psychological dimensions experienced by parents after preterm birth, and that could be related to depressive symptomatology, is a high level of stress . Several studies have indeed found a moderate–high amount of stress experienced by preterm babies’ mothers and fathers during baby hospitalization and also after discharge ,25,26,27Another factor potentially contributing to a higher risk of depression in fathers might be the level of mothers’ depressive symptomatology. In general, the literature focusing on perinatal depression in parents has frequently analyzed the relationship between maternal and paternal depressive symptoms, often finding a significant association in terms of correlational and predictive analyses ,32. AccoBased on all these premises, a longitudinal study was developed with the aim of better understanding the occurrence of depressive symptoms in fathers during the first postpartum year and the relationship between symptomatology, severity of prematurity, parenting stress, and mothers’ depressive symptoms.The first aim of the study was to investigate whether depressive symptoms in fathers differed according to categories of birth weight during the first postpartum year; based on the evidence of the literature, we expected to find higher levels of depressive symptoms in correspondence to a more severe preterm birth (ELBW).A second aim was to investigate if the level of parenting stress in fathers was different according to the severity of prematurity during the first postpartum year; according to the previous literature, we expected a higher score in more severe preterm babies’ fathers across time.A third aim was to identify which variables could better predict fathers’ perinatal depressive symptoms at 12 months after birth. We specifically aimed at exploring the role played by the severity of prematurity, depressive symptoms in fathers and mothers at 3 and 9 months after birth, and levels of paternal parenting stress.This study was part of wider longitudinal research aimed at assessing the parental affective states and infants’ development from 3 to 12 months postpartum after preterm birth.Families were recruited at the Neonatal Intensive Care Unit (NICU) of Bufalini Hospital  during the period between April 2013 and December 2015; at the same time, the study was presented at the antenatal classes held at Health Services in the same town, in order to recruit a control group composed by parents of healthy FT infants. Eligible participants received complete information about all the aspects of the research from a member of the research team at the moment of NICU discharge or during antenatal classes. Exclusion criteria for all participants were: absence of fluency in Italian language, presence of previous or present psychiatric illness, presence of infants’ chromosomal abnormalities, cerebral palsy, malformations, fetopathy, severe complications . In case of twin birth, only the first-born one was included. Infants were monitored during the first year and in case of delays or severe complications they were excluded from the study.At the end of the recruitment, the sample included 153 participants: 78 were fathers of FT infants, with a birth weight > 2500 g and gestational age > 36 weeks (FT group) and the remaining 75 were fathers of PT infants. According to infant birth weight, 42 fathers were included in VLBW group (birth weight between 1000 and 1500 g) and 33 in ELBW group (birth weight < 1000 g).The study was approved by the Ethical Committee of the Department of Psychology (University of Bologna) before its start.The assessments took place at 3 months (T1), 9 months (T2), and 12 months (T3) postpartum (corrected age for PT infants) at Developmental Psychodynamic Laboratory . At first assessment, a psychologist, blind to infant birth weight, gave all parents a written informed consent to sign and asked them to complete an ad hoc questionnaire regarding socio-demographic and infant clinical information. In addition, during all steps of assessment  the same psychologist met parents and administer two self-report questionnaires to evaluate the presence of depressive symptomatology in both fathers and mothers and the levels of paternal parenting stress.The Edinburgh Postnatal Depression Scale (EPDS)  is the mThe Parenting Stress Index-Short Form (PSI-SF)  is a 36-All statistical analyses were carried out using the IBM SPSS statistical package version 25.0 .Pearson’s chi-square test and univariate ANOVA were run to verify the homogeneity regarding sociodemographic and clinical variables among ELBW, VLBW, and FT groups. In case of non-homogeneity, we considered the possibility to include those variables in subsequent analyses.In line with our first aim, we ran repeated measures univariate analysis of variance to compare fathers’ depressive symptoms as a function of birth weight  and time of assessment . Bonferroni’s post hoc analyses were used for comparison within and between groups. Similarly, in line with our second aim, repeated measures multivariate analysis of variance was performed for exploring the impact of birth weight  and time of assessment  on total and 3 subscale scores of PSI-SF .According to the third aim, a linear regression model was performed to identify possible predictors for fathers’ EPDS scores at 12 months (dependent variable). Regression models were tested by backward method in order to reduce the risk of Type II error . Selecte2(2) = 38.85; p < 0.005), and level of education (X2(2) = 7.47; p = 0.024). Specifically, FT fathers, compared to VLBW and ELBW ones, were nulliparous in a higher percentage, while FT and VLBW fathers had a higher level of education than ELBW ones  = 48.41; p < 0.005), multiple birth (X2(2) = 26.78; p < 0.005), and gestational age  = 937.63; p < 0.005). Specifically, in the FT group, cesarean section delivery and multiple births were less frequent compared to preterm groups, while a lower gestational age was found in preterm groups. Since these variables, along with the differences that emerged, were strictly linked to preterm status and are coherent with group belonging based on birth weight, they were not included in subsequent analyses.Additionally, as expected, significant differences among the three groups emerged regarding type of delivery . =0.20, p = 0.817), meaning that fathers, independently from the birth weight group, showed similar EPDS mean scores  = 4.40, p = 0.014)   : ELBW factively) ; conversctively) . Moreove = 0.33; p = 0.718] nor in any of the PSI-SF subscales: Parental Distress ; Parent–Child Dysfunctional Interaction ; Difficult Child   = 4.56; p = 0.012]: the level of distress in ELBW fathers significantly decreased from 3 months to 9 and 12 months   , while nctively) . No diff = 3.29; p = 0.040] (p = 0.044); moreover, ELBW fathers’ scores significantly decreased from 3 to 9 and 12 months   .No significant differences emerged when PCDI and DC subscales were considered .r ≤ 0.70).At a preliminary level, to explore possible multicollinearity among variables, we ran correlation analyses considering if EPDS paternal