A tumor extends its effects beyond its local site, and one such effect is cancer cachexia which is caused by a state of systemic inflammation in response to cancer. Though the prominent effect of cancer cachexia is seen on skeletal muscles, it shows deterioration in other organs’ smooth muscle, adipose tissue, blood, bone marrow, liver, and immunity. Interleukin (IL)-6 plays an imminent role along with tissue necrosis factor-alpha, IL-1 beta, interferon-gamma, myostatin, adiponectin, growth differentiation factor-15, activin A, etc. These cytokines through nuclear factor-kappa beta, mitogen-activated protein kinase, suppressor of mothers against decapentaplegic, and Janus activated kinase/signal transducer and activator of transcription pathway activate genes inducing ubiquitin-proteosome system and reactive oxidative species. Apart from these, they participate in causing anemia and immunosuppression. Adipose tissue acts as a source of cytokines and place of action of cytokines leading to lipolysis. Moreover, these cytokines act at the hypothalamic-pituitary-adrenal axis change metabolism and add to anorexia which already exists in cancer patients. The involvement of multiple cytokines necessitates the development and testing of anti-cytokines in combinations. According to the World Health Organization (WHO), most cancers account for approximately 10 million deaths withinside the year or one in six deaths worldwide. Breast cancer is the leading cancer type but the cancer that is causing the highest number of deaths is lung cancer .Cancer cachexia is a complex multifactorial syndrome that affects about half of cancer patients and three-fourths of those with advanced cancer -5. They According to international consensus, cancer cachexia is defined as “weight loss of more than 5% over past six months in absence of starvation and/or BMI less than 20 kg/m² and more than 2% ongoing weight loss and/or sarcopenia and more than 2% ongoing weight loss” . It is cCancer cachexia is usually diagnosed only after a weight loss of 7-15%  and decrSource of cytokinesCancer cachexia is a state of systemic inflammation, and inflammatory cytokines play the first-rate component in this. Tumors express proteolysis-inducing factor (PIF) that activates the nuclear factor-kappa B (NF-κB) pathway which leads to the activation of targeted genes to produce cytokines and chemokines resulting in inflammation. It activates the signal transducer and transcription factor 3 (STAT 3) pathway and leads to the synthesis and release of interleukin (IL)-8 (IL-8), IL-6, tissue necrosis factor-alpha (TNF-α), interleukin-1-beta (IL-1beta), monocyte chemoattractant protein-1 (MCP-1), and interferon-gamma (IFN‐γ) . As a reEffect of cytokines on muscle lossMuscle loss is the most imperative feature of cachexia. It not only affects skeletal muscle but also visceral muscle. In addition to losing weight and strength for day-to-day activities, it also leads to cardiac and diaphragmatic muscle damage leading to death due to cardiac failure and respiratory arrest, respectively . Table 1There are a few ways by which cytokines cause muscle loss. One of these is by augmenting the synthesis of cortisol. Cytokines such as TNF-α, IL-1-beta, and IL-6 act on the hypothalamic-pituitary-adrenal axis (HPA) to release corticotropin-releasing hormone (CRH) from the paraventricular nucleus. CRH acts on the anterior pituitary to release adrenocorticotropic hormone (ACTH) that binds to mineralocorticoid 2 (MC2) receptors on the adrenal cortex to initiate adrenal cortisol synthesis. 11-beta-hydroxysteroid dehydrogenase-1 (11-beta-HSD-1) is synthesized in the liver, adipose tissue, muscle, bones, and immune cells. 11-beta-HSD-1 mediates the conversion of inactive glucocorticoids into active cortisol. It has been proven that cortisol causes muscle wasting [Cytokines contribute to muscle loss by increasing muscle proteolysis and diminishing muscle synthesis. Muscle proteolysis produces energy substrates for the growing needs of tumor growth, such as glutamine is used in the synthesis of nucleic acids which is essential for rapidly generating tumor cells. Similarly, alanine derived from this process participates in liver gluconeogenesis for the production of glucose which becomes the energy source for tumor cells . IL-6 isNF-κB is upregulated rapidly in the nucleus . It is iThe ubiquitin-proteasome system is proteasome-mediated proteolysis where protein is marked with a ubiquitin chain . It inclMuRF-1 and Atrogin-1 gene activation with UPS muscle proteolysis can also occur via Janus kinase (JAK)/signal transducer and activator of transcription (STAT) and mitogen-activated protein kinase (MAPK) signally . IL-6 inIn addition, muscle damage also occurs by autophagy, myotube atrophy, and myocyte apoptosis . Autopha-. This induces oxidative stress, muscle fiber loss, and a reduction in mRNA levels of MyoD [However, inflammatory cytokines cause muscle loss by inhibiting myocyte regeneration, proliferation, and differentiation. The last step in muscle regeneration requires satellite cells in which few remain in the quiescent stage while the remaining multiply and differentiate into myocytes. Early differentiation requires MyoD protein and late differentiation needs MyoG ,25. FOXO of MyoD . MAPK pa of MyoD ,26.IL-6, TNF-α, and TGF-beta also reduce mitochondrial biogenesis, which reduces mitochondrial function and ATP synthesis in myocytes . On the Effect of cytokines on adipose tissue lossAdipose tissue is involved in both metabolism and immunity. WAT is a major source of adipokines such as adiponectin, leptin, VEGF, MCF-1, TNF-α, IL-6, and IL-8 . WAT is Effect of cytokines on fibrosisCancer cachexia is a chronic state of systemic inflammation that leads to fibrosis of the extracellular matrix. TGF-beta initiates the SMAD pathway by phosphorylation of SMAD2/3 target genes causing the differentiation of fibroblasts into myofibroblasts. Cytokines such as TNF-α, IL-1, IL-13, and TGF-beta are responsible for stimulating the multiplication and endurance of these cells. As subcutaneous adipose tissue and adipocyte size reduce, fibrotic areas are formed. There is growth in collagen fiber, elastic fiber, and fibronectin. Type I and III collagen multiply with fibrosis .Effect of cytokines on anorexiaAnorexia refers to the loss of appetite associated with nutritional deficit ,29. SeveThe paraventricular nucleus (PVN) and arcuate nucleus express receptors for cytokines such as IL-1beta, IL-6, TNF-α, and LIF . These cEffect of cytokines on tumor growth and negative energy balanceA negative energy balance is when the energy requirement is significantly higher than the energy produced. Simply, the output does not meet the needs. This occurs because of an upsurge in the energy requirements of a growing tumor, metastasis, escalation of basal metabolic rate, the decline in energy provision to the body due to anorexia, and alteration in metabolism. TNF-α, IL-1-beta, IFN‐γ, and MCP-1-like cytokines acting via NF-kB are associated with a protein angiopoietin-like 4 (ANGPTL-4) which is produced majorly in adipose tissue as an adipokine and liver. This protein is involved in increasing the vascular supply to tumors by angiogenesis and increasing vascular permeability. By allowing the travel of tumor cells through endothelial cells, ANGPTL-4 also aids in tumor metastasis . IL-6 isPro-inflammatory cytokines affect metabolism via numerous approaches. Changes caused by inflammatory cytokines in melanocortin change the way the body utilizes glucose and increase lipolysis . WAT undEffect of cytokines on the liverIL-6 plays an important role in causing cancer cachexia. It changes protein production and synthesizes acute-phase proteins . CRP levEffect of cytokines on blood and bone marrowAnemia is seen in one-third of cancer cachectic patients who are usually normocytic. Hepcidin is an acute-phase protein seen in response to systemic inflammation that decreases the absorption of iron in the gastrointestinal tract, thus decreasing the iron availability for the production of red blood cells. Pro-inflammatory cytokines also inhibit the production of erythropoietin from the kidney, thus reducing the production of erythroblasts from bone marrow. IL-6 along with other elements produces myeloid-derived suppressor cells directing to immune suppression. THPO produced from the liver produces platelets and is activated by IL-6 and IL-7 .Future of cancer cachexia treatmentAlthough anti-cytokines are considered a potential future in the field of cancer cachexia, successful drugs are not available. This can be attributed to a lack of adherence due to disease progression, death, voluntary withdrawal, and drug toxicity. Thalidomide inhibits TNF-α, IL-6 and NF-kB have shown mixed results in drug trials; however, when given in combination with appetite stimulants megestrol acetate (MA) and medroxyprogesterone acetate (MPA) the results were better than those with only MA or MPA -37. CertIt is important to observe that even though single anti-cytokines have not been proven to be effective, drugs which inhibit multiple cytokines such as thalidomide and ghrelin containing anti-cancer or appetite stimulants are more effective in treating cancer cachexia. This is consistent with the observation that cancer cachexia is caused by a cascade of events involving multiple cytokines. Hence, it would be better to conduct more drug trials for combinations of anti-cytokines and anti-cytokines along with other drugs used in cachexia treatment.LimitationsThis is a literature review of only English-language papers. Though this review includes various ways cytokines affect the body in cancer cachexia, it does not discuss molecular mechanisms by which they bring these changes and the pharmacological outcomes of drugs acting against these cytokines. In addition, this review only included free and full-text papers published after 2002 into consideration.Cancer cachexia reduces the lifetime of cancer patients and decreases the quality of life. In addition, they have been proven to decrease the body’s response to chemotherapy in battling cancer. This study aims to understand the pathological role of pro-inflammatory cytokines in cancer cachexia. Currently, the majority of treatment of cachexia is about palliation. Drugs against inflammatory cytokines are being developed and are in different stages of trials for application in cachexia. With a clear picture of the role of multiple inflammatory cytokines in causing cancer cachexia, we hope drugs that can act on multiple inflammatory cytokine targets and combinations of anti-cytokines with other drugs can be developed and open a new avenue in the care and treatment of cancer patients.