scores at 12 months were associated with mothers’ and fathers’ EPDS and PSI at 3 and 9 months. Results showed that these variables were significantly but moderately correlated  = 45.523, p < 0.005], with an R2 Adjusted = 0.648. According to the model, fathers’ EPDS scores at 12 months were significantly predicted by the following variables: birth weight condition (to be a father of a VLBW or FT infant); high fathers’ EPDS scores at 3 and 9 months; high level of distress related to PCDI at 3 months and to DC at 9 months . Additionally, it aimed to shed light on the predictive role of specific variables, at infant (birth weight), paternal , and maternal (PND symptoms) levels, on fathers’ long-term depressive risk after preterm birth. This is one of the first research studies focused on the long-term emotional and psychological adaptation of fathers considering the severity of prematurity. Therefore, it will contribute to deepening the knowledge of fathers’ postpartum well-being, given it is recognized as a potential risk or protective factor for child development, family, and parental functioning .The first aim of this study was to investigate the impact of the severity of preterm birth on paternal PND symptomatology during the first postpartum year. A first result seemed to suggest that, as a function of birth weight, significant differences among ELBW, VLBW, and FT groups did not emerge. This result is in line with a recent study  reportinComparable levels of PND symptoms in ELBW, VLBW, and FT fathers at 3, 9, and 12 months postpartum emerged also when we considered the interaction between birth weight and time of assessment. Our results whereby at 3 months postpartum VLBW and FT fathers showed comparable depression levels are in line with previous investigations on PT and FT samples , but areHowever, in line with recent studies ,11,19, aThe second aim of this study was to investigate the impact of the severity of prematurity on parental distress during the first year after birth. As a function of birth weight, we did not find differences  among ELBW, VLBW, and FT groups. These results are partially in line with a recent study , which oHowever, it is noteworthy that the comparable levels of stress observed in our VLBW and FT fathers are not in line with previous longitudinal investigations where: for VPT infants’ fathers an increase in stress levels was observed from 6 to 12 months postpartum ; in caseFor an accurate clinical interpretation of these findings, it is important to consider the specific characteristics of NICU care intervention . Our preThe third aim of this study was to explore to what extent fathers’ depressive symptoms at 12 months were predicted by birth weight, depressive symptoms in fathers and mothers, and paternal sources of parenting stress at 3 and at 9 months postpartum. First, birth weight condition significantly predicted higher levels of paternal depressive symptoms at 12 months postpartum in the case of the VLBW or FT condition, but not ELBW. This result is somehow unexpected but is coherent with our ANOVA results whereby the impact of severely preterm birth on fathers’ emotional adaptation seems to be acute rather than chronic, configuring more a reaction of exogenous nature , which tends to gradually go into remission across time, when the risks for infant’s survival and health decrease and fathers are reassured by new developmental skills reached by their infants ,53. On tSecond, higher levels of paternal depressive symptoms at 3 and 9 months predicted higher EPDS scores at 12 months postpartum. This result is in line with the previous literature on both FT  and PT sRegarding the influence of maternal depressive symptoms at 3 and 9 months on fathers’ depression at 12 months, our results did not show any significant contribution, and this is partially in line with a previous investigation by Neri et al. , where aSpecific dimensions of parental distress, that is high PDCI scores at 3 months and high DC scores at 9 months, significantly contributed to fathers’ depressive symptoms at 12 months postpartum. These findings are in line with cross-sectional studies on VLBW and FT fathers ,55, wherWe must acknowledge some limitations of this study. First, the sample should be enlarged, and the three birth-weight groups should reach a similar size for further confirmation of the findings. Second, the EPDS, originally developed for screening in mothers, may not be fully appropriate for detecting gender-related differences in the expression of PND symptoms . AdditioTo sum up, given the paucity of longitudinal studies on fathers’ psychological adjustment after preterm birth, these results shed new light on this field of research, highlighting the relevance of paying particular attention to the situations where fathers may be more vulnerable to perinatal mental health problems, such as a highly severe preterm birth.The findings of this study strengthen the clinical relevance of including routine screening programs for fathers in perinatal health services, for identifying those cases that, given a complex interplay between exogenous and endogenous risk factors, are at higher risk for a chronic course. This early identification would enable the implementation of targeted specialist interventions for fathers both for reducing the symptomatology and for supporting their parenting role ,58. The


For the preparation of diamond heat sinks with ultra-high thermal conductivity by Chemical Vapor Deposition (CVD) technology, the influence of diamond growth direction and electric field on thermal conductivity is worth exploring. In this work, the phonon and thermal transport properties of diamond in three crystal orientation groups  were investigated using first-principles calculations by electric field. The results show that the response of the diamond in the three-crystal orientation groups presented an obvious anisotropy under positive and negative electric fields. The electric field can break the symmetry of the diamond lattice, causing the electron density around the C atoms to be segregated with the direction of the electric field. Then the phonon spectrum and the thermodynamic properties of diamond were changed. At the same time, due to the coupling relationship between electrons and phonons, the electric field can affect the phonon group velocity, phonon mean free path, phonon–phonon interaction strength and phonon lifetime of the diamond. In the crystal orientation [111], when the electric field strength is ±0.004 a.u., the thermal conductivity is 2654 and 1283  With the continuous improvement in synthetic diamond technology, the application of diamond in quantum sensors, semiconductor components, and heat sinks of integrated circuits is becoming feasible. Generally, the band-gap of diamond is about 4.5 eV ,2,3. L. W·m−1K−1 . P. Chakat 0 GPa . It can W·m−1K−1 . DiamondW·m−1K−1 ,10,11,12W·m−1K−1 ,14,15. FW·m−1K−1 ,17,18,193 and KTaO3 single crystals. The thermal conductivity of the SrTiO3 was measured to increase by a factor of about 4 using a conventional steady-state heat flow technique  crystal orientation is the most obvious. The U(T) decreased to 0.361 eV/cell, then F(T)+ZPE decreased to 0.342 eV/cell, the S(T) increased to 6 × 10−5 eV/cell, and the CV increased to 1.5 × 10−4 eV/cell. Under the action of a negative electric field. The U(T) and F(T)+ZPE are increased to 0.379 eV/cell and 0.365 eV/cell, respectively. The S(T) and CV drop to 4.2 × 10−5 eV/cell and 1.25 × 10−4 eV/cell, respectively, at 300 K. The effect of the negative electric field is just the opposite of that of the positive electric field, and the U(T) and F(T)+ZPE of diamond are increased to varying degrees. The S(T) and CV of diamond are reduced under the action of the positive electric field. However, the overall improvement or reduction is not as obvious as that of the positive electric field. In the [001] and [110] crystallographic orientations, the effect of positive and negative electric fields is basically the same as that of the [111] crystallographic orientation, but the effect is slightly weaker. From the above analysis, the following conclusions can be drawn: Applying a positive electric field to the diamond will increase the energy in the diamond unit cell. The reason is that the electric field interacts with the free electrons of the diamond, increasing the chaos of the microscopic particles inside the diamond. It is the acceleration of free electrons and the increased scattering of free electrons caused by the electric field which reduces the U(T) and F(T)+ZPE of the diamond unit cell. However, on the contrary, due to the increase in the disorder of the microscopic particles inside the diamond, the potential energy and kinetic energy of the microscopic particles in the diamond unit cell increase, that is, the thermal energy that the C atoms in the diamond can carry increases, increasing the specific heat of constant volume. According to Equation (12), the increase in the diamond’s constant volume specific heat capacity will increase the lattice’s thermal conductivity. Therefore, applying a positive electric field to diamond will improve its thermal conductivity.The diamond e–ph matrix elements under the action of electric field are calculated by Equations (1) and (2), and the imaginary part of the phonon self-energy is calculated, and the thermodynamic properties are calculated and plotted in the harmonic approximation as shown in As described in The change in the thermal conductivity of diamond with or without an electric field is shown in terature ,5,7,8,50As can be seen from In order to further explore the reasons why the positive and negative electric fields lead to changes in the thermal conductivity of diamond, the relationships among the lattice thermal conductivity, the maximum interatomic force, the average interatomic force and the electric field strength are shown in 45 nm to about 1 × 102 nm. It can be seen that the low frequency phonons show a more “brisk” state, and therefore, the mean free path is larger. The high-frequency phonons show the characteristics of “heavy and slow”, so the mean free path is small. For the contribution of the phonon mean free path to the lattice thermal conductivity, the longer the phonon free path, the better the energy transfer. It can be seen that the mean free path of phonons with frequencies less than 30 THz in diamond is basically greater than 1 × 102 nm. Therefore, this part of the phonons contributes more to the lattice thermal conductivity. After the external electric field is applied, the phonons’ mean free path of is shifted significantly, especially the “brisk” phonons with smaller frequency shifts. In As can be seen from The phonon–phonon interaction strengths were calculated using the linear tetrahedron method for the three crystallographic orientations of the diamond. The phonon–phonon interaction strength results of the three crystallographic directions of diamond are shown in By applying an electric field to three crystallographic directions of diamond, the effect of the electric field on the thermal conductivity of the diamond lattice was studied by the first-principles calculation method. The response mechanism of the diamond lattice’s thermal transport to an electric field was revealed. The following conclusions are drawn:(1)The response of diamond to the external electric field has anisotropy in three crystallographic directions. Moreover, the damage of positive and negative electric fields to the diamond phonon dispersion relationship is different. The three low-frequency acoustic branches are more sensitive to the electric field than the three high-frequency optical branches. The low-frequency lattice vibration of the diamond is more sensitive to the electric field.(2)−4 eV/cell and 1.22 × 10−4 eV/cell, which are increased and decreased by 9.8% and −7.6%, respectively. The electric field causes changes in the extranuclear electron potential and kinetic energy of the C atoms in diamond, and the electroacoustic coupling causes the electrons to transfer part of the energy of the electric field to the phonons.In the case of considering the electro-acoustic coupling, it is found by calculating the thermodynamic properties of a diamond under the electric field. The electric field will change the internal energy, free energy, entropy and specific heat capacity of the diamond. The [001] and [111] orientations of diamond are more sensitive to electric field than the [110] orientation. In the [111] crystallographic orientation, when the electric field strength is ±0.000736 a.u., the constant volume specific heat capacities are 1.45 × 10(3)The electric field will lead to a change in the thermal conductivity of the diamond lattice. Under the positive electric field, the thermal conductivity of the diamond lattice will increase, and conversely, the thermal conductivity of the diamond lattice will decrease under the negative electric field. When an electric field of ±0.004 a.u. is applied in the diamond [111] crystallographic direction and the temperature is 300 K, the thermal conductivity is 2654 (4)By calculating and analyzing the thermal transport properties of diamond phonons under the electric field, it is found that the electric field does not significantly change the phonon group velocity of the diamond. The response of diamond phonon thermal transport characteristics to electric field mainly focuses on the change of phonon mean free path, phonon–phonon interaction strength and phonon lifetime. Under a positive electric field, the increase in the mean free path of phonons, the enhancement of phonon–phonon interaction strength, and the prolongation of phonon lifetime all significantly promote the thermal conductivity of diamond lattice. On the contrary, under the negative electric field, the decrease in the phonon mean free path, the decrease in phonon–phonon interaction strength and the shortening of phonon lifetime significantly reduce the thermal conductivity of the diamond lattice. The response of the diamond phonon’s thermal transport to an electric field is mainly concentrated in the phonon part with a frequency of less than 30 THz.