This study aimed to assess the association between interpregnancy interval (IPI)—the time from childbirth to conception of the next pregnancy—and maternal and neonatal morbidity. The World Health Organization (WHO) currently recommends an IPI of at least 24 months after a live birth to reduce adverse birth outcomes. However, assessing the relationship between IPI and perinatal outcome is complicated by confounding factors. We conducted a nationwide population-based cohort study using Swedish registry data, allowing for adjustment of maternal characteristics and health at first birth. The study population consisted of all women with a singleton, live, and vaginal first birth with a second singleton birth within five years during 1997–2017, covering 327,912 women and 655,824 neonates. IPI was grouped into six-month intervals with 24–29 months as the reference. The association between IPI and morbidity was examined using multivariate logistic regression. For women having a vaginal delivery at their first birth, intervals < 24–29 months were associated with decreased maternal morbidity and unaffected neonatal morbidity. Intervals > 24–29 months were associated with increased maternal and neonatal morbidity. Our findings question the relevance of WHO’s recommendation of an IPI of at least 24 months in a high-income country. A short IPI has also been associated with preterm birth6, small for gestational age/low birthweight at term7, and preterm prelabor rupture of membranes9. Other observed associated risks are maternal nutrient deficiencies, especially in lactating and malnourished women12. As a consequence, the World Health Organization (WHO) has issued a recommendation suggesting an IPI of at least 24 months after a live birth and 6 months after an early pregnancy loss13.The interpregnancy interval (IPI), i.e. the time from childbirth to conception of the next pregnancy, may affect health at childbirth for the mother and neonate. A short IPI has been linked to adverse pregnancy outcomes14, preterm birth15, small for gestational age/low birthweight16, and pre-eclampsia17. In addition, a long IPI may be associated with the loss of adaptive benefits in the woman from a previous birth but can also entail effects of aging, change of partner, and change in socioeconomic status21.On the other hand, a long IPI has been associated with increased risk of fetal death13, while the effects of IPI in high-resource countries are less clear. As an example, a cohort study with data from USA, Australia, Finland, and Norway showed that the association between IPI and preterm birth was modified by whether or not the previous pregnancy was preterm22. Due to confounding factors, assessing the association between IPI and perinatal outcome is challenging. These factors include underlying health of the woman, previous induced and spontaneous abortions, and other health behavior and preferences23.Moreover, many of the studies behind the recommended IPI from WHO emanate from low- and middle-income countries23. The aim of this study was to examine the association between IPI and maternal and neonatal morbidity using nationwide health registers and population statistics in Sweden. We also examined the importance of confounding factors in explaining the relationship between IPI and maternal and neonatal outcomes.While the literature on the impact of short IPIs for maternal and neonatal health is extensive, the impact of long IPIs and the causal link has yet to be established and the mechanisms by which IPI affects specific birth outcomes are not well understoodInformation on maternal and neonatal pregnancy outcomes was retrieved from the Swedish Medical Birth Register. These data, provided by the Swedish National Board of Health and Welfare, contain extensive prospectively collected information on pregnancy, delivery, and postpartum conditions for pregnancies beyond 22 weeks of gestational age, for both stillbirths and livebirths.The link between each woman and child was retrieved from the Multi-Generation Register (Statistics Sweden). Information on previous hospitalizations came from the National Patient Register . Information on maternal educational attainment and income from sickness benefits were retrieved from the Longitudinal Integration Database for Health Insurance and Labor Market Studies (Statistics Sweden).We retrieved a sample based on all births during 1997–2017 identified via the Swedish Medical Birth Register and the Multi-Generation Register  at the first visit in antenatal health care, age , born in Sweden (yes/no), smoking tobacco in early pregnancy (yes/no), in vitro fertilization , and less than 5 prenatal visits (yes/no). These characteristics were included in the multivariate logistic regression analyses. In addition, we controlled for receiving sickness benefits and hospitalization prior the first birth, and severe and moderate maternal and neonatal morbidity in the first birth (defined below).The exposure IPI is defined from birth to conception and was computed using the time elapsed between the first and the second birth date after subtracting gestational age in weeks of the second child. The IPI was grouped into six-month intervals  up to five years after the first birth. The distribution of IPIs is presented in Supporting information Fig.  and showMaternal and neonatal morbidity were defined using medical diagnoses and surgical procedures according to the International Classification of Diseases—10th Revision (ICD-10) Sweden and the classification of care procedures (Swedish “KVÅ codes”). A core outcome set has not yet been defined for IPI exposure. Composite outcome sets for severe and moderate morbidity were constructed for women and neonates, respectively. A binary indicator was constructed for each class of morbidity, which was set to 1 for individuals with at least one case of morbidity, and 0 for the remainder. Each component of the composite index for, severe and moderate, maternal and neonatal morbidity is presented in Tables Differences in maternal characteristics across IPIs were examined using Kruskal–Wallis tests. Characteristics that differed across IPIs based on this test were considered potential confounders and adjusted for in the regression analysis. The associations between IPI and maternal and neonatal morbidity were assessed using logistic regression, calculating the unadjusted and adjusted odds ratio (OR and aOR), using 24–29 months as reference. We constructed the IPIs as indicator variables to flexibly allow the effect to vary across the distribution and focused on 6-month intervals up to five years after the first birth. An IPI less than 24 months is termed a short IPI, while more than 29 months is termed a long IPI.2) at the first visit in antenatal health care, age , born in Sweden (yes/no), smoking tobacco in early pregnancy (yes/no), in vitro fertilization , less than 5 prenatal visits (yes/no) in the second birth, and receiving sickness benefits or hospitalization prior the first birth, and severe and moderate maternal and neonatal morbidity in the first birth. To explore the importance of maternal selection behind the results, we examined how estimates were affected by the inclusion of maternal covariates and outcomes at first birth. We postulated that selection based on observables provides information on selection on unobservable characteristics24. Finally, we examined sensitivity to the inclusion of women with missing information on covariates by estimating the same unadjusted model for the women with missing information on maternal characteristics. Data analyses were conducted using STATA 14.0 . This study is reported according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline25.In the adjusted analyses, we controlled for a full set of confounders: educational attainment , body mass index .The study was conducted after it was approved by the Swedish Ethical Review Authority on November 25, 2019 (2019-05125) and all methods were performed in accordance with the relevant guidelines and regulations of the Swedish Ethical Review Authority. According to Swedish law, information from these registers is collected and available for research after permission from the Swedish Ethical Review Authority. The authors are willing to assist anyone who wishes to access this data set. In protection of the integrity and anonymity of the individuals and legal entities, data are pseudomized. Individual consent is not collected for participation in these registers, nor is is it collected for research conducted on the information obtained in the registers. Thus, informed consent on individual level is waived by the Swedish Ethical Review Authority  may prevent or cure fetal hypoxia and thereby reduce neonatal morbidity, while induction of labor preterm  can prevent eclampsia . We also constructed two levels of severity to present both severe and less severe outcomes to nuance the risks.Our results are supported by previous studies from other high-resource settings like Canada, Australia, and NorwayWe believe that our results are generalizable to many high-resource countries, but there are some specific circumstances to consider. Most women giving birth in Sweden are healthy and well-nourished. On the other hand, approximately one in four women giving birth in Sweden are not born in Sweden, contributing to a mixed risk population. Then again, the high availability and use of the Swedish maternal health care system may compensate for potential risks with short and long IPIs.The clinical implication of our findings is that women in high-resource settings, with a normal previous birth, may choose to have children at a short time interval without increasing the risk of morbidity in the next pregnancy. However, the characteristics, behavior, and medical history of the woman may result in higher risks than the IPI itself and must be considered.In conclusion, short IPIs were protective for women and neutral for neonates, while long intervals were associated with increased maternal and neonatal morbidity. The lowest risk was seen at 6–11 months’ interval. In a high-resource setting, the relevance of the policy formulated by the WHO of a recommended 24 months’ IPI may be questioned and women may choose shorter IPI without increased risks.Supplementary Information.