What is the association of the birth year of pregnant individuals with trends in hypertensive disorders of pregnancy, adjusting for age of pregnant individuals and delivery year between 1995 and 2019?In this cross-sectional study of 38 141 561 nulliparous pregnant individuals, the incidence of hypertensive disorders of pregnancy was higher among individuals born in 1996 to 2004 than among individuals born in 1951 to 1959. Rate ratios were similar in each self-reported racial and ethnic group.This study suggests that public health efforts increasing awareness of and focusing on prevention among younger individuals are needed to reverse adverse trends in hypertensive disorders of pregnancy. Hypertensive disorders of pregnancy are leading causes of morbidity and mortality among pregnant individuals as well as newborns, with increasing incidence during the past decade. Understanding the individual associations of advancing age of pregnant individuals at delivery, more recent delivery year (period), and more recent birth year of pregnant individuals (cohort) with adverse trends in hypertensive disorders of pregnancy could help guide public health efforts to improve the health of pregnant individuals.To clarify the independent associations of delivery year and birth year of pregnant individuals, independent of age of pregnant individuals, with incident rates of hypertensive disorders of pregnancy.This serial cross-sectional study of 38 141 561 nulliparous individuals aged 15 to 44 years with a singleton, live birth used 1995-2019 natality data from the National Vital Statistics System.Year of delivery (period) and birth year (cohort) of pregnant individuals.Rates of incident hypertensive disorders of pregnancy, defined as gestational hypertension, preeclampsia, or eclampsia, recorded on birth certificates. Generalized linear mixed models were used to calculate adjusted rate ratios (aRRs) comparing the incidence of hypertensive disorders of pregnancy in each delivery period (adjusted for age and cohort) and birth cohort (adjusted for age and period) with the baseline group as the reference for each. Analyses were additionally stratified by the self-reported racial and ethnic group of pregnant individuals.Of 38 141 561 individuals, 20.2% were Hispanic, 0.8% were non-Hispanic American Indian or Alaska Native, 6.5% were non-Hispanic Asian or Pacific Islander, 13.9% were non-Hispanic Black, and 57.8% were non-Hispanic White. Among pregnant individuals who delivered in 2015 to 2019 compared with 1995 to 1999, the aRR for the incidence of hypertensive disorders of pregnancy was 1.59 , adjusted for age and cohort. Among pregnant individuals born in 1996 to 2004 compared with 1951 to 1959, the aRR for the incidence of hypertensive disorders of pregnancy was 2.61 , adjusted for age and period. The incidence was higher among self-identified non-Hispanic Black individuals in each birth cohort, with similar relative changes for period  and cohort  compared with non-Hispanic White individuals .This cross-sectional study suggests that more recent birth cohorts of pregnant individuals have experienced a doubling of rates of hypertensive disorders of pregnancy, even after adjustment for age and delivery period. Substantial racial and ethnic disparities persisted across generations. This cross-sectional study uses an age-period-cohort analysis to clarify the independent associations of delivery year and birth year of pregnant individuals, independent of age of pregnant individuals, with incident rates of hypertensive disorders of pregnancy. Given known racial and ethnic differences in the incidence of new-onset HDP, we additionally conducted subgroup analyses by self-identified racial and ethnic group of pregnant individuals. Knowledge of the independent associations of age, period, and cohort with trends in HDP overall and in each racial and ethnic group may help guide public health efforts to equitably improve the health of pregnant individuals and their offspring.8 All data included in this analysis are publicly available online.9 We included all individuals aged 15 to 44 years of age with a singleton, first live birth. We restricted our analysis to nulliparous individuals given the known association between nulliparity and higher risk of HDP.10 We additionally excluded individuals with chronic or prepregnancy hypertension to focus on incidence of new-onset HDP. For this analysis, we defined new-onset HDP based on the NVSS definition as gestational hypertension or preeclampsia with or without a diagnosis of eclampsia. Given that data are deidentified and publicly available, the Northwestern University institutional review board deemed the study exempt from review. Our methods follow the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.11We used data from the National Vitals Statistics System (NVSS) natality files, which include demographic and health information of birthing individuals and offspring for all live births in the US. Data were recorded onto birth registration records by the professional attendant at birth using information obtained from the birthing individual and medical records.Age-specific new-onset HDP incidence (per 1000 live births) among pregnant individuals was estimated by birth year of pregnant individuals (cohort: 1955-2004) and year of delivery (period: 1995-2019). We created six 5-year age groups  and five 5-year delivery periods , spanning ten 9-year, partially overlapping cohorts of pregnant individuals referenced by their midpoint . We first used unadjusted rate ratios (RRs) to compare the incidence of new-onset HDP in each 5-year age group with the incidence in the youngest age group (15-19 years); this reference age group was selected because they experienced the lowest incidence of HDP among this sample of nulliparous individuals.14 We used the age-period-cohort model to estimate the factors associated with period  as RRs comparing incidence of new-onset HDP with the baseline period (1995-1999). We then estimated the net drift—a parameter that approximates the estimated annual percentage change for an age-standardized rate—across 5-year delivery periods  for new-onset HDP in each age group.We then used parametric age-period-cohort models to calculate rates in addition to parameters and functions that characterize the roles of age, period, and cohort in the descriptive trends. These models are described in the eMethods in the 14 For example, the modeled RR for 1971-1979:1951-1959 would be equal to the product of the RRs for 1971-1979:1966-1974, 1966-1974:1961-1969, 1961-1969:1956-1964, and 1956-1964:1951-1959.Cohort RRs were calculated as incidence ratios adjusted for age and period that compared the incidence of HDP for a given cohort with that in the reference cohort . Cohort RRs are particularly difficult to interpret because cohorts born far apart in time can never be directly compared at the same age. For example, the 1951-1959 cohort was observed for individuals aged 36 to 44 years, while the 1996-2004 cohort was observed for individuals aged 15 to 23 years. Estimation of the RR for any pair of cohorts requires an assumption that is integral to our age-period-cohort model: that the age-specific rates for any pair of cohorts are proportional after adjusting for period . Owing to large sample sizes, differences in incidence rates and trends were interpreted based on effect sizes and nonoverlapping 95% CIs. Analyses were completed with Stata, version 14.2 (StataCorp LLC) and software from the National Cancer Institute .From 1995 to 2019, there were 38 771 194 nulliparous individuals aged 15 to 44 years with a singleton live birth. We excluded 217 015 individuals (0.6%) without available data on HDP and 412 618 individuals (1.1%) with prepregnancy hypertension , with an annual mean percentage change of 2.1% per year  after adjustment for age of pregnant individuals at delivery and cohort . Period RRs were initially stable (1995-2009) and increased during the past decade (2010-2019). Pregnant individuals who delivered during the 2010-2014 and 2015-2019 periods were 1.13  and 1.59  times more likely, respectively, to experience a new-onset HDP than those who delivered during the baseline period (1995-1999) . In eachLater birth year of pregnant individuals (more recent birth cohort) was associated with a higher incidence of new-onset HDP than earlier birth year of pregnant individuals, even after adjusting for age and period ; Table 3This nationwide age-period-cohort analysis demonstrated 3 key findings: The incidence of new-onset HDP was higher among pregnant individuals with (1) older age at delivery, (2) more recent period , and (3) more recent cohort . Nulliparous pregnant individuals who were born in more recent years experienced significantly higher rates of new-onset HDP, even after adjustment for age of pregnant individuals and calendar year at delivery, which accounts for secular period factors. Specifically, pregnant individuals born in the 1990s and 2000s were more than twice as likely than those born in the 1950s to have new-onset HDP. Persistent racial and ethnic differences in the incidence of new-onset HDP were observed across age of pregnant individuals, delivery period, and birth cohort, with the highest rates observed among self-identified non-Hispanic American Indian or Alaska Native individuals and non-Hispanic Black individuals.18 We demonstrate that the incidence of HDP has increased during the past 2 decades, with accelerating rates from 2010 to 2019, similar to prior studies,17 but now additionally controlling for factors associated with birth cohort. In addition, we add to the literature by describing the independent association of birth cohort of pregnant individuals with trends in rates of HDP among nulliparous individuals in the US between 1995 and 2019. Our findings thus complement and build on previously published data, such as an analysis from the National Inpatient Sample from 1980 to 2010. That analysis included only a subset of delivery hospitalizations in the US and similarly demonstrated that pregnant individuals born in the 1970 birth cohort were 1.2 times more likely than those born in the 1955 birth cohort to have preeclampsia.18 Our analysis, which used a contemporary sample of live births in the US up to 2019, included all new-onset cases of HDP and all live births .The present study expands on prior analyses that previously demonstrated increases in the incidence of HDP across age groups of pregnant individuals and delivery periods by additionally considering the interrelated factors of age, period, and cohort simultaneously.24 In the Hyperglycemia and Adverse Pregnancy Outcome Study, pregnant individuals with poor cardiovascular health at a mean gestational age of 28 weeks were more than 9 times more likely than those with ideal cardiovascular health to develop preeclampsia.24 A recent report from the NVSS highlighted the decline in preconception health among pregnant individuals, with the overall percentage of individuals in the US entering pregnancy with favorable cardiovascular health decreasing from 42.1% to 37.7% between 2011 and 2019.20 Among the components of cardiovascular health, obesity has had the largest increase in prevalence from 6.2% in the 1976-1980 period to 32.7% in the 2017-2018 period.25 The population-attributable fraction for HDP associated with obesity is estimated to be between 25% and 30% and has not changed significantly between 2011 and 2019,21 which suggests that obesity may be only partially associated with trends in HDP. Given that data on obesity and other cardiovascular health factors and behaviors were not available in the present study, further detailed work with pregnancy-specific cohorts with long-term follow-up is needed to understand the association of the obesity epidemic, as well as the decline in prepregnancy cardiovascular health, with trends in HDP and to inform strategies to target morbidity and mortality among pregnant individuals, as highlighted by the recent call to action policy statement by the American Heart Association and supported by the American College of Obstetrics and Gynecology.26Although our study is ecological and cannot identify factors associated with trends, increasing incidence of HDP among younger generations may reflect adverse trends in preconception health. Poor cardiovascular health prior to pregnancy is an important risk factor for HDP, as well as other important outcomes, including severe morbidity of pregnant individuals, mortality of pregnant individuals, and cardiovascular health of offspring into adolescence.The increasing rates of HDP among younger individuals from more recent generations, as shown in our study, highlight the urgency with which these strategies need to be implemented. At the clinical level, increased awareness of adverse trends in HDP among younger generations informs practitioners about the importance of HDP prevention and management among individuals of all ages, not only among older individuals. Assessing cardiovascular risk early in the life course and developing strategies with patients to optimize cardiovascular health prior to a first pregnancy could have an effect on reducing the incidence of HDP. Multidisciplinary teams composed of primary care physicians, cardiologists, and obstetricians-gynecologists are needed to comprehensively manage HDP risk factors before, during, and after pregnancy.29 The present study is an epidemiologic analysis of trends and is, therefore, not well suited to examine causal factors, such as social or structural determinants of health, that may be associated with trends and disparities. Prior work has implicated residential segregation and racism in race- and ethnicity-based disparities, with greater rates of HDP among pregnant individuals residing in more racially and ethnically segregated areas.31 Race- and ethnicity-based differences in related birth outcomes (preterm birth and low birth weight) have also been associated with individual-level reports of racial and ethnic discrimination as well as neighborhood-level factors, such as census-block reports of excessive use of force by law enforcement officers.33We also identified significant associations with birth cohort among all racial and ethnic groups and demonstrated that racial and ethnic disparities have persisted across 4 generations. The present analyses specifically inform a growing body of work focusing on the root structural causes of racial and ethnic differences in adverse health outcomes of pregnant individuals and infants.34 Previous data from the National Center for Health Statistics demonstrated that from 2014 to 2017, the gap between Black and White individuals in the delivery of low-birth-weight infants was 2-fold higher across age, from 5.2% among 15-year-old individuals to 10.0% among 40-year-old individuals.28 Because these disparities likely reflect upstream social determinants, including structural barriers perpetuated by systemic racism, focusing policy efforts on social factors 35 could have a meaningful effect on equitably improving health among pregnant individuals from all age groups.Our analyses also demonstrate greater RRs for the incidence of new-onset HDP among older pregnant individuals at delivery who did not identify as White. This dynamic was associated with widening racial and ethnic gaps for new-onset HDP among older age groups. This may be partially explained by the weathering hypothesis, which postulates that groups with cumulative exposure to systemic and structural disadvantage experience an acceleration in the deterioration of health.36 In addition, birth certificates were revised in 2003 to include additional risk factors of pregnant individuals and pregnancy complications, as well as a standardized worksheet to assist pregnant individuals and hospital staff with birth certificate completion. Although it is possible that these changes may have influenced the reporting and classification of HDP, the Centers for Disease Control and Prevention User Guide to the natality Public Use File reported these variables as comparable across these birth certificate revisions.37 In 2013, the definition of preeclampsia was revised by the American College of Obstetricians and Gynecologists to include pregnancies that otherwise met criteria for preeclampsia even if proteinuria was not present.10 By using a composite definition of HDP that included both gestational hypertension and preeclampsia, we mitigated the potential association of this changing definition with trends in HDP. Furthermore, birth cohort trends of pregnant individuals were adjusted for the factors associated with delivery period that accounted for changing practice patterns at the time of delivery. Given that available NVSS data combine, and do not distinguish between, gestational hypertension and preeclampsia, we were unable to investigate these trends separately. However, because gestational hypertension and preeclampsia are managed similarly, the combined definition of new-onset HDP represents a clinically relevant outcome for the study. In addition, this study is ecological in nature, and, therefore, the goal is not to identify causes of the observed trends and disparities; also, data on potential risk factors for HDP, such as diet, physical activity, and body mass index, were not available from all states across the duration of the study period.The limitations of this work should be noted. There is the potential for misclassification of a diagnosis of new-onset HDP based on birth registration records in the NVSS. However, the NVSS birth data represent the most robust source of national surveillance of birth records and include data from more than 38 million individuals with rates similar to those identified in administrative hospitalization data sets.This study found that the incidence of new-onset HDP among nulliparous pregnant individuals has more than doubled for those born in the 1990s and 2000s compared with those born in the 1950s, even after adjustment for age of pregnant individuals and delivery period. Furthermore, racial and ethnic disparities in new-onset HDP have persisted without narrowing across 4 generations. This work underscores the need for future investigations to identify potential interventions to reduce the frequency of HDP and guide public health reforms to equitably improve the health of pregnant individuals.