This study aimed to examine the prevalence and the related risk factors of congenital heart disease (CHD) in children with different birth weights in China and the relationship between the subtypes of CHD and birth weight (BW).This study conducted a cross-sectional survey on the data collected in the children’s congenital heart disease database (CHDD) established in China. This database contained data from one Grade A, Level III Children’s Public Hospital in Zhengzhou, Henan. The study included all the children and their parents in the database from 2014 to 2020 as the study subjects, and the missing data were processed by means of imputation. Diagnoses of CHD were coded using the International Classification of Diseases version 10 (ICD-10), and subtypes were classified by the codes Q20 to Q26. We reported the prevalence of CHD based on birth weight and gestational age and analyzed the related risk factors for children with CHD in different birth weight groups and factors for children of the same birth weight groups between the CHD groups and the non-CHD groups. The generalized linear model was used to assess the association between the subtypes of CHD and BW by establishing three adjusting models, and the data were stratified for further analysis by urban-rural and infant gender.A total of 42,814 children were identified as having CHD among 5,071,799 live children; the overall prevalence of CHD was 8.44 per 1,000 live births during 2014–2020; and the three subtypes with the highest prevalence of CHD were atrial septal defect (ASD) (2.75‰), ventricular septal defect (VSD) (2.57‰), and patent foramen ovale (PFO) (1.12‰). The prevalence of CHD was 18.87‰ in the group with BW <1,500 g, 12.84‰ in the group with BW 1,500–2,500 g, 8.24‰ in the group with BW 2,500–4,000 g, and 4.80‰ in the group with BW ≥4,000 g. The prevalence of CHD was 16.62‰ in the small for gestational age (SGA) group, 6.99‰ in the appropriate for gestational age (AGA) group, and 6.40‰ in the larger for gestational age (LGA) group. Parental factors such as drinking, smoking, viral infections, peri-pregnancy exposure to radioactive substances, low family monthly expenditure, and low Apgar scores at 1 and 5 min were related to the increased risk of CHD in the offspring. Parental supplementation of folic acid and exercise during the peri-pregnancy period could reduce the risk of CHD in the offspring. The results of Model 3 adjusting for confounding variables showed that infants with ASD had a birth weight 461 g lower , infants with VSD had a birth weight 426 g lower , infants with tetralogy of Fallot (TOF) had a birth weight 532 g lower , and without classification, infants with CHD had a birth weight 973 g lower .In very low birth weight (VLBW) and low birth weight (LBW) infants, CHDs are more prevalent than in the general live-born population. Moreover, some peri-pregnancy factors of parents are closely related to the occurrence of CHD in offspring; different types of heart defects can lead to LBW. Therefore, if the fetus is found to have a heart defect during the prenatal examination, the mother should pay more attention to maintaining weight and ensuring that the fetus is within the normal weight range, thereby increasing the postpartum survival rate, reducing complications, and promoting children’s health. Congenital heart disease (CHD) is one of the most common congenital malformations. It refers to the abnormal anatomy caused by the formation of the heart and large blood vessels during the development of the embryo, or abnormal development, or channel that should be closed but failed to shut down after birth . It was Some studies have shown that there is an association between CHD and LBW, which is a known comorbidity of CHD. A study based on the population of Sudan shows that infants with CHD are 2.6 times more likely to develop LBW than the general Sudanese population . CHDs thIn China, the prevalence of CHD varies from 7 to 22.9 per 1,000 live births or perinatal infants , causingThis study conducted a cross-sectional survey on the data collected from the children’s CHDD established in China. The database center was established by a university-affiliated children’s hospital in Henan Province, China . The CHDD contained childbirth information, such as date of birth, birth weight, feeding method, congenital abnormalities, apgar score of newborn, current health status, and medical history data, and parental sociodemographic information, such as maternal perinatal information , parents’ socioeconomic factors , parents’ lifestyle factors , parents’ exposure to virus, toxic, and harmful substances, and radioactive substances during the perinatal period. The CHDD was connected to the doctor’s medical record system, which could simultaneously obtain the child’s birth information, medical treatment, and record data. The sociodemographic information of the parents was obtained by the investigator through questionnaires and imported into the database in real-time. Data had been collected since 2014; all data were collected prospectively by the hospital data management center, which was equipped with 10 data management specialists for real-time data quality inspections; and then the supervisor completed the review before the data were locked every year.The study included all the children and their parents in the database from 2014 to 2020 as the study subjects, excluding those with insufficient medical records, transfers after birth, and those who did not want to participate in the study. The study was reviewed and approved by the Ethics Committee of Zhengzhou University, and all respondents signed informed consent. The whole process and all methods of the study were performed in accordance with the relevant guidelines and regulations for the construction of clinical diagnosis and treatment and clinical research ethics review committees.10) of the average gestational age; infants with birth weight above the 90th percentile (P90) of the same gestational age were defined as larger for gestational age (LGA); and between P10 and P90 of the same gestational age was appropriate for gestational age (AGA)  infant; when the newborn weighed 1,500–2,500 g, it was defined as low birth weight (LBW) infant; when the newborn birth weighed 2,500–4,000 g, it was defined as normal weight infant (NBW); and when the newborn weighed ≥4,000 g, it was defined as macrosomia . Referrige (AGA) .In this study, those with positive records of prenatal echocardiography or with abnormal findings in CHD screening were offered neonatal ultrasound screening for CHD. The final diagnosis was based on neonatal echocardiographic findings from a scan and confirmed by the pediatrician. Diagnoses of CHD were coded using the International Classification of Diseases version 10 (ICD-10), and subtypes were classified by the codes Q20–Q26 . We defi) and standard deviation (SD) and median (M) and quartile (Q1~Q3); categorical variables were described by composition ratio and rate. For missing values, we used the mean padding method for processing. The X2 test or, when appropriate, Fisher’s exact test was used to compare the prevalence of various types of congenital heart disease in different birth weight groups and characteristics of children with CHD at different birth weight groups and characteristics of children of the same birth weight groups between CHD and non-CHD groups. Chi-square trend analysis was used to track changes in the prevalence of CHD over time. The means were compared by one-way ANOVA; medians were compared with the Wilcoxon Mann–Whitney rank-sum test. The generalized linear model was used to analyze the relationship between BW and each subtype of CHD, taking BW as the dependent variable, whether each subtype of CHD was diseased as an independent variable, and adjusting possible confounding factors. The research model was as follows: 0 + β1xg(μi) = β (whether each subtype of CHD was diseased) + 2xβ (adjusted variable) + εi. Three models were mainly established as follows: Model 1: no variable was adjusted; Model 2: adjusting fetal sex, gestational age, gravidity, parity, and apgar score at 1 min and 5 min; Model 3: on the basis of Model 2, continuing to adjust the parents’ age, residence , education level, occupation, folic acid supplementation, whether drink, smoke, viral infection, radioactive material exposure, doing physical exercise or not, and family monthly expenditure. And the data were stratified for further analysis by urban-rural and infant gender in the gender-specific model; the baby’s gender was no longer adjusted. These analyses were performed using SAS.9.4 and SPSS25.0; the drawing process was carried out using Microsoft Office 2010 Excel and GraphPad Prism software. P values < 0.05 (two-sided) were considered statistically significant, unless indicated otherwise.Data were electronically registered. The prevalence of CHD in children with different birth weights was shown as the number of cases per 1,000 births, and any type of CHD was calculated as the total prevalence of CHD per 1,000 births. The continuous variables were statistically described by mean . The prevalence of CHD in the group with birth weight 1,500–2,500 g increased from 5.22 per 1,000 births in 2014 to 18.33 per 1,000 births in 2020 . The prevalence of CHD in the group with birth weight 2,500–4,000 g increased from 3.92 per 1,000 births in 2014 to 10.91 per 1,000 births in 2020 . The prevalence of CHD in the group with birth weight ≥4,000 g increased from 1.82 per 1,000 births in 2014 to 6.41 per 1,000 births in 2020 . It was worth noting that the prevalence of CHD in each birth weight group had a peak in 2017 , VSD (2.57‰), and PFO (1.12‰). In the VLBW group, the three subtypes with the highest prevalence of CHD were TOF (5.73‰), VSD (4.23‰), and ASD (3.55‰). In the LBW group, the three subtypes with the highest prevalence of CHD were PFO (2.84‰), TOF (2.05‰), and PHT (2.05‰). In the NBW group, the three subtypes with the highest prevalence of CHD were ASD (2.52‰), VSD (2.28‰), and PFO (1.26‰). In the macrosomia group, the three subtypes with the highest prevalence of CHD were PFO (1.33‰), VSD (0.98‰), and ASD (0.87‰). Comparing the prevalence of various types of congenital heart disease within different birth weight groups, there were differences in the prevalence of ASD, VSD, PFO, PDA, TOF, AVSD, and PHT among different weight groups. In the group of SGA, the three subtypes with the highest prevalence of CHD were TOF (3.36‰), ASD (2.57‰), and VSD (2.19‰). In the group AGA, the three subtypes with the highest prevalence of CHD were ASD (2.11‰), VSD (1.92‰), and PFO (1.00‰). In the group of LGA, the three subtypes with the highest prevalence of CHD were PFO (1.84‰), VSD (1.30‰), and ASD (1.09‰). Comparing the prevalence of different types of congenital heart disease in different gestational age groups of birth