Non-invasive ventilation (NIV) treatment has been developed to minimize lung damage and to avoid invasive mechanical ventilation (IMV) in preterm infants, especially in those with a gestational age of <30 weeks. Our hypothesis is that for preterm infants <30 weeks with potential to develop respiratory distress syndrome (RDS), nasal continuous positive airway pressure (NCPAP) is non-inferior to the nasal intermittent positive pressure ventilation (NIPPV) as primary respiratory support before minimal invasive surfactant administration (MISA).+6 weeks of gestational age who have spontaneous breaths at birth and require primary NIV support for RDS. Infants are randomized 1:1 to treatment with either NCPAP or NIPPV once admitted into NICUs. If an infant presents progressively aggravated respiratory distress and is clinically diagnosed as having RDS, pulmonary surfactant will be supplemented by MISA in the first 2 h of life. The primary outcome is NIV treatment failure within 72 h after birth. With a specified non-inferiority margin of 10%, using a two-sided 95% CI and 80% power, the study requires 480 infants per group .The NIV-MISA-RDS trial is planned as an unblinded, multicenter, randomized, non-inferiority trial at 14 tertiary neonatal intensive care units (NICUs) in China. Eligible infants are preterm infants of 24–29Current evidence shows that NIV and MISA may be the most effective strategy for minimizing IMV in preterm infants with RDS. However, there are few large randomized controlled trials to compare the effectiveness of NCPAP and NIPPV as the primary respiratory support after birth and before surfactant administration. We will conduct this trial to test the hypothesis that NCPAP is not inferior to NIPPV as the initial respiratory support in reducing the use of IMV in premature infants who have spontaneous breaths after birth and who do not require intubation in the first 2 h after birth. The study will provide clinical data for the selection of the initial non-invasive ventilation mode in preterm infants with a gestational age of <30 weeks with spontaneous breaths after birth.https://register.clinicaltrials.gov, identifier: NCT05137340. Although nearly 90% of newly born infants breathe spontaneously within 30–60 s after birth, the remaining 10% of newborns do not breathe within the first 60 s after birth or are persistently bradycardic . They maAccording to the guidelines of neonatal resuscitation, positive end-expiratory pressure provides low positive pressure to the airway, which prevents lung collapse at the end of expiration and maintains functional residual capacity . For som2O) and may be delivered by short binasal prongs to very preterm infants. NIPPV has been used in NICUs for a variety of indications, especially for extubation ventilation support. It could reduce intubation due to frequent primary apnea, asynchronous thoracoabdominal motion, and inspiratory effort, and improve the stabilization of the chest wall and the tidal and minute volumes  are the two most common non-invasive ventilation (NIV) modes for the initial respiratory support in NICUs . NIPPV i volumes , 9. Howe volumes , 11. In RDS remains a significant problem for preterm infants, although its management has evolved in the “post-surfactant era”, resulting in improved survival of the very preterm infants . The optEuropean Consensus Guidelines on the Management of Respiratory Distress Syndrome-−2019 Update recommends NCPAP combined with LISA as the main treatment of respiratory distress syndrome (RDS) in preterm infants with spontaneous breaths  ≤ 0.40] immediately after birth in a delivery room and during transfer to a NICU.Infants with spontaneous breaths and signs of respiratory distress that will receive non-invasive respiratory support [positive end expiratory pressure (PEEP) of 6 cmH2) > 0.3 for (SpO2) > 85%, or the Silverman Anderson Score (SAS) > 5 points, or the SAS increases > 2 points per hour.They have a clinical diagnosis of RDS within 2 h of life. The diagnosis of RDS will be based on clinical manifestations  and  or NIPPV (active control group) as the initial respiratory support. Treatment allocations will be based on a pre-specified random number table and concealed in sealed opaque envelopes. The treatment allocations sequence will be generated using computer programs (R software) by an independent statistician. Multiple-birth infants will be randomized separately.This trial follows the Good Clinical Practice (GCP) standards. This trail also meets the requirements of the Ethics Committees and is carried out under the supervision of the Ethics Committees of the participating institutions. A Data Safety Monitoring Board (DSMC) will be established, consisting of two independent neonatologists and an independent statistician. DSMC review points will be set up for trial progress and safety.Operators, clinicians and nurses will not be blinded to the intervention allocation, but independent outcome evaluators and data analysts will be blinded to the allocation. To reduce bias, predefined objective criteria will be specified for the main outcomes of treatment failure in order to provide clear guidance to outcome evaluators.The assessments will be performed at predetermined points after randomization . The pri2O and FiO2 ≤ 0.40) in the delivery room and during admission to NICUs, and then randomly selected to start NCPAP or NIPPV within 30 min of birth.Preterm infants with spontaneous breaths will be stabilized on non-invasive respiratory support (PEEP of 6 cmH2O (adjustment range 6–8 cmH2O) and an FiO2 of 0.21–0.40, in order to maintain an oxygen saturation level of 90–95%.The ventilators parameter of the NCPAP group will be set with a PEEP of 6 cmH2O (adjustment range 6–8 cmH2O), peak inspiratory pressure (PIP) of 15 cmH2O (regulation range 15–20 cmH2O), inspiratory time of 0.3 s (regulation range 0.3–0.4 s), respiratory rate of 30 times/min (regulation range 20–40 times/min) and FiO2 of 0.21–0.40.NIPPV will be set in a synchronized mode with a PEEP of 6 cmHvia MISA method within 120 min after birth if infants are clinically diagnosed with RDS. While the infants are on ventilator support by NCPAP or NIPPV, a direct laryngoscope and a specifically designed thin catheter with 1.67 mm in diameter  will be used to finish the surfactant administration. A direct laryngoscope will be introduced to provide a glottal view before the operator inserts the LISA catheter® 0.5–1.0 cm below the inverted V-shaped vocal cords. After withdrawing the laryngoscope, the operator will fix the thin catheter at the infant's mouth corner with the forefinger and thumb, and the end of the LISA catheter® will be connected to a 5 ml syringe containing surfactant solution. The surfactant will be administered through the LISA catheter® by a nurse within 120–300 s by mini-boluses. The LISA catheter® will be immediately removed after surfactant administration. If an infant develops bradycardia or desaturation (SPO2 <85%), stop surfactant administration, keep the LISA catheter® in place, gently touch the infant's back to stimulate