weights, it was found that there were differences in the prevalence among SGA, AGA, and LGA groups .Further analysis showed that factors that differed between those with and without CHD in the VLBW group included parents’ characteristics , family monthly expenditure, and child factors (apgar score at 1 min). The factors that differed between those with and without CHD in the LBW group included parents’ characteristics , family monthly expenditure, and child factors (apgar score at 1 min and 5 min). The factors that differed between those with and without CHD in the NBW and macrosomia group were identical, including parents’ characteristics  and child factors (apgar score at 5 min) .In the absence of stratified analysis, the ASD, VSD, TOF, and total CHD status had a statistically significant detrimental effect on birth weight in Model 1; after adjusting for some confounding factors (Model 2), similar results were still obtained; and after further adjusting for other confounding factors (Model 3), the results had not changed. On average, infants with ASD had a birth weight 461 g lower , infants with VSD had a birth weight 426 g lower , infants with TOF had a birth weight 532 g lower , and without classification, infants with CHD had a birth weight 973 g lower . After stratifying by gender of children, among boys, multiple models showed that VSD and TOF had significant adverse effects on birth weight. Infants with VSD were associated with a mean loss of birth weight of 467 g , and infants with TOF were associated with a mean loss of birth weight of 1,056 g  in Model 3. Among girls, multiple models showed that ASD, TOF, and total CHD had significant adverse effects on birth weight. Infants with ASD were associated with a mean loss of birth weight of 738 g , infants with TOF were associated with a mean loss of birth weight of 544 g , and infants with CHD were associated with a mean loss of birth weight of 812 g  in Model 3. In addition, infants with PDA were associated with a mean loss of birth weight of 283 g  only in Model 3 .After stratified by residence, children with urban households showed that TOF and total CHD had a significant adverse effect on birth weight under multiple models. On average, infants with TOF had a birth weight 875 g lower , and infants with CHD had a birth weight 649 g lower  in Model 3. In addition, infants with ASD had a birth weight 507 g lower , and infants with VSD had a birth weight 345 g lower  only in Model 3. For rural children, the ASD, VSD, TOF, and total CHD status had a statistically significant detrimental effect on birth weight in multiple models. Infants with ASD would cause an average reduction in birth weight of 688 g , infants with VSD would cause an average weight loss of 392 g , infants with TOF would cause an average weight loss of 631 g , and infants with CHD would cause an average weight loss of 879 g  in Model 3 .At present, there have been some reports on the prevalence of CHD in LBW infants and premature infants, and some studies have revealed that there is a certain correlation between CHD and birth weight in the world. However, in China, there are few reports on the prevalence of CHD in VLBW and macrosomia, and there is also a lack of relevant research on the relationship between CHD and birth weight. This study with a large sample size described the epidemiology of CHD in Central Plains of China and could accurately reflect the occurrence of CHD, including the prevalence of some rare subtypes. And we explored the relationship between the subtypes of CHD and birth weight and provided theoretical and practical references for Chinese children to reduce the occurrence of CHD and abnormal birth weight.We observed that the overall prevalence of CHD was 8.44 per 1,000 live births, and the three subtypes with the highest prevalence of CHD were ASD, VSD, and PFO, which was similar to most of the previous studies  –21. The Our results showed the influencing factors of children with CHD in different birth weight groups, among them, the factors that could be changed included folic acid supplementation before and during pregnancy, more exercise, drinking, and smoking. Folic acid is a water-soluble vitamin, which is indispensable in human metabolism as a coenzyme. Folic acid promotes the development of the fetal nervous system, and the lack of folic acid in the first trimester can lead to neural tube defects in infants . Due to Previous researches had proved that CHD was a multifactorial disease. Our study found that several maternal and paternal factors during pregnancy were associated with an increased risk of their children’s CHD in each birth weight group. These factors included pregnancy viral infection, smoking and drinking, exposure to radioactive substances, folic acid supplementation, exercise, family monthly expenditure, and apgar score. It has been suggested that the key period of heart embryonic development is the second to eighth weeks of pregnancy. Some studies indicated that maternal factors, including viral infection, smoking and drinking, exposure to radioactive substances, or treatment of such infections during the first trimester of pregnancy might precipitate CHD in the children , 31. TheOur findings clearly demonstrated that infants with CHDs were more likely to be of low birth weight than the general China children. And infants with ASD had a birth weight 461 g lower , infants with VSD had a birth weight 426 g lower , infants with TOF had a birth weight 532 g lower , and without classification, infants with CHD had a birth weight 973 g lower . It closely mirrored previous research done on this topic. Kramer et al. pointed out that the CHD group had significantly lower birth weights, and the decrease in birth weight was distinct only in children with TOF and ASD . Other sThe advantage of this research is that the survey has been strictly scientifically designed, the data management personnel are of high quality, the data collection work is organized and planned, and the data collected is relatively accurate. This study is with large sample size, and the possible confounding factors are controlled as much as possible during the analysis to increase the reliability of the conclusion. However, there are still some limitations to our study. First of all, we mainly adopt the cross-sectional research method, which cannot verify the causal relationship. Second, we cannot fully monitor all factors that affect birth weight. Peri-pregnancy factors of parents are acquired through recall, which has a certain recall bias. Eventually, some potential confounding factors may not be controlled during the analysis process. This study is an ongoing project, and we will obtain more data on children with continuous improvement of our database system. In this study, we used a database with a large sample size to describe the prevalence of CHD in different birth weights of children in central China from 2014 to 2020, analyzed the parental peri-pregnancy risk factors related to CHD, and explored the relationship between different types of CHD and birth weights. It fills up the gaps in related research in China, and the research results have important reference significance for parents’ peri-pregnancy healthcare, the reduction of CHD, and the improvement of birth weight.This study confirms that the prevalence of CHD in VLBW and LBW infants is higher than that of NBW infants in China. Moreover, some peri-pregnancy factors of the parents are closely related to the occurrence of CHD in the offspring; ASD, VSD, and TOF are the main types of CHD that cause LBW in infants. Therefore, prenatal care and other public health efforts such as folic acid supplementation and exercise by parents are expected to reduce the occurrence of CHD and improve the birth weight of the children. And if the fetus is found to have a heart defect during the prenatal examination, the mother should pay more attention to maintaining weight and ensuring that the fetus is within the normal weight range, so as to improve the survival rate after birth, reduce complications, and promote the children’s health.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by Ethics Committee of Zhengzhou University. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin. Written informed consent was obtained from the individual(s), and minor(s)’ legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.HY contributed to conceptualization, methodology, software, statistical analysis of data, writing—original draft preparation, review and editing, investigation, and data curation. BZ contributed to management and coordination responsibility for the research activity planning and execution, data curation, resources, project administration, and validation. RF contributed to formal analysis, data collection and curation, supervision, investigation, and validation. PW contributed to oversight and leadership responsibility for the research activity planning and execution, including mentorship external to the core team, and investigation. YZha contributed to conducting a research and investigation process, specifically performing the data/evidence collection, and investigation and validation. YW contributed to data collection, scrub data, and maintain research data. YH contributed to data collection and data quality control. YZho contributed to visualization, investigation, data curation, supervision, project administration, resources, article revision, and project financial support. 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. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The lower body temperature of preterm newborns at admission to neonatal intensive care units (NICUs) is inversely associated with their morbidities and mortalities before discharge. This retrospective cohort study aimed to determine whether admission rectal temperature in very low birth weight infants (VLBWIs) is independently associated with a composite outcome of death or moderate-to-severe neurodevelopmental impairments as defined by a performance developmental quotient of < 70 at three years of age. VLBWIs admitted to the NICU between April 2010 and March 2016 were assesed. Developmental assessment was completed in 216 newborns. Nine and two infants died before and after discharge, respectively. A higher admission temperature was associated with a lower incidence of death or moderate-to-severe neurodevelopmental impairments with adjustment for gestational age, sex, antenatal steroid use, Apgar score, severe intraventricular hemorrhage, and severe bronchopulmonary dysplasia . The admission temperature remained as an independent variable of adverse outcome at three years of age even when the study cohort was limited to surviving infants . Further studies are needed to assess whether avoiding low body temperature at admission results in better long-term neurodevelopmental outcomes in VLBWIs. Therefore, maintaining a body temperature of 36.5 °C to 37.5 °C is recommended when resuscitating preterm infants4. Despite an increasing concern for body temperature maintenance during resuscitation after birth, more than one-third of preterm infants still experience a low admission temperature of < 36.5 °C even in developed countries6. Further, insufficient clinical evidence exists regarding whether low admission temperature at birth is associated with short-term outcomes only or has extensive influence on long-term neurodevelopmental outcomes. Ting et al. assessed the relationship between the admission temperatures  of preterm infants (born at less than 29 weeks’ gestation) and their outcomes using a dataset from a large-scale registry. They found that lower admission temperatures (< 36.5 °C) were associated with the composite outcome of death or significant neurodevelopmental impairment at 18 to 21 months of corrected age 7. However, of a number of secondary outcomes, only severe language delay showed a weak relationship with admission hypothermia , leaving uncertainty around whetehr admission hypothermia is associated with both short-term mortality and long-term neurodevelopmental impairments. The lack of robust relationships between admission temperature and outcomes in this register-based study might be attributed to the heterogeneity of the patient background, location of birth, temperature management, and location of temperature monitoring. Recent studies have suggested that short-term outcomes of preterm infants have improved to a convincingly high level in developed countries9. However, if admission temperature in preterm infants is associated with their long-term neurodevelopmental outcomes, the strategy during neonatal resuscitation of maintaining the body temperature may require further improvement.The lower body temperature of preterm newborns at admission to neonatal intensive care units (NICUs) is inversely associated with their morbidities and mortalities before dischargeThis study aimed to determine whether admission rectal temperature in very low birth weight infants (VLBWIs) is associated with a long-term composite outcome of death or moderate-to-severe neurodevelopmental impairment at three years of age.Of the 245 newborns in the final study cohort, 29 11.8%) were lost to follow up. The remaining 216 newborns were born after 28.8 (3.4) weeks of gestation and 1040 (315) g at birth , singleton (p = 0.006), low Apgar scores p = 0.004), symptomatic patent ductus arteriosus p = 0.003), septicemia (p = 0.001), severe intraventricular hemorrhage (IVH) (p < 0.001), severe bronchopulmonary dysplasia (BPD) (p = 0.001), and lower admission temperature (p < 0.001) were associated with worse primary outcomes Table . In the , septice, symptomBuilding on previous studies, our study confirmed that admission rectal temperature in VLBWIs is associated with long-term composite outcomes of death or moderate-to-severe neurodevelopmental impairments at three years of age. Furthermore, an association was consistently observed between admission temperature and neurodevelopmental impairments in the secondary analysis of the survivors.10, other studies have identified associations between admission temperature and short-term adverse events, such as in-hospital death and neonatal complications7. Hence, clinical guidelines for neonatal resuscitation have emphasized the importance of body temperature monitoring in preterm infants from the early period of establishing the resuscitation programs11. Although the incidence of low admission temperature and related short-term outcomes of preterm infants has improved13, the question remains of whether the admission temperature is associated with long-term outcomes of preterm infants despite excluding the influence of short-term morbidities. In a study of more than 2700 registered preterm neonates < 29 weeks gestation, Ting et al. reported that the admission temperature measured at various locations showed a modest relationship with the composite outcome of death or significant neurodevelopmental impairments7. However, the relationship was relatively less robust compared to the large sample size, and the composite outcome was mostly contributed by mortality. In our study, we aimed to investigate whether admission core temperature is associated with the outcome in a high-survival cohort of VLBWIs, who were born at a single tertiary NICU and provided with similar temperature management after birth. Subsequently, admission temperature showed robust associations with the outcome of VLBWIs, even when the cohort was restricted to those who survived to the three years of age, suggesting the importance of early temperature management of VLBWIs to improve their survival and long-term neurodevelopmental outcomes.Since Silverman et al. first reported the benefit of using relatively higher ambient temperature to reduce mortality in preterm infants15. In addition, failure in the transition to the extrauterine environment, and subsequent requirement for prolonged intensive care might lead to worse neurodevelopmental outcomes in the affected newborns17. In term-born infants, complex relationships between the body temperature and neurodevelopmental outcomes have been reported. In asphyxiated infants, therapeutic hypothermia commenced within 6 h of birth could ameliorate death and improve neurodevelopmental outcomes by 18 months of corrected age18. However, recent studies have highlighted a paradoxical relationship between low admission temperature and adverse short- and long-term outcomes of asphyxiated newborns20. The authors of these studies speculated that reduced thermogenesis, following the most severe hypoxia–ischemia, resulted in low admission temperature and adverse outcomes in affected infants. Considering this, in our current study, newborns who experienced relatively greater difficulties in birth transition might have required more extended resuscitation, possibly leading to greater heat loss and adverse short- and long-term outcomes. In contrast to the results of previous studies, our study found that the duration of resuscitation time was not associated with low admission temperature and the primary outcome in our current dataset. Prospective studies are required to determine whether improved insulation of preterm infants after birth ameliorates their long-term outcomes.Our current findings support the potential benefit of relatively more rigorous maintenance of body temperature during the resuscitation of preterm infants. However, the mechanisms behind adverse long-term outcomes in preterm infants due to hypothermia shortly after birth remain unclear. In preterm infants, hypothermia is linked to increased oxygen consumption and energy depletion, metabolic acidosis, surfactant deficiency, and pulmonary hypertension21. Although the cohort size was relatively small, the follow-up rate to three years of age was 88.2%, allowing the assessment of the primary and secondary analyses in > 200 newborns. The cohort included 57% of extremely low gestational age newborns born at < 28 weeks of gestation. Considering that these newborns are most susceptible to admission hypothermia, morbidity, and mortality, and that the resuscitation strategy is not fully established for these vulnerable newborns, our study cohort might be most suitable for investigating the relationship between admission temperature and long-term outcomes. Additionally, body temperature at admission was measured rectally, which is more reliable than peripheral measurement22. Finally, this study was based on a retrospective analysis of prospectively collected data from a single center. The study period of over six years is relatively long, during which the treatment strategy and subsequent outcomes of newborns might change.Our study population was a high survival cohort, which is typical for Japanese tertiary NICUsHigher admission temperature was associated with better outcomes at three years of age in VLBWIs, which was consistently observed even when the study cohort was limited only to surviving infants. Further studies are needed to assess whether avoiding low body temperature at admission leads to better long-term neurodevelopmental outcomes, as well as reduced short-term complications.This was a retrospective analysis of clinical data that were prospectively accumulated from newborns hospitalized at a tertiary NICU of the Japanese Red Cross Nagoya Daini Hospital, Nagoya, Japan, as a part of a domestic follow-up program for high-risk newborns.Among 2369 newborns admitted to the NICU between April 2010 and March 2016, 277 were VLBWIs (< 1500 g) , and long-term outcomes were collected from the medical records. Resuscitation time was calculated as the duration between birth and admission to the NICU. Symptomatic ductus arteriosus was defined as hemodynamically symptomatic ductus arteriosus requiring therapeutic doses of indomethacin infusion (excluding prophylactic use) or surgical closure. Grade III/IV IVH was defined using the criteria defined by Papile et al.26, which is based on the Consensus on Science with Treatment Recommendations, published by the International Liaison Committee on Resuscitation27. After birth, the infants were kept warm using a plastic wrap and radiant heater. Rectal temperature was routinely recorded on admission to the NICU.In this hospital, approximately 90% of VLBWIs are delivered via Cesarean section. All resuscitation procedures were performed in accordance with the Neonatal Cardiopulmonary Resuscitation program of Japan28. The secondary outcome was moderate-to-severe neurodevelopmental impairment in survivors to the age of three years  unless otherwise specified. Multiple missing value imputations were performed to reduce the attrition biases due to missing data (n = 5 imputations) based on the correlation between variables with missing values and other subject characteristics. The crude effects of antenatal and postnatal variables on outcomes were assessed using univariate logistic regression analysis. The dependence of primary and secondary outcomes on admission temperature was assessed using multivariate logistic regression analysis. Known independent variables of the outcome for preterm infants were used as a priori covariates, including gestational age, sex, antenatal steroid use, 5-min Apgar score, severe IVH, and severe BPD. Statistical analysis was performed using the IBM SPSS Statistics package version 25.0 .The study protocol was approved by the Institutional Review Board of the Japanese Red Cross Nagoya Daini Hospital (#1344S). Parental informed consent was waived by the Institutional Review Board of the Japanese Red Cross Nagoya Daini Hospital, because no patient identifiers were used. All methods were carried out in accordance with relevant guidelines and regulations.Supplementary Table S1.