spontaneous breaths, increase FiO2 and wait for the heart rate and SPO2 to return to normal range before finishing the remaining surfactant with cautions. If the heart rate and SPO2 continue to drop with the occurrence of apnea, the NIPPV or NCPAP ventilator should be used for positive pressure ventilation immediately, and the operation will be continued after heart rate and SPO2 return to normal. If surfactant regurgitation occurs, suspend administration and slow down the infusion until there is no regurgitation in the mouth.Under NCPAP or NIPPV, the calf pulmonary surfactant  will be administered The first dose of pulmonary surfactant is 100 mg/kg, and the criteria of repeated use of surfactant are as follows: (1) within 72 h after birth; (2) progressively aggravated respiratory distress after first dose with a minimum interval of 4–6 h; (3) chest X-ray is consistent with the imaging findings of RDS; (4) dyspnea caused by other causes is excepted.2 > 65 mmHg and pH <7.2; (2) hypoxemia with SpO2 of <0.85 on FiO2 > 0.4; (3) recurrent apnea with ≥3 episodes per hour or a single episode of apnea requiring positive pressure ventilation within 24 h; (4) SAS increasing > 2 points per hour, or SAS > 5 points lasting more than 2 h after first or second dose of surfactant administration; (5) pulmonary hemorrhage; (6) cardiopulmonary arrest requiring intubation; (7) neonatologists in the NICU believe that invasive respiratory support should be given to patient. Extubation criteria are established as mean airway pressure (MAP) <8 cm H2O and FiO2 <0.3.The decision for intubation and IMV within 72 h and 7 days after birth of life is based on the following criteria: (1) severe respiratory acidosis with PaCO2O, or when NIPPV with MAP <6–7 cmH2O and FiO2 ≤ 25%; (4) without apnea or intermittent hypoxia.The decision for weaning of NCPAP or NIPPV is based on the following criteria: (1) the infant has recovered from RDS; (2) the signs of respiratory distress have disappeared and SAS <3 points; (3) when NCPAP with PEEP <3–5 cmHAfter being assessed by the NICU clinicians to meet all the conditions and lasting for more than 24 h, withdrawal of NIV can be considered.All of the enrolled infants will be started on caffeine soon after admission at a loading dose of 20 mg/kg followed by a maintenance dose of 5–10 mg/kg.The primary outcome is NIV treatment failure within 72 h after birth, as determined by objective oxygenation, blood gas, and apnea criteria, or the need for intubation and mechanical ventilation.The secondary outcomes are as follows:NIV treatment failure within 7 days after birthRate of intubationRate of pneumothoraxRate of nasal traumaRate of pulmonary hemorrhageRate of hemodynamically significant patent ductus arteriosus (hsPDA)Rate of intraventricular hemorrhages Rate of white matter injuryRate of blood culture-confirmed sepsisRate of bronchopulmonary dysplasia (BPD)Rate of necrotizing enterocolitis Rate of retinopathy of prematurity (ROP)Duration of NCPAP/NIPPV, duration of IMV, and days on supplemental oxygenCosts associated with hospital care and treatment.Patient demographic data mainly include: gestational age, birth weight, sex, multiple births, antenatal corticosteroids use, mode of delivery, maternal complications, Apgar score and cord blood gas. Clinical data mainly include: SAS, requiring more than one dose of surfactant, blood gas, the need for IMV within 72 h and 7 days after birth, duration of NCPAP/NIPPV, days on IMV, days on supplemental oxygen, costs associated with hospital care, morbidity of BPD, pneumothorax, nasal trauma, pulmonary hemorrhage, hsPDA, IVH, white matter injury, blood culture-confirmed sepsis, NEC and ROP.2) > 0.3 for (SpO2) > 85%, or SAS > 5 points or SAS increasing > 2 points per hour  and  in preterm infants aged <32 weeks with RDS . There wDemographic and clinical characteristics for the NCPAP group and the NIPPV group at baseline will be described in mean and standard deviation, median and range, or rate and percentage. Continuous variables will be presented in mean ± standard deviation or median (minimum-maximum), and categorical variables will be presented in numbers and proportions. We will not test the hypothesis with the two sets of baseline data.t-test for continuous variables , the Mann-Whitney U test (if skewed) and the chi-squared test for categorical variables. In addition to the p-value of the outcomes, results are to be given in terms of differences and 95% CIs. Preplanned exploratory subgroup analyses are to be performed for the primary and other pre-specified outcomes by gestational age, and birth weight. All data will be analyzed using SPSS version 20.0. Two-tailed p-values <0.05 will be considered as statistically significant.The data will be analyzed based on the original treatment allocation of the participants in accordance with the intention-to-treat principle. To compare the primary and secondary outcomes between the two groups, we will use the Student's In recent years, most studies have shown that NIV reduces the risk of BPD in preterm infants when compared to intubation and IMV , 22. Prep = 0.005) and the rate of moderate-to-severe BPD  compared with NCPAP, however, this was not seen for the subgroup of preterm infants of a gestational age of <30 weeks   Preterm infants with spontaneous breaths will not be grouped immediately after birth, but upon arrival in NICUs. We stipulate that non-invasive respiratory should be supported with transport ventilator or T-piece during delivery room resuscitation and transfer, and we will limit the time to arrive at the NICUs to within 30 min after birth. (2) Treatment allocations (in a 1:1 ratio) will be based on a pre-specified random number table, without stratification according to gestational age and birth weight. This is due to the fact that the estimated sample size of premature infants at 24–26 weeks with spontaneous breaths after birth and without intubation during delivery room resuscitation is relatively small. . Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.HZ and TH: concept and design. HZ, TH, LZ, YG, and WZ: acquisition, analysis, and interpretation of data. HZ, TH, and JL: drafting of the manuscript. HZ and LZ: statistical analysis. TH and XT: supervision. All authors: critical revision of important intellectual content in the manuscript. All authors contributed to the article 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. 