N = 780) responded to a survey addressing purchasing intentions and consumption motives in relation to buying sustainable groceries at a local food market. These intentions and motives were contrasted for two consumption contexts: on vacation vs. at home. An initial analysis of the data indicated that self-reported purchasing intentions were weaker for a vacation scenario than for a home scenario. Further analyses suggested that motives associated with purchasing intentions were not universal between contexts. At home, normative motives  were positively associated with intentions, whereas other motives failed to explain significant variance . On vacation, associations with intentions followed a similar pattern, except for the finding that hedonic motives  added explanatory variance. Despite the increased importance of hedonic motives on vacation compared to at home, normative motives showed the strongest association with purchasing intentions in both consumption contexts. The findings are discussed with reference to the literature on contextual discrepancies in environmental behavior, while noting possible implications for promoting sustainable consumption among tourists.A sample of tourists ( The tourism sector is associated with a range of environmental and sociocultural changes, in addition to having impacts on the economy, especially in developing countries . This be1 Some consumers may choose the cheapest available option because it leaves room in their remaining travel budget, others may prefer products that provide a pleasant experience such as through the consumption of luxurious food, some may end up choosing a product based on the desire to escape the boredom of their regular shopping routines back home, and yet others may opt for an option that adheres to sustainable development goals. This study focuses on the latter and draws upon psychological literature that delineates motives that could drive decisions favoring products with sustainability attributes; see With respect to consumption decisions that take place after people have arrived at their destination, the reasons for diverting from everyday life can be as manifold as the motivations for which people choose to travel in the first place.The effort a person may invest to protect the environment in everyday life rarely accounts for their respective activities as tourists. Goal-framing theory  asserts This theoretical perspective has been employed in several empirical studies seeking to understand individual differences in consumer behavior. When it comes to empirical studies that have explored the role of these motives for understanding tourism activities in particular, there has been a focus on hotel guests. 2 In the following, we report an empirical study that tests this claim, based on scenarios in which participants were asked to imagine buying groceries at a local food market. Several studies have pointed to the importance of food in shaping consumer experiences in tourism, especially when it is locally produced  were slightly more represented in comparison to male respondents (45.6%). For more details on the socio-demographic characteristics of the sample, including participants’ last night accommodation, see Participants were recruited among tourists who were visiting the city of Bergen (Norway) during the holiday (summer) season, Each participant filled out a paper-and-pen questionnaire. To enable us to test whether the motivational underpinning of intentions to buy sustainable groceries differs between contexts, participants filled out the measures of the target variables after having been asked to imagine visiting a local food market in a home scenario vs. a vacation scenario. Using imagined scenarios compared to standard questions helps to make the situations more concrete and approximate of real-life situations . While tat home? … when you are on vacation?]”.Consumption motives were measured with seven items adopted from the Consumer Motivation Scale CMS; ,b. Each at home? … when you are on vacation?]”. Purchasing intentions were analyzed with composite scores that reflected average scores across the four items, computed separately for the home scenario  and the vacation scenario .Purchasing intentions were assessed with four items, each concerned with the likelihood to which participants would purchase grocery products with different sustainability attributes . This selection of attributes  was informed by prior research indicating that environmental and social aspects are common in consumers’ concept of sustainable groceries . Items wt-test based on the composite scores of purchasing intentions yielded significant mean differences. More precisely, participants were on average more likely to intend purchasing sustainable groceries at a food market when being at home than when being on vacation .t-tests (Bonferroni corrected) indicated that perceived importance of specific consumption motives differed between the imagined scenarios. In connection with the vacation scenario, participants were less likely to emphasize gain motives such as value for money  and that the purchase would fulfill expectations . They also put less emphasis on normative motives in the form of having a good conscience . Participants were in the meantime more likely to consider hedonic motives such as avoiding boredom  and seeking pleasure , when they considered consumption at a local food market on vacation compared to at home. Two additional motives that were labeled as calm and safe  and good impression  did not differ in their perceived importance between the context scenarios.3 Results indicate that having a good conscience (as a normative motive) was significantly and positively associated with intentions to make sustainable purchases, both at home and on vacation. However, pleasure (as a hedonic motive) showed differential associations. It was significantly and negatively associated with intentions to buy sustainable groceries on vacation, but not significantly associated with purchasing intentions in the home scenario. The remaining consumption motives failed to show any significant associations with purchasing intentions, irrespective of whether consumption decisions were imagined as taking place at home or on vacation.Tourism comprises the “activities of persons traveling to and staying in places outside their usual environment for not more than one consecutive year for leisure, business and other purposes” , p. 1. MThese activities—despite their heterogeneity—can provide a means by which people can break out from the boundaries that are imposed on them in everyday life. This becomes reflected in the desire for an interim escape from regular routines and responsibilities, along with the wish to encounter positive experiences whilst being at the destination, both of which are traditionally viewed as core motivations for why people travel away from home . The repIt is a core premise in goal-framing theory that cues supporting hedonic and/or gain goals can push normative goals into the cognitive background, which for the latter implies less influence on behavioral decisions . DrawingThere was one consumption motive that showed a negative significant association with product purchases when participants were asked to imagine visiting a local food market on vacation: the more participants regarded the pleasantness and agreeableness of a product as important, the less likely were they to choose sustainable groceries in this scenario. However, and contrary to our initial assumption, the predictive value of this hedonic motive continued to be comparatively lower than that for the normative motive of having a good conscience. The latter was also the only consumption motive showing a consistent significant association with purchasing intentions, regardless of where these decisions were imagined taking place. While the results support the view that a situational focus on personal comfort may constrain environmentally friendly behavior, they do not corroborate prior studies in which this particular motive outperformed normative considerations as a predictor for conservation efforts among hotel guests .In sum, the current findings would seem to suggest that signaling the importance of behaving responsibly as a consumer could be a strategy to motivate purchases of products with sustainability attributes across contexts. This can be done, for instance, by means of persuasive messages that express gratitude toward grocery shoppers for doing their part in supporting the environment (e.g., reusing their plastic bags; Since the identified motives explained only a small fraction of the variance in each regression model, there is room to speculate about other factors that may determine individual differences in dietary habits and food preferences (for an overview and discussion, see The following issues remain to be addressed by future studies. First, each participant was approached at the same destination, which may have introduced a sampling bias as specific destinations may be particularly appealing to a certain visitor profile. Replications that comprise visitors at other destinations are warranted to test if the identified associations remain robust. Second, the questionnaire asked participants to imagine the scenario of visiting a local food market at home vs. on vacation. While there are cases in which mental simulation can substitute for actual experience in terms of having similar cognitive and behavioral effects , the preIt is known that people employ various justifications to explain their reduced environmental engagement when they are away from home, such as for instance by emphasizing that holidays are an exception . Rather The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation, to any qualified researcher.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Informed consent was inferred by participants filling out the questionnaire.RD and DH contributed to the conception and design of the study. RD organized the data collection and wrote the first draft of the manuscript. RD and SB performed the statistical analysis. SB and DH wrote sections of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.