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To examine severe birth‐related injuries in neonates among mothers with different types of diabetes.n = 623 649) after 35+0 weeks of gestation. The primary outcome variable was severe birth injury. Incidences, crude and adjusted odds ratios, and probabilities in regression analysis were calculated for different types of diabetes.Retrospective cohort study based on Finnish Medical Birth Register data from 2004 to 2017. The study included singleton neonates born vaginally with cephalic presentation (There were 1952/623 649 (0.3%) severe birth injuries of which brachial plexus injury occurred most frequently. The injury incidence was highest in neonates of women with type 1 or type 2 diabetes, 42/1659 (2.5%) and 10/548 (1.8%), respectively. For gestational diabetes, the injury incidence was comparable to non‐diabetic women: 422/77 810 (0.5%) and 1478/543 632 (0.3%), respectively. Shoulder dystocia, high birthweight, and vacuum‐assisted delivery were associated with the highest probability for injury. Birthweight and obesity had a stronger impact on injury risk in women with pregestational diabetes compared to other pregnancies.Neonates of women with pregestational diabetes have a higher risk for severe birth injury than other neonates. The injury risk in neonates delivered by women with gestational diabetes or non‐diabetic women is generally low. The study aims to describe the type of injuries, calculate the incidence rates, and determine the risk factors for severe injuries in a nationwide birth cohort study.This study addresses severe birth injuries in vaginal deliveries after 352This nationwide population‐based cohort study was conducted using data from the Finnish Medical Birth Register (MBR) and the Care Register for Health Care (CRHC), which are maintained by the Finnish Institute for Health and Welfare. The MBR includes data on all deliveries in Finland. The MBR comprises information on the health of the mothers and neonates, interventions needed during pregnancy, delivery, and the first 7 days after birth. The data are completed by information obtained from the Central Population Register and the Cause‐of‐Death Register. The CRHC contains information on patient characteristics, diagnoses, and operations performed during the hospital stay. The coverage and accuracy of these registers have been shown to be excellent.+0 and 42+6, as birth injuries were infrequent before 35 weeks of gestation. After excluding those neonates delivered by forceps  or those with major congenital anomalies , 623 649 singleton live born neonates born vaginally with cephalic presentation were included. The outcome variables were severe birth‐related injuries coded with the Finnish implementation of the 10th Revision of International Statistical Classification of Diseases and Related Health Problems (ICD‐10) codes. The ICD‐10 codes for birth injuries detected at 0–6 days, information on the type of mothers’ diabetes, mode of delivery, and baseline characteristics were collected from the MBR. Moreover, hospital visits related to any severe birth injury diagnosis recorded in the CRHC during the first year after birth were included to increase the coverage.The study was based on register data from the years 2004 to 2017. Gestational age was limited to between 352) were included after 2006, as values from several hospitals were missing for the years 2004 and 2005. Birthweights above +2 standard deviation (SD) were defined as large for gestational age (LGA) standardized for parity, sex and gestational age in a Finnish population.Diagnosis of T1D and T2D were based on ICD‐10 codes gathered from the MBR , and GDM was defined as pathologic 2‐h 75‐g oral glucose tolerance test with at least one elevated plasma glucose value determined as ≥5.3 mmol/L (95.4 mg/dl) (fasting), ≥10.0 mmol/L (180.0 mg/dl) (1 h), and ≥8.6 mmol/L (154.8 mg/dl) (2 h) .+3 for dietary treated GDM. The decision of the mode of delivery is based on the obstetrical indications if the estimated fetal weight by antenatal ultrasound is between 4000 and 4250 g in pregestational diabetes and up to 4500 g in medication treated GDM. Furthermore, an elective cesarean section is recommended if the estimated fetal weight is >4500 g in pregnancies with T1D, T2D and medication treated GDM.Management of diabetic pregnancies are based on national guidelines2.1t‐test and Mann–Whitney U‐test for continuous variables. The risk factor analysis was calculated using a composite severe birth injury as an outcome variable. The results are presented as odds ratios (ORs), risk differences (RDs), and ratio of odds ratios , with 95% confidence intervals (CIs). A logistic regression analysis was performed for the variables associated with the highest risk for injury. P‐value of <0.05 was considered significant. Statistical analysis was performed using R Statistical Software version 4.0.3 .The incidences of composite severe birth injury as well as individual types of injuries were calculated. Baseline characteristics were described as proportions for categorical variables and as means and SDs or medians with inter‐quartile ranges for continuous variables. The background characteristics in different diabetes categories were compared using chi squared‐test and Fisher's exact test for categorical variables and Welch Two Sample 2.2Only pseudonymized data were used. This study was approved by the Ethics committee of Tampere University Hospital (reference number R17069). Institutional approval was also obtained from the Finnish Institute for Health and Welfare (reference number THL/1659/5.05.00/2017).3n = 1670), accounting for 85.6% of all severe injuries. Other severe birth injuries were infrequent.The study population consisted of 623 649 neonates with 1952 severe birth injuries in 1934 neonates. The total incidence of injuries was 1952/623 649 (0.3%) of live births in vaginal deliveries ,Baseline characteristics differed considerably between the types of diabetes, as reported earlier by others.High birthweight was the most important risk factor for birth injury. Although ShD is unpredictable, it is often associated with high birthweight, and high birthweight is suggested to be an independent risk factor for birth injury among neonates with ShD.There is no standardized screening system or criteria for GDM. Indeed, it has been recently questioned whether the comprehensive screening of GDM and the treatment of mild hyperglycemia are worthwhile, and is the current system only increasing the number of women with GDM without improvement in outcomes.The strengths of the present study are the statutory Finnish MBR and CRHC data with national coverage ruling out selection bias and increasing generalizability. The precision and completeness of the data have been reported to be good.5The neonates of women with pregestational diabetes have a higher risk for severe birth injury than other neonates. The risk is strongly associated with ShD, higher birthweight and further strengthened by VAD. The incidence of injury in pregnancies with GDM is comparable with pregnancies without diabetes. Moreover, the impact of high birthweight and obesity on the risk for injury in GDM and non‐diabetic pregnancies is less important than in women with pregestational diabetes.The authors have no conflicts of interest.MK, TH, KT, HL, and AS designed the study. TH, AS, and MG contributed to the acquisition of the data. MK, TH, and TK were responsible for data analysis. All authors contributed to the interpretation of the data. MK was a major contributor in the writing of the manuscript. All authors participated in drafting and revising the manuscript. All authors read and approved the final manuscript.