Independent factors that increase the risk of perineal laceration during childbirth are an older age of the woman giving birth, a history of cesarean section, a higher birth weight of the newborn, and factors that reduce the risk of spontaneous perineal trauma are a higher number of deliveries and home birth.Childbirth-related perineal trauma (CRPT) is defined as damage to the skin, muscles of the perineum, as well as to the anal sphincter complex and anal epithelium. The aim of the study was to analyze the risk factors for spontaneous injuries to the soft tissues of the birth canal during non-operative delivery. This was a single-center retrospective case-control study. The study included the analysis of two groups, the study group featured 7238 patients with spontaneous perineal laceration  and the control group featured patients without perineal laceration with 7879 cases. The analysis of single-factor logistic regression showed that the factors related to perineal laceration during childbirth are the age of the patients giving birth ( Labor is one of the most important and unique events in the life of a woman and her relatives ; howeverChildbirth-related perineal trauma (CRPT) is defined as damage to the skin, muscles of the perineum, as well as to the anal sphincter complex and anal epithelium. This injury occurs because of spontaneous laceration or incision of the perineum during vaginal delivery . There aTrauma of the perineum during childbirth may be associated with numerous health consequences of varying duration and, at the same time, on women’s quality of life. These consequences include, inter alia, perineal pain, wound dehiscence, infections, dyspareunia and sexual dysfunctions, and urinary and fecal incontinence ,4,8,10. It should be emphasized that in the literature on the subject, there are numerous reports of spontaneous perineal trauma, in particular, severe perineal trauma. Perineal lacerations of the third and fourth degree are the most severe forms of spontaneous perineal trauma, and at the same time, are associated with numerous negative and long-term consequences for women’s health ,23,24,25However, the issue of perineal lacerations  is not analyzed so widely, which was the basis for our research. In addition, deepening and analyzing factors affecting spontaneous perineal injuries during childbirth allows for the verification of current guidelines for childbirth management; therefore, the aim of the study was to analyze the risk factors for spontaneous injuries to the soft tissues of the birth canal during non-operative delivery.This was a single-center retrospective case-control study. Strobe guidelines for case-control studies were used to ensure proper reporting of results . The eleDeliveries at Saint Sophia’s Hospital take place in two areas, the hospital delivery room or the birth house, which is an intermediate form between inpatient delivery and home birth. This dataset was generated using electronic medical records collected by medical personnel; therefore, there is no recall bias. Additionally, the dataset was cross-checked for inconsistencies and any detected were verified. Data on the woman giving birth, the course of childbirth, and the condition of the newborn are recorded in a computer database by midwives during and immediately after Childbirth The first perineal injury assessment is performed by the midwife. The first- and second-degree injuries and the incision are surgically treated by the midwife. In the case of major injuries, they ask a doctor for consultation and the doctor sutures the perineum. An analysis of the documentation covering 40,007 deliveries at the analyzed time was carried out. The study included the analysis of two groups, the study group of patients with spontaneous perineal laceration, any degree of perineal laceration: I—6910 cases, II—308 cases, III and IV—20 cases , and the control group of patients without perineal laceration. Patients who had an episiotomy at labor were excluded from the analysis.The inclusion criterion for the study group was the occurrence of one of the perineal traumas during labor, first-, second-, third-, or fourth-degree perineal laceration. On the other hand, the inclusion criterion for the control group was the absence of any perineal trauma during labor .Deliveries before 38 weeks of gestation, multiple pregnancies, the occurrence of shoulder dystocia, operative deliveries, neonates with major birth defects or abnormal karyotype, and intrauterine fetal death were also excluded from the analysis. The analysis also did not consider data in which there were deficiencies in the medical records. Based on the adopted criteria, 15,117 cases were qualified for the analysis: study group—7238 cases; control group—7897 cases .In the process of analyzing electronic documentation, the following information was obtained: demographic data, obstetric history, course and complications of pregnancy, diseases coexisting with pregnancy, the course of childbirth, conduct of labor, and delivery data.The study has received approval from the Bioethics Committee of the Medical University of Warsaw (No. AKBE/204/2021). This was a retrospective anonymized data analysis; therefore, no individual patient consent was needed.p < 0.05.The data obtained in the documentation analysis process were subjected to statistical analysis, which was performed using the R language in the RStudio environment. Qualitative data are presented as numbers (n) and case percentages (%). Quantitative data are presented as mean (M) and standard deviation (SD). The normality of the distribution of quantitative variables was checked using the Kolmogorov–Smirnov test and the Lilliefors test. The Pearson’s chi-squared test was used to assess the dependence within the qualitative variables. Quantitative variables were compared using the Student’s T-test with the assessment of homogeneity of variance with the Brown Forsythe test. A logistic regression model was developed to assess risk factors for a perineal laceration. The backward stepwise method was used in the construction. Model data are presented as odds ratios (ORs) together with the 95% confidence interval (95% CI). The usefulness of the model was assessed using the ROC method with the determination of the cutoff point by the tangent method. The level of statistical significance was set at p < 0.05). There was no relationship between the occurrence of perineal rupture and the place of residence, pregnancy hypertension, or pregnancy cholestasis (p > 0.05). Detailed data are shown in The conducted statistical analysis showed that the examined women with spontaneous perineal laceration were older (M = 31.9) and had a higher BMI (27.4 vs. 26.9) than in the control group. They had higher education (89.6%) and were in a stable relationship (85.1%) more often, compared to the control group. Subjects who experienced perineal laceration were more likely to be pregnant for the first time (29.9%), primiparous (35.1%), and diagnosed with gestational diabetes (8.9%). The above-mentioned relationships were statistically significant (p < 0.05). There was no relationship between the occurrence of perineal laceration and the use of oxytocin in the first stage of labor, the administration of oxytocin in the first and second stage of labor, the performance of epidural anesthesia, the duration of the first stage of labor and the Apgar score of the neonate in 5th and 10th minute (p > 0.05)—The spontaneous perineal laceration in the respondents occurred more often when they gave birth in a hospital (81.2%), with vaginal birth after cesarean (VBAC) (4.9%), they received oxytocin in the second stage of childbirth (0.8%). The duration of the second stage of labor was longer (23.4 vs. 21.6 min) compared to the control group. Neonates of mothers who had perineal laceration more often received 7 or more points on the Apgar scale in the first minute after delivery (99.3%). In addition, these neonates had a higher birth weight (3529.1 vs. 3464.4 grams) and head circumference (34.8 vs. 34.6 cm) compared to neonates of mothers who did not have the perineal laceration. The indicated correlations were statistically significant (p < 0.05). There were no significant relationships between the degrees of perineal laceration and the BMI index, the place of delivery, the use of oxytocin in the second stage of labor and the circumference of the neonatal head (p > 0.05)—In patients of higher age, the first-degree perineal laceration occurred more often (M = 31.9); in younger patients (M = 29.9), spontaneous third- and fourth-degree perineal trauma. In women who were pregnant for the first time and during the first childbirth, the second-degree perineal laceration  and third- and fourth-degree  perineal trauma occurred more often. In the second pregnancy and during the second childbirth  and in the third and subsequent one , the first-degree spontaneous trauma was found. In the case of VBAC, second-degree perineal spontaneous trauma was found (10.7%). A longer duration of the second stage of labor contributed to the occurrence of third- and fourth-degree perineal trauma (M = 40.1) and a shorter duration (M = 22.9) contributed to the occurrence of first-degree perineal lacerations. In addition, the second-degree perineal lacerations (M = 3583.3) occurred in the case of the larger birth weight of the neonate, and in the smaller birth weight of the neonate (M = 3526.5), first-degree trauma occurred. The above-mentioned relationships were statistically significant (p < 0.05), VBAC , and higher birth weight of the neonate . On the other hand, the factors reducing the risk of spontaneous perineal trauma are a higher number of deliveries  and home birth .Spontaneous trauma to the perineum during childbirth may have numerous consequences on the health of women and may affect their life and functioning ,4,8,10, The result of the logistic regression analysis of our own research showed that the more advanced age of the woman giving birth predisposes her to spontaneous perineal trauma during childbirth (OR = 1.06). Research by Bodner-Adler et al. (2017) showed that, among others, maternal age was an independent risk factor for perineal trauma . In addiIn turn, interesting research results in the field of risk factors for obstetric anal sphincter injury, which is a serious form of trauma/injury to the perineum following vaginal delivery, were presented by Nolan et al. (2021). They found that a maternal age over 35 has a protective effect on the perineum (OR = 0.68), which should be an important aspect of counseling pregnant women when deciding on the method of delivery , which mThis is due to the more frequently observed phenomenon of pregnancies of women at an advanced age, i.e., 35 and over, which is often associated with numerous complications such as gestational diabetes mellitus, gestational hypertension, preeclampsia, preterm delivery, and cesarean section ,29,30. TOur own research shows that one of the factors influencing the occurrence of perineal laceration is the antenatal BMI of the mother. Reports on relationships between obesity and birth-related perineal trauma are contradictory. Some studies have reported a lower risk of obstetric anal sphincter injuries with increasing BMI in comparison with women with BMI within the normal range, while others have demonstrated a significant relationship between obesity and remarkable perineal trauma, whereby the probability of trauma is increased for obese women ,16,17,18Studies by MacArthur and MacArthur (2004) showed that perineal traumas were more often found in the primiparas, women after natural childbirth, and epidural anesthesia in the second stage of labor . SimilarAnalyses of our own research have shown that the place of childbirth is an important factor having a protective impact on the risk of spontaneous perineal laceration (OR = 0.82).The results of the study by Bodner-Adler et al. 2017) showed that the lack of midwife care was also a significant risk factor for perineal trauma , which i showed tAnother important aspect analyzed in this paper was the VBAC and the perineal laceration. Studies by Elvander et al. 2019) showed that women undergoing vaginal birth after cesarean (VBAC) compared to nulliparous women have an increased risk of severe perineal injury (regardless of the indications and date of the primary cesarean section)—OR = 1.40 [ showed tOxytocin is one of the most used drugs in delivery rooms, used to induce or stimulate childbirth, which is the subject of interest to researchers around the world ,38,39. NThe second stage of childbirth is the most stressful part of the birth process (childbearing process). Decisions concerning the management of this stage, considering the optimal course for the mother and the child, have been under discussion for years . AccordiIn addition to maternal and postpartum risk factors for perineal lacerations, the researchers also identified fetal–neonatal determinants. Komorowski et al. (2014) attempted to answer the question of whether a newborn’s large head increases the risk of perineal trauma or not. They found that in low-risk nulliparous women, a larger circumference of the baby’s head during labor increases the likelihood of perineal trauma; although the effect is small , similarIdentifying individual factors that may lead to spontaneous perineal trauma during non-operative delivery is difficult because, in the majority of women, several risk factors seem to interact. Experienced medical personnel taking care during childbirth should decide on the choice of perineal protection techniques based on both their own clinical judgment and the use of evidence-based medicine from current and reliable research and source materials: evidence-based medicine (EBM) as well as evidence-based midwifery practice (EBMP).The strong part of our study is the large sample size, covering a long time period. In addition, several disruptive variables known to affect the risk of perineal injury were excluded from the analysis. We also did not include incomplete data in the analyses, which resulted in the exclusion of 1521 women from the study cohort. Another advantage is the quality of the collected data. Data have been collected from one institution, which reduces the risk of bias caused by differences in data collection or practices. Ultimately, the analyzed data included ethnically heterogeneous populations. However, the study we conducted has some limitations. It was a retrospective study that included only data contained in the hospital’s electronic medical records. This may result in non-uniformity regarding the documentation, keeping deficiencies in the documentation. The study was conducted based on the analysis of medical records from one center, which is also a limitation. In addition, despite a large number of respondents, on the basis of regression analysis, statistically significant predictors affecting perineal lacerations during delivery were found; however, the actual impact of the risk factor from OR is negligible. Data on preparation for childbirth by women, such as perineal massage, physical activity, or lifestyle, were not included.It is necessary to conduct further research on the risk factors of spontaneous perineal injuries during childbirth, which will allow for updating the standards of childbirth management and, at the same time, improving the staff competencies of people responsible for the care and the quality-of-care improvement.Birth age, BMI during childbirth, number of pregnancies and deliveries, diagnosed gestational diabetes, home birth, condition after cesarean section, use of oxytocin during the second stage of childbirth, duration of the second stage of childbirth, body weight, and circumference of the neonatal head are factors related to perineal laceration during childbirth.Independent factors that increase the risk of perineal laceration during childbirth are the advanced age of the woman giving birth, the history of cesarean section, a higher birth weight of the newborn, and factors that reduce the risk of spontaneous perineal trauma are a higher number of deliveries and home birth.The knowledge of the above factors can be used as part of preconception education when designing a birth plan with a specific patient and during delivery to avoid medically unjustified procedures that may generate a given complication. It is necessary to conduct further research on the issue of perineal trauma during childbirth to minimize their negative consequences.


Epidermoid and dermoid cysts constitute the common benign masses that involve the skin. They are classified as epidermoid cyst when the lining contains only squamous epithelium, “true” dermoid cysts when skin adnexa such as hair follicles, sebaceous glands, and sweat glands are present and teratoid cysts when tissues from all three germ layers, such as cartilage, bone, muscle, and respiratory or gastrointestinal epithelium are present.These lesions may arise anywhere in the body. Dermoid and epidremoid cyst of the head and neck account for 7% of all dermoid epidermoid cysts.A 13-year-old boy, medically free, presented with swelling in the suprasternal region for more than 4 years. The swelling increased in size in the last one month prior to his presentation. Past medical history revealed an attack of upper respiratory tract infection aggravating the condition. The child had a history of painful swallowing for the one month, as well as weight loss of about 2–3 kg within the same period. There was no history of hoarseness of voice, shortness of breath or nasal obstruction. No history of trauma or previous surgical procedures. Family history was negative for similar condition.Neck examination revealed 2.5 cm × 2.5 cm mass in the suprasternal region. The mass was firm, not tender, with no overlying skin changes discoloration or ulceration. The lower margin of the mass was difficult to palpate. No movement of the mass could be elicited with swallowing or protrusion of the tongue. No other neck swelling or lymphadenopathy noted. Systemic examination was unremarkable.Routine laboratory investigations including complete blood count, liver function and renal function, all were normal.CT scan of the neck showed a cystic mass in the suprasternal region, not attached to deep structure, located in the midline, at the anterior side of the neck below the thyroid gland, and measuring 23 mm × 14 mm × 20 mm. It was very well defined and has fluid contents showing wall enhancement on contrast scan A and B.FThe cyst was removed by surgical excision under general anesthesia. A transverse incision was placed 2 cm above the sternum, dissecting around the capsule of mass . Access Histopathologic examination demonstrated a cyst in the dermis lined by stratified squamous epithelium with keratinization. No adenexal structures (hair follicles or eccrine glands) were present in the cyst wall. The epithelium contains granular cell layer. The keratin consists of lamellar eosinophilic flakes. No cells were identified. This appearance was consistent with epidermoid cyst A and B.FThe child was followed-up for 1 year with no recurrence.Neck mass in children is a common lesion. However, suprasternal epidermoid cyst is very rare. Epidermoid and dermoid cysts can be congenital or acquired even if the presentation or histology is similar.In exception of very few cases , they are generally benign lesions.Subcutaneous epidermoid cysts are usually very small and commonly diagnosed clinically without imaging. Rarely, they grow sufficiently large to necessitate additional workup. Large or medium epidermoid cysts might be located at unusual sites close to specific organs mimicking tumors originating from that tissue as in our case.The natural history of epidermoid cysts is slow and progressive growth and they remain asymptomatic unless they enlarge in size. The rapid growth of the cyst may indicate either an infectious processes or malignancy.The weight loss observed in our case was not related to a neoplastic process, as proved by histopathology. We believe the weight loss in our patient resulted from poor feeding due to the painful swallow caused by this large cyst.The differential diagnosis of anterior neck mass in children includes thyroglossal duct cyst, thyroid mass, cystic hygroma, cervical bronchogenic cyst and ectopic thymic mass.Surgical excision of epidermoid cyst is the treatment of choice.Epidermoid cyst involving the suprasternal region is an extremely rare condition. So they might be misdiagnosed as malgninancy, especially when presenting with ominous sign like recent weight loss. Epidermoid cyst should be included in the differential diagnosis of cystic lesion of the neck especially in the young age group.The authors declare no conflicts